Knowledge Synthesis in the Science of Psilocybin: Scoping Reviews of Clinical and Preclinical Research

Abstract

i
Abstract
Psilocybin is a psychedelic compound of interest to clinicians, researchers and the general public for its unique effects on perception, cognition and emotion. Fifteen years of clinical trials, reviewed here using the scoping review method of knowledge synthesis , provide evidence for the safety and therapeutic efficacy of psilocybin when combined with psychological supports. A similar review of more than 50 years of research on non-human animals shows the safety of psilocybin and demonstrates persisting positive effects of psilocybin on self-regulation. To provide context to these scoping reviews, I conducted a detailed literature review and a separate narrative review on the neuroscience of psilocybin, with a marked interest in the dynamics of neuroplasticity and how habits of self-regulation are formed, revised and updated. While my working hypothesis considered mystical states as the mechanism of therapeutic action underlying psilocybin’s apparent benefits, the evidence was stronger to support a revised hypothesis: that psilocybin improves self-regulation. It does so by disrupting habit, potentiating new learning and promoting improvements to health behaviours. I offer here a novel contribution to the literature: a time-based Transition State Model of Psychedelic Effect which views psilocybin as a catalyst to improved flexibility of thought and behaviour. Psilocybin appears to attenuate or loosen the effects of past conditioning which appear as habits and which have become hard-wired into brain networks. This learning model heavily weights the activities undertaken in the days and weeks following psilocybin administration, providing a basis for psilocybin-assisted therapies to leverage this critical period for improvements to health behaviours.

Full text

KNOWLEDGE SYNTHESIS IN THE SCIENCE OF PSILOCYBIN:
SCOPING REVIEWS OF CLINICAL AND PRE-CLINICAL RESEARCH
by
Ron Shore
A Thesis Submitted to the Graduate Program in
The School of Kinesiology and Health Studies
In Conformity with the Requirements for The Degree of
Doctor of Philosophy
Queen’s University
Kingston, Ontario, Canada
June 2023
Copyright © Ron Shore, 2023

i
Abstract
Psilocybin is a psychedelic compound of interest to clinicians, researchers and the
general public for its unique effects on perception, cognition and emotion. Fifteen years of
clinical trials, reviewed here using the scoping review method of knowledge synthesis , provide
evidence for the safety and therapeutic efficacy of psilocybin when combined with
psychological supports. A similar review of more than 50 years of research on non-human
animals shows the safety of psilocybin and demonstrates persisting positive effects of
psilocybin on self-regulation. To provide context to these scoping reviews, I conducted a
detailed literature review and a separate narrative review on the neuroscience of psilocybin,
with a marked interest in the dynamics of neuroplasticity and how habits of self-regulation are
formed, revised and updated. While my working hypothesis considered mystical states as the
mechanism of therapeutic action underlying psilocybin’s apparent benefits, the evidence was
stronger to support a revised hypothesis: that psilocybin improves self-regulation. It does so by
disrupting habit, potentiating new learning and promoting improvements to health behaviours.
I offer here a novel contribution to the literature: a time-based Transition State Model of
Psychedelic Effect which views psilocybin as a catalyst to improved flexibility of thought and
behaviour. Psilocybin appears to attenuate or loosen the effects of past conditioning which
appear as habits and which have become hard-wired into brain networks. This learning model
heavily weights the activities undertaken in the days and weeks following psilocybin
administration, providing a basis for psilocybin-assisted therapies to leverage this critical period
for improvements to health behaviours.

ii
Co-authorship
This thesis presents the work of Ron Shore, under the supervision of Drs. Eric Dumont
and Craig Goldie. While this thesis is written and presented in traditional, as opposed to
manuscript thesis style, the core of the thesis is formed on the reporting of 2 investigations to
be submitted as two separate publications, with each reported under Methodology, Results
and Conclusions and Discussion. The full authorship team for each manuscript is reported
below. The remaining chapters of the thesis (Introduction, Literature Review, Narrative
Reviews, General Discussion and Appendices) are the work of Ron Shore alone.
Study 1: “Mapping Psilocybin-assisted Therapies: A Scoping Review”, by Ron Shore
1
, Paul
Ioudovski
2
, Nina Thompson3, Sandra McKeown4, Eric Dumont5 and Craig Goldie6 . This
manuscript has been in preprint with medRxiv since December 2019 at:
https://doi.org/10.1101/2019.12.04.19013896.
Ron Shore was responsible for study design, for literature review and for draft of the
manuscript, for study screening, data extraction and presentation of results. Paul Ioudovskii
assisted with study screening, data extraction and review. Nina Thompson assisted with study
screening and data extraction. Sandra McKeown completed the literature searches. Craig
Goldie suggested the use of scoping review methodology and both he and Eric Dumont
provided overall guidance and provided editorial feedback.
1
School of Kinesiology and Health Studies, Queen’s University, Kingston On, Canada
2
Public Health Sciences, Queen’s University
3Department of Biomedical and Molecular Sciences, Queen’s University
4Health Sciences Library, Queen’s University
5Department of Biomedical and Molecular Sciences, Queen’s University
6Department of Oncology, Queen’s University

iii
Study 2: “Behavioural Investigations of Psilocybin in Animals: A Scoping Review, by Ron
Shore1, Kat Dobson2, Nina Thompson
3
, Nigel Barnum3, Hailey Bergman3, Katie Rideout3,
Sandra McKeown
4
, Mary Olmstead
5
, Craig Goldie
6
, and Eric Dumont3.
Ron Shore was responsible for study design, literature review, for draft of the article,
and for study screening, data extraction and review. Katrina Dobson assisted with study
screening, data extraction and review, developed several tables, and contributed to the
interpretation and presentation of results. Nina Thompson, Nigel Barnum, Hailey Bergman and
Katie Rideout all helped with study screening and data extraction. Mary Olmstead suggested
mapping results across the RDoC Framework, Sandra McKeown completed the literature
searches, Craig Goldie provided editorial review and Eric Dumont provided student supervision
for the project as well editorial review.
Additionally, excerpts from this thesis were contributed to a recently released rapid
review report cited as: Rush, B., Marcus, O., Shore, R., Cunningham, L., Thompson, N., &
Rideout, K. (2022). Psychedelic medicine: A rapid review of therapeutic applications and
implications for future research. Homewood Research Institute.
https://hriresearch.com/research/exploratory- research/exploratory-research-reports/.
1 School of Kinesiology and Health Studies, Queen’s University, Kingston ON, Canada
2 University of Groningen, Groningen, the Netherlands
3 Department of Biomedical and Molecular Sciences, Queen’s University
4 Health Sciences Library, Queen’s University
5 Department of Psychology, Queen’s University
6 Department of Oncology, Queen’s University

iv
Acknowledgements
For my family.
Thank you to my supervisors Dr. Eric Dumont and Dr. Craig Goldie.

v
Declaration of Conflict of Interests
The Dimensions Fund for Health Research provided funding to several undergraduate
students, supervised by Dr. Eric Dumont, to help with study selection (acting as second
reviewers) and data extraction in this program of research.
Ron Shore has provided research and consultation services to private psychedelics
companies operating for profit; in particular RS has received financial compensation to help
design and develop evidence-based psilocybin protocols for Dimensions Health Centres.
Given the rapid expansion of psilocybin and psychedelic assisted therapies as well as
therapist training programs, the research and conclusions in this thesis may be of financial
benefit to the author.

vi
Knowledge Synthesis in the Science of Psilocybin:
Scoping Reviews of Clinical and Preclinical Research
R. Shore
Table of Contents
Abstract
i
Co-authorship
ii
Acknowledgements
iv
Declaration of Conflict of Interests
v
List of Tables
x
List of Figures and Illustrations
xi
List of Common Abbreviations
xii
Chapter One: Introduction
1
Chapter Two: Literature Review
6
2.1 Psilocybin: A Social and Cultural History
6
2.2 Psychedelics, Psilocybin and Population Health
10
2.3 Drug, Set and Setting: The Importance of Extra-pharmacological Variables
12
2.4 Human Psychedelic Research: History and Challenges
13
2.5 Legal and Regulatory Frameworks for Psilocybin Research
16
2.6 Psilocybin and Models of Psychedelic-Assisted Therapies
18
2.6.1 Proposed Mechanisms of Therapeutic Effect in Psychedelic-assisted Therapies
20
2.6.2 Multiple Variables Construct Total Therapeutic Effect
23
2.7 Pre-Clinical Studies and Psilocybin Non-human Animal Paradigms
24
2.7.1 Non-human Animal Studies as Translational Models.
25
2.7.2 Habit Learning: Findings from Non-human Animal Studies
29
2.7.3 Challenges in Knowledge Translation
31
2.7.4 The Research Domains Criteria Framework of Translational Research
33
2.8 Thesis Research Question
34
Chapter Three: The Neuroscience of Psilocybin: A Narrative Review
37
3.1 Psilocybin Chemistry, Pharmacology and Pharmacodynamics
37
3.1.1 Chemistry of Psilocybin and Related Serotonergic Psychedelics
37
3.1.2 Psilocybin Pharmacokinetics
39
3.1.3 The Pharmacodynamics of Serotonergic Psychedelics
40
3.1.4 Physiological and Behavioural Effects of Psilocybin
44
3.2 Neurophysiological Mechanisms of Psychedelic Drugs
47
3.2.1 Molecular Signalling Pathways
49
3.2.2 Anatomic Localization
55
3.3 Psychedelics, Psilocybin and Neuroplasticity
62

vii
3.4 Psychedelics and the Disruption of Habit
67
Chapter Four: Methodology and Study Methods
78
4.1. Knowledge Synthesis Methodologies: Scoping Reviews in Psychedelic Research
78
4.1.1 Types of Knowledge Synthesis and Review
78
4.1.2 Defining the Scoping Review
81
4.1.3 Indications for Scoping Reviews
85
4.1.4 Scoping Review Methodological Framework
86
4.1.5 Strengths of Scoping Reviews
88
4.1.6 Limitations of Scoping Reviews
88
4.1.7 Suitability to Research on Psychedelics
89
4.2. Methods: Mapping Psilocybin-assisted Therapies
91
4.2.1 Search Strategy
93
4.2.2 Citation Management
94
4.2.3 Eligibility Criteria
94
4.2.4 Study Selection and Screening
95
4.2.5 Data Extraction
95
4.2.6 Data Summary, Synthesis and Charting
96
4.3 Methods: Behavioural Investigations of Psilocybin in Non-human Animals
96
4.3.1 Search Strategy
97
4.3.2 Citation Management
98
4.3.3 Eligibility Criteria
98
4.3.4 Study Selection and Screening
99
4.3.5 Data Extraction
99
4.3.6 Data Summary, Synthesis and Charting
100
4.3.7 Classification of Results by RDoC Matrix
100
Chapter Five: Results
103
5.1: Results: Mapping Psilocybin-assisted Therapies (MPAT)
103
5.1.1 Psilocybin Clinical Trial Characteristics
104
5.1.2 Psilocybin Formulation and Trial Dosing
108
5.1.3 Psilocybin Clinical Trial Study Populations
113
5.1.4 Psilocybin Trial Clinical Outcomes and Follow-up Periods
115
5.1.5 Results for Substance Use Disorder
117
5.1.6 Results for Depression
119
5.1.7 Results for Anxiety-related Disorders
125
5.1.8 Secondary Publications
128
5.1.8.1 Qualitative Studies, Further Clinical Outcomes, Therapeutic Processes
128
5.1.8.2 Psilocybin Clinical Trial Neuroimaging Studies
130
5.2 Results: Behavioural Investigations of Psilocybin in Non-human Animals (BIPA)
132
5.2.1 Study Characteristics
133
5.2.2 Research Animals
135

viii
5.2.3 Trial Characteristics and Experiment Design
137
5.2.4 Sex as a Biological Variable
141
5.2.5 Behavioural Research Domains
142
5.2.5.1 Negative Valence Systems
147
5.2.5.1.1 Fear Conditioning
147
5.2.5.1.2 Forced Swim Test
149
5.2.5.1.3 Tail Suspension Test
153
5.2.5.1.4 Aggressive Behaviour
153
5.2.5.1.5 Elevated Plus Maze
154
5.2.5.1.6 Open Field Test
155
5.2.5.2 Positive Valence Systems
159
5.2.5.3 Cognitive Systems
164
5.2.5.4. Systems for Social Processes
166
5.2.5.5 Arousal and Regulatory Systems
169
5.2.5.5.1 General Arousal and Physiological Measures
169
5.2.5.5.2 Sleep-Wake Behaviour
171
5.5.5.5.3 Startle Reflex
171
5.2.5.6 Sensorimotor Systems
175
5.2.5.6.1 Motor Coordination
175
5.2.5.6.2 Stereotyped Behaviours
177
5.2.5.6.3 Grooming
184
5.2.5.6.4 Prepulse Inhibition
187
5.2.5.7 Adverse Events
189
Chapter Six: Discussion and Conclusions
192
Discussion
192
6.1 Mapping Psilocybin-assisted Therapies
192
6.1.1 Quality of the Subjective Experience Predicts Degree of Positive Outcome
192
6.1.2 Transient Psychological Distress and Post-session Headaches
194
6.1.3 Program Variables and Psychological Supports
196
6.1.4 Concerns Regarding Trial Design
198
6.1.5 Therapeutic Models
204
6.1.6 A Program of Psilocybin Health Research
205
6.1.7 Scoping Reviews and the Importance of Knowledge Synthesis
208
6.1.8 Public Policy and Regulatory Implications
209
6.1.9 Limitations
209
6.2 Behavioural Investigations of Psilocybin in Non-human Animals
210
6.2.1 Therapeutic Dose Range of Psilocybin
211
6.2.2 Sex as a Biological Variable
212
6.2.3 Time of Day: The Impact of Circadian Rhythm
213
6.2.4 Research Domains Criteria Matrix Constructs
214

ix
6.2.4.1 Negative Valence Systems
214
6.2.4.2 Positive Valence Systems
216
6.2.4.3 Cognitive Systems
217
6.2.4.4 Systems for Social Processes
219
6.2.4.5 Arousal Systems
221
6.2.4.6 Sensorimotor Systems
222
6.2.5 Limitations
224
6.3 Mapping RDoC Domains onto Human Clinical Trials
226
6.4 Research Gaps and Contributions to the Literature
229
6.5 A Transition State Model of Psychedelic Action
232
6.5.1 The Role of Set and Setting in the Transition State Model
235
6.6 Public Policy and Program Implications
238
6.7 Bridging Worlds: From Traditional Plant Medicines to Psilocybin Therapies
241
Conclusions
243
6.8 Mapping Psilocybin-assisted Therapies
243
6.9 Behavioural Investigations of Psilocybin in Non-human Animals
244
6.10 Synthesis Conclusions Considering the Results of Both Scoping Reviews
246
6.11 Proposed Mechanism of Action
248
6.12 Concluding Remarks
252
Glossary of Key Terms
256
References
267
Appendices
288
Appendix A: Thesis Proposal
288
Appendix B: Supporting Documents, Mapping Psilocybin-assisted Therapies
290
Appendix B.1 Scoping Review Protocol
290
Appendix B.2 Electronic Search Strategies
296
Appendix B.3: Clinical Data Tables
303
Appendix B.4 Included and Excluded Studies
313
Appendix C: Supporting Documents, Behavioural Investigations of Psilocybin in Non-human
Animals
342
Appendix C.1 Scoping Review Protocol
342
Appendix C.2: Electronic Search Strategies
347
Appendix C.3 Included and Excluded Studies
369

x
List of Tables
Table Page
Table 4.1. Animal Paradigms by RDoC Domain Classification
101
Table 5.1. MPAT Trial Characteristics, Outcomes & Reported Adverse Effects
104
Table 5.2. Psilocybin (PSI) Dosing Formulation and Regimen, By Trial
109
Table 5.3. Psychotherapies Provided, by PSI-AT Trial
111
Table 5.4: Study Population Characteristics
114
Table 5.5: Characteristics of Included Studies: BIPA
133
Table 5.6: Housing Conditions Reported in Journal Articles, by Year of Publication
136
Table 5.7: Characteristics of PSI Treatment
138
Table 5.8.: Animal Behavioural Paradigms by RDoC Framework Domains
143
Table 5.9: Effect on Behaviour in the Forced Swim Test
150
Table 5.10. Induced Defensive Aggression Paradigm, Negative Valence Construct
154
Table 5.11: Effects on Behaviour in the Open Field Test
156
Table 5.12: Acute Time-Dependent Effects in Open Field Test
158
Table 5.13: Positive Valence Systems Results
159
Table 5.14. Visual Discrimination Paradigms
166
Table 5.15: Effects on Social Aggression Behaviours
167
Table 5.16: Acute Effects on Physiological Responses
170
Table 5.17: Effects on Startle Response by Dose and Time Period
172
Table 5.18: Effects on Startle Response by Species
172
Table 5.19: Effects on Locomotor Activity
173
Table 5.20 : Effects on Motor Coordination
176
Table 5.21: Effects on Stereotyped Behaviour
179
Table 5.22: Effects on Grooming
185
Table 5.23: Effects of on Prepulse Inhibition of the Acoustic Startle Response
188
Table 5.24. Studies Reporting Trial-related Adverse Events
191
Table 6.1. Common Clinical Trial Exclusion Criteria
200
Table 6.2. RDoC Domains of Particular Relevance to Targets of PSI-AT
227

xi
List of Figures and Illustrations
Figure Page
Figure 5.1: PRISMA Flow Diagram, MPAT Scoping Review
103
Figure 5.2. PSI Doses by Trial
109
Figure 5.3: Follow-up Periods by Trial
116
Figure 5.4: PRISMA Flow Diagram, BIPA Scoping Review
132
Figure 5.5: Year of Publication of Included Studies (BIPA)
134
Figure 6.1: A Transition State Model of Psychedelic Action
233

xii
List of Common Abbreviations
5-HT2A
Serotonin 2A receptor
AE
Adverse Experiences
ARRIVE
Animal Research: Reporting In Vivo
Experiments
ASL
Arterial Spin Labelling
ASR
Acoustic Startle Response
AUD
Alcohol Use Disorder
BDNF
Brain Derived Neurotrophic Factor
BIPA
Behavioural Investigations of Psilocybin in
Non-human Animals
BOLD
Blood-oxygen-level-dependent imaging
BPD
Borderline Personality Disorder
CBT
Cognitive-behavioural Therapy
CS
Conditioned Stimulus
DMN
Default Mode Network
DMT
Dimethyl tryptamine
DSM
Diagnostic and Statistical Manual of
Mental Disorders
EEG
Electroencephalography
EMG
Electromyography
EPM
Elevated Plus Maze
EOLD
End-of-Life Distress
FRL
Flinders Resistant Line (rat)
FSL
Flinders Sensitive Line (rat)
FST
Forced Swim Test
fMRI
Functional Magnetic Resonance Imaging
GABA
Gamma-Aminobutyric Acid
GCP
Good Clinical Practices
GPCR
G-protein coupled receptors
HPA
Hypothalamic-pituitary-adrenal axis
HPPD
Hallucinogen Persisting Perception
Disorder
HTR
Head-twitch Response
ICD
International Statistical Classification of
Diseases and Related Health Problems
IM
Intramuscular (injection)
IP
Intraperitoneal (injection)
IV
Intravenous (injection)
LTP
Long-term Potentiation

xiii
LSD
Lysergic Acid Diethylamide
MDD
Major Depressive Disorder
MDMA
3,4-Methylenedioxymethamphetamine
MEG
Magnetoencephalography
MEQ
Mystical Experiences Questionnaire
MPAT
Mapping Psilocybin-assisted Therapies
mPFC
Medial Prefrontal Cortex
(mTOR)
Mammalian target of rapamycin
NHP
Non-human Primate
OCD
Obsessive-compulsive Disorder
OFT
Open-field Test
OPS
Object Pattern Separation
PAT
Psychedelic-assisted Therapy
PCC
Posterior Cingulate Cortex
PET
Positron Emission Tomography
PEQ
Persisting Effects Questionnaire
PFC
Prefrontal Cortex
PPI
Prepulse Inhibition
PSI
Preparation-Session-Integration
Psi
Psilocin, psilocybin
PSI-AT
Psilocybin-assisted Therapy
PTSD
Post-traumatic Stress Disorder
RCT
Randomized Controlled Trial
RDoC
Research Domains Criteria
REBUS
Relaxed Expectations and Beliefs Under
Psychedelics
REM
Rapid Eye Movement
SC
Subcutaneous (injection)
TDE
Total Drug Effect
TRD
Treatment Resistant Depression
TRKB
tyrosine receptor kinase B
TSM
Transition State Model of Psychedelic
Effect
US
Unconditioned Stimulus
V1
Primary Visual Cortex
WKY
Wistar-Kyoto (rat)
WME
Whole Mushroom Extract

1
Chapter One:
Introduction
The purpose of this introduction is to situate this study of psilocybin in time and place
and to describe the evolution of this program of research. My basic question of research was,
“what is the evidence for the potential health benefits, or clinical application, of psilocybin?”. I
answered this question by the use of the scoping review, a methodology of knowledge
synthesis. In conducting this research, I had hoped to also possibly identify the variables
associated with any potential psilocybin-related health benefit or risk. Given the absences of
best practices for psilocybin-assisted therapy, and the lack of low-risk guidelines for psilocybin
use (as exist for cannabis or alcohol), this project of knowledge synthesis serves to translate the
pre-clinical and clinical trial literature to an audience of clinicians, scientists and policy-makers.
This dissertation contains the results of two separate, distinct but complementary
scoping reviews, one mapping the literature related to the human clinical trials using psilocybin,
and the other synthesizing and summarizing the psilocybin-specific behavioural investigations
on non-human animals. Together, they present a comprehensive and rigorously derived footing
of evidence to influence and inform future research, clinical trials, therapies, practices and
public policy. My original intention was to better understand the role psilocybin can play in the
treatment of PTSD, addiction, anxiety, depression and other disorders of self-regulation (June,
2017, original research proposal). While I had originally intended to complete a novel
behavioural investigation of psilocybin in rodents or conduct qualitative interviews with people

2
who have used psilocybin, the global COVID pandemic prevented the initiation of new in-
person and laboratory research for some time, forcing a turn to knowledge synthesis.
The hypothesis guiding this research project on psilocybin-assisted therapies has
evolved since I presented my working hypothesis in 2017. Referring to an emerging conceptual
model arising from the early clinical trials, my original working hypothesis was that mystical
experiences under psilocybin can improve personal emotional self-regulation, which in turn
creates the conditions for real and sustained behaviour change. In this way, I wanted to test the
hypothesis that the experience of mystical states under psilocybin effect was itself the
therapeutic mechanism, with such altered states of consciousness acting as the therapeutic
mechanism of action prompting behavioural change and underlying subsequent improvements
to health.
It was difficult to prove this original working hypothesis. As the trial data were
extracted, synthesized and reviewed, other potential mechanisms presented with stronger
validity. The concept of mysticism is itself problematic, somewhat vague and not-well
considered within contemporary health care and mental health settings. The weight of the
research evidence identified psilocybin’s unique interplay with context (setting but also pre and
psilocybin conditioning) and its clear effect on disrupting established habits of thought,
behaviour and action as perhaps a more germane locus of therapeutic mechanism. This
prompted a revision to my original hypothesis.
The neuroscientific and preclinical literature on psychedelics and psilocybin is
considerable, and as a discipline neuroscience is more observable and testable than exploring
the diverse and entirely subjective phenomenology of mystical states in a society which has

3
historically pathologized altered states of consciousness. It also became clear early, upon
reviewing study publications, that not all of psilocybin’s therapeutic effect could be rooted in
mysticism as not all people have mystical experiences while under a therapeutic dose of
psilocybin yet they still demonstrate and report health improvements and meaningful,
emotional experiences.
My revised hypothesis is that psilocybin improves self-regulation, and that it does so by
attenuating past conditioning, disrupting habit while potentiating new learning and behavioural
flexibility. I present a limbic learning model of temporal psilocybin effect, whereby the
persisting neurophysiological effects of psilocybin create a pivotal window, or critical period, of
heightened neuroplasticity in the afterglow period following psilocybin. Rather than mysticism,
my research supports psilocybin’s post-acute and persisting effects on learning as the
mechanism of therapeutic benefit. I have referred to this as a Transition State Model of
Psychedelic Effect. A transition state is a critical and time-limited period of enhanced energy
potential. Given the sustained and persisting effects of even a single dose of psilocybin on
mood and behaviour, psilocybin’s effects appear bi-phasic, whereby psilocybin first inhibits
established routines of thought, feeling and behaviour, and secondarily potentiates the learning
of new behaviours. These phases have unique subjective phenomenology as well as different
underlying cellular mechanisms.
Due to its inhibitory effects on habits of thought, feeling and behaviour, psilocybin can
loosen the hold of habitual sub-routines encoded in cellular memory; the psychedelic pause
makes space for change. Psilocybin occasions a subsequent critical period of cognitive,
behavioural and synaptic plasticity which can promote the long-term potentiation of new

4
learning and new health behaviours. In this way psilocybin has salutary effect via its
adaptogenic and plastogenic functions. By the catalyst-based Transition State model, pre-drug
preparation efforts may create a priming effect, while the post-drug time period of integration
is where the subsequent pruning of neural networks can result in the consolidation of
therapeutic benefit and long-term potentiation of new habits. This conceptual two-phase
process aligns with the dynamics of neural plasticity, the cellular basis of new learning, memory
and adaptation.
This dissertation is an act of knowledge synthesis, the methodologies of which are well
suited to this stage of psychedelic sciences. By conducting two large-scale scoping reviews, we
have spanned the clinical and pre-clinical literature. Considering the results together allowed
for greater insights into psilocybin’s therapeutic potential. Given the growing body of clinical
trials with psilocybin, it is critical to synthesize and summarize the existing bodies of literature,
identifying gaps and areas of future research, in order to help translate findings into rapidly
emerging clinical practices and new public policy.
This thesis contains several complementary projects of knowledge synthesis. Chapter
Two presents a comprehensive literature review relevant to psilocybin, diving into its
fascinating social and cultural history and the rise of psychedelic sciences, while Chapter Three
presents a narrative review on the neurobiology of psilocybin and the relevance of the habit
construct. Chapter Four presents the Methodology and Study Methods to the two scoping
reviews, while Chapter Five presents Results for both. Finally, Chapter Six presents Conclusions
and Discussion, including the consideration of combined results, and presents my Transition

5
State Model of Psychedelic Effect. The appendices contain the protocols and search terms for
each scoping review as well as tables of included articles and other supporting data.

6
Chapter Two:
Literature Review
2.1 Psilocybin: A Social and Cultural History
Psilocybe genus mushrooms are world-wide in their distribution (Froese et al., 2016;
Guzmán et al., 1997) and archaeological evidence supports their ritualistic use in Mesoamerica
to at least 500 B.C (Guzmán, 2008). Cave paintings containing reference to mushroom worship
date to at least 6000 B.C. (Akers et al., 2011; Guerra-Doce, 2015). Amanita muscaria (fly agaric)
is a separate genus of mushroom and muscarinic receptor agonist, of great importance in
Siberian and Sami shamanism (Schultes, 1979), and is the most likely botanical candidate to be
the source of Vedic Soma , considered the elixir of immortality (Wasson, 1968).
As Vedic cultures spread south and eastward in warmer climates, the botanical basis of
Soma changed, perhaps replaced by the more available Psilocybe genus mushrooms (Crowley &
Shulgin, 2019; Winkelman, 2021). Classical scholar Carl Ruck posits that ancient mushroom cults
contributed to the civilization of Europe in pre-classical times (Ruck, 2011). The famed
Eleusinian mysteries lasted for 2000 years, ending in the 4th century C.E., and most likely
employed an ergot-based (mushroom) decoction derived from a plant fungus while being
overseen by a mystery school of female priestesses honouring the goddesses Persephone
(agriculture, fertility) and her daughter Demeter (underworld, death & rebirth) (Baker, 2005).
The earliest documentation of traditional Aztec mushroom ceremonies is found in the
Magliabechiano Codex (circa 1570) created by Franciscan missionary Fray Bernardino de
Sahagún, which included full colour illustrations of a blue-staining mushroom he labeled

7
teonanácatl, roughly translated as “flesh of the gods'' which was venerated and consumed at
spiritual celebrations, the “feasts of revelation” (Smith, 2016). Several Indigenous groupings in
current Mesoamerica have subsequent histories of shamanic mushroom rituals, including the
Mazatec, Nahuatls, Matlazines, Totonacs, Zapotecs and Chatins (Guzmán, 2008).
Aztec mushroom rituals were violently repressed and persecuted by the Spanish
(Schultes, 1940); the sacred use of teonanactl (“flesh of the gods”) was driven underground and
somehow preserved and protected for centuries by healers who carried out mushrooms
veladas in the home. Jean Basset Johnson was the first Western anthropologies to participate in
a mushroom velada, reporting on the sacred use of mushrooms in Huatla de Jiménez in 1937
(Davis, 1997). Typically occurring in someone’s home, valedas are a kind of night vigil,
conducted only in the dark at night and under the guidance of a recognized
curandera/curandero (folk healers). Mushrooms would be eaten only in pairs, after a period of
abstinence and fasting, and typically only when there was illness or a sickness to be
cured. Curanderas/curanderos would commonly also employ strong tobacco and copal as well
as common folk-healing practices, while rhythmically chanting, quietly singing, or expressing
long lyrical poetry appearing as the voice of the mushroom (Harner, 1973, Feinberg, 1997).
Maria Sabina, so central to the history of psilocybin, would refer to mushrooms as los niños
santos, the “little saints”.
Mainstream awareness of the medicinal potential of Psilocybe mushrooms dates to
1957 with the publication of G. Wasson’s Life Magazine article, “Seeking the Magic Mushroom”.
It is now recognized that Sabina, the Mazatec curandera portrayed in the article did not and
could not have given full informed consent to this mass sharing of what had been a culturally

8
protected and secretive tradition. From a contemporary perspective, this can now be seen as
bio-extraction and colonialism. Sabina herself suffered greatly as a result of Wasson’s
publication. Indigenous communities in contemporary Mexico, especially in the Mazatec region
of Oaxaca, have more recently become the subject of intense and disruptive Western/Northern
consumer interest, with droves of tourists also seeking “the magic mushroom” (Faudree, 2015),
raising similar concerns as has been documented with ayahuasca tourism in the Amazonian
regions of several South American countries, including Brazil, Peru, Columbia and Ecuador
(Fotiou, 2012; Wolff et al., 2019).
Botanical exploration of the Neotropics led to documentation in the 19th century of
Amazonian hallucinogenic snuffs, mescaline-containing trichocereus cacti, datura inoxia,
banisteriopsis and psychotria (Schultes, 2002). Anthropologist Weston La Barre (1964) studied
the Native American use of peyote (mescaline) in the 1930’s and his colleague Jean Johnson’s
participation in a mushroom velada in the Oaxaca region of Mexico (Thiselton-Dyer, 1940) lead
to greater scientific awareness of traditional indigenous plant medicine practices. Through the
1940s and 50s, Richard Evans Schultes, the leading ethnobotanist of our times, would identify
teonanacatl as the Psilocybe mushroom genus, and identified dozens of Amazonian botanical
species (including datura, yopo, virola, and various ayahuasca decoctions) with hallucinogenic
effect and cultural usage (Davis, 1996). After Gordon Wasson’s Life Magazine article of 1957
brought attention to the “magic mushroom”, an era of greater scientific interest emerged and
led to Timothy Leary’s Harvard Psilocybin Project (Hartogsohn, 2017; Wark & Galliher, 2010).
Meanwhile, in Europe, a model of psychotomimetic therapy using LSD had begun, first as a
means to understand psychosis and the unconscious, later evolving into the psycholitic model

9
combining psychedelics with psychoanalysis and talk-therapy (Dyck, 2006; Krebs & Johansen,
2012; Sloshower et al., 2020).
Mushrooms taken by Wasson from Sabina ended up in Switzerland with Albert
Hoffman, who first isolated psilocybin and psilocin from the whole organic biomass in 1958 (Chi
& Gold, 2020). Psilocybin is a pro-drug to psilocin, an alkaloid tryptamine serotonergic agonist.
Psilocybin was later synthesized by chemists in 1963 and in 2017, a "one pot" method of
synthesizing psilocybin was developed after sequencing the genomes of organic Psilocybe
biomass to identity the four enzymes involved in the natural production of psilocybin (Fricke et
al., 2017). This made the commercialization of psilocybin and the production of pharmaceutical
grade products viable on a large-scale basis. A comparatively simple 5-step method has been
popularized for the mass synthesis of psilocybin (Sherwood et al., 2020).
Albert Hoffman’s re-synthesis of lysergic acid diethylamide (LSD) in 1943 led to the birth
of contemporary psychedelic studies (Bogenschutz & Johnson, 2016; Rucker et al., 2018). The
first Western academic psilocybin research program – the Harvard Psilocybin Project -- ran at
Harvard University from 1961-1963, overseen by Drs. Timothy Leary and Richard Alpert, who
would go on to become the spiritual teacher Ram Dass, author of the counter-cultural
touchstone Be Here Now (Wark & Galliher, 2010). Terence and Dennis McKenna subsequently
contributed to widespread trends of home mushroom cultivation through the 1970s,
popularizing Psilocybe mushrooms and making them easily accessible for recreational use.
Today, legal (or legally-tolerated) psilocybin retreats exist in The Netherlands, Jamaica,
Costa Rica and Mexico, and various U.S jurisdictions including Oregon and California have
recently decriminalized natural psychedelics such as psilocybin. The Oregon model of legal

10
psilocybin service centres may provide a template for other jurisdictions. Personal, or
naturalistic use of psilocybin is most likely increasing (though population surveys are lacking), as
mushroom “dispensaries” have opened in Vancouver, British Columbia and a number of
companies are openly selling magic mushrooms online in Canada. Health Canada has recently
returned psilocybin and other psychedelics into the Special Access Program
7
, ostensibly making
psilocybin available to patients by physician prescription when other modes of treatment have
failed. The recent rise of public interest in psychedelics may very well fit the psychointegrator
theory of cross-cultural psychedelic use, facilitating psychosocial adaptations required by rapid
social change and changing psycho-social circumstances (Winkelman, 2001).
2.2 Psychedelics, Psilocybin and Population Health
Serotonergic psychedelics such as psilocybin possess relatively low physiological toxicity
and have not been shown to lead to neurological deficits, organ damage or to cause genetic
damage or birth defects (Gable, 2004; Johnson et al., 2008a; Strassman, 1984). Psychedelics
have a low potential for abuse or dependence and have not been found to lead to compulsive
drug seeking (Carbonaro et al., 2016; Johansen & Krebs, 2015; Krebs & Johansen, 2013a; Rucker
et al., 2018). Non-human animals do not reliably self-administer psychedelics (Fantegrossi et al.,
2004; Rucker et al., 2016a, 2018). Euphoria is not a consistent feature of the psychedelic
experience, tolerance develops quickly and completely and there is no known withdrawal
7
https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-
products/announcements/requests-special-access-program-psychedelic-assisted-psychotherapy.html

11
syndrome; psychological dependence appears to be rare with no indication of physical or
psychological tolerance (Amsterdam et al., 2011; Rucker et al., 2018).
Psychedelics are not regarded as promoting aggression or violence, dangerous behavior
or suicide and accidental death under the influence of psychedelics is regarded as extremely
rare (Johansen & Krebs, 2015; Krebs & Johansen, 2013a; Strassman, 1984). However,
psychedelics can produce acute and (sometimes) persisting adverse psychological reactions
(Johnson et al., 2008; Strassman, 1984). Case reports document acute adverse effects of
psilocybin in non-research settings including: short-term psychological distress and fear,
individuals putting themselves at risk for harm, seeking medical help as well as persistent
negative psychological or psychiatric problems (Carbonaro et al., 2016). Emergency room and
poison control data also confirm that psilocybin ingestion is associated with seeking medical
treatment; however, the incidence of psilocybin toxicity is extremely low relative to other
substances used non-medically (Amsterdam et al., 2011; Carbonaro et al., 2016; Gable, 2004).
Psychedelics have not been found to decrease mental health; the use of psychedelics
may in fact be a protective factor associated with better mental health status (Johansen &
Krebs, 2015). At population health levels, lifetime use of psilocybin or mescaline and past year
LSD use were found to be associated with lower rates of serious psychological distress (Krebs &
Johansen, 2013b). Lifetime psilocybin use was also significantly associated with lower rates of
inpatient mental health treatment and psychiatric medication prescription, lower rates of panic
attacks and lower rates of agoraphobia. No significant association was found between lifetime
psychedelic use and greater risk of any negative mental health outcomes. No relation was
found between lifetime use of psychedelics and any undesirable past year mental health

12
outcomes, including serious psychological distress, mental health treatment or symptoms of
panic disorder, major depressive episode, mania, social phobia, generalized anxiety disorder,
agoraphobia, post-traumatic stress disorder, or non-affective psychosis. There were some
associations between use of any psychedelic or use of specific psychedelics and lower rate of
mental health problems (Johansen & Krebs, 2015; Krebs & Johansen, 2012).
2.3 Drug, Set and Setting: The Importance of Extra-pharmacological Variables
Research suggests that nonpharmacological variables are responsible for a major part of
therapeutic benefits in a variety of accepted drug treatments beyond psychedelics (Hartogsohn,
2017) and the psychological supports provided in preparation to clinical psychedelic research
settings remain a confounding factor and limitation of study findings (Rucker et al., 2018;
Sellers et al., 2018). Important for the planning of clinical trial research, results suggest that
moderate doses of psilocybin given to healthy, high-functioning and well-prepared subjects in
the context of a carefully monitored research environment is associated with an acceptable
level of risk (Studerus et al., 2011). The high variability found within and between subjects of a
pooled analysis of healthy human volunteer investigations indicate that psilocybin effects are
not predicted by dose alone; other pharmacological variables such as plasma levels of psilocin,
as well as non-pharmacological variables such as user expectations, personality structure, and
the availability of interpersonal support, and the setting of the experience play determinant
roles (Studerus et al., 2011).
Timothy Leary first identified the importance of set and setting during his psilocybin
research at Harvard in the early 1960’s. As Ido Hartogsohn points out, “no other group of drugs

13
appears to be as plastic and responsive to conditions of set and setting as the psychedelics—
mind-manifesting drugs whose very name points to their character as nonspecific reflectors of
extra-drug conditions” (Hartogsohn, 2017). The set and setting “hypothesis” holds that the set
of the user (their expectations, mental and emotional state, psychological history) and the
setting of the use (both the immediate physical setting but also the social environment and
cultural values assigned to the drug) combine with the basic potential pharmacology of the
drug to together create the drug experience. The heavy influences of set and setting pose a
significant challenge to modern pharmaceutical research and the prioritization of randomized
controlled trials which seek to minimize, if not eliminate, extra-drug variables as confounding
factors.
2.4 Human Psychedelic Research: History and Challenges
Early LSD research in Canada saw significant clinical application in Weyburn,
Saskatchewan and at the Hollywood Hospital in Vancouver, British Columbia; both used LSD to
treat alcoholism (Dyck, 2006). This first wave of LSD research resulted in the publication of an
estimated 10 000 academic papers on psychedelics (Passie et al., 2008). Psychedelic research
came to an abrupt demise with the criminalization of psychedelics through the late 1960s and
early 1970’s (Johnson & Griffiths, 2017, Nichols et al., 2017) with the publication of psychedelic-
related papers peaking in 1973 (source: PubMed, retrieved by author October 2021).
Early psychedelic research, termed psychotomimetic (1940s-1950s) principally used LSD
to mimic psychosis and to investigate the biochemical origins of mental illness. Later, European
psychiatrists began to use low-dose LSD in combination with analysis, a model termed

14
psycholitic therapy, while Canadian and American therapists used a model of high-dose, peak
psychedelic therapy, to elicit dramatic emotional and psychological changes and were
principally used in the treatment of alcoholism and neurosis (Krebs & Johansen, 2012). Early
psychopharmacological research was extensive and produced over 10,000 scientific
publications (Passie et al., 2008).
While an extensive literature exists cataloging a multitude of naturally occurring plant-
based and newly synthesized chemicals, most psychedelic research in humans has been
conducted on only small, relatively homogenous sample sizes and principally using synthetic
derivatives such as psilocybin (Sellers et al., 2018). Further, trial methodology has been often
descriptive, open-labelled and uncontrolled (Phase 1 and Phase 2a of regulatory drug approval
processes) (Rucker et al., 2018; Sellers & Leiderman, 2018). The combination of psychedelic
drug administration with extensive psychological counselling and support in preparation for the
drug session significantly confounds study of the drug’s therapeutic effect. The obvious
behavioural effects of psychedelic drugs also impairs the ability of researchers to blind both
participants and observers (M. W. Johnson et al., 2008b; Rucker et al., 2018; Sellers et al.,
2018). The minimal effective and maximum tolerated doses and optimal dosage of psilocybin
remains unproven (Sellers et al., 2018).
Interest in psychedelics returned with the publication of Roland Griffith’s 2006 paper on
psilocybin and mystical experiences (Griffiths et al., 2006). Rick Strassman’s 15 years of quiet
DMT research through the 1980s and 90s is thought to be the lone scientific investigation of
psychedelics through that time period (Strassman, 2001). Hans Vollenweider’s neuroscientific
investigations of psychedelics (Vollenweider et al., 1998; Vollenweider & Kometer, 2010) laid

15
the groundwork for subsequent neuroimaging of the neural correlates to the psychedelic state
picked up later by Robin Carhart- Harris (Carhart-Harris et al., 2012) among others. Over the last
two decades, more psychedelic research has been conducted on healthy volunteers than in
clinical trial settings, reflecting a scientific curiosity in brain states and the neural underpinnings
to human consciousness.
Modern clinical trials using psilocybin began in 2006 with investigation into the
application of psilocybin to treat obsessive-compulsive disorder (Moreno et al., 2015). A recent
review identified 70 currently actively registered psychedelic trials, with 41.4% of those
involving psilocybin as the trial drug (Siegel et al., 2021). Psilocybin has been investigated as a
therapy for a range of mental health disorders including unipolar, treatment-resistant
depression, obsessive compulsive disorder, substance use disorder, anxiety and distress related
to terminal diagnosis, and demoralization among long term AIDS survivors. Trial participants
have been largely homogenous and lacking in racial equity (Fogg et al., 2021; Michaels et al.,
2018). The only Phase 3 clinical trial with psilocybin is currently enrolling in the United
Kingdom; treatment effectiveness has not yet been established in the literature.
The scientific literature pertaining to the therapeutic application is early, still emerging,
with a heterogenous body of literature and no yet-established effectiveness in phase 3 clinical
trials (Rucker et al., 2018; Sellers & Leiderman, 2018). Data sources are varied and
heterogenous as are the populations and contexts studied, lacking the maturity, specificity and
effectiveness data required for regulatory drug approval. Effectiveness trials require large size,
randomized and double-blinded, multi-site studies with a diversity of patient populations
(Schulz et al., 2010). Recent clinical trials with psilocybin have shown significant effect sizes in

16
trials for distress related to life threatening illness; however, these studies provided extensive
psychological support and gains were often noted even prior to psilocybin administration, The
difficulty in maintaining blinding creates expectancy effects for both researchers and subjects,
potentially biasing outcome measurements and inflating effect sizes (Rucker et al., 2018; Sellers
et al., 2018; Sellers & Leiderman, 2018).
2.5 Legal and Regulatory Frameworks for Psilocybin Research
Psilocybin is classified in Canada as a Schedule 3 controlled substance under the
Controlled Drugs and Substances Act of 1996 making the production, possession and sale of
psilocybin illegal. While the CDSA largely prohibits access to or use of controlled substances
though exemptions for research or humanitarian purposes may be granted under Section 56 of
the CDSA or under the Special Access Program of Health Canada. Researchers have suggested
that the national and international regulatory restrictions on psychedelic compounds have been
barriers to the growth of quality clinical research (Sellers et al., 2018).
Internationally, by the Convention on Psychotropic Substances (1971) psychedelics tend
to be regulated as Schedule 1 narcotics with the highest potential for abuse and no known
medical indication (Rucker et al., 2018; Sellers et al., 2018; Sellers & Leiderman, 2018). While
the scientific literature is largely at odds with such a classification, it is felt that the strict
international control is not so much due to its (weak) potential for dependence as much as the
relative risk of psychosis (Sellers et al., 2018).
Recent history does provide examples of drugs being reclassified from Schedule 1 to
regulatory drug approval for medical use. Dronabinol (synthetic delta-9- tetrahydrocannabinol)

17
is one such example, initially approved as an orphan drug for AIDS- related anorexia in 1985 and
now approved for cancer chemotherapy related nausea and vomiting. Xyrem (sodium g-
hydroxybutyrate) was approved for the treatment of cataplexy associated with narcolepsy in
2004 , and an extract of cannabis sativa has been licensed for medical application even in
regimes of cannabis prohibition (Rucker et al., 2018).
Clinical trials require exemptions from narcotics law to access psilocybin and other
psychedelics, which is largely only approved for serious or unmet medical needs. As unmet
need is defined as providing a therapy where none exists or way a novel treatment may be
potentially superior to available therapies, it does appear that psychedelic research can
gradually build the scientific case, meet regulatory drug approval standards and endpoints, and
eventually result in the reclassification of at least some of the psychedelic substances (Rucker et
al., 2018; Sellers & Leiderman, 2018).
Regulatory drug approval is generally a gradual process, as trials evolve historically from
early investigative, open-labelled and uncontrolled trials to establish safety and tolerability
(Phase One). Phase Two trials add more methodological rigour and slightly larger sample sizes
to establish preliminary indications of therapeutic efficacy. Effectiveness is only established
with Phase Three trials, which tend to be much larger, multi-site randomized controlled trials,
with much more diverse patient populations. Given the profound and obvious behavioural
effects of psychedelics and the imperative of blinded, unbiased and unconfounded randomized
controlled trials (RCTs) for regulatory drug approval processes and as the gold standard for
evaluating healthcare interventions (Schulz et al., 2010), RCTs with psychedelics face significant
challenges. Due to regulatory controls, special licenses are required to process and administer

18
Schedule I drugs in human trials, and strict security, control and monitoring protocols are
necessary, requiring dedicated infrastructure (Rucker et al., 2018).
2.6 Psilocybin and Models of Psychedelic-Assisted Therapies
The use of psilocybin as a potential therapy represents a paradigm shift in our approach
to disorders of mental health (Daniel & Haberman, 2017; Nichols et al., 2017; Rochester et al.,
2021) towards a recognition of trans-diagnostic effects (Kelly et al., 2021) across multiple
disorders including addiction (Daniel & Haberman, 2017; Johnson et al., 2019), depression
(Galvão-Coelho et al., 2021; Rucker et al., 2016b), obsessive-compulsive disorder (Moreno et
al., 2015), end-of-life distress (Reiche et al., 2018; Rosa et al., 2019), neuroinflammation
(Flanagan & Nichols, 2018; Inserra, De Gregorio, & Gobbi, 2021; Kuypers, 2019; Schindler et al.,
2018; Szabo, 2015) and disorders of the endocrine system (Schindler et al., 2018) .
Models for the provision of psychedelic-assisted therapy (PAT) are largely based on the
premise that psychedelics can act as catalysts or non-specific amplifiers of psychotherapeutic
processes (Koslowski et al., 2022; Sloshower et al., 2020) but remain under development as
part of ongoing clinical trials (Watts & Luoma, 2020). The current standard model of
Preparation-Session-Integration (PSI) (Koslowski et al., 2022) provides psychological support
before, during and after psychedelic therapies to ensure safety and encourage positive
treatment outcomes (M. W. Johnson et al., 2008b; Phelps, 2017; Rochester et al., 2021;
Sloshower et al., 2020; Watts & Luoma, 2020). Greater benefit to the participant is likely to be
achieved when psychedelics are provided in a psychologically supportive setting (Carhart-Harris

19
& Goodwin, 2017), providing containment, safety and practices to help guide the participant
experience (Carhart-Harris et al., 2016).
In addition to general psychological supports along the PSI model, several psilocybin
clinical trials combine psychedelic-assisted therapy with manualized cognitive-behavioural
therapies targeting the main health indication -- tobacco cessation, for example (Johnson et al.,
2017; Sloshower et al., 2020). Drug dosing sessions of the clinical trials also follow a common,
standard model involving quiet, living-room type atmospheres, the use of eyeshades and
musical playlists (Gukasyan & Nayak, 2021; M. W. Johnson et al., 2008b). Music has been found
to increase emotional responsiveness and mental imagery (Kaelen et al., 2018).
The grouping of new behaviourism Third Wave therapies have been suggested for
psychedelic therapies (Walsh & Thiessen, 2018). These integrate practices from spiritual and
contemplative practices (e.g. mindfulness); similarly, Third Wave theories often conceptualize
psychological suffering as emerging from attachment, much as with Buddhism. The goal of
psycho-therapies provided should be to assist the client in increasing their capacity for emotion
processing, including regulation. Spirituality has been proposed as a mechanism of action
promoting such improvements in emotional health and self-regulation (Callon et al., 2021;
Lafrance et al., 2021). Third Wave therapies emphasize decentering, emotional regulation, and
the ability to tolerate difficulty and distress (Fauvel et al., 2021; Hayes & Hofmann, 2017; Walsh
& Thiessen, 2018).
Examples of Third Wave behavioural therapies include Dialectical Behaviour Therapy,
Acceptance and Commitment Therapy and Mindfulness Based Cognitive Therapy. Several
psilocybin trials used models of cognitive-behavioural therapy (Sloshower et al., 2020; P. J.

20
Teixeira et al., 2022; Watts et al., 2017) such as motivational enhancement (Bogenschutz et al.,
2015), Acceptance-Connection-Embodiment (ACE) therapy (Watts & Luoma, 2020) and
Acceptance and Commitment Therapy (ACT) (Sloshower et al., 2020) . Certain methods and
processes are similar across many Third Wave modalities, including mindfulness methods,
acceptance-based procedures, decentering, cognitive diffusion, values, dialectics, spirituality
and psychological flexibility processes. Narrative and art therapy can equally be considered
complementary therapies (Walsh & Thiessen, 2018).
Research on retreat centers which combine meditation practices and psychedelics
indicate rapid increase in mindfulness-related parameters, decreased self-judgement and
increased decentering, leading investigators to conclude that the therapeutic effects of the
psychedelic may be largely attributable to improved mindfulness practices (Heuschkel &
Kuypers, 2020; Smigielski et al., 2019). Griffiths similarly reports improved outcomes when
meditation and support for spirituality is provided in the context of psilocybin therapy (Griffiths.
et al., 2018).
2.6.1 Proposed Mechanisms of Therapeutic Effect in Psychedelic-assisted Therapies
Efficacy associated with psychedelic-assisted therapies has been attributed to a dynamic
of persisting shift from experiential avoidance to acceptance (Malone et al., 2018; Watts et al.,
2017; Wheeler & Dyer, 2020; Wolff et al., 2020). Cognitive and psychological flexibility are
considered key therapeutic outcomes associated with psychedelic-assisted therapies (Davis et
al., 2020; Doss, Považan, et al., 2021; Fauvel et al., 2021; Foldi et al., 2020; Kočárová et al.,
2021; Kuypers et al., 2016; Kuypers, 2020). Increases in personality traits of openness (Erritzoe

21
et al., 2018; Garcia-Romeu et al., 2014; MacLean et al., 2011) and states of increased
integrative connectivity (Carhart-Harris et al., 2012; Preller et al., 2020), including to nature
(Forstmann & Sagioglou, 2021; Lyons & Carhart-Harris, 2018) have been observed after
psychedelics. Systematic reviews (Aday et al., 2021; Romeo et al., 2021) have demonstrated
that the quality of the psychedelic experience is the main predictor of positive therapeutic
outcomes.
Psychedelics may create periods of sub-acute and persisting plasticity and encourage
the ability to develop and practice new habits of thought, feeling and action (Watts & Luoma,
2020) with decreased rumination (Fauvel et al., 2021; Kuypers, 2020) with a relaxation of
previous meta-cognitive assumptions (Koslowski et al., 2022) and increased sensory or somatic
awareness (Watts & Luoma, 2020). Contact with nature may enhance the gains of psychedelic-
assisted therapies (Gandy et al., 2020), as would mindfulness and meditation programming
(Fauvel et al., 2021). Group experiences may further enhance therapeutic outcomes,
modulated by feelings of communitas (Kettner et al., 2021).
Two distinct processes of psychedelic healing have been described recently by
psychedelic researchers (Lafrance et al., 2021; Watts et al., 2017). The first change process
relates to the stages through which participants reported having evolved from feeling
disconnected to connected to self, others, and the world, including deeper connections to
spirituality. The second is a process of change shifting from an avoidant style of emotion
processing to acceptance with improved emotional responsiveness, as measured by sustained
increases in the capacity to connect with emotion and to be in-relationship. Watts has
identified three key themes to patient experiences: self as context, commitment to values, and

22
committed action (Watts & Luoma, 2020). To this end, psychotherapeutic interventions
encourage movement from separation to connection, and from avoidance to acceptance
(Watts et al., 2017; Watts & Luoma, 2020). Improving spirituality may predict a greater
adaptability in the capacity to confront life’s challenges and improved ability to regulate
emotional pain (Lafrance et al., 2021). After psychedelics, participants display a trend towards
increased values-based action (Sloshower et al., 2020). Further, participants demonstrate
relaxed avoidance-related beliefs, long-term increases in acceptance and responsiveness to
corrective information (Wolff et al., 2020).
The possibility exists for some participants to experience significantly challenging
experiences, with long-term negative impact. In a pooled analysis of healthy volunteers taking
psilocybin, found that acute dysphoria, panic and severe anxiety occurred only in the two
highest dose conditions. Overall, 12% of participants reported having experienced negative
changes in psychological well-being and or mental functioning after psilocybin (Studerus et al.,
2011). Research suggests reducing the duration, rather than the peak difficulty, of challenging
psilocybin experiences.
Attachment avoidance is associated with challenging experiences and peak plateau
latency, while sociability is negatively associated with spiritual experiences. Further predictors
of positive outcomes include: intensity of drug effect, quality of positive speech prior to the
psychedelic session, confidence to make behavioral change, acceptance, reappraisal of emotion
and past cannabis consumption. Interestingly, “bad trips” may be more common among female
participants, but females are also more likely to have mystical experiences. Therapists and
facilitators can be instrumental in coaching participants how to find reassurance, how to remain

23
safe throughout the experience, and ways to journey through ups and downs of the psychedelic
experience (Gorman et al., 2021).
2.6.2 Multiple Variables Construct Total Therapeutic Effect
Specific testable models to guide preparation and integration are currently lacking (Watts &
Luoma, 2020). While most clinical trials have followed the established standard model of PSI,
there is considerable variety in the content of the preparation and integration sessions across
the various studies (Sloshower et al., 2020) and best practices in the integration of PSI into
structured behavioural change treatment programs targeting specific disorders are not yet clear
(Bogenschutz & Forcehimes, 2017; Sloshower et al., 2020
Psychedelics have a demonstrated sensitivity to setting (Hartogsohn, 2017; Rucker et al.,
2018; Sellers & Leiderman, 2018), to suggestibility (Carhart-Harris et al., 2015; Hartogsohn,
2018) and to language (Family et al., 2016; Spitzer et al., 1996). The many variables associated
with either positive therapeutic outcomes or negative experiences can be deliberated and
thoughtfully curated to optimize the therapeutic potential on the whole and reduce potential
harms, allowing for a kind of precision-medicine specific to the genetic, environmental and
biological needs of the person (Kelly et al., 2021).
The Common Factors Theory of psychotherapy is a useful and well-evaluated framework
to help guide models of psychedelic-assisted therapy. By this framework, four significant
contextual common factors influence the outcomes of therapy and are shared across disparate
traditions of healing: 1) the therapeutic relationship, 2) the healing setting, 3) the rationale,
concept or belief-myth framework, and 4) the ritual (Gukasyan & Nayak, 2021).

24
Here, Feeney’s Total Drug Effect (Feeney, 2014) is a helpful reminder to contextualize
the importance of non-pharmacological variables in psychedelic healing. In his study of Native
American Church peyote rituals, Feeney found five factors which synergistically modulate the
psychedelic experience: the pharmacology of the medicine; participant beliefs about the
themselves and the medicine; participant belief and trust in the healer; the immediate setting
of the ceremony, including the rituals involved; and the larger cultural matrix of beliefs and
values. Similarly, ayahuasca studies have demonstrated the importance of belief in the spiritual
worldview represented by the healer (Fotiou, 2010, 2012; Franquesa et al., 2018) and
psychedelics themselves can be viewed as a kind of ethno-pharmacology (Blum et al., 1977)
involving metaphysical beliefs (Timmermann et al., 2021) and spirituality (Cohen, 2018;
Lafrance et al., 2021).
2.7 Pre-Clinical Studies and Psilocybin Non-human Animal Paradigms
While there has been a surge of interest in the potential clinical application of
psychedelics such as psilocybin for the treatment of a range of mental health conditions, the
underlying mechanisms of action remain an area of exploration. Pre-clinical research such as
animal investigations can potentially provide insight into pharmacokinetics, neurodynamics,
and behavioural changes associated with psychedelic action (de Gregorio et al., 2021; Hanks &
González-Maeso, 2013).
Psilocybin has been demonstrated to promote structural and functional neuroplasticity,
promote dendritic spine growth, increase dendritic arbor complexity, and stimulate synapse
formation (Ly et al., 2018a; Savalia et al., 2020) while modulating functional brain connectivity

25
(Carhart-Harris et al., 2012, 2014; Muthukumaraswamy et al., 2013). Serotonergic psychedelics
have also been shown to promote cell survival , have neuroprotective effects and modulate the
neuroimmune systems of the brain (Calvey & Howells, 2018; Szabo, 2015).
2.7.1 Non-human Animal Studies as Translational Models
Drug toxicity studies on non-human animals became legislated as a requirement for new
drug development under food and drug regulatory frameworks in the late 1930s, and the
requirement of animal research before human trials was written into both the Nuremberg code
(1946) and the Helsinki Declaration (Van Norman, 2019). Animal research has continued despite
criticisms based on ethics (Barré-Sinoussi & Montagutelli, 2015), lack of translational success
(Leenaars et al., 2019), bias towards anthropomorphism (Anderzhanova et al., 2017) and
methodological concerns such as lack of replicability and inter-species variability (Herzog et al.,
2018) as well as the limitations implicit in generalizing results from the adolescent-aged, in-bred
rodent strains standard to animal investigations (Duque et al., 2021). Living in controlled
experimental conditions results in chronic stress on study animals with resultant effects on
neuromodulatory and self-regulatory systems (Alexander et al., 1981).
Behavioural models of animal study are of use in psychopharmacology as simulations to
study aspects of more complex psychiatric states, and as screening tests in the development of
novel treatments (Willner & Belzung, 2015). Various psychedelic compounds produce markedly
similar effects in both non-human animals and humans, demonstrating cross-tolerance and
sharing similar metabolic pathways, and affecting common anatomical brain regions (Calvey &
Howells, 2018; de Gregorio et al., 2021; Halberstadt, 2015). Evidence for the involvement of 5-

26
HT-2A is found in both human as well as preclinical literature (Calvey & Howells, 2018; Glennon
et al., 1984; López-Giménez, Juan F., González-Maeso, 2018). Pre-clinical studies include drug
discrimination, tolerance, and behavioural assays such as head-twitch response (HTR), pre-
pulse inhibition (PPI) of startle, interval timing, locomotor response and exploratory studies (de
Gregorio et al., 2021; Halberstadt et al., 2017; Hanks & González-Maeso, 2013).
Rodent studies have established the half-life of psilocin in plasma to be 2.5 after oral
ingestion and 1.23 hours after intravenous administration of psilocybin, while psilocybin’s
affinity for human 5-HT2A receptors is 15 times that of rats (Tylš et al., 2014). Behavioural assays
such as head-twitching, limb flicks and wet-dog shakes have been established as representative
of 5-HT2A receptor stimulation (Strumila et al., 2021). Non-human animals tend to be dosed
within a range of 0.25-10mg/kg for behavioural assays, a dose range substantially lower than
the LD50 (lethal dose of psilocin in 50 % of animals tested) of 293mg/kg (Geiger et al., 2018).
1mg/kg has been identified as the minimal dose to achieve behavioural effects (Meinhardt et
al., 2020). Sex differences have been psychiatric animal research paradigms (Kokras & Dalla,
2014), in the biological expression of serotonin and psilocybin effect in rats (Tyls et al., 2016),
but not a robust predictor of drug effect in human psychedelic-assisted therapy research (Aday
et al., 2021;). Animal models have also demonstrated the importance of time-of-day on drug
effect outcomes. Measuring time points is important in the design of psychedelic animal
paradigms: LSD disrupts locomotor activity when administered early in the light phase of
crickets but not late, has no acute effects on day of dose administration but reversed locomotor
rhythms in house crickets twenty-four hours later, and occasions more head twitches in mice in
periods of darkness (Schindler et al., 2018).

27
Behavioural investigations employing other classical serotonergic psychedelics such as
DMT have provided evidence of anti-depressant effect as well as the facilitation of fear
extinction learning (Cameron et al., 2019), decreasing exploratory behaviours, decreasing
rearing and promoting avoidance of the centre of an area (Geyer et al., 1979). Chronic
administration of ayahuasca did not lead to impairment of spatial memory (as measured by the
Morris water maze assay) but did enhance both foreground and background contextual fear
memory (Cameron et al., 2018). Extinction learning in mice has been found to both enhanced
by psilocybin (Catlow et al., 2013; Stackman et al., 2013) in a dose-dependent manner;
psilocybin does not enhance trace fear conditioning in rodents (Doss, Madden, et al., 2021).
Evidence from animal investigations, particularly studies of prepulse inhibition (PPI) and
inhibition of return (ROI) reflect pre-attentive sensory gating processes, disruption of lower
levels of sensory memory and impairment to thalamocortical gating of sensory information;
psilocybin similarly acutely impairs the encoding of recollection memory during acute drug
effect (Doss, Madden, et al., 2021). Animal models demonstrate that both LSD and DOI reduce
PPI of the acoustic startle response (Geyer et al., 2001).
Animal studies indicate that psychedelics promote structural and functional
heterosynaptic plasticity, as evidenced by its action on brain-derived neurotrophic factor
(BDNF), the expression of genes related to neuroplasticity, and to in vivo studies which have
demonstrated an increase in density, strength and complexity of neuronal connections in mice
by about 10% after psilocybin (Ly et al., 2018b). Growth of dendritic spines has been
documented at 24 hours post-drug administration and found to persist for up to one month (Ly
et al., 2018a). Greater neural diversity is associated with cognitive flexibility. 5-HT2A agonists

28
attenuate models of such flexibility in rats (Boulougouris et al., 2008) while in mice,
psychedelics have little or no effect on cognitive flexibility (Amodeo et al., 2020) while in
humans, LSD has been shown to acutely impair cognitive flexibility (Doss, Madden, et al., 2021).
Animal studies have been found to be inconsistent predictors of even pharmacological
toxicity in humans (Van Norman, 2019). Animal models of complex, multi-factorial psychiatric
conditions such as depression, anxiety or substance use disorder remain a challenge limited by
significant differences in language capacity, perceptual and sensory systems (Hanks & González-
Maeso, 2013). Interpreting any single animal behaviours as reflective of human depressive-like
symptoms lacks constructive validity, especially without the communication required to
understand internal states of feeling (Commons et al., 2017; Slattery & Cryan, 2012). There is
yet no clear “gold-standard” protocol for investigating the behavioral effects of psychedelics in
non-human animals and the value of translational models of animal research remains
somewhat controversial (De Gregorio et al., 2018).
The study of animal paradigms is useful in the manner in which they may elicit
observable, biological phenomenon of organisms not entirely dissimilar from humans and
identify areas of possible consistency between animal and human behaviour. Animal research,
particularly in areas of neuropsychology, can provide bottom-up information for the
identification of underlying mechanisms and are useful in stimulating new conceptual
paradigms. Similarly, animal paradigms can be of value in identifying the pharmacological
effects of psilocybin outside of the psychological supports included in human trials (Meinhardt
et al., 2020).

29
Generalizing results from animal to human trials is problematic. Animal research does
not in itself create a pipeline of new drug discovery for clinical application, but does help
provoke new paradigms, as has been the case with neuroplasticity literature (Macpherson &
Hikida, 2019). The study of the molecular biology of relatively simple Aplysia sea slug
contributed to contemporary understandings of neuronal plasticity and implicit memory
(Kandel et al., 2014). Animal research previously contributed to the development of new
scientific theories of learning and memory (Nadel & Maurer, 2020). While depression or
addiction would be problematic as cross-species concepts, the mechanisms of habit learning
are largely conserved and consistent across mammalian species, not replaced by the higher
cortical functions of the human brain (Wood & Rünger, 2016). Addiction has been understood
as a learned behaviour (Lewis, 2018), and disorders of compulsivity demonstrate a common
bias towards learning habits (Voon et al., 2015). To better understand such biases certain areas
of behavioural research are of particular interest. Areas I have identified, which are largely
governed by neural networks originating in subcortical regions or linked from limbic structures
to the neocortex, include: habit formation, reward valuation, behavioural sequencing, fear
learning extinction, activation of sensorimotor systems, cognitive control, goal-directed
behaviour, arousal and social processes.
2.7.2 Habit Learning: Findings from Non-human Animal Studies
Habit learning mechanisms are thought to be conserved across differing mammalian
species; common elements are habit learning through the repetition of response and the
formation of context-response associations stored in memory so that performance becomes

30
relatively automated and conditioned to respond to environmental cues, insensitive to changes
in value or outcomes, and with a narrowing of cognitive accessibility to alternatives (Wood &
Rünger, 2016). An established trope of animal learning is that habit learning is strengthened
when rewards are provided on interval schedules, with response rewards coming only after
some passing of time; interval rewards are likely to endorse habit learning because context-
response associations are able to form without the inclusion of a representation of any action-
goal or in relation to the outcome of the activity (Wood & Rünger, 2016). This mechanism is of
interest given the hypothesized role for psilocybin in disrupting default habit activity (habit cues
automatically prompting habit representations), highlighting the importance of stored
conceptual representations in guiding free behaviours.
Habit learning is most likely consolidated in cortical brain regions, with evidence
implicating the sensorimotor cortico-basal ganglia loop as the primary neural substrate of habit
learning and performance (Khamassi & Humphries, 2012; Macpherson & Hikida, 2019; Wood &
Rünger, 2016). Following maze tasks, hippocampal cells have been demonstrated to reconfigure
following a change in context; the hippocampus in this way may contribute to model-based
action planning and is central to the study of habit disruption (Khamassi & Humphries, 2012).
Rodents with lesioned hippocampal afferents have intact place responses, but difficulty in
constructing paths to them, can swim to pre-lesioned platform locations in the Morris water
maze, but not to a new one, and lesioned rats lack path integration in returning to home base
in open-field tests; all indicating an important role for the ventral striatal core in linking
sequential episodes and for representing and encoding transition-conditioned probability of
action selection outputs (Khamassi & Humphries, 2012). 5-HT2A receptor activation in mice

31
enhances NMDA transmission, effectively gating the induction of temporal plasticity and
rescuing deficits in associative memory; presynaptic 5-HT2A receptors located at thalamo-cortical
synapses play a role in the control of thalamo-frontal connectivity and associated cognitive
functions (Barre et al., 2016).
2.7.3 Challenges in Knowledge Translation from Non-human Animal Studies:
As translational research, animal models are assessed for their validity in application to
humans by way of construct validity, face validity and predictive validity (Willner, 1984).
Construct validity is met if there is coherence in the concept being tested, face validity requires
the identification of common or similar underlying physiological mechanisms between the two,
and predictive validity is the capacity to predict findings in human populations (Herzog et al.,
2018; McOmish et al., 2014). Building on Wilner’s three primary criteria for translational
validity, Belzung and Lemoine present a more nuanced and comprehensive framework for
quality of validity assessment. While there is partial overlap of criteria, the latter present five
categories of validity in comparison to Willner’s two, disentangling different dimensions while
redefining face and predictive validity (Belzung & Lemoine, 2011) (see Table 1, Appendices).
Quality standards for the conduct and reporting of scientific animal studies have been
developed. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were
published in 2010 (Physiol, 2010), identifying the minimum standards of reporting necessary to
transparently describe in vivo experiments. Revised in 2020, the guidelines have seen limited
uptake and many animal model publications fail to report on the information necessary to
interpret the validity of the investigation (du Sert et al., 2020; Smith, 2020). A validated Risk of
Bias (RoB) assessment tool for animal intervention studies (the SYRCLE’s RoB tool) has been

32
developed (Hooijmans et al., 2014). Based on the Cochrane RoB tool, the SYRCLE RoB tool has
been adjusted to the differences between randomized controlled human trials and animal
studies. The tool assesses the risk for biases such as selection bias, performance bias, detection
bias, attrition and reporting biases.
While it may be difficult to fully model a complex human disorder such as depression in
animal models, diagnostic disorders and their distinctive symptomologies or traits can
themselves be understood to have associated endophenotypes. Endophenotypes are
measurable, trait-related deficits which can be assessed by laboratory study (Braff et al., 2007).
Major depressive disorder, for example, is characterized by several distinct endophenotypes
such as amotivation, anhedonia, and impaired cognition (Higgins et al., 2021). Behavioural
assays such as exploratory and approach-avoidance conflict paradigms, forced swim test, tail
suspension test and associative learning paradigms have been developed in animal research to
capture elements of human psychiatric conditions (Teixeira & Quevedo, 2013; Willner &
Belzung, 2015).
Animal studies which model such endophenotypes may have value in translation to
more complex human dynamics as contributing to our understanding of the composite
characteristics of mental health diagnoses (Slattery & Cryan, 2012) . Phenotype measures have
the additional value of being more proximal to actual genetic expression, physiology and
behaviour than the more abstract structures of mental health diagnostic criteria (Iacono, 2018),
and may be more translatable across the preclinical to clinical spectrum with better predictive
and construct validity (Day et al., 2008, Markou et al., 2009). While animal investigations may
not be able to completely model a pathology, they can simulate certain aspects as reflected in

33
their behavioural endpoints (Willner & Belzung, 2015). To improve validity, animal
investigations have increasingly adopted domain-based inclusion criteria and moved away from
the adoption of disorder-based nosology (Herzog et al., 2018).
2.7.4 The Research Domains Criteria Framework of Translational Research
The Research Domain Criteria (RDoC) is a framework for endophenotype-oriented
translational neuroscience and presents a new framework for categorizing psychopathologies
based on dimensions of observable behavior and neurobiological measures (Cuthbert & Insel,
2013). The RDoC matrix provides a dimensional and trans-diagnostic epistemic framework by
which to understand pre-clinical and clinical sciences in the service of knowledge translation. In
doing so, it provides an alternative nosology for the understanding of mental health distinct,
more nuanced, and biologically valid framework than the definitions and categorizations of
mental and emotional health as described in the DSM-V, the Diagnostic and Statistical Manual
of the American Psychiatric Association. Under the RDoC framework, traditional psychiatric
symptoms are understood as functions of a domain of biological activity, and dysfunctions can
span both multiple domains and multiple disorders (Macpherson & Hikida, 2019).
The RDoC framework has recently been applied to psychedelic-assisted psychotherapy
in a review of its’ transdiagnostic effects (Kelly et al., 2021). By its focus on smaller units of
analysis, RDoC proposes an interdisciplinary science of psychopathologies, identifying basic
mechanisms which cut across diagnostic boundaries (Zoellner & Foa, 2016). The domains of
analysis within RDoC serve as a matrix for model validation; homologies between human and
experimental non-human animals in the domains justifies the validity, reliably and

34
translatability of animal models appearing as endophenotypes of negative and positive affect,
social interaction and general arousal/modulatory systems, while the complexity of the RDoC
cognitive behavioural domain requires ongoing clarification (Anderzhanova et al., 2017).
Animal assays with psychedelics may not capture the interiority of psychedelic drug-
induced experiences but rather demonstrate related behavioural outcomes, in this way
assisting in our understanding of what exactly psychedelics do. While much is made of the
clinical potential for psychedelic compounds in treating disorders of mental health, less is
written about their cognitive, motivational and habit-related effects. Common to both scoping
reviews (animal and human studies) reported later is the noticeable effect of psilocybin on
established, habitual behavioural programs. Depression itself can be understood as a previously
bound (conditioned), high-level neural assemblage which has become sustained, or integrated,
in to the homeostasis of the organism, characterized by repetitive closed-loop thoughts and
feelings which have become disconnected from environmental stimuli or reward outcomes
(Davis et al., 2020; Fauvel et al., 2021); depression as a habitual neural network can be
potentially loosened, inhibited and somewhat unlearned through the psilocybin experience due
to the unique cellular and network desynchronization effects of serotonergic psychedelics
(Carhart-Harris et al., 2014; Muthukumaraswamy et al., 2013).
2.8 Thesis Research Question
The research question guiding this program of research (see Appendix A.1 Thesis
Proposal) was to investigate the therapeutic potential of psilocybin in the treatment of mood
and self-regulatory disorders:

35
Can psilocybin have clinical benefit in the treatment of mood and self-regulatory
disorders, including end-of-life distress? If so, what are the program/practice variables
associated with treatment outcomes?
Subsequently to address this research question I conducted two distinct scoping reviews; each
had a guiding research question of their own.
The first, Mapping Psilocybin-Assisted Therapies, is a scoping review conducted of the
publications associated with human psilocybin clinical trials, and was guided by the research
question:
What are the treatment variables and outcomes associated with psilocybin-assisted
therapy?
Variables include both patient and intervention characteristics. Outcomes include changes in
health status and both positive and negative outcomes noted. This research question helps to
map the state of psilocybin-therapy research and to identify both treatment variables and
patient characteristics. In this way, any effectiveness found in psilocybin therapy may lead to
evidence-based program and policy developments. By opening the “opaque box” of psilocybin
therapies, we can understand which inputs lead to desirable outcomes.
The second scoping review study, Behavioural Investigations of Psilocybin in Non-human
Animals, was guided by a separate research question:
What are the neurological and behavioural effects of psilocybin administered in non-
human animal studies?
As the scope of this study was limited to behavioural investigations, I was primarily interested
in the observable effects of psilocybin as demonstrated within behavioural assays. From these

36
studies, pharmacological effects of psilocybin can be mapped, and the studies were scoped to
identify variables found to influence drug effect (such as pre and post conditioning programs).
Within the larger scope of this research into the clinical potential of psilocybin, findings
from the non-human animal research could complement and add additional insight to findings
from human clinical trials – in part because they are not bound by the specificities of mental
health diagnostics and clinical trial design. In this way I cast my net wide into a large and diverse
body of scientific literature. In reporting the findings of both human clinical trials and non-
human animal investigations side-by-side, novel insights into program variables (the conditions
found to influence drug effect) may arise. Further, by mapping such a wide and diverse body of
literature, new hypotheses about psilocybin’s therapeutic potential may present and I can test
my hypothesis regarding psilocybin’s effects on self-regulation and habit against empirical
evidence from both clinical and pre-clinical science.
Before reporting on the scoping review findings, I next present a thorough narrative
review on the neuroscience of psilocybin. Here, I present the pharmacology and
pharmacodynamics of psilocybin before exploring the neuroscientific literature on brain state
and network connectivity changes associated with psilocybin and other serotonergic
psychedelics. I highlight in the importance of the habit construct in order to better understand
psilocybin’s neuroplastic and putative therapeutic effects.

37
Chapter Three:
The Neuroscience of Psilocybin: A Narrative Review
This narrative review covers areas of significance to understanding the chemical effects
of psilocybin on the brain, nervous system and ultimately behaviour. After reviewing
psilocybin’s chemistry, pharmacology and pharmacodynamics I examine the evidence on
neurophysiological mechanisms linking psychedelics to neuroplasticity. Finally, the importance
of subcortical and limbic-associated regions and network processes in the potentiation of
therapeutic effect is addressed, positioning the habit construct and habit learning as central to
the psychoplastogenic effect of psilocybin.
3.1. Psilocybin Chemistry, Pharmacology and Pharmacodynamics
3.1.1 Chemistry of Psilocybin and Related Serotonergic Psychedelics
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a naturally-occurring
tryptamine indolealkylamine and a prodrug to psilocin (4-Hydroxy-N,N-dimethyltryptamine), a
central serotonin 5HT2A receptor agonist. In their pure chemical form, both are white crystalline
powders unstable in light (especially in solution) but relatively stable in inert dark conditions at
low temperature; while psilocybin is water-soluble, psilocin is more lipid-soluble (Tylš et al.,
2014) . Along with lysergic acid diethylamide (LSD) and N, N-Dimethyltryptamine (DMT),
psilocybin is considered a classic serotonergic psychedelic and to be structurally related to the
monoamine neurotransmitter serotonin (Nichols, 2016; Tylš et al., 2014).

38
The therapeutic potential of Psilocybe mushrooms may not be limited to the psilocybin
compound alone; psilocin, baeocystin, norbaeocystin, aeruginascens, norpsilocin and
phenylethylamines are also found in Psilocybe mushrooms and may themselves have value
alone or in entourage(Kuypers, 2019; Kuypers et al., 2019; Wieczorek et al., 2015). Recent
investigations have found the presence of beta-Carbolines in Psilocybe mushrooms resulting in
an ayahuasca-type synergy of psychoactive alkaloids and potent monoamine oxidase inhibitors
which also themselves have antidepressant effects and potentiate the psychedelic serotonergic
effects (Blei et al., 2020).
Psychedelics are divided into classic, and non-classic or atypical. Classical psychedelics
include two structural types: indoleamines (lysergic acid diethylamide or LSD,
dimethyltryptamine or DMT, and psilocybin from Psilocybe mushrooms) and phenylalkylamines
(mescaline from peyote and modern synthetics such as the 2C-X family). Atypical psychedelic
compounds include dissociatives such as ketamine and entactogens such as 3, 4-
methylenedioxy-N-methamphetamine (MDMA), as well as ibogaine, an NMDA agonist and
tryptamine compound (Calvey & Howells, 2018; Halberstadt et al., 2017; Nichols, 2018; Sellers
et al., 2018).
Classic psychedelics include two structural classes: a) indoleamines and b)
phenylalkylamines (Nichols, 2018). Indoleamines are further sub-classified into a1) ergolines
such as lysergic acid diethylamide (LSD), and the chemically simpler a2) indolealkylamines,
which include N,N-dimethyltryptamine (DMT), 5-methoxy-dimethyltryptamine (5-MeO-DMT),
psilocybin (4-phosphoryloxy-dimethyltryptamne) derived from psychoactive fungi, principally of
the Psilocybe genus and its dephosphorylated metabolite psilocin (4-hydroxy-

39
dimethyltryptamine) (Calvey & Howells, 2018; Halberstadt, 2015). Ergolines are characterized
by a complex and rigid structure with an indole system and tetracyclic ring, while the simpler
indole tryptamines have a bicyclical benzene and pyrrole ring combined to an amine group by a
two-carbon side chain. The presence of a 4-hydroxy or 5-methoxy substituent on the indole ring
increases drug potency. Like serotonin, some tryptamine derivatives (DMT, 5-MeO-DMT) are
extensively metabolized by oxidative deamination, mediated by monoamine oxidase A (MAO-
A)(Araújo et al., 2015). Indolealkylamines are characterized by a promiscuous binding profile,
demonstrating affinity to a variety of 5-HT1 and 5-HT2 receptor subtypes. (Araújo et al., 2015).
With an indole nucleus at their basic structure, indoleamines have high structural
similarity with the endogenous tryptamine serotonin (5-hydroxytryptamine), a monoamine
neurotransmitter (synthesized from the essential amino acid tryptophan) with a range of
biologic functions, including smooth muscle contractile effects, vasoconstriction, mood
modulation, and the regulation of cortical function (Araújo et al., 2015; Nichols, 2018). As 5-HT
cannot pass the blood-brain barrier, serotonin is synthesized in the brain from tryptophan in
the raphe nucleus of the brainstem, with axons originating from such neurons innervating
almost the whole brain and projecting terminals both into the forebrain and the spinal column
(De Gregorio et al., 2018, González-Maeso, 2018).
3.1.2 Psilocybin Pharmacokinetics
Upon oral ingestion, alkaline phosphatase and nonspecific esterase from intestinal
mucosa rapidly dephosphorylate psilocybin to psilocin. Psilocin is further glucuronidated by
endoplasmic enzymes UDP-glucuronosyltransferase (UGTs) to psilocin-O-glucuronide; in this

40
form 80% is excreted from the body (Passie et al., 2002; Tylš et al., 2014). Psilocin is itself
subject to oxidative metabolism, undergoing demethylation and deamination to 4-hydroxyin-
dol-3-yl-acetaldehyde (4-HIA) and subsequent oxidation to 4-hydroxyindol-3-acetic acid (4-
HIAA) and 4- hydroxytryptofol (4-HT) (Hasler et al., 1997; Passie et al., 2002).
The half-life of psilocin in plasma is 2.5 hours after oral ingestion of psilocybin (1.23
hours following intravenous administration) (Passie et al., 2002; Tylš et al., 2014). In humans,
psilocybin and psilocin can be found in blood plasma 20–40 minutes after oral administration of
psilocybin; maximum levels of psilocin are achieved between 80 and 105 min and can be
detected for up to 6 hours (Hasler et al., 1997; Passie et al., 2002). In non-human animals,
maximum plasma levels of psilocin have been found to occur after approximately 90 minutes
(Chen et al., 2011). Psilocin is distributed to all tissues; prior to the brain, psilocin accumulates
in kidneys and the liver. Psilocin is excreted within 24 hours, with the majority in the first 8
hours. Trace amounts of psilocin can be detected in the urine even after a week. The
elimination half-life of psilocybin is 50 minutes; the elimination constant is 0.307/hour
(Lindenblatt et al., 1998). Most is excreted within 3 hours after oral administration and is
completely eliminated from the body within 24 hours (Hasler et al., 2002). In studies of non-
human animals highest concentrations of psilocin have been detected in the neocortex,
hippocampus, extrapyramidal motor system and reticular formation (Hopf and Eckert, 1974).
3.1.3 The Pharmacodynamics of Serotonergic Psychedelics
The pharmacology of psychedelics is diverse and includes complex agonist and partial
agonist/antagonist actions on 5HT2A, 5HT2C, 5HT1A, dopamine D₂, trace amine associated receptors

41
1 (TAAR), kappa receptors, various transporters (e.g., serotonergic, dopaminergic,
norepinephrine), intracellular messengers, effects on gene expression and epigenetic regulators
(Sellers et al., 2018). Such a wide range of pharmacologic mechanisms and targets raises the
probability of unexpected acute and chronic off-target toxicity and an elevated risk of
interactions with concurrent diseases and drugs that will vary for different psychedelics (Sellers
et al., 2018).
Serotonin (5-hydroxytryptamine;5-HT) receptors regulate a range of processes including
learning and memory, sleep and wake cycles, thermoregulation, appetite, sexual behaviour,
pain, motor activity and aspects of autonomic function (Flanagan & Nichols, 2018). Nichols
identifies the 5-HT 2A receptor principally expressed in the cortex as the key site of action,
conjecturing that the novel patterns of global neurological connectivity (Carhart-Harris et al.,
2012), entropy (Carhart-Harris et al., 2014) or cortical desynchronization (Muthukumaraswamy
et al., 2013) produced by psilocybin, when combined with the appropriate clinical preparation
and setting, can result in a subsequent, beneficial “rewiring” of brain networks away from
previous pathological patterns and more similar to pre-disease states (Carhart-Harris et al.,
2017; Carhart-Harris & Goodwin, 2017; Nichols et al., 2017) characterized by positive mood and
sustained improvements in mental health (Calvey & Howells, 2018; de Gregorio et al., 2021; De
Gregorio et al., 2018).
Fourteen different serotonin receptors, classified into 7 subfamilies, have been
identified; all but one are G-protein coupled receptors (David E Nichols, 2018, González-Maeso,
2018). Serotonin receptors themselves can depolarize or hyperpolarize neurons by altering
ionic conductance and concentration within cells, able to affect excitability within a range of

42
brain networks (Calvey & Howells, 2018). Serotonin is also the main neurotransmitter
implicated in major depression (De Gregorio et al., 2018), and psychedelic compounds have
affinity (and perhaps their main mechanism of action) with the 5-HT2A receptor (Glennon et al.,
1984; González-Maeso et al., 2007; Nichols, 2018). While discriminative stimulus studies
indicate the principal role played by the neuronal serotonergic system, critical discussion
continues regarding which receptor subtypes are implicated and whether various compounds
are agonists, partial agonists or antagonists (Eshleman et al., 2014). 5-HT2 receptor agonism is
what loosely binds psychedelic chemicals into a unitary class (Muthukumaraswamy et al.,
2013). Both indole and phenylalkylamine psychedelics bind principally to 5-HT1, 2, 5 and 7 receptors
(Vollenweider et al., 1998). Classic psychedelics display weak reinforcing effects in both animal
and human studies (Calvey & Howells, 2018; Hamill et al., 2018)
Psychedelics share discriminative stimulative effects and selective agonism of serotonin-
1 and 2 receptor subtypes. Classic psychedelics stimulate dopamine via D2 receptors and
indirectly stimulate glutamatergic and GABAergic (gamma-aminobutyric acid) systems (David E
Nichols, 2018). Psychedelics commonly stimulate 5HT2A cortical layer V pyramidal neurons,
triggering disruptive signalling pathways and cortical desynchronization across various key brain
regions, creating a time-limited state of entropy and allowing for the loosening of rigid
neurological and cognitive patterns (Carhart-Harris, 2016; Muthukumaraswamy et al., 2013;
Rucker et al., 2018).
Classic psychedelics further stimulate the dopaminergic system principally via D2
receptors and indirectly stimulate the glutamatergic and GABAergic (the inhibitory gamma-
aminobutyric acid) systems (Calvey & Howells, 2018). Brain state entropy and

43
desynchronization of cortical states are also common to the psychedelic states affected by
numerous compounds, prompting belief that the mechanism of action to the psychedelics be
the experience which results – that the experience of entropy/uncertainty and the altered state
of consciousness experienced promote brain criticality and well-being in both psychological and
neurobiological measures (Carhart-Harris, Muthukumaraswamy, et al., 2016;
Muthukumaraswamy et al., 2013)
LSD, first synthesized in 1938, is a potent chemical and tetracyclic ergoline considered a
prototypical psychedelic (Calvey & Howells, 2018; Carhart-Harris et al., 2012; Nichols, 2018).
LSD displays high affinity for 5-HT receptors (Halberstadt, 2015) as well as stereospecific binding
to the dopamine (D2) receptor as well as partial agonist activity at D1 type receptors (De
Gregorio et al., 2018). Both LSD and psilocybin demonstrate mood-altering properties, perhaps
due to their pleiotropic effect on serotonergic (5-HT), dopaminergic (DA) and glutamatergic
systems (De Gregorio et al., 2018; González-Maeso, 2018). Psilocybin has been shown to have
an indirect influence on dopaminergic systems as a neuro-modulator (Vollenweider et al.,
1998).
DMT, another tryptamine and classic serotonergic psychedelic found in the Ayahuasca
decoction as well as in 5-MeO-DMT, binds non-selectively to 5-HT receptors, as well as to
sigma-1 receptors, the trace amine receptor, and is a substrate for the 5-HT transporter (SERT);
however, animal studies and bioassays have established that tryptamines are more potent at 5-
HT receptor sites by a several orders of magnitude (Halberstadt, 2015). The beta-carbolines
contained in the ayahuasca liana are themselves tricyclic indole alkaloids resembling
tryptamines with affinity for the 5-HT-2A binding site, and have known antidepressant effects

44
(Hamill et al., 2018). It has been suggested that due to the varying nature and substituents in
the molecules, all tryptamines most likely do not share a common metabolic pathway after
receptor agonism (Araújo et al., 2015). Several animal studies have indicated a biphasic process
of psychedelic effect, prompting suggestions that 5-HT2A receptors mediate initial responses to
tryptamine psychedelics, while D2 receptors mediate subsequent stages of neural metabolism
(De Gregorio et al., 2018). Further, it is known that 5-HT2A receptor agonism leads to the
inhibition of dopamine release in the mesolimbic, nigro-striatal and mesocortical pathways
(Hamill et al., 2018). Dopamine dysregulation is implicated in psychosis and schizophrenia
(Calvey & Howells, 2018; De Gregorio et al., 2018).
3.1.4 Physiological and Behavioural Effects of Psilocybin
Psilocybin increases blood pressure and heart rate (Passie et al., 2002) and may result in
transient hypertension, tachyarrhythmias and hyperthermia. Other possible side effects include
nausea, vomiting, acute and delayed headaches, dizziness, paresthesia, blurred vision, dilated
pupils and increased tendon reflex (Johnson et al., 2008a; Sellers & Leiderman, 2018; Studerus
et al., 2011). Psilocybin disrupts sleep patterns, prolonging REM sleep-latency and decreasing
overall REM sleep duration (Dudysová et al., 2020). Psilocybin has also been demonstrated to
alter perceptual visual constants and contract nearby visual space (Fischer et al., 1970),
increase sensitivity to music and sound (Kaelen et al., 2018), promote synaesthesia (Luke &
Terhune, 2013)and to increase semantic network activation and cognitive associations (Family
et al., 2016; K. R. Smith, 2016; Spitzer et al., 1996).

45
Psilocybin administration moderately increases pupil dilation, heart rate as well and
both systolic and diastolic blood pressure and may result in transient hypertension,
tachyarrhythmias and hyperthermia. Other physiological effects which may be considered
adverse including: dizziness, weakness, impaired perception, impaired proprioception, tremors,
nausea, drowsiness, paresthesia, blurred vision, dilated pupils and increased tendon reflexes
(Johnson et al., 2008a; Sellers et al., 2018). Psychedelics affect time perception, synchronization
and tapping tempo, and working memory which impairs driving and operation of machinery
(Amsterdam et al., 2011). Other commonly reported subjective effects include visual and
auditory hallucinations, synesthesia, interactions with entities/persons not physically present,
past life experiences and experiences of jamais vu. (Carbonaro et al., 2016). Some known
biologic effects of psychedelics such as increased corticotropin, beta-endorphin, prolactin,
cortisol, growth hormone, may have implications for clinical efficacy or safety after repeated
dosing (Sellers et al., 2018). As well, due to the non-selective agonism of the 5HT2B receptor,
chronic microdosing may lead to ventricle heart disease, as a result of cardiac valvulopathies
and valvular hyperplasia (Kuypers et al., 2019).
Clinical studies have not reported serious safety issues due to these physiologic effects,
though some observed significant increases in blood pressure, which may pose a risk for
subjects with untreated hypertension or related disorders (Sellers et al., 2018). Psilocybin
increases respiratory rate and is associated with tachypnea and irregular respirations; these
may be somewhat secondary to experiences of anxiety, but it is of note that the biomass of
Psilocybe mushrooms does contain phenethylamines, which do have an amphetamine chemical

46
structure (Kuypers et al., 2019). One of the few reports of psilocybin-associated mortality
describes a patient who had unusual, irregular respiration prior to death (Sutter et al., 2014).
Psilocybin has peak effects on emotional excitation and sensitivity, heightened mood,
and concentration in the early phase of drug metabolism (60–180min after drug intake). Effects
such as dreaminess, dazed state, inactivation, and introversion were more pronounced in later
phases (260–400min) (Studerus et al., 2011). Subjects tend to be more active, emotional,
extroverted and cognitively impaired in the early phase of the psilocybin session relative to the
later phase; derealization and depersonalization take precedence over visual hallucinations
about 90–120min after drug intake. During the later phase, subjects increasingly turn inwards,
appear absent-minded and show reduced facial expressions (Studerus et al., 2011).
While psilocybin is biologically safe and relatively non-toxic compared to other
psychoactive compounds (Amsterdam et al., 2011; Carbonaro et al., 2016; Gable, 2004), it has
been associated with psychological distress, erratic behavior, and a small possibility of harmful
behavior while under drug effect (Johnson et al., 2008a; Rucker et al., 2016b; Sellers et al.,
2018; Studerus et al., 2011). The majority of published case reports of acute lethal toxicity due
to psychedelics indicate the presence of other inebriants, most commonly alcohol (Gable,
2004). Studies which calculate safety ratios varied between various substances consistently
demonstrate several hallucinogens as having the least direct physiological toxicity (Gable,
2004). The oral lethal dose (LD-50) value of psilocybin in rats is 280 mg/kg; 17 kg of fresh
mushrooms (at average potency) would need to be consumed by a human for a 50% chance of
overdose(Amsterdam et al., 2011). Interactions which potentiate toxicity include alcohol and
tobacco via their metabolic effect on monoamine oxidase (MAO) inhibiting enzymes

47
(Amsterdam et al., 2011). Non-human animals receiving doses of psilocybin exhibit dose-
dependent irregularities in heart and breathing rate as well as mydriasis, piloerection,
hyperglycaemia and hypertonia (Kuypers et al., 2019).
3.2. Neurophysiological Mechanisms of Psychedelic Drugs
Though they originate in diverse and multiple chemical families, the various
psychedelics produce markedly similar effects in both non-human animal species and humans,
demonstrate cross-tolerance, and increasingly are understood to have similar metabolic
pathways and effect common anatomical regions of the brain (Calvey & Howells, 2018;
Halberstadt, 2015). Psychedelics share discriminative stimulus effects and act as agonists of the
serotonin-1 and 2 receptor types, with the 5-HT-2A (5-HT-2a) receptor identified as key to visual
hallucinations (Calvey & Howells, 2018; Glennon et al., 1984; González-Maeso, 2018). Evidence
for the involvement of 5-HT-2A is found in both preclinical animal studies as well as in studies
involving healthy human volunteers. The pre-clinical literature includes drug discrimination,
tolerance, head twitch response (HTR), pre-pulse inhibition, interval timing and
exploratory/investigative behaviour studies (Halberstadt et al., 2017).
Psychedelics present an opportunity to investigate the neural correlates and
hemodynamics of various psychological states through the use of brain imaging techniques
such as electroencephalogram (EEG), functional magnetic resonance imaging (fMRI),
magnetoencephalography (MEG), arterial spin labelling (ASL), and positive emission
tomography (PET) (Carhart-Harris et al., 2012). Drugs considered to be psychedelic continue to
increase in number and variety, with many appearing in recent years online for sale as

48
“research chemicals” (Araújo et al., 2015; Halberstadt, 2017). The prohibited legal status of
psychedelics, implemented in the late 1960’s and early 1970’s had complicated and limited
research into these drugs, but a “renaissance” of psychedelic science is underway.(De Gregorio
et al., 2018). Psychedelic drugs commonly stimulate 5-HT2A cortical layer V pyramidal neurons,
triggering unique cellular signaling pathways, altering epigenetic expression and modulating the
activity of dopaminergic, GABAergic and other key neurochemical systems. A cortical
desynchronization across various key brain regions results, creating a time-bound entropic
experiential state of heightened neuroplasticity which disrupts previously established and
potentially pathological brain network patterns.
Recent evidence supports this concept of neuronal rewiring, as serotonergic
psychedelics have been demonstrated to induce neuroplasticity, promote dendritic spine
growth, increase dendritic arbor complexity, and stimulate synapse formation (Ly et al., 2018b;
Savalia et al., 2020). Serotonergic psychedelics have also been shown to promote cell survival,
have neuroprotective effects and modulate the neuroimmune systems of the brain (Calvey &
Howells, 2018) while reducing neuroinflammation (Flanagan & Nichols, 2018). The use of
psychedelics as a potential therapy represents a paradigm shift in our approach to disorders of
mental health (Carhart-Harris & Goodwin, 2017; Kyzar et al., 2017a; Rochester et al., 2021)
including addiction (Daniel & Haberman, 2017; Kyzar et al., 2017b; Noorani et al., 2018) and
neuroinflammation (Flanagan & Nichols, 2018; Strumila et al., 2021; Szabo, 2015).
Investigations have indicated that the phenotypic expression of the 5-HT-2A receptor
genotypes is tethered to and dependent on environmental context (Jokela et al., 2007), and this
sensitivity to setting is integral to the functioning of 5-HT-2A signaling (Carhart-Harris & Nutt,

49
2017; Carhart-Harris et al., 2018). In preclinical studies assessing measures of exploratory and
investigative behavior, psilocybin results in reduced locomotor activity and enhanced
neophobia in rodents, analogous to the sensitivity to context shown in humans under the
influence of psychedelics (Araújo et al., 2015; Halberstadt et al., 2017). Psychedelic therapy has
long paid heed to the importance of both set — personality, mindset, affect, expectations
(Metzner and Leary, 1967), and setting – physical environment and presence of others (Leary,
Litwin & Metzner R. 1963, Hartogsohn, 2017). The triad of drug, set and setting is foundational
to understanding the total drug effect of any psycho-active substance (Zinberg, 1984) and
central to harm reduction (McElrath and McEvoy, 2002; Shewan et al., 2000).
3.2.1 Molecular Signalling Pathways
Pre-clinical drug discrimination studies, using operant conditioning techniques,
demonstrate cross-generalization across multiple psychedelics including LSD, mescaline, DOM
(2,5-Dimethoxy-4-methylamphetamine), DOB (4-bromo-2,5-dimethoxyamphetamine), DOI (2,5-
Dimethoxy-4-iodoamphetamine), psilocybin, and DMT, indicating they create comparable
interoceptive stimuli, and the evidence suggests the effect is modulated by 5-HT-2A (Quednow et
al., 2012). Pre-treatment with the selective, non-hallucinogenic 5-HT-2A antagonists ketanserin or
pirenperone, blocks the stimulus effects of psychedelics (Araújo et al., 2015). The psychosis-
type effects of psilocybin and LSD have been reversed in human volunteers by the
administration of ketanserin (González-Maeso, 2018). Psychedelic 5-HT2A agonists also increase
pre-pulse inhibition (PPI) in rodents; PPI is an operational measure of sensory gating, reflecting
central cognitive mechanisms which filter out irrelevant sensory stimuli. Rats treated with LSD,
DOI, mescaline and psilocybin all demonstrate reductions in PPI (Halberstadt et al., 2017;

50
Quednow et al., 2012). Head-twitch response (HTR) in rodents, a paroxysmal rotating of the
head due to irritation of the pinna, is one of few behavioural measures which help differentiate
hallucinogenic from non-hallucinogenic 5-HT2A agonists. Indoleamines, mescaline and
phenylisopropylamine psychedelics reliably induce HTR, but less so for phenthylamines of the
2C-X family (Halberstadt et al., 2017). HTR in response to hallucinogenic compounds is absent in
5-HT2A knockout mice (González-Maeso, 2018). In pre-clinical studies assessing measures of
exploratory and investigative behaviour, mescaline, DOM, LSD, DMT, psilocybin and 5-Me-DMT
all result in reduced locomotor activity and enhanced neophobia in rodents, analogous to the
sensitivity to context shown with humans under the influence of psychedelics (Araújo et al.,
2015; Halberstadt et al., 2017). It is of note that neo-phobic effects are not observed in non-
human animals tested in familiar locations.
While the various psychedelics commonly agonize the 5-HT2A receptor subtype, closely
related 5-HT2A agonists such as liseride are non-hallucinogenic, indicating variation in
subsequent electrophysiology and intra-cellular signalling (González-Maeso, 2018).
Hallucinogenic and non-hallucinogenic 5-HT2A agonists both regulate signaling in the same 5-
HT2A cortical neurons to different effects, indicating distinct signaling pathways. Though liseride
and LSD both act on 5-HT-2A receptors to regulate phospholipase C, LSD also triggers pertussis
toxin-sensitive heterotrimic Gi/o proteins and Src (González-Maeso, 2018). Non-hallucinogenic
compounds such as lisuride and ergotamine share structural similarities and comparative
agonism at 2AR as the psychedelics, but seemingly lack psycho-active properties and differ in
their regulation of signaling in the same neurons, both in vivo and in vitro (González-Maeso,
2018).

51
Cortical neurons may indeed be unique in their ability to generate the signaling
pathways specific to the psychedelic effect. Sub-cortical populations of 5-HT2A receptors are
seemingly not required for this effect; 2AR is most densely expressed in layer V pyramidal
neurons, the “output” layer of the cortex implicated in gating functions and of critical
importance in the balance of cortical to subcortical communications. (González-Maeso, 2018).
5-HT2A mediated signalling perturbs, disrupts and alters normal gating functions of layer V
neurons, affecting cognition and sensory processing.
Activation of postsynaptic 5-HT2A receptors in layer V of the medial prefrontal cortex is
considered responsible for the visual imagery and hallucinations associated with psychedelic
drugs (Calvey & Howells, 2018; Glennon et al., 1984; González-Maeso, 2018). Stimulation of the
5-HT2A receptor enhances spontaneous excitatory postsynaptic potential and currents in
neocortical layer V pyramidal cells, reducing outward potassium currents and increasing
glutamatergic activity (Muthukumaraswamy et al., 2013). The hyper activation of cortical 5HT2A
receptors in turn affects cortico-striatal-thalamo-cortical circuit activity, resulting in the
disruption of thalamic gating of sensory input and cognitive information and subsequent visual
hallucinations (Calvey & Howells, 2018). One complicating factor in establishing the
psychopharmacology of psychedelics is that receptors themselves may couple to multiple
effectors, and different agonists can produce different intracellular signals; agonists with
particular substitution patterns may selectively activate a subset of different effectors, a
phenomenon termed functional selectivity (Nichols, 2018). Receptor signaling responses to
hallucinogens induce different genetic transcription responses in cortical neurons (González-
Maeso, 2018).

52
Classification of 5-HT receptors and subtypes is made according to genetic homologies,
as determined by their amino acid sequence which results in the functional properties of cell
membrane proteins (Nichols, 2018). 5-HT receptors are G-coupled protein receptors (GCPRs),
with seven trans-membrane helical segments interpenetrating the cell membrane and have a
short helical segment at the C-terminus parallel to the membrane’s inner leaflet (Nichols,
2018). The final response is generated by the activation of heterotrimeric G proteins (González-
Maeso, 2018). After their interaction with an activated receptor, Gα monomeric proteins
detach from Gβγ subunits, and exchange GDP guanine nucleotide for guanosine-5'-triphosphate
(GTP) (Halberstadt, 2015; González-Maeso, 2018). Gα subunits bound to GTP initiate different
second messenger cascades at the intracellular level by interacting with other proteins
(adenylyl cyclases and/or phospholipases). This sequential activation/ inhibition of different
elements in cascade fashion is the process of cell signaling. Signalling can be initiated at the cell
surface by the activation of receptors and often concludes in the cell nucleus with modulated
transcription of different genes (González-Maeso, 2018).
GPCR’s demonstrate an “intricate amalgam” of interactions, resulting in a complexity of
potential cellular pathways and molecular mechanisms (González-Maeso, 2018; Nichols, 2018)
Approximately 900 different GPCRs have been identified in the human genome; GPCRs play a
role in the vast majority of human physiological processes including sense perception,
neuropsychological, cardiovascular and endocrine functions (González-Maeso, 2018).
The binding affinity of a psychedelic drug to the 5-HT2A receptor predicts the molecule’s
potency for evoking the hallmark visual imagery of psychedelics (Glennon et al., 1984). The 5-
HT2A receptor couples to Gq, activating phospholipase Cβ (PLCβ) signaling, which results in the

53
hydrolysis of membrane phospholipids to inositol triphosphate (IP3) and diacylglycerol, as well
as mobilization of intracellular Ca2+ (Halberstadt et al., 2017). Further, “there is evidence that
5- HT2A is coupled to several non-canonical signaling pathways, including β-arrestin-2, Src
(potentially involving Gi/o-associated Gβγ subunits), extracellular-regulated kinase (ERK), p38
mitogen-activated protein (MAP) kinase, phospholipase A2 (downstream from ERK 1, 2
and p38 MAP kinase), Akt, and phospholipase D (dependent on the small G protein ADP-
ribosylation factor-1 (ARF1)” (Halberstadt et al., 2017). Both 5-HT2A and 2C receptors (which have
high sequence homology and similar second messenger signaling) activate phospholipase A2 via
Ga12/13, liberating AA from membrane phospholipids and activate phospholipase C via Gq/11,
resulting in the second messengers inositol trisphosphate and diacylglycerol and the
subsequent release of calcium from intracellular stores and the activation of protein kinase C
(Eshleman et al., 2014).
Findings indicate that the characteristic hallucinogenic effect of psychedelic compounds
results from the stabilization of specific 2AR conformational states, leading to distinctive
regulation of intracellular signaling pathways (González-Maeso, 2018). This is further supported
by the ternary complex model of GPCR activation, which posits that the efficacy of ligands
depends on their capacity to shift cellular equilibrium between two conformational states
(active and inactive). GPCRs adopt multiple conformational states when activated by differing
agonists, indicating that different receptor agonists stabilize distinct conformations which each
activate specific cellular signaling pathways; agonists show a preference, by way of binding
affinity, for a subset of receptor conformational states, a phenomenon known as biased
agonism (González-Maeso, 2018).The signalling pathways responsible for mediating the

54
signature effects of psychedelics have not been conclusively demonstrated, and multiple
signalling pathways are most likely involved.
While G proteins are canonical for the signal transmissions of GPCRs, they are not the
only elements connecting these receptors to signalling pathways (González-Maeso, 2018).
Multiple signalling pathways are implicated, as evidenced by partially blunted behavioural
response Gq knockout mice show in response to the universal psychedelic DOI; β-arrestin-2 is
also not necessary for behavioral effects of DOI and 5-MeO-DMT to manifest in laboratory
animals, and there does not seem to be a direct relationship between phospholipase A2
activation and the production of hallucinogenic effects (Halberstadt et al., 2017). Inhibitor
studies using primary neuronal cultures demonstrate that the characteristic transcriptome
response to LSD is dependent on its specific regulation of Gi/o proteins and Src (González-
Maeso, 2018).
There is strong evidence to suggest that psychedelics influence the expression and
modulation of genes. While most signaling pathways modulate gene expression in response to
extracellular stimuli, GPCR activation can induce concentration-dependent changes in the levels
of expression for certain genes (González-Maeso, 2018). Psychedelics result in structural and
functional changes in cortical neurons, with plasticity-facilitating changes comparable to brain-
derived neurotrophic factor (BDNF)(Calvey & Howells, 2018). LSD effects dopaminergic systems
at the level of gene expression by decreasing the mRNA expression of DRD1 and DRD2
receptors; psychedelics commonly activate TrkB, mTOR (effects RNA stability and degradation)
SIMAR1 and 5-HT2A signalling pathways, all implicated in epigenetic modification (Calvey &
Howells, 2018).

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3.2.2 Anatomic Localization
5-HT2A is densely expressed in the prefrontal cingulate cortex (PCC); most of the cells in
primate and human prefrontal cortex (PFC) express 5-HT-2A mRNA (Halberstadt et al., 2017). The
spatial localization of PET, fMRI, EEG, and MEG-measures psychedelic effects are relatively
consistent in identifying high-level cortical areas (Carhart-Harris et al., 2016). Multiple areas of
the neocortex demonstrate increased activity under ayahuasca, explaining the reported
experience of heightened self-awareness and insight (Hamill et al., 2018); a SPECT study on
ayahuasca also reported significant increase in blood perfusion in the anterior cingulate cortex
(ACC), left amygdala and parahippocampal region and a separate SPECT ayahuasca study
documented increased perfusion of the subgenual, nucleus accumbens and insula areas, areas
in which hypo-activation is associated with depression (De Gregorio et al., 2018). A single dose
of LSD increased blood oxygen levels in the prefrontal cortex in response to music, suggesting
enhanced personal processing enmeshed with sensory stimuli (De Gregorio et al., 2018). LSD
has been shown to increase visual cortex cerebral blood flow and resting state functional
connectivity (Carhart-Harris et al., 2016). The visual imagery associated with psychedelics are
most likely due to the excitation of primary visual cortex (V1) neurons and increased cerebral
blood flow in the visual cortex (Carhart-Harris et al., 2016; Hamill et al., 2018). Excitation of V1
neurons is likely driven by 5-HT2A neurons, given the ability of 5-HT2A antagonists to block visual
hallucinations (Halberstadt et al., 2017).
While there is widespread distribution throughout different brain regions, the area with
the highest density of 5-HT2A binding sites is the neocortex. 5-HT2A receptors can also be detected
in the hippocampus, thalamic nuclei, hypothalamus and nuclei of the midbrain (González-

56
Maeso, 2018) as well as regions adjacent to the PFC, particularly lamina V (Halberstadt et al.,
2017). Almost all prefrontal pyramidal neurons express 5-HT2A, with the receptor localized to
proximal apical dendrites; these receptors are also expressed in parvalbumin and calbindin-
positive interneurons, and 20-25% of glutamic acid decarboxylase-positive cells in the PFC
express 5-HT2A mRNA (Halberstadt et al., 2017). GABAergic interneurons contribute to the
synchronization of oscillatory firing of large clusters of pyramidal neurons (Halberstadt et al.,
2017). 5-HT2A activation results in cellular depolarization, reduction in spike-frequency
accommodation, and slow depolarization afterpotential effects; hallucinogenic 5-HT2A agonists
produce a marked enhancement of both frequency and amplitude in the spontaneous
excitatory postsynaptic currents in most layer V pyramidal neurons in the medial prefrontal
cortex (mPFC), effects mediated by the release of glutamate (Halberstadt et al., 2017). PET and
SPECT studies using mescaline and ayahuasca have demonstrated hyperactivity in the
prefrontal cortex as a result of psychedelics, with robust metabolic increases in frontolateral
and fronto medial cortical regions (Halberstadt et al., 2017); in contrast, Carhart-Harris’ studies
on psilocybin using fMRI techniques have found reductions in resting brain state activity in the
frontal cortex (Carhart-Harris et al., 2012). The difference in results may indicate that fMRI
studies are better correlated with cortical oscillatory activity than with neuronal firing
(Halberstadt et al., 2017).
Findings demonstrate that psychedelics disrupt established oscillatory activity patterns
of cortical neurons, reducing the likelihood they fire in synchrony (Carhart-Harris et al., 2016;
De Gregorio et al., 2018; Halberstadt et al., 2017; Muthukumaraswamy et al., 2013).
Neuroimaging studies have consistently demonstrated the ability of psychedelics to disrupt

57
activity in the frontal cortex. MEG studies have shown that psilocybin reduces cortical
oscillatory power and reduces cortical synchrony by increasing the excitability of deep layer
pyramidal neurons (Muthukumaraswamy et al., 2013). Similarly, DMT and beta-carboline
containing ayahuasca has been found to reduce cortical oscillatory power across multiple
frequency bands (Hamill et al., 2018; Riba et al., 2002). Cortical oscillations play a foundational
role in the regulation of various mental processes and are required for neural processing; this
disruption of neural synchrony may be key to understanding the mechanism of action in the
therapeutic application of psychedelics in the treatment of various psychiatric disorders.
Reduced blood flow and BOLD (blood-oxygen-level-dependent) signaling in the mPFC
and reduced coupling between mPFC and the PCC indicate a reduction in activity and
connectivity in the default mode network (DMN)(Carhart-Harris et al., 2012) and ayahuasca
studies using functional MRI techniques as well demonstrate decreased activity in the DMN
(Hamill et al., 2018). The prefrontal cortex overall exercises hierarchical, top-down control over
neural processing in the temporal and parietal cortices. The DMN consumes more energy,
attracts more perfusion, and is more widely connected than other cortical regions
(Muthukumaraswamy et al., 2013). The DMN plays a key integrative and efficiency function in
the brain, hosting the highest number of cortico-cortical connections and known to be active
during self-referential thinking (Carhart-Harris et al., 2012).
Vollenweider’s psilocybin studies have documented an increase in absolute cerebral
metabolism in the parietal and temporal cortices, suggesting that psychedelics may enhance
neural activity in these regions by increasing the firing of glutamatergic projections originating
in the PFC and increases in extracellular glutamate release in the synaptic cleft (Halberstadt et

58
al., 2017; Vollenweider et al., 1998) . Such changes to glutamatergic regulation may be a
downstream effect of the 5-HT2A5-HT-2A agonism of hallucinogenic compounds (De Gregorio et
al., 2018). The amygdala is likewise a subcortical structure affected by changes in the activity of
mPFC neural projections (Halberstadt et al., 2017). Psilocybin reduces activation of the
amygdala by negative and neutral pictures and impairs processing of facial expression valence
in the amygdala and other limbic regions implicated in the processing of fear and emotional
context (Halberstadt et al., 2017). The amygdala displays increased utilization of monoamines
under ayahuasca, potentially explaining the heightening of emotional recall under psychedelics
(Hamill et al., 2018). A MEG study reported that psilocybin, LSD and ketamine all increased
signal diversity within occipital cortices, extending over parietal cortex with LSD and over full
cortex (but not medial frontal brain) with ketamine (De Gregorio et al., 2018)
A psilocybin fMRI study documented decreased hemodynamics in the thalamus as well
as the anterior and posterior cingulate cortices, suggesting decreased neural activity with 5-
HT2A receptor agonism (Muthukumaraswamy et al., 2013). An MDMA arterial spin investigation
reported decreased hemodynamics localized to the rMTL, thalamus, inferior visual cortex and
somatosensory cortex (Carhart-Harris et al., 2016), and phenethylamine hallucinogens such as
DOI have been found to decrease the spontaneous activity of cells in the locus coeruleus
(Halberstadt et al., 2017). Patients who received psilocybin displayed significant reductions in
depressive states, decreased parahippocampal-prefrontal cortex resting state connectivity, and
decreased cerebral blood flow to the amygdala even 5 weeks post-treatment (De Gregorio et
al., 2018). LSD as well results in disintegration of Default Mode Network integrity; increased
DMN activity is found in both depression and schizophrenia and is correlated with deficits in

59
working memory and attention (Carhart-Harris et al., 2016). The normalizing effects of
psychedelics on the DMN may help explain their purported anti-depressant effects. Ayahuasca
also causes decreased activity in the DMN; transfer entropy analyses showed that frontal
sources experienced decreased influence over central, parietal and occipital locations, and
posterior locations had increased influence over frontal area signaling (Hamill et al., 2018).
Intensity of subjective effects is significantly correlated with decreases in anterior to posterior
transfer entropy; psychedelics disrupt top-down neural control and allow increased bottom-up
flow of information in the brain (Hamill et al., 2018).
The apparent ability of psychedelics to disrupt pathological brain activity patterns and to
temporarily break down patterns of brain region inter-connectivity may be at the root of their
therapeutic promise. The effect of psilocybin, due to its 5-HT2A prompted glutamatergic
regulation effect, has been described as “a general disorganization of network-level brain
activity”(Muthukumaraswamy et al., 2013). Psilocybin has been measured to have no effect on
the low-level, visually cued and motor-induced gamma oscillations, suggesting that some basic
elements of brain oscillatory activity patterns are preserved under psychedelics
(Muthukumaraswamy et al., 2013). fMRI studies found decreased hemodynamic activity within
the thalamus and anterior and posterior cingulate cortex, with decreases in activity in the
posterior cingulate cortex (PCC) correlated with hallucinogenic power (Carhart-Harris et al.,
2016). Psilocybin does however, markedly decrease alpha power band oscillation, and such
decreases in alpha power are directly correlated with hallucinatory experience (De Gregorio et
al., 2018; Muthukumaraswamy et al., 2013).

60
Ayahuasca EEG studies also document decreases in absolute power across all bands,
particularly theta, delta and alpha frequency bands, as well as dose-dependent decreases in
power density in alpha-2, delta and beta-1 frequency bands found mainly in the temporo-
parieto-occipital junction(Hamill et al., 2018). Changes to alpha power are most likely the result
of deep layer pyramidal neuron stimulation via the 5-HT2A receptor; (Muthukumaraswamy et al.,
2013). Human trials document the experience of “ego dissolution” as a result of psychedelics;
high ratings on ego dissolution scales were positively correlated with decreases in PCC alpha
power (Muthukumaraswamy et al., 2013). The desynchronization of the PCC is rooted in the
excitability of deep layer pyramidal neurons rich in 5-HT2A receptors, and the hallmark
subjective effects of psychedelics result from the desynchronization of regular oscillatory
rhythms in the cortex (Muthukumaraswamy et al., 2013). As cortical alpha power may play an
inhibitory function, reduced alpha power, coupled with increased CBF to the visual cortex and
excitation of V1 5-HT2A receptors, results in the emergence of geometric patterns via self-
organized patterns of neuronal excitation (Carhart-Harris et al., 2016). Reduced alpha power
facilitates the “release of anarchic patterns of excitation” manifesting as visual hallucinations
(Carhart-Harris et al., 2016)
Decreased oscillation power is evidence of the desynchronization of brain states.
Imaging studies measuring hemodynamics indicate acute increases and decreases in several
brain regions; electromagnetic studies report reductions in neural activity, notably in the alpha
band frequency, and reductions in frontal activity with increases in parietal activity (Calvey &
Howells, 2018). Such disruptions have been termed entropic by Robin Carhart-Harris and reflect
a time-bound and wide-ranging disintegration of previous functional connectivity (Carhart-

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Harris et al., 2014). Psychedelics disrupt and reduce stability and integration of normative brain
networks, and simultaneously reduce segregation and separateness between them; they
induce network disintegration (Carhart-Harris et al., 2016).
Entropy, or uncertainty, is of benefit to organic self-organizing systems as it allows for
criticality and interrupts pathological, rigid patterns of rumination (Carhart-Harris et al., 2014).
Uncertainty is a challenge to the predictive and inferential tendencies of cognition, which
predicts present and future data-points by inference from past experience. Friston’s free-
energy principle is a unified brain theory which states that value (expected reward) is optimized
by limiting surprise (prediction error or expected cost). Friston asserts “any self-organizing
system that is at equilibrium with its environment must minimize its free energy”; adaptive
systems resist the natural tendency to disorder through the bounds or limits put on surprise via
Bayesian inference (Friston, 2010). The probabilistic predictive model generated by the brain is
radically disrupted by the psychedelic experience, leading to revisions in inference as well as
recognition of the upstream processes of meta-cognition. In this way, the entropy introduced
by psychedelics creates opportunities for neuro-plasticity, psychological insight, and the re-set
of brain networking patterns and integration into more optimal, or critical, states. Psychedelics
have been shown to result in positive and sustained improvements in mental health (Calvey &
Howells, 2018; De Gregorio et al., 2018); the time-bound, neuro-modulatory psychedelic drug
experience appears to reset brain networking patterns with resultant improvements in mood,
optimism, and self-regulation.

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3.3 Psychedelics, Psilocybin and Neuroplasticity
There is a growing body of evidence that psychedelics promote both structural and
functional synaptic plasticity (Ly et al., 2018b; Savalia et al., 2020; Shao et al., 2021). This is an
area of interest as a possible mechanism of action underlying its therapeutic benefits as a rapid-
acting antidepressant (Kadriu et al., 2021), and as a neurotherapeutic psychoplastogen (Olson,
2018). The scientific literature to support the neuroplasticity effects of psychedelics is still
emergent, and largely relies on preclinical translational research. A recent systematic review
(de Vos et al., 2021) identified twenty individual studies (preclinical n= 16, clinical trials n=4)
demonstrating that a single administration of a classical psychedelic results in rapid changes to
plasticity systems on molecular, neuronal, synaptic and dendritic levels, including changes to
plasticity-related genes and proteins including Brain-Derived Neurotrophic factor, increased
dendritic branching complexity and dendritic spine formation. Structural and functional
changes associated with classical psychedelics include increased synaptogenesis, which appears
to be mediated through activation of 5-HT2A receptor, tyrosine receptor kinase B (TRKB) and
mammalian target of rapamycin (mTOR) signalling pathways (Ly et al., 2018b; Vollenweider &
Preller, 2020). Serotonergic psychedelics could acutely modulate dendritic excitability via
idiosyncratic ligand-receptor interactions which induce local gradients of Ca2+ influx, driving
neurotrophic factors and biochemical cascades, biases certain synapses favourably towards
long-term plasticity (Savalia et al., 2020). Dopaminergic, glutamatergic, and GABAergic systems
are additionally involved in both the underlying mechanisms of psychedelic action and of
neuroplasticity (Schindler et al., 2018).

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The physical change in neural circuit connectivity via plasticity potentially explains the
persistence of symptomatic improvements associated with the administration of serotonergic
psychedelics (Carhart-Harris et al., 2012, 2017; Lukasiewicz et al., 2021; Muthukumaraswamy et
al., 2013). Sub-optimal network organization, as measured by high wiring cost, low clustering or
connectedness, and long pathlength (indicating poor global integration), have all been
identified as factors commonly underlying psychiatric and neurological disease (Nichols et al.,
2017). The number of significant resting-state functional connections across the brain increase
after a single dose of psilocybin have been found to outlast the drug effects for up to one
month (Barrett et al., 2020). In vivo that psilocybin administration leads to long-lasting
modifications to the neural architecture in mice, persisting at one month (Shao et al., 2021).
Brain connectivity between and among a number of key brain networks is increased during the
days to weeks after the administration of psilocybin and ayahuasca (Barrett et al., 2020;
Carhart-Harris et al., 2017; Majić et al., 2015; Sampedro et al., 2017; Smigielski et al., 2019).
The formation of new dendritic spines represents the addition of new synapses to the
neuronal circuitry (Knott et al., 2006). From an initial pool of less precise synaptic connections,
experience modifies connections by removing some and selectively stabilizing others, shaping
the activity patterns of the neuron (Fu & Zuo, 2011). 5-HT2a, the glutamatergic α-amino-3-
hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) pathway, and brain-derived neurotrophic
factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathways are each engaged both
by plasticity processes and serotonergic psychedelics (Kadriu et al., 2021). Given that dendritic
branches are mostly stable in adulthood and that novel sensory experiences promote new
dendritic spine stabilization (Fu & Zuo, 2011), psychedelics may act to release the brakes on

64
normal developmental neuroplasticity (Lepow et al., 2021). Single doses of serotonergic
psychedelics have been demonstrated to induce a number of immediate early genes in the
cortex, amygdala, nucleus accumbens and striatum of the rodent brain, genes implicated in
memory and synaptic plasticity remaining active for hours after drug effect (Nichols & Sanders-
Bush, 2002; Schindler et al., 2018).
5-HT2A receptor activation has been shown to drive neuroplastic adaptations
(Vollenweider & Preller, 2020). Presynaptic 5-HT2A receptors located at thalamocortical synapses
may play a role in the modulation of thalamo-frontal connectivity and the associated cognitive
functions, enhancing NMDA transmission, gating the induction of temporal-dependent
plasticity, and improving associative learning (Barre et al., 2016). Brain imaging and in vivo
animal studies have established the effects of serotonergic psychedelics in the modulation of
thalamocortical gating via alterations of connectivity within the cortico-striato-thalamo-cortical
(CSTC) circuit (Inserra, De Gregorio, Rezai, et al., 2021).
Plasticity in and of itself may not be of benefit; increased plasticity in the mesolimbic
pathway is associated with addiction, whereas the 5-HT2A neurons stimulated by psychedelics
are more richly expressed in layer V pyramidal neurons of the cortex (Olson, 2018). Similarly, all
experience modulates synaptic function and structure, so any experience results in plasticity,
given the tendency of organisms towards homeostasis. If the therapeutic value of psychedelics
can be in some way explained by underlying biological mechanisms of neuroplasticity, it may be
that the particular circuits engaged by psychedelics are separately known to have value.
Psychedelics may open critical, time-bound periods of enhanced learning. This could
explain the behavioural change, cognitive flexibility, psychological flexibility, increased

65
openness and relatedness reported as results in psychedelic clinical trials. The afterglow
experienced in the days-to-weeks after psychedelics (Majić et al., 2015) may serve as
developmental critical periods of heightened plasticity and learning (Lepow et al., 2021). Critical
periods are considered developmental epochs necessary to overall circuit organization of the
brain and learning. During critical periods the nervous system is expressly sensitive to specific
environmental stimuli; oxytocin-mediated synaptic plasticity in the nucleus accumbens has
been found to underlie the reopening of social reward learning in such critical periods (Nardou
et al., 2019). Generally, constraints are imposed on these mechanisms as the brain matures and
ages; disease states further limit the ability of the brain to adapt. Atrophy of neurons in the
prefrontal cortex (PFC) is thought to play a central role in the pathophysiology of depression (Ly
et al., 2018b).
Cognitive neuroscience has identified the existence of critical periods for social
behaviour during childhood and adolescence. The critical period after psychedelics has been
recognized as a pivotal mental state of hyper-plasticity, enhanced associative learning and
behavioural change potential (Brouwer & Carhart-Harris, 2021). Such states can be primed by
conditions of stress, or periods of neuroses. In similar ways, the increased cortisol resulting
from psychedelic administration may serve as an inoculation against future stress events.
The afterglow period following a psychedelic session has been found to be a period of
increased emotional responsiveness (Roseman et al., 2018) in particular sensitivity to positive
emotional stimuli, with alterations and enhancement to reward learning and salience detection
(Barrett, 2021). Significant decreases in self-rumination and increases in self-compassion have
been observed after psychedelic experiences, and the level of psychological insight obtained is

66
correlated with participant reductions in depression, anxiety and stress (Fauvel et al., 2021).
Psychedelics decrease judgmental processing of experiences while increasing the ability of the
individual to decenter (Soler et al., 2016). Psychedelics increase measures of mindfulness
(Smigielski et al., 2019). Psychedelics have been categorized as meaning-response magnifiers
enhancing the effects of placebo and set and setting (Hartogsohn, 2017, 2018) and have been
found to enhance suggestibility in human subjects (R. L. Carhart-Harris et al., 2015; Schindler et
al., 2018)
Individuals who regularly consume ayahuasca in a ritual setting score higher on scales
measuring positive self and decentering (Franquesa et al., 2018). Participants report being
more spiritual after psilocybin administration (Goldberg et al., 2020), and demonstrate
increased cognitive and neural flexibility (Doss, Považan, et al., 2021). Measurable increases in
traits of openness and extroversion have been documented during this time, alongside
numerical decreases in neuroticism; however, strongest improvements have been found in the
trait of conscientiousness (Erritzoe et al., 2018; MacLean et al., 2011). Further, reductions in
negative affect and increases in positive mood underlie reductions in rumination, and
improvements in self-compassion and self-forgiveness have been noticed and may be key
therapeutic effects. Administration of serotonergic psychedelics is associated with long-term
improvements in mood, attitude, and well-being (Barrett et al., 2020; Goldberg et al., 2020; R.
R. Griffiths et al., 2006).

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3.4 Psychedelics and the Disruption of Habit
Components of the limbic system and limbic-associated proximal regions have been
implicated in the mechanisms of both acute and persisting effects of psychedelics including the
role of the amygdala (Barrett et al., 2020; Cameron et al., 2019; Kraehenmann et al., 2015;
Mertens et al., 2020; Roseman et al., 2018), hippocampus (Catlow et al., 2013; Hesselgrave et
al., 2021; Jefsen et al., 2021; Muttoni et al., 2019; Nunes et al., 2016), basal ganglia (González-
Maeso, 2018; Vollenweider & Hell, 1999), and the thalamus (Barre et al., 2016; Grandjean et al.,
2021; Inserra, De Gregorio, Rezai, et al., 2021; Preller et al., 2019, 2020; Vollenweider & Preller,
2020), the cingulate gyrus (Muthukumaraswamy et al., 2013; Smigielski et al., 2019), the
cortico-striatal thalamo-cortical loops of the ventral striatum (Vollenweider et al., 2000), and
the nucleus accumbens (González-Maeso, 2018; Sakashita et al., 2015; Sanches et al., 2016).
Psychedelics have been found to modulate the limbic system as a whole (Heuschkel & Kuypers,
2020; Kuypers, 2019; Lepow et al., 2021; Sampedro et al., 2017; Spain et al., 2015) and the
valence network (Mason et al., 2021) as well as the modulating effects of limbic components on
the neuroendocrine and immunomodulatory systems of the nervous system (Donovan et al.,
2021; Holze et al., 2020; Kuypers, 2019; Schindler et al., 2018; Szabo, 2015).
The potential therapeutic value of psilocybin, like other serotonergic psychedelics, may
be in its function as a psychoplastogen. Psychoplastogenic compounds produce measurable
changes in plasticity, within a short period of time (typically 24-72 hours) following a single
administration, enabling subsequent stimuli to reshape neural circuits and producing relatively
long-lasting changes in behavior extending beyond the acute effects of the drug (Olson, 2018).

68
Hebbian Learning theory is premised on the rule of cell assemblage which is both
weighted and fluid. Cell assemblies are distributed subsets of neurons with strong reciprocal
connections, largely influenced by neuromodulators such as serotonin and dopamine and
implicated in heterosynaptic plasticity. (Woodward et al., 2015). If the neurons which fire
together wire together, then neural networks can also separate due to inhibitory connections
(Nadel & Maurer, 2020). The psychedelic pause (Rech et al., 1975) is the suppression of
previously established and dominant operating system neural networks. There may be a lasting
inhibitory effect on these previous networks given the sustained improvements demonstrated
in the clinical trials and the post-acute effects of psilocybin noted in the animal studies.
Inhibition is a key concept in behaviour change; to reduce inferences from established patterns,
behavioural change interventions commonly employ mechanisms of inhibition (Fritz et al.,
2020; Wood & Rünger, 2016).
Psilocybin endorses sustained changes to both psychological states and traits of
personality which persist long after the resolution of drug effect. Persisting trait openness
improvements have been replicated in several psilocybin studies (Erritzoe et al., 2018; Garcia-
Romeu et al., 2014; R. R. Griffiths et al., 2006) and remains significantly higher than baseline
more than one year after psilocybin administration (MacLean et al., 2011). Similarly, the post-
acute face of ayahuasca has been found to be represented by sustained and persisting
increases in self-compassion and mindfulness while reducing judgmental attitudes (Sampedro
et al., 2017) and LSD administration similarly leads to increases in trait openness (R. L. Carhart-
Harris et al., 2016). While past era psychedelic research had identified lasting changes to

69
personality and life attitude (Pahnke et al., 1971), more recent neuroimaging has helped
identify possible neurobiological mechanisms.
Data suggest the “after-glow” period may be supported by enhanced interplay between
the ACC (anterior cingulate cortex) and limbic structures with key roles in salience, emotion and
memory processes (Barrett et al., 2020; Sampedro et al., 2017). Pleasing or aversive events are
better remembered than neutral experiences, with data suggesting the amygdala enhances
episodic memory in part through modulation of the hippocampus; emotional enhancement of
episodic memory is tethered to amygdala function in both human and animal studies (Hamann
et al., 1999).
Researchers have identified abnormal interactions between the rostral anterior
cingulate cortex and the amygdala in depressed patients (Fales et al., 2008), possibly indicating
decreased self-regulation due to impaired cognitive control over negative emotionality.
Alterations in functional and directed connectivity between the thalamus and cortical areas
have been reported across different analysis techniques. Neuroimaging studies have identified
increased functional connectivity between the thalamus and sensory cortical regions as well has
increased connectivity between thalamus and ventral striatum as a result of psychedelic
compounds with coinciding decreasing in thalamic connectivity with association areas of the
brain (Vollenweider & Kometer, 2010). The integration of functional connectivity in sensory
areas and somatic brain networks and the disintegration of associative brain region networks
has been reported after both LSD (Preller et al., 2019) and psilocybin administration (Preller et
al., 2020). LSD increased effective connectivity from the thalamus to the PCC in a way that
depended on 5-HT2A receptor activation while also decreasing effective connectivity from the

70
ventral striatum to the thalamus, but independently of 5-HT2A receptor activation (Preller et al.,
2019).
Sensorimotor loop networks are critical to the development of habit learning and
central to the psychedelic effect. Thalamic functions include integrative roles in cognition from
learning and memory to flexibility and adaptation to changes circumstances; the thalamus is
thought to be key to maintaining and updating cognitive representations, the encoded
representational models we hold of the world (Duerler et al., 2021; Karl, 2012; Wolff & Vann,
2019). The cognitive effects of psychedelics may be related to their unique entropy action on
episodic memory hubs (Carhart-Harris & Friston, 2019; Doss, Madden, et al., 2021). Earlier drug
studies established a key role for the bed nucleus of the stria terminalis in synaptic plasticity, an
area known to be involved in reward-seeking behaviors and habit formation (Dumont et al.,
2005).
To say that psychedelics inhibit or loosen previous high-level chunking of networks and
behavioural routines puts the study of psychedelics clearly in the larger study of habit, and of
habit-related activity. Habits can be understood as behavioural patterns (including thought,
affect and action) operating mostly below conscious awareness, acquired over time through
context-sensitive repetition, which have developed some degree of automaticity without
requiring executive control (Fritz et al., 2020). Packaged behavioural routines account for much
of typical human and animal behaviour, and disorders of sequence and repetitiveness are
displayed across a wide range of both neurological and neuropsychiatric disorders (Martiros et
al., 2018). The habit construct has been explored and developed through behaviourism,
operant conditioning and reward learning investigations, and often through animal research

71
paradigms (Barandiaran & Di Paolo, 2014; Fritz et al., 2020; Wood & Rünger, 2016), and picked
up more recently through computational neuroscience, artificial intelligence and decision-
making literature. The term habit has its origin in the Latin term habitus, a common root word
for habitat; both signify an accustomed place and indicate recognition of the manner in which
habits create a kind of “second nature” in the practice of meaningful self-modification or
incorporated manners of being-in-the-world (Barandiaran & Di Paolo, 2014).
Behaviour change literature has identified cortico-basal ganglia loops as containing the
molecular signalling patterns which hold together habitual behavioural programs, or habits, a
kind of higher-level abstract coding which determines behavioural movement (Khamassi &
Humphries, 2012; Macpherson & Hikida, 2019; Martiros et al., 2018; Vollenweider & Hell,
1999). The reward literature makes a distinction between goal-directed, or model-based
behaviour, and that which is habitual, or model-free (Wood & Rünger, 2016). Model-free
behaviour is habitual and response-based, resistant to change or reward valuation as stimuli
provoke automatized past-conditioned behavioural responses; model-based behaviour is more
“place-based”, sensitive to reward devaluation and able to adapt across contexts (Bonaiuto et
al., 2016; Khamassi & Humphries, 2012). Habits create ease and efficiency for the nervous
system, free concentration from repetitive processes and reduce the stress of uncertainty.
Acting out of habit requires less deliberation; the repeated activation of a similar response in
any context reduces cognitive access to alternative responses and narrows the range of
potential behavioural paths and values (Wood & Rünger, 2016). Excessive habituation
manifests as repetitive thought and behaviour, and potentially compulsivity (Voon et al., 2015).

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Human cognition is premised on integrated sensorimotor units and as such habitual
responses are represented by perceptual features and mental representations. In this way habit
cues trigger not just a motor program, but a multimodal representation (thought experience) of
the habitual response (Feldman & Friston, 2010; Lewis, 2018; Wood & Rünger, 2016).
Behaviour-related functions of the dorsolateral striatum are thought to include context-specific,
higher-order representations of sensorimotor activity (Martiros et al., 2018). Ventral striatum-
hippocampal networks have been implicated in this process of model-building, serving as the
locus for the formation neural networks as codes providing representations of the world which
then are consolidated synaptically at higher regions of the cortex (Khamassi & Humphries,
2012). Thalamic nuclei also contribute to higher order cognition, including in memory, learning,
flexibility and adaptation through network activity which maintains and updates mental
representations (Wolff & Vann, 2019). The animal assays of pre-pulse inhibition and -of-return
reflect perturbations to pre-attentive sensory gating systems, processes facilitated by thalamic
nuclei and thalamocortical circuits (Doss, Madden, et al., 2021).
Habits strengthen slowly and incrementally; with repetition, changes occur in the neural
substrates to procedural memory and by Hebbian learning cognitive network associations are
made between the environment or other context cues and the habit response is strengthened
such that context cues can automatically prompt habitual responses (Kometer et al., 2012;
Lewis, 2018; Wood & Rünger, 2016; Woodward et al., 2015). Memory consolidation occurs at a
synaptic level, and memory consolidation is the root of long-term learning. While memories
may be stored in different parts of the brain, and while there is empirical evidence of memory
storage in the medial temporal lobe, during memory consolidation memories are first stored in

73
the hippocampus to be transferred to other areas (Clopath, 2012). Disorders of compulsivity
such as OCD and SUD share a common bias towards learning habits (Voon et al., 2015). Habit
formation bias and the favoring of model-free learning underlie the repetitive behaviors
characteristic of these disorders; lower gray matter volumes in the caudate, medial OFC and
lateral prefrontal cortices are associated with a greater shift towards model-free habit
formation. (Voon et al., 2015). Ideally, we are best served by the integration of goal-directed
and habitual control.
Animal paradigms have helped develop an understanding of the neural representation
of such behavioural routines. Striatal projection neurons and fast-spiking striatal interneuron
networks of the striatum may underlie the acquisition of habits as chunked behavioral units; in
the sequencing of habitual routines striatal SPN populations rats fire preferentially at the
initiation and termination of its acquired sequence but not during the habitual behavior itself,
forming a kind of task-bracketing (Martiros et al., 2018; Wood & Rünger, 2016). These findings
support the hypothesized role of the dorsolateral striatum in promoting habitual behavior
through the representation of repeatedly rewarded behaviours (linked to basal ganglia
function) as single-unit action sequences, or task-chunking (Martiros et al., 2018). Imaging
studies of rodents performing fixed-ratio lever-press or T-maze assays reveal neuronal firing
peaks at the initiation and the end of trials, chunking the involved behavioural sequences into
framed neuronal patterns (Martiros et al., 2018).
Impaired basal ganglia function is implicated in multiple psychiatric disorders including
obsessive–compulsive disorder, substance use disorder, major depressive disorder, generalized
anxiety disorder, and schizophrenia (Macpherson & Hikida, 2019), all areas of interest to

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psychedelic science and thought to play a significant role in both abnormal and normal
functioning of the RDoC domains. Habitual and goal-directed behaviours are similarly thought
to be mediated by neural circuits linking cortical brain areas and the basal ganglia (Wood &
Rünger, 2016). Recent researches confirm the importance of subcortical regions in emotional
regulation and reward learning; pathways connecting the thalamus to the basal ganglia and
cerebellum regulate cortical oscillations which guide learning and strengthen associated
behaviours and neural patterns to achieve goal states (Pierce & Péron, 2020). Learning involves
planning, decision making, inhibitory control, salience and reward processes (Lewis, 2018).
By this dimensional approach to understanding the psychiatric disorders for which
psilocybin has been proposed, dysfunctions of reward learning, reward valuation (positive
valence domain), as well as dysfunctions of memory consolidation, attention and cognitive
control (cognitive processes domain) are of particular relevance. Rodent studies have identified
striatal output pathways to be crucial for effective functioning in several positive valence
domain constructs (Grandjean et al., 2021; Martiros et al., 2018; Trulson et al., 1977), the basal
ganglia has been shown to play an important role in arousal and regulatory systems including
the regulation of sleep-wakefulness (Kuypers, 2019; Macpherson & Hikida, 2019; Vollenweider
& Hell, 1999), and under the social processes domain the nucleus accumbens has been
implicated in the development and control of attachment (Macpherson & Hikida, 2019).
Together, these data indicate a role for limbic and endocrine systems in psychedelic research
beyond the amygdala, which has not yet been fully investigated. Alterations to basal ganglia
pathways may underlie dysfunctions across multiple RDoC domains.

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Cutting across both cognitive neuroscience and psychedelic studies is the importance of
context (Carhart-Harris et al., 2018; Wood & Rünger, 2016). Context is critical in habit formation
(Fritz et al., 2020), in the expression of serotonin (Jokela et al., 2007) , the pharmacodynamics
of serotonergic psychedelics (Hartogsohn, 2017; Rucker et al., 2018; Strassman, 1984), in the
functioning of the amygdala in emotional context (Halberstadt et al., 2017) and in the processes
of psychedelic assisted therapies (Ona & Bouso, 2020). As context is a signal of the interior-
exterior connection of consciousness, if psychedelics could theoretically shift one’s experience
of self-in-context to one of greater connectivity and heightened relationship, with a decentring
of the ego and self-rumination and towards a sense of greater unity, then perhaps this shift in
self-context perception can contribute to the dishabituation of established habits of cognition
and affect. Habit learning is the repetition of responses so that context-response associations
are consolidated in memory and behaviours become relatively automatic, disconnected from
context and insensitive to changes in value or outcome (Wood & Rünger, 2016).
Habitual and goal-directed behaviors are mediated by neural circuits organized into two
loops linking cortical brain areas and the basal ganglia: an associative cortico-BG loop supports
working memory functions and goal-directed action while connecting the prefrontal cortex
(PFC) with two striatal BG regions (the caudate nucleus and the anterior putamen) while the
sensorimotor loop underlies automatic, habitual behaviors while connecting the somatosensory
and motor cortex with the medial and posterior putamen (Wood & Rünger, 2016). As a result of
extensive practice, habit learning is consolidated in cortical brain regions as long-term and
encoded representations of learned skill. Stress and addiction are known to impair executive
decision-making and deliberate action control, promoting habit formation (Lamontagne &

76
Olmstead, 2019; Wood & Rünger, 2016). In this way established habits are activated by
recurring environmental cues (Lewis, 2018). However, learning is not simply an automatic
response to the environment, but a process of active engagement with a meaningful
environment, becoming “embodied cognition” (Lewis, 2018).
As a result of habitual performance, network circuits become over-trained, and behavior
strategies shift from place-based to response-based strategies (Khamassi & Humphries, 2012).
It context shift, habit response strategies become impaired; goal-directed responding transfers
more successfully across multiple contexts or places (Corlett et al., 2009; Kruschke, 2008; Wood
& Rünger, 2016). Disorders of habit are symptomatic of over-trained neural networks lacking
sensitivity to change, context or reward valuation. Perturbations to the neural network, in the
form of entropy, surprise or novelty, may be critical to establishing self-optimization (Carhart-
Harris & Friston, 2019; Carhart-Harris et al., 2014; Friston, 2010; Woodward et al., 2015) and
act as a kind of rest of neural pathways. As networks reconfigure, they are drawn to novel
attractors, and may form new state configurations; variety increases the networks ability to
generalize and converge on forms of neural coordination which may be of greater general
benefit (Woodward et al., 2015). Sleep and rest, regulated by the hypothalamus and governed
by circadian rhythm, are critical to heterosynaptic plasticity and help reset networks to optimal
function (Kuypers, 2019; Schindler et al., 2018). Similar resets may result from states of trance
ritual (Woodward et al., 2015), deep relaxation or absorption such as with meditation (Desai et
al., 2015; Fischer, 1971; Millière et al., 2018), or due to the pharmacological actions of
psychedelics such as psilocybin (Carhart-Harris et al., 2014; Muthukumaraswamy et al., 2013;
Woodward et al., 2015). Psychedelics promote new interpretations of familiar sensory cues;

77
these novel experiences may themselves beget novel behavioural responses (Doss, Považan, et
al., 2021)
Network state disruption via psychedelics has been explained as a result of reduced
thalamic gating leading to sensory information overload in higher cortical areas (Geyer &
Vollenweider, 2008; Vollenweider & Kometer, 2010), a relaxation of previously weighted
predictive codes, beliefs and expectations (Carhart-Harris & Friston, 2019), the inhibition of
areas of higher executive control (Carhart-Harris et al., 2014) and alterations in cortical-
claustrum connectivity leading to the attenuation of canonical cortical networks during
psychedelic drug effect (Doss, Madden, et al., 2021).
While several reviews mention the role of subcortical units in the modulation of
psychedelic effect (Carhart-Harris & Friston, 2019; Doss, Madden, et al., 2021; Vollenweider &
Preller, 2020) others make minimal reference to subcortical, midbrain regions or processes
(Johnson et al., 2019) , and more recent reviews point towards an appreciation of an expanded
role of the limbic system and the immunomodulatory and endocrine functions regulated by
regions of, or directly associated with, the limbic system (Inserra, De Gregorio, & Gobbi, 2021;
Kelly et al., 2021; Kuypers, 2019; Szabo, 2015). Recognition of the role of the limbic system and
subcortical brain regions may contribute to future models explaining psychedelic action. Such
recognition may also help recast mental health as emotional health, given the important role in
emotion in limbic regions and its influence over endocrine functions, and helps to prioritize
concepts of learning, memory, habit, context and adaptation within the scientific discourse on
psychedelics.

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Chapter Four:
Methodology & Study Methods
4.1 Knowledge Synthesis Methodologies: Scoping Reviews in Psychedelic Research
Given the developmental state of the psychedelic science literature, the scoping review
methodology is well suited as a knowledge synthesis activity to broadly capture the state of the
literature, clarify conceptual concepts in the field, identify gaps in research, and to inform
future clinical trials and systematic reviews. Scoping review in this area may assist in generating
hypotheses in potential new modalities of treatment and in generating hypotheses regarding
the therapeutic application of particular psychedelic drugs.
4.1.1 Types of Knowledge Synthesis and Review
Reviews of primary research, in the form of knowledge synthesis, have grown in both
frequency and significance since the 1970s, as evidence-informed practice has become the
benchmark for care (Khalil et al., 2019; Munn Z, 2017). Systematic reviews began to appear in
publication in the 1970s (Munn et al., 2018), are considered the pillar of evidence-based health
care and serve as a basis for clinical guidelines (Munn et al., 2018). Systematic reviews are a
kind of research synthesis conducted by review groups with special skills, who identify and
retrieve international evidence pertaining to a particular question. They further synthesize,
appraise and evaluate the results in order to inform policy, practice and further research (Munn
et al., 2018). Systematic reviews provide high-level evidence (Lockwood et al., 2019). The
objective of a systematic review is to provide a comprehensive, critical and unbiased synthesis

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of relevant clinical studies using robust, reproducible, structured and rigorous methods of
inquiry (Lockwood et al., 2019; Munn et al., 2018).
Systematic reviews of psychedelics have been previously been conducted on modern-
era clinical trials (Andersen et al., 2021) and human studies (dos Santos et al., 2016),
psychedelic-assisted psychotherapy (Wheeler & Dyer, 2020), psychedelics and depression
(Galvão-Coelho et al., 2021; Romeo et al., 2020; Rucker et al., 2016a), long-term effects of
psychedelic drugs (Aday et al., 2020), psychedelics and neuroplasticity (de Vos et al., 2021),
post-acute psychological effects (Goldberg et al., 2020), clinical and biological predictors of
psychedelic response (Romeo et al., 2021), states and traits predicting response to psychedelics
(Aday et al., 2021), recognition of facial emotion expressions (Rocha et al., 2019), patient
experiences in qualitative studies (Breeksema et al., 2020), psychedelics and personality (Bouso
et al., 2018), psychedelics and depression and anxiety (Muttoni et al., 2019), psychedelics in the
treatment of anxiety and depression in patients with life-threatening disease (Reiche et al.,
2018), psychedelic treatment of functional neurological disorder (Butler et al., 2020), post-
traumatic stress disorder (Varker, 2021), chronic pain (Castellanos et al., 2020), psychedelics
and suicidality (Zeifman et al., 2021), psychedelic-assisted group therapy (Trope et al., 2019),
microdosing (Ona & Bouso, 2020) and ethno-racial health disparities (Fogg et al., 2021) .
Systematic reviews specific to psilocybin in the treatment of psychiatric disorders (Castro
Santos & Gama Marques, 2021), psilocybin-based therapy for cancer-related distress (Bahi,
2018), psilocybin for depression and anxiety in the context of life-threatening disease (Vargas et
al., 2020), the risk of psilocybin in the treatment of bipolar depression (Gard et al., 2021) and of
the clinical evidence on psilocybin in the treatment of psychiatric disorders (Castro Santos &

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Gama Marques, 2021). One scoping review has been published on the importance of setting in
psychedelic-assisted therapies (Golden et al., 2022).
Knowledge synthesis in the form of literature synthesis dates back to 12th century
philosophy, and statistical methods of synthesizing literature were common in 17th century
astronomy. Early pooled data meta-analysis of health literature can be found dated to 1904
(Tricco, Soobiah, et al., 2016). Traditionally, literature reviews examined research reports in
addition to theoretical literature and history in order to provide an overview of a topic (Munn
et al., 2018), a method which relied heavily on the author’s experience and abilities, allowing
room for bias and a lack of comprehensiveness. Different forms of evidence, different review
goals, a need for evidence-based health practice, and the growth of information technologies
have all contributed to a growth in knowledge synthesis methodologies. Researchers identified
14 different review types in 2009, and more recently, in 2016 Tricco and her team identified 25
unique methods of knowledge synthesis (Munn Z, 2017; Peters et al., 2015a; Tricco, Lillie, et al.,
2016).
Organizations such as Cochrane Reviews and the Joanna Briggs Institute have developed
in order to provide methodological guidance, quality assurance and reporting guidelines for
knowledge synthesis. While systematic reviews have traditionally “brought together
quantitative literature on a particular condition or intervention to establish
effectiveness”(Peters et al., 2015a), questions pertaining to feasibility, meaning and
appropriateness are also pertinent and require other methodologies. While systematic reviews
have changed the landscape of health research(Tricco, Soobiah, et al., 2016), the method itself
has limitations. Systematic reviews have limited ability to address more complex questions,

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questions pertaining to patient perceptions and experiences or to identify the factors in the
uptake of a clinical practice (Tricco, Soobiah, et al., 2016). As such, other methods have evolved.
Since 2005, there has been significant growth in newer, emerging forms of knowledge
synthesis, including the scoping review (Tricco, Soobiah, et al., 2016).
Other emergent forms of knowledge synthesis include meta-analysis, meta-synthesis,
thematic analysis, grounded theory, narrative review, rapid review, concept analysis, evidence
maps and traditional literature review (Arksey & O’Malley, 2005; Munn et al., 2018; Tricco,
Soobiah, et al., 2016). All review methods offer benefit when used appropriately, and
researchers must be able to align their chosen method with the objectives of their
investigation. However, a lack of guidance has been identified, leaving researchers often unsure
how to select the appropriate method of synthesis (Tricco, Soobiah, et al., 2016). This creates a
risk that authors may define their review as systematic, but not all adopt the same practices
and standards to assure against protection of bias and meet the proper requirements of
systematic review (Arksey & O’Malley, 2005). Well-designed research studies of any
methodology are sources of potential credible evidence to aid decision-making in healthcare
(Peters et al., 2015b).
4.1.2 Defining the Scoping Review
Scoping reviews are a relatively new and increasingly popular approach to synthesizing
research evidence (Daudt et al., 2013; Levac et al., 2010; Pham et al., 2014) and were first given
conceptual clarity and definition by Arksey and O’Malley in 2005,
“Scoping studies aim to map rapidly the key concepts underpinning a research area and
the main sources of evidence available and can be undertaken as standalone projects in

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their own right, especially where an area is complex or has not been reviewed
comprehensively before”.
The scoping “study” was defined as a kind of literature review and technique to “map” relevant
literature in a field of interest in terms of volumes, nature and characteristics of primary
research (Arksey & O’Malley, 2005), of particular use when a topic has not yet been
comprehensively reviewed or if it is a complex or heterogenous nature and not suitable for a
more precise systematic review (Peters et al., 2015a). Scoping reviews have been increasing in
frequency since 2000. More recent definitions of scoping review have been proposed,
“Scoping studies aim to map the literature on a particular topic or research area and
provide an opportunity to identify key concepts, gaps in the research, and types and
sources of evidence to inform practice, policy-making and research (Daudt et al., 2013)
A scoping review is a form of knowledge synthesis that addresses an exploratory
research question aimed at mapping key concepts, types of evidence, and gaps in
research related to an emerging area or field by systematically and iteratively searching,
selecting, summarizing and potentially synthesizing existing knowledge (Colquhoun et
al., 2014)”
Early scoping reviews had employed a range of terms – scoping studies, scoping
exercises, scoping literature reviews – since replaced with the more consistent and appropriate
scoping review nomenclature (Pham et al., 2014) to capture its legitimacy and rigor (O’Brien et
al., 2016) . Scoping reviews present a broad overview of the evidence pertaining to an area of
interest irrespective of study quality and have utility when investigating areas which are new
and emerging, or when there is a need to clarify key concepts set research agendas and identify
implications for policy (Tricco, Lillie, et al., 2016). Whereas Arksey and O’Malley reference that
scoping reviews are to map “rapidly”, subsequent authors have encouraged removal of
reference to speed in order for the reviews to be done thoroughly and thoughtfully (Daudt et

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al., 2013). One evaluation found that 74% of scoping reviews surveyed took longer than six
months to complete (Khalil et al., 2019)
Scoping reviews utilize a rigorous and transparent methodology to comprehensively
explore, identify and analyze all relevant literature pertaining to a research area (Pham et al.,
2014). However, they differ from systematic reviews in several important ways. The purpose of
a scoping review is to “map” the literature, providing an overview of a potentially large and
diverse body of literature, while a systematic review sums up the available evidence on a very
specific question (Pham et al., 2014). Further, systematic reviews rely on randomized controlled
trials to provide evidence of effectiveness, whereas scoping reviews can consider a much
broader range of study designs and evidence (Arksey & O’Malley, 2005; Pham et al., 2014). In
addition to having a broader scope than systematic reviews, scoping reviews have more
expansive inclusion criteria (Munn et al., 2018). They also differ in their overall purpose. Given
these differences, scoping reviews should also have different reporting items from systematic
reviews (Tricco et al., 2018).
While systematic reviews appraise and assess the quality of evidence in the literature
they synthesized, scoping reviews do not universally critically assess the quality of the evidence
considered (O’Brien et al., 2016; Pham et al., 2014). Scoping reviews have adopted
structural elements of the systematic review methodology, such as comprehensive search
strategies and a priori protocols (Khalil et al., 2019), inclusion criteria (Munn Z, 2017) and
guidelines for reporting (Tricco et al., 2018) while retaining a more flexible and iterative process
(Peters, 2016). Similar to scoping reviews, evidence mapping can be used to characterize a
wide body of literature and identify gaps but differ in the production of a visual database or

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schematic (Munn et al., 2018). They differ from traditional literature reviews by their more
structured, systematic and rigorous methodology (O’Brien et al., 2016). It should not however
be assumed that scoping reviews have their sole utility in emerging areas, as their ability to
provide an understanding of the “lay of the land” makes them suitable to both emerging and
established areas of research (Arksey & O’Malley, 2005).
Given their usefulness in bringing together literature from emerging disciplines and the
fact they are suited to investigations beyond those pertaining to effectiveness (Peters et al.,
2015a), scoping reviews are well suited to the field of psychedelic research. Systematic reviews
are suited to clearly defined inquiries, while scoping reviews are helpful in answering much
broader questions (Tricco et al., 2018). The process is intended to by hypothesis-generating
(“can psychedelics be used in the treatment of substance use disorder”), and not hypothesis-
proving (“psychedelics are effective in treating substance use disorder”), which is the proper
role of future systematic reviews (Tricco, Lillie, et al., 2016) once the literature is more
developed and Phase 3 clinical trials have been completed. In this situation scoping reviews are
ideal as they can incorporate a range of study designs in both published and grey literature
(Levac et al., 2010). Systematic reviews typically focus on a well-defined question where the
targeted study designs can be known in advance and aim to answer questions from a narrowly-
defined range of quality-assured studies; scoping reviews in contrast address broader topics
from a range of study designs, answer less specific and more exploratory questions, and are not
required to assess the quality of studies included for review (Arksey & O’Malley, 2005).

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4.1.3 Indications for Scoping Reviews
Arksey and O’Malley (2005) identified 4 common reasons for scoping reviews:
1. To examine the extent, range and nature of research activity in a given area
2. To determine the value of undertaking a full systematic review
3. To summarize and disseminate research findings
4. To identify research gaps in the literature.
Building on the work of Munn and colleagues (2018), Lockwood and colleagues (2019) later
defined additional objectives that indicate the rationale for conducting a scoping review:
1. To provide indications for and act as precursor to future systematic reviews
2. To examine a broad range of evidence and identify gaps in the research or knowledge
base
3. To clarify and map key concepts and definitions in the literature
4. To clarify working definitions and the conceptual boundaries of a field
5. To report the types of evidence published in a certain field
6. To examine emerging evidence when it remains unclear what other more specific
questions can be posed
7. To examine the conduct of research in a field so as to inform future study design
In addition to ensuring there is a fit between the chosen methodology and reason for
review, researchers need to ensure a clear purpose for undertaking a scoping review (Levac et
al., 2010). Linking a clear purpose to a well-articulated research question helps to provide a
clear rationale for study completion and will assist in guiding decision making through the
search, study selection and data charting stages of the review (Levac et al., 2010). Researchers
must consider the rationale for their study and the implications this will have on research,
practice and policy (Levac et al., 2010). Scoping reviews are commonly used for the exploration,
or “reconnaissance” of a body of literature and to clarify the working definitions and conceptual
boundaries of a field of study (Peters et al., 2015a).

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Should researchers aim to address feasibility, appropriateness, meaningfulness or
effectiveness of a certain intervention, then systematic review would most likely be the
appropriate methodology (Munn Z, 2017). Systematic review is also indicated if authors wish to
use their results as a basis for clinical guidelines or to inform clinical practice (Munn Z, 2017).
Should researchers aim to ask broader, less precise questions or are more interested in
characterizing the state of the literature, then scoping reviews are a more suited methodology
(Munn Z, 2017). Although the frequency of scoping reviews is increasing, several authors have
addressed the need for improved methodological rigour and reporting quality (Colquhoun et
al., 2014; O’Brien et al., 2016; Tricco et al., 2018). To date, the most common reasons for
choosing to conduct a scoping review have been to identify gaps and opportunities for future
research (Tricco, Soobiah, et al., 2016).
4.1.4 Scoping Review Methodological Framework
Arksey and O’Malley laid out a five-stage framework with an optional and parallel sixth
stage (Arksey & O’Malley, 2005). The framework has been largely adopted and modified by
other researchers since publication (Colquhoun et al., 2014; Levac et al., 2010) or simplified into
a smaller number of stages but maintaining the same core activities (Lockwood et al., 2019).
1. Identifying the research question
2. Identifying the relevant studies
3. Study selection
4. Charting the data
5. Collating, summarizing and reporting results
6. (optional, and parallel element) Consultation exercise
The authors were clear that the methods employed through each stage were to be rigorous and
transparent, documented in sufficient detail to allow replication (Arksey & O’Malley, 2005). This

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explicit approach is intended to increase reliability of the scoping review findings, and ensures
the review has a methodological rigour as with a systematic review. The consultation process
provides a role for key stakeholders while the framework itself reflects the important role of
information technologies and technical knowledge (search capacities, information science)
while distancing itself from sole reliance on the expert knowledge which would be more typical
of a traditional literature review (Arksey & O’Malley, 2005). The consultation stage can be
helpful in the translation of preliminary results and in the development of knowledge transfer
and dissemination strategies with relevant stakeholders in the field of study (Levac et al.,
2010).
Subsequent authors have expressed concerns that the Arksey and O’Malley framework
lacks reference to critical assessment of the quality of the literature scoped (Daudt et al., 2013;
Levac et al., 2010), stating this weakens the reliability of findings. The PRISMA Extension for
Scoping Reviews (PRISMA-ScR) includes “critical appraisal of individual sources of evidence” as
a category in its scoping review reporting guidance checklist, with a note “if done, provide a
rationale for conducting a critical appraisal of included sources of evidence; describe the
methods used and how this information was used in any data synthesis (if appropriate)” (Tricco
et al., 2018).
However, the PRISMA-ScR Checklist does state that risk of bias across studies is not
applicable to scoping reviews, a position which rightfully separates scoping from systematic
reviews (among other differences, such as scope) (Tricco et al., 2018). Further, Levac has
advocated that the Arksey and O’Malley framework requires additional attention to the

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purpose and that researchers need to better clarify the concepts of the research question
driving the scoping review (Levac et al., 2010).
4.1.5 Strengths of Scoping Reviews
Scoping reviews, conducted properly, have several significant strengths as a form of
knowledge synthesis. They are able to map a body of literature, identify research gaps, include
a wide variety of literature sources and study designs, possess a dynamic, transparent, rigorous,
iterative and team-based process, can effectively produce research findings in a reasonable
time period, allow for consultative involvement of stakeholders and integrate knowledge
transfer activities (Khalil et al., 2019; O’Brien et al., 2016; Pham et al., 2014; Tricco, Lillie, et al.,
2016).
4.1.6 Limitations of Scoping Reviews
Scoping reviews have many limitations by definition. They do not appraise quality of
evidence and do not synthesize to assign relative weight of evidence in favour of the
effectiveness of a studied intervention (Arksey & O’Malley, 2005), so therefore cannot be used
as a basis for the development of clinical guidelines. As scoping reviews are still a relatively new
methodology, great variation in practice still exists allowing for potential abuse of the concept.
Some researchers may choose scoping reviews as a “short-cut” to systematic reviews to avoid
critical appraisal of sources. Some may attempt to “map” an area where there is no need, and
some may choose broad questions to bypass the time needed to develop more specific lines of
scoping inquiry (Munn et al., 2018). Scoping reviews generate considerable data, which can
lead to difficult decisions in balanced breadth with depth of investigation (Arksey & O’Malley,

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2005) and making it difficult to know how in-depth to carry out the data charting (Levac et al.,
2010). Researchers are encouraged to not simply follow previous scoping review publications
should they wish for a publishable article (Lockwood et al., 2019).
Scoping review literature on the whole has been found to lack consistency in
terminology, methodological application and reporting (O’Brien et al., 2016; Pham et al., 2014;
Tricco, Lillie, et al., 2016), shortcomings which have been addressed by the development of the
JBI Reviewer’s Manual and the PRISMA-ScR reporting guidelines. One recent peer-reviewed
“scoping review” publication on the role of nurses in psychedelic-assisted therapy (Denis-
Lalonde & Estefan, 2020) makes no mention of inclusion criteria, search strategy or protocol
and fails to adhere to the PRISMA-ScR reporting guidelines, instead referring to itself as a
“discursive” scoping review. In fact, by report alone it qualifies as a traditional literature review
but adopts the scoping review terminology, lacking the methodological rigour, processes and
transparency required of a proper scoping review. Lack of clarity or transparency related to
methodology makes it difficult for readers to assess validity and reliability, and to use research
findings appropriately (Pham et al., 2014; Tricco, Lillie, et al., 2016).
4.1.7 Suitability to Research on Psychedelics
Scoping reviews are intended to “examine the extent (that is, size), range (variety), and
nature (characteristics) of the evidence on a topic or question; determine the value of
undertaking a full systematic review; summarize findings from a body of knowledge that is
heterogeneous in methods or discipline; or identify gaps in the literature to aid in the planning
of future research” (Tricco et al., 2018). As such, they are well suited to exploring emerging and
diverse bodies of literature such as psychedelic-assisted therapies. Further, they are intended

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to by exploratory and hypothesis-generating, well suited to the current psychedelic renaissance
investigating the potential role of psychedelics in treating a whole range of mental health
(Johnson & Griffiths, 2017; Sellers & Leiderman, 2018) and neurobiological disorders (Flanagan
& Nichols, 2018). Different psychedelics are being investigated for a range of potential
applications; at this time knowledge synthesis is critical, and conduct of synthesis by
standardized, reputable, rigorous, transparent and replicable reviews can contribute to the
advancement of the literature on the whole.
Scoping reviews on topics related to psychedelics conform to the objectives of scoping
reviews, and the methodology is well-suited to its stage of development. Psychedelic-assisted
therapy is only just now reaching stage 3 clinical trials, with little confirmation yet of
effectiveness (Rucker et al., 2018). Further, the literature on psychedelic-assisted therapies is
heterogeneous and comprised of a wide range of disciplines, including neuroscience (Carhart-
Harris et al., 2012), behavioural neurobiology (Vollenweider & Kometer, 2010), psychiatry
(Johnson et al., 2014), chemistry (D. E. Nichols et al., 2017), and palliative care (Ross et al.,
2016).
As classical serotonergic psychedelics remain prohibited in most jurisdictions, for
psychedelic therapies to develop, the standard requirements for regulatory drug approval will
need to be met (Sellers & Leiderman, 2018). As such, the literature on the whole needs to
mature on several fronts, including the conduct of new pre-clinical and human clinical trials
(Rucker et al., 2018) . Which trials, how and with what psychedelics can all be informed by the
conduct of scoping reviews. Scoping reviews allow for maps of the current literature,
synthesized knowledge which has been developed to date, indicate areas for new research and

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provide the basis for new systematic reviews. As such, they are a critical methodology,
appropriate to this stage of the psychedelic sciences, and will provide much value to the field as
a whole.
This program of doctoral research includes two separate scoping reviews: one on the
clinical application of psilocybin in human trials, the other specific to behavioural investigations
of psilocybin in non-human animal studies. Combined, these reviews map the evidence for
psilocybin’s putative therapeutic effects. The putative therapeutic effect of psilocybin may
depend on its ability to disrupt rigid and repetitive, habitual patterns of thought, behaviour and
affect. In doing so psilocybin promotes new learning and facilitates changes in health
behaviours. In reviewing the results of these two separate scoping reviews together, a multi-
dimensional framework for understanding the putative therapeutic effects of psilocybin was
made possible.
4.2 Methods: Mapping Psilocybin-assisted Therapies
Scoping review methodology was selected to rapidly map the quickly emerging
literature around psilocybin-assisted therapies and to inform future clinical trial design. Given
the rapidly emerging state of the field, scoping review methodology is well suited as a
knowledge synthesis activity to broadly capture the state of the literature, clarify conceptual
concepts, identify gaps in research, and inform future clinical trials and systematic reviews.
Scoping review in this area may also assist in generating hypotheses in potential new modalities
of treatment and the therapeutic application of particular psychedelic drugs.

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We conducted a scoping review to identify, summarize and map the literature on
psilocybin-assisted therapeutic trials. Scoping reviews utilize a rigorous, transparent and
replicable methodology to comprehensively explore, identify and analyze all relevant literature
pertaining to a research area (Arksey & O’Malley, 2005; Pham et al., 2014). Scoping reviews
provide a basis in evidence for the evolution of both research and clinical practice, in this case
by understanding the patients selected, the interventions used, and the outcomes noted for
psilocybin-assisted therapies (PSI-AT). Our scoping review was guided by the research question,
“what are the treatment variables and outcomes associated with psilocybin-assisted therapy?”
and was guided by an a priori study protocol (see Appendix B.1). This research question was
designed to help map the state of psilocybin-therapy research, and to identify both treatment
variables and patient characteristics. In this way, any effectiveness found in psilocybin therapy
may lead to evidence-based program and policy developments. By opening the opaque box of
psilocybin therapies, we hoped to understand which inputs lead to desirable outcomes.
The study protocol was published in QSpace, an open access repository for scholarship
and research produced at Queen’s University, under School of Kinesiology and Health Studies
Faculty Publications. Reporting has been completed in accordance with the PRISMA-ScR
Reporting Guidelines.
This scoping review search was specific to psilocybin-assisted therapies. Variables
included both patient and intervention characteristics. By understanding the patients selected,
the interventions used, and the outcomes noted for psilocybin-assisted therapies, we aimed to
better understand the program variables and standards of practices for these emerging
treatments. This scoping review extracted, reviewed and charted data related to psilocybin-

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assisted therapy in three domains: 1) Patients, including cohort size and presenting conditions;
2) Interventions, including location, setting, dosage, and ancillary services provided; and 3)
Outcomes, including measured changes, evidence for safety and efficacy, trial results, and
author conclusions including limitations.
Outcomes included any documented changes in health status with both positive and
negative outcomes noted. Through librarian-conducted literature searches (see Appendix B.1)
and defined inclusion criteria (see Appendix B.4), the relevant number of internationally
published, peer-reviewed academic articles in addition to grey area literature were identified,
and the findings charted to identify the current state of psilocybin animal study research. As a
preliminary stage, authors completed multiple preliminary reviews, literature research, scanned
abstracts for keywords, identified pilot inclusion criteria, developed a pilot data extraction tool,
and conducted background research into the history of psilocybin-assisted therapies prior to
conducting the actual scoping review.
4.2.1 Search Strategy
A comprehensive search approach (see Appendix B.1) was used by an experienced
health sciences librarian to locate published and unpublished studies. A preliminary search was
conducted in Ovid MEDLINE using a combination of keywords and subject headings, followed
by an analysis of relevant citations to identify additional relevant keywords and subject
headings. A refined search using all identified keywords and subject headings was then
executed in Ovid MEDLINE (1946 onward) and translated in the following resources: Ovid
Embase (1947 onward), PsycINFO (1806 onward), EBM Reviews: Cochrane Central Register of

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Controlled Trials (1991-present), Web of Science Core Collection (1900 onward), and ProQuest
Dissertations and Theses (1861 onward). Database searches were conducted in December 2018
and updated in October 2019, December 2020 and finally October 2021; no language or date
restrictions were applied though non-English texts would eventually be excluded. Finally, the
reference lists of all eligible reports and articles were hand-searched to identify any additional
studies.
From records identified through database screening and using Covidence (Cochrane)
online software, duplications were removed, records screened, assessed for eligibility and
included or excluded from full-text review based on established inclusion and exclusion criteria
in the a priori protocol (see Appendix B.4). Reviewers (RS and PI, then RS and NT) read the full
text of selected studies and each extracted data using an a priori data extraction spreadsheet.
Reviewers cross-checked for homogenous process quality control and consensus was necessary
when conflicts arose.
4.2.2 Citation Management
All citations were imported into Covidence, duplicate citations were removed.
4.2.3 Eligibility Criteria
Eligibility was determined by an a priori protocol; studies were included which met the
stated eligibility inclusion criteria: psilocybin, therapy/treatment, outcomes measured, meets
search terms/ keywords. Studies were excluded if duplicates, not a research study, no
outcomes measured, no therapeutic goal, and not about psilocybin.

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4.2.4 Study Selection and Screening
Articles were included through a two-pass review. In the first pass, two
reviewers evaluated the abstracts in Covidence for basic inclusion criteria. Each reviewer opted
to a) exclude the study as it was already evident it did not meet at least one of the
predetermined criteria (NO), b) push the study forward as it remained unclear whether or not
all criteria were met and the article required further review – or perhaps not enough
information was available to make a judgement (MAYBE), or c) accept the study, to pass
through to the full read. The second pass included full-paper scanning to ensure all criteria
were met. All steps were completed within Covidence.
4.2.5 Data Extraction
The included studies were divided between reviewers (RS, PI) with reviewers extracting
relevant information to a shared extraction Excel spreadsheet. Data extraction was
corroborated by a second reviewer. Information in the summary table included. Core trial
publications were identified and separated out for more detailed extraction data including year
of publication, originating country, journal type, sample size, presenting condition, dose-dosing
regimen and method of administration, psychotherapies provided, duration of treatment,
practice description, outcomes measured, measurements tools used, adverse effects reported,
effectiveness (quantitative), follow-up period, research question and reported limitations. Data
was extracted separately for the secondary publications and included core clinical trial
identification, and summary of findings.

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4.2.6 Data Summary, Synthesis and Charting
Data from extraction tables was subsequently synthesized and reported via distinct
tables reporting study characteristics, clinical trial outcomes, adverse experiences, trial cohort
demographics and dosage regimens among others. Tables were reviewed and vetted by both
reviewers and subsequently by study team members.
4.3. Methods: Behavioural Investigations of Psilocybin in Non-human Animals
Scoping review methodology was selected to identify, summarize and map the literature
on pre-clinical behavioural studies of non-human animals and psilocybin, psilocin and Psilocybe
mushrooms. Scoping reviews utilize a rigorous, transparent and replicable methodology to
comprehensively explore, identify and analyze all relevant literature pertaining to a research
area (Arksey & O’Malley, 2005; Pham et al., 2014). Scoping reviews provide a basis in evidence
for the evolution of both research and clinical practice, in this case by understanding the
behavioural outcomes in translational models of animal research.
The scoping review was guided by an a priori protocol (see Appendix C.1). The objective
was to determine the effects of psilocybin (PSI) in animal studies across behavioural task
clusters and neurological measures and to chart: what studies have been done,
what behavioural tests have been used, what neurological measures have been implemented
and which dosing modalities have been used and to what effect. Through librarian-conducted
literature searches (see Appendix C.2) and defined inclusion criteria, the relevant number of
internationally published, peer-reviewed academic articles in addition to grey area literature

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was identified, and the findings charted to identify the current state of psilocybin animal study
research.
As a preliminary stage, we completed multiple preliminary reviews, literature research,
scanned abstracts for keywords, identified pilot inclusion criteria, developed a pilot data
extraction tool, and conducted background research into the history of psilocybin in animal
models prior to conducting the actual scoping review. The study protocol was published
in QSpace, an open access repository for scholarship and research produced at Queen’s
University, under School of Kinesiology and Health Studies Faculty Publications. Reporting has
been completed in accordance with the PRISMA-ScR Reporting Guidelines.
4.3.1 Search Strategy
A comprehensive search approach was employed by an experienced health services
librarian to locate published studies and conference materials. A preliminary search was
conducted in Ovid Embase using a combination of keywords and subject headings, followed by
an analysis of relevant citations to identify other relevant keywords and subject headings. The
optimized Ovid Embase search strategy was then adapted for Ovid MEDLINE, Ovid EBM
Reviews – Cochrane Central Register of Controlled Trials, Ovid PsycINFO, Web of Science Core
Collection, and BIOSIS Previews. All databases were searched from inception up to October
2019, with a search update performed in October 2021. No publication date limits were
applied. The complete search strategies for all databases are presented in Appendix C.2. The
reference lists of all eligible studies were screened to identify any additional studies.
A librarian-conducted literature search was performed through MEDLINE, Embase and
PsycINFO, using predefined key terms and search criteria (SM – Queen’s Bracken Health

98
Sciences Library). Additional searching was conducted by reviewers, using electronic databases,
grey literature sources, and reference lists of relevant articles or reviews. The first search was
conducted in Fall of 2019, the second in the Spring of 2021 and finally October, 2021.
4.3.2 Citation Management
All citations were imported into Covidence, duplicate citations were removed.
4.3.3 Eligibility Criteria
Studies were included which reported behavioural parameters in an animal model
following the administration of psilocybin, psilocin or whole mushroom/whole mushroom
extracts (WME). Only included primary research investigating behavioural effects in mammals
was included in the scope of this review.
We excluded review articles (meta-analyses, etc.), but referred to their references to
scope for primary research that may fit the inclusion criteria. Duplicates and studies that were
not reported in English were excluded. We excluded publications that did not have an adequate
control group, to which changes in behaviour could be compared. These included studies that
only investigated interactive effects of PSI treatment and another compound (for example, in a
competitive binding paradigm) or drug discrimination studies (where the behaviour is
dependent on reinforcement trained by a separate compound), as we wanted to investigate
the effects of PSI treatment alone on behaviour. Multiple studies investigated the effects of
multiple drugs, so we included those studies as long as there was an experimental paradigm
that included a control and reporting of behavioural outcomes following psilocybin
administration without other pharmacological interventions.

99
4.3.4 Study Selection and Screening
Like with our first scoping review, articles were included through a two-pass review
system. In the first pass, two reviewers again evaluated the abstracts in Covidence for
compliance with basic inclusion criteria. Each reviewer opted to a) exclude the study as it was
already evident it did not meet at least one of the predetermined criteria (NO), b) push the
study forward as it remained unclear whether or not all criteria were met and the article
required further review – or perhaps not enough information was available to make a
judgement (Maybe), or c) accept the study, to pass through to the full read. The second pass
again included full-paper scanning to ensure all inclusion criteria were met.
4.3.5 Data Extraction
The included studies were divided between reviewers (RS, KD, NB, NT, KR) with
reviewers extracting relevant information to a shared extraction spreadsheet. Data extraction
was corroborated by a second reviewer, and a third reviewer went through all final exactions to
ensure accuracy. Information in the summary table included article characteristics (year of
publication, country of institutions), details of the study design and animal model used (number
of experimental groups, type of experimental groups, total number of animals included; strain,
sex, age, weight, and housing conditions of animals), dosing regimen (specific substance, route
of administration, number and concentration of doses, control substance, time between drug
administration and testing), behavioural test administered (including type of test, which
behavioural parameters were recorded, setting of tests, training period), and outcomes

100
(behaviour results, other mechanisms recorded, adverse outcomes). Following data extraction,
the main outcomes were grouped by behavioural category.
4.3.6 Data Summary, Synthesis and Charting
Given the broad scope of the review, outcomes were grouped by the type of
behavioural test administered and clustered under the construct domains of the Research
Domains Criteria (RDoC) of the National Institute of Mental Health. Mapping outcomes
depended on the type of behavioural test used; results were further categorized by parameters
that may contribute to behavioural outcome, including dose or time between administration
and testing. To provide dose equivalencies, the 0.71:1 equimolar psilocin to psilocin conversion
is used; the predominantly used compound is used as the base comparison in each table. This
does not account for differences that may result from metabolism, or other variables, but
serves as a rough comparison across different study drug formulations.
From records identified through database screening and using Covidence online
software, duplications were removed, records screened, assessed for eligibility and included or
excluded from full-text review (Figure 1.) Reviewers (RS, KD, NB, NT, KR) read the full text of
selected studies and each extracted data using an a priori data extraction spreadsheet.
Reviewers cross-checked for homogenous process quality control and consensus was necessary
when conflicts arose.
4.3.7 Classification of Results by RDoC Matrix
Results were allocated across the RDoC framework (see Table 3.1). Our team assigned
the various individual animal assays to one of the domains after a thorough review of each

101
study design, consultation with the larger body of literature specific to the paradigms (Angoa-
Pérez et al., 2013; Commons et al., 2017; Kalueff et al., 2016; Kelly et al., 2021; Pittenger et al.,
2019; Scheggi et al., 2018; Slattery & Cryan, 2012; Willner & Belzung, 2015) and by consensus
within the team. Each of the seventy-seven individual publications was then located within the
domain classifications. Using the RDoC framework in this way allowed for the presentation of
our scoping review results within an established and valid epistemic framework of health
research and knowledge translation.
Table 4.1: Animal Paradigms by RDoC Domain Classification
1. Negative Valence
Systems
Fear conditioning task
2. Positive Valence Systems
Fixed training
schedule
Defensive Aggression
Sucrose preference
test
Open field test
Female urine test
Elevated plus maze
Two-choice swim
test
Chronic mild stress
Marble burying
Chronic multimodal stress
paradigm
Drug discrimination
Learned helplessness
Morris water maze
Tail suspension
Progressive ratio
task
Forced swim test
Serial task
Aggressive behaviour
Lever preference
Carousel maze
operant conditioning can be
both 1 & 2
3. Cognitive Systems
Visual discrimination
4. Social Processes
Sexual behaviour
Object pattern test
Prolonged Isolation
Classical conditioning tests
Social Aggression
Long-term behavioural
consolidation
5. Arousal & Regulatory
Systems
Startle Response
6. Sensorimotor Systems
Self-grooming
Locomotor Activity
Pre-pulse inhibition

102
Sleep Study
Motor coordination
Food intake
Limb jerks
Piloerection / reactivity
Head-twitch
Restlessness / alertness
Stereotypic
behaviours
Exploratory behaviour
Locomotion
The development of this table to be in itself a novel and significant contribution to knowledge
translation. By assigning known animal model paradigms to the six domains of the RDoC
framework, we are able to group or cluster the results of the individual studies within specific
process-oriented higher-order domains of function. Study results were mapped directly onto
this epistemological framework as part of an overall scoping of psilocybin pre-clinical health
research using animal models. This adds considerably to the translation value of this scoping
review by mapping results onto this recognized and validated framework. Applying the RDoC
criteria in this manner is intended to strengthen the interpretation and presentation of findings,
increasing validity by situating the study findings within more specific, localized data points and
providing an epistemic framework for the interpretation of study results. In this way, the
diagnostic validity of DSM-V or ICD-10 definitions of such things as depression are less relevant,
and study findings can more meaningfully be nested within areas of behavioural function and
known biological systems.

103
Chapter Five: Results
5.1. Results: Mapping Psilocybin-assisted Therapies (MPAT)
Database searching identified 4459 potential articles; after duplicates were removed
1893 records remained, and from these 216 articles were subjected to full-text review (see
Figure 5.1: PRISMA Diagram). 167 articles were excluded for not meeting inclusion criteria,
leaving 49 published studies included in the review (see Results Appendix B.4 for list of studies
by date of publication).
Figure 5.1: PRISMA Diagram, MPAT Scoping Review Process
Of the 49 publications, 12 were identified as original clinical trial results publications;
the remaining 37 articles were secondary investigations pertaining to the core trials, or follow-
ups to original trials. Core trial publications are defined as the primary publication of trial

104
outcomes; secondary publications may be in follow-up, examine elements of the patient
experience, or report results of neuroimaging completed within the scope of the trial design.
5.1.1. Psilocybin Clinical Trial Characteristics
Eight of the twelve core interventional studies used a controlled trial methodology and
four were trials were single-group open label trials lacking control groups (see Table 5.1.) A
total of 259 participants completed the trials, with 198 (76.4%) enrolled in controlled trials, 106
(41%) enrolled in trials for major depressive disorder or treatment-resistant depression, and a
further 97 (37.5%) enrolled in trials pertaining to cancer-related anxiety and depression. Other
presenting conditions studied include obsessive compulsive disorder, tobacco addiction, alcohol
use disorder, treatment resistant depression, demoralization among long-term AIDS survivors,
and migraine headaches (Table 5.1.) Ten of the trials took place in the United States, and the
remaining two in the United Kingdom. The oldest trial published results in 2006 and the most
recent in April 2021 (see Appendix B.4 for list of publications by date).
Table 5.1. MPAT Trial Characteristics, Outcomes & Reported Adverse Effects
Reference
Presenting
Condition
# Subjects
Recruited/Usabl
e
Data/Completed
All Measures
Study Design
Type &
Duration of
Psycho-
Therapy
Outcomes
Adverse
Effects
Follow-
Up
Period
(Weeks)
Moreno et al.
(2006)
Obsessive-
Compulsive
Disorder
09/09/09
Modified
Randomized
Double Blinda
None
Acute
reductions in
OCD
symptoms at
24 hours
Transient
Hypertensio
n (11%)
24

105
(>= 25%
decrease in 8
patients,
>=50%
decrease in 6
patients)
Grob et al.
(2011)
Cancer-related
anxiety and
depression
12/12/08
Randomized,
double-blind,
crossover
None
Significant
reductions in
anxiety at 1-
and 3-months
follow-up and
depression at
6 months
follow up
None
clinically
significant
12, 16,
24
Johnson et
al. (2014)
Tobacco
addiction
15/15/15
Single Group,
Open-Label
CBT, 15
weeks
12 of 15 (80%)
participants
demonstrated
abstinence at
6 months
follow-up
Extreme or
strong fear
(40%),
headache
(53%),
elevated BP
and HR (NR)
24
Bogenschutz
et al. (2015)
Alcohol use
disorder
10/09/09
Single Group,
Open-Label
MET, 4
months
Percent
drinking days
decreased 1-7
weeks after
psilocybin
session with
large effect
size
Nausea and
abdominal
pain (1),
Headaches
(5), IBS-
based
diarrhea
(1),
insomnia
following
session (1)
36
Griffiths et al.
(2016)
Cancer-related
anxiety and
depression
56/51/46
Randomized,
double-blind,
crossover
PSI, 9
months
Significant
decreases in
depression
and anxiety at
6 months
follow-up
Headache
(4%),
nausea/vo
miting (8%),
physical
discomfort
(15%),
psychologic
al
discomfort
(22%),
anxiety
(21%),
paranoia
(2%)
24

106
Ross et al.
(2016)
Cancer-related
anxiety and
depression
29/29/22
Randomized
Double Blind
Crossover
PSI, 10
weeks
Significant and
sustained anti-
depressant
and anxiolytic
effects up 6.5
months
follow-up
Headaches
and
migraines
(28%),
anxiety
(14%),
psychotic-
like
symptoms
(7%),
Elevated BP
and HR
(76%),
nausea
(14%)
24
Carhart-
Harris et al.
(2018)
Treatment
resistant
depression
20/19/19
Single Group,
Open-Label
PSI, 2
months
Maximal
reduction in
depressive
symptoms for
5 weeks post-
treatment
with benefits
persisting to 3
and 6 months
Anxiety
(79%),
headaches
(42%),
nausea
(26%),
paranoia
(16%)
12
Bogenschutz
et al. (2018)a
Alcohol use
disorder
180/ n/a /3
Randomized
Double blind
Parallel
CBT+MET, 3
months
Self-reported
decreased
craving and
alcohol-
associated
problems,
anxiety and
depression at
final follow-up
Nausea and
abdominal
pain (33%)
54, 104
Anderson et
al. (2020)
Demoralizatio
n among
older, long-
term AIDS
survivor men
18/18/18
Open-Label,
Single Group
Group-
based SEGT,
4 weeks
Rapid
improvements
in mood and
anxiety
symptoms
Moderate/s
evere
anxiety
(44%),
paranoia
(22%),
transient
thought
disorder
(6%),
hypertensio
n (22%),
severe
hypertensio
n and
severe
anxiety
(11%),
severe
nausea and
12

107
hallucinatio
ns (6%)
Davis et al.
(2021)
Major
Depressive
Disorder
27/24/24
Randomized
Waiting List
Control Trial
PSI, 16
weeks
71% of
participants
had clinically
significant
response at 1
and 4 weeks;
54% in
remission
week 4.
Panic (40%),
fear (54%),
anxiety
(56%)
4
Schindler et
al. (2020)
Migraine
headaches
14/10/10
Exploratory
double-blind
placebo-
controlled
crossover
None
Significant
reduction in
migraine
frequency,
severity of
pain,
impairment
None
clinically
significant.
4
Carhart-
Harris et al.
(2021)
Major
Depressive
Disorder
59/51/51
Double-blind,
randomized,
placebo-
controlled
PSI, 4 weeks
No significant
difference in
antidepressan
t effects
between
psilocybin and
escitalopram
Similar
percentage
of adverse
effects in
psilocybin
(87%) and
escitalopra
m (83%)
groups.
24
Legend. aStudy is ongoing. PSI = Preparation, Support, and Integration, CBT = Cognitive Behavioural Therapy, MET =
Motivational Enhancement Therapy. SEGT =Supportive Expressive Group Therapy
The trials themselves ranged in cohort sizes from 3 to 59, with one ongoing trial
(Bogenschutz, 2018) which reported preliminary results planning to enroll a total of 180
subjects over time (see Table 5.1.). Studies themselves lasted from 4 to 57 weeks (where
reported). Data was collected by various standardized tools and metrics including self-report,
clinical assessments and biomarkers; two trials included neuroimaging of trial participants
(Carhart-Harris et al., 2021; Carhart-Harris et al., 2016) reported later under secondary
publications.
The majority of trials provided significant levels of therapy including preparation and
integration, but also general psychological support and, in the case of substance use disorder,

108
additional therapies specific to addiction (see Table 5.3). Three trials did not report including
psychotherapy or psychological support (Grob et al., 2011; Moreno et al., 2015; Schindler et al.,
2021). While psilocybin sessions were conducted individually in each trial, several of the trials
provided collective group therapy (Anderson et al., 2020; Bogenschutz et al., 2015; Johnson et
al., 2014). Detailed descriptions of the therapies provided by trial are contained in Appendix
B.3.
5.1.2 Psilocybin Formulation and Trial Dosing
With the exception of the Schindler migraine study, trials used a similar approach to
psilocybin dosage and the setting for dose administration sessions. All trials used a synthetic
formulation with psilocybin administered orally in all except the migraine trial, which
administered psilocybin intravenously (see Table 5.2.). Of the five randomized control trials,
three followed a crossover design, one followed a parallel design, and one followed a modified
escalating-dose design. In the crossover studies, each patient was exposed to both placebo
(niacin, DP, or a very low dose of psilocybin) and an experimental dose of psilocybin in two
sessions which varied between one to seven weeks apart (see Table 5.2). Across the trials,
dosage was calculated by one of three methods: mg, mg/k or mg/70kg. Doses were generally
calibrated at 20 then 30mg/70kg of body weight, .3mg/kg, or 10 then 25mg PO (by oral). The
lowest dose used was the migraine trial at .143/kg (Schindler et al., 2020), a dosage considered
to be between a low and a moderate dose (Moreno et al., 2015) (see Figure 5.2).
The majority of trials administered psilocybin in multiple sessions (up to 3), separated by
at least 1 week (Carhart-Harris et al., 2016) to a maximum of 7 weeks (Ross et al., 2016), and

109
starting with lower doses. often over multiple sessions with a minimum of a week break
(Carhart-Harris et al., 2016) to a maximum of seven weeks (Ross et al., 2016) in between. Most
commonly, doses fell in the medium to high-ranges (25-40mg/70 kg); and many trials reported
a greater benefit correlation with higher doses. Sessions lasted up to 8 hours, some trials
provided overnight accommodation, and all provided medical oversight and symptom
management.
Figure 5.2. PSI Doses by Trial
Table 5.2. Psilocybin Dosing Formulation and Regimen, By Trial
Trial
Dosing
Dose in mg/70kg,
MOA
Placebo
Dosing Schedule
Moreno et al.
(2006)
0.1, 0.2, 0.3 mg/kg
7, 14, 21 P.O.
0.0025 mg/kg PSI
4 sessions (one placebo) sessions,
progressive doses 1-2 weeks apart
Grob et al.
(2011)
0.2 mg/kg
14 P.O.
250 mg niacin
2 sessions (one placebo) over 2
weeks
Johnson et al.
(2014)
20, 30 mg/70kg
20, 30 P.O.
N/A (open-label)
2 sessions 2 weeks apart, starting
at week 5; progressive dose with
optional third dose week 13
0
10
20
30
40
50
Dose of Psilocybin Provided
(mg/70kg)
Name of Core Trial
Psilocybin Doses (mg/70kg) Provided in Clinical Trials
Dose 1 Dose 2 Dose 3

110
Bogenschutz
et al. (2015)
0.3, 0.4 mg/kg
21, 28 P.O.
N/A (proof-of-
concept)
2 sessions, 4 weeks apart starting
at week 4
Griffiths et al.
(2016)
22, 30 mg/70kg
22, 30 P.O.
1 or 3 mg PSI
2 sessions, progressive doses, 2
weeks apart
Ross et al.
(2016)
0.3 mg/kg
21 P.O.
250 mg niacin
2 sessions, 3 weeks apart starting
at week 4
Carhart-Harris
et al. (2016)
10 mg and 25 mg
10, 25 P.O.
N/A (open-label)
2 sessions, 7 days apart
Bogenschutz
et al. (2018)
25, 30, 40 mg/70kg
25, 30, 40 P.O.
50 mg
diphenhydramine
optional 2nd dose 4 weeks after
first, which occurred at week 4
Anderson et
al. (2020)
0.3, 0.36 mg/kg
21, 25.2 P.O.
N/A (open-label)
single session, 3 cohorts with
differing doses
Davis et al.
(2021)
20, 30 mg/70 kg
20, 30 P.O.
N/A (waitlist
controlled)
Mean of 1.6 weeks between
progressive doses
Schindler et
al. (2020)
0.143 mg/kg
10 I.V.
0.143 mg/kg
microcrystalline
cellulose
2 sessions at least 14 days apart
Carhart-Harris
et al. (2021)
25 mg
25 P.O.
1 mg PSI or
microcrystalline
cellulose
2 sessions 3 weeks apart
After varying degrees of preparation, trial subjects were given an oral dose of synthetic
psilocybin in a quiet, protected and comfortable setting. Trials tended to use curated musical
playlists, eyeshades, and encouraged subjects to, in the words of one trial investigator “trust,
let go, and be open” (Griffiths et al., 2016). Where reported, trials included two guides (usually
of differing genders), or sitters, who would accompany the subject through the sessions in a

111
non-interventional, and supportive manner, later to debrief and help integrate the contents of
the session.
Table 5.3. Psychotherapies Provided, by PSI-AT Trial
Trial
Type
of
PsyT
Pre PSI PsyT
Hours
Suppo
rt
Hours
Durin
g PSI
Hours of
PsyT
Between
PSI
(average)
Hours of
therapy
after PSI
(average)
PsyT Descriptors
Durati
on of
PsyT
Moreno
et al.
(2006)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Grob et
al. (2011)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Johnson
et al.
(2014)
CBT
4 x 90 = 6
hours
8
N/A
1 hour
integratio
n, 45 min
follow up
= 1.75
hours
Four weekly prep
meeting, participants
received smoking
cessation CBT based on
Quit for Life program
15
weeks
Bogensch
utz et al.
(2015)
MET
4 sessions
(unspecifi
ed length
of time)
2 x 8
4 sessions
after first
psilocybin
session
before
second
psilocybin
session
(unspecifi
ed length
of time)
4 sessions
after the
second
psilocybin
session
(unspecifi
ed length
of time)
7 sessions of MET
(focused on changing
drinking behaviour), 3
preparatory sessions and
2 debriefing sessions for
the 2 psilocybin sessions.
MET was structured using
principles of motivational
interviewing.
4
mont
hs
Griffiths
et al.
(2016)
PSI
7.9 h
2 x 7
5.3 h
2.4 h
In preparatory meetings,
participants discuss
meaningful aspects of
their life and prepare for
psilocybin session. During
session, monitors were
nondirective and
supportive. In post
session meetings, focus
on novel thoughts and
feelings that arose during
sessions
9
mont
hs

112
Ross et al.
(2016)
PSI
3x 2hour
= 6 hours
total
2 x 8
three 2-
hour
sessions =
6hr total
three 2-
hour
sessions =
6hr total
Medication-assisted
psychotherapy' included
preparatory
psychotherapy,
medication dosing
sessions, and post-
integrative
psychotherapy. Therapy
was constructed with
components of
supportive
psychotherapy, CBT, and
existentially oriented,
psychodynamic/psychoan
alytic.
10
weeks
Carhart-
Harris et
al. (2016)
PSI
4 hrs
6
6hr
sessions
not
specified
Psychological support
consisted of preparation,
acute and peri-acute
support, and integration.
Therapy was described as
'nondirective and
supportive'.
2
mont
hs
Bogensch
utz et al.
(2018)
CBT,
MET
2x1hr
META
sessions +
2x2hr
prep
session =
6hrs total
3 x
8.5
2 hrs
debrief +
(2) 1 hr
META
sessions,
then 1hr
prep
session
for
second
PSI. After
second
PSI, 2 hr
debrief +
(3) 1hr
META,
sessions 1
hr prep
for third
open
label
session.
11 hrs
total
2 hr
debrief +
(2)1 hr
META
session. 4
hrs total
Team of two therapists,
one conducting alcohol
related therapy MET and
CBT, and the other the
psychedelic-specific
treatment, including
Preparation, Support and
Integration.
3
mont
hs

113
Anderson
et al.
(2020)
Grou
p-
base
d CBT
3.5 hours
over 4
sessions
8 hrs
N/A
Cohort 1
received
4 group
based INT
sessions,
cohort 2
and 3
received
6 group
based INT
sessions
(12-15
hrs)
Three group therapy
cohorts (n=6). Group
therapy was modelled on
brief supportive
expressive group therapy
(SEGT).
NR
Davis et
al. (2021)
PSI
8 hrs
11
hrs
2 hrs
post-
session 1
integratio
n
2-3 hours
in total
Adhered to guidelines of
supportive psychotherapy
(Johnson et al., 2008)
16
weeks
Schindler
et al.
(2020)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Carhart-
Harris et
al. (2021)
N/A
N/A
N/A
N/A
N/A
Preparatory therapeutic
session and support
provided by professionals,
but no psychotherapy and
for unspecified length of
time.
N/A
INT= Integration
5.1.3 Psilocybin Clinical Trial Study Populations
The trial study populations combined have an age range of 21-74 (aggregate mean,
46.9), with 44% of subjects identifying biological sex as female (see Table 5.4.). No trial to our
knowledge reported on gender so it is unknown if transgendered or non-binary participants
were included. Ten of the 12 trials reported data on previous use of psychedelics among trial
subjects; among the trials which did report, 46.7% had previous psychedelic experience (PPE).
Ten of the 12 trials also reported data on race, with 76.5% of participants reporting as white.
Overall, subjects tended to be male, white and middle aged; trials which reported education

114
and employment data found high-levels of post-secondary education and professional
vocations.
Table 5.4: Study Population Characteristics
Trial
Age Range
(Mean)
Biological Sex
Distribution
Trial Reported
on Gender
(Y/N)
Participants
with Previous
Psychedelic
Experience
(PPE)
Race
Distribution
as Reported
Moreno et al.
(2006)
26-62 (40.9)
7 M, 2 F
N
9
NR
Grob et al.
(2011)
36-58 (NR)
1 M, 11 F
N
8
NR
Johnson et al.
(2014)
26-65 (51)
10 M, 5 F
N
10
White: 14
Asian: 1
Bogenschutz
et al. (2015)
25-65 (40.1)
5 M, 4 F
N
23
Native
American/Ala
ska Native: 2
African
American: 1
Hispanic: 4
White non-
Hispanic: 3
Griffiths et al.
(2016)
NR (56.3)
26 M, 25 F
N
23
White: 48
Black/African
American: 2
Asian: 1
Ross et al.
(2016)
22-75 (56.28)
11 M, 18 F
N
16
White: 13
“Other”: 1
Carhart-Harris
et al. (2018)
27-64 (44.1)
13 M, 6 F
N
7
White: 15
Black: 3
Hispanic: 1
Bogenschutz
et al. (2018)a
NR (NR)
2 M, 1 F
N
NR
White non-
Hispanic: 1
Black/African
American: 1
Hispanic/Othe
r Latin
American: 1
Anderson et
al. (2020)
50-66 (59.2)
18 M
N
7
Black/African
American: 1
Multiracial: 3

115
White: 14
Davis et al.
(2021)
21-64 (39.8)
9 M, 16 F
N
NR
White: 22
Other: 2
Schindler et
al. (2020)
23-63 (40.5)
3 M, 7 F
N
2
White: 10
Carhart-Harris
et al. (2021)
NR (41)
39 M, 20 F
N
16
White: 52
Other: 7
Overall
46.9
144/259
(56%)M
0
46.70%
10/12
reported
(21-75)
115/259
(44%)F
Non-white:
26%
Legend: aStudy is ongoing
5.1.4 Psilocybin Trial Clinical Outcomes and Follow-up Periods
Trial outcomes are positive with demonstration of effect power and rapid, sustained
onset of clinical improvement, particularly in psilocybin’s anti-depressant effects. Rapid
improvement of mood may separate PAT from standard pharmacotherapies today, which have
a delayed onset of therapeutic effect (four-six weeks for most). Follow-up periods
demonstrated sustained, persisting benefits; follow-up periods ranged from 4-104 weeks
(average 26.3) with five of the twelve trials ending follow up at 24 weeks. The Bogenschutz
(Bogenschutz et al., 2015) trial provided the longest follow up at 104 weeks; the shortest were
the 4-week follow up periods of the recent Davis (Davis, Barrett, May, et al., 2020) and
Schindler (Schindler et al., 2021) trials (see Figure 5.2).
Trials reported a range of adverse experiences, most commonly elevated blood pressure
and heart rate, transient anxiety and distress, nausea and post-session headaches. Trials used
numerous standardized outcomes measurement tools, with most commonly employed
including assessments of mystical experience (primarily the Mystical Experiences Questionnaire
(MEQ-30) but also Hood’s Mysticism Scale), State-Trait-Anxiety-Inventory (STAI), Beck

116
Depression Index (BDI), Altered States of Consciousness Questionnaire, Persisting Effects
Questionnaire, Quick Inventory of Depressive Symptomology (QIDS), Profile of Mood States
(POMS) Questionnaire, and GRID-Hamilton Rating Scale for Depression (GRID-HAM). Outcome
measurement tools are reported fully in Appendix B.3.
Figure 5.3: Follow-up Periods by Trial
There is a notable shift in psilocybin-assisted therapy methodologies to parallel designs,
as, of the 14 ongoing psilocybin clinical trials, 11 of them follow a parallel design. Parallel
designs give the advantage of avoiding carryover effects. They are also favoured in larger
studies which corresponds to the much larger sample size of ongoing trials relative to the
completed trials outlined in this review.
020 40 60 80 100 120
Moreno et al. (2006)
Grob et al. (2011)
Johnson et al. (2014)
Bogenschutz et al. (2015)
Griffiths et al. (2016)
Ross et al. (2016)
Carhart-Harris et al. (2016)
Bogenschutz et al. (2018)
Anderson et al. (2020)
Davis et al. (2021)
Schindler et al. (2020)
Carhart-Harris et al. (2021)
Folloq-Up Period (Weeks)
Name of Core Trial
Follow-Up Period Length (weeks) in Core Trials
Follow-Up Period 3 Follow-Up Period 2 Follow-Up Period 1

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The most recent Carhart-Harris trial (Carhart-Harris et al., 2021) comparing psilocybin
with the SSRI antidepressant escitalopram is the sole trial to competitively investigate in
comparison to standard treatment. This trial failed to demonstrate benefit of psilocybin in
comparison to the escitalopram control when measured by the chosen primary outcome
measurement; psilocybin was however associated with a range of superior benefits in 10 of 11
secondary measures.
The most commonly cited trial publications are, in order: Griffiths, 2016 (n=203),
Carhart-Harris, 2016 (n=191), Grob, 2011 (n=172), Ross, 2016 (n=170) and Bogenschutz 2015
(n=155)
8
. Considering the popular interest in “ego loss” as a principal them in the psychedelic
experience, it is of interest that only 3 core trials made any mention of the phenomenon, with
the Grob (2011) having 6 mentions, Bogenschutz (2015) with 2, and Griffiths (2016) a singular
mention.
5.1.5 Results for Substance Use Disorder
Psilocybin-assisted therapy has been trialed for both Tobacco Use Disorder (Johnson,
2014) and Alcohol Use Disorder (Bogenschutz, 2015). As an initial pilot study, Johnson and
colleagues enrolled 15 participants who smoked at least 10 cigarettes a day and had multiple
previous and unsuccessful attempts to quit. At six-month follow-up, biological markers verified
abstinence among 12 (80%) of participants. Experiences of mysticism or transcendence were
both positively correlated with smoking outcomes (Garcia-Romeu et al., 2014) and found not
8
Author conducted citations search in Google Scholar, January 2022.

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necessary to positive outcomes (Bogenschutz et al., 2016; Bogenschutz et al., 2018). In the
Bogenshutz (Bogenschutz et al., 2015) study on alcohol use disorder, only 3 of the 17 (17.6%)
participants reported mystical-type experiences.
Noorani et al. (2018) later reported on follow-up interviews (on average, 30 months
post psilocybin) with 12 of the pilot study participants and identified potential mechanisms of
change through qualitative interviews. Participants reported a number of changes which
persisted over time, well after drug-effect had worn off. Insights into self-identification, reasons
for smoking, increased feelings of interconnectedness, awe and curiosity were sustained over
time. Participants also reported increased altruism, prosocial behavior and aesthetic
appreciation, while identifying preparatory counselling as a key variable to treatment success
(Noorani et al., 2018). CBT was provided for 15 weeks within this trial in addition to psilocybin.
The Bogenschutz (2015) trial for alcoholism combined pre and post Motivational
Enhancement Therapy (MET) with one or two PSI sessions in a small sample of ten subjects.
Self-reported drinking days and heavy drinking days were reduced by more than half from
baseline measures. Qualitative content analysis notes made by therapists during debriefing
highlight the variables associated with treatment outcome, including transcendent experiences,
ego-dissolution, enhanced motivation, commitment to change, and changes in relationship to
alcohol (Nielson et al., 2018). Bogenschutz reported preliminary outcomes (n=3/180) from a
new larger, randomized double blind parallel design clinical trial of PSI for Alcohol Use disorder,
reporting decreased craving and reductions in alcohol-associated problems, anxiety and
depression among participants (Bogenschutz et al., 2018). This trial, still underway, provides

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three months of Cognitive Behavioural Therapy (CBT) plus MET therapies, and has longer follow
up periods of up to 104 weeks.
5.1.6 Results for Depression
The first small-scale feasibility trial on psilocybin for depression was an open label,
single-arm pilot study reported by Carhart-Harris et al. (2016). In this open-label trial with no
control group testing feasibility of this new modality, 12 patients (equally female to male), all
with moderate-to-severe treatment resistant unipolar depression, each received two doses of
psilocybin (10mg and 25mg) 7 days apart.
In a possibly confounding manner, psychological support was provided before, during
and after each dosing session. Depressive symptoms were assessed from 1 week to 3 months
post-treatment using the Quick Inventory of Depressive Symptoms (QIDS) as the primary
efficacy measurement. Feasibility was measured by patient-reported intensity of effect.
Psilocybin was well tolerated by all patients, and no serious adverse events were observed.
Adverse reactions documented include transient anxiety during drug onset (n=12), transient
confusion (n=9), mild nausea (n=4) and transient headaches (n=4). Psilocybin’s acute effects
were observable after 30-60 minutes of dosing, peaked at 2-3 hours and were negligible by 6
hours after dosing.
Depressive symptoms were markedly reduced at 1 week and 3 months after the high-
dose treatment session. The response rate was 67% (n=8) at 1 week after treatment (HAM-D
and BDI), with seven of these eight patients also meeting criteria for remission. 58% (n=7) of

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the trial subjects maintained their response for 3 months, and 42% (n=5) remained in
remission, suggesting sustained and persisting effects. Marked and sustained improvements in
both anxiety and anhedonia were also observed. Data suggested further research is warranted.
This trial was relatively small, demonstrating possible expectancy bias with significant
suggestibility noted.
It is unknown how the preparatory session (4 hours pre-treatment) provided by study
psychiatrists may have affected outcomes. The role of the setting is also noted, as study
subjects reclined in a comfortable position for the psilocybin dosing sessions, listening to a
curated playlist of music with high-quality sound and earphones, accompanied at all times by
two psychiatrists. Therapists were non-directive but could provide support and checked in with
patients at pre-set intervals. Debriefing (integration) was provided at one-week follow-up.
This study provided preliminary support for the safety, feasibility, and efficacy of
psilocybin for treatment-resistant depression and laid the groundwork to subsequent
randomized controlled trials. The authors concluded that, with appropriate safeguards and a
supportive setting, psilocybin can be safely administered to this patient group.
Carhart-Harris would later provide updated and extended data outcomes with six-
month follow-up on 20 (6 female) patients with Treatment-resistant Depression treated with
psilocybin (Carhart-Harris et al., 2018). An extension of the previously noted trial, this was an
open-label feasibility trial involving two oral doses (10mg and 25mg) administered seven days
apart. Primary outcome was change in severity of self-reported depressive symptoms (Quick
Inventory of Depressive Symptoms, QIDS-SR16) at 1-3 and 5 weeks, as well as 3- and 6-months
post-treatment. Five weeks was considered the primary endpoint. Secondary measures

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included the Beck Depression Index, STAI (anxiety) ratings, SHAPS (anhedonia), HAM-D
(depression) and GAF (global functioning).
The main trial inclusion criteria were unipolar major depression of at least moderate
severity with no improvement despite at least two courses of different antidepressant
medications for a 6-week minimum within the current depressive episode. Exclusion criteria
included: current or previously diagnosed psychotic disorder or an immediate family member
with a diagnosed psychotic disorder. Preparation via psychological support, acute support
during session, and post-session integration support were all provided.
A rapid and sustained response above what would be expected from placebo was
observed in many patients, and most notably all 19 patients who completed the trial showed
some reductions in the primary outcomes at 1-week post treatment, with (nominally) maximal
effects demonstrated at five weeks. Safety was again maintained, and a considerable portion of
the group demonstrated benefit on a persisting basis.
All 19 trial completers showed reductions in depressive symptoms at 1-week post-
treatment and (nominally) maximal effects were demonstrated at 5 weeks. Suicidality scores
were significantly reduced 1- and 2-weeks post-treatment. Consistent with the earlier report on
the initial 12 patients from this trial (Carhart-Harris et al. 2016), no severe adverse experiences
were documented, and the treatment was generally well-tolerated. The most common adverse
effects were transient anxiety lasting for minutes (n = 15) and headaches lasting for no more
than one-two days (n = 8). Five patents reported transient nausea and three reported transient
paranoia.

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Conclusions on efficacy are limited by the absence of a control group, the open-label
design, the possibly confounding role of psychological support provided and the lack of
diversity in the trial cohort. Results suggest proof-of-principle with a caveat that control of
context and preparation are critical to treatment outcomes. Further, the authors suggest an
additional exclusion criterion for future psilocybin trials to include psychiatric conditions
incompatible with establishment of therapeutic rapport and/or safe exposure to psilocybin,
such as suspected borderline personality disorder.
After this early proof-of-principle trial established safety and tolerability and highlighted
the relatively quick onset of antidepressant effects due to treatment with psilocybin, Carhart-
Harris would next trial psilocybin in direct comparison to treatment with escitalopram (Carhart-
Harris et al., 2021).In this six-week, phase 2, double-blind, randomized, controlled trial involving
patients with long-standing, moderate-to-severe major depressive disorder, psilocybin was
compared with the selective-serotonin reuptake inhibitor escitalopram over a 6-week period.
Patients received either two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks
of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart
plus 6 weeks of daily oral escitalopram (escitalopram group), and all patients received
psychological support. The primary outcome measured was change from baseline in the score
on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) along
with 16 secondary outcomes.
A total of 59 (average age of 41, 35% female) patients were enrolled in the study; 30
were assigned to the psilocybin group and 29 to the escitalopram group. Trial results did not
demonstrate significant difference in antidepressant effects between psilocybin and

123
escitalopram in a selected group of patients. Mean change from baseline in QIDS-SR-16 at week
6 showed no statistical difference between trial groups.
Secondary outcomes generally favoured psilocybin, but the analyses of secondary
outcomes lack confidence and correction for multiple comparisons. QIDS-SR-16 response at 6
weeks occurred in 21 patients (70%) in the psilocybin group and in 14 patients (48%) in the
escitalopram group (difference, 22 percentage points; 95% CI) and QIDS-SR-16 remission at
week 6 occurred in 17 patients (57%) in the psilocybin group and in 8 patients (28%) in the
escitalopram group (difference, 28.1 percentage points; 95% CI). No conclusions can be drawn
from this data.
No serious adverse events were observed in either trial group, and psilocybin-related
adverse experiences typically occurred within 24 hours after dosing. Headache and nausea
were most common. No changes in visual perceptual phenomenon, psychotic-symptoms or
dependency-related behavior were found at six-week follow up. In both trial groups, depression
scores at week six were lower than baseline scores. However, the absence of a placebo group
limits the ability to assign conclusions about the effect of either trial agent. Incidence of adverse
events was comparable between the trial groups, though the percentages of patients who
experienced anxiety, dry mouth, sexual dysfunction, or reduced emotional responsiveness were
higher in the escitalopram group than with psilocybin.
One clear limitation of this trial is the brief duration of escitalopram treatment provided,
given its delayed onset of antidepressant effects. Further, the trial lacked diversity in its patient
population, limiting the generalizability of results. The confounding factors of psychological
support and suggestibility remain as with previous trials. Considering the difficulty in blinding to

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the effect of psilocybin, expectancy bias is also noted. Escitalopram and psilocybin-assisted
therapy are also usually delivered in quite different modalities; combining the two in this trial
design may account for some of its more interesting outcomes. The trial may not have been
significantly powered to properly detect differences in outcome.
As the trial group was characterized by mild-to-moderate depression, extension to more
severe or to treatment-resistant depression populations is limited. Study authors also noted
that their selection of primary outcome measurement characterized the somewhat surprising
outcomes to this trial. Larger and longer trials are required to investigate the relative advantage
of psilocybin over standard antidepressant treatments. These trial results also raise the
question of outcome measures, and by what criteria we advance novel treatments for
depression. Studies to date have been driven by the measurements of negative
symptomatology and not overall well-being or positive affect.
Most recently, Davis (2021) reported results from a randomized, waiting list–controlled
clinical trial conducted with adults from 21 to 75 years old (mean age 39.2) with MDD, not
currently using antidepressant medications, and without histories of psychotic disorder, serious
suicide attempt, or hospitalization. 27 (16 women) participants were randomized into
immediate treatment (15) or to the delayed treatment group (12). Primary outcomes were
measured for 4 weeks; 2 doses of psilocybin were given, along with 11 hours of psychological
support. Measurements of HAM-D were taken at baseline and weeks 5 and 8 as the main
outcome measurement; participants also completed the QIDS-SR as secondary outcome. Effect
sizes were found to be large at weeks 5 and 8: 71% had a clinically significant response at week
4, compared to 58% at week 1 and 54% at week 4.

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The Davis (2021) trial suggests that psilocybin-assisted therapy results in substantial,
rapid, and enduring antidepressant effects among people with MDD. Of particular note is that
while the rapid antidepressant effects are similarly reported for ketamine, psilocybin
demonstrated no addiction risk, few adverse effects, and greater durability or persistence of
therapeutic effect than has been demonstrated for ketamine. The authors report findings 2.5
times greater than the effect sizes found in psychotherapy and greater than 4 times the effect
sizes found in contemporary psycho-pharmacological depression treatment studies.
Psilocybin for depression requires larger multi-site randomized control trials of
significant size and power and with a more diverse, less self-selecting population in order to
establish effectiveness. Trials at the current stage cannot be conclusive, the results of this trial
are not surprising, but still contribute to the planning and development of more robust Phase 3
trials to establish effectiveness outside of an experimental setting. These still early Phase 1 and
more current Phase 2 clinical trials do suggest that psilocybin, when administered with
psychological support and in a supportive setting, has an antidepressant effect among
individuals with major depressive disorder. These trials also seem to indicate that drug delivery
combined with psychological supports is a synergistic modality with beneficial outcomes. Phase
3 trials are currently underway in the U.K. and U.S.
5.1.7 Results for Anxiety-related Disorders
Serotonin (5-HT) is thought to play an important role in the pathology of obsessive-
compulsive disorder (Pittenger et al., 2019). The regulation of 5-HT receptors is effective in

126
lessening the symptoms of Obsessive-Compulsive Disorder (Delgado & Moreno, 1998); drugs
which effect the inhibition of serotonin reuptake reduce obsessive-compulsive symptoms
significantly better than other medication (Goodman et al., 1990). Psilocybin has established
anxiolytic effects (Griffiths et al., 2016; Ross et al. 2016), though only one trial has occurred for
anxiety-related disorders not related to serious illness. In an open-label study of psilocybin for
OCD, participants (n=9) were administered four doses ranging from low to high, with each dose
separated by one week (Moreno et al., 2006). All participants reported a marked reduction in
OCD symptoms after at least one dosing session, with improvements generally lasting more
than 24 hours.
In 2011, a small pilot study conducted by Grob and colleagues (2011) investigated the
effects of a moderate dose of oral psilocybin (0.2 mg/kg) in 12 participants with advanced-stage
cancer who were experiencing cancer-related anxiety significant enough to meet DSM criteria
for anxiety-related disorder. At 2-weeks follow-up, psilocybin relative to (niacin) placebo
demonstrated decreased depression severity as measured by the Beck Depression Inventory, as
well as reduced anxiety severity as measured by the State-Trait Anxiety Inventory. Outcomes of
the trial included clinically significant reductions in anxiety symptoms at 3 months and reduced
depressive symptoms at 6 months.
Two larger studies were later completed using higher doses of psilocybin (Griffiths et
al., 2016; Ross et al., 2016). In the Griffith (2016) phase two clinical trial (2016,) 51 patients with
a life-threatening cancer diagnosis who met criteria for at least one DSM-IV mood- or anxiety-
related disorder in relation to their cancer had two PSI drug administration sessions: one in
which a high oral dose of psilocybin (22 or 30 mg/70 kg) was administered; and one in which a

127
very low dose of psilocybin (1 or 3 mg/70 kg) was administered as a comparator condition. The
high psilocybin dose, compared to the very low dose, significantly improved a variety of
outcomes after five weeks, and effects remained strong at six-month follow-up when
approximately 60% of participants demonstrated scores consistent with remission; experiences
of mysticism were significantly associated with positive outcomes.
The Ross et. al (2016) trial was conducted with 29 patients who had a life-threatening
cancer diagnosis who also met the DSM criteria for an anxiety disorder. Participants had two
drug administration sessions: one a high dose of psilocybin (0.3 mg/kg), the other niacin as a
separate comparator control in a randomized order. Consistent with the results of the larger
Griffiths (2016) high-dose study, high doses of psilocybin resulted in significant improvements
on a variety of outcome measures regardless of order of treatment. Six months after PSI,
anxiety and depression symptoms remained significantly and substantially reduced compared
to baseline, with again an approximately 60% remission rate for key anxiety and depression
outcome measures. Ratings of mystical experience were demonstrated to mediate the relation
between PSI and the documented therapeutic effects on anxiety and depression.
In follow-up interviews with five participants, Belser (Belser et al., 2017) identified
psychological processes associated with PSI-AT including improved relationships, forgiveness of
others, a feeling of becoming unstuck, and more likely to engage in healthy behaviours. A
second qualitative study of these same study participants occurred one- year post-treatment
(Swift et al., 2017) concluded that the experiential and immersive qualities of PSI-AT led to
enduring psychological and behavioural changes with participants reporting increased personal
meaning and improved mindsets.

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5.1.8. Secondary Publications
Of the fourty-nine publications included in this scoping review, thirty-seven are
identified as secondary publications, affiliated with one of the twelve core clinical trials, but
publishing additional, secondary, or follow-up results. Four neuroimaging studies are included
among the thirty-seven articles. Spreadsheet extraction domains included: author, title, year,
type of publication, core trial affiliation, indication, cohort size and descriptors, program model
used, trial design, limitations, outcomes measured, research question and key results.
A distribution analysis of the secondary publications shows the greatest number of
secondary publications coming from the Carhart-Harris, 2016 trial, which had twice (n=14) the
number of publications compared to the next most prolific, the Ross, 2016 trial (n=7), and
accounted for 37.8% of all secondary trial publications included in this review. This may be a
proxy measure of demonstrating degree of influence in the scientific literature.
5.1.8.1 Qualitative Studies, Further Clinical Outcomes, and Therapeutic Processes
A review of the thirty-seven secondary publications found psilocybin-assisted therapy
(PSI-AT) to be associated with experiences of vivid psychological insight (Belser et al., 2017;
Bogenschutz et al., 2018; Erritzoe et al., 2018; Garcia-Romeu et al., 2015; Malone et al., 2018;
Noorani et al., 2018; Swift et al., 2017; Sevanick et al., 2014), revived and improved emotional
responsiveness (Belser et al., 2017; Carhart-Harris, 2016; L.J. Mertens et al., 2019; Mertens et
al., 2020; Roseman et al., 2018; Stroud et al., 2018, Shukurogolou, 2019), feelings of movement
from separation and disconnection to wholeness and connectedness (Belser et al., 2017;
Nielson et al., 2018; Noorani et al., 2018; Swift et al., 2017; Watts et al., 2017), changes in self-

129
perception (Bogenschutz et al., 2018; Erritzoe et al., 2018; Nielson et al., 2018; Sevanick et al.,
2014 Watts et al., 2017) and powerful emotions (Bogenschutz et al., 2018; Bogenschutz &
Johnson, 2016; Carhart-Harris et al., 2017; Garcia-Romeu et al., 2015).
PSI-AT is associated with motivation to change (Amegdazie et al., 2018; Bogenschutz et
al., 2018; Nielson et al., 2018; Noorani et al., 2018), increased self-compassion (Agin-Liebes et
al., 2020; Bogenschutz et al., 2018; Malone et al., 2018), increased cognitive flexibility (Barrett
et al., 2019), increased acceptance (Agin-Liebes et al., 2020; Watts et al., 2017), and changes to
personality (Erritzoe et al., 2018; Sevanick et al., 2014), openness (Erritzoe et al., 2018; Watts
et al., 2017), extraversion (Erritzoe et al., 2018), conscientiousness (Erritzoe et al., 2018), and
nature-relatedness (Lyons & Carhart-Harris, 2018a).
PSI-AT is associated with rapid and sustained reductions in depression (Agin-Liebes et
al., 2020; Barrett, 2019; Carhart-Harris et al., 2018; Carhart-Harris et al., 2017; Davis, Barrett, &
Griffiths, 2020; Lyons & Carhart-Harris, 2018b; Roseman et al., 2018) as well as decreased
pessimism, rumination and anhedonia (Carhart-Harris, 2015; Carhart-Harris, 2016; Lyons &
Carhart-Harris, 2018b, 2018a; Mertens et al., 2019; Mertens et al., 2020), reduced anxiety
among individuals with depression (Carhart-Harris et al., 2018), reduced demoralization and
reduced death anxiety (Agin-Liebes et al., 2020; Benville et al., 2021; Ross et al., 2021), reduced
compulsivity (Moreno et al., 2003) reduced suicidal ideation (Benville et al., 2021, Ross et al.,
2021), reduced smoking behaviours (Garcia-Romeu et al., 2014; Garcia-Romeu et al., 2015;
Johnson et al., 2017; Johnson & Griffiths, 2017; Noorani et al., 2018), reductions in alcohol
drinking (Agin-Liebes et al., 2020; Amegdazie, 2018), decreased attachment anxiety (Stauffer et
al., 2021) and reduced fear response to negative stimuli (Barrett, 2019; Carhart-Harris, 2017).

130
PSI-AT has been found to have positive sustained effect upon long-term follow-up when
measured at three months (Carhart-Harris et al., 2016), six months (Carhart-Harris et al., 2018)
(Garcia-Romeu et al., 2015), six and-a-half months (Ross et al., 2021), twelve months (Johnson
et al., 2017) and to four years (Agin-Liebes et al., 2020). Participating in PSI-AT has been rated
by subjects as one of the top 5 experiences of their lives (Griffiths et al., 2016; Johnson et al.,
2014) but is also associated with a great range, variety and individuation of subjective
experiences (Belser et al., 2017; Malone et al., 2018) including experiences of dysphoria (Belser
et al., 2017; Nielsen et al., 2018) and difficulty integrating the experience (Belser et al., 2017).
Experiences of mysticism are both considered essential (Garcia-Romeu et al., 2014) and not
necessary (Bogenschutz et al., 2016; Bogenschutz et al., 2018) to positive outcomes. Powerful
experiences under psilocybin are associated with subsequent positive mood states
(Bogenschutz et al., 2015; Carhart-Harris et al., 2017; Garcia-Romeu et al., 2015). Music is
considered an important modulator of the psilocybin experience (Belser et al., 2017; Kaelen et
al., 2018) with greater hedonic response to music documented after treatment with PSI
(Shukurogolou, 2019). A good rapport with study staff was associated with positive trial
experiences (Garcia-Romeau et al., 2015; (Noorani et al., 2018).
5.1.8.2 Psilocybin Clinical Trial Neuroimaging Studies
Seven publications reported results of neuroimaging conducted within one of the twelve
core clinical trials. All were conducted on study subjects with treatment-resistant depression.
Carhart-Harris reports (Carhart-Harris et al, 2019) that psilocybin provokes profound changes in
consciousness due to decreased integrity of brain networks and a decrease in between network

131
segregation, resulting in an entropic brain state.
Whole-brain analyses revealed post-treatment decreases in cerebral blood flow in the
temporal cortex, including the amygdala, and increased RSFC was observed within the default-
mode network (DMN) post-treatment (Carhart-Harris et., 2017). Additional imaging also
documented changes in amygdala and prefrontal functional connectivity during emotional
processing after psilocybin for treatment-resistant depression with decreased ventral medial
prefrontal context-right amygdala functional connectivity during face processing post- (versus
pre-) treatment; independent whole-brain analyses also revealed a post-treatment increase in
functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-
parietal cortices during face processing tasks (Mertens et al., 2019; Mertens et al., 2020).
At one-week post-treatment psilocybin with psychological support was associated with
increased amygdala responses to emotional stimuli, an opposite effect to previous findings with
selective serotonin reuptake inhibitor drugs (SSRIs) (Roseman et al., 2018). Decreased nucleus
accumbens functional connectivity with the default-mode network (DMN) was observed
following psilocybin treatment during music listening, indicating enhanced hedonic response
after treatment with PSI (Shukuroglou et al., 2019 ). One week after PSI-AT, investigations
revealed increased glutamate in the right hippocampus and decreased glutamate in the
anterior cingulate cortex, as well as reduced amygdala response to negative affective stimuli
one week after two PSI sessions for treatment-resistant depression (Barret et al., 2019). These
studies, conducted with PSI clinical trial participants indicate underlying neural correlates,
network connectivity and changes in brain function, helping to identify underlying mechanisms
of action for PSI within the context of therapy for depression.

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5.2. Results: Behavioural Investigations of Psilocybin in Non-human Animals (BIPA)
Seventy-seven publications met eligibility criteria and are included in this scoping
review. From 4124 records identified through database searching, 2646 duplicate records were
removed and two additional hand-sorted studies meeting eligibility criteria were added. From
1480 records screened, 1220 records were excluded for not meeting eligibility criteria
established in our a priori protocol (see Appendix C.1). 260 articles were subject to full-text
review, and finally 77 studies were included in this scoping review (Figure 5.4).
Figure 5.4: Prisma Flow Diagram, BIPA Scoping Review

133
5.2.1 Study Characteristics
Publications are primarily scientific journal articles (n = 63), but given the wide purview
of scoping reviews, some conference abstracts are also included (n = 14) (Table 5.5), including
abstracts which may then have been followed by full publications on the same research. All
included studies investigate the behavioural effects of psilocybin in non-human animals, and all
investigations were with non-human mammals. This review captures research published over
six decades between 1962 and 2021. Fourty-six studies were published in or before 1987,
thirty-one studies were published in 2005 or later, and interestingly, no study publications were
found for the time period 1988 to 2004 (Figure 5.5). The decade with the most publications was
the 1970s. Institutional affiliations of Primary Investigators span 14 different countries, with
more than half of the studies based in the United States (n = 43) (Table 5.5).
Table 5.5: Characteristics of Included Studies: BIPA
Publication Information
Number (n
= 77)
Percentage
Publication Type
Journal articles
Conference abstracts
63
14
81.8%
18.2%
Publication Year by Decade
1961 – 1970
1971 – 1980
1981 – 1990
1991 – 2000
2001 – 2010
2011 – 2020
2021
11
25
10
-
3
22
6
14.3%
32.5%
13.0%
-
3.9%
28.6%
7.8%
Country of Author Affiliation*
United States
United Kingdom
Czech Republic
43
11
7
55.8%
14.3%
9.1%

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Brazil
Canada
Denmark
Japan
Poland
Sweden
Other**
3
3
3
3
2
2
5
3.9%
3.9%
3.9%
3.9%
2.6%
2.6%
6.5%
Species*
Non-human primates
Pigs
Dogs
Cats
Rabbits
Guinea pigs
Rats
Mice
9
1
2
5
2
2
41
19
11.7%
1.3%
2.6%
6.5%
2.6%
2.6%
53.2%
24.7%
PSI Treatment Formulation*
Psilocin
Psilocybin
Whole mushroom extract
33
51
4
42.9%
66.2%
5.2%
Sex of Research Animals
Male
Female
Both
Not reported
40
13
11
13
52.0%
16.9%
14.3%
16.9%
* Values represent the number of studies that include the country affiliation, animal species, or treatment compound, with some studies
including multiple affiliations, species, or treatments. Therefore, total number is greater than 77 and total percentage is greater than 100%.
** Other reported countries of author affiliation, including those of co-authors, are France, Iran, Israel, Italy, and Senegal.
Figure 5.5: Year of Publication of Included Studies

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5.2.2 Research Animals
All studies investigate the effect of psilocybin (Psi) treatment on behaviour in
mammalian species. The preponderance of studies investigate behavioural outcomes in
rodents, specifically rats (n = 41) or mice (n = 19) and four studies report behavioural outcomes
in both rats and mice (Bourn et al., 1978; Bourn et al., 1979; Kostowski et al., 1972; Thompson,
2019) (see Table 5.5). Fewer studies use non-human primates (NHPs; n = 9) or other larger
mammals, like cats (n = 5), dogs (n = 2), or pigs (n = 1). Rabbits (n = 2) and guinea pigs (n = 2) are
also studied. Studies published in 2005 or later almost exclusively investigate the effects of Psi
treatment in rats or mice, with the exception of only one experiment with pigs (Donovan et al.,
2020).
More than half of the included studies investigate the effects of Psi treatment in rats
(n=41, or 53.2%). Various strains are used, including Sprague-Dawley (n = 14), Wistar (n = 12),
Wistar-Kyoto (WKY) (n = 3), Long-Evans (n = 3), Flinders Sensitive (FSL) and Flinders Resistant
Lines (FRL) (n = 1). Despite differential outcomes between rat strain performance, several
studies (n = 8) failed to report strain. We report which strain was investigated when available.
Reporting of animal housing conditions provides context for the interpretation of
behavioural outcomes reported and is an indication of study quality. Animal Research:
Reporting of In Vivo Experiments (ARRIVE) guidelines (2010) outline essential information
preferentially included in animal research publications to provide context for the interpretation
of experimental outcomes and help determine reliability of study findings (du Sert et al., 2020).
Evaluating all studies for their inclusion of essential ARRIVE information was beyond the scope
of this review and most were published prior to the ARRIVE guidelines; however, study

136
inclusion of some relevant parameters (such as reporting of animal housing conditions) is noted
by us as a proxy measure of methodological quality by modern standards. Behavioural
responses of research animals are sensitive to differing environmental factors and to the
housing conditions of the study. We note where studies provide information about housing
condition, length of animal training and reports of biological sex as well as the developmental
age of animal. All are variables known to effect outcomes.
Only 43 of the included studies (55.8%) report to any degree on housing conditions,
whether describing the primary housing enclosure, food or light schedule, or whether animals
are housed individually or together in groups. Conference abstracts are also included in this
review but typically do not report all study details. Two of fourteen (14.3%) conference
abstracts report housing conditions, compared to fourty-one of sixty-three journal articles
(65.1%). The reporting of housing conditions in journal articles varies over time (see Table 5.6).
53.5% (23 / 43) of journal articles published from 1962 to 1987 report housing conditions,
compared to 90.0% (18 / 20) of journal articles published from 2005 to 2021, reflecting a trend
towards improved study quality over time.
Table 5.6: Housing Conditions Reported in Journal Articles, by Year of Publication
Date Range
Reported Housing
Conditions
No Information
1961 – 1970
1971 – 1980
1981 – 1990
1991 – 2000
2001 – 2010
2011 – 2020
2021
4 (36.4%)
14 (58.3%)
5 (62.5%)
-
2 (100%)
10 (83.3%)
6 (100%)
7 (63.6%)
10 (41.7%)
3 (37.5%)
-
0 (0%)
2 (16.7%)
0 (0%)

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Total
41 (65.1%)
22 (34.9%)
The number of included journal articles that report housing conditions or provide no information, reported with
percentage per years of publication.
Sixty studies (77.9%) report the number of non-human animals included in experiments, leaving
seventeen studies (22.1%) failing to report study sample size. Of the publications that do not
report study sample size, eight are peer-reviewed academic journal articles and nine are
conference abstract presentations. The number of non-human animals included in each study
varies from as few as two rats receiving Psi treatment (Cameron & Appel, 1976) to groups of
twenty per treatment condition (Collins et al., 1966).
5.2.3 Trial Characteristics and Experiment Design
All studies investigate behavioural outcomes following drug administration: fifty-one
studies (66.2%) use psilocybin, thirty studies (42.9%) administer it’s active metabolite psilocin
(42.9%), and four studies (5.2%) administer extracts from whole mushrooms containing both
psilocybin and psilocin as well as other active alkaloids which together may create a synergistic
entourage effect (Table 5.5). Eight studies investigate the effects of both psilocin and
psilocybin, one study reports the effects of both psilocin and whole mushroom extracts (WME)
(Zhuk et al., 2015), and one study investigates behavioural outcomes following administration
of psilocin, psilocybin and WME (Matsushima et al., 2009). Four studies investigate the alkaloid
composition, toxicity, and behavioural effects of full mushroom extracts. Extracts are prepared
from Psilocybe cubensis (Kirsten & Bernardi, 2010; Mahmoudi et al., 2018), Psilocybe argentipes
(Matsushima et al., 2009), Psilocybe semilanceata and Pholiotina cyanopus species (Zhuk et al.,
2005).

138
The most common route of administration for Psi treatment is intraperitoneal injection
(n = 49) (see Table 5.7). Intraperitoneal injection (IP) is the most common method of
administration for rats (n = 26), mice (n = 15), and cats (n = 4). Subcutaneous injections (SC) are
also sometimes used in rats (n = 9). Intravenous injections (IV) were used in non-human
primates (n = 3), rabbits (n = 3), and pigs (n = 1). Two studies administer Psi orally to mice
(Collins et al., 1966; Matsushima et al., 2009). Two studies administer Psi via intramuscular
injection (IM) to non-human primates (Schlemmer & Davis, 1986; Sink et al., 1983) and in one
study, psilocybin was administered intraventricularly to macaque monkeys (Wada, 1962).
Table 5.7: Characteristics of Psilocybin Treatment
Dosing Information
Number (n
= 77)
Percentage
Route of Administration*
Intraperitoneal injection
Subcutaneous injection
Intravenous injection
Intramuscular injection
Oral administration
Intraventricular injection
Not reported
49
11
7
2
2
1
7
63.6%
14.3%
9.1%
2.6%
2.6%
1.3%
9.1%
Number of Doses
Only 1
More than 1
19
58
24.7%
75.3%
* Values represent the number of studies that use the type of administration method, with some studies including
multiple methods (thus cumulative percentage is greater than 100%).
Experimental doses used range from 0.01 to greater than 100 mg/kg psilocybin for a
single administration. Most included studies (58 / 77; 75.3%) investigate the effects of more
than one treatment dose (Table 5.7). Many studies report dose-dependent as well as time-

139
dependent effects of Psi treatment; both effects appear to be significant and are separately
reported below. Despite the range of treatment doses investigated, most studies include doses
that are equal to or less than 1.0 mg/kg psilocybin (n = 56). Some studies (n=17) only include
doses greater than 1 mg/kg. The translational value of these doses may be less clear as they far
exceed doses tested in clinical or research use in humans. However, administration of these
exceedingly high doses -- 100 mg/kg psilocybin (Horita & Weber, 1962) and 120 mg/kg
psilocybin (Schneider, 1968) – occurs with no reported biological adverse effects, providing
evidence toward the strong biological safety profile of Psi.
Psilocybin is rapidly converted to psilocin in vivo (Horita & Weber, 1962). Equimolar
doses of psilocin and psilocybin are believed to yield comparable behavioural effects (Davis &
Walters, 1977). The relative potency of psilocin to psilocybin is estimated to be 1:1.4 based on
the ratio of their molecular weights: 0.71 mg/kg psilocin is equivalent to 1 mg/kg psilocybin and
believed to result in similar behavioural effects (Wolbach et al., 1962). The relative potency of
whole mushroom extracts is unclear, as psilocybin-containing mushrooms typically contain a
variety of other potentially bioactive alkaloids in addition to psilocybin, and psilocin in varying
concentrations resulting from strain as well as growing and drying conditions (Tsujikawa et al.,
2003; Wieczorek et al., 2015). When reporting behavioural outcomes in this review, studies
using psilocybin and psilocin are compared by converting the treatment dose of one compound
to its equivalent dose in the other.
Studies widely vary in methodology for investigation of drug effect on behavioural
outcome, in the number or frequency of dosing, and/or in the timing between treatment
administration and behavioural measures. Some studies investigate the acute effects of a single

140
Psi treatment and assess behaviour within the minutes-to-hours following dose administration,
time-points to the understanding of the various phases of acute drug effect. Other studies
investigate the persisting effects of single or repeated psilocybin doses, with behavioural
assessments occurring weeks after drug administration. Some studies administered psilocybin
repeatedly on dosing regimens reported as “microdosing”.
Some studies investigate the effects of multiple compounds, comparing the effects of
psilocybin with other serotonergic hallucinogens or stimulants; with these we report only the
behavioural outcomes specific to psilocybin. In some studies, the effects of multiple compounds
were tested in a single subject, with reported wash-out periods or intervals between drug
administration ranging from 3 days (e.g., Harris et al., 1981) to 2 weeks (e.g., Roberts & Bradley,
1967). Since cross-tolerance has been demonstrated across various serotonergic psychedelics,
in some instances there may be interference in behavioural measures when study drugs are
administered within shorter wash-out periods.
Of the studies which investigate acute behavioural effects, there is large variability
across studies in the time between Psi administration and behavioural testing. Behavioural
testing may begin immediately following injection or up to 90 minutes following administration
(Kostowski et al., 1972). The duration of behavioural measurement varies as well; some assays
have a four-minute testing period (as with FST, TST) while many measure behaviours across a
longer time-course of acute drug behavioural effect.
Studies used a variety of experimental controls. Some employed separate control
groups while others used the same animal as its own control. This is of note due to evidence of
persisting effects for up to one-month and the need for sufficient wash-out periods between

141
doses. The behavioural effects are documented along a time course of drug effect, but it is not
entirely clear when an animal has entirely shed the downstream secondary effects of drug
metabolism within this period lasting perhaps weeks. In experiments using the same animal as
their own control, the time between active and sham drug administration varied. Careful
consideration should be given to interpretation of these experiments. Further, the majority of
studies investigated only one test of behavior. In assessing trial quality, the assessment of
multiple behavioural reflects positively; multiple assessments provide more and richer
information, possibly allowing the ability to compare, contrast information, and to better
identify potential underlying mechanisms of action while giving a better behavioural profile of
the animal
9
.
5.2.4 Sex as a Biological Variable
Fourty studies (52%) included in the scope of investigate the effects of psilocybin
treatment on behaviour in only males, while 24 studies include females (31.2%) including
studies with only females and studies with both sexes (Table 5.5). Thirteen studies (16.5%) fail
to report the sex of research animals included in experimentation. Of the 11 studies that
investigate both sexes, five studies did not report behavioural outcomes separately per sex
(Martin et al., 1978; Roberts & Bradley, 1967; Steiner & Sulman, 1963; Trulson et al., 1984;
Vaupel et al., 1979) and one did not incorporate sex as a factor in the analysis of behavioural
outcomes (Everitt & Fuxe, 1977). Four studies (5.2%) incorporate sex as a variable in study
design and analysis, and of those, two studies report sex-specific differences in behavioural
9
For this insight I am grateful to Dr. Eric Dumont.

142
outcomes. Halberstadt et al. (2011) report no significant effect of sex on head-twitch response
in mice following treatment with psilocin and report no significant interaction between sex and
other variables or behavioural outcomes, collapsing data across sexes (2011).
Conversely, mice treated with whole mushroom extract had significant differences
between sexes in wet-dog shakes, gnawing behaviour and locomotion (Kirsten & Bernardi,
2010). Tyls et al. report a significant effect of sex on locomotor activity, rearing behaviour, and
wet-dog shakes; female rats appear less affected by psilocybin than male rats with the
exception of wet-dog shake behaviours (Tyls, 2016). Shao (2021) reports more pronounced
increased spine formation rate and density among female rats compared to males as a result of
Psi but does not separately report behavioural outcomes (2021). Kirsten & Bernardi (2010)
report sex differences in self-grooming behaviour after psiloycbin, with increases in self-
grooming noted among females after dosing and reduced self-grooming among males
compared to controls. One study separates female rats into separate pre-oestrus, oestrus and
metoestrus, and dioestrus groups (Tyls et al., 2016).
5.2.5 Behavioural Research Domains
We report behavioural outcomes under the six domain constructs of the Research
Domain Criteria (RDoC) framework. Within each domain, experimental outcomes are reported
by the test administered. Where trial numbers justify, we further grouped and summarized
results by sub-construct or behavioural assay. Sensorimotor Systems is the RDoC domain most
studied when measured by the number of distinct behavioural tests reported (n=47), followed
by Negative Valence (n=34), Arousal and Regulatory Systems (n=26), Positive Valence (n=14),

143
Social Processes (n=6) and Cognitive Systems (n=3). One-hundred and thirty distinct
behavioural investigations into the effects of psilocybin in non-human animals are captured in
these seventy-seven studies , and we identified fifty different behavioural paradigms used in
this body of research.
Table 5.8.: Animal Behavioural Paradigms by RDoC Framework Domains
Overview
Included Studies
1. Negative Valence Systems
N=34
Fear Conditioning
N = 11
Low doses of Psi decrease response
latency, perhaps indicating
heightened sensitivity.
Doses of 5 mg/kg demonstrate
dynamic time-dependent, biphasic
effects with a corresponding
decrease then increase in
avoidance proficiency.
Bourn et al., 1978
Bourn et al., 1979
Calil, 1978
Catlow et al., 2013
Collins et al., 1966
Davis & Hatoum, 1987
Hagsater et al., 2021
Marquis et al., 1973
Rambousek et al., 2014
Shao et al., 2021
Sugrue, 1969
Forced Swim Test (FST)
N = 6
Three studies show no effect of Psi
on FST behavior, and three studies.
report decreased time spent
immobile following treatment
(indicating less despair). Peak
behavioural effect noted at 35 days
post Psi. Persisting, more than
acute effects, demonstrated. Psi
reverses effects of chronic stress.
Hesselgrave et al., 2021
Hibicke et al., 2019
Hibicke et al., 2020
Jefsen et al., 2019
Mahmoudi et al., 2018
Nichols & Hibicke, 2020
Tail Suspension Test (TST)
N = 1 No effect noted.
Mahmoudi et al., 2018
Defensive Aggression
N = 2
Both studies demonstrate dose-
dependent inhibition of aggressive
behaviour, with strongest effect 30
minutes post Psi administration.
Sbordone et al., 1979
Uyeno, 1967
Elevated Plus Maze (EPM)
N = 3
Increased time in open arms at 2
and at 41 days.
Microdoses elicited a mild
increased entry to and time spent
open arms of maze.
Horsley et al., 2018
Hibicke et al., 2019
Hibicke et al., 2020

144
Open Field Test (OFT)
N = 11
Time, dose, and sex-dependent
effects on behavior.
Decreased locomotion, decreased
time in OF.
Collins et al., 1966
Cunha & Masur, 1978
Hesselgrave et al., 2021
Hibicke et al., 2019
Jefsen et al., 2010
Kirsten & Bernardi, 2010
Mahmoudi et al., 2018
Palenicek et al., 2005
Tyls et al., 2011
Tyls et al., 2014
Tyls et al., 2016
2. Positive Valence Systems
Five-choice task, binge-like
feeding, drug as discriminative
stimulus, drug-induced
conditioned suppression, female
urine sniffing test, intra-cranial
self-stimulation, Y-water maze,
lever preference, marble-burying
task, Morris water maze,
progressive ratio task, serial task,
sucrose preference test, two-
choice swim test
N=14
Psi reduces binge-eating behaviour
at several doses. Psi inhibits
compulsive marble-burying
behaviour throughout in a dose-
dependent manner, with most
effect evident at the medium-high
but not highest dose range. Psi
exerts rapid antianhedonic actions
in chronically stressed mice.
Psilocybin demonstrates a biphasic
dose and time response, with
decreases in behavioural response
evidenced early followed by
subsequent increases in hedonic
behaviours. At lower doses Psi
demonstrates discriminative
properties with fewer grossly
disruptive effects on behaviour
Cameron & Appel, 1976
Castellano, 1978
Harris et al., 1981
Hesselgrave et al., 2021
Hesselgrave et al., 2021b
Higgins et al., 2021
Hurley et al., 2020
Koerner & Appel, 1982
Marquis et al., 1973
Matsushima et al., 2009
Rambousek et al., 2014
Rech et al., 1975
Sakloth et al., 2019
Thompson, 2019
3. Cognitive Systems
Visual discrimination tasks, object
pattern separation
N = 3
Psi treatment dose-dependently
disrupts size discrimination and
visual accuracy. Psi’s persisting
effects rescue chronic stress-
induced visual system
impairments.
Nichols & Hibicke, 2020
Roberts & Bradley, 1967
Uyeno, 1969
4. Systems for Social Processes
Female sexual receptivity, and
social isolation-induced aggression
paradigms
N = 6
Acute decrease (reduced social
grooming, increased distancing) in
affiliative social behaviour in NHPs.
Biphasic, dose-dependent effect on
sexual receptivity among rats, with
lower doses significantly increasing
sexual receptivity and higher doses
having a non-significant effect. Psi
Everitt & Fuxe, 1977
Schlemmer & Davis, 1986
Sink et al., 1983
Uyeno, 1966
Meldrum & Naquet, 1971
Kostowski et al., 1972

145
treatment is consistent in reducing
aggressive behaviour, with greater
inhibition of aggressive behaviour
as a function of increasing dose,
and with greater treatment effect
the longer the pre-testing isolation
period.
5. Arousal and Regulatory Systems
N=26
General Arousal and Physiological
Responses
N = 12
Acute changes in general arousal
are observed, accompanied by
mydriasis, piloerection, elevated
heart rate and respiratory rate, and
decreased appetite.
Guest & Consroe, 1979
Horibe, 1974
Horita & Weber, 1962
Martin et al., 1978
Meldrum & Naquet, 1971
Schlemmer & Davis, 1986
Sink et al., 1983
Steiner & Sulman, 1963
Sugrue, 1969
Vaupel et al., 1979
Wada, 1962
Wilson et al., 1981
Sleep-Wake Behaviour
N = 1
Psi is acutely wake-promoting, at
the expense of REM sleep, with no
persisting changes in sleep-wake
behaviour observed.
Thomas et al., 2020
Locomotor Activity
N=4
Mixed results. Among some
animals and in some tests at lower
doses Psi increased total activity
while reducing in other tests.
Evidence of reduced locomotor
activities at higher doses, and some
stimulation of activity at lower
doses.
Bert et al., 1968
Bourn et al., 1978
Bourn et al., 1979
Collins et al., 1966
Startle Response
N = 2
Dose-dependent effect of Psi on
startle response. Low doses
increase startle amplitude or have
no effect while higher doses
depress startle response
Davis & Walters, 1977
Geyer et al., 1978
Investigatory/ Exploratory
Behaviour
N=7
Geyer et al., 1979
Halberstadt et al., 2011
Jacobs et al., 1977(a)
Jacobs et al., 1977(b)

146
Sakashita et al., 2015
Trulson et al., 1981
Trulson et al., 1984
6. Sensorimotor Systems
N=47
Stereotyped Behaviour
N=27
Stereotyped behaviours such as
head-twitch response are reliably
induced in animals following Psi
treatment, once the dose crosses a
threshold of efficacy, and are
potentially suppressed at higher
doses. Extremely high doses also
induce myoclonus or head rotation
in a dose-dependent manner.
Donovan et al., 1977
Everitt & Fuxe, 1977
Guest & Consroe, 1979
Halberstadt et al., 2011
Hesselgrave et al., 2020
Hesselgrave et al., 2021
Higgins et al., 2021
Jacobs et al., 1976
Jacobs et al., 1977(a)
Jacobs et al., 1977(b)
Jenner et al., 1981
Kiilerich et al., 2019
Kirsten & Bernardi, 2010
Klein et al., 2021
Luscombe et al., 1984
Martin et al., 1978
Meldrum & Naquet, 1971
Sakashita et al., 2015
Schlemmer & Davis, 1986
Schneider, 1968
Shao et al., 2021
Sherwood et al., 2020
Sink et al., 1983
Trulson et al., 1981
Trulson et al., 1984
Tyls et al., 2016
Zhuk et al., 2015
Grooming
N = 10
Biphasic effects, with no reductions
in grooming at lower doses but
disruptions evident at standard
doses and above. Effects on
grooming may be related to the
time-course of the drug effect Sex-
dependent differences are
reported in mice.
Cunha & Masur, 1978
Guest & Consroe, 1979
Higgins et al., 2021
Kiilerich et al., 2019
Kirsten & Bernardi, 2010
Schlemmer & Davis, 1986
Sink et al., 1983
Trulson et al., 1981
Trulson et al., 1984
Tyls et al., 2016
Motor Coordination
N = 5
Dose-dependent effect on
discoordination with no effect at
lower doses and discoordination at
very doses.
Bourn et al., 1978
Bourn et al., 1979
Horibe, 1974
Schneider, 1968
Trulson et al., 1977
Prepulse Inhibition
N = 5
Kiilerich et al., 2019
Palenicek et al., 2005

147
Psi effectively disrupts PPI in rats.
This effect may be dose-dependent
and have sex-specific effects. 1
mg/kg psilocin (IP) effectively
disrupts PPI ASR in rats, but lower
doses (0.25 mg/kg) have no effect
and higher doses (4 mg/kg) have
variable effects.
Tyls et al., 2011
Tyls et al., 2013
Tyls et al., 2016
5.2.5.1 Negative Valence Systems
Within the RDoC framework, Negative Valence systems coordinate neurobiological and
behavioural responses to aversive stimuli or context, including acute threat, potential threat,
sustained threat, frustrative non-reward (including defensive aggression)
10
, and loss. Paradigms
of learned helplessness are considered as a general stress response.
11
Both valence and arousal
are critical to self-regulatory behavior or an organism interacting with a dynamic environment.
Negative Valence includes sub-constructs of fear and aggression, as well as distress. Sadness
may also be considered under Negative Valence.
12
5.2.5.1.1 Fear Conditioning
Fear conditioning reflects the construct of acute threat: an immediate aversive stimulus
that needs to be avoided, or the associated conditioning whereby a conditioned stimulus
signals the presence of an aversive stimulus. Fear conditioning tasks involve associative
learning, whereby a behavioural response is instigated by a neutral stimulus (such as a tone or
light) that has been paired with an aversive stimulus (a foot shock, for example). Resultant
10
Negative valence systems are implicated in defensive aggression, while proactive aggression in considered under
the social processes construct.
11
https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/constructs/negative-valence-systems
12
https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/negative-valence-systems-workshop-
proceedings

148
behaviours (such as freezing, transiting or bar-pressing) are reflective of the aversive context
and represent associative, conditioned learning. When neutral and aversive stimuli are
presented together in training, animals learn to perform the avoidance behaviour with the
aversive unconditioned stimulus (US) or with the neutral conditioned stimulus (CS) alone.
Eleven studies included in this review investigate the effect of psilocybin treatment on
fear-conditioned behaviour, measuring the effects of Psi on behavioural acquisition and
conditioning retention. In these investigations, Psi is administered at different points in training
and behavioural testing, as outlined below. In one study protocol used, animals were trained to
acquire the conditioned behaviour in the presence of either both the conditioned and
unconditioned (shock) presentation, or with the conditioned stimulus (light or tone) alone.
Low doses of Psi treatment have been reported to significantly decrease response
latency and enhance the conditioned behavioural response, perhaps an indication of
heightened sensitivity. Treatment with 0.045 – 0.18 mg/kg psilocin or psilocybin 25 minutes
before testing led to decreased response latency (Bourn et al., 1978; Bourn et al., 1979). In
contrast, doses of 2 mg/kg psilocybin as well as 3 mg/kg psilocin led to increased number of
premature responses – those made prior to the onset of the discriminative stimulus (Calil,
1978). Higher doses of psilocin led to increased number of late responses, decreasing efficiency
in responding. 10 mg/kg resulted in increased response latency with a corresponding reduction
in avoidance of the conditioned stimuli (Davis & Hatoum, 1987). Doses of 5 mg/kg demonstrate
a more dynamic process of time-dependent, biphasic effects. An initial increase in response
latency is followed by a decrease, with a corresponding decrease then increase in avoidance
proficiency. The response was rescued over subsequent trials (Davis & Hatoum, 1987).

149
There are a few considerations to note when reviewing these studies. Studies widely
vary in the length of animal training – from hours to month -- to achieve the conditioned
behaviour. Secondly, higher doses of Psi may impede animal mobility such that evaluation of
conditioned fear behaviour may reflect impairment of locomotor activity rather than reduced
acquisition or retention of the fear-conditioned behaviour. Mice administered 10 mg/kg
psilocin one hour before testing on five consecutive treatment and testing days were found to
have increased starting latency compared to untreated mice but achieved a similar number of
avoidances (Collins et al., 1966). This increased avoidance latency did not persist in the five
washout testing days that followed, where both groups were given placebo treatment. In a
separate Carousel maze assay, 4 mg/kg psilocin impaired locomotor activity while 1 mg/kg
psilocin did not (Rambousek et al., 2014). Collins (1966) further demonstrates development of
behavioural tolerance by day 2 of Psi behavioural testing, and that behavioural measures in this
test are not serotonin dependent.
5.2.5.1.2 Forced Swim Test
The forced swim test (FST) was developed in the context of anti-depressant drug
development as an evaluation of behavioural despair, when an animal is perceived to have
given up hope in escaping distressing circumstances (Macpherson & Hikida, 2019) . It measures
behavioural response in coping with an acute, inescapable stressor (Molendijk & de Kloet,
2019). Rodents are placed in water, from which they cannot escape, and the time spent
swimming compared to immobility is measured.
Six included studies investigate the effect of Psi on immobility behaviour in the forced
swim test. Three studies show no effect of Psi on FST behaviour (Hesselgrave et al., 2021; Jefsen

150
et al., 2019; Mahmoudi et al., 2018) and three studies report decreased time spent immobile
following treatment (Hibicke et al., 2019; Hibicke et al., 2020; Nichols & Hibicke, 2020) (see
Table 5.9). There was no effect of treatment on time spent immobile in the FST when behaviour
was assessed in the hours following treatment (30 minutes to 24 hours; Mahmoudi et al., 2018;
Jefsen et al., 2019). Two studies report no significant effect when FST was assessed seven- or
eight-days following treatment (Jefsen et al., 2019; Hesselgrave et al., 2021).
Table 5.9: Effects on Behaviour in the Forced Swim Test
Citation
Species (Strain)
Treatment
Time Between
Treatment and
FST
Outcome
No Effect Reported
Mahmoudi et
al., 2018
♂ Mice (NMRI)
10, 40 mg/kg
Psilocybe cubensis
extract
30 minutes
No significant effect of
treatment on immobility time
Jefsen et al.,
2019
♂ Rats (FSL, FRL)
0.5, 2 mg/kg
psilocin
10 mg/kg psilocybin
3 mg/kg psilocybin
x 3 administrations
(1 per day for 3
days)
2, 3 mg/kg
psilocybin
24 hours
24 hours
8 days
4 hours
No significant effect of
treatment on immobility
swimming, or struggling time
Hesselgrave et
al., 2021
♀♂ Mice
(C57BL/6J)
1 mg/kg psilocybin
1, 3, 7 days
No significant effect (see SI
Appendix)
Treatment Effect Reported
Hibicke et al.,
2019*
♂ Rats (WKY)
1 mg/kg psilocybin
7, 14, 21, 28, 35
days
“Antidepressant-like” effects
reported, as measured by the
FST
Hibicke et al.,
2020*
♂ Rats (WKY)
1 mg/kg psilocybin
7, 14, 21, 28, 35
days
Psi-treated rats were
significantly less immobile
than saline-treated controls

151
35 days
7, 35 days
on 28- and 35-days following
treatment (but not earlier)
and only after additional
environmental exposure.
Psi-treated rats were
significantly less immobile and
more likely to swim and
climb.
Psi-treated rats were
significantly less immobile and
more likely to swim, on 7- and
35-days following treatment
(with weekly exposure in an
open field arena)
Nichols &
Hibicke, 2020
♀ Rats
1 mg/kg psilocybin
5 weeks
Psi treatment reverses
increased immobility in the
FST induced by chronic stress
(following Psi treatment,
behaviour of stressed rats was
similar to unstressed controls,
an effect not seen in control
(saline-treated) rats
FRL: Flinders Resistant Line; FSL: Flinders Sensitive Line; WKY: Wistar-Kyoto. All treatments administered
intraperitoneally.
* Data from Hibicke et al., 2019 (abstract) may be identical to data presented in Hibicke et al., 2020 (publication).
In a small pilot study (no data presented), Hibicke et al.(2020) noted that “anti-
depressant-like effects” (significant change in immobility behaviour) may not appear for a week
or more following Psi administration in Sprague-Dawley rats. In their main study publication,
Hibicke et al. (2020b) opt to evaluate the behaviour of Wistar-Kyoto (WKY) rats in the FST, using
three different protocols: FST is evaluated every week for five weeks following Psi
administration, FST is evaluated once five weeks following Psi administration, and FST is
evaluated one- and five-weeks following Psi administration, with weekly exposure to an open-
field arena during the three weeks in-between. Psi-treated rats were significantly less immobile
than saline-treated controls on 28- and 35-days following treatment (but not earlier) and only
after additional environmental exposure.

152
In the first protocol with repeated testing, Psi-treated rats show significant reduction in
immobility behaviour compared to saline-treated controls 28 and 35 days following treatment,
but not earlier. In the second protocol, rats show significantly decreased immobility when
assessed once, five weeks (35 days) following Psi administration. In the third protocol, rats
show significantly reduced immobility both one- and five-weeks (7 and 35 days) following
treatment administration, with open field arena exposure weeks two to four. In the first
protocol significance is not reported at seven days, but in the third, significant difference is
reported. Hibicke et al. note that pre-exposure to the FST is needed to elicit depressive-like
behaviour in otherwise healthy rats and include a pre-exposure session in their protocol (2020).
Jefsen et al. omit the pre-swim session, citing that FSL rats respond to traditional
antidepressants in the FST without it (2019).
While Hibicke et al. (2019, 2020) report reduced time spent immobile in Wistar-Kyoto
(WKY) rats following Psi treatment, while no effects were seen in the Flinders Sensitive Line
(FSL) and Flinders Resistant Line (FRL) rats (Jefsen et al., 2019) or mice (Hesselgrave et al., 2021;
Mahmoudi et al., 2018). Hibicke et al. describe the rational for selecting WKY rats for the FST,
excluding FSL rats for abnormally low central 5-HT2A receptor mRNA expression (2020).
One study evaluates behaviour in FST following adolescent-based chronic restraint
stress (aCRS) (Nichols & Hibicke 2020). Rats that were exposed to chronic stress exhibited
increased immobility in FST; following Psi treatment, immobility behaviour is reduced to a level
comparable to unstressed controls. Changes in immobility behaviour were reported in certain
experimental models when FST was evaluated in the weeks following treatment, suggesting
persistent treatment effect but not acute behavioural effects. Of note is that changes in FST

153
behavior in the Hibicke trials were only observed after Psi and repeated environmental
exposure, indicating a possible role for Psi in priming or strengthening subsequent behavioural
changes occurring in response to environmental and training variables.
5.2.5.1.3 Tail Suspension Test
The tail suspension test (TST) evaluates response to an acute, inescapable stressor,
whereby the animal is suspended by their tail. Psi treatment has not been reported to have an
immediate “antidepressant-like” effect in reducing time spent immobile in the TST. Whole
mushroom extracts had no effect on the time spent immobile in the TST (Mahmoudi et al.,
2018). Mice were evaluated thirty minutes following the administration of 10 or 40 mg/kg of
Psilocybe cubensis alkaloid extract, whose main component was identified as psilocin (11.5%).
5.2.5.1.4 Aggressive Behaviour
Under the negative valence RDoC construct, defensive aggression may be elicited by
perceived or real threats which lead to behaviours directed at the termination of threat, and as
such fall under responses to acute threat. Such defensive aggression is considered different
from offensive, or proactive aggression, which is considered separately under the Social
Processes construct.
13
The two studies with aggression paradigms which would properly fit
under Negative Valence employ either foot shock or food deprivation assays; both
demonstrated dose-dependent inhibition of aggressive behaviour, with strongest effect 30
minutes post Psi administration. Overall, five studies evaluated and reported reductions in
13
NIMH Research Domain Criteria (RDOC) Project Negative Valence Systems: Workshop Proceeedings. March
13, 2011 – March 15, 2011. https://www.nimh.nih.gov/sites/default/files/documents/research/research-funded-by-
nimh/rdoc/negative-valence-systems-workshop.pdf

154
aggressive behaviour following Psi treatment (Kostowski et al., 1972; Meldrum & Naquet, 1972;
Sbordone et al., 1979; Uyeno, 1966; Uyeno, 1967), but three fall under Social Processes due to
conditioned isolation and are reported separately there.
Table 5.10. Induced Defensive Aggression Paradigm, Negative Valence Construct
Induced
Aggression
Paradigm
Treatment
Time Between
Treatment and
Testing
Effect*
Outcome
Food
deprivation
0.05 – 0.25
mg/kg
psilocybin
5 – 45 minutes
↓
(D)
(T)
Decrease in time spent dominant at
food dispenser; (D) all doses had
inhibitory effects but there was a
trend as inhibition of dominance
behaviour was an increasing function
of dose; (T) greatest effect was
reported when testing occurred 30
minutes following treatment
administration (Uyeno, 1967)
Foot shock
0.4 – 10 mg/kg
20 minutes
↓
(D)
Reduction in aggressive behaviour
with greater effects seen at highest
dose (10 mg/kg) (Sbordone et al.,
1979)
5.2.5.1.5 Elevated Plus Maze
The elevated plus maze (EPM) is an assay widely used to evaluate anxiety-like responses
in rodents and potential anxiolytic effects of pharmacological intervention (Walf & Frye, 2007).
Anxiety-like behaviour in the EPM is unconditioned, as rodents may innately prefer the dark,
sheltered areas of the closed arms and avoid the open arms. Three included studies investigate
the effect of Psi treatment on behaviour in an elevated plus maze (Hibicke et al., 2019; Hibicke
et al., 2020; Horsley et al., 2018). Horsley et al. administered low doses of psilocin (0.05 or
0.075 mg/kg) to rats three times over a period of six days, in a “microdosing” regime, and
evaluated behaviour in the EPM 48 hours after the final dose was administered (2018). Psi
treatment did not have a strong anxiolytic effect, as evaluated by the EPM, and elicited a mild

155
anxiogenic effect in mice as evidenced by increased entry to and time spent in the open arms,
with no concomitant effect on locomotion.
Hibicke et al. report increased time spent in the open arms of the EPM when evaluated
fourty-one days following a single administration of psilocybin (1.0 mg/kg) in WKY rats (2019,
2020). Rats spent increased time in open arms and decreased time in closed arms in
experimental protocols where animals were evaluated every week, or exposed to the open field
arena every week, but not when they were not evaluated in between treatment administration
and final EPM testing. There is a role of environmental sensitivity in the effect of Psi treatment
on behaviour in the EPM that appears to be dependent on treatment, as control rats exposed
to environmental testing did not similarly decrease time spent in open arms.
5.2.5.1.6 Open Field Test
The open field test (OFT) is used to evaluate locomotor activity and anxiety-like behaviour in
rodents (Kraeuter et al., 2019). Rats or mice are placed in a novel, brightly lit open arena. The
time spent in the center of the arena and in the periphery are recorded, as well as the
occurrence of stereotyped behaviours like grooming and rearing. Stressed mice demonstrate
less activity in the center of the open field with preferential movement near the peripheral wall
(thigmotaxis) and demonstrate increased stereotypical behaviours. Evaluation of locomotor
behaviour and anxiety-like behaviours are difficult to separate; the effects of locomotor activity
will also be included in the summary of locomotor activity in the Sensorimotor Systems section
below. Eleven studies evaluate the effect of Psi treatment on OFT behaviour (Table 5.11).

156
Table 5.11: Effect on Behaviour in the Open Field Test
Citation
Species (Strain)
Treatment
Time Between
Treatment and
FST
Outcome
Tyls et al.,
2016
♂♀ Rats (Wistar)
0.25, 1, 4 mg/kg
psilocin
15 – 20 minutes
(D)
Decreased time spent rearing,
grooming and sniffing
Immobility and flat body
posture increased
Kirsten &
Bernardi,
2010
♂♀ Mice (Swiss)
Whole mushroom
extract (0.1 mL/ 10
g)
10 – 19 minutes
29 – 38 minutes
↓ (T)
Decreased rearing frequency
in only female mice
(untreated control females
had higher rearing frequency
than control males)
Decreased locomotion
frequency (male and female);
decreased rearing frequency
(male and female)
Mahmoudi et
al., 2018
♂ Mice (NMRI)
Whole mushroom
extract (10, 40, 100
mg/kg) (IP)
30 – 35 minutes
↓ (D) Only the highest dose
had a significant effect on
distance moved and total
velocity in the OFT
Hesselgrave et
al., 2021
♂ Mice
(C57BL/6J)
5 mg/kg psilocybin
(IP)
Treatment
administration
immediately
before testing.
Behaviour
evaluated 0 – 90
minutes following
treatment
↓ (T) Psi treated mice had
significant decrease in
distance travelled and time
spent in the center of the OFT
at 30 – 60 minutes following
treatment, but not before or
after.
Palenicek et
al., 2005
♂ Rats (Wistar)
1 mg/kg psilocin
Not reported
↓ Reduced locomotion
Tyls et al.,
2011
Rats
0.25, 1, 4 mg/kg
psilocin (SC)
Not reported
↓ (D) Dose-dependent
decrease in locomotion
Tyls et al.,
2014
Rats
0.25, 1, 4 mg/kg
psilocin (SC)
Not reported
↓ (D) Dose-dependent
decrease in locomotion
Cunha &
Masur, 1978
♂ Rats (Wistar)
0.5, 1 mg/kg
psilocybin
10 – 30 minutes
In a modified open field test,
with dark, odor, sound, and
light sessions.
↓ (D) Decreased ambulation
frequency following only the
high dose.
↓ (D) Decreased rearing
frequency in all doses.
Increased immobility time in
all doses.

157
↓ (D) Decreased grooming
frequency with all doses.
Collins et al.,
1966
♀ Mice
(C57BL/10J),
10 mg/kg psilocin
(P.O.)
60 minutes
Mice in an open-field test
were given psilocin 1 hour
before testing for 5
consecutive days, followed by
5 days of testing with placebo.
Measures include latency to
move from square and
number of squares traversed.
Jefsen et al.,
2019
♂ Rats (Flinders),
0.50, 2.00 psilocin,
2, 3 and 10
psilocybin (IP)
4 hours, 8 hours
and 28 days
Treatment with psilocin or
psilocybin show no impact on
immobility and no significant
effect on locomotor activity in
the OFT.
Hibicke et al.,
2020
♂ Rats (Wistar-
Kyoto)
1mg/kg psilocybin
(IP)
7 - 41 days after
acute injection
Significantly less immobility in
weeks 4 and 5 (with a
nonsignificant trend of
reduced immobility observed
in weeks 2 and 3); Psi rats
treated with psilocybin were
significantly less immobile 5
weeks following treatment
compared to saline controls,
with increased time spent
swimming and climbing
Following a single administration of Psi, there were time, dose, and sex-dependent effects on
behaviour in the open field test. Two studies showed time-dependent effects, with effects on
distance travelled and time spent in the center of the maze (Hesselgrave et al., 2021) and
locomotion and rearing frequency (Kirsten & Bernardi, 2010) evident after thirty minutes
following treatment but not before. No effect of treatment on behaviour was seen 60 – 90
minutes following treatment (Hesselgrave et al., 2021). Higher doses had a greater effect on
behaviours (Tyls et al., 2011; Tyls et al., 2014) or were only evident at higher doses, particularly
with whole mushroom extract (Mahmoudi et al., 2018). Many studies showed reduced
locomotor activity in the OFT (Palenicek et al., 2005; Tyls et al., 2011; Tyls et al., 2014). One

158
modified open field test introduced variables including odor, sound, and light (Cunha & Masur,
1978).
Table 5.12: Acute Time-Dependent Effects on Open Field Test
Citation
Species
(Strain)
Treatment
Time Between
Treatment and
FST
Outcome
Hesselgrave
et al., 2021
♂ Mice
(C57BL/6J)
5 mg/kg
psilocybin (IP)
0 – 30 minutes
=
No effect on distance travelled or
time spent in the center of the OFT
Kirsten &
Bernardi,
2010
♂♀ Mice
(Swiss)
Whole
mushroom
extract
10 – 19
minutes
↓
Decreased rearing frequency in
male, but not female, mice
Cunha &
Masur, 1978
♂ Rats (Wistar)
0.5, 1 mg/kg
psilocybin
10 – 30
minutes
↓
Decreased ambulation, rearing and
grooming frequency, increased
time spent immobile
Tyls et al.,
2016
♂♀ Rats
(Wistar)
0.25, 1, 4 mg/kg
psilocin
15 – 20
minutes
↓
Decreased time spent rearing,
grooming, and sniffing, increased
time spent immobile and with flat
body posture
Mahmoudi et
al., 2018
♂ Mice (NMRI)
Whole
mushroom
extract (10, 40,
100 mg/kg) (IP)
30 – 35
minutes
↓
Only the highest dose had
significant effect on the distance
moved and total velocity
Hesselgrave
et al., 2021
♂ Mice
(C57BL/6J)
5 mg/kg
psilocybin (IP)
30 – 60
minutes
↓
Significant decrease in distance
travelled and time spent in the
center of the OFT
Kirsten &
Bernardi,
2010
♂♀ Mice
(Swiss)
Whole
mushroom
extract
29 – 38
minutes
↓
Decreased locomotion and rearing
frequency in male and female mice
Hesselgrave
et al., 2021
♂ Mice
(C57BL/6J)
5 mg/kg
psilocybin (IP)
60 – 90
minutes
=
No effect on distance travelled or
time spent in the center of the OFT
The interpretation of anxiety-like behaviours in the OFT should be made with caution, as
compounds which typically demonstrate therapeutic efficacy for anxiety disorders in humans
do not have predictable response on anxiety-like behaviours in the open field test (Prut &
Belzung, 2003).

159
5.2.5.2. Positive Valence Systems
Positive Valence (PV) systems are processes that govern hedonic response to impending
or possible reward, the receipt of reward (initial response) and following repeated receipt of
reward (reward satiation). PV systems are primarily responsible for responses to positive
motivational situations or contexts, and are thought to govern reward seeking, consummatory
behaviours and reward/habit learning.
14
Reward pathway dysfunction is associated with mood,
anxiety, addiction and eating disorders (Kelly et al., 2021).
This review identified twelve individual studies meeting the positive valence
classification; one study had three related publications, for a total of fourteen individual
included articles. All of the positive valence behavioural investigations used rodents (male=9,
female=1, not reported=4) as study animals in a range of doses, demonstrating dose-dependent
and biphasic results. Seven studies investigated psilocybin (IP) alone, three studied the effects
of psilocin (two via IP, one SC injection), one studied the effects of both psilocybin and psilocin
(IP), and one study used an extract of P. argentipes administered orally. Time between dose
administration and behavioural assay ranged from 2 minutes to 24 hours, with three studies
using multiple timepoints; the most common time intervals was 30 minutes (n=5).
Table 5.13: Positive Valence Systems Results
Citation
Animal
Model
Measure
Treatment
Time
Between
Dose and
Testing
Outcome
14
https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/constructs/positive-valence-systems

160
Cameron
and Appel,
1976
♂ Rats
(Sprague-
Dawley)
Lever press,
water
reinforcement
Psilocybin
2mg/kg
(IP)
Once per 30
min session
at a random
time
excluding
the first or
last 5 min
Conditioning (suppression of
bar-pressing in the presence of
CS) was demonstrated with
psilocybin
Castellano
1978
♂Mice
(DBA/2J
and
C57B1/6J
strains), 25
grams
Y-water maze
Psilocin
0.5, 1, 2,
and
4mg/kg.
(IP)
15 minutes
Psilocin improved the innate
tendencies (directionality
toward the light) of both
strains. However, the
acquisition of a new kind of
behavior (directionality
toward the dark) was strain-
dependent: performance
improvements were evident in
the 'slow'
learning C57 strain, while the
performance of the
'quick' learning DBA mice was
impaired by the treatment.
Harris et
al., 1981
Rats (no
specifics)
Lever pressing
under a fixed-
interval 5-
minute
schedule of
food
presentation
Psilocin 0.8
mg/kg (IP)
2 minutes
Psilocin decreased responding
during the first 60 - 90 minutes,
but increased responding
above control levels between
180 and 240 minutes
Higgins et.
al, 2021
♂Long-
Evans
strain rats
Progressive
ratio (PR) and
serial 5-choice
(5-CSRT) food
tasks
Psilocybin
doses 0.03,
0.1, 0.3, 1,
3, and 10
mg/kg (SC)
10 minutes
Psilocybin (0.05–0.1 mg/kg SC)
pre-treatment increased break
point for food (PR task) and
improved attentional accuracy
and a measure of impulsive
action (5-CSRT task). In each
case, effect size was modest
and
largely restricted to test
subjects characterized as “low
performing”.
♂ Mice
(C57BL/6J)
Mice subjected to chronic
multi-modal stress displayed a

161
Hesselgrav
e et al.,
2021
Sucrose
Preference Test
(SPT) + Female
Urine Sniff Test
(FUST)
Psilocybin
1mg/kg
(IP)
24 hours
significant restoration of their
preference for sucrose solution
and female urine 24 to 48 h
after psilocybin
Hesselgrav
e et al.,
2021
(ACNP
Abstract)
♂Mice
(C57Bl/6J),
8-9 weeks
old
Sucrose
Preference Test
(SPT)
Psilocybin
1mg/kg
(IP)
24 hours
(reported in
Hesselgrave,
2021)
Psilocybin exerted rapid
antianhedonic actions in
chronically stressed mice
Thompson
, 2019
(ACNP
Abstract)
Mice and
rats
Sucrose
Preference Test
(SPT)
Psilocybin
1, 3, or 10
mg/kg (IP)
24 hours
(reported in
Hesselgrave,
2021)
A single injection of psilocybin
restores sucrose preference
within 24 hrs among
chronically stressed rodents
Hurley et
al., 2020
(ACNP
Abstract)
Wistar rats
Binge eating
behaviour
Psilocybin
1, 3, or 10
mg/kg (IP)
1 hour, 5
days, and 24
hours post-
second dose
Psilocybin specifically reduced
bingeing on chocolate at 1 hour
post-treatment, with no
significant effect on
consumption of normal chow;
effects persisted at 24 hours
post-treatment for the high
dose of psilocybin (10 mg/kg).
Koerner &
Appel,
1982
♂Rat
(Sprague-
Dawley),
370-470
grams
Lever
preference test
Psilocybin
0.0312,
0.0625,
0.125,
0.25, 0.5,
1.0 and 2.0
mg/kg ;
Psilocin
0.125,
0.25, 0.5
mg/kg
(IP.)
15 minutes
1.0 mg/kg psilocybin can exert
strong discriminative control
over behavior in a two-choice,
appetitively motivated task; At
the 1.0mg/kg psilocybin dose,
responding was suppressed
and frequently disrupted

162
Marquis et
al., 1973
♀ adult
albino rats
Differential
Reinforcement
of Low Rates of
responding
(DRL)
Psilocin .1-
.75
mg/kg(IP)
not reported
Psilocybin at lower doses
demonstrated no behavioural
effects but higher doses
tended to decrease DRL
response.
Matsushi
ma et al.,
2009
♂ ICR mice,
5 weeks
old
dosed 30
minutes before
marble burying
task +
locomotor
activity
Psilocybe
argentipes
extract 05,
.1, .5, 1
1.5, 2mg
/kg of (p
argentipes
at a dose
of .1-1g/kg
contained
about
23.8-238
ug/kg
psilocybin
and .8-
8ug/kg
psilocin);
(volume of
.1ml/10g
of body
weight),
PO
30 minutes
P argentipes in a dose of .05,
1.5 and 2.0 mg/kg showed a
trend toward inhibited marble-
burying behaviour, while a
dose of 1.5mg/kg significantly
reduced the number of buried
marbles.
Psilocybin dose required was
higher than that required for
whole biomass.
Rambouse
k et al.,
2014
♂Winstar
rats, 250-
350g
tested 30
minutes after
injection,
Carousel Maze,
Morris Water
Maze
Psilocin 1
and 4
mg/kg
(SC)
30 minutes
The dose of 4 mg/kg disrupted
reinforced retrieval in the
MWM. However, the
application of a lower dose was
without any significant effect.
Finally, neither the low nor
high dose of psilocin injected
post-training caused a deficit in
memory consolidation in the
MWM
Rech et
al., 1975
Rats (no
specifics)
fixed ratio food
reinforcement
Psilocybin
1mg/kg
(IP)
30 minutes
Pause in fixed-ration response
pattern of food reinforcement
after psilocybin

163
Sakloth et
al., 2019
♂ Adult
Rats
(Sprague-
Dawley)
Lever press,
frequency rate
procedure, ICSS
mode
Psilocybin
.032
mg/kg-
1.0mg/kg
in acute
dose
effect, .1-
1.0mg/kg
in time
course
study, (IP)
10, 30, 100,
180, and 300
min
Evidence for abuse-related ICSS
facilitation was weak and
inconsistent; the predominant
effect was dose- and time-
dependent ICSS depression
Psilocybin and psilocin demonstrate positive reinforcement in models of conditioning
(Cameron & Appel, 1976). The relatively standard does of 1.0 mg/kg psilocybin (at .16/mg
human equivalency would be a low dose in human psilocybin therapeutics; clinical trials tended
towards .3mg/kg, with the lowest dose migraine trial using .143mg/kg) exerts strong
discriminative control over behavior in a two-choice, appetitively motivated task; at this dose
level, responding was suppressed and frequently disrupted, suggesting that a slightly lower
doses may have discriminative properties with fewer grossly disruptive effects on behaviour
(Koerner & Appel, 1982). Psilocybin at lower doses demonstrated no behavioural effects but
higher doses tended to decrease differential reinforcement of low rates of responding (Marquis
et al., 1973).
Psilocybin reduced binge-eating behaviour at several doses, with high doses
demonstrating sustained effect at 24 hours (Hurley, 2020, Gysling et al., 2020). Psilocybin-
containing whole mushroom extract inhibited compulsive marble-burying behaviour
throughout in a dose-dependent manner, but with most effect evident at the medium-high but
not highest dose range (Matsushima et al., 2009). Psilocybin treatment exerted rapid
antianhedonic actions in chronically stressed mice, restoring sucrose preference following
chronic multi-model stress (Hesselgrave et al., 2021). A positive effect of low doses of

164
psilocybin (0.05–0.1 mg/kg [psilocin plasma] 7–12 ng/ml) was observed on behaviors related to
endophenotypes of amotivation and anhedonia (Higgins et al., 2021). While psilocybin was
found to improve the performance of innate behavioural tendencies among study animals;
strain differences among rodents resulted in the improved acquisition of new behaviours and of
memory consolidation among “slow learning” mice (Castellano, 1978).
Psilocybin demonstrates a biphasic dose response, with decreases in behavioural response
evidenced early, and increases in hedonic behaviours after 180 minutes (Harris et al., 1981).
High doses disrupted memory retrieval (suggestive of an amnestic effect, which persisted for
five days), but lower doses were without significant effect; neither low nor high doses resulted
in deficit of memory consolidation in the Morris Water Maze (Rambousek et al., 2014).
Psilocybin increased starting hesitancy in an underwater swim test in a dose-dependent
manner, with peak effect at 20 minutes; high doses did not increase swim time (Uyeno, 1971).
A time-bound disruption of conditioned behavioural responses, a “hallucinogenic pause”, was
found in fixed-ratio response pattern of food reinforcement after psilocybin (Rech et al., 1975).
Evidence for abuse is lacking; facilitation was weak and inconsistent with predominant effects
found to be dose and time-dependent (Sakloth et al., 2019).
5.2.5.3. Cognitive Systems
Within the RDoC framework, the construct Cognitive Systems captures systems
responsible for various cognitive processes, including attention, perception, declarative
memory, language, cognitive control (including goal selection and performance monitoring),

165
and working memory.
15
A subconstruct of Cognitive Systems of special relevance to psychedelic
drugs is cognitive control, the system that is thought to modulate other cognitive and
emotional systems, is vital to adaptation and related to goal-directed behaviour when current
habits do not adequately meet the demands of current context, and is engaged in the selection
of responses to novel contexts; underlying neural systems to cognitive control include executive
systems, salience, and the Default Mode Network (Kelly et al., 2021). Both cognitive and
behavioural flexibility fall under the broad category of executive functions (Uddin, 2021).
Three studies evaluate the effect of Psi treatment on cognitive systems, including visual
discrimination tasks. Acute effects of Psi treatment include impairment in visual discrimination
tasks in non-human primates (Roberts & Bradley, 1967; Uyeno, 1969). Accuracy was decreased
with a strong trend for greater response latency in a visual (colour) discrimination task (1.5
mg/kg psilocybin (IP) administered 20 minutes before testing) (Roberts & Bradley, 1967). Psi
treatment dose-dependently disrupts size discrimination (Uyeno, 1969).
Beyond induced acute impairment in visual discrimination, Psi had persisting effects that
rescued chronic-stress induced impairment in an Object Pattern Separation (OPS) task (Nichols
& Hibicke, 2020). OPS may be used to measure object memory processes that are mediated by
hippocampal circuitry (Van Hagen et al., 2014). Chronic stress in adolescence impairs
performance in OPS in adulthood. A single psilocybin treatment (1 mg/kg) administered 5
weeks before testing rescued impairments in the OPS task induced by adolescent-based chronic
15
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166
restraint stress in rats, and performance was similar to that of unstressed controls (Nichols &
Hibicke, 2020).
Table 5.14. Visual Discrimination Paradigms
Citation
Species
Test
Treatment
Time
Between
Outcomes
Nichols &
Hibecke, 2020
Rats (NS)
Object Pattern
Separation Task
1mg/kg
5 weeks
Single treatment of psilocybin
rescued stress-induced cognitive
deficits
Roberts &
Bradley, 1967
African
Green
monkey
Delayed visual
discrimination
1.5mg/kg
20 mins
Acute reductions in visual accuracy
Significant improvement in
accuracy over pre-control levels 72
and 96 hours post injection
Uyeno, 1969
Squirrel
monkey
Wisconsin
General Test
Apparatus
1-8 3.5 7.0
30 mins
Psi markedly disruptive at high
doses and with some disruption
across range of doses.
Alteration of a learned response by
Psi.
Tolerance evident.
5.2.5.4 Systems for Social Processes
Systems for social processes mediate behavioural responses to inter-individual
circumstances including perception and interpretation of others’ actions (Kelly et al., 2021).
One behavioural element within the Social Processes domain is affiliation, or engagement in
positive social interactions with others, which may in turn be moderated by social motivation
(NIMH, 2012). Three included studies evaluate the effect of Psi treatment on social behaviours.
Psi treatment has a significant effect on affiliative behaviours in non-human primates, with
reduced social grooming behaviour and increased distancing from other individuals, within the
observation period 15 – 75 minutes post-administration (Schlemmer & Davis, 1986; Sink et al.,
1983). Psi treatment also had a significant effect on sexual receptivity in female rats (Everitt &

167
Fuxe, 1977). Biphasic, dose-dependent effect on sexual receptivity, with lower doses
significantly increasing sexual receptivity and higher doses having a non-significant effect, with
behaviour returning to baseline with the highest tested dose.
Two studies evaluate aggressive behaviour induced by prolonged social isolation (2 to 5
weeks) in mice and rats (Kostoswki et al., 1972; Uyeno, 1966). In one study investigating the
effect of Psi treatment on aggressive behaviour, the length of isolation time contributed to the
significance of treatment effect (Kostowski et al., 1972), with 4 weeks of isolation having a
greater effect on subsequently reduced aggressive behaviour than 2 weeks of isolation.
Another study investigated dominance behaviour at a food dispenser, following a period of
food deprivation (Uyeno, 1967) and one used exposure to foot shocks to elicit aggression
(Sbordone et al., 1979). Meldrum & Naquet report reduced aggressive responses in baboons in
the hour following injection of 1 – 2 mg/kg psilocybin (1971).
Psi treatment is consistent in reducing aggressive behaviour, with greater inhibition of
aggressive behaviour as a function of increasing dose. The effect of Psi treatment on behaviour
is an acute effect, dependent on time between administration and behavioural assessment –
however this timing effect is not clear consistent. Two studies suggest peak effect at 30 minutes
in both rats and mice (Uyeno, 1966, 1967), while another study suggests effect is not significant
at 30 minutes, but only later, at 90 minutes (Kostowski et al., 1972).
Table 5.15: Effects on Social Aggression Behaviours
Induced Aggression
Paradigm
Treatment
Time Between
Treatment and
Testing
Effect*
Outcome

168
Social isolation
1, 2, 4, 8 mg/kg
psilocybin
30 minutes
↓
(D)
Attack behaviour
was inhibited in Psi-
treated mice, with
inhibitory effect
increasing as a
“monotonic
function of dose”
(Uyeno, 1966)
4 mg/kg psilocybin
5 - 45 minutes
↓
(T)
Attack behaviour
was inhibited in
mice, with the
greatest inhibitory
effect observed
when mice were
evaluated 30
minutes following
treatment (and
reduced inhibitory
effect reported
when assessed 15-
and 45-minutes
following
treatment) (Uyeno,
1966)
10 mg/kg psilocybin
30 minutes
90 minutes
-
↓
(T)
No significant effect
of Psi treatment on
aggressive
behaviour in mice
(Kostowski et al.,
1972)
Significant effect of
Psi treatment on
aggressive
behaviour when
mice were assessed
90 minutes
following
treatment, but not
earlier
(Kostowski et al.,
1972)
10 mg/kg psilocybin
45 minutes
↓
Significant decrease
in muricide
behaviour in rats
following treatment
(Kostowski et al.,
1972)
All treatments administered intraperitoneally. Studies investigate the effect of Psi treatment on behaviour in mice
and rats.

169
* (-): no effect of Psi treatment on behaviour; ↓ : Psi treatment significantly decreased aggressive behaviour; (D):
dose-dependent effect; (T): time-dependent effect – the significance of the effect of treatment on behaviour is
dependent on the time between treatment administration and behavioural testing.
5.2.5.5. Arousal and Regulatory Systems
Arousal and Regulatory Systems are responsible for generating the activation of neural
systems as appropriate for various contexts and provide homeostatic regulation of such
systems as sleep and energy balance. General arousal, circadian rhythms and sleep-wakefulness
are subconstructs to Arousal and Regulatory Systems.
16
Arousal is considered a continuum of
sensitivity of the organism to both external and internal stimuli (Kelly et al., 2021).
5.2.5.5.1 General Arousal and Physiological Measures
Twelve studies report acute effects of Psi treatment on general arousal and associated
physiological measures. Some studies with non-human primates (NHPs) report a sedative effect
following Psi treatment (Schlemmer & Davis, 1986), in one study characterized by an increase in
lying down (Sink et al., 1983). Following psilocybin administration (2 mg/kg), an initial increase
in dynamic behaviour of rhesus monkeys is observed, followed by a decrease in visual
responses and the onset of drowsiness (Horibe, 1974). Similarly, an initial restlessness followed
by a gradual stillness was observed in macaque monkeys, though this shift between dynamic
and static behaviour happened quite rapidly (3 – 5 minutes), following intraventricular injection
(Wada, 1962). Cynomolgus monkeys also demonstrate visual fixation behaviour, attentively
staring at no apparent stimulus, following administration of 4 mg/kg psilocybin (Wilson et al.,
1981). Conversely, administration of 50 mg/kg psilocybin elicits gross behavioural excitation in
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170
rats (Sugrue, 1969) and lower doses in rabbits lead to increased reactivity, including to sonic
and photic stimuli (Steiner & Sulman, 1963).
Mydriasis (pupillary dilation) is observed in rabbits, dogs, and NHPs (Table 5.16).
Relatively low doses (0.025 – 0.05 mg/kg psilocin) give rise to elevated heart rate. Increased
respiratory rate, elevated blood sugar levels, piloerection, and salivation are observed. An
increase in temperature was noted at lower doses. At higher doses, temperature changes in
NHPs are described as a brief initial hyperthermia followed by a prolonged hypothermia; A
dose-dependent decrease in appetite was also noted. (Wilson et al., 1981).
Table 5.16: Acute Effects on Physiological Responses
Physiological Measures
Research Species
Studies
Mydriasis
Rabbits
Guest & Consroe, 1979
Dogs
Martin et al., 1978
NHPs
Horibe, 1974
Meldrum & Naquet, 1971
Wilson et al., 1981
↑ Elevated heart rate
Dogs
Martin et al., 1978
NHPs
Wilson et al., 1981
↑ Elevated respiratory rate
Dogs
Martin et al., 1978
NHPs
Wilson et al., 1981
↑ Elevated blood sugar levels
Rabbits
Steiner & Sulman, 1963
Piloerection
Mice
Horita & Weber, 1962
NHPs
Horibe, 1974
Wilson et al., 1981
↑ Increased salivation
NHPs
Meldrum & Naquet, 1971
Wilson et al., 1981

171
Changes in temperature
Dogs
Martin et al., 1978
NHPs
Wilson et al., 1981
↓ Decreased appetite
Dogs
Martin et al., 1978
Vaupel et al., 1979
NHPs
Wilson et al., 1981
5.2.5.5.2 Sleep-Wake Behaviour
One study investigates the effect of Psi on sleep-wake behaviour (Thomas et al., 2020).
Psilocybin (1 – 10 mg/kg) is acutely wake-promoting in rats, increasing the time spent awake in
the four hours following treatment. Rapid eye movement (REM) sleep decreases for seven
hours following treatment. No persisting effects are reported, with no significant differences in
sleep-wake behaviour between treated animals and controls in the six days following
treatment. In other literature, psychedelic disruption of sleep architecture and reduced REM
sleep has been associated with their potential therapeutic benefit, contributing to sub-acute
plasticity and anti-depressant effects (de Vos et al., 2021; Dudysová et al., 2020; Inserra et al.,
2021; Kuypers, 2019).
5.2.5.5.3 Startle Reflex
Two included studies investigate the effect of Psi treatment on startle reflex, a
behaviour of rapid muscular contraction occurring in response to high-intensity stimuli
presentation (Curzon et al., 2009). Both acoustic (Davis & Walters, 1977) and tactile (Geyer et
al., 1978) stimuli are used to provoke the startle response in rats. Startle response is measured
via stabilimeter, which detects the frequency and amplitude of motion. There is a dose-
dependent effect of Psi on startle response. Low doses increase startle amplitude (Davis &

172
Walters, 1977) or have no effect (Geyer et al., 1978) while higher doses depress startle
response (Table 5.18). When acoustic startle is measured continuously for up to sixty minutes
following injection of a lower treatment dose, there is an increase in startle response compared
to controls, followed by a decrease in startle (beginning around 30 minutes following injection),
with less variation in startle amplitude over time (Davis & Walters, 1977).
Table 5.17: Effects on Startle Response by Dose and Time Period
Treatment
Time Between
Treatment and
Testing
Effect
Outcome
0.35 – 1.5 mg/kg
psilocin*
5 minutes
↑
Lower treatment doses increased
amplitude of acoustic startle response
(Davis & Walters, 1977)
2.5 mg/kg psilocin
35 minutes
-
No significant effect on tactile startle
(Geyer et al., 1978)
2.8 – 5.7 mg/kg
psilocin*
5 minutes
↓
Higher treatment doses depressed
acoustic startle response (Davis &
Walters, 1977)
5 mg/kg psilocin
35 minutes
-
No significant effect on tactile startle
(Geyer et al., 1978)
10 mg/kg psilocin
35 minutes
↓
Significant decrease in amplitude of tactile
startle response (Geyer et al., 1978)
* For comparison, equimolar doses of psilocin are listed.
Table 5.18: Effects on Startle Response by Species
Research Species
Sex
Effect on Grooming
Studies
Non-human primates
NR
NR
↓ Decrease
↓ Decrease
Schlemmer & Davis, 1986
Sink et al., 1983
Cats
♂♀
♀
↑ Increase
No significant effect
Trulson et al., 1984
Trulson et al., 1981
Rabbits
NR
↓ Decrease
Guest & Consroe, 1979
Rats
♂
↓ Decrease (OFT)
Cunha & Masur, 1978

173
♂♀
♂
NR
↓ Decrease (OFT)
No significant effect
No significant effect
Tyls et al., 2016
Higgins et al., 2021
Kiilerich et al., 2019
Mice
♂
♀
No significant effect
↑ Increase
Kirsten & Bernardi, 2010
Kirsten & Bernardi, 2010
* NR: Not reported
Table 5.19: Effects on Locomotor Activity
Citation
Animal
Model
Measure
Treatment
Outcome
Bert et al.,
1968
♀ NHPs
(Baboons)
Spontaneous mobility
(# lines crossed by
free-moving animal,
in confined space of
three square meters)
3 mg psilocybin
(not reported per
kg) (IV)
Usually, treatment did not modify
spontaneous mobility; sometimes a
slight reduction of spontaneous
mobility was seen
Bourn et al.,
1978
♂ Rats
(Sprague
Dawley)
Sensor-monitored
activity
0.045 - 0.36
mg/kg psilocin
(IP)
All doses produced significant
increases in total activity count 20 -
60 minutes post-injection. 0.09 -
0.36 had a greater increase on total
activity count than 0.045 mg/kg
(lower dose). Increased number of
pauses of shorter duration (higher
doses having greater effect)
(average of 5 minute intervals over
60 minutes post-injection).
Bourn et al.,
1979
♂ Rats
(Sprague
Dawley)
Sensor-monitored
activity
0.045 - 0.36
mg/kg psilocybin
(IP)
All doses produced significant
increases in total activity count 20 -
60 minutes post-injection. 0.09
mg/kg was most effective at
increasing activity, then 0.18 and
0.36, then 0.045 mg/kg. Increased
number of pauses of shorter
duration - higher doses had greater
decrease on pause duration
(average of 5 minute intervals over
60 minutes)

174
Collins et al.,
1966
♀ Mice
(C57BL/10J)
Wheel running
(spontaneous
locomotor activity)
10, 50 mg/kg
psilocin (oral)
Treatment administered on 5
consecutive days to mice trained to
wheel run; dose-dependent
decrease in motor activity rescued
by the second day
Guest &
Consroe,
1979
Rabbits
Experiment-
operated digital
event recorder
1, 3 mg/kg
psilocybin (IV)
Decrease in locomotion
Halberstadt
et al., 2011
♂♀ Mice
(C57BL/6J, 5-
HT2AR
knockout)
Distance travelled in
BPM (Sensor-
monitored activity)
0.3, 0.6, 1.2, 2.4,
4.8 mg/kg
psilocin
Psilocin reduced locomotor and
investigatory activity, with the
highest dose being the most
effective
Higgins et
al., 2021
♂ Rats (Long
Evans)
Exploratory behavior
/spontaneous activity
1mg/kg
Psilocybin produced dose related
increase in incidence of locomotor
behaviours
Horsley et
al., 2018
♂ Rats
(Wistar)
Open Field Test
0.05mg/kg,
0.075mg/kg
subcutaneous
psilocin
Drug treatment did not affect total
distance travelled, nor distance
travelled per visit to open or closed
arms. No effect on frequency of
stretch-attend postures.
Kiilerich et
al., 2019
Rats (Long-
Evans)
Behavioural assays
including locomotor
activity, grooming,
rearing, and pre-
pulse inhibition of
the acoustic startle
reflex plus HTR
0.05 and 1 mg/kg
psilocybin
Locomotor activities impeded by
sedation after 1mg/kg
Matsushima
et al., 2009
♂ mice (ICR),
5 weeks old
Sensor-monitored
activity
0.025 - 1.5 mg/kg
psilocybin; 0.05 -
2 g/kg whole
mushroom
extract
No dose had a significant effect on
locomotor activity
Rambousek
et al., 2014
♂ Rats
(Wistar)
Carousel maze
1, 4 mg/kg
psilocin
Decrease in locomotion in first
three session; effect of treatment
and session

175
Sakashita et
al., 2015
♂ Rats
(Wistar)
Locomotor activity
1, 5, 10 mg/kg
psilocin (IP)
Only higher doses of psilocin (5, 10
mg/kg) reduced locomotor activity
Schlemmer &
Davis, 19861
NHPs
(Macaca
arctoides)
Locomotion
0.4 mg/kg
psilocin (IP)
Non-significant decrease in
locomotion
Steiner &
Sulman,
1983
♀♂ Rabbits
General motor
activity
3.5mg/kg
psilocybin (IV)
Reduced spontaneous movement.
Transient motor activity of short
duration (1-2 minutes).
Animals produced a special sound
similar to that heard in sexual play.
5.2.5.6 Sensorimotor Systems
Sensorimotor systems are responsible for the control and execution of motor
behaviours as well as their refinement as a result of development or learning. Sensorimotor
constructs include motor actions, agency and ownership, innate motor patterns and
sensorimotor habits. Motor actions include subconstructs of action planning and selection,
sensorimotor dynamics, action initiation, execution as well as action inhibition and
termination
17
.
5.2.5.6.1 Motor Coordination
Five studies report on the effects of Psi treatment on motor coordination (Bourn et al.,
1978; Bourn et al., 1979; Horibe, 1974; Schneider,1968; Trulson et al., 1977). Rotarod testing is
a broad assessment for motor coordination or impairment, assessing changes in behaviour but
with too wide a lens to determine underlying mechanism. Low doses (0.045 – 0.36 mg/kg
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176
psilocin and psilocybin) did not have a significant effect on the time mice spent on a rotating
rod (Bourn et al., 1978; 1979). Higher doses of psilocybin (80, 120 mg/kg) elicited
discoordination in rats, impairing head turning, pivoting behaviour, circle turning, walking
backwards and performance on a rotating drum (Schneider, 1968).
High doses did not produce full discoordination, though higher doses appear to have a
greater effect. Horibe (1974) notes staggering gait or unstable sitting posture 20 – 40 minutes
following injection of 2 – 4 mg/kg of psilocybin in rhesus monkeys. Moderate doses of psilocin
(1 – 20 mg/kg) do not produce significant effects on turning behaviour in rats with unilateral 6-
hydroxydopamine lesions of the nigrostriatal pathway (Trulson et al., 1977). This investigation
of the activity of psilocin on pre- or post-synaptic dopamine receptors indicates non-significant
contribution of dopamine receptors in moderating treatment effect on behaviour (Halberstadt,
2015). Additionally, as noted below in Adverse Events, some ataxia has been noted following
PSI administration (Horita & Weber, 1962; Schneider, 1968) including in doses that were
prohibitive to further behavioural testing due to immobility (Geyer et al., 1979).
Table 5.20 : Effects on Motor Coordination
Citation
Animal
Model
Measure
Treatment
Outcome
Bourn et
al., 1978
♂ Mice
(Swiss-
Webster)
Rotarod Testing
(30 minute training, injection, 15
minutes interval, 90 second testing)
0.045 - 0.36
mg/kg psilocin
(IP) (15
minutes before
testing)
Treatment did not have a
significant effect on time
spent on the rod

177
Bourn et
al., 1979
♂ Mice
(Swiss-
Webster)
Rotarod Testing
(30 minute training, injection, 15
minutes, testing)
0.045 - 0.36
mg/kg
psilocybin (IP)
(15 minutes
before testing)
Treatment did not have a
significant effect on time
spent on the rod
Horibe,
1974
NHPs
(rhesus
monkeys)
Rabbits
General observation
0.1 - 4 mg/kg
psilocybin (IP)
2 mg/kg
psilocybin (IV)
Between 20 and 40
minutes following
injection, a staggering
gait or unstable sitting
posture was observed (2 -
4 mg/kg).
Schneider,
1968
♂ Rats
(Wistar)
Circle turning. Pivoted in a semicircle
or full circle or walked backward.
Animal placed on surface of drum
rotating at 1 rpm to test for
discoordination;
80, 120 mg/kg
psilocybin (SC)
Treatment 20
minutes prior
to behavioural
testing
Dose-dependent effect
on discoordination,
assessed on rotating
drum; 40%
discoordinated at 80
mg/kg; 80%
discoordinated at 120
mg/kg.
Trulson et
al., 1977
♂ Rats
(Sprague-
Dawley)
Ipsilateral turning (rotational)
behaviour with unilateral 6-
hydroxydopamine lesions
Paradigm: following unilateral
destruction of nigrostriatal dopamine
system, compounds that directly
stimulate post-synaptic dopamine
receptors or increase synaptic
dopamine content produce unilateral
turning directionality whether the
compound acts pre- or post-
synaptically
1, 5, 10, 20
mg/kg psilocin
(IP)
Psilocin produced no
significant turning in
either direction.
No significant
behavioural changes.
Indicates stimulation of
dopamine receptors.
5.2.5.6.2 Stereotyped Behaviours
The head-twitch response (HTR) has been used as an assay for hallucinogenic drug
effect, particularly discriminating serotonergic psychedelic effects, with low within- and
between subject variability (Canal & Morgan, 2012). HTR is a sudden rotational movement of
the head (Halberstadt et al., 2011) and is a behaviour rarely seen in untreated animals. Head-

178
twitch response has construct (induced by pharmacological effect necessary to induce
hallucinogenic effects in humans) and predictive (dose in animals predicts dose in humans)
validity.
Head-twitch response has been used to detect activity of serotonergic hallucinogens at
the 5-HT2A receptor (Halberstadt, 2015). These stereotyped behaviours are reliably induced in
non-human animals following Psi treatment, once the dose crosses a threshold of efficacy, and
are potentially suppressed at higher doses. However, extremely high doses also induce
myoclonus or head rotation in a dose-dependent manner (Jenner et al., 1981). HTR was not
observed in a 5-HT2A receptor knockout mouse, suggesting 5-HT2A is necessary for HTR
(Halberstadt et al., 2011). Similarly, interactions with 5-HT antagonists prohibit HTR in non-
human animals (Tyls et al., 2016). The timing of peak induction of HTR corresponded with
increase in extracellular 5-HT.
In investigations of dose-dependence response, peak effect was reported following 1
mg/kg whole mushroom extract. Authors suggest the decreasing effect of higher doses may be
due to saturation at 5-HT2A receptors and subsequent binding with other receptors that may
inhibit HTR (Halberstadt et al., 2011). Comparing studies that compress observations over time
may confound outcomes. One study suggested HTR behaviour peaks 20 – 40 minutes following
injection (Sakashita et al., 2015). Significant induction of HTR was only detected in the same
period (20 – 40 minutes post-injection) in another study, and not before or after (Kirsten &
Bernardi, 2010). Halberstadt et al. report no effect of sex or interaction of sex and other factors
on the induction of HTR (2011). Kirsten & Bernardi report sex-dependent differences in shaking
behaviour of mice following injection of a whole mushroom extract (2010).

179
Other stereotyped motor behaviours were observed following Psi administration,
including limb flicks and head shakes in cats (Jacobs et al., 1976, 1977a, 1977b; Trulson et al.,
1981, 1984). These behaviours occur infrequently, if at all, in untreated animals. Limb flick
behaviour was dose- and time-dependent, with larger doses more likely to elicit the behaviour
and frequency peaking about 30 minutes following injection (Trulson et al., 1981). Single and
repeated administration of Psi produced acute limb jerking in non-human primates (Schlemmer
& Davis, 1986; Sink et al., 1983).
Table 5.21: Effects on Stereotyped Behaviour
Citation
Animal Model
Measure
Treatment
Outcome
Donovan et
al., 2020
♀ Pigs
Headshakes (first
30 minutes
following
psilocybin
administration)
Hind-leg scratching
Rubbing
0.08 mg/kg
psilocybin (IV)
Treatment
immediately
before testing
Behaviour
reported for 30
minutes
Headshakes significantly increased
following psilocybin
administration, most pronounced
within the first 10 - 15 minutes
following administration and
dissipating by 30 minutes
following administration
Hindleg scratching: Significantly
increased for first 20 minutes
following administration
Rubbing against the pen wall:
Most pronounced in the first 10 -
15 minutes following
administration, but also more
intermittent than scratching
behaviour.
Scratching and rubbing showed
higher inter-individual variability
than stereotyped headshakes.
All three behaviours disappeared
after 30 minutes

180
Everitt &
Fuxe, 1977
♂♀ Rats
(Sprague-
Dawley)
Extensor hindlimb
reflex
0.1, 1.0 mg/kg
psilocybin
Increased extensor reflex activity
with higher but not lower dose of
psilocybin - reached significance in
in ovariectomized females but not
normal males
Guest &
Consroe,
1979
Rabbits
Spontaneous
behaviours
(including
standing, rearing
and locomotion)
immediately
assessed by an
experimenter-
operated digital
event recorder
1, 3 mg/kg
psilocybin (IV)
Normal behaviours replaced by
overt behavioural disturbances
including hind limb stamping and
head bobbing
Halberstadt
et al., 2011
♂♀ Mice
(C57BL/6J, 5-
HT2AR
knockout)
♂♀ Mice
(C57BL/6J, 5-
HT2AR
knockout)
Head-twitch
response (number
of occurrences
during 10-minute
observation)
0.3, 0.6, 1.2, 2.4,
4.8 mg/kg psilocin
Administered
immediately prior
to testing
0.6 mg/kg psilocin
Psilocin induced head twitch
response in wild-type but not 5-
HT2AR knockout mice
Head twitch (counts/ 10 minutes)
increased significantly with higher
doses 0.6 - 4.8 mg/kg psilocin (but
not at lower - 0.3 mg/kg doses)
Psilocin induced head twitch
response in wild-type but not 5-
HT2AR knockout mice
Hesselgrave
et al., 2020
(2032)
♂ Mice
(C57BL/6J)
Head-twitch
response
1mg/kg psilocybin
(IP)
Ketanserin did not impair synaptic
nor behavioural response to HTR
but did significantly reduce HTR
Hesselgrave
et al., 2021
(1887)
♂ Mice (C57)
Head-twitch
response
Immediately to 20
minutes following
administration
0.05 - 0.1 mg/kg
psilocybin (SC)
Ketanserin reduced HTR, similar to
control
Evaluating other behaviours by
high- and low-HTR response in
individuals - no differences
between groups? Restoration of
reward behaviour independent of

181
Higgins et
al., 2021
♂ Rats (Long
Evans)
Wet dog shakes
(WDS)
Evaluated
immediately post
dose - 2 hours
0.03, 0.1, 0.3, 1, 3,
10 mg/kg
psilocybin (SC)
Significant increase in WDS 0.3 -
10 mg/kg
Jacobs et al.,
1976
♀ Cats
Limb flick
0.05, 0.1 mg/kg
psilocybin (IP)
Treatment elicited limb flicking in
cats; behaviour occurred more
frequently with higher dose (0.1
mg/kg)
Jacobs et al.,
1977(a)
♀ Cats
Limb flickª; head
and body shakes
0.025, 0.1, 0.75
mg/kg psilocin
Limb flicking significantly
increased following administration
of 0.1 mg/kg psilocin, but not
lower or higher doses; no
significant changes in head and
body shakes
Jacobs et al.,
1977(b)
♀ Cats
Limb flickª
0.025, 0.1, 0.5
mg/kg psilocybin
(IP)
Significant increase in limb flicking
behaviour at all doses; 0.1 mg/kg
psilocybin elicited larger
behavioural effects than lower or
higher doses
Jenner et al.,
1981
♀ Guinea pigs
20 - 60 mg/kg
psilocin, psilocybin
Myoclonus
Dose-dependent myoclonus
Kiilerich et
al., 2019
Rats (Long
Evans)
0.05 - 1 mg/kg
psilocybin
Head-twitch
response
0.05 mg/kg did not induce head-
twitch response. Dose-dependent
increase in head-twitch response,
until 1 mg/kg, where locomotor
abilities were impaired by
sedation.
Kirsten &
Bernardi,
2010
♂♀ Mice
(Swiss)
Whole mushroom
extract
Wet-dog shakes
(in evaluation of
acute toxicity)
Female mice more sensitive than
males; significance arose in time-
dependent manner, significant in
females 19 - 29 minutes following
administration (different temporal
trend, with non-significant
increase, in males)
Klein et al.,
2021
♂ Mice
(C57BL/6J)
HTR
Evaluated
immediately after
0.1, 0.3, 1, 3
mg/kg psilocin (IP)
Dose-dependent curve, significant
at 0.3, 1 mg/kg but not lower or
higher

182
treatment to 30
minutes
Luscombe et
al., 1984
♀ Guinea pigs
(Dunkin-
Hartley)
Myoclonus
10 mg/kg psilocin
(threshold dose)
Threshold dose - 10 mg/kg
psilocin, with mean duration of 50
minutes
Martin et al.,
1978
♀ Dogs
Flexor reflex,
stepping reflex
0.025 - 0.05 mg/kg
psilocin
Increase in flexor reflex, induction
of stepping reflex
Meldrum &
Naquet,
1971
(REMOVE)
NHPs
(Baboons)
ILS-provoked
myoclonus
4 mg/kg psilocybin
(IV)
Photic stimulation induced limb
myoclonus…
Sakashita et
al., 2015
♂ Rats
(Wistar)
10 mg/kg psilocin
(IP)
Head-twitch
response (counts/
20 minutes)
0 - 20, 20 - 40, and
40 - 60 minutes
post injection
Significant increase in head twitch
response, with no effect of time
(measurements occurred 0 - 60
minutes following drug
administration)
Schlemmer &
Davis, 1986
NHPs (Macaca
arctoides)
Limb jerk; body
shake
0.4 mg/kg psilocin
Significant increase in limb jerks,
but not body shakes, following
treatment
Schneider,
1968
♂ Rats
(Wistar)
Head-turning
behaviour
80, 120 mg/kg
psilocybin (SC)
Treatment 20
minutes prior to
behavioural
testing
Dose-dependent increase in head-
turning behaviour
Shao et al.,
2021
♂♀ Mice
(C57BL/6J)
HTR
0.25, 0.5, 1.0, 2.0
mg/kg psilocybin
(IP)
Dose-dependence curve - peak at
1 mg/kg
Time - peak 6 - 8 minutes after
administration, gradually declined
until deceasing at 2 hours

183
Sherwood et
al., 2020
♂ Mice
(C57BL/6J)
HTR
Assessed for 20
minutes
0.3 - 3 mg/kg
psilocybin
ED50
HTR in dose-dependent manner -
threshold, no significant effect
with 0.3 mg/kg
Sink et al.,
1983
NHPs (Macaca
arctoides)
Limb jerk; body
shakes
0.01 - 1.0 mg/kg
psilocybin; 5 doses
over 10 weeks
(IM)
Psilocybin induced limb jerks, but
not body shakes
Trulson et
al., 1981
♀ Cats
Limb flickª; head
shake
0.025, 0.1, 0.75
mg/kg psilocin (IP)
Only lower doses (0.25, 0.1 mg/kg)
significantly increased limb flick
behaviour, with 0.1 mg/kg having
the most significant and sustained
effect; effect of treatment was
time-dependent, with behaviour
peaking about 30 minutes
following injection
Trulson et
al., 1984
♂♀ Cats
Limb flickª; head
shake
0.025, 0.1, 0.75
mg/kg psilocin (IP)
Only 0.1 mg/kg psilocin
significantly increased limb flick
behaviour; no significant increase
in head shaking behaviour
Tyls et al.,
2016
♂♀ Rats
(Wistar)
Wet dog shakes
(head twitch
behaviour)
measured in a 5-
minute open-field
test
0.25, 1.0, 4.0
mg/kg psilocin
Treatment increased wet-dog
shakes; frequency of wet-dog
shakes increased after 0.25 mg/kg
psilocin in only female rats (more
sensitive to lower doses…)
See discussion…
Zhuk et al.,
2015
♀ Mice
HTR
0.25 - 2 mg/kg
psilocin
(behaviour
observed after 10
minutes)
Two whole
mushroom
extracts
Dose-dependent increase in HTR
(less prominent at 0.25 mg/kg),
slight biphasic curve

184
5.2.5.6.3 Grooming
Grooming in animal research can refer to social (allogroooming) or individual self-grooming
(autogrooming). Grooming is generally indicative of self-care, and in social grooming is known
to stimulate the health of an animal (Kalueff et al., 2016). Self-grooming can lead to changes in
states of arousal for animals, and social grooming strengthens social bonds. Allogrooming aids
individual rodents in thermoregulation and provides markers such as scent for social
recognition (identification as part of a social set). The broad value of studying self-grooming in
animals is as a model of complex, repetitive and self-directed, sequentially patterned
behaviours (Kalueff et al., 2016), an example of a coordinated activity and not so much a
pathological endophenotype (Anderzhanova et al., 2017). Ten studies identified in this scoping
review investigate the effect of Psi on grooming behaviour.
In non-human primates, Psi elicits a dose-dependent decrease in social as well as self-
grooming behaviour (Schlemmer & Davis, 1986), reduced normal affiliative behaviour including
reductions in social grooming and increased distancing from other animals with dose-
dependent reductions in self-grooming while increasing lying down postures (Sink et al., 1983).
The effects of Psi on grooming in cats is inconclusive, as one study reports a significant
increase in the behaviour following the lowest dose administered (0.025 mg/kg psilocin)
(Trulson et al., 1984) while another study reports no significant effect– though a non-significant
increase in grooming is reported at the same dose (Trulson et al., 1981). One study reports a
decrease in autogrooming behaviour in rabbits tested in an individual box (Guest & Consroe,
1979).

185
Rats observed in the open field test spend less time grooming following Psi administration
(Cunha & Masur, 1978; Tyls et al., 2016). Other studies report no acute effect of low doses of
Psi on grooming behaviour when rats are evaluated in an automated activity test chamber
(Higgins et al., 2021) and no persisting effect of a “microdosing” regime on grooming (0.05
mg/kg psilocybin administered every second day for 3 weeks) (Kiilerich et al., 2019). Following
administration of a whole mushroom extract, a significant increase in the frequency of
individual grooming behaviour is reported in female mice but not in male mice (Kirsten &
Bernardi, 2010). Reductions in grooming behaviour in rodent studies are associated with
reductions in other activity including sniffing and rearing (Tyls, 2016).
Table 5.22: Effects on Grooming
Citation
Animal
Model
Measure
Treatment
Outcome
Guest &
Consroe, 1979
Rabbits
(Albino-
NZ)
Grooming, standing,
rearing behaviour in
individual test
chamber
1, 3 mg/kg
psilocybin (IV)
In rabbits, psilocybin treatment led
to decreases in grooming, rearing
and locomotion
Kiilerich et al.,
2019
Rats, Long
Evans
Grooming
0.5mg/kg (IP)
No induction of behavioural changes
was observed for the very low dose
treatment regimen.
Kirsten &
Bernardi, 2010
Mice
(Swiss,
Mus
musculus),
male and
female
Acute toxicity glass
box test, self-
grooming frequency
0.1mL extract/
10g, P. cubensis
aqueous extract
(IP)
Increased self-grooming among
females vs. control, reduced self-
grooming among males vs. control
Schlemmer &
Davis, 1986
Feral
Stumptail
macaques,
adult
Observation of
behaviour (each
monkey observed for
30 seconds every 5
minutes for 60
minutes
.4mg/kg Psilocin
& Psilocybin (IM)
Reductions in social and self-
grooming

186
Sink et al., 1983
Adult
Stumptail
macaques
General behavioural
observation using
'focal sampling
technique'
0.1-1mg/kg
psilocybin (IM)
Reduced normal affiliative behaviour
(less grooming/more distance from
other animals. Dose dependent
reduction in self-grooming and
increase in lying down.
Trulson 1981
Adult
female
cats
Increase in
investigatory of play
behaviour at 100 ug.
Behavioural
observation
25, 100, or 750
micrograms/kg
psilocin (IP)
Significant reductions in activity at
various timepoints for 100/750 ug
doses.
Trulson 1984
Adult cats,
male and
female
Behavioural
observation of freely
moving cats
25, 100, or 750
micrograms/kg
psilocin (IP)
Minimal changes to abortive
grooming observed
Cunha and
Masur,
Rats
(Wistar),
male, 90-
110 days
old
Measured frequency
in open field test;
observation for 20
minutes, with
application of dark,
vanillin odor, sound,
and light (5 minutes
each stimulus)
0.50, 1.00mg/kg
psilocybin (IP)
Reduced self-grooming
Tyls, 2016
Rats
(Wistar;
Hannover
breed),
male and
female
adult
Emergent
observational, 5-
minute OFT
0.25, 1.00, 4.00
psilocin (SC)
psilocin, especially
at the highest dose used,
significantly attenuated the
total time spent rearing, grooming
and sniffing in all
groups
Higgins, 2021
Rats (Long-
Evans),
male
Behavioural
observation during
testing period
psilocybin ( 0.05
- 0.1 mg/kg) (SC)
No main treatment effect of
psilocybin
Grooming may not be a helpful assay in the understanding of psychedelic drug effect as
it is reduced across a range of drugs (Cuhna and Masur, 1978). Psilocybin displays biphasic
effects, with no reductions in grooming at very low doses but disruptions evident at standard
doses and above. Effects on grooming may be related to the time-course of the drug effect as
disruptions to usual grooming behaviours occurred prior to observations of increased

187
immobility, especially at higher doses. Grooming can be considered reward behaviour as well as
affiliative behaviour; grooming also indicates or can change states of arousal in animals.
Grooming assays should be considered across Positive Valence, Social Processes, Arousal and
Self-Regulatory Systems domain constructs, as well as Sensorimotor Systems.
5.2.5.6.4 Prepulse Inhibition
Five studies investigate the effect of PSI treatment on prepulse inhibition (PPI) of
acoustic startle response (ASR) (Kiilerich et al., 2019; Palenicek et al., 2005; Tyls et al., 2011; Tyls
et al., 2013; Tyls et al., 2016). PPI is a phenomenon of sensorimotor gating. When a low-
intensity stimulus (the prepulse) is presented shortly before a high-intensity, startling stimulus,
the amplitude of the startle response is subsequently reduced (Hanks & Gonzalez-Maeso,
2013). Psi is effective at disrupting prepulse inhibition in rats, such that the startle response is
no longer dampened following the presentation of a prepulse (Palenicek et al., 2005; Tyls et al.,
2011; 2013; 2016). This effect may be dose-dependent and have sex-specific effects. 1 mg/kg
psilocin (IP) effectively disrupts PPI ASR in rats, but lower doses (0.25 mg/kg) have no effect and
higher doses (4 mg/kg) have variable effects. One study showed no significant effect of
psilocybin on PPI, but with a positive trend to approach significance (Kiilerich et al., 2019).
Following similar treatment, Psi did not significantly disrupt PPI in female rats, but did have a
significant effect in males (Tyls et al., 2016).
Psi impairs prepulse inhibition of the startle response such that the amplitude or
intensity of startle-stimuli-induced motor response is larger than untreated controls. This may
not occur following administration of higher doses, as it was also shown that startle amplitude
is reduced following treatment with higher doses (see Startle Reflex). It is unclear whether high

188
doses of Psi may depress motor responses non-specifically, akin to previously described
reduction in locomotor activity.
The modulatory effects of psilocybin on acoustic startle response and prepulse
inhibition have also been investigated in humans (Gouzoulis-Mayfrank et al., 1998; Quednow et
al., 2012; Vollenweider et al., 2007). In human studies, Psi-induced increases in PPI at long ISIS,
decreases in PPI at short ISIs, phenomena correlated with impaired attention and consistent
with the deficient PPI found in schizophrenia (Vollenweider et al., 2007). Co-administration of
5-HT2A, 5-HT2B, and 5-HT2C receptor antagonists did not impair the effect of Psi on PPI (Tyls et
al., 2016); the full mechanisms contributing to psilocybin’s impairment of PPI remain unclear
though consistent with thalamic filter models of psychedelics action (Grandjean et al., 2021;
Preller & Vollenweider, 2018; Vollenweider, 2001).
Table 5.23: Effects on Prepulse Inhibition of the Acoustic Startle Response
Treatment
Time Between
Treatment and
Testing
Effect*
Outcome
0.25 mg/kg
psilocin
-
No significant effect of treatment on PPI
(Tyls et al., 2011; 2013; 2016)
1 mg/kg psilocin
-
↓
↓♂
No significant effect of treatment on PPI,
but positive trend (Kiilerich et al., 2019)
Significant deficits in PPI ASR (Palenicek et
al., 2005; Tyls et al., 2011; 2013)
Significant deficits in PPI ASR in male, but
not female rats (Tyls et al., 2016)
4 mg/kg psilocin
-
↓
Significant deficits in PPI ASR (Tyls et al.,
2013)
No significant effect of treatment on PPI
behaviour (Tyls et al., 2011; 2016)
All experiments performed in rats.

189
5.2.5.7. Adverse Events
Few adverse events were reported in the scope of this review. We identified seven
studies as reporting adverse events. In some cases, these events were communicated in passing
and not identified as adverse events in the publication itself. Overall, across the seventy-seven
publications and one hundred and thirty paradigms reported, the safety profile of psilocybin at
a biological level appears exceedingly safe. As reported earlier, some of the physiological
effects reported earlier (increased heart rate, for example) could be considered adverse as
could some of the stereotyped behaviours reported (such as head-twitch or limb flick). Many
trials report sedation at high doses, if that can be considered adverse. Of the seven trials
reported adverse effects, none are correlated with psilocybin drug-effect, but rather, most
likely related to animal housing conditions. Respiratory infections were reported, surgical
infections, as well as one “premature” death with no reference to causation or relation to drug
effect. Several studies mention deaths of study animals during pre-drug training schedules prior
to Psi administration.
Exceedingly high doses of psilocin, psilocybin and whole mushroom extracts were
tolerated. No toxic effects were reported following intraperitoneal administration of 180 – 250
mg/kg psilocin in mice (Zhuk et al., 2015). However, the reported range of lethal effect is
narrow, with the median lethal dose (LD50) of psilocin only a slightly higher concentration
(293.07 ± 1.02 mg/kg). LD50 value for whole mushrooms extracts was greater than those of pure
psilocin and the application of psilocin exhibited the highest toxicity compared to the extracts.
Other investigations with high doses were tolerated. Subcutaneous administration of 80 – 120
mg/kg psilocybin to rats induced ataxia and unusual behavioural effects as evidenced by motor

190
discoordination (Schneider, 1968). Intraperitoneal injection of 100 mg/kg psilocybin and 72
mg/kg psilocin in mice led to piloerection, exophthalmos, and hind-leg ataxia, with effects
completely reversible and animals appearing completely normal within three to four hours
following treatment, except for some depression of activity (Horita & Weber, 1962). In
evaluating the acute toxicity of an aqueous Psilocybe cubensis extract, increased gnawing
behaviour and stereotyped shaking was reported, but no other harmful physical effects or
mortality (Kirsten & Bernardi, 2010). Vomiting and restless behaviour was reported among
macaque monkeys, adverse events common to humans. This study investigating electrocortical
activity with concomitant electrical stimulation reported that intraperitoneal injection of
psilocybin (1 – 3 mg) in macaque monkeys (weighing 5 – 6 kg) produced occasional vomiting
(Wada, 1962).
Overall, few studies report adverse events following Psi treatment, even with
exceedingly high doses. However, some doses were assessed in pilot studies and not used in
experiment as the doses impaired movement in such a way that would interfere with the
behavioural task. Higher doses of psilocin (5 and 10 mg/kg) were not included in a study of
investigatory behaviour in rats, as the animals became ataxic (Geyer et al., 1979). Dose-
dependent responses were investigated in pigs (Donovan et al., 2021). Doses of 0.04 and 0.08
mg/kg psilocybin had an observable effect on behaviour, while 0.16 mg//kg led to the animal
lying down with its eyes closed and without moving. The lower dose (0.08 mg/kg) was selected
for further behavioural testing.

191
Table 5.24. Studies Reporting Trial-related Adverse Events
Study
Adverse Events Reported
Guest and Consroe,
1979
Normal behaviours were replaced by overt behavioural disturbances,
consisting of cataleptic episodes of frozen off-balance postures, and
extreme mydriasis
Everitt & Fuxe, 1977
Higher doses of psilocin were tested (5.0 and 10.0 mg/kg), data was not
included as the animals became ataxic
Horita & Weber,
1962
Some depression persisted over 3 - 4 hours following psilocybin
administration
Meldrum, B. S.;
Naquet, R., 1971
9 baboons had surgical complications in the brain (1 corpus collosum, 7
small unilateral cortical ablation of fronto-rolandic cortex region, and 1 a
similar ablation bilaterally).
Roberts, M. H. T.;
Bradley, P. B., 1967
One monkey died prematurely but adverse events not reported and
multiple drug compounds were used.
Wada, Juhn A., 1962
I.P. injection of 1 - 3 mg psilocybin produced restless behaviour
accompanied by occasional vomiting among macaque monkeys
Koerner & Appel.
1982
3 rats died of respiratory infection

192
Chapter Six:
Discussion and Conclusions
Discussion
6.1. Mapping Psilocybin-assisted Therapies
What emerges from the scoping review on psilocybin-assisted human clinical trials is a
new, but relatively consistently applied and experientially-oriented psycho-pharmacotherapy,
best combined with psychological support and conducted in a thoughtful, appropriate setting
with prepared and pre-screened individuals. A relative consensus emerges of a medium to high
dose protocol (with the exception of the migraine trial) with an escalation of dosage over 2-3
treatment sessions, prefaced by intensive psychological preparation and post-treatment
integration in the treatment of mental health conditions. Therapies for neurological pathologies
may require lower doses; psilocybin for migraines is unique in that no other single drug has
been reported to abort attacks, induce remission from migraines, and to prolong duration of
remission (Schindler et al., 2020). In addition to the characteristics and outcomes reported in
our summary tables, several reportable and common themes emerged from the literature
included in this review. Each is identified and discussed within the larger field of psilocybin
research, which includes important observational, naturalistic and survey studies in addition to
those controlled trials carried out with healthy volunteer subjects.
6.1.1 Quality of the Subjective Psilocybin Experience Predicts Degree of Positive Outcome
One finding consistent across several of the trials was that the quality of psilocybin
experience is strongly correlated with positive treatment outcomes (Bogenschutz et al., 2015;

193
Carhart-Harris et al., 2016a; Garcia-Romeu et al., 2014; Griffiths et al., 2016; Roseman, Nutt, et
al., 2018; Ross et al., 2016); however, the OCD trial and migraine trial demonstrated no such
correlation (Moreno et al., 2015; Schindler et al., 2020). The acute subjective experience of the
trial subject was the focus of many of the metrics employed to assess the quality of psilocybin
experience, most commonly measured in Oceanic Boundlessness (OB), Dread of Ego Dissolution
(DED) and Altered States of Consciousness scales. Many of the trial subjects reported mystical-
type experiences characterized by a deep sense of oneness and interconnectivity. Similarly, the
intensity of mystical-type experiences during psilocybin-assisted therapy has been correlated
with treatment outcomes for alcohol dependence (Bogenschutz et al., 2015) and nicotine
dependence (Garcia-Romeu et al., 2015; Johnson et al., 2014; 2017).
However, not all the trials found high rates of mystical experience. In the Bogenshutz
(Bogenschutz et al., 2015) study on alcohol use disorder, only 3 of the 17 (17.6%) participants
had mysticomimetic experiences, perhaps indicating a possible blunting effect from alcohol
dependence, and Schindler’s migraine study (Schindler et al., 2021) reported no mystical
experiences although dosing was lower (0.143mg/kg) than most other studies. In general,
attributions of meaning or positive experience both correlated with improved clinical
outcomes. While mysticism as a proposed mechanism of change has been a dominant
discourse in the psychedelic literature, it is clear that meeting the criteria for a mystical
experience is not necessary to experience clinical benefit, and that psilocybin may be best
conceived as an experience of deep emotion and personal insight. Trials report wide variation
in experiences among subjects; psilocybin experiences are rich, highly variable, deeply
emotional, personalized and memorable.

194
6.1.2 Transient Psychological Distress and Post-session Headaches
No serious or life-threatening adverse effects were experienced in any of the trials
significant enough to question the safety of psilocybin in a controlled setting. However,
transient side effects during psilocybin sessions, often experienced as challenging, were
reported: acute reactions of confusion, fear, paranoia, anxiety, nausea, headache,
disorientation and transient psychological distress were reported; in some trials upwards of
40% of trial subjects reported significant transient distress (Anderson et al., 2020; Carhart-
Harris et al., 2016b; Davis et al., 2020; Johnson et al., 2014). Psychedelics often cause periods
of confusion, disorientation, anxiety, fear, panic, dysphoria, paranoia and emotional turmoil
during the immediate drug effects; such adverse effects can last for a few days (Johnson et al.,
2008a; Krebs & Johansen, 2012; Strassman, 1984) and have been documented in “naturalistic”
in addition to clinical settings (Carbonaro et al., 2015, 2016).
Notably, several trials found post-treatment headaches to be common in 40-50% of
subjects. (Grob, et al., 2011, Carhart-Harris, et al, 2016); a pattern of dose-dependent, delayed
and transient headaches has been documented in healthy volunteers administered psilocybin
(Johnson et al., 2011). The role of serotonergic psychedelics in both causing and relieving
headaches has been explored elsewhere (Matthew W. Johnson et al., 2012).
While their physiological safety is relatively well established, psychologically toxic
reactions do occur, in part due to the demonstrated sensitivity to context and setting found
with psychedelics (Hartogsohn, 2017; Rucker et al., 2018; Strassman, 1984). Risks of adverse
effects are mitigated by appropriate client selection, the provision of psychological support, a
safe and comfortable setting, and the availability of psychiatric and medical aid (Johnson et al.,

195
2008a; Rucker et al., 2018; Strassman, 1984). Elsewhere, the duration of psychologically
challenging experiences under psilocybin has been negatively correlated with personal
meaning, spiritual significance and increased well-being, suggesting that therapeutic
interventions provided during transient distress should be preferentially aimed at reducing the
duration rather than the peak difficulty (Carbonaro et al., 2016).
In research among healthy volunteers, risk factors for challenging experiences include
younger age, higher emotional excitability and being confined to brain imaging equipment
(Studerus et al., 2011). Low baseline emotional excitability, high scores on the ability to
experience absorption and having few recent emotional problems are all associated with having
a pleasant mystical-type experience (Studerus et al., 2011). Dosing may be implicated in the
likelihood of adverse experiences. Trials used a range of doses, often escalating from low to
medium to high. Griffiths’ study with healthy volunteers found a dose-dependent relationship
between dosage level and improvements in well-being (Griffiths et al., 2011); experiences of
fear and feeling trapped were most prominent at the highest dose range, suggesting optimal
experiences for a broad range of participants may be found at the 20mg/70 kg dose (Aday et
al., 2021).
Adverse effects such as strong dysphoria, anxiety and panic occurred only at high doses,
and follow-up found no subsequent psychedelic use, persisting perceptual disorders, psychosis
or other long-term impairments. The possibility exists for some participants to experience
significantly challenging experiences, with long-term negative impact. In a pooled analysis of
healthy volunteers taking psilocybin, found that that acute dysphoria, panic and severe anxiety
occurred only in the two highest dose conditions (highest dose condition reported = 28mg) and

196
in a small proportion of subjects. Overall, 12% of participants reported having experienced
negative changes in psychological well-being and or mental functioning after psilocybin (n=11,
though 4 of the 11 report the difficulties as unrelated to psilocybin) (Studerus et al., 2011). One
broad-based naturalistic research survey of challenging experiences under psilocybin found that
39% of respondents reported psilocybin as among the top five most challenging experiences of
an individual’s life: 11% of respondents put themselves or others at risk under the influence,
2.5% became aggressive and 2.7% received medical help (Carbonaro et al., 2016). Research
suggests reducing the duration, rather than the peak difficulty, of challenging psilocybin
experiences.
The notion of ordeal may be considered a therapeutic dynamic in the context of
psychedelic-assisted therapy. Psilocybin has been found to acutely increase blood cortisol and
corticotropin, and the acute stress experienced under psilocybin may serve to increase
resilience to future stress events (Shao et al., 2021). However, the challenging experiences
documented do indicate the need to reduce possible harms by adequate client selection,
preparation and the curation of non-pharmacological variables such as setting and support.
6.1.3 Program Variables and Psychological Supports
A number of studies cite the importance of non-psilocybin factors including music,
which has been found to be both a negative and a positive variable (Belser et al., 2017; Kaelen
et al., 2018). Research suggests that nonpharmacological variables are responsible for a
significant part of therapeutic benefits in a variety of drug treatments beyond psychedelics
(Hartogsohn, 2017). Psychedelics have a demonstrated sensitivity to setting (Hartogsohn, 2017;

197
Rucker et al., 2018; Sellers & Leiderman, 2018), to suggestibility (Carhart-Harris et al., 2015;
Hartogsohn, 2018), and to language (Family et al., 2016; Spitzer et al., 1996). The psychological
support provided remains a confounding factor and limitation of study findings (Rucker et al.,
2018; Sellers et al., 2018).
The addiction-related trials used classical and manualized programs of Cognitive
Behavioural Therapy or Motivational Enhancement Therapy in addition to preparation and
integration sessions, ostensibly for amplification and synergistic effect. So-called Third-Wave
behaviourist therapies appear to fit well with the dynamics of psilocybin-assisted therapies
(Walsh & Thiessen, 2018). However, the exact interaction between pharmacological and
psychological effects and their relevant contributions to symptom reductions remains unknown
and unexplored (Koslowski et al., 2022). Given the potential for challenging experiences and the
dramatic effects psychedelics may occasion, it would be considered unethical to not provide at
least some degree of psychological preparation and support given the psychoactive nature of
psilocybin (Johnson et al., 2008a; Rucker et al., 2018; Strassman, 1984).
The therapeutic dose range of psilocybin has yet to be confirmed, however the
convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential
advantage of weight-adjusted dosing, as was done in several of the trials (Garcia-Romeu et al.,
2021). Drug effects tend to be dose-dependent, and psilocybin displays both dose and time-
dependent effects (Preller et al., 2020). Challenging experiences are more likely to occur with
higher doses, and lower doses produce acute anxiogenic-type effects. Even after acute drug
effects have subsided and 5-HT agonism is resolved, studies have documented downstream
sub-acute and persisting effects to psilocybin (Barrett, Doss, et al., 2020). Measurement of

198
psilocybin’s effects should consider both time-of-day of dose administration and conduct
outcome measures at various points (Schindler et al., 2018) along a time course of at least one -
month up to several years to fully understand the effects of psilocybin therapies.
6.1.4 Concerns Regarding Trial Design
Trials reported several limitations which significantly limit the generalizability of
findings. Several of the trials were not controlled, but rather open label exploratory trials to
determine safety and efficacy. In addition, several of the trials included a significant number of
widespread metrics and multiple assessment tools, indicating a lack of specificity in identifying
mechanisms of action. Consistently and despite various approaches, trials reported a strong
difficulty in truly blinding and staff due to the obvious effects of psilocybin. Given the nature of
participation in these clinical trials, coupled with the prevalence of past psychedelic use among
participants, expectancy bias appears strong; at least one trial reported improvements in
participant well-being prior to their first psilocybin session, perhaps due to the confounding
influence of psychotherapeutic services provided beforehand (Griffiths et al., 2016).
Cancer trials showed the highest level of methodological rigor, as each used a controlled
crossover design. The nature of the crossover design in the included clinical trials led to
reported unblinding of both participant and investigator, allowing for influencing of
expectations (Grob et al., 2011; Griffiths et al., 2016, Ross et al., 2016) and limited the
assessment of efficacy and clinical benefit after the crossing over of treatments (Griffiths et al.,
2016; Ross et al., 2016). Crossover designs which employ a placebo also suffer from the
potential of carryover effects for the experiment-first, placebo-second group. This can be
minimized, but not eliminated, through a wash-out period, which varied between one to seven

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weeks for the three studies (Grob et al., 2011; Griffiths et al., 2016, Ross et al., 2016). A major
advantage of the crossover design is, as participants act as their own control, the effect of
extraneous participant variables is minimized. Crossover designs are favoured when the sample
size is small, as the same statistical power can be achieved as a parallel-designed study with
twice the sample size (Ofori-Asenso & Agyeman, 2015). The nature of the crossover design led
to reported unblinding of both participant and investigator allowing for influencing of
expectations (Grob et al., 2011; Griffiths et al., 2016, Ross et al., 2016). Crossover designs also
reportedly limited efficacy assessment and clinical benefit after the crossing over of treatments
(Griffiths et al., 2016; Ross et al., 2016). Given the documented persisting and downstream
effects of psilocybin and lack of a standardized wash-out period, parallel designs may be better
suited to psilocybin trials.
Trials also tended to have small subject sample sizes, reducing internal and external
validity. In addition, the relatively homogenous patient demographics limit the generalizability
of the psilocybin trial findings. The pool of trial subjects was predominantly white, older, and
were often professionals with post-secondary education. The combination of self-selecting and
motivated trial subjects, combined with highly motivated trial investigators, may create strong
expectancy and placebo biases in these trials (Koslowski et al., 2022). It is not clear if this
modality would be effective with patients characterized by greater mental health co-morbidity,
marginalization, poverty, instability or relative youth. Trials reported common exclusion
criteria: personal or family history of schizophrenia/other psychotic disorders or bipolar
disorders, personal cocaine, psycho-stimulant or opioid dependence, or family history of
suicide. The Anderson trial with long-term AIDS survivors is in this way unique, enrolling

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patients with borderline personality disorder (BPD) (Anderson et al., 2020). Trials required
subjects to be free of selective-serotonin reuptake inhibitor class anti-depressant medications
and screened out pregnant women and individuals with relevant chronic medical conditions
such as unmanaged hypertension.
Table 6.1. Common Clinical Trial Exclusion Criteria
Psychiatric Conditions
Schizophrenia / Psychotic Disorders
Bipolar Disorder
Substance Use Disorder
Obsessive-Compulsive Disorder
Dysthymic Disorder
Anxiety / Panic Disorder
Dissociative Disorder
Anorexia Nervosa
Bulimia
Suicidality
Avoidance
Narcissism
History of repeated violence
Family History (1st /2nd degree) major psychiatric disorder
High rigidity scores
High emotional lability scores
Health Conditions
uncontrolled hypertension
pregnancy
breast-feeding
serious neurological disease
serious renal or liver disease
serious cardiac disease
Medications
SSRIs
tricyclic antidepressants
lithium
haloperidol
antipsychotics
MAO inhibitors
fluoxetine
benzodiazepines

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Serotonin supplements
St. John's Wort
(M. W. Johnson et al., 2008b; Rucker et al., 2018; Strassman, 1984)(Robin L. Carhart-Harris et al., 2016a; Roland R.
Griffiths et al., 2016; Ross et al., 2016)
Lack of inclusion and representation of Black communities, Indigenous peoples and
People of Colour is a widespread and concerning characteristic of psychedelic research (Fogg et
al., 2021; George et al., 2019; Michaels et al., 2018) and of clinical trials for mental health
conditions in general (Williams et al., 2010) . BIPOC communities are greatly underrepresented
in psychedelic studies; one recent review of 17 contemporary psychedelic clinical trials found
82.5% of all trial subjects were white (George et al., 2019). Improved recruitment strategies are
necessary to better understand potential efficacy, and to provide equal opportunities for
involvement in these potentially beneficial therapies (Michaels et al., 2018). Without such
inclusion, it remains an empirical question whether these research findings apply to diverse
populations (George et al., 2019). There is a clear need for consideration of ethno-psycho-
pharmacological variables in future clinical trial design (Fogg et al., 2021); greater
representation of historically disenfranchised communities among research teams may lead to
less cultural bias in study design (Johnson et al., 2008 ).
The study and measurement of self-reported mystical experiences in these trials may
also be problematic and carries clear limitations. Mysticism refers to non-ordinary experiences
of a transpersonal, spiritual or religious nature, which can occur spontaneously, or as a result of
techniques to alter consciousness including psychedelic drug use. Many of psilocybin trial
subjects self-report mystical-type experiences characterized by a deep sense of oneness and
interconnectivity. The standard tools used to measure mysticism in these trials are the
Mysticism Scale (MS) and more commonly the Mystical Experience Questionnaire (MEQ), both

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developed in an earlier era of psychedelic research (1975). Both share an underlying concept of
mysticism as an experience of undifferentiated unity, a concept which may be overly narrow as
a framework and which negates the difficulty or ordeal experiences often found with
psychedelics (Taves, 2020). The development of metrics more inclusive to a range of
transpersonal or spiritual experiences would be of benefit to future trials, as would the
expansion of measures not dependent on self-report such as biomarkers of neuroinflammation
or heart-rate variability.
Unexpectedly, the most recent Carhart-Harris for depression (Carhart-Harris et al., 2021)
failed to establish benefit for psilocybin over escitalopram. One clear limitation of this trial is
the brief duration of escitalopram treatment (6 weeks) provided, given its delayed onset of
antidepressant effects. The confounding factors of psychological support and suggestibility
remain as with previous trials. Considering the difficulty in blinding to the effect of psilocybin,
expectancy bias is also noted. Escitalopram and psilocybin-assisted therapy are also usually
delivered in quite different modalities; combining the two in this trial design may account for
some of its more interesting outcomes. The trial may not have been significantly powered to
properly detect differences in outcome. As the trial group was characterized by mild-to-
moderate depression, extension to more severe or to treatment-resistant depression
populations is limited. Study authors also noted that their selection of primary outcome
measurement characterized the somewhat surprising outcomes to this trial. Larger and longer
trials are required to investigate the relative advantage of psilocybin over standard anti-
depressant treatments. This trial’s results also raise the question of outcome measures, and by
what criteria we advance novel treatments for depression. Studies to date have been driven by

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the measurements of negative symptomatology and not overall well-being or positive affect.
Further, given the number of secondary publications emerging from the Carhart-Harris
psilocybin trials, a significant amount of research, including multiple neuroimaging studies, has
been conducted on the same, relatively small pool of depressed study patients.
An assessment of registered psilocybin trials at clinicaltrials.gov (November, 2021)
identified 62 new clinical trials registered, recruiting or planned in the U.S. and Europe and an
updated search (April 2023) identified 138 registered studies. Compared to the trials reviewed
here, more now are structured as randomized, double blind parallel designs. Parallel designs
give the advantage of avoiding carryover effects. They are also favored in larger studies; the
newer trials are trending to be larger than those reviewed here. Novel indications include
psilocybin for body dysmorphic disorder, anorexia nervosa, cocaine use disorder,
methamphetamine use disorder, bipolar disorder, concurrent disorders, cluster headaches,
concussion-related headaches, and for depression among people with mild cognitive
impairment or early Alzheimer’s disorder as well as for depression and anxiety among
individuals with Parkinson’s.
Control conditions in the PSI trials reported here varied, ranging from not controlled
open-label trials to randomized controlled trials. Trials used a variety of drug controls as
placebo, including very low-dose psilocybin, niacin or methylphenidate. Waiting lists were used
as controls in some trials (introducing the possibility of nocebo effect), while one study
employed a double-dummy RCT to compare psilocybin to a six-week course of escitalopram.
Trials report difficulties in blinding, as the effects of psilocybin become clear to study
investigators during drug sessions. Randomized controlled trials with psychedelics remain

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challenging due to expectancy bias, the difficulty in blinding study participants, and because of
the confounding variable of the psychotherapies provided. Effectiveness trials require large
size, randomized and double-blinded, multi-site studies with a diversity of patient populations
(Schulz et al., 2010). A number of recommendations have been made for future trials, including
improved and transparent descriptions of psychotherapy protocols, the reporting of therapist
experience and training, dismantling studies, and strategies to control for inter-therapist
differences (Gukasyan & Nayak, 2021).
6.1.5 Therapeutic Models
Psychological therapies given in addition to psilocybin confound the study outcomes
when assessing the therapeutic potential of psilocybin. The dominant clinical model in the
reviewed trials invests heavily in pre-treatment preparation with skilled therapists, provides
little intervention during psilocybin sessions other than a comfortable atmosphere and a
supportive presence, and concludes with the provision of psychological support to help
integrate psychological material generated. This model has elsewhere been termed “peak-
psychedelic” (Bogenschutz & Forcehimes, 2017).
As opposed to the suppression of emotions typical of many psycho-pharmacological
treatments, clinical psychedelic-therapy supports increased awareness and release of
emotion. However, this model has not been independently validated nor have best practices in
psilocybin-assisted therapy yet been confirmed. Clinical trials are designed as investigations to
inform and advance regulatory drug approval; the models of practice cannot be extended to
general practice without significant translation, as the clinical trial is a controlled experiment

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(highly artificial and shaped by restrictive inclusion criteria) principally designed to evaluate the
study drug, and not the accompanying psychological supports or therapies.
Psilocybin experiences are often ones of deep personal vulnerability and openness.
Given that psychedelics increase psychological suggestibility (Dobkin-deRios, 1972, Carhart-
Harris 2015) as they alter cognition, increase emotion, perception and cognition, creating states
of vulnerability (Passie, 2018). The ethics of psychedelic therapy require attention, and models
of training, certification and oversight remain to be developed (Haden et al., 2016; Rochester et
al., 2021). A 2019 bulletin from the Multi-disciplinary Association for Psychedelic Studies
documents therapist sexual abuse of a female client by a MAPS-affiliated MDMA-assisted
psychotherapist (MAPS, 2019a).
The Total Drug Effect model proposed by Feeney (Feeney, 2014) identifies the
importance not only of drug, set and setting, but also belief in the healing ability of the
practitioner and the cultural values assigned to the drug as contributing to healing potential.
The high variability found within and between subjects of the pooled analysis of psilocybin trials
with healthy individuals indicate that psilocybin effects are not predicted by dose alone; other
pharmacological variables such as plasma levels of psilocin, as well as non-pharmacological
variables such as user expectations, personality structure, and the availability of interpersonal
support, and the setting of the experience play determinant roles (Studerus et al., 2011).
6.1.6 A Program of Psilocybin Health Research
Other potentially viable practice models also warrant further investigation; regimens of
lower doses, micro-doses, and collective-group or ceremonial models remain to be
investigated. Reviews of controlled psychedelic micro-dosing trials report changes in time

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perception, increased stimulation, distance from ordinary reality and sense of peace (Kuypers,
2019) improved mood, energy, and cognition, increases in convergent and divergent thinking,
and reduced negativity and increased open-mindedness (Polito & Stevenson, 2019). Increased
anxiety and a cyclical pattern of depressive and euphoric mood states were also found (Kuypers
et al., 2019). A self-report study of microdosers found reductions in depression, stress and
distractibility with increased absorption and neuroticism (Anderson et al., 2019). Smaller sub-
perceptual doses would allow for more relaxed trial inclusion criteria and could possibly be
used in the treatment of PTSD given the role of low-dose psilocybin in reducing fear response in
laboratory non-human animals (Catlow et al., 2013b).
Very low doses of psilocybin have also been found to have anti-inflammatory effects
(Flanagan & Nichols, 2018; Yu et al., 2008) and may be beneficial to microbiome health and
brain-gut communication (Kuypers et al., 2019). It is plausible that, similarly to regular doses,
the improvements in mood and reductions in depression symptoms are due to the psychedelic
compound’s agonism of 5-HT-1A, 2A & 2C receptors and subsequent glutamate release
(Halberstadt, 2015; Ona & Bouso, 2020). Low doses of psychedelics could play a role in treating
affective disorders by increasing cognitive flexibility and subsequently decreasing rumination
(Kuypers, 2019). Preliminary findings support the exploration of the safety and therapeutic
efficacy of microdosing psychedelics for depression and future trials should consider added
blinding mechanisms to reduce expectancy bias, as well as comparative studies between people
with psychedelic experiences and those without (Kuypers et al., 2019). Low-dose, but not high-
dose PSI could be of value in lessening the symptoms of PTSD given the role of low- dose PSI in
reducing fear conditioning in animal models (Catlow et al., 2013a), but the potential for adverse

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and challenging experiences is high in this patient population and at this time psilocybin has not
been investigated for PTSD.
Collective ceremonial models of mushroom use also require further study. There are a
few precedents. The ayahausca church model has been associated with lower rates of
substance use disorder and overall improvements in health (Bouso et al., 2012; Barbosa et al.,
2012; McKenna, 2004) while ceremonial peyote rituals have been proposed as a model of
ethnopharmacological treatment for alcohol and other forms of substance use disorder (Blum
et al., 1977; Prue, 2013; Prue & Voss, 2014). A recent observational study of individuals who
attended legal group psilocybin retreats found that a feeling of communitas during ceremony
was significantly correlated with increases in psychological well-being (Kettner et al., 2021).
Collective ritual ceremony has the added benefits of socialization, peer support and structure,
all factors thought to be beneficial in the process of recovery, and characteristic of the 12-step
recovery model. Further, while much has been made of the potential for psilocybin to induce
mystical-type experiences (Garcia-Romeu et al., 2014; Griffiths et al., 2016; Johnson et al.,
2017; Ross et al., 2016), studies have found this to be not always be the norm; Cummins and
Lyke (Cummins & Lyke, 2013) found 47% of naturalistic users to report peak experiences while
under psilocybin. Subjects reported a range of powerful experiences in these trials; meaningful
and often challenging but not always mystical. A more sophisticated mapping of consciousness
and understanding of altered states remain necessary.
To complement the insights afforded by clinical trials, other forms of research require
attention. Naturalistic, observational and qualitative surveys provide important insights into
psilocybin effects in multiple settings. Psilocybin has a rich cultural and spiritual history, and

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many traditional lineages such as the Indigenous Mazatec remain active and influential today.
Legal psilocybin retreat centres have appeared in multiple jurisdictions. Studies documenting
the experiences of individuals and facilitators of these and of underground mushroom
ceremonies can provide helpful information to inform a contemporary and comprehensive
research agenda on psilocybin. Psychedelic-assisted therapy is but one model of working with
psilocybin; the clinical trial trajectory of medically managed PSI-AT as a “new paradigm” of
psychiatry must be contextualized along with other traditions of use, individual recreational
use, underground ceremonies and other future possibilities. Given the popular interest in
psilocybin, the development of low-risk guidelines such as exist for alcohol and cannabis is
suggested.
6.1.7 Scoping Reviews and the Importance of Knowledge Synthesis
Scoping reviews are an increasingly popular approach to synthesizing research evidence
(Daudt et al., 2013; Levac et al., 2010; Pham et al., 2014) used to map relevant literature in a
field of interest in terms of volumes, nature and characteristics of primary research (Arksey &
O’Malley, 2005). They are also of particular use when a topic has not yet been comprehensively
reviewed or if it is of a complex and heterogeneous nature and not yet suitable for more
precise systematic reviews (Peters et al., 2015). Given their usefulness in bringing together
literature from emerging disciplines and suitability to investigations beyond those pertaining to
effectiveness (Peters et al., 2015), scoping reviews are well suited to the field of psychedelic
research. Further reviews scoping the literature on psilocybin, psychedelics and their
therapeutic application are clearly indicated, as our reviews of psilocybin research on healthy
volunteers and of naturalistic use. In addition to further knowledge synthesis projects,

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knowledge translation activities are indicated, as the field of psychedelic-assisted therapies is
rapidly expanding without validated guidelines or evidence-based clinical recommendations.
6.1.8 Public Policy and Regulatory Implications
Popular interest in the potential benefit of serotonergic psychedelics will necessitate
new models of policy, regulation and practice (McKenna, 2004; Rucker et al., 2018; Sellers &
Leiderman, 2018). Haden has proposed a public health model of oversight including the
regulation of a new classification of psychedelic therapists (Haden et al., 2016). While core
competencies for psychedelic-assisted therapies have been suggested (Phelps, 2017), training
programs, certification and validated practices remain to be developed and a new paradigm of
regulation and policy is required (Rochester et al., 2021). The current prohibition of psilocybin
(as well as other psychedelics) remains a barrier to science: researchers must currently apply
for difficult and time-consuming special access and many countries may lack domestic
suppliers.
Following cannabis, the decriminalization patterns (such as the open, online sale of
Psilocybe mushrooms in Canada) newly evidenced may evolve more quickly than the scientific
research, necessitating the rapid development of evidence-informed clinical practice standards
and lower-risk psilocybin use guidelines while we continue to investigate the potential clinical
benefits by rigorous scientific method.
6.1.9 Limitations
There are several limitations to our scoping review. There is a clear possibility we have
missed relevant studies and given the rapid pace of new publications in psychedelic sciences,

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there are certainly studies we would have missed since our most recent search of the literature.
The data reported here will require update as new trials report results. We excluded studies
which were not available in English, and which were not available to our reviewers within a
reasonable time-frame. There is also a clear balance we struck between the breadth of the
literature and the depth of our analysis. While we did eventually post our a priori study
protocol on the Queen’s University open science platform, we did not register this scoping
reviews or post the study protocol publicly outside of this portal.
Unlike a systematic review, there was no critical analysis of the quality of the literature
included in this review, and as mentioned earlier, several conference abstracts were included.
While this resulted in more comprehensive coverage of the literature pertaining to the clinical
application of psilocybin, it does limit the translation of findings into suggested policies and
practice. Further, while we had the same two reviewers consistently extracting data and cross-
checking findings, there is room of human error. Lack of a clear methodological apparatus to
analyze data extraction also meant that author bias is present in the identification of core
themes and conclusions.
6.2 Behavioural Investigations of Psilocybin in Non-human Animals
With seventy-seven publications spanning greater than half-a-century, there is huge
variation in study design and quality across the articles reported in this review. The validity of
the individual studies has not been systematically evaluated according to current ARRIVE
guidelines for health research; this review assessed trial quality by assigning a number of
variables as proxy measures providing some reflection of study quality. These metrics include
the reporting of housing conditions, sex of animals and the number of behavioural assays

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conducted per publication. Many studies failed to report important study variables such as
housing, sex of the animals and pre-training protocols.
Laboratory research on non-human animals is conducted in stressful and artificial
environments. Serotonin is particularly context sensitive; comparable elevations in brain
serotonin in rats are found in both prolonged forced activity (such as forced 15-minute cold
swim assays) and from relatively mild handling of the animal alone, resulting in the clear
possibility of confounding due to environmental stressors (Collins et al., 1966).
6.2.1 Therapeutic Dose Range of Psilocybin
It is not entirely clear how treatment doses used in animal studies compare to those
investigated in healthy human volunteers or clinical trials, or if humans and the various non-
human animals investigated demonstrate comparable behavioural responses. Care should be
taken when comparing dose-dependent effects across non-human animal species and in
considering translation of results to humans. In modern human subject clinical trials psilocybin
doses typically fall in the 20 – 30 mg/ 70 kg (0.29 – 0.43 mg/kg) dose range (Garcia-Romeu et
al., 2021). Animal doses should not be converted into human equivalent doses; rather,
allometric approaches consider the differences in body surface area when extrapolating doses
of therapeutic agents (Nair & Jacob, 2016). Body surface area (BSA) normalization correlates
well across several mammalian species and factors in several biological parameters including
oxygen utilization, caloric expenditure, basal metabolism, blood volume and plasma proteins as
well as renal function (Reagan‐Shaw et al., 2008). One study in our review determined a
comparable dose range between pigs and humans by assessing characteristic behavioural

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effects, cerebral 5-HT2A receptor occupancy, and plasma psilocin levels following psilocybin
injection (Donovan et al., 2020). Dose conversion estimates are different for mice, rats, and
other species. What is clear is that even at doses far exceeding those generally administered to
humans, psilocybin displays a strong biological safety profile.
6.2.2 Sex as a Biological Variable
Sex as a biological variable is critical to research design, analysis and reporting. To
address the overrepresentation of males in biomedical research, the U.S. National Institute of
Health instituted a policy in 2015 requiring investigators to consider sex as a biological variable
in all vertebrate animal and human research
18
. Female mammals have been underrepresented,
often under the mistaken belief that non-human female animals display excessive variability
(Beery & Zucker, 2011). One influential review conducted across ten biological fields in 2009
found male bias evident and most prominent in neuroscience, with single-sex studies
outnumbering those of females by a factor of 5.5:1 (Beery & Zucker, 2011). A follow up study in
2019 searched thirty-four journals across nine biological disciplines, finding a significant
increase in the proportion of studies that included both sexes but with little change at all in the
proportion of studies which reported data analyzed by sex (Woitowich et al., 2020).
Fourty of the 77 studies in this review investigated exclusively males, this body of animal
research is characteristic of the larger body of biased literature in preclinical neuroscience and
pharmacology. One study noted their rationale for exclusion of female rats by citing the lack of
previous research investigating baseline behavioural parameters in Wistar-Kyoto rats (Meghan
18
https://grants.nih.gov/grants/guide/notice-files/not-od-15-102.html

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Hibicke et al., 2020) while another concludes that further studies are required evaluating anti-
depressant life effects of psilocybin in female mice, in particular the identification of robust
stress-sensitive endpoints (Hesselgrave et al., 2021).
Greater understanding of the sex and gender differences in psilocybin, psilocin and
whole-mushroom effects are needed. Many studies in this review did identify differential
effects between male and female study animals. Among human, subjective effects of
psychedelic compounds may differ between sexes (Liechti & Vollenweider, 2001); female sex is
identified as a risk factor for adverse drug reactions (Bale & Epperson, 2017) and for
challenging experiences under psychedelics (Bienemann et al., 2020).
6.2.3 Time of Day: The Impact of Circadian Rhythm
Time of day of PSI dose administration was rarely reported. Like human trials, which
commonly administered drug doses early in the day, animal studies are generally conducted in
day-time, and animal subjects are commonly housed in conditions of artificial light with a
twelve-hour light and dark cycle. Animal models not covered in this review have demonstrated
the significance of timing for psychedelic drug administration; in crickets LSD disrupted
locomotor activity when administered in early in the light phase but not later suggesting that
serotonin participates in the regulation of circadian rhythm of locomotor activity
(Cymborowski, 1963), while DOI induced wet dog shakes in rats were found to peak late in the
light phase (Nagayama & Lu, 1996). Time of dose administration has been found to have
variable effects on human behavioural outcomes including sleep (Schindler et al., 2018). In
addition to differences among species, between sexes, and different routes of administration

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and drug formulation, the methods of measuring time points and of what duration must be
considered in the effects of psychedelics.
6.2.4 Research Domains Criteria Matrix Constructs
We mapped the results of behavioural investigations of psilocybin in non-human
animals within the units of analysis provided by the Research Domains Criteria (RDoC)
framework, providing our results with an additional level of model validation. The RDoC
behavioural domains have been shown to provide basic construct, network and
phenomenological homologies across human and non-human experimental animals; while the
Cognitive Systems requires further clarification, animal models in the domains of Negative and
Positive Valence, Social Processes and Arousal Systems as well as general biological regulation
are considered valid, reliable and translatable as phenotypes of human function and pathology
(Anderzhanova et al., 2017).
6.2.4.1 Negative Valence Systems
Psychedelics have been elsewhere reported to modulate fear and threat responses,
decrease emotional avoidance, lessen rumination and reduce rejection sensitivity (Kelly et al.,
2021). In the area of fear conditioning, this review found low doses to decrease response
latency, perhaps indicating heightened sensitivity, while larger doses demonstrate time-
dependent effects. While three studies show no effect of Psi on FST behavior, and three studies
report decreased time spent immobile following treatment (indicating less despair), peak
behavioural effects are noted at 35 days post Psi demonstrating time-dependent persisting
therapeutic effects. The FST is perhaps better considered a measure of stress coping strategies

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than depression-type symptoms (Commons et al., 2017). Psi reversed the effects of chronic
stress in adolescent rodents while demonstrating acute dose-dependent inhibition of defensive
aggressive behaviours. Animals demonstrated increased time in open arms in post-acute and in
persisting effect time periods in the elevated plus maze but decreased exploratory time, along
with decreased locomotion, in the open field test during acute drug effects. Time, dose and sex-
dependent variables all effect the behaviour of experimental animals in negative valence
constructs.
Psilocybin attenuates acute and sustained fear or threat responses. Human studies
demonstrate the manner in which psilocybin, in a dose and time-dependent manner reduces
hyper-reactivity of the amygdala, associated with negative affect and attentional bias to
negatively valanced stimuli in the time period after Psi administration for up to one-month
(Barrett, Doss, et al., 2020), though increases have been noted in the day immediately following
(Roseman, Demetriou, et al., 2018a). Low doses of Psi have been found to enhance the
extinction of fear conditioned responses more rapidly than high doses or in control groups,
indicating that Psi produces alterations in hippocampal neurogenesis (Catlow et al., 2013a).
Psi has been found to acutely increase plasma corticosterone and anxiety-type
behaviours in the OFT with acute anxiogenic effects correlated with post-acute anxiolytic
effects; in this way Psi administration may be protective against future stressful events (Shao et
al., 2021). Hibicke et al. conjecture that Psi administration may open a period of subsequent
behavioural flexibility, noting that a single treatment with Psi produced context-dependent,
long-lasting antidepressant-like and anxiolytic effects in male WKY rats in both FST and EPM
assays (Hibicke & Nichols, 2020; Hibicke et al., 2019, 2020). In providing evidence that Psi

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ameliorates stress-related behavioral deficits in mice, Shao et al., further establish that Psi
increases spine density and spine size in frontal cortical pyramidal cells, evoking structural
remodeling which persistent for at least 1 month and that this documented dendritic rewiring is
accompanied by elevated excitatory neurotransmission (Shao et al., 2021). In pigs, a single dose
of Psi resulted in increased levels of hippocampal synaptic vesicle protein 2A and lowered
hippocampal and PFC 5-HT2AR density (Raval et al., 2020).
6.2.4.2 Positive Valence Systems
Psychedelic compounds have been reported to increase responsiveness to reward,
approach motivation and reward learning, suggesting that psychedelic therapies may help to
recalibrate negative hyper-responsivity and increase positive valence across a range of
neuropsychiatric disorders of human health by altering maladaptive signaling in mesolimbic
reward circuitry (Kelly et al., 2021). Studies included in this review demonstrate that Psi reduces
binge-eating behaviour at several doses. Psi inhibits compulsive marble-burying behaviour
throughout in a dose-dependent manner, with most effect evident at the medium-high but not
highest dose range. Psi exerts rapid antianhedonic actions in chronically stressed mice.
Psilocybin demonstrates a biphasic dose and time response, with decreases in behavioural
response evidenced early followed by subsequent increases in hedonic behaviours. At lower
doses Psi demonstrates discriminative properties with fewer grossly disruptive effects on
behaviour. While one investigation into alcohol relapse behavior among rodents included in
this study found only sub-chronic Psi treatment to have a short-lasting anti-relapse effect
(Meinhardt et al., 2020), a separate study found psilocybin was capable of restoring mGluR2

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expression and reducing alcoholic relapse behavior (Meinhardt et al., 2021). A rodent food-
reward model found low dose Psi enhanced motivation and attention while reducing
impulsivity in low performing rats (Higgins et al., 2021).
6.2.4.3 Cognitive Systems
The Cognitive Systems domain includes subconstructs such as attention, perception,
working memory, declarative memory, language behavior and cognitive control. Dysfunctions
in cognitive control are common across multiple psycho-pathologies, including depression,
addiction and obsessive-compulsive disorder. Investigations of cognitive flexibility are captured
across multiple domains, including assays of behavioural flexibility. The animal paradigms
reported here consist solely of tests of the visual system Psi treatment dose-dependently
disrupts size discrimination and visual accuracy. Psi’s persisting effects rescue chronic stress-
induced visual system impairments.
The results found in animal paradigms mirror those from human trials. 5-HT-2A
receptors are richly expressed in the visual cortex. Classical psychedelics such as psilocybin have
significant acute effects on the visual system, including contraction of nearby visual space
(Fischer et al., 1970) and a reduced rate of binocular rivalry, a visual process thought to be
linked to levels of arousal and attention (Carter et al., 2007). Psi reduces coherent motion
sensitivity but does not significantly affect local motion contrast sensitivity, meaning study
subjects were still capable of attending to stimuli and accurately reporting perceptions while
under psilocybin (Carter et al., 2005). The closed-eye visual perceptions which occur under
psychedelics occur as the early visual system of the brain behaves as if it were perceiving

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spatially-localized visual inputs (Roseman et al., 2016), a dynamic consistent with reduced top-
down inhibition of visual constraints and relaxed thalamic gating.
The impact of psilocybin on visual processes may be key to its therapeutic effects. Visual
processes are considered ancient and pre-verbal cognitive processes; the top-down inhibition
affected by psychedelics may induce psychological changes while overwriting stress-related
neuroepigenetic coding of past fears, and as such, the visual effects of psychedelics may be
associated with their demonstrated effects in resetting fear-responses (Csaszar Nagy, 2019).
The visual cortex is itself highly associated with working memory. Memory is an essential
cognitive process necessary for learning and therefore critical to the adaptability of an
organism.
Psilocybin produces dose-dependent impairments in memory task performance while
increasing the vividness of autobiographical memories (Healy, 2021). Psi impairs high level but
not low-level motor perception (Carter et al., 2005). Consistently, the experience of listening to
music while under psychedelics has been demonstrated to increase flow of information from
the parahippocampus to the visual cortex, a phenomenon consistent with increases in bottom-
up signaling and reduced top-down cognitive control under both Psi and LSD (Carhart-Harris &
Friston, 2019; Kaelen, 2017). Impairments in visual tasks are associated with deficits in working
memory. Mechanistically, basal ganglia function is also implicit in working memory, acting to
enhance focus on a target while suppressing irrelevant distractors during working memory
tasks, a function critical to the initial encoding of memory (Tyng et al., 2017). Working memory
lays the foundation for later, and other cognitive controls.

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The constructs of cognitive and behavioural flexibility are intertwined (Uddin, 2021).
While behavioural flexibility refers to adaptive changes in behaviour in response to changes in
the environment as demonstrated in animal assays mapped across other RDoC domains,
cognitive flexibility is understood as the ability to switch between thinking about different
concepts in a shared context. Cognitive task switching and salience processing are associated
with functioning of the claustrum, situated between the putamen and the insular cortex and
known to hold dense supplies of serotonergic receptors and glutamatergic connectivity to areas
of the cerebral cortex (Kelly et al., 2021). Psi acutely reduces claustrum activity and alters
connectivity to the default mode network (DMN) and frontoparietal task control network
(FPTC) (Barrett, Krimmel, et al., 2020). The claustrum has been identified as a possible hub in a
“two-hit” model of psychedelic action modulating sub-cortical activity (Doss, Madden, et al.,
2021); disruptions in the prefrontal cortex account for acute effects, and the claustrum
mediates connectivity to the thalamus, striatum and parahippocampal gyrus to produce
downstream effects. In this way, psilocybin may assist in pausing, or disrupting established
negatively-valenced habits and in potentiating revived emotion and improved learning within
the period of persisting effects.
6.2.4.4 Systems for Social Processes
Our review found that psilocybin produces acute decreases (reduced social grooming,
increased distancing) in affiliative social behaviour in non-human primates. Biphasic, dose-
dependent effect on sexual receptivity among rats were also found, with lower doses
significantly increasing sexual receptivity and higher doses having a non-significant effect.
Psilocybin treatment is consistent in reducing aggressive behaviour, with greater inhibition of

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aggressive behaviour as a function of increasing dose, and with greater treatment effect the
longer the pre-testing isolation period of study animals.
In human trials, psilocybin induced changes in social processing systems; specifically,
social reward processing (Kelly et al., 2021). The administration of Psi is associated with post
treatment increases in openness (Erritzoe et al., 2018), connectedness (Carhart-Harris et al.,
2018; Watts & Luoma, 2020) and nature relatedness (Lyons & Carhart-Harris, 2018).
Psychedelics, including Psi, have been found to have the potential to modulate social
processing, increasing emotional empathy and altruistic behaviours while reducing negative
emotional recognition and sensitivity to social rejection (Preller & Vollenweider, 2019).
Increases in interpersonal closeness have been sustained for up to fourteen months after Psi
administration (Griffiths et al., 2011). A recent animal study in pre-publication found psilocybin
reduces social deficits characteristic of autism (Mollinedo-Gajate, 2020).
Social cognition falls under the Social Processes construct of the RDoC framework but is
also related to visual, cognitive, threat processing. Psilocybin decreases threat sensitivity in the
visual cortex during emotional processing, suggesting the therapeutic potential of psilocybin
may again be found in its ability to shift emotional biases away from negative and towards
positive valence, enhancing the processing of positive stimuli (Kraehenmann et al., 2016) and
again suggesting the implication of limbic system components such as the amygdala as an
associated with the underlying biological mechanisms of action. In both the Negative Valence
and Social Processes domains, Psi has been shown to reduce the effects of fear conditioning,
indicating therapeutic potential in the treatment response to psychopathologies related to fear,
chronic threat (anxiety) and chronic stress. Psi has been trialed in health conditions of anxiety

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rooted in fear or loss (advanced cancer diagnosis and demoralization) but given its acute effects
in producing anxiety-type physiological responses and the potential for challenging experiences,
psilocybin should be considered carefully before its use in therapy for Generalized Anxiety
Disorder, an indication for which it has not yet been tested in human trials.
6.2.4.5 Arousal Systems
Our review found acute changes in general arousal as a result of psilocybin
administration, accompanied by mydriasis, piloerection, elevated heart rate and respiratory
rate, and decreased appetite. Psilocybin is acutely wake-promoting, at the expense of REM
sleep, with no persisting changes in sleep-wake behaviour observed. Among some animals and
in some tests at lower doses Psi increased total activity while reducing in other tests. Evidence
of reduced locomotor activities at higher doses is clear, as is some stimulation of activity at
lower doses. Psilocybin demonstrates dose-dependent effects on startle response. Low doses
increase startle amplitude or have no effect while higher doses acutely depress startle
response.
Psychedelics have been found to acutely modulate the Autonomic Nervous System, the
neuroendocrine and immune systems and do so in part by modulating activities of the
corticolimbic networks and reducing inflammation (Flanagan & Nichols, 2018; Kelly et al., 2021;
K. P.C. Kuypers, 2019; Schindler et al., 2018). Psilocybin acutely activates components of the
sympathetic nervous system across animal species, including humans, producing increases in
heart rate, blood pressure, pupillary dilation and body temperature. Psilocybin also acutely
stimulates the endocrine system, resulting in acute increases in cortisol and
corticotrophin (Woody, 2015). Psychedelics are also believed to have immunomodulatory and

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anti-inflammatory effects (Thompson & Szabo, 2020), most likely due to via 5-HT1, 5-HT2, and
sigma-1 receptor activity (Flanagan & Nichols, 2018).
Given the established sensitivity to context found with psilocybin and other classical
psychedelics, arousal is a key domain to the understanding of therapeutic effect. Arousal is
considered a continuum of sensitivity of the organism to both internal and external stimuli,
facilitates interaction with the environment in a context-specific manner, can be modulated by
the significance of the stimuli, is distinct from motivation, and is also regulated by basic
biological homeostatic drives such as hunger, sleep, thirst and sex. Disruptions of the cortico-
limbic circuit are associated with levels of heart rate variability, reflecting the physiological
capacity for flexible emotional regulation in response to stress (Woody, 2015) and suggesting
heart rate variability (HRV) as a relevant biomarker in assessing any potential therapeutic
improvements after psilocybin administration as would cerebral spinal fluid markers of
neuroinflammation. The safety and efficacy demonstrated in the psilocybin migraine trial is of
note, not simply due to that trial being the sole Psi trial for a health condition not considered a
psychiatric condition, and because it highlights the impact of Psi on neuroendocrine and
immunomodulatory processes which may underlie it’s therapeutic effects.
6.2.4.6 Sensorimotor Systems
Our review of animal studies found that stereotyped behaviours such as head-twitch
response are reliably induced in non-human animals following Psi treatment, once the dose
crosses a threshold of efficacy, and are potentially suppressed at higher doses. Extremely high
doses also induce myoclonus or head rotation in a dose-dependent manner. Other stereotyped

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motor behaviours have been observed following Psi administration in rodents, cats, and non-
human primates, including myoclonic spasm and limb flicking. Biphasic effects, with no
reductions in grooming at lower doses but disruptions evident at standard doses and above.
Effects on grooming may be related to the time-course of the drug effect. Sex-dependent
differences are reported in mice. Dose-dependent effect on discoordination with no effect at
lower doses and discoordination at very doses are also reported. Psi effectively disrupts PPI in
rats. This effect may be dose-dependent and have sex-specific effects. 1 mg/kg psilocin (IP)
effectively disrupts PPI ASR in rats, but lower doses (0.25 mg/kg) have no effect and higher
doses (4 mg/kg) have variable effects.
Sensorimotor systems are responsible for the control and execution of motor
behaviours and include processes involved in the parametrization of action plans and programs
based on the integration of internal and external information and on the modeling of body
dynamics; they are continually refined through new sensory information and the reinforcement
of information via reward learning (Kelly et al., 2021). Given the manner in which psilocybin
increases sensory awareness while reducing top-down cognitive processes associated with
rumination, further investigation into sensorimotor systems under psychedelics would be
beneficial. Pertinent to our hypothesis is that psilocybin recalibrates global brain networks to
more greatly value cortical and subcortical networks including sensory, sensorimotor and limbic
systems, sensorimotor experience lays the groundwork for visual thought. Sensorimotor
structures are derived from repeated patterns of organism-environment interaction, becoming
encoded in neural processes as representations of external objects to the degree that even
imagined motor actions engage the same networks as actual physical movements, a

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phenomenon comparable to the closed-eye visual processes evidenced under psychedelics and
perhaps associated with the workings of mirror neurons in the brain (Winkelman, 2017). If
symbolic values are rooted in primarily sensorimotor processes, then a globally reintegrated
brain with greater valuation of attentional processes will look to continued sensorimotor
activity in the update, revision and improvement of predictive mental constructs and
behavioural routines.
6.2.5 Limitations
There are several limitations to this scoping review. There is a clear possibility we have
missed relevant studies and given the rapid pace of new publications in psychedelic sciences
including recent animal investigations, there are certainly studies we would have missed since
our most recent database search of the literature. We excluded studies which were not
available in English, and which were not available to our reviewers within a reasonable time-
frame. There is also a clear balance we struck between the breadth of the literature and the
depth of our analysis. Several conference abstracts were included and may report duplicate
results.
While we did report on housing conditions, sex as a biological variable and the number
of assays per publication as proxy measurements of trial quality, there was no critical analysis
of the quality of the literature included in this review and we did not assess if individual trials
met modern ARRIVE Guidelines for animal research. While this resulted in more comprehensive
coverage of the literature pertaining to the clinical application of psilocybin, it does limit
somewhat the translation of findings into suggested policies and practice. The a priori protocol

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guiding this scoping review was posted in a timely manner on Queen’s University open access
repository (QSpace) but was not registered or published elsewhere.
Multiple reviewers extracted data from study publications, raising the possibility of
inconsistency in addition to human error. This scoping review took years to complete as part of
a program of doctoral research, raising the possibility of inconsistency in analysis over time.
Given the large volume of articles identified in this review, providing an accurate and
comprehensive synthesis of the literature has been challenging. Lack of a clear methodological
apparatus to analyze data extraction also meant that author bias is present in the identification
of core themes and conclusions. Our sense of shortcoming in this area in a previous scoping
review, Mapping Psilocybin-assisted Therapies: A Scoping Review, prompted the use of the
Research Domain Criteria framework as an epistemic map to organize results in this review.
Further, translation from animal studies to human trials or to the understanding of human
health is plagued with challenges. We have done our best to identify common biological
systems across species to aid in this act of knowledge translation.
Behavioural studies are characterized by their own limitations, and behavioural studies
of non-human animals are particularly limited by lack of ability to self-report subjective
experiences. As subjective experiences are considered critical to psychedelic therapies and
given the clear effects of psilocybin on unique aspects of human consciousness, behavioural
studies in animal paradigms can help in our understanding of psilocybin but must be taken in
context alongside human trial and naturalistic or population-health level data. The RDoC
framework itself emphasizes the importance of integrating multiple levels of analysis, including
genes, molecules, cells, circuits, physiology, behavior, self-report and investigational paradigms.

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6.3. Mapping RDoC Domains onto Human Clinical Trials
As the RDoC framework is intended to provide a trans-diagnostic framework to better
understanding and addressing the heterogeneity and underlying biological substrates to human
health, it is worth understanding the relative importance of the various domain constructs to
the neuro-psychopathologies proposed as targets or indications for psilocybin-assisted
therapies. Our scoping review on psilocybin human trials produced evidence for safety and
efficacy of psilocybin in the treatment of depression, substance use disorder, anxiety and
depression associated with advanced cancer diagnosis, demoralization due to long term AIDS
survival and migraine headaches.
In identifying possible trans-diagnostic mechanisms, mapping the trial indications
against RDoC constructs, negative valence and cognitive systems appear of particular relevance,
as do positive valence and arousal systems (see Table 6.2.). What emerges is a trans-diagnostic
theory that psilocybin may be of therapeutic value due to improved valence, lessened
persistent threat response activation, revised strategies and behavior change, sensitivity to
positive reward, and persisting alterations to cognitive systems with reduced rumination and
more attention to present circumstances, including improved embodiment and sensory
awareness. The acute disruptions to arousal and self-regulatory systems and the dose and time-
dependent acute effects may act as temporal stressors resulting in long-term, positive
persisting effects in which improvements in social processing and sensory awareness are
coupled with persisting inhibition of past conditioned programs of behavior, thought and affect.
The migraine clinical trial highlights the potential for psychedelics to affect the modulation of
neuroendocrine and immunomodulatory systems, processes regulated by sub-cortical limbic

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systems. My hypothesis – that psilocybin improves self-regulation, seems corroborated by the
evidence of both the human and animal trials. Psilocybin appears to attenuate past
conditioning, promoting behavior change and stimulating natural learning (updating revisions
to past conditioning) . What remains to be developed is a theoretical model outlining this
model of psychedelic action indicating underlying neural correlates and brain network
alterations.
Table 6.2. RDoC Domains of Particular Relevance to Targets of PSI-AT
Indication
Negative
Valence
Positive
Valence
Social
Processes
Cognitive
Systems
Arousal
Systems
Sensorimotor
Systems
Depression
x
x
x
Substance Use
Disorder
x
x
x
x
x
Death Anxiety
x
x
x
x
Obsessive-
compulsive Disorder
x
x
x
x
x
Demoralization
x
x
x
Migraines
x
x
x
Each indication has phenomenology in each RDoC domain; highlighted here are the domains which may appear
most implicated based on symptomology and identified biological substrates.
In depressed patients, trait rumination, bias towards negative valence interferes with
the recall of negative but not positive words; rumination is related to a decrease in the ability to
inhibit no-longer-relevant information, a deficit in cognitive process which increases the
likelihood that negative information will be retrieved repeatedly from long-term memory,
making thoughts repetitive and no longer sensitive to update or to context (Whitmer & Gotlib,

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2013). Depression, in this way, becomes a cognitive bias of learning, and interrupts the ability
to overwrite past learned reward contingencies, thereby limiting the scope of attention
(reduced attentional scope) and decreasing novel exploration of the environment and reducing
new, or the updating of old, responses to environmental or internal stimuli (Whitmer & Gotlib,
2013). Rumination predicts prospective changes not only in depression, but anxiety, substance
use disorder, self-harm and eating disorders as well (Woody, 2015). Patients with advanced
cancer diagnosis tend to ruminate on their death. Loss is similarly a subconstruct of negative
valence, and clearly indicated in depression, as well as being implicated in anxiety and
depression due to advanced disease diagnosis, demoralization due to long-term health
conditions, and substance use disorder.
Within the RDoC matrix, habits are defined as sequential, repetitive motor or cognitive
behaviours elicited by internal or external triggers, that once initiated can go to completion
without conscious oversight. Habits can serve adaptation by increasing the reliability of routine
behaviours, saving cognitive and attentional resources for tasks which require more attention
or flexibility; over-reliance on habits, or habits which are no longer situationally appropriate,
can lead to undesirable outcomes and the over-training of habit circuits can create rigidity,
rumination, obsessions and compulsions (Pittenger et al., 2019). The cortico-striatal circuits
implicated in habit formation and execution are associated with the clinical pathology of
Obsessive-compulsive Disorder. OCD is also associated with the subconstructs of potential
threat, habit and cognitive control. Reward subconstructs, cognitive control and negative
valence are all associated with substance use disorder (Boness et al., 2021).

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6.4. Research Gaps and Contributions to the Literature
Several gaps in research are evident when considering the results of these researches.
Certainly, more human clinical trials are required, especially large-scale, multi-site randomized,
double-blind placebo controlled trials to meet the Phase 3 requirements of regulatory drug
approval. However, further proof-of-concept, safety and efficacy trials are required with
populations not yet studied, and for health conditions not yet robustly investigated, and for
formulations of psilocybin not yet well-investigated, including the use of whole mushroom
extracts (WME) or whole Psilocybe mushrooms. Trials in group settings have yet to be fully
explored. Further, the use of MDMA as an active precursor to serotonergic psychedelics has
been proposed as a manner to reduce transient anxiety and is worth study considering the risks
of prolonged negative and challenging experiences. A recent study using a group therapy model
employed MDMA to first strengthen therapeutic alliance and enhance motivation, before
introducing LSD in sessions intended to intensify and deepen the therapeutic processes (Oehen
& Gasser, 2022). Such combination therapies may be of particular benefit to individuals with
PTSD.
Naturalistic studies investigating psilocybin use outside of controlled trial settings
provide real-world value to understanding safety, risk reduction, and self-reported effects. We
would be wise to monitor emergency department health data related to psychedelics to
monitor emerging public health and safety trends. While self-report and survey tools are useful
and common especially in the microdosing literature, the use of objective measures provides
added certainty and for this reason the use of biomarkers would add value to contemporary
clinical trials. And, as the non-human animal studies here suggest, broadening the scope of

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psilocybin research beyond its strict effect on narrow mental health diagnostics would provide
a richer, more nuanced understanding of psilocybin effect. In particular, research on
sensorimotor processes, cognition, fear conditioning, memory consolidation, reward
revaluation and concentration/focus/awareness would be particularly helpful, especially when
plotted along the timelines of the temporal model of persisting effect suggested here. Imaging
studies may help further clarify the roles suggested here for limbic-system brain regions.
Certainly, the effects of psilocybin on the habit construct require validation.
In psilocybin research there is an evident a need for new biomarker research (to predict
sensitivity and metabolism of psilocin), research on genetic and metabolic differentiation and
phenotypes, and a clear suggestion for more limbic-centred (corticosteroid and stress response)
pre-clinical and clinical research helping to understand the effect of psilocybin on the H-P Axis.
Certainly, more longitudinal data is required, and specific research in the post-acute and
persisting effects time periods is suggested, especially regarding therapies and changes to
health behaviours in weeks to months after psilocybin. Non-human animals studies can add
scientific value, especially when conducted along ARRIVE guidelines, but further research on
healthy human volunteers will help to confirm or change the unified models presented here.
This thesis makes several contributions to the literature. It presents the results of novel
scoping reviews in areas which had not yet been scoped. Further, this thesis considers the
findings of human clinical trials and non-human animal studies side-by-side. My use of the RDoC
framework, and the manner in which I have plotted the individual research paradigms onto the
framework certainly provide a more nuanced and multi-dimensional understanding of
psilocybin beyond the strict categories of DSM-V based nosology.

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The proposed Transition State Model is unique and builds on earlier literature
identifying the afterglow effect of psychedelics. This temporal model is more dynamic and
useful than static models which consider only acute drug effect. By emphasizing the post-acute
and persisting effects phenomenology, I elongate the understanding of set and setting and
identify mechanisms by which psilocybin has therapeutic potential, providing a basis in
evidence upon which to build therapeutic supports and interventions. This contributes to an
improved understanding the total drug effect of psilocybin, especially over time and once acute
and observable pharmacologic effects have subsided.
The emphasis on habit disruption and the long-term potentiation of new learning of
behavioural change strategies is a significant contribution to the literature on psychedelic-
assisted therapies, not comprehensively explored elsewhere. This is a unique learning model
which revives interest in behaviorist paradigms, and a model which is consistent with the
science of brain plasticity and the dynamics of behavioural flexibility. This thesis uniquely
positions psilocybin studies within the literature on behavior change, and within the larger body
of literature on health behavior change. Lastly, by reviewing the evidence of psilocybin’s
putative therapeutic benefit and relatively low safety risks, I present here evidence to support
the development of new therapeutic programs and regulatory frameworks to safely guide the
implementation of psilocybin-assisted therapies and to reconsider the current legal prohibition
on psilocybin.

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6.5. A Transition State Model of Psychedelic Action
The afterglow critical period may underlie the gains of psychedelic therapies, giving
credence to the early hunch that post-session integration is key to sustained therapeutic gains.
We now understand this period to be the result of the psychedelic creating a period of brain
optimization, during which environmental inputs have enduring effects; as such, the afterglow
period is a rare adult developmental critical period with exquisite sensitivity to environmental
input (Lepow et al., 2021). The afterglow period may include positive experiences such as
improved mood, psychological flexibility, openness and mindfulness. During this period,
cognition and behavior are more susceptible to the influence of novel insights recently gained
by the individual, thus enabling individuals to explore new ways of thinking and behaving (Majić
et al., 2015). Individuals demonstrate increases in pro-sociality, interpersonal closeness and
forgiveness after psilocybin (Eleftheriou & Thomas, 2021). This provides an important basis
upon which integration therapies can contribute to meaningful, lasting change and in this way
psilocybin-assisted therapies can be considered an important intervention to encourage change
in health behaviours (Teixeira et al., 2022).
Psilocybin may best be considered a catalyst which creates a transition state of
maximum energy potential (see Figure 6.1.). Catalysts are chemical agents which initiate and
accelerate change processes, increasing rates of reaction, stimulating and accelerating natural
processes. In its Greek origin, catalyst means “to dissolve”. Catalysts create a time-bound
transition state of maximum energy potential. Transition states are relatively short-lived, create
only partial bonds and cannot be isolated. The catalytic model proposed here is endothermic,
as more energy is gained by the individual than is lost in the process.

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A transition state (Figure 6.1) is a point on a reaction-energy diagram corresponding to
the highest potential energy along the reaction coordinate. Within psilocybin-assisted
therapies, the transition state is acute psychedelic state characterized at its highest reaches by
ego-dissolution and entropy (a state of novelty and surprise that does not correspond with
previous conceptual assumptions). It is a state of maximum energy potential because it
contains all possibilities of the potential change reaction.
Figure 6.1: A Transition State Model of Psychedelic Action
The weeks and month following psilocybin can be time-stamped in the post-acute phase
of afterglow, followed by an even longer period of sustained change and persisting therapeutic
effect in which behavioural changes have become routinized, requiring less conscious effort
and thereby succeeding past habits of rigidity and pathology with revised programs of behavior,

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thought and action. To say integration is key to the therapeutic effect of psilocybin is to
underplay the importance of new learning potential in the weeks and months following
psilocybin. This afterglow period is better understood as a revised state of awareness
characterized by the attenuation of rumination, repetition and rigidity. This period may be
characterized by increased attentional scope, improved awareness of present external and
internal stimuli and increased flexibility. These states are rooted in reconfigured brain network
connectivity with rich potential for new learning and revised health behaviours.
Psychedelics display biphasic effects: firstly, a kind of long-term inhibition (LTI) of
previously established and sub-optimal neural routines, maps or programs, and secondarily by
potentiating a critical afterglow period of heightened learning and heterosynaptic plasticity.
The neural imprint of the acute psychedelic experience has significant weight due to the high
novelty, emotionality and meaningful experiences reported and effects persist, in part due to
the heightened value of memories stored with such emotionality and meaningful context, but
also due to the downstream molecular signalling effects which together establish persisting
effect after and beyond states of acute drug effect. In this afterglow phase, the long-term
potentiation of new cellular memory and of new operating neural networks can be
consolidated (the integration phase of psychedelic-assisted therapies is reflective of this shift in
neurodynamics towards consolidation and new memory formation). That the psychedelic
pause, effected through the course of pharmacokinetics and drug metabolism may result in a
subsequent stage of revised connectivity and a re-weighting of neuronal signals is overlooked if
we consider only the time-bound connectomics of the acute psychedelic experience and fail to

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continue neuroimaging and scientific investigation into the post-acute phase identified as
lasting up to one-month (Barrett et al., 2020).
Consistent with this literature, it is feasible to propose a biphasic model the psilocybin
effect: first, a primary effect of serotonergic signalling and the consequent shifts in perception,
cognition and affect, and then secondarily, a downstream activation of dopaminergic,
glutamatergic and GABAergic systems implicated in motivation, reward valuation and habit
formation. The first dissolves previously understood boundaries and self-in-context beliefs,
while the second encodes new neural pathways in the primarily limbic-endocrine system to
sustain new behavioural programs of thought, behaviour and action. The claustrum has been
identified as a possible hub in such a “two-hit” model and as a modulator of sub-cortical activity
(Doss, Madden, et al., 2021): disruptions in the prefrontal cortex account for the initial primary
effects, and the claustrum mediates connectivity to the thalamus, striatum and the
parahippocampal gyrus to produce downstream effects. In this way psychedelics may assist in
both pausing, or disrupting established pathological habits, and in potentiating the encoding of
more optimal processes via its persisting effects of revived emotion and improved learning in
the time-bound period of persisting effects.
6.5.1. The Role of Set and Setting in the Transition State Model: A Longitudinal Model of
Psilocybin Effect
With sensitivity to context so evident in psilocybin’s effect, the variables of set and
setting are important to address in the Transition State model. Given the evidence for the
importance of learning in the post-acute and persisting effect time stages, it is important to

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elongate our understanding of both set and setting along the extended timelines presented
here in our understanding of total drug effect for psilocybin. To that end, it seems reasonable
to describe psilocybin’s drug effect as one which persists long after it’s acute pharmacological
effects subside. Such a longitudinal model of psilocybin drug effect requires similarly extended
conceptions for set and setting.
While set has been the concern principally of the preparation stage of the PSI model, it
is important to recognize the continued effect of set (the psychology of the participant) in the
days and weeks following psilocybin administration. Set is a variable at each identified stage of
this proposed model: first, in preparation or priming for psilocybin, secondly in how the subject
responds to the entropy of the bemushroomed state, and finally set manifests in the revised
learning dynamics of the critical neuroplastic window. Addressing set requires going beyond
preparation. Skills of use to subjects under psilocybin tend to be those of acceptance and
mindfulness (“let go and surrender”, as encouraged in the Johns Hopkins studies). Finally, and
something which is largely ignored in clinical practice, set is a significant variable in the weeks
of persisting effect by the manner in which in potentiates new learning. Learning is the main
concern of set in the weeks following Psi, and learning is most likely to achieve long-term
potentiation through repetition and with positive emotionality. Set, here, is focused on the
development of new health behaviours – a key time period to improve mindfulness and stress
reduction skills, improved self-regulation, meditation, yoga and other movement practices, or
to develop new hobbies and outlets of creativity.
Setting as a variable similarly courses through the priming/catalyst/persisting Effect
stages of the Transition State model. The importance of an appropriate setting for psilocybin

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administration is well-established, and many preventable harms are due to unsafe or
problematic settings. Setting is particularly important in the Persisting Effect phase for two
reasons: 1) after psilocybin people may have improved sensory connectivity and somatic
awareness, and 2) human learning is, generally, socially mediated. With the exquisite sensitivity
to context enduring through the weeks of persisting effect, the environment is a key variable in
conditioning outcomes. Negative environments after Psi will limit potential benefits, could even
hasten an early resolution to positive persisting effects. Setting in the time period of persisting
effect is as important as the environment of young children, whose development is known to
be modulated by their environment. Post psilocybin, environments with encourage oxytocin
release and relaxation could potentially maximize and extend persisting effects. In Hebbian
Learning models of human learning, long-term potentiation is promoted by sensory-motor
patterns, by acts of repetition, and by positive emotional environmental stimuli (such as the
support of others, or by supportive environments). Setting is key to the development of habits,
especially given the context-dependence of habit, and the manner in which habits may
continually be updated or revised in response to internal or external changes.
Under the Transition State Model, the preparation stage is best understood as a time of
priming, and the post-session integration stage is noteworthy for the pruning of neuroplastic
potential into alterations made and sustained by long-term potentiation. Both human and non-
human animal studies demonstrate the sensitivity of psilocybin effect to both pre and post-
conditioning. The psilocybin dosing session serves as a catalyst to change, creating a period of
activation energy that is influenced by the expectations, skills and views established in the

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priming of preparation sessions; this energy potential (potential for change) is subsequently
conditioned by post-session environmental cues and behaviour.
6.6 Public Policy and Program Implications
The Transition State longitudinal models provides a basis in evidence, gathered across
both non-human animal and human clinical trials, for the development of future psilocybin-
assisted therapy programs and policy. While the proposed model do not necessarily directly
vitiate against standard Preparation-Session-Integration approaches of “peak” psychedelic
therapy; rather, these models extend and expand our concepts of psilocybin’s potential
therapeutic effect. They also indicate that, to align with the underlying mechanisms identified
here (disruption of habit and the neuroplastic potential for behaviour change), programs ought
to consider significant post-session activities, with less emphasis on psychotherapy and more
on the development of new health behaviours. This would include an expanded role for
therapists beyond the psychological, including somatic therapists, movement, yoga and
meditation teachers. The limbic learning processes in play after psilocybin may result in feelings
of enhanced embodiment, and of increase awareness of sensory input. These conditions
contribute to the ability to revise habit, which are integrated packages of thought, affect and
behaviour. Through enhanced embodiment, negative psychological symptoms may lessen. New
forms of embodied cognition can arise.
Today’s public policy makers are challenged to develop models of regulating
psychedelics such as psilocybin in manners consistent with the scientific evidence concerning
their potential effects, which include both potential benefits and known risks and harms. In this

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way, psilocybin is not unlike other prohibited substances; fentanyl as well has applications of
clear clinical benefit. Drug regulators may view potential benefits through a lens or risk
aversion, not only due to institutional path dependency, but also out of concern for experiences
of psilocybin “gone wrong”. To reduce the risk of severe adverse experiences is a sentinel
consideration for both clinical guidelines and a public policy. Currently, clinical guidelines for
the use of psilocybin do not exist, and best practices have yet to be developed. It does occur
however, the multiple jurisdictions across North America are decriminalizing psilocybin, and
psychedelics are of significant public interest. Regulators will need to adapt.
This Transition State learning model contains suggestions for improved policy, and for
better practice concerning safety. Informed consent should include the recognition of
prolonged drug effect demonstrated in clinical and pre-clinical researches. Risk can be better
mitigated both by the recognition of psilocybin’s catalyst effect, and by the need for continued
protection of set and setting in the days and weeks following drug resolution. A focus on
improved and updated habits of thought, feeling and behaviour results in a more behavioural
learning model, with less emphasis on psychological processes and psycho-therapy. There are
clear cost implications. Group therapy may be a more affordable model of psychedelic-assisted
therapy and groups are well suited to this limbic learning model, given the importance of
environment and positive sociality.
Finally, public policy is provided with a model to consider legislative change. The
evidence regarding psilocybin reviewed in this thesis is one of potential overall salutary benefit
and improved self-regulation due to updated learning and improved integrated habitual
packages of thought, feeling and action. The risk presented are of transient anxiety and

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distress, and of prolonged negative and challenging experiences. Psilocybin does carry with it
psychological risk and has demonstrated persisting effects (which can be negative). For this
reason, access to psilocybin has to be considered with regard to the risks faced by young people
or to those who may be vulnerable to its effects. But there is no basis in evidence to make
psilocybin illegal and to completely prohibit its use. And while restricting its’ access to medical
usage may reduce risks (or will it, if one considers the role of medical oxycontin in the opioid
overdose epidemic?), psilocybin does not present as a strictly medical compound. While it may
have therapeutic benefit, it most likely does so by altering embodied cognition. Such a learning
model takes it squarely out of the strictly medical, though treatments for Attention Deficit
Disorder clearly intend for improved focus and learning. Psilocybin may not fit neatly into any
category; not only trans-diagnostic, but trans-dimensional, both medical and educational.
Mazatec curanderas such as Maria Sabina have spoken consistently not only of the healing
powers of the sacred mushroom, but that this is a path of knowledge. How does this translate
to modern Canadian settings?
Canadian researchers have earlier called for the establishment of novel regulatory
processes for psilocybin and comparable psychedelics, including the creation of new overseeing
regulatory bodies particular to psychedelics and to psychedelic-assisted therapy (Haden et al.,
2016; Rochester et al., 2021). It’s hard to see how such new bodies cannot come to be.
Psychedelics do not neatly fit our current regulatory categories, and then exceed the grasp of
medicine and psychiatry while crossing into ritual and culture. As policy considerations
regarding psychedelics come to a head, this thesis provides an argument against the strict
medicalization of psilocybin. What is needed is a harm reduction approach, one which provides

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channels of safe access while mitigating risk. Oregon’s Psilocybin Service Centres are one such
model worth considering. Under the Oregon framework, psilocybin is not legalized, but was
decriminalized. This averts the pressures of commercialization and profit but lessens prohibitive
and punitive social sanctions. Access is provided by regulated and qualified service centres
staffed by specialized trained facilitators but who are non-medical: no diagnosis required.
Decriminalization allows for continued recreational access without prohibition, and the service
centres allow for public access to psilocybin in a manner which reduces the known risks. It is
hard to imagine a better policy solution for Canada at this time though accessibility and cost
remain concerns.
6.7 Bridging Worlds: From Traditional Plant Medicines to Psilocybin Therapies
While it may be difficult to see at first, consistencies do run through the histories of
traditional entheogenic use and the findings of modern psychedelic sciences reviewed here. For
traditional Mazatec curanderas such as Maria Sabina, like the ayahuascaros of the Amazonian
basin, health and disease have their origin in the unseen world. Within such traditional
cosmologies, health is viewed as a matter of balance, and requires healthy connection to
supernatural or spiritual realms. Healing in these traditions is predicated on access to the non-
ordinary, guided by historical traditions of rituals and compelling cosmologies which provided
humans a sense of their place in natural and cosmic orders. Ceremony becomes an eruption of
the sacred in the material, occasioned by the ritual use of entheogens; in this place the spirits of
the world can be encountered, and relations repaired.

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Contemporary interest in psychedelics may be stimulated at least in part by the
fascinating experiences of interiority they occasion. In this regard, psychedelics can be situated
among the spiritual-but-not-religious movements of modern times. While modern
psychotherapy is premised on the resolution of internal psychological processes via internal
reflection, psychedelics effectively reverse this internal turn, and like the animist cultures which
valued power plants for their ability to restore relations with a world-alive-with-spirit,
psychedelics today can be valued for their persisting effects of enhanced embodiment and
relationality with an enchanted world. While we have been fascinated for decades with the rich
subjective phenomenology of the acute psychedelic experience, we have neglected the after-
effects, the jewels along the path. Conceived as a path of learning and knowledge, psychedelic
rituals can help return our awareness to connectivity with the world-around-us and help us to
integrate those parts of ourselves subsumed by separation, ego and rumination. While the
catalyst event is one of vast interior experience, the time period following psychedelics is
marked by experiences of heightened relationality, due to the heightened sensory awareness
and improved presence occasioned by the psilocybin’s downstream effects and the healthy
reintegration of cortical sub-cortical regions of the brain.
Ritual predates human language, dating back to at least Neanderthal epochs. The power
of ritual may be an underlying attraction of psychedelics – a return to communal experiences of
spirit which exceed contemporary diagnostics. Perhaps, in some way at least, the trans-
diagnostic potential of psychedelics lay in their ability to restore a more robust and meaningful
experience of consciousness which goes beyond that of ordinary reality and modern social
expectations. The hidden realm to which entheogens provide access, described in more

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contemporary language, is the panoply of unconscious structures underlying perception,
cognition and habit. In this way, we learn to see the unseen.
Conclusions
6.8 Mapping Psilocybin-assisted Therapies
Psilocybin trials have demonstrated safety and tolerability while suggesting efficacy in
treating a range of health conditions including mood and self-regulatory disorders, possibly
indicating a common underlying basis to distinct pathologies. Psilocybin is unique in its rapid
onset of anti-depressant and mood improving effects, outcomes which appear to be sustained.
Serious adverse effects are rare, though common side effects include transient anxiety, nausea
and post-treatment headaches. Psilocybin’s persisting effects have been confirmed in study
follow-up periods, and brain imaging indicates persisting alterations to global brain connectivity
lasting to at least one-month.
Trial participants consistently report a range of psychological benefits, including
increased meaning and relationality in addition to improved cognitive and behavioural
flexibility. Psilocybin clinical trials have provided psychological supports and most have
provided some kind of structured therapy (such as Motivational Enhancement Therapy) in
addition to the psychedelic compound as psilocybin is thought to have an amplifying effect on
therapeutic interventions. The psilocybin trials have refined a peak-psychedelic model of
threshold doses correlated with ego dissolution and mysticism and trial subjects were largely
treated with a Preparation-Session-Integration model of psychedelic therapy, indicating the

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importance of conditioning prior to and after psilocybin administration. Leading adverse
experiences of transient anxiety and distress as well as post-session headache can be addressed
with careful therapeutic intervention and client preparation. The careful selection of trial
subjects speaks to the need to mitigate known risks of psychedelics, including negative and
challenging experiences which will occur in at least a portion of participants. Evidence of trans-
diagnostic effect is evident, suggesting a common underlying basis to at least some disorders of
mental health.
The psilocybin trials have established a marked ability to interrupt disordered psycho-
pathological processes and to lead to sustained clinical improvements within phase 1 and phase
2 clinical trial formats. Phase 3 clinical trials are necessary to clearly establish effectiveness, to
ensure generalizability to diverse populations, and to lay the basis for evidence-informed
practice. The mechanism of action is not yet fully understood. Current legal prohibition on
psilocybin hinders basic science and continued clinical investigation.
6.9 Behavioural Investigations of Psilocybin in Non-human Animals
The scoped literature on behavioural investigations of psilocybin in non-human animals
is marked by heterogeneity in quality and study design with variations in findings over a period
of greater than fifty years. Overall, psilocybin presents a unique and strong safety profile with
no evidence of biological toxicity even at massive doses which far exceed those studied in
humans. Psilocybin is characterized by unique time and dose-dependent effects which can be
divided into distinct units of analysis: acute effects, sub-acute and persisting effects. Mapped
against the RDoC domain constructs, what emerges from our scoping review is a pattern of
drug action which is significantly context and training-sensitive. Problems with study quality,

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such as widespread failure to investigate sex differences or report housing conditions, limit the
generalizability of results but the body of trial publications trend towards improved quality of
research design and of reporting over time.
Psilocybin acutely disrupts cognition, arousal and sensorimotor dynamics in a dose-
dependent manner in investigatory animals. Psilocybin’s acute physiological effects resolve, but
studies which measure outcomes as later time-points provide a second layer of data pertaining
to sub-acute and persisting effects. Demonstrated effects of Psi include heightened acute
arousal, dose-dependent sedation, reductions in fear conditioning at low doses, reduced
aggression, improved valence, acute disruption of working memory, the rescuing of deficits
resulting from chronic stress, and improved learning when Psi is combined with subsequent
repeated environmental exposure after the resolution of drug effect. The “psychedelic pause”
was first identified through an animal paradigm and captures the disruption of repetitive,
conditioned associated behavioural patterns stored in memory. Psilocybin is best understood to
have biphasic effects, with inhibition of past conditioning evident under acute effects, and
stimulation of new behaviours in the follow-up time periods persisting for several weeks after
psilocybin.
Together, these data provide credence to a proposed “two-hit” model of psychedelic
action, with acute effects primarily mediated by 5-HT agonism, and downstream effects
persisting after the resolution of acute drug effect and 5-HT- receptor agonism. Psilocybin is
best understood as dose-dependent, time-dependent, and variable in its effects depending on
pre-dose training and post-effect environmental exposures.

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Behavioural research in non-human animals allows for the investigation of psilocybin in
dimensions and domains which far exceed those of strict DSM-V nosology. Going beyond such
diagnostics as depression and substance use disorder allows for a much more nuanced
understanding of psilocybin’s biologic effects across multiple dimensions as captured in the
RDoC framework. The results of this study of behavioural investigations of psilocybin in non-
human animals provided evidence for a temporal model of psilocybin, highlighted psilocybin’s
effects on past conditioning and the importance of additional conditioning during the time
periods of persisting effect. Supporting a Transition State Model of psilocybin effect, these non-
human animal studies revealed behavioural phenomenology of drug effect not captured in
human clinical trials, providing a biological and behavioural basis for understanding psilocybin’s
potential therapeutic effect beyond the narrow and static conceptions of DSM-V based
diagnostic categories.
6.10 Synthesis Conclusions Considering the Results of Both Scoping Reviews
Phase 2 clinical trials have established therapeutic efficacy for psilocybin-assisted
therapies for depression, addiction, and advanced cancer-related anxiety and depression. To
help evaluate the therapeutic potential of psilocybin, and to translate scientific findings into the
rapidly-changing fields of practice and public policy, we conducted two complementary scoping
reviews. Our hypothesis was that psilocybin’s therapeutic potential lay in its ability to improve
self-regulation by disrupting habit and promoting updated habits of thought, behaviour and
action.

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Systematic database searches were conducted in Ovid MEDLINE and translated in Ovid,
PsycINFO, EBM Reviews: Cochrane Central Register of Controlled Trials, Web of Science Core
Collection and ProQuest Dissertations and Theses from October 2019 to September 2021. From
records identified through database screening and using Covidence online software,
duplications were removed, records screened, assessed for eligibility and included or excluded
from full-text review. 8583 articles were screened and 126 included in these two reviews: 49
studies met inclusion criteria for our scoping review on psilocybin-assisted therapies, and 77 for
our scoping review of behavioural investigations of psilocybin in non-human animals. To give a
more nuanced understanding of psilocybin’s effects, we mapped the animal review results onto
the Research Domains Criteria framework of the National Institutes of Mental Health.
Psilocybin-assisted therapies have been demonstrated to be safe and have clinical
efficacy in the treatment of obsessive-compulsive disorder, depression, substance use disorder,
demoralization due to long-term AIDS-related survival, and in the treatment of migraine
headaches. Psilocybin shows evidence of trans-diagnostic effect, with persisting effects lasting
up to eighteen months. In behavioural investigations of non-human animals, psilocybin has
been shown to have a biphasic drug effect related to both dosage and to time-course.
Psilocybin reduces the effects of past conditioning, increases sensitivity to context, and reduces
the effects of chronic stress in non-human animals. The effect of psilocybin in neuroendocrine
and immunomodulatory systems is may explain its potential to lessen migraine headaches, and
those systems are also implicated in therapeutic effects on other health conditions as psilocybin
can potentially trigger the reintegration of cortical to subcortical and limbic systems which help
in the regulation of hormones and of the immune system. Trial quality is strong in recent

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human trials, though subjects tended to lack diversity and the provision of psychotherapy in
addition to psilocybin confounds study results.
Psilocybin has a strong safety profile, with transient psychological distress the most
common adverse experience. Psilocybin for PTSD is untested, but low doses reduce fear
conditioning. By disrupting past habitual programs of thought, feeling and behaviour, psilocybin
effects a pause on past conditioning. Post-acute effects included improved mood, enhanced
openness and acceptance, heightened sensory awareness and heightened sensitivity to
context. Goal-oriented, associative and social learning appears improved after psilocybin and
habits of psychopathology are weakened. Further Phase Three clinical trials with wider patient
populations are warranted. New programs of research in pre-clinical and healthy human
volunteers can add a level of translatability by embracing an RDoC framework in the
presentation of results.
6.11 Proposed Mechanism of Action
While the mechanism of action underlying the therapeutic effects of classical
psychedelics has been variously proposed to be ego dissolution (Smigielski et al., 2019),
mysticism (Griffiths et al., 2016), relaxed expectations and beliefs (Carhart-Harris & Friston,
2019), alterations to thalamic gating (Vollenweider, 2001), reintegrated cortical to sub-cortical
brain network connectivity (Doss, Madden, et al., 2021), spirituality (Lafrance et al., 2021),
experiential intelligence (Tupper, 2002), and neuroplasticity (de Vos et al., 2021), the combined
findings of our two scoping reviews, one on human clinical trials, the other behavioural

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investigations of psilocybin in non-human animals, suggests post-psilocybin learning as the
underlying mechanism of action and mediator of therapeutic effect.
Psilocybin acutely reduces connectivity in associative networks of the brain including
medial and lateral prefrontal cortex, cingulum, temporoparietal junction and insula, but
concurrently increases sensory, brain-wide connectivity and induces hyper-connectivity in
sensory areas; the integration of functional connectivity in sensory regions and the
disintegration in associative regions may underlie the psychedelic effect (Preller et al., 2020).
Recent neuroimaging studies have better documented the brain network reintegration
dynamics which occur after the widespread, global desynchronization of brain networks and
entropic dynamics of acute psilocybin effect (Daws et al., 2022; Doss, Madden, et al., 2021;
Mertens et al., 2020). As revised networks form following drug effect, greater connectivity and
revised network dynamics have been found between regions of the neocortex and sub-cortical
regions including components of the limbic system. A recently published study of twenty-four
patients with major depressive disorder treated in a psilocybin clinical trial (Davis et al., 2021),
psilocybin-assisted therapy increased cognitive flexibility for at least 4 weeks post-treatment;
one week after PSI, glutamate and N-acetylaspartate concentrations were decreased in the
anterior cingulate cortex and dynamic functional connectivity was increased between the
anterior cingulate cortex and posterior cingulate cortex (Doss, Považan, et al., 2021).
As sub-cortical and limbic system-associated regions are largely associated with threat
response, emotional regulation, sensory awareness and habit formation, a theoretical model
emerges to help explain psilocybin’s persisting and therapeutic effects. Psilocybin attenuates
past conditioning, promotes behaviour change and facilitates processes of new learning and

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does so via a two-hit, or biphasic model: first disrupting rumination and prefrontal cortex
network connectivity via serotonergic agonism, and afterwards in a process of downstream
effects largely regulated by dopaminergic, glutamatergic and GABAergic systems (Vollenweider
and Kometer, 2010; Nichols, 2016; Martin and Nichols, 2017) producing a time-bound critical
period of improved affect and heightened meaning – two predictors of the long-term
potentiation of learned associations. This period of heightened behavioural and cognitive
flexibility lays the groundwork for health-related behavioural change via increased positive
valence, the attenuation of past habit, increased motivation to change, improved ability to
revise past associative-reward learning and improved cognitive and behavioural flexibility.
While much has been made of the entropy under psychedelics, there is limited research
into the post-session afterglow stage of heightened neuroplasticity and improved affect (Doss,
Považan, et al., 2021; Goldberg et al., 2020; Majić et al., 2015; Sampedro et al., 2017), a period
thought to last at least to 4 weeks (Barrett, 2020). This proposed model of psychedelic action
views psychedelics as catalysts to change, and heavily weighs the activities and processes which
occur in the days to weeks following the psychedelic experience. The afterglow period following
a psychedelic session has been found to be a period of increased emotional responsiveness
(Roseman, Demetriou, et al., 2018b) in particular sensitivity to positive emotional stimuli, with
alterations and enhancement to reward learning and salience detection (Barrett, 2021). Strong,
and positive emotionality is known to positively affect the long-term potentiation of new
learning (Tyng et al., 2017).
Salience is an attentional mechanism by which some things stand out in cognition, and
often with striking emotions. Further, the salience network is considered a neural system for

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perceiving and responding to homeostatic demands (Seeley, 2019). Salience is considered a
bottom-up process of presence, as opposed to a top-down, memory dependent and
anticipatory constructions of meaning. Salience is key to learning and to emotional regulation.
Researchers have demonstrated reductions in negative affect and reductions in response to
negative affective stimuli one-week post psilocybin; these changes reverted to baseline at
about the one-month period, suggesting an open, or critical period of neuroplasticity, lasting
about four weeks. Psilocybin displays not only neuroplastic, but also adaptogenic effects,
assisting in the rescue of deficits caused by chronic stress, and facilitating revisions and updates
to symbolic representations of the world, in reward revaluation and in the updating of coping
strategies.
Significant decreases in self-rumination and increases in self-compassion have been
observed after psychedelic experiences, and the level of psychological insight obtained is
correlated with participant reductions in depression, anxiety and stress (Fauvel et al., 2021).
Psychedelics decrease judgmental processing of experiences while increasing the ability of the
individual to decenter (Soler et al., 2016). Psychedelics increase measures of mindfulness
(Smigielski et al., 2019). Individuals who regularly consume the serotonergic psychedelic
ayahuasca in a ritual setting score higher on scales measuring positive self and
decentering (Franquesa et al., 2018). Participants report being more spiritual after psilocybin
administration (Goldberg et al., 2020), and demonstrate increased cognitive and neural
flexibility (Doss, Považan, et al., 2021). Measurable increases in traits of openness and
extroversion have been documented during this time, alongside numerical decreases in

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neuroticism; however, strongest improvements have been found in the trait of
conscientiousness (Erritzoe et al., 2018; MacLean et al., 2011).
Further, reductions in negative affect and increases in positive mood underlie
reductions in rumination, and improvements in self-compassion and self-forgiveness have been
noticed and may be key therapeutic effects. Administration of serotonergic psychedelics is
associated with long-term improvements in mood, attitude, and well-being (Barrett, Doss, et
al., 2020; Goldberg et al., 2020; Griffiths et al., 2006). Psychedelics are known to effect
broadband cortical desynchronization during the period of pharmacological effect
(Muthukumaraswamy et al., 2013), quieting alpha activity during the entropic period and
resulting in healthier brain wave synchronization and coherence post-psychedelics (Acosta-
Urquidi, 2015; Schartner et al., 2017; Valle et al., 2016) . Similarly, increased inter-hemispheric
coherence and symmetry with yoga training has been reported in multiple studies (Desai et al.,
2015) and the effects of psilocybin are consistent with, and improved by, mindfulness and
meditation programs (Eleftheriou & Thomas, 2021; Griffiths et al., 2018; Smigielski et al., 2019).
6.12 Concluding Remarks
This thesis presents the findings of two distinct but complementary scoping reviews:
one presents findings of more than 50 years of pre-clinical investigations of psilocybin in non-
human animals, the other reviews 15 years of clinical trial findings. To contextualize these
reviews, I conducted a significant literature review of psilocybin and a narrative review specific
to the neurophysiology of psilocybin with a particular emphasis on neuroplasticity and the habit

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construct. Together, these reviews provide evidence towards a Transition State model of
longitudinal psilocybin effect and for an underlying therapeutic mechanism whereby
psilocybin attenuates past conditioning, disrupting habit and potentiating behaviour change,
including the improvement of health behaviours.
Evidence points towards a critical period of improved and new learning in the post-
acute time period of persisting effect. This hypothesis has two corollaries: 1) that psilocybin is
an adaptogenic catalyst, disrupting and loosening the hold of maladaptive, unresponsive and
past-prior patterns of thought, feeling, memory and action; and 2) that psilocybin is
plastogenic, potentiating and consolidating new learning, revised beliefs and new health
behaviours in the post-acute period of persisting effect, or afterglow. This longitudinal model of
psilocybin effect highlight the importance of the days and weeks following psilocybin,
suggesting psychedelic-assisted therapies could have greater effect by a focus on the adoption
of new and improved health behaviours. This is a learning model of therapeutic effect; a limbic
learning model premised on improved brain network integration with cortical and sub-cortical
brain regions. This enhanced somatic awareness, combined with the general salutary effect of
psilocybin, provide the conditions to long-term potentiate new habits (integrated packages of
thought, feeling and action).
Given the sustained and persisting effects of even a single dose of psilocybin on mood
and behaviour, psilocybin’s effects present as bi-phasic, whereby it first inhibits established
routines of thought, feeling and behaviour, and secondarily potentiates the learning of new
behaviours. These phases have unique subjective phenomenology as well as different
underlying cellular mechanisms. Due to its inhibitory effects on habits of thought, feeling and

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behaviour, psilocybin can loosen the hold of habitual sub-routines encoded in cellular memory;
the psychedelic pause makes space for change. Psilocybin occasions a subsequent critical period
of cognitive, behavioural and synaptic plasticity which can promote the consolidation of new
learning and new health behaviours. In this way psilocybin has salutary effect via its
adaptogenic and plastogenic functions.
This conceptual two-phase process aligns with the dynamics of neural plasticity, the
cellular basis of new learning, memory and adaptation. Synaptic plasticity occurs when new
cellular growth or new patterns of connectivity (excitation) are shaped via subsequent
reductions or pruning (inhibitory) in the creation of updated neural networks. While
psychedelics are well-understood to promote new and increased synaptic network connectivity
between brain regions (the study of connectomics), less attention has been given the
subsequent afterglow period. This time-bound critical period, lasting up to one month after
psilocybin administration, was the important space for therapeutic gains to occur, and that the
focus of this time period should be the consolidation and long-term potentiation of new
learning and improved health behaviours. Both non-human animal studies and human clinical
trials provide evidence to support an attribution to psilocybin that it can, in combination with
pre and post-dosing conditioning, rescue the effects of chronic stress and improve emotional
valence while decreasing fear conditioning. These variables support the updating of habitual
patterns of thought, feeling and action in a manner that is more responsive to current needs.
Given the strong safety profile of psilocybin and the popular interest in psychedelics, it
seems clear that regulatory reform is required. While drugs with therapeutic application may
require some form of regulation, outright prohibition is scientifically unjustified. An accessible

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and inclusive practice model aligned with the findings of this thesis is the Oregon model of
Psilocybin Service Centres, in which non-medical but qualified facilities and facilitators ensure
safer practice and risk mitigation with oversight and accountability. While pressures to provide
medical access to psilocybin mount, largely with a focus on access at end-of-life, the strict
medicalization of psilocybin could conceivably increase cost, reduce access, and require of
physicians a rather abrupt turn into consciousness medicine and the navigation of altered
states. The evidence contained in this thesis, culled from the extant scientific literature on
psilocybin, supports an end to the regulatory and legal prohibition of psilocybin. From a
population health perspective, Canadian health authorities would be wise to support
psychedelics harm reduction practices and education, including safer-use psilocybin guidelines.
Best practices in psilocybin-assisted therapy require development in the near future .
Biologically, mushrooms are organisms somewhere in the between of plants and
animals, tasked with breaking down matter and recirculating nutrients through entangled
networks of shared information and energy. When considering the effects of psilocybin on the
thoughts, feelings and behaviour of people and non-human animals, perhaps there is a doctrine
of signatures at play in which the biology infers the therapeutic effect. Mushrooms are the
fruiting body of underground networks of shared intelligence: perhaps a fitting symbol for
consciousness itself. For health, health-care and health policy, psilocybin and Psilocybe
mushrooms are truly disruptive and require updated models of practice and public policy if
their therapeutic potential is to be truly understood and realized.

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Glossary of Key Terms
Acute effects are the immediate, noticeable, short-lived and primary physiological and
psychological pharmacologic effects occurring during active drug metabolism (thought to be an
8-12 hour period for psilocybin, but with metabolites detectable for 3 days). With psilocybin,
acute effects include increases to heart rate and blood pressure, as well as the profound
alterations in perception, cognition and mood characteristic of the psychedelic experience.
Acute effects occur along the pharmacokinetic timeline from absorption and distribution to
metabolism and finally through excretion. Acute effects subside when subjective and
behavioural effects have subsided, and such a portion of the drug metabolite has been
metabolized and excreted as to mark a return to homeostasis.
Adaptogenic refers to a drug effect which increases an organism's resistance to stress.
Adaptogens are natural substances sourced from roots, herb, plant substances or fungi which
promote biological homeostasis and which may help counter-balance the physiological and
psychological deficit-effects of stress. Adaptogens have a non-specific restorative, protective or
resilience effect. Common examples include reishi mushrooms, ashwaganda, and ginseng.
Given their non-toxicity, evidence of their effect in rescuing deficits of chronic stress, and that
they do so without increasing oxygen consumption, Psilocybe genus mushrooms can be
considered adaptogenic. The stress-repairing biological effects of plant or fungal adaptogens
are related to their biological complexity; Psilocybe genus mushrooms have rich phytochemical
composition, containing many active alkaloid compounds in addition to psilocybin and psilocin,
and also containing harmalines, known to have anti-depressant effects.
Adverse effects occur when a drug has unintended undesired pharmacological effects, or when
there is an occurrence of undesired harmful effects from an intervention such as in a clinical
trial. Adverse effects occur when a medication or treatment is administered correctly; the
transparent reporting of adverse effects is a sign of trial quality and is generally mandated by
government or sponsoring agencies. Serious adverse effects are rare in psilocybin trials, though
common adverse effects include transient anxiety and distress, nausea and post-treatment
headaches. Risks of adverse effects are mitigated by appropriate client selection, the provision
of psychological supports, a safe and comfortable setting, and the availability of psychiatric and
medical aid. The duration of psychologically challenging experiences under psilocybin has been
negatively correlated with personal meaning, spiritual significance and increased well-being,
suggesting that therapeutic interventions provided during transient anxiety or distress should
be preferentially aimed at reducing the duration rather than the peak difficulty.
Afterglow refers to the period of elevated mood following the resolution of primary drug
effect, in the days to weeks following psilocybin administration
Altered States of Consciousness (ASC), often referred to as Non-ordinary States of
Consciousness (NOSC) are states of consciousness which can be brought about by psychedelic
compounds, hypnosis meditation, yoga, breath practices, sleep and sensory deprivation,
fasting, drumming and ritual dance or other spiritual experiences. Such states are subjective,

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time-limited and characterized by changes to ordinary ways of perceiving the world, and
historically have included dream states, trance, visions and ecstatic states. Such non-ordinary
states are valued by many Indigenous cultures which may view such states as places of
communication with spiritual dimensions underlying mundane, everyday waking reality.
Attenuation refers to the weakening of signal, or the lessening of intensity, value, quality of a
stimulus and can be considered the opposite of amplification. Psilocybin attenuates past
conditioning, loosening the effects of habits developed in the past and thereby potentiates the
development of new patterns of cognition, behaviour and affect.
Behavioural investigations are studies which assess the observable behaviours subsequent to
and related to a study drug or intervention.
Biphasic refers to a two-phase model for understanding psilocybin drug effect: a primary
serotonergic-mediated cascade acutely affecting perception, cognition and affect by
suppressing Default Mode Network activity, followed by downstream dopaminergic,
glutamatergic and GABAergic mediated effects which largely occur in limbic-system brain
regions are associated with reduced negative valence, improved mood and heightened
plasticity (behavioural, cognitive and neural flexibility). In both non-human animal research and
in human clinical trials, psilocybin displays effects both time-dependent (with different effects
appearing at different points along a time-line) and also dose-dependent, with effects varying in
correlation to dose.
Catalysts are chemical agents which initiate and accelerate change processes, increasing the
rate of reaction and thereby stimulating and accelerating natural change processes. Psilocybin
may best be considered a catalyst which creates a transition state of maximum energy/change
potential. Catalysts create a time-bound transition state of maximum energy potential.
Transition states are relatively short-lived, create only partial bonds and cannot be isolated. The
catalytic model proposed here is endothermic, as more energy (change potential) is gained by
the individual than is lost in the process.
Clinical trials are research studies which prospectively assign human participants to one or
more interventions (medical, behavioural or surgical intervention) to evaluate effects on health
outcomes. Differing from healthy human trial (treating healthy volunteers), clinical trials
provide an investigative intervention in order to treat a recognized health condition or disorder
such as depression or substance use disorder. Clinical trials must prove safety, efficacy, and
ultimately treatment effectiveness and occur over 4 phases in the regulatory drug approval
process.
Conditioning is a primary form of learning which involves the formation, strengthening, or
weakening of an association between stimulus and response. Psilocybin disrupts habit,
weakening the hold of past conditioning while priming or improving the potential for improved
health behaviours. Evidence for this effect is found in both non-human animal research with

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psilocybin, and in human clinical trials. In this regard, psilocybin is best understood
therapeutically as an amplifier, or catalyst, of health behaviour change.
Confounding variable: a factor in a treatment intervention which is external to the study drug
which effects outcomes, making it difficult to discern the true effect of the primary
independent variable. In psilocybin research, the provision of therapies and psychological
counselling in addition to psilocybin means that the therapy provided may be a confounding
variable. This makes it difficult to separate the strictly pharmacologic effect of the psilocybin as
an investigative drug from the effects of the therapy provided along with psilocybin.
Context is an extra-pharmacological factor in a comprehensive understanding of total
psilocybin drug effect. The psychedelic experience has been demonstrated to be exceptionally
sensitive to context -- including physical setting, cultural context, the presence of others
including guides or therapists. Psilocybin also has clear sensitivity to pre and post-conditioning,
evident in both non-human animal and human clinical trials, meaning that what occurs in the
stages of preparation (pre-psilocybin dosing) and integration (post-psilocybin dosing) has a
direct effect on outcomes.
Cortical desynchronization refers to the general collapse of normal rhythmic structures of
cortical activity under psilocybin as measured via magnetoencephalography. Brain imaging
studies have found evidence of psilocybin-induced changes in spontaneous brain activity and
cortical oscillatory rhythms indicating changes from resting-state networks, including acute
decreased brain network integrity. This is thought to be mediated by layer V pyramidal neurons
via stimulation of 5-HT-2AR and postulated as a mechanism of action underlying the altered
state of consciousness associated with psilocybin.
The Default Mode Network, or DMN, is a hypothesized network of brain regions and neuron
groups active and interacting when one is not focused on the outside world or particular tasks,
active in mind-wandering and at passive rest. High DMN activity is associated with ego-
construct and autobiographical memory. In general, the DMN receives more blood flow and
consumes more energy than other brain regions; under psilocybin, DMN activity is disrupted
and dampened, with an increase in global inter-region connectivity across the brain but
reduced activity and intra-connectivity within the DMN-related brain regions. Brain scans show
decreased blood flow and oxygen in DMN-related regions during psilocybin’s acute effects, and
follow-up imaging has established changes to amygdala connectivity persisting up to one-
month post psilocybin dose.
Dose-dependent refers to the relationship between dose and drug effect and is studied to
understand the pharmacodynamics of a drug. Dose-dependent drug effects vary in direct
correlation to drug dosage.
Drug Effect is the framework or complex by which we understand the impact or consequences
of drug administration on an individual; drug effect is conditioned by a variety of individual

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variables but also set and setting. Feeney's Total Drug Effect model adds two further variables:
cultural context and belief in and relationship to the healer.
Ego Loss/ Ego Death: clinically referred to as depersonalization, ego loss, ego disintegration or
ego death refers to the temporary suppression of usual ways of understanding one's sense of
self and constructing self-identity induced acutely by psilocybin and other serotonergic
psychedelics. Under psilocybin, our usual cognitive structures and assumptions are paused or
loosened, allowing for novelty, new perspectives and immersive experiences experienced as
novel and meaningful, and which may promote cognitive and behavioural flexibility. In spiritual
traditions, it may be believed that the old sense of self must die to allow for a personal rebirth,
or transcendence. People may become disoriented, or feeling lost under psilocybin effect,
reflecting the temporary loosening of higher-order cognitive schema which organize sensory
input and other information into an abiding sense of self.
Embodied Cognition is a term developed by neuroscientist and addiction researcher Mark
Lewis to refers to the manner in which psychopathologies are not diseases but learned
behaviours encoded in cellular memory within synaptic configurations of the brain. In this way,
mind is inherently embodied.
Entheogen is alternative nomenclature for psychedelic, more often applied to traditional plant
or fungal psychedelic compounds with associated ritual histories such as with ayahuasca or
Psilocybe genus mushrooms. The word is derived from an ancient Greek term meaning to
manifest the divine from within. Unlike psychedelic, entheogen is not associated with Western
medical models or the concept of therapy. Entheogenic rituals such as ayahuasca ceremonies or
mushroom veladas have historically been overseen by shamans (wise ones), ritual leaders and
ceremonialists, occur in a group format, involve darkness, chanting and music, and have
accompanying preparations (special diets, abstinence from sex) and follow-up activities.
Entropy is a measure of uncertainty, randomness, disorder; elevated entropy under
psychedelics is characterized by a collapse of usually highly organized activity within the default
mode network, resulting in subject puzzlement, confusion, and potentially ego loss. Experiences
of entropy may be critical to optimal brain health, allowing for revision and update to existing
patterns of connectivity, thought and behaviour.
Ethnopharmacology is the interdisciplinary study of human and cultural use of the bioactive
chemical compounds found in plants, fungi, animals, microorganisms and minerals and their
associated pharmacological, biological and psychological effects.
Expectation bias is the phenomena whereby a person's expectation contributes to bringing
about the desired effect of an investigational drug. Observer-expectancy occurs when
investigator expectations effect outcomes. Expectancy biases may be reduced by double-blind
and placebo controlled trial design.

260
Extra-pharmacological refers to the variables outside of the strict pharmacological basis of the
drug which contribute to drug effect, such as setting, the role of music and the effects of pre-
drug conditioning or the presence of guides in psychedelic therapies.
Habit learning is the repetition of responses so that context-response associations are
consolidated in memory and behaviours become relatively automatic, disconnected from
context and insensitive to changes in value or outcome; habits are consolidated in cortical brain
regions as long-term and encoded representations of learned skill. Habit is best understood as
an integrated package, program or pattern of thought, feeling and behaviour and a cognitive
bias which highly values or weights past behaviour, valuing predictability over novelty or
uncertainty.
Harm reduction is the non-judgmental and inclusive practice, philosophy and policy of reducing
prospective harms of a drug or a health behaviour by making small alterations to the rituals of
practice so that better health outcomes occur. A harm reduction approach to psilocybin seeks
to reduce those adverse experiences not related to therapeutic benefit and recognizes that by
far most psilocybin use occurs recreationally in naturalistic settings; low-risk guidelines for
psilocybin use would be of public health benefit and are suggested in the Conclusion section to
this thesis.
Health behaviours are behaviours, individual and social, which have a direct impact on overall
health or which are intended to improve overall health. Behaviour is the way people act -- the
things that we do and action we take, and behaviour may be in response to a particular
stimulus in the environment. Intentional behaviour involves agency, autonomy, decision-
making, behavioural control, the evaluation of possibilities and temporal thinking. Behavioural
choices are conditioned by past experiences which have formed the neural pathways of habit,
and these habits are accompanied by cognitive schema (constructs which assign meaning, or
valence, and which aid in metabolic efficiency by simplifying the demands of decision-making.
Common examples of health behaviours include smoking, substance use as coping mechanisms
potentially negatively-impacting health, and yoga, meditation, exercise and healthy eating to
improve health.
Hebbian Learning, also known as Cell Assemblage theory is an integrated approach to
understanding the neural underpinning to learning, in which learning occurs and is preserved in
the activation of neurons and the formation of networked assemblies of neurons. Hebbian
Learning holds that the neurons which fire together wire together. Cell assemblies are
distributed subsets of neurons with strong reciprocal connections. By Hebbian learning,
cognitive network associations are made between the environment or other context cues and
the habit response is strengthened such that context cues can automatically prompt habitual
responses
Knowledge synthesis is an act of evidence identification; knowledge synthesis projects are
reviews of primary research conducted with the aim of identifying, assessing and synthesizing in
succinct summaries wider bodies of literature in order to contribute towards evidence-based

261
care and the development of best practices. Knowledge synthesis reviews have a range of
methodological rigour or generalizability (ranging from rigorous systematic to more subjective
narrative reviews) conducted to identify bases in evidence, intended to inform practice and
policy for improved health outcomes. Knowledge synthesis is foundational to the development
of evidence-informed practice guidelines, especially helpful when a field is still emergent or
diverse, as with contemporary psychedelic sciences.
Limbic system is a collective term for a set of structures in the brain (of all vertebrates) involved
in emotion (including emotional processing of sensory input), memory and arousal. The limbic
system is thought to regulate autonomous and endocrine function. Consisting of the limbic lobe
and other sub-cortical structures and their various connections, covering both sides of the
thalamus, the limbic system includes the hippocampus and amygdala. These structures have
extensive connections to the hypothalamus and upper brain stem sites involved in regulation of
organs of the body. The limbic system should be viewed in wide perspective and in association
with many neocortical as well as basal ganglia-implicated systems, neuro-endocrine regulation
and the Hypothalamic-Pituitary-Axis, critical in the regulation of cortisol and maintenance of
homeostasis in stress response. I use the term limbic learning to refer to the period of
heightened sensory awareness, social learning and embodied absorption characteristic of the
afterglow period following psilocybin.
Long-term potentiation (LTP) is he process by which synaptic connections between individual
neurons are strengthened by frequent activation. This persistent strengthening of associations,
occurring at a synaptic level, forms the cellular basis of memory. As neural associations
(synaptic networks) are repeated, signal transmission is increased in a long-lasting manner. LTP
is associated with activity in the hippocampus, an area of the brain associated with learning and
memory. LTP is associated with neuroplasticity and with behavioural flexibility.
Magic mushrooms is the popular name for psychoactive mushrooms, principally of the
Psilocybe genus. The name derives from an editorial decision from Life Magazine when
publishing a 1957 article on Maria Sabina, the now-famous Mazatec mushroom curandera, or
wise woman healer, and subsequently entered the popular lexicon. Sabina herself referred to
the mushrooms as los ninos santos, the little saint children. Clinical trials reviewed in this thesis
all used a synthetic version of psilocybin; whole-mushroom extracts or whole biomass
mushrooms contain multiple alkaloids. The therapeutic potential of Psilocybe mushrooms may
not be limited to the psilocybin compound alone; psilocin, baeocystin, norbaeocystin,
aeruginascens, norpsilocin and phenylethylamines are also found in Psilocybe mushrooms and
may themselves have value alone or in entourage. Recent investigations have found the
presence of beta-Carbolines in Psilocybe mushrooms resulting in an ayahuasca-type synergy of
psychoactive alkaloids and potent monoamine oxidase inhibitors which also themselves have
antidepressant effects and potentiate the psychedelic serotonergic effects
Microdosing refers to the regular consumption of very small/functionally low doses of
psychedelic compounds (such as magic mushrooms and LSD) at one-tenth to one-twentieth of
regular psychedelic doses for health or psychological benefit; micro-doses are classified as sub-

262
perceptual or sub-threshold doses. The absence of the classical psychoactive psychedelic
effects does not mean a lack of total effects; users have self-reported benefits from decreased
depression to increased attention, energy, and creativity.
Mysticism refers to non-ordinary experiences of a transpersonal, spiritual or religious nature,
which can occur spontaneously, or as a result of techniques to alter consciousness including
psychedelic drug use. Many of the psilocybin trial subjects report mystical-type experiences
characterized by a deep sense of oneness and interconnectivity. The standard tool used to
measure mysticism in these trials is the Pahnke–Richards Mystical Experience Questionnaire
which provides scale scores in seven domains of mystical experiences including internal and
external unity, the transcendence of time and space, ineffability and paradoxicality, a sense of
sacredness, a noetic quality (claim of intuitive knowledge of ultimate reality) as well as deeply
felt positive mood. The MEQ has a number of limitations and can be critiqued as culture-bound,
expressing Western-Christian conception and an overly narrow framework for the range of
possible non-ordinary experiences. It is important to remember that psilocybin’s profound
effects may be experienced as debilitating or negative by some and that challenging
experiences under psilocybin are frequently reported. There is considerable overlap between
the MEQ conception of mysticism and the experience of ego dissolution.
Neural correlates are the underlying brain activities associated or necessary to result in a
particular subjective experience. In this thesis, we are principally interested in the neural
correlates which form the biological basis to the psilocybin experience. In general, psychedelic
science is interested in understanding the neural correlates to consciousness, and to different
states of consciousness, including the non-ordinary.
Neuroplasticity or neural plasticity, is the cellular basis to new learning, memory and
adaptation. Synaptic plasticity occurs when new cellular growth or new patterns of connectivity
(excitation) are shaped via subsequent reductions or pruning (inhibitory) in the creation of
updated neural networks. Plasticity occurs when the nervous system develops new, or
reorganizes neural structures, functions or connections.
Persisting effects are the longer-lasting effects beyond the acute state of pharmacokinetics,
when psilocybin has been metabolized by the body to the point that noticeable physiological or
psychological phenomenon have subsided, and immediately after the post-acute phase of
recalibration. Many of the psilocybin clinical trials adopted the Persisting Effects Questionnaire.,
which investigates in the weeks to months following psilocybin dosing any persisting changes in
attitudes, mood, or behavior as well as possible changes in standardized measures of
personality, mood and spirituality, and life satisfaction. The biological processes and
mechanisms underlying persisting effects is an area of current research; I proposed increased
global brain integration and improved connectivity to limbic system brain regions serve as the
underlying basis to the persisting effects of improved mood, decreased negativity, and
improved flexibility (cognitive and behavioural).

263
Post-acute refers to the time-period immediately after the immediate pharmacological effect
of psilocybin has subsided and includes the period of immediate homeostatic recalibration.
Post-acute refers to the time phase after the immediate resolution of psilocybin's
psychoactive/psychedelic effect (8-12hrs after administration, generally) as measured in days,
but before the evidence of persisting effect (measured in weeks, months and years). Post-acute
effects of psilocybin commonly include headaches (starting 7 hours after) and sometimes a
delayed and dose related rebound period of lowered mod . In some clinical trials, subjects have
scored higher on depression scores in day 2, with higher scores trending from day 3 onward.
Lack of sleep, sleep disruption and headache occurrence may explain lower affect. Potential
mechanisms included repressed activity of serotonin and super sensitivity in some brain parts.
The day after, both healthy and clinical trial subjects report higher levels of fatigue, irritability
and sensitivity to external stimuli with reduced concentration ability. Amygdala responses to
fearful faces were increased one day after psilocybin dosing. Psilocin itself is detectable in drug
assays for 3 days. Psilocybin suppressed slow wave activity (SWA) in the first sleep cycle
following drug administration. However, it has been demonstrated that one full night of sleep
deprivation can alleviate symptoms of depression, perhaps by resetting circadian rhythms.
Priming refers to the action of prompting or preparing something for action in such a way as to
improve outcome or increase efficiency. Behavioural priming is when the exposure to one
stimulus influences the response to different, subsequent stimuli. Primed nodes or networks
(such as a semantic network) are recognized and accessed more readily in subsequent
tasks, improving performance of a task relative to baseline due to prior exposure to a priming
stimulus.
Psychedelics are a loosely-grouped class of psychoactive compounds with tell-tale and dose-
dependent effects on perception, cognition and mood. Psychedelics commonly effect closed
and open-eye visuals and are often experienced as expanding consciousness beyond everyday
experiences into the non-ordinary. Psychedelic experiences are often described as mystical, and
generally involve psychological and emotional processes of insight, self-reflection and meaning.
Classical psychedelics such as psilocybin, LSD, DMT/ayahuasca and peyote commonly effect
serotonin regulation and display evidence of cross-tolerance, while atypical psychedelics
include MDMA (more precisely categorized as an entactogen) and ketamine (dissociative
psychedelic).
Psychedelic-assisted Therapy (PAT) is a form of treatment for mental health conditions such as
depression, substance use dependence and existential distress, among other emerging
indications. PAT leverages the catalyst of effect of psychedelic compounds to prime or amplify
therapeutic processes by providing psychological supports during preparation and integration
stages and may include the provision of additional manualized, group or other structured
therapies aimed at improving the underlying health condition. Psilocybin-assisted therapy (PSI-
AT) is a form of PAT combining dosing sessions of psilocin with psychological therapies including
but generally exceeding those related to preparation for and integration of the psychedelic
experience.

264
Psychoplastogens are a newly recognized category of fast-acting therapeutic drugs which
rapidly promote structural and functional neural plasticity. Psychoplastogens commonly
produce measurable changes in plasticity (as measured by new growth of neurons, increased
dendritic spine density, and increased intrinsic excitability) within 24-72 hours following a single
administration. Their primary effect on neural plasticity is thought to enable subsequent stimuli
and experiences to reshape neural circuits, producing persisting changes in behavior that
extend beyond the acute effects of the drug. Examples include serotonergic psychedelics,
ketamine and some recent fast-acting anti-depressants.
Reverse Translation is a process of using real-time clinical data to inform new discoveries and
improved basic research. While usual the usual knowledge translation pipeline runs from bench
(preclinical studies) to bedside and (clinical trials and other clinical data) to generating new
hypotheses, reverse translation is a more dynamic process which includes return from bedside
back to the bench in developing next generation science .
Salutary refers to a generalized, overall benefit to the health of an organism, etymologically
rooted in earlier terms for remedy, health, and wholeness.
Scoping reviews, like systematic reviews, are a rigorous and reproducible methodology of
knowledge synthesis intended to broadly capture the state of the literature, clarify conceptual
concepts, identify gaps in research, and inform future clinical trials and systematic reviews.
Scoping reviews may also assist in generating hypotheses in potential new modalities of
treatment and the therapeutic application of particular psychedelics drugs. Scoping reviews
help to identify, summarize and map the evidence from a broad section of literature, using a
rigorous, transparent and replicable methodology to comprehensively explore, identify and
analyze all relevant literature pertaining to a research area. Scoping reviews provide a basis in
evidence for the evolution of both research and clinical practice, in this case by understanding
the patients selected, the interventions used, and the outcomes noted for psilocybin-assisted
therapies (PSI-AT).
Self-regulation is the biological ability of any organism to adapt in response to its environment
or to changing needs based in its own development. It generally refers to the ability to modify
inner states and responses of thought, feeling and action for your own well-being. Disorders of
mental-health have in common pathological habits of poor, or diminished, self-regulation
encoded as habits.
Sensitivity to context refers to the phenomenon in which psilocybin administration or use is
directly sensitive to and mediated by the context of use including setting, but also to past
conditioning (such as preparation or training) and to what happens after the resolution of drug
effect (integration).
Set refers to the state and traits of an individual, including predispositions, expectations and
personality character. Drug effect is a mix of drug, set and setting.

265
Setting refers to the immediate context in which psilocybin is administered, including the
physical environment, aesthetic, music and presence of therapists, guides or it is a clinical site,
clinical trial, or be it in a naturalistic (formerly recreational, and meant to refer to non-clinical
and non-research) setting.
Subjective effects include the visual, spatial, and temporal perception, loosened associations,
and vivified imagination associated with psilocybin effect. More profound effects such as
depersonalization or “ego disintegration”, as well as the negative and challenging effects of
psilocybin are included among its subjective effects.
Threshold dose is the dose required to result in either a clear psychedelic effect, or in the
absence of tell-tale visual imagery, the experience of intense psychological processes
experienced as profound, personally meaningful, and often spiritual. The therapeutic dose
range of psilocybin is yet to be confirmed, and a range of effects exist in both a dose and time-
dependent manner.
Time-dependent effect is a framework for understanding the time course of drug effects using
pharmacokinetic–pharmacodynamic models. the study of pharmacokinetics investigates the
time course of drug concentration in the body.
Transition State is a critical time-period, after a catalyst event, characterized by heightened
cognitive and behavioural flexibility and an acceleration of change processes. Refers to a liminal
state, or bardo, between the horns of change. Psilocybin is a catalyst agent, beginning with drug
administration a rapid increase in energy (change) potential is experienced as novel brain states
are experienced. As drug effect resolves, a transition state of heightened change potential is
experienced in the sub-acute and persisting effect periods. During this transition state there
appears to better long-term potentiation of behaviour change, meaning new habits or practices
developed in the days and weeks following psilocybin have an enhanced ability to last.

266
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Zoellner, L. A., & Foa, E. B. (2016). Applying Research Domain Criteria (RDoC) to the study of
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Appendices
Appendix A:
Thesis Proposal
Ron Shore
Therapeutic Potential of Psilocybin and Psilocybin-assisted Therapies
June 2019
1. Research Question:
Can psilocybin have clinical benefit in the treatment of mood and self-regulatory
disorders, including end-of-life distress? If so, what are the program/practice variables
associated with treatment outcomes?
2. Research Program:
2.1. Coursework: understanding theoretical and conceptual issues pertaining to
psilocybin-occasioned altered states of consciousness.
2.2. Methodology: understanding and mastering scoping review methodology as well as
qualitative ethnographic study methodology.
2.3. Core Content Scholarship: the neuroscience of psilocybin, history of psycho-active
plant and drug use, chemistry/pharmacology and the botany of psychedelic substances,
components of effective psychedelic-assisted psychotherapy.
2.4. Psychedelics Learning Lab: community of practice to develop knowledge, skills,
infrastructure and capacities to conduct effective and quality research related to
psychedelics.
2.5. Complete scoping review on psilocybin assisted therapy.

289
2.6. Develop protocol framework for psilocybin assisted clinical trials.
2.7. Conduct original research project interviewing individuals who have used psilocybin
recreationally and who have experienced mental health symptomology related to
depression and/or substance use. Via qualitative interviews, explore ethnographically
the phenomenology and functionality of naturalistic psilocybin use.
3. Dissertation Components:
3.1. Introduction and overview
3.2. Scoping Review: Mapping Psilocybin-assisted Therapy
3.3. Protocol Framework for Psilocybin-assisted therapy research trials
3.4. Qualitative Ethnographic Analysis of Naturalistic Psilocybin Use: Phenomenology,
Functionality and Self-medication for Mental Health
3.5. Best Practices in Psilocybin Therapy
3.6. Conclusions and future Directions
Supervisors: Dr. Eric Dumont, Dr. Craig Goldie
Note:
As a result of the global COVID-19 pandemic, new challenges and limits emerged on the
ability to conduct in-person human research. This research proposal changed as a result.
Specifically, component 3.4 which was intended as a qualitative ethnographic study was
changed later in 2019 to a second scoping review, this time on non-human animal psilocybin
research.
Appendix B: Mapping Psilocybin-assisted Therapies Supporting Documents

290
Appendix B.1 Scoping Review Protocol
Protocol
Scoping Review: Mapping Psilocybin Therapy Research
November 27, 2018
Team Members:
Ron Shore, PhD Student, School of Kinesiology & Health Studies, Queen’s University, Kingston,
ON (31rjs7@queensu.ca)
Paul Ioudovski, 4th year Life Sciences Student, Queen’s University
Sandra McKeown, Librarian, Health Sciences, Queen’s University
Dr. Eric Dumont, Department of Biomedical and Molecular Sciences, Queen’s University
Dr. Craig Goldie, Department of Medicine, Queen’s University (Corresponding Author:
craig.goldie@queensu.ca)
Objective:
By understanding the patients selected, the interventions used, and the outcomes noted
for psilocybin-assisted therapies, we may better understand the program variables and best
practices of these emerging treatments.
This scoping review will extract, review and chart data related to psilocybin-assisted
therapy in three domains.
1. Patients — cohort size, presenting conditions,
2. Interventions — location, dosage, ancillary services
3. Outcomes — changes, indications, conclusions
Through librarian-conducted literature searches and defined inclusion criteria, the relevant
number of internationally published, peer-reviewed academic articles in addition to grey area
literature will be identified, and the findings charted to identify the current state of both the
literature and this treatment modality.

291
Stages of Scoping Review:
A scoping review methodology was selected given the heterogeneous and emergent nature
of the psilocybin-therapy research publications. Following the framework methodology
proposed by Arksey and O’Malley (Arksey & O’Malley, 2005), and further discussed by Levac et.
al (Levac et al., 2010) Colquhaun et. al(Colquhoun et al., 2014), and Peters et.al (Peters et al.,
2015) this scoping review has 6 specific stages.
1. Development and formulation of research question
2. Identifying relevant studies
3. Study selection
4. Charting the data
5. Collating, summarizing and reporting results
6. Consultation with relevant stakeholders
Research Question:
What are the treatment variables and outcomes associated with psilocybin-assisted
therapy? Variables include both patient and intervention characteristics. Outcomes include
changes in health status and both positive and negative outcomes noted.
This research question will help to map the state of psilocybin-therapy research, and to
identify both treatment variables and patient characteristics. In this way, any effectiveness
found in psilocybin therapy may lead to evidence-based program and policy developments. By

292
opening the opaque box of psilocybin therapies, we can understand which inputs lead to
desirable outcomes.
Preparation / preliminary work:
Reviewers will complete multiple preliminary reviews, literature research, scan abstracts
for keywords, pilot inclusion criteria, pilot data extraction tool, and research background and
history of psilocybin therapy prior to conducting the actual scoping review. Reviewers will also
familiarize themselves with scoping review methodology and existing reviews.
Literature Searches / Methodology:
A librarian from Queen’s Bracken Health Sciences Library has conducted two preliminary
searches and one Embase preliminary search. A final search for the purpose of this scoping
review will include electronic databases, grey literature sources and the reference lists of
identified key studies to identify possible for inclusion. Bibliographic data, study and patient
characteristics as well as other indicators will be collected and analyzed using a data extraction
tool developed by the research team.
Key extraction fields / data extraction tool:

293
Screening/Identifying Relevant Studies:
Librarian to complete literature search with agreed upon keywords, filtering out for
duplication.
Study Selection:
Two reviewers (RS & PI) to review each article abstract using Covidence (Cochrane)
software. Same reviewers. Articles must meet inclusion criteria to be selected.
Inclusion Criteria: psilocybin, therapy/treatment, outcomes measured, meets search
terms/ keywords.
Exclusion Criteria: duplication, not research study, no outcomes measured, no
therapeutic goal, not about psilocybin.
Table 1. Psilocybin Scoping Review Data Extraction Tool Summary Table
Study Characteristics
Intervention
Characteristics
Research
Orientation
Implications
citation
presenting condition(s)
outcomes
measured
research question
year of publication
dose
effectiveness
conclusions
source/country of
origin
schedule
follow-up
limitations
journal type
psychotherapy provided?
methodology
suggestions for further research
sample size
# of sessions
study design
other practice variables

294
# included =
# excluded =
# duplicates=
# studies selected =
Charting the Data:
Reviewers to read entirety of selected studies and extract data using original data
extraction tool. Reviewers to cross-check for homogenous process quality control. Data entered
form selected studies in agreed upon categories.
Collating/Summarizing Data:
After consultation with Queen’s Biostatistician, data to be summarized using
standardized methodology. Key findings to be highlighted, and both practice and patient
variables to be summarized. Indications for future research to also be identified.
Consultation with Relevant Stakeholders:
Draft results to be shared and reviewed by relevant stakeholders, including all team
members and associated biostatistician, and recognized experts in the field of psilocybin and
psychedelic therapies, as well as individuals with scoping review research experience.
Results Mapping / Knowledge Distribution and Reporting:
Data from the scoping review will be mapped in at least the following manners:

295
1. Geographically map countries of research and density of publications
2. Chart time distribution of publication dates
3. Compare and contrast disciplines of research and program aims/objectives
As per Protocol Overview, study results would be presented under three categories:
1. Patients — cohort size, presenting conditions
2. Interventions — dosage, schedule, ancillary services
3. Outcomes — outcomes measured, effectiveness, follow-up
Additional Findings:
1. Gaps in literature to be identified
2. Indications for Further Research identified
3. Interpretation of Key Findings
4. Identification of Best Practices in psilocybin therapy.
Authorship:
Scoping review authorship to include all team members. Publication to be sought within
relevant academic journals. Opportunities to present as poster/paper or as conference
presentation to be sought. Protocol to be published in Prospero.

296
Appendix B.2 Electronic Search Strategies
Ovid MEDLINE(R), Ovid MEDLINE(R) Daily and Epub Ahead of Print, In-Process & Other Non-
Indexed Citations 1946 to Present
1 Psilocybin/
2 psilocybin*.mp.
3 indocybin.mp.
4 psilocibin*.mp.
5 psilocin phosphate ester.mp.
6 psilotsibin.mp.
7 teonanacatl.mp.
8 1 or 2 or 3 or 4 or 5 or 6 or 7
9 mood disorders/ or depressive disorder/ or depression, postpartum/ or depressive
disorder, major/ or depressive disorder, treatment-resistant/ or dysthymic disorder/ or
premenstrual dysphoric disorder/ or seasonal affective disorder/ or cyclothymic
disorder/
10 depression/
11 depressed.mp.
12 depression.mp.
13 depressive.mp.
14 mood.mp.
15 affective disorder*.mp.
16 anxiety/ or anxiety, castration/ or catastrophization/ or dental anxiety/ or performance
anxiety/
17 anxiety disorders/ or agoraphobia/ or anxiety, separation/ or neurocirculatory asthenia/
or neurotic disorders/ or obsessive-compulsive disorder/ or hoarding disorder/ or panic
disorder/ or phobic disorders/ or phobia, social/
18 anxiety.mp.
19 stress disorders, traumatic/ or battered child syndrome/ or combat disorders/ or
psychological trauma/ or stress disorders, post-traumatic/ or stress disorders, traumatic,
acute/
20 obsessive compulsive disorder*.mp.
21 phobia*.mp.
22 psychasthenia.mp.
23 stress disorder*.mp.
24 PTSD.mp.

297
25 psychotrauma.mp.
26 psychological trauma.mp.
27 behavior, addictive/ or food addiction/
28 substance-related disorders/ or alcohol-related disorders/ or alcohol-induced disorders/
or alcohol-induced disorders, nervous system/ or alcohol amnestic disorder/ or alcoholic
korsakoff syndrome/ or alcohol withdrawal delirium/ or alcohol withdrawal seizures/ or
alcoholic neuropathy/ or cardiomyopathy, alcoholic/ or fetal alcohol spectrum
disorders/ or liver diseases, alcoholic/ or fatty liver, alcoholic/ or hepatitis, alcoholic/ or
liver cirrhosis, alcoholic/ or pancreatitis, alcoholic/ or psychoses, alcoholic/ or alcoholic
intoxication/ or alcoholism/ or binge drinking/ or wernicke encephalopathy/ or
amphetamine-related disorders/ or cocaine-related disorders/ or drug overdose/ or
heroin dependence/ or inhalant abuse/ or marijuana abuse/ or neonatal abstinence
syndrome/ or opioid-related disorders/ or morphine dependence/ or opium
dependence/ or phencyclidine abuse/ or psychoses, substance-induced/ or substance
abuse, intravenous/ or substance abuse, oral/ or substance withdrawal syndrome/ or
"tobacco use disorder"/
29 addict*.mp.
30 dependen*.mp.
31 "substance use".mp.
32 misus*.mp.
33 abuse*.mp.
34 abusing.mp.
35 Addiction Medicine/
36 withdrawal*.mp.
37 or/9-36
38 8 and 37
Embase Classic+Embase 1947 to 2018 December 04
1 psilocybine/
2 psilocybin*.mp.
3 indocybin.mp.
4 psilocibin*.mp.
5 psilocin phosphate ester.mp.
6 psilotsibin.mp.
7 teonanacatl.mp.

298
8 1 or 2 or 3 or 4 or 5 or 6 or 7
9 mood disorder/ or exp depression/ or major affective disorder/ or minor affective
disorder/
10 depressed.mp.
11 depression.mp.
12 depressive.mp.
13 mood.mp.
14 affective disorder*.mp.
15 exp anxiety/
16 anxiety disorder/ or acute stress disorder/ or anxiety neurosis/ or generalized anxiety
disorder/ or "mixed anxiety and depression"/ or exp obsessive compulsive disorder/ or
panic/ or exp phobia/ or posttraumatic stress disorder/ or psychasthenia/ or separation
anxiety/
17 anxiety.mp.
18 obsessive compulsive disorder*.mp.
19 phobia*.mp.
20 psychasthenia.mp.
21 stress disorder*.mp.
22 PTSD.mp.
23 psychotrauma/
24 psychological trauma.mp.
25 addiction/ or exp behavioral addiction/ or exp drug dependence/ or food addiction/ or exp
withdrawal syndrome/
26 addict*.mp.
27 dependen*.mp.
28 "substance use".mp.
29 misus*.mp.
30 abuse*.mp.
31 abusing.mp.
32 addiction medicine/
33 withdrawal*.mp.
34 or/9-33
35 8 and 34

299
PsycINFO 1806 to November Week 4 2018
1 psilocybin/
2 psilocybin*.mp.
3 indocybin.mp.
4 psilocibin*.mp.
5 psilocin phosphate ester.mp.
6 psilotsibin.mp.
7 teonanacatl.mp.
8 1 or 2 or 3 or 4 or 5 or 6 or 7
9 affective disorders/ or exp bipolar disorder/ or disruptive mood dysregulation disorder/
or exp major depression/ or exp mania/ or seasonal affective disorder/
10 major depression/ or anaclitic depression/ or dysthymic disorder/ or endogenous
depression/ or late life depression/ or postpartum depression/ or reactive depression/ or
recurrent depression/ or treatment resistant depression/
11 atypical depression/
12 "depression (emotion)"/
13 depressed.mp.
14 depression.mp.
15 depressive.mp.
16 mood.mp.
17 affective disorder*.mp.
18 anxiety/ or computer anxiety/ or mathematics anxiety/ or performance anxiety/ or social
anxiety/ or speech anxiety/ or test anxiety/
19 anxiety disorders/ or acute stress disorder/ or castration anxiety/ or death anxiety/ or
generalized anxiety disorder/ or exp obsessive compulsive disorder/ or panic disorder/ or
exp phobias/ or post-traumatic stress/ or exp posttraumatic stress disorder/ or
separation anxiety disorder/
20 anxiety.mp.
21 obsessive compulsive disorder*.mp.
22 phobia*.mp.
23 psychasthenia.mp.
24 stress disorder*.mp.
25 PTSD.mp.
26 psychotrauma.mp.
27 psychological trauma.mp.

300
28 addiction/ or exp alcoholism/ or exp drug addiction/ or internet addiction/ or exp
process addiction/ or sexual addiction/
29 addict*.mp.
30 dependen*.mp.
31 "substance use".mp.
32 misus*.mp.
33 abuse*.mp.
34 abusing.mp.
35 drug abuse/ or exp alcohol abuse/ or exp drug dependency/ or exp inhalant abuse/ or
polydrug abuse/
36 "substance use disorder"/
37 withdrawal*.mp.
38 or/9-37
39 8 and 38
EBM Reviews - Cochrane Central Register of Controlled Trials October 2018
1 Psilocybin/
2 psilocybin*.mp.
3 indocybin.mp.
4 psilocibin*.mp.
5 psilocin phosphate ester.mp.
6 psilotsibin.mp.
7 teonanacatl.mp.
8 1 or 2 or 3 or 4 or 5 or 6 or 7
9 mood disorders/ or depressive disorder/ or depression, postpartum/ or depressive
disorder, major/ or depressive disorder, treatment-resistant/ or dysthymic disorder/ or
premenstrual dysphoric disorder/ or seasonal affective disorder/ or cyclothymic
disorder/
10 depression/
11 depressed.mp.
12 depression.mp.
13 depressive.mp.
14 mood.mp.
15 affective disorder*.mp.

301
16 anxiety/ or anxiety, castration/ or catastrophization/ or dental anxiety/ or performance
anxiety/
17 anxiety disorders/ or agoraphobia/ or anxiety, separation/ or neurocirculatory asthenia/
or neurotic disorders/ or obsessive-compulsive disorder/ or hoarding disorder/ or panic
disorder/ or phobic disorders/ or phobia, social/
18 anxiety.mp.
19 stress disorders, traumatic/ or battered child syndrome/ or combat disorders/ or
psychological trauma/ or stress disorders, post-traumatic/ or stress disorders, traumatic,
acute/
20 obsessive compulsive disorder*.mp.
21 phobia*.mp.
22 psychasthenia.mp.
23 stress disorder*.mp.
24 PTSD.mp.
25 psychotrauma.mp.
26 psychological trauma.mp.
27 behavior, addictive/ or food addiction/
28 substance-related disorders/ or alcohol-related disorders/ or alcohol-induced disorders/
or alcohol-induced disorders, nervous system/ or alcohol amnestic disorder/ or alcoholic
korsakoff syndrome/ or alcohol withdrawal delirium/ or alcohol withdrawal seizures/ or
alcoholic neuropathy/ or cardiomyopathy, alcoholic/ or fetal alcohol spectrum disorders/
or liver diseases, alcoholic/ or fatty liver, alcoholic/ or hepatitis, alcoholic/ or liver
cirrhosis, alcoholic/ or pancreatitis, alcoholic/ or psychoses, alcoholic/ or alcoholic
intoxication/ or alcoholism/ or binge drinking/ or wernicke encephalopathy/ or
amphetamine-related disorders/ or cocaine-related disorders/ or drug overdose/ or
heroin dependence/ or inhalant abuse/ or marijuana abuse/ or neonatal abstinence
syndrome/ or opioid-related disorders/ or morphine dependence/ or opium
dependence/ or phencyclidine abuse/ or psychoses, substance-induced/ or substance
abuse, intravenous/ or substance abuse, oral/ or substance withdrawal syndrome/ or
"tobacco use disorder"/
29 addict*.mp.
30 dependen*.mp.
31 "substance use".mp.
32 misus*.mp.
33 abuse*.mp.
34 abusing.mp.

302
35 Addiction Medicine/
36 withdrawal*.mp.
37 or/9-36
38 8 and 37
Web of Science Core Collection
Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI
Timespan=All years
# 23
#22 AND #1
# 22
#21 OR #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR
#13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR
#4 OR #3 OR #2
# 21
ALL FIELDS: (withdrawal*)
# 20
ALL FIELDS: (abusing)
# 19
ALL FIELDS: (abuse*)
# 18
ALL FIELDS: (misus*)
# 17
ALL FIELDS: ("substance use")
# 16
ALL FIELDS: (dependen*)
# 15
ALL FIELDS: (addict*)
# 14
ALL FIELDS: (psychotrauma)
# 13
ALL FIELDS: ("psychological trauma")
# 12
ALL FIELDS: (PTSD)
# 11
ALL=("stress disorder*")
# 10
ALL FIELDS: (psychasthenia)
# 9
ALL FIELDS: (phobia*)
# 8
ALL FIELDS: ("obsessive compulsive disorder*")
# 7
ALL FIELDS: (anxiety)
# 6
ALL FIELDS: ("affective disorder*")
# 5
ALL FIELDS: (mood)
# 4
ALL FIELDS: (depressive)
# 3
ALL FIELDS: (depression)
# 2
ALL FIELDS: (depressed)
# 1
ALL=(psilocybin* OR indocybin OR psilocibin* OR "psilocin
phosphate ester" OR psilotsibin OR teonanacatl)

303
ProQuest Dissertations and Theses Global
noft(psilocybin* OR indocybin OR psilocibin* OR "psilocin phosphate ester" OR psilotsibin OR
teonanacatl) AND (noft(depressed OR depression OR depressive) OR noft(mood) OR
noft("affective disorder*") OR noft(anxiety) OR noft("obsessive compulsive disorder*") OR
noft(phobia*) OR noft(psychasthenia) OR noft("stress disorder*") OR noft(PTSD) OR
noft(psychotrauma OR "psychological trauma") OR noft(addict*) OR noft(dependen*) OR
noft("substance use") OR noft(misus*) OR noft(abuse* OR abusing) OR noft(withdrawal*))
Appendix B.3 Clinical Data Tables
Table B.3.1. Psilocybin Trials and Investigations, Documented Adverse Effects

304
Table B.3.2. Possible Acute Adverse Effects, Psilocybin & Psilocybe Mushrooms
Physiological
pupil dilation
Cognitive
altered time perception
increased heart rate
impaired tempo
increased respiratory rate
working memory deficits
increased systolic pressure
concentration problems
increased diastolic pressure
impaired perception
facial flushing
alterations in colour
hyperreflexia
altered visuospatial perception
dizziness/disequilibrium
impaired proprioception
impaired coordination
visual abnormalities
weakness
auditory hallucinations
tremors
synesthesia
nausea
Affective /
acute anxiety
vomiting
Psychological
panic
abdominal pain
fear
drowsiness
paranoia
paresthesia
heightened emotion
blurred vision
past memory retrieval
headache (acute & delayed)
derealization
Spiritual
past life experiences
depersonalization
contact with spirits/entities
putting self or other at risk
aggression
Sources: (Amsterdam et al., 2011; Hartogsohn, 2017; Johansen & Krebs, 2015; Johnson et al., 2008; Krebs &
Johansen, 2012; Studerus et al., 2011; Sutter et al., 2014)
Table B.3.3. Risk Factors for Challenging or Negative Experiences with Psilocybin & Psilocybe
Mushrooms
Past week emotional difficulty
High emotional excitability
Combining with other drugs, esp. alcohol
Multiple doses
Single high dose
Lack of interpersonal support
Non-supportive setting
Younger age
Necessity of performing structured tasks

305
References: (Amsterdam et al., 2011; Carbonaro et al., 2016; Gable, 2004; Johansen & Krebs, 2015; Johnson et al.,
2008; Strassman, 1984)
Table B.3.4. Psilocybin Trial Exclusion Criteria
Psychiatric Conditions
Schizophrenia / Psychotic Disorders
Bipolar Disorder
Substance Use Disorder
Obsessive-Compulsive Disorder
Dysthymic Disorder
Anxiety / Panic Disorder
Dissociative Disorder
Anorexia Nervosa
Bulimia
Suicidality
Avoidance
Narcissism
History of repeated violence
Family History (1st /2nd degree) major psychiatric
disorder
High rigidity scores
High emotional lability scores
Health Conditions
uncontrolled hypertension
pregnancy
breast-feeding
serious neurological disease
serious renal or liver disease
serious cardiac disease
Medications
SSRIs
tricyclic antidepressants
lithium
haloperidol
antipsychotics
MAO inhibitors
fluoxetine
benzodiazepines
Serotonin supplements
St. John's Wort
References:

306
(Johnson et al., 2008; Rucker et al., 2018; Strassman, 1984)(Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et
al., 2016)
Table B.3.5: Predictors of Therapeutic Outcomes (source: (Aday et al., 2021; Romeo et al.,
2021)
Variable
State/Trait
Correlation
Outcome
history of psychedelic use
T
negative
acute impaired control and cognition
negative
difficulty of experience
negative
acute disembodiment
negative
visionary restructuralization
positive
well-being
negative
acute changed meaning of precepts
absorption
T
positive
mystical experience
positive
challenging experience
positive
visual effects
positive
ego dissolution
negative
dread
negative
stimulus-colour consistency
emotional excitability
S
positive
spiritual experience
positive
acute anxiety
positive
acute general consciousness alteration
positive
insightfulness
positive
synesthesia
openness
T
positive
well-being
negative
adverse experience
positive
oceanic boundlessness
positive
mystical experience
general psychological distress
S
negative
oceanic boundlessness
negative
acute blissful state
negative
complex imagery
apprehension
S
negative
mystical experience
negative
ego dissolution
positive
adverse experience
age
S
negative
difficulty of experience
negative
mystical experience
negative
acute imparied control and cognition
optimism
T
positive
visionary restructuralization

307
positive
oceanic boundlessness
positive
mystical experiences
sex / female
S
positive
bad trip
positive
apprehension/mystical experience
spiritual motivations
S
positive
mystical experience
positive
ego dissolution
preoccupation
S
positive
adverse experience
S
negative
dread
deservingness
S
negative
mystical experience
negative
ego dissolution
confusion
S
positive
adverse experience
positive
dread
surrender
S
positive
mystical experience
negative
dread
meditation depth
T
positive
mystical experience
positive
oceanic boundlessness
attachment avoidance
T
positive
challenging experience
negative
peak plateau latency
5-HT2AR binding potential
T
positive
subjective drug intensity comedown latency
negative
mystical experience
alcohol consumption
T
positive
synesthesia
positive
complex imagery
sociability
T
negative
spiritual experience
positive
synesthesia
intensity of drug effect
positive
positive outcomes
quality of speech (positive)
positive
positive outcomes
number of previous SSRI tx
negative
positive outcomes
confidence to abstain (SUD)
positive
positive outcomes
acceptance
T
positive
mystical experiences
executive node network diversity
T
negative
ego dissolution
reappraisal of emotion
T
negative
anxious ego dissolution
attachment anxiety
T
positive
mystical experience
cannabis consumption
T
positive
acute blissful state
Table B.3.6: MPAT Appendix: Psychotherapies(PT) by PSI-AT Trial

308
PsyT
Provide
d?
Type
of
PsyT
Hours of
PsyT
BEFORE
psilocybi
n session
(avg.)
Hours
of
Suppor
t
DURIN
G
psilocy
bin
session
s
(averag
e)
Hours of
therapy
BETWEE
N
psilocybi
n
sessions
(average
)
Hours of
therapy
AFTER
psilocybi
n
sessions
(average
)
Other Details
Durati
on of
PsyT
Moreno
et al.
(2006)
No
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Grob et
al. (2011)
No
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Johnson
et al.
(2014)
Yes
CBT
4
sessions,
90 min
each,
total 6
hours
8 hrs
N/A
1 hour
integrati
on, 45
min
follow up
= 1.75
hours
Four weekly prep
meeting, participants
received smoking
cessation CBT based on
Quit for Life program
15
weeks
Bogensch
utz et al.
(2015)
Yes
MET
4
sessions
(unspecif
ied
length of
time)
two 8hr
session
s
4
sessions
after first
psilocybi
n session
before
second
psilocybi
n session
(unspecif
ied
length of
time)
4
sessions
after the
second
psilocybi
n session
(unspecif
ied
length of
time)
7 sessions of MET
(focused on changing
drinking behaviour), 3
preparatory sessions
and 2 debriefing
sessions for the 2
psilocybin sessions. MET
was structured using
principles of
motivational
interviewing.
4
month
s
Griffiths
et al.
(2016)
Yes
PSI
7.9 h
two 7h
session
s
5.3 h
2.4 h
In preparatory
meetings, participants
discuss meaningful
aspects of their life and
prepare for psilocybin
session. During session,
monitors were
nondirective and
supportive. In post
session meetings, focus
on novel thoughts and
feelings that arose
during sessions
9
month
s

309
Ross et
al. (2016)
Yes
PSI
three 2
hour
preparat
ory
sessions
= 6 hours
total
2 x 8 hr
three 2-
hour
sessions
= 6hr
total
three 2-
hour
sessions
= 6hr
total
Medication-assisted
psychotherapy' included
preparatory
psychotherapy,
medication dosing
sessions, and post-
integrative
psychotherapy. Therapy
was constructed with
components of
supportive
psychotherapy, CBT,
and existentially
oriented,
psychodynamic/psycho
analytic.
10
weeks
Carhart-
Harris et
al. (2016)
Yes
PSI
4h
6 hrs
6hr
sessions
not
specified
Psychological support
consisted of
preparation, acute and
peri-acute support, and
integration. Therapy
was described as
'nondirective and
supportive'.
2
month
s
Bogensch
utz et al.
(2018)
Yes
CBT,
MET
two 1hr
META
sessions,
two 2hr
prep
session =
6hrs
total
three
8.5 hr
session
s = 25.5
hrs
2 hrs
debriefin
g, then
two 1 hr
META
sessions,
then 1hr
prep
session
for
second
medicati
on
session.
After
second
medicati
on
session,
2 hr
debriefin
g, then
three 1hr
META,
sessions
1 hr prep
for third
open
2 hr
debriefin
g session
and two
1 hr
META
session.
4 hrs
total
Team of two therapists,
one conducting alcohol
related therapy MET
and CBT, and the other
the psychedelic-specific
treatment, including
Preparation, Support
and Integration.
3
month
s

310
label
session.
11 hrs
total
Anderson
et al.
(2020)
Yes
Grou
p-
base
d
CBT
4 prep
sessions
= 3.5
hours
total
8 hrs
N/A
Cohort 1
received
4 group
based
integrati
on
sessions,
cohort 2
and 3
received
6 group
based
integrati
on
sessions
(12-15
hrs)
Three group therapy
cohorts (n=6). Group
therapy was modelled
on brief supportive
expressive group
therapy (SEGT).
NR
Davis et
al. (2021)
Yes
PSI
8 hours
11 hrs
2 hrs
post-
session 1
integrati
on
2-3
hours in
total
Adhered to guidelines
of supportive
psychotherapy (Johnson
et al., 2008)
16
weeks
Schindler
et al.
(2020)
No
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Carhart-
Harris et
al. (2021)
No
N/A
N/A
N/A
N/A
N/A
Preparatory therapeutic
session and support
provided by
professionals, but no
psychotherapy and for
unspecified length of
time.
N/A
Alternate version:

311
PsyT
Provid
ed
(y/n)
Type of
Psychother
apy
Hours of
therapy
BEFORE
psilocybi
n session
(average
)
Hours
of
therap
y
DURIN
G
psilocy
bin
session
s
(averag
e)
Hours of
therapy
BETWEE
N
psilocybi
n
sessions
(average
)
Hours of
therapy
AFTER
psilocybi
n
sessions
(average
)
Other Details
Total
Duration
of
Psychother
apy
Moreno
et al.
(2006)
No
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Grob et
al. (2011)
No
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Johnson
et al.
(2014)
Yes
CBT
4
sessions,
90 min
each,
total 6
hours
8 hrs
N/A
1 hour
integrati
on, 45
min
follow up
= 1.75
hours
Four weekly prep
meeting, participants
received smoking
cessation CBT based on
Quit for Life program
15 weeks
Bogensch
utz et al.
(2015)
Yes
MET
4
sessions
(unspecif
ied
length of
time)
two 8hr
session
s
4
sessions
after first
psilocybi
n session
before
second
psilocybi
n session
(unspecif
ied
length of
time)
4
sessions
after the
second
psilocybi
n session
(unspecif
ied
length of
time)
7 sessions of MET
(focused on changing
drinking behaviour), 3
preparatory sessions
and 2 debriefing
sessions for the 2
psilocybin sessions. MET
was structured using
principles of
motivational
interviewing.
4 months
Griffiths
et al.
(2016)
Yes
PSI
7.9 h
two 7h
session
s
5.3 h
2.4 h
In preparatory
meetings, participants
discuss meaningful
aspects of their life and
prepare for psilocybin
session. During session,
monitors were
nondirective and
supportive. In post
session meetings, focus
on novel thoughts and
feelings that arose
during sessions
9 months

312
Ross et
al. (2016)
Yes
PSI
three 2
hour
preparat
ory
sessions
= 6 hours
total
2 x 8 hr
three 2-
hour
sessions
= 6hr
total
three 2-
hour
sessions
= 6hr
total
Medication-assisted
psychotherapy' included
preparatory
psychotherapy,
medication dosing
sessions, and post-
integrative
psychotherapy. Therapy
was constructed with
components of
supportive
psychotherapy, CBT,
and existentially
oriented,
psychodynamic/psycho
analytic.
10 weeks
Carhart-
Harris et
al. (2016)
Yes
PSI
4h
6 hrs
6hr
sessions?
not
specified
Psychological support
consisted of
preparation, acute and
peri-acute support, and
integration. Therapy
was described as
'nondirective and
supportive'.
2 months
Bogensch
utz et al.
(2018)
Yes
CBT, MET
two 1hr
META
sessions,
two 2hr
prep
session =
6hrs
total
three
8.5 hr
session
s = 25.5
hrs
2 hrs
debriefin
g, then
two 1 hr
META
sessions,
then 1hr
prep
session
for
second
medicati
on
session.
After
second
medicati
on
session,
2 hr
debriefin
g, then
three 1hr
META,
sessions
1 hr prep
for third
open
label
session.
11 hrs
total
2 hr
debriefin
g session
and two
1 hr
META
session.
4 hrs
total
Team of two therapists,
one conducting alcohol
related therapy MET
and CBT, and the other
the psychedelic-specific
treatment, including
Preparation, Support
and Integration.
3 months

313
Anderson
et al.
(2020)
Yes
Group-
based CBT
4 prep
sessions
= 3.5
hours
total
8 hrs
N/A
Cohort 1
received
4 group
based
integrati
on
sessions,
cohort 2
and 3
received
6 group
based
integrati
on
sessions
(12-15
hrs)
Three group therapy
cohorts (n=6). Group
therapy was modelled
on brief supportive
expressive group
therapy (SEGT).
NR
Davis et
al. (2021)
Yes
PSI
8 hours
11 hrs
2 hrs
post-
session 1
integrati
on
2-3
hours in
total
Adhered to guidelines
of supportive
psychotherapy (Johnson
et al., 2008)
16 weeks
Schindler
et al.
(2020)
No
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Carhart-
Harris et
al. (2021)
No
N/A
N/A
N/A
N/A
N/A
Preparatory therapeutic
session and support
provided by
professionals, but no
psychotherapy and for
unspecified length of
time.
N/A
Appendix B.4: Included and Excluded Studies, Mapping Psilocybin-assisted Therapies: A Scoping
Review
List of Included Studies by Date
Title
Authors
Year
Journal
Safety, tolerability, and efficacy
of psilocybin in treatment-
refractory obsessive-
compulsive disorder:
Preliminary findings
Moreno, F. A.; Wiegand, C. B.;
Delgado, P. L.; Taitano, K.
2003
Biological Psychiatry
Safety, tolerability, and efficacy
of psilocybin in 9 patients with
obsessive-compulsive
disorder.*
Moreno, Francisco A; Wiegand,
Christopher B; Taitano, E Keolani;
Delgado, Pedro L
2006
The Journal of
clinical psychiatry

314
Pilot study of psilocybin
treatment for anxiety in
patients with advanced-stage
cancer.*
Grob, Charles S; Danforth, Alicia L;
Chopra, Gurpreet S; Hagerty,
Marycie; McKay, Charles R;
Halberstadt, Adam L; Greer, George
R
2011
Archives of general
psychiatry
Psilocybin treatment for anxiety
in patients with advanced-stage
cancer*
Grob C.
2012
Neuropsychopharm
acology
A pilot study of psilocybin-
assisted treatment for alcohol
dependence: Acute effects and
short-termalcohol use, self-
efficacy, and craving *
Bogenschutz M.P.; Forcehimes A.A.;
Pommy J.A.; Wilcox C.E.; Bigelow R.;
Barbosa P.C.R.
2014
Alcoholism: Clinical
and Experimental
Research
Pilot study of the 5-HT2AR
agonist psilocybin in the
treatment of tobacco
addiction.*
Johnson, Matthew W; Garcia-
Romeu, Albert; Cosimano, Mary P;
Griffiths, Roland R
2014
Journal of
psychopharmacolog
y (Oxford, England)
Psilocybin-assisted
psychotherapy in the treatment
of cancer-related psychosocial
distress/anxiety
Sevanick L.
2014
Psycho-Oncology
Psilocybin-occasioned mystical
experiences in the treatment of
tobacco addiction.
Garcia-Romeu, Albert; Griffiths,
Roland R; Johnson, Matthew W
2014
Current drug abuse
reviews
Psilocybin-assisted treatment
for alcohol dependence: a
proof-of-concept study.*
Bogenschutz, Michael P;
Forcehimes, Alyssa A; Pommy,
Jessica A; Wilcox, Claire E; Barbosa,
P C R; Strassman, Rick J
2015
Journal of
psychopharmacolog
y (Oxford, England)
A single dose of psilocybin
produces substantial and
enduring decreases in anxiety
and depression in patients with
a life-threatening cancer
diagnosis: A randomized
double-blind trial*
Griffiths R.
2015
Neuropsychopharm
acology
Long-term follow-up of
psilocybin-facilitated smoking
cessation: Abstinence outcomes
and qualitative analysis of
participant accounts
Garcia-Romeu A.P.; Noorani T.;
Griffiths R.R.; Johnson M.W.
2015
Drug and Alcohol
Dependence
Results: Of a multi-modal
neuroimaging study of LSD and
a psilocybin for treatment-
resistant depression clinical trial
Carhart-Harris R.
2015
Neuropsychopharm
acology

315
Mood, craving, and self-efficacy
in psilocybin-assisted treatment
of alcoholism
Bogenschutz M.
2015
Neuropsychopharm
acology
Psilocybin produces substantial
and sustained decreases in
depression and anxiety in
patients with life-threatening
cancer: A randomized double-
blind trial.*
Griffiths, Roland R; Johnson,
Matthew W; Carducci, Michael A;
Umbricht, Annie; Richards, William
A; Richards, Brian D; Cosimano,
Mary P; Klinedinst, Margaret A
2016
Journal of
psychopharmacolog
y (Oxford, England)
5-HT2A agonist drugs as new
treatments in psychiatry
Carhart-Harris R.
2016
European
Neuropsychopharm
acology
Rapid and sustained symptom
reduction following psilocybin
treatment for anxiety and
depression in patients with life-
threatening cancer: a
randomized controlled trial.*
Ross, Stephen; Bossis, Anthony;
Guss, Jeffrey; Agin-Liebes, Gabrielle;
Malone, Tara; Cohen, Barry;
Mennenga, Sarah E; Belser,
Alexander; Kalliontzi, Krystallia;
Babb, James; Su, Zhe; Corby,
Patricia; Schmidt, Brian L
2016
Journal of
psychopharmacolog
y (Oxford, England)
Psilocybin with psychological
support for treatment-resistant
depression: an open-label
feasibility study.*
Carhart-Harris, Robin L; Bolstridge,
Mark; Rucker, James; Day, Camilla
M J; Erritzoe, David; Kaelen,
Mendel; Bloomfield, Michael;
Rickard, James A; Forbes, Ben;
Feilding, Amanda; Taylor, David;
Pilling, Steve; Curran, Valerie H;
Nutt, David J
2016
The lancet.
Psychiatry
Long-term follow-up of
psilocybin-facilitated smoking
cessation.
Johnson, Matthew W; Garcia-
Romeu, Albert; Griffiths, Roland R
2017
The American
journal of drug and
alcohol abuse
Patient experiences of
psilocybin-assisted
psychotherapy: An
interpretative
phenomenological analysis.
Belser, Alexander B; Agin-Liebes,
Gabrielle; Swift, T. Cody; Terrana,
Sara; Devenot, Nese; Friedman,
Harris L; Guss, Jeffrey; Bossis,
Anthony; Ross, Stephen
2017
Journal of
Humanistic
Psychology
Patients' accounts of increased
"connectedness" and
"acceptance" after psilocybin
for treatment-resistant
depression.
Watts, Rosalind; Day, Camilla;
Krzanowski, Jacob; Nutt, David;
Carhart-Harris, Robin
2017
Journal of
Humanistic
Psychology
Cancer at the dinner table:
Experiences of psilocybin-
assisted psychotherapy for the
treatment of cancer-related
distress.
Swift, Thomas C; Belser, Alexander
B; Agin-Liebes, Gabrielle; Devenot,
Nese; Terrana, Sara; Friedman,
Harris L; Guss, Jeffrey; Bossis,
Anthony P; Ross, Stephen
2017
Journal of
Humanistic
Psychology

316
Psilocybin for treatment-
resistant depression: fMRI-
measured brain mechanisms.
Carhart-Harris, Robin L; Roseman,
Leor; Bolstridge, Mark; Demetriou,
Lysia; Pannekoek, J Nienke; Wall,
Matthew B; Tanner, Mark; Kaelen,
Mendel; McGonigle, John; Murphy,
Kevin; Leech, Robert; Curran, H
Valerie; Nutt, David J
2017
Scientific reports
Psilocybin-assisted treatment
for alcohol use disorder: A
clinical perspective
Amegadzie S.; Mennenga S.;
Podrebarac S.; Duane H.; Ross S.;
Bogenschutz M.
2018
American Journal
on Addictions
Psychedelic therapy for
smoking cessation: Qualitative
analysis of participant accounts.
Noorani, Tehseen; Garcia-Romeu,
Albert; Swift, Thomas C; Griffiths,
Roland R; Johnson, Matthew W
2018
Journal of
psychopharmacolog
y (Oxford, England)
Increased nature relatedness
and decreased authoritarian
political views after psilocybin
for treatment-resistant
depression.
Lyons, Taylor; Carhart-Harris, Robin
L
2018
Journal of
psychopharmacolog
y (Oxford, England)
Increased amygdala responses
to emotional faces after
psilocybin for treatment-
resistant depression.
Roseman, Leor; Demetriou, Lysia;
Wall, Matthew B; Nutt, David J;
Carhart-Harris, Robin L
2018
Neuropharmacolog
y
The hidden therapist: evidence
for a central role of music in
psychedelic therapy.
Kaelen, Mendel; Giribaldi, Bruna;
Raine, Jordan; Evans, Lisa;
Timmerman, Christopher;
Rodriguez, Natalie; Roseman, Leor;
Feilding, Amanda; Nutt, David;
Carhart-Harris, Robin
2018
Psychopharmacolog
y
Psilocybin with psychological
support improves emotional
face recognition in treatment-
resistant depression.
Stroud, J B; Freeman, T P; Leech, R;
Hindocha, C; Lawn, W; Nutt, D J;
Curran, H V; Carhart-Harris, R L
2018
Psychopharmacolog
y
Quality of acute psychedelic
experience predicts therapeutic
efficacy of psilocybin for
treatment-resistant depression
Roseman L.; Nutt D.J.; Carhart-
Harris R.L.
2018
Frontiers in
Pharmacology
The Psychedelic Debriefing in
Alcohol Dependence
Treatment: Illustrating Key
Change Phenomena through
Qualitative Content Analysis of
Clinical Sessions.
Nielson, Elizabeth M; May, Darrick
G; Forcehimes, Alyssa A;
Bogenschutz, Michael P
2018
Frontiers in
pharmacology

317
Individual Experiences in Four
Cancer Patients Following
Psilocybin-Assisted
Psychotherapy.
Malone, Tara C; Mennenga, Sarah E;
Guss, Jeffrey; Podrebarac,
Samantha K; Owens, Lindsey T;
Bossis, Anthony P; Belser, Alexander
B; Agin-Liebes, Gabrielle;
Bogenschutz, Michael P; Ross,
Stephen
2018
Frontiers in
pharmacology
More Realistic Forecasting of
Future Life Events After
Psilocybin for Treatment-
Resistant Depression.
Lyons, Taylor; Carhart-Harris, Robin
Lester
2018
Frontiers in
psychology
Effects of psilocybin therapy on
personality structure.
Erritzoe, D; Roseman, L; Nour, M M;
MacLean, K; Kaelen, M; Nutt, D J;
Carhart-Harris, R L
2018
Acta psychiatrica
Scandinavica
Psilocybin with psychological
support for treatment-resistant
depression: six-month follow-
up.*
Carhart-Harris, R L; Bolstridge, M;
Day, C M J; Rucker, J; Watts, R;
Erritzoe, D E; Kaelen, M; Giribaldi, B;
Bloomfield, M; Pilling, S; Rickard, J
A; Forbes, B; Feilding, A; Taylor, D;
Curran, H V; Nutt, D J
2018
Psychopharmacolog
y
Clinical Interpretations of
Patient Experience in a Trial of
Psilocybin-Assisted
Psychotherapy for Alcohol Use
Disorder.
Bogenschutz, Michael P;
Podrebarac, Samantha K; Duane,
Jessie H; Amegadzie, Sean S;
Malone, Tara C; Owens, Lindsey T;
Ross, Stephen; Mennenga, Sarah E
2018
Frontiers in
pharmacology
Therapeutic mechanisms of
psychedelic drugs: Changes in
amygdala and prefrontal
functional connectivity during
emotional processing after
psilocybin for treatment-
resistant depression
Mertens, L. J.; Wall, M. B.;
Roseman, L.; Demetriou, L.; Nutt, D.
J.; Carhart-Harris, R. L.
2019
European
Neuropsychopharm
acology
Psilocybin-assisted treatment of
major depressive disorder:
results from a randomized trial*
Griffiths R, Barrett F, Darrick M,
Johnson M, Mary C, Patrick F, Alan
D
2019
In patients with major
depressive disorder, psilocybin
administration is associated
with reduced amygdala
response to negative affective
stimuli and normalization of
cortical glutamate one week
after psilocybin, and improved
cognitive flexibility one and
Barrett F
2019

318
Changes in music-evoked
emotion and ventral-striatum
functional connectivity
following psilocybin therapy for
depression
Shukuroglou M.; Roseman L.; Wall
M.; Nutt D.; Carhart-Harris R.;
Kaelen M.
2019
Brain and
Neuroscience
Advances
Preliminary analysis of the
sustained effects of a single low
oral dose of psilocybin in
migraine headache
Schindler, Emmanuelle A D; Sewell,
R Andrew; Gottschalk, Christopher
H; Luddy, Christina; Flynn, L Taylor;
Lindsey, Hayley; Pittman, Brian P;
Cozzi, Nicholas V; D'Souza, Deepak
C
2020
Abstract
presentation
Exploratory Controlled Study of
the Migraine-Suppressing
Effects of Psilocybin.*
Schindler, Emmanuelle A D; Sewell,
R Andrew; Gottschalk, Christopher
H; Luddy, Christina; Flynn, L Taylor;
Lindsey, Hayley; Pittman, Brian P;
Cozzi, Nicholas V; D'Souza, Deepak
C
2020
Neurotherapeutics :
the journal of the
American Society
for Experimental
NeuroTherapeutics
Therapeutic mechanisms of
psilocybin: Changes in
amygdala and prefrontal
functional connectivity during
emotional processing after
psilocybin for treatment-
resistant depression.
Mertens, Lea J; Wall, Matthew B;
Roseman, Leor; Demetriou, Lysia;
Nutt, David J; Carhart-Harris, Robin
L
2020
Journal of
psychopharmacolog
y (Oxford, England)
Psilocybin-assisted group
therapy for demoralized older
long-term AIDS survivor men:
An open-label safety and
feasibility pilot study.*
Anderson, Brian T; Danforth, Alicia;
Daroff, Prof Robert; Stauffer,
Christopher; Ekman, Eve; Agin-
Liebes, Gabrielle; Trope, Alexander;
Boden, Matthew Tyler; Dilley, Prof
James; Mitchell, Jennifer; Woolley,
Joshua
2020
EClinicalMedicine
Long-term follow-up of
psilocybin-assisted
psychotherapy for psychiatric
and existential distress in
patients with life-threatening
cancer.
Agin-Liebes, Gabrielle I; Malone,
Tara; Yalch, Matthew M;
Mennenga, Sarah E; Ponte, K
Linnae; Guss, Jeffrey; Bossis,
Anthony P; Grigsby, Jim; Fischer,
Stacy; Ross, Stephen
2020
Journal of
psychopharmacolog
y (Oxford, England)
Acute and Sustained Reductions
in Loss of Meaning and Suicidal
Ideation Following Psilocybin-
Assisted Psychotherapy for
Psychiatric and Existential
Distress in Life-Threatening
Cancer.
Ross, Stephen; Agin-Liebes,
Gabrielle; Lo, Sharon; Zeifman,
Richard J; Ghazal, Leila; Benville,
Julia; Franco Corso, Silvia; Bjerre
Real, Christian; Guss, Jeffrey; Bossis,
Anthony; Mennenga, Sarah E
2021
ACS pharmacology
& translational
science

319
Psilocybin-Assisted Group
Therapy and Attachment:
Observed Reduction in
Attachment Anxiety and
Influences of Attachment
Insecurity on the Psilocybin
Experience.
Stauffer, Christopher S; Anderson,
Brian T; Ortigo, Kile M; Woolley,
Joshua
2021
ACS pharmacology
& translational
science
Effects of Psilocybin on Suicidal
Ideation in Patients With Life-
Threatening Cancer
Benville, Julia; Roberts, Daniel E.;
Ghazal, Leila; Ross, Stephen; Agin-
Liebes, Gabrielle; Lo, Sharon;
Franco-Corso, Silvia J.
2021
Biological Psychiatry
Trial of Psilocybin versus
Escitalopram for Depression.*
Carhart-Harris, Robin; Giribaldi,
Bruna; Watts, Rosalind; Baker-
Jones, Michelle; Murphy-Beiner,
Ashleigh; Murphy, Roberta; Martell,
Jonny; Blemings, Allan; Erritzoe,
David; Nutt, David J
2021
The New England
journal of medicine
Effects of Psilocybin-Assisted
Therapy on Major Depressive
Disorder:A Randomized Clinical
Trial*
Davis, AK; Barrett, FS; May, DG
2021
JAMA PSYCHIATRY
The role of self-compassion in
psilocybin-assisted motivational
enhancement therapy to treat
alcohol dependence: A
randomized controlled trial.
Agin-Liebes, Gabrielle
2021
Dissertation
Abstracts
International:
Section B: The
Sciences and
Engineering
*denotes core trial publication
MPAT List of Excluded Studies by Date:
Title
Authors
Publis
hed
Year
Journal
Notes
Therapeutic effect of
psilocybin on convulsive
neurosis
Delay J.; Pichot
P.; Lemperiere
T.; Quetin A.-M.
1959
Annales Medico-
Psychologiques
Exclusion reason:
Not english
language;
[Therapeutic effect of
psilocybin on convulsive
neurosis].
DELAY, J;
PICHOT, P;
LEMPERIERE, T;
QUETIN, A M
1959
Annales medico-
psychologiques
Exclusion reason:
Duplicate;

320
The use of dysleptic
substances in
psychotherapy.
Favourable results of
repeated sessions
Stevenin L.;
Benoit J.C.
1960
Encephale
Exclusion reason:
Not english
language;
Psilocybine - Its
therapeutic aspects
Delay J.; Pichot
P.; Lemperiere T.
1961
Sud Medical et
Chirurgical
Exclusion reason:
Not english
language
Clinical experiences with
psilocybin
Sercl M.; Kovarik
J.; Jaros O.
1961
Exclusion reason:
Not english
language;
[Clinical experiences with
psilocybin (CY 39
Sandoz)].
SERCL, M;
KOVARIK, J;
JAROS, O
1961
Psychiatria et
neurologia
Exclusion reason:
Not english
language;
Clinical, EEG and
biological data on
psylocibine
Gamna G.;
Gobbi L.; Ferrio
L.; Rivolta A.;
Gandiglio G.;
Vercellino F.
1962
Exclusion reason:
Full text
unavailable;
[On the treatment of
therapy-resistant
neuroses with model
psychoses (psilocybin)].
HEIMANN, H
1962
Schweizer Archiv fur
Neurologie,
Neurochirurgie und
Psychiatrie = Archives
suisses de neurologie,
neurochirurgie et de
psychiatrie
Exclusion reason:
Not english
language;
On the effect of some
hallucinogen drugs in
furthering
psychotherapy.
Boszormenyi,
Zoltan.
1962
Magyar Pszichologiai
Szemle
Exclusion reason:
Not english
language;
[OUR CLINICAL
EXPERIENCE WITH A NEW
PHARMACOLOGICAL
PREPARATION
PSILOCYBIN].
DORDEVIC, D
1963
Neuropsihijatrija
Exclusion reason:
Not english
language;
[COMPARISON OF
PSYCHOPHARMACA LSD-
25, BOL-148 AND
PSILOCYBIN IN CLINICAL
PRACTICE].
KANDIC, B;
DORDEVIC, D
1963
Vojnosanitetski
pregled
Exclusion reason:
Not english
language;

321
Trials with psilocybin
administration in organic
cerebra amage. v.
significance and value of
psilocybin in clinical neur
ology (german)
Ub Ans K B D.;
Kilaffk J.;
VyhnankovaM;
Sevctk M.
1964
Exclusion reason:
Full text
unavailable;
Clinical experiences with
the new psychodrug
psilocybin
Dordevic D.
1964
Exclusion reason:
Full text
unavailable;
[CLINICAL AND
PSYCHOPATHOLOGICAL
STUDY OF PSILOCYBIN].
REDA, G C;
VELLA, G;
CANCRINI, L; D
AGOSTINO, E
1964
Rivista sperimentale di
freniatria e medicina
legale delle alienazioni
mentali
Exclusion reason:
Not english
language;
THERAPEUTIC
APPLICATION OF THE
CHANGE IN
CONSCIOUSNESS
PRODUCED BY
PSYCHOLYTICA (LSD,
PSILOCYBIN, ETC.). THE
PSYCHEDELIC
EXPERIENCE IN THE
TREATEMENT OF
NEUROSIS.
Alnaes, R
1964
Acta psychiatrica
Scandinavica
Exclusion reason:
No clinical
outcome(s)
measured;
Psilocybin and chronic
alcoholism.
Albuquerque
Fortes, Jose R
1966
Arquivos da
Coordenadoria de
Saude Mental do
Estado de Sao Paulo
Exclusion reason:
Not english
language;
Short-term
psychotherapy with the
aid of psychedelic drugs.
Volterra, Vittorio
1967
Rivista di Psichiatria
Exclusion reason:
Not english
language;
Prelminary report on the
experience with
psychosomimetic drugs in
the treatment of
alcobolism.
Rydzynski, Z;
Cwynar, S;
Grzelak, L;
Jagiello, W
1968
Activitas nervosa
superior
Exclusion reason:
Wrong
intervention;
Further observations
regarding hallucinogenic
treatment.
Geert-
Jorgensen, E
1968
Acta psychiatrica
Scandinavica.
Supplementum
Exclusion reason:
Wrong study
design;
Personality trait
dependent performance
under psilocybin. II.
Thatcher, K;
Kappeler, T;
Wisecup, P;
Fischer, R
1970
Diseases of the
nervous system
Exclusion reason:
No clinical
outcome(s)
measured;

322
Psilocybin
Anonymous.
1973
Exclusion reason:
Full text
unavailable;
Treatment methods in
large numbers of
ambulatory psychotics
and drug abusers
Abruzzi W.
1975
Journal of
Contemporary
Psychotherapy
Exclusion reason:
Wrong study
design;
Treatment of alcoholism
with psychotomimetic
drugs. A follow-up study.
Rydzynski, Z;
Gruszczynski, W
1978
Activitas nervosa
superior
Exclusion reason:
Wrong
intervention;
Overview of drugs used in
treating drug-induced
dependence: A treatise
interrelating existing
hypotheses in order to
attain maximal
therapeutic benefits
Segal M.
1986
International Journal
of the Addictions
Exclusion reason:
Wrong study
design;
Relief of obsessive-
compulsive symptoms by
LSD and psilocin.
Leonard, H L;
Rapoport, J L
1987
The American journal
of psychiatry
Exclusion reason:
Wrong study
design;
The significance of
hallucinogenic research in
psychiatry: History and
present status
Hermle L.;
Gouzoulis E.;
Oepen G.;
Spitzer M.;
Kovar K.A.;
Borchardt D.;
Funfgeld M.;
Berger M.
1993
Nervenarzt
Exclusion reason:
Wrong study
design;
Hallucinogenic drugs in
psychiatric research and
treatment
Strassman R.J.
1995
Journal of Nervous
and Mental Disease
Exclusion reason:
Wrong study
design;
Serotonin, psilocybin, and
body dysmorphic
disorder: A case report
[1]
Hanes K.R.
1996
Journal of Clinical
Psychopharmacology
Exclusion reason:
Wrong study
design;
Hallucinogen-induced
relief of obsessions and
compulsions [2]
Moreno F.A.;
Delgado P.L.
1997
American Journal of
Psychiatry
Exclusion reason:
Wrong study
design;
Hallucinogen-induced
relief of obsessions and
compulsions.
Moreno, F A;
Delgado, P L
1997
The American journal
of psychiatry
Exclusion reason:
Wrong study
design;

323
Hallucinogens, serotonin
and obsessive-compulsive
disorder
Delgado P.L.
1998
Journal of
Psychoactive Drugs
Exclusion reason:
Wrong study
design;
Hallucinogens and
obsessive-compulsive
disorder.
Perrine, D M
1999
The American journal
of psychiatry
Exclusion reason:
Duplicate;
Hallucinogens and
obsessive-compulsive
disorder [17]
Perrine D.M.
1999
American Journal of
Psychiatry
Exclusion reason:
Wrong study
design;
Can psychedelics have a
role in psychiatry once
again?
Sessa B.
2005
British Journal of
Psychiatry
Exclusion reason:
Wrong study
design;
Response of cluster
headache to psilocybin
and LSD
Sewell, R. A.;
Halpern, J. H.;
Harrison, G. P.
2006
Neurology
Exclusion reason:
Wrong study
design;
Psilocybin treatment of
obsessive-compulsive
disorder.
Moreno,
Francisco A;
Delgado, Pedro L
2007
Psychedelic medicine:
New evidence for
hallucinogenic
substances as
treatments., Vol. 1
Exclusion reason:
Wrong study
design
Psychedelic medicine:
New evidence for
hallucinogenic substances
as treatments.
Winkelman,
Michael J [Ed];
Roberts, Thomas
B [Ed]
2007
Psychedelic medicine:
New evidence for
hallucinogenic
substances as
treatments.
Exclusion reason:
Wrong study
design;
Psychopharmacology of
Psilocybin in Cancer
Patients
Griffiths RR
2007
Exclusion reason:
Duplicate;
The use of psilocybin in
patients with advanced
cancer and existential
anxiety.
Grob, Charles S
2007
Psychedelic medicine:
New evidence for
hallucinogenic
substances as
treatments., Vol. 1
Exclusion reason:
Wrong study
design;
Psilocybin can occasion
mystical-type experiences
having substantial and
sustained personal
meaning and spiritual
significance.
Griffiths, Roland
R; Richards,
William A;
McCann, Una D;
Jesse, Robert
2007
Psychedelic medicine:
New evidence for
hallucinogenic
substances as
treatments., Vol. 2
Exclusion reason:
Wrong patient
population;
Are psychedelic drug
treatments seeing a
comeback in psychiatry?
Sessa B.St.J.
2008
Progress in Neurology
and Psychiatry
Exclusion reason:
Wrong study
design;

324
Psilocybin-Assisted
Psychotherapy for
Anxiety in People With
Stage IV Melanoma
NCT00979693
2009
Psilocybin-assisted
Psychotherapy in the
Management of
Anxiety Associated
With Stage IV
Melanoma
Exclusion reason:
No clinical
outcome(s)
measured;
Psychosocial distress in
advanced cancer
patients: An overview of
psilocybin-assisted
psychotherapy and the
ongoing New York
University Phase II pilot
study
Belser A.
2010
Journal of the Society
for Integrative
Oncology
Exclusion reason:
Wrong study
design
Cancer and
hallucinogens: a long,
strange trip
Anonymous.
2010
The Lancet Oncology
Exclusion reason:
Wrong study
design;
Psilocybin occasioned
mystical-type
experiences: immediate
and persisting dose-
related effects.
Griffiths, Roland
R; Johnson,
Matthew W;
Richards,
William A;
Richards, Brian
D; McCann, Una;
Jesse, Robert
2011
Psychopharmacology
Exclusion reason:
Wrong patient
population;
Effects of psilocybin in
the treatment of
addictions: A review and
preliminary results from
two ongoing trials
Bogenschutz
M.P.
2012
Neuropsychopharmac
ology
Exclusion reason:
Duplicate;
Shaping the renaissance
of psychedelic research
Sessa B.
2012
The Lancet
Exclusion reason:
Wrong study
design;
Neuroimaging: a scanner,
colourfully.
Roiser, Jonathan
P; Rees, Geraint
2012
Current biology : CB
Exclusion reason:
Wrong study
design;
Serotonergic
hallucinogens and
emerging targets for
addiction
pharmacotherapies.
Ross, Stephen
2012
The Psychiatric clinics
of North America
Exclusion reason:
Wrong study
design;

325
Opening doors of
perception: Psychedelic
drugs and end-of-life care
MacReady N.
2012
Journal of the National
Cancer Institute
Exclusion reason:
Wrong study
design;
Research on psychedelic
substances
Brandt, S. D.;
Passie, T.
2012
Drug Testing and
Analysis
Exclusion reason:
Wrong study
design;
The potential of
psychedelics as a
preventative and auxiliary
therapy for drug abuse
Vargas-Perez H.
2013
Current Drug Abuse
Reviews
Exclusion reason:
Wrong study
design;
Psilocybin-facilitated
Smoking Cessation
Treatment: a Pilot Study
NCT01943994
2013
Psilocybin-facilitated
Smoking Cessation
Treatment: a Pilot
Study
Exclusion reason:
No clinical
outcome(s)
measured;
Psychedelic-assisted
psychotherapy for the
treatment of addiction
Doblin R.
2013
Current Drug Abuse
Reviews
Exclusion reason:
Wrong study
design;
Studying the effects of
classic hallucinogens in
the treatment of
alcoholism: rationale,
methodology, and
current research with
psilocybin.
Bogenschutz,
Michael P
2013
Current drug abuse
reviews
Exclusion reason:
Wrong study
design;
Single treatments that
have lasting effects: some
thoughts on the
antidepressant effects of
ketamine and botulinum
toxin and the anxiolytic
effect of psilocybin.
Young, Simon N
2013
Journal of psychiatry &
neuroscience : JPN
Exclusion reason:
Wrong study
design;
A Double-Blind Trial of
Psilocybin-Assisted
Treatment of Alcohol
Dependence
NCT02061293
2014
A Double-Blind Trial of
Psilocybin-Assisted
Treatment of Alcohol
Dependence
Exclusion reason:
No clinical
outcome(s)
measured;
Psilocybin-facilitated
Treatment for Cocaine
Use
NCT02037126
2014
Psilocybin-facilitated
Treatment for Cocaine
Use: a Pilot Study
Exclusion reason:
No clinical
outcome(s)
measured;
Back to the future: a
return to psychedelic
treatment models for
addiction.
Hendricks, Peter
S
2014
Journal of
psychopharmacology
(Oxford, England)
Exclusion reason:
Wrong study
design;

326
Psychedelics: Entering a
new age of addiction
therapy
Lawrence J.
2014
Pharmaceutical
Journal
Exclusion reason:
Wrong study
design;
The Heffter Research
Institute: past and
hopeful future.
Nichols, David E
2014
Journal of
psychoactive drugs
Exclusion reason:
Wrong study
design;
The path toward making
psilocybin available for
medical use: New
findings and analyses
related to abuse potential
and safety
Nichols D.;
Johnson M.;
Griffiths R.;
Henningfield J.
2014
Neuropsychopharmac
ology
Exclusion reason:
Wrong study
design;
Classical hallucinogens as
antidepressants? A
review of
pharmacodynamics and
putative clinical roles.
Baumeister,
David; Barnes,
Georgina;
Giaroli,
Giovanni; Tracy,
Derek
2014
Therapeutic advances
in
psychopharmacology
Exclusion reason:
Wrong study
design;
Neurobiology of
psilocybin in the context
of its potential
therapeutic use
Tyls F.
2015
Psychiatrie
Exclusion reason:
Wrong study
design;
Turn on and tune in to
evidence-based
psychedelic research
Sessa B.
2015
The Lancet Psychiatry
Exclusion reason:
Wrong study
design;
The 5-HT2A/1A agonist
psilocybin reduces social
pain and enhances
empathy in healthy
volunteers
Preller K.H.;
Pokorny T.;
Krahenmann R.;
Scheidegger M.;
Dziobek I.;
Stampfli P.;
Vollenweider
F.X.
2015
European
Neuropsychopharmac
ology
Exclusion reason:
Wrong patient
population;
The 5-HT2A/1A agonist
psilocybin enhances
empathy and reduces
social pain in healthy
volunteers
Preller K.H.;
Pokorny T.;
Krahenmann R.;
Dziobek I.;
Stampfli P.;
Vollenweider
F.X.
2015
Biological Psychiatry
Exclusion reason:
Wrong patient
population;

327
5HT2A receptors-a new
target for depression?
Nutt D.
2015
European Psychiatry
Exclusion reason:
Wrong study
design;
Psilocybin, psychological
distress, and suicidality
Hendricks P.S.;
Johnson M.W.;
Griffiths R.R.
2015
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
Psychedelic medicine: A
re-emerging therapeutic
paradigm
Tupper K.W.;
Wood E.; Yensen
R.; Johnson
M.W.
2015
CMAJ
Exclusion reason:
Wrong study
design;
Do magic mushrooms
help against depression?
Controlled intake of
psilocybin in pilot study is
effective
Bruhn C.
2016
Deutsche Apotheker
Zeitung
Exclusion reason:
Not english
language;
Psilocybine: Hallucinogen
relieves anxieties in the
case of cancer
Grafe K.A.
2016
Pharmazeutische
Zeitung
Exclusion reason:
Not english
language;
Magic mushroom
compound is a potential
treatment for patients
with major depression.
Anonymous
2016
Nursing standard
(Royal College of
Nursing (Great Britain)
: 1987)
Exclusion reason:
Wrong study
design;
Treating Addiction:
Perspectives from EEG
and Imaging Studies on
Psychedelics.
Tofoli, L F; de
Araujo, D B
2016
International review of
neurobiology
Exclusion reason:
Wrong study
design;
Psilocybin: panacea or
placebo?
Hendrie C.;
Pickles A.
2016
The Lancet Psychiatry
Exclusion reason:
Wrong study
design;
Psilocybin as an
alternative medicine for
patients suffering from
depression
Dydak K.;
Sliwinska-
Mosson M.;
Milnerowicz H.
2016
Psychiatria i
Psychologia Kliniczna
Exclusion reason:
Wrong study
design;
Psilocybin: Promising
results in double-blind
trials require
confirmation by real-
world evidence
Breckenridge A.;
Grobbee D.E.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
Psycho-existential
distress in cancer
Blinderman C.D.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;

328
patients: A return to
"entheogens"
Psilocybin in end of life
care: Implications for
further research
Summergrad P.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
Psilocybin-assisted
psychotherapy for dying
cancer patients - Aiding
the final trip
Spiegel D.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
Psilocybin and palliative
end-of-life care
Shelton R.C.;
Hendricks P.S.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
Psychedelics in the
treatment of unipolar
mood disorders: a
systematic review.
Rucker, James
Jh; Jelen, Luke A;
Flynn, Sarah;
Frowde, Kyle D;
Young, Allan H
2016
Journal of
psychopharmacology
(Oxford, England)
Exclusion reason:
Wrong study
design;
Psilocybin for anxiety and
depression in cancer
care? Lessons from the
past and prospects for
the future.
Nutt, David
2016
Journal of
psychopharmacology
(Oxford, England)
Exclusion reason:
Wrong study
design;
Novel
psychopharmacological
therapies for psychiatric
disorders: psilocybin and
MDMA.
Mithoefer,
Michael C; Grob,
Charles S;
Brewerton,
Timothy D
2016
The lancet. Psychiatry
Exclusion reason:
Wrong study
design;
Psilocybin for depression
and anxiety associated
with life-threatening
illnesses.
McCorvy, John
D; Olsen, Reid
Hj; Roth, Bryan L
2016
Journal of
psychopharmacology
(Oxford, England)
Exclusion reason:
Wrong study
design;
Back to the future:
Research renewed on the
clinical utility of
psychedelic drugs
Lieberman J.A.;
Shalev D.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
The successful return of
psychedelics to
psychiatry
Kleber H.D.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;

329
The role of psychedelics
in palliative care
reconsidered: A case for
psilocybin
Kelmendi B.;
Corlett P.;
Ranganathan
M.; D'Souza C.;
Krystal J.H.
2016
Journal of
Psychopharmacology
Exclusion reason:
Wrong study
design;
Return of the
psychedelics: Psilocybin
for treatment resistant
depression.
Patra, Suravi
2016
Asian journal of
psychiatry
Exclusion reason:
Wrong study
design;
Psychedelics.
Nichols, David E
2016
Pharmacological
reviews
Exclusion reason:
Wrong study
design;
Antidepressive,
anxiolytic, and
antiaddictive effects of
ayahuasca, psilocybin and
lysergic acid diethylamide
(LSD): a systematic
review of clinical trials
published in the last 25
years.
Dos Santos,
Rafael G; Osorio,
Flavia L; Crippa,
Jose Alexandre
S; Riba, Jordi;
Zuardi, Antonio
W; Hallak, Jaime
E C
2016
Therapeutic advances
in
psychopharmacology
Exclusion reason:
Wrong study
design;
Altered states: psilocybin
for treatment-resistant
depression.
Cowen, Phil
2016
The lancet. Psychiatry
Exclusion reason:
Wrong study
design;
Classic hallucinogens in
the treatment of
addictions.
Bogenschutz,
Michael P;
Johnson,
Matthew W
2016
Progress in neuro-
psychopharmacology
& biological psychiatry
Exclusion reason:
Wrong study
design;
A novel group
psychotherapy modality
for psychosocial distress
that employs the
psychotherapeutic
catalyst psilocybin
Anderson B.;
Stauffer C.;
Vinogradov S.;
Woolley J.
2016
Psycho-Oncology
Exclusion reason:
Wrong study
design;

330
Psilocybin with
psychological support for
treatment-resistant
depression: six-month
follow-up
Carhart-Harris
RL, Bolstridge M,
Day CMJ, Rucker
J, Watts R,
Erritzoe DE,
Kaelen M,
Giribaldi B,
Bloomfield M,
Pilling S, Rickard
JA, Forbes B,
Feilding A,
Taylor D, Curran
HV, Nutt DJ
2017
Exclusion reason:
Duplicate;
Quality of Acute
Psychedelic Experience
Predicts Therapeutic
Efficacy of Psilocybin for
Treatment-Resistant
Depression.
Roseman, Leor;
Nutt, David J;
Carhart-Harris,
Robin L
2017
Frontiers in
pharmacology
Exclusion reason:
Duplicate;
Increased amygdala
responses to emotional
faces after psilocybin for
treatment-resistant
depression.
Roseman, Leor;
Demetriou,
Lysia; Wall,
Matthew B;
Nutt, David J;
Carhart-Harris,
Robin L
2017
Neuropharmacology
Exclusion reason:
Duplicate;
Development of a
psychotherapeutic model
for psilocybin-assisted
treatment of alcoholism.
Bogenschutz,
Michael P;
Forcehimes,
Alyssa A
2017
Journal of Humanistic
Psychology
Exclusion reason:
Wrong study
design;
The resurgence of the
clinical research with
hallucinogens.
Velder, Anja
Loizaga; Trevino,
Carlos Viesca
2017
Psiquis
Exclusion reason:
Wrong study
design;

331
Psychiatry & the
psychedelic drugs. Past,
present & future.
Rucker, James
J.H; Iliff,
Jonathan; Nutt,
David J
2017
Neuropharmacology
Exclusion reason:
Wrong study
design;
Psilocybin and
Depression
NCT03380442
2017
Psilocybin and
Depression - Assessing
the Long-term Effects
of a Single
Administration of
Psilocybin on the
Psychiatric Symptoms
and Brain Activity of
Patients With Severe
Depression
Exclusion reason:
No clinical
outcome(s)
measured;
Effects of Psilocybin in
Major Depressive
Disorder
NCT03181529
2017
Effects of Psilocybin in
Major Depressive
Disorder
Exclusion reason:
No clinical
outcome(s)
measured;
Re-emergence of
psychedelic medicine
Ljuslin M.;
Schaller A.
2017
Schweizer Archiv fur
Neurologie und
Psychiatrie
Exclusion reason:
Wrong study
design;
Nutraceutical and
alternative treatments
for obsessive-compulsive
and related disorders.
Camfield, David
A; Sarris, Jerome
2017
Obsessive-compulsive
disorder:
Phenomenology,
pathophysiology, and
treatment.
Exclusion reason:
Wrong study
design;
Alleviating Depression,
Anxiety, and Existential
Distress in Cancer
Through Psychotropic
Enhanced Therapy: Might
Psilocybin Be a Magic
Bullet?
Wayne P.
2017
Journal of Alternative
and Complementary
Medicine
Exclusion reason:
Wrong study
design;
The psychological and
human brain effects of
music in combination
with psychedelic drugs
Kaelen, Mendel
2017
PQDT - UK & Ireland
Exclusion reason:
Wrong study
design;

332
Corrigendum to: Long-
term follow-up of
psilocybin-facilitated
smoking cessation (The
American Journal of Drug
and Alcohol Abuse,
(2017), 43, 1, (55-60),
10.3109/00952990.2016.
1170135)
Anonymous.
2017
American Journal of
Drug and Alcohol
Abuse
Exclusion reason:
Corrigendum to
previous study;
Psilocybin-Assisted
Therapy: A Review of a
Novel Treatment for
Psychiatric Disorders.
Thomas, Kelan;
Malcolm,
Benjamin;
Lastra, Dan
2017
Journal of
psychoactive drugs
Exclusion reason:
Wrong study
design;
Clinical potential of
psilocybin as a treatment
for mental health
conditions.
Daniel, Jeremy;
Haberman,
Margaret
2017
The mental health
clinician
Exclusion reason:
Wrong study
design;
Psilocybin for treating
substance use disorders?.
de Veen, Bas T
H; Schellekens,
Arnt F A; Verheij,
Michel M M;
Homberg, Judith
R
2017
Expert review of
neurotherapeutics
Exclusion reason:
Wrong study
design;
Long-term follow-up of
psilocybin-facilitated
smoking cessation (vol
43, pg 55, 2017)
Johnson, M. W.;
Garcia-Romeu,
A.; Griffiths, R. R.
2017
American Journal of
Drug and Alcohol
Abuse
Exclusion reason:
Corrigendum to
previous study;
"Long-term follow-up of
psilocybin-facilitated
smoking cessation":
Corrigendum.
Johnson,
Matthew W;
Garcia-Romeu,
Albert; Griffiths,
Roland R
2017
The American Journal
of Drug and Alcohol
Abuse
Exclusion reason:
Corrigendum to
previous study;

333
Potential Therapeutic
Effects of Psilocybin.
Johnson,
Matthew W;
Griffiths, Roland
R
2017
Neurotherapeutics :
the journal of the
American Society for
Experimental
NeuroTherapeutics
Exclusion reason:
Wrong study
design;
New medications for
treatment-resistant
depression: A brief
review of recent
developments
Thase M.E.
2017
CNS Spectrums
Exclusion reason:
Wrong study
design;
Psilocybin-assisted
therapy for anxiety and
depression: implications
for euthanasia.
Strauss, Nigel
2017
The Medical journal of
Australia
Exclusion reason:
Wrong study
design;
Moving Beyond
Serendipity to
Mechanism-Driven
Psychiatric Therapeutics
Pieper A.A.;
Baraban J.M.
2017
Neurotherapeutics
Exclusion reason:
Wrong study
design;
Tripping up addiction: the
use of psychedelic drugs
in the treatment of
problematic drug and
alcohol use
Morgan C.;
McAndrew A.;
Stevens T.; Nutt
D.; Lawn W.
2017
Current Opinion in
Behavioral Sciences
Exclusion reason:
Wrong study
design;
Role of psilocybin in the
treatment of depression.
Mahapatra,
Ananya; Gupta,
Rishi
2017
Therapeutic advances
in
psychopharmacology
Exclusion reason:
Wrong study
design;
Psychedelic Drugs in
Biomedicine.
Kyzar, Evan J;
Nichols, Charles
D; Gainetdinov,
Raul R; Nichols,
David E; Kalueff,
Allan V
2017
Trends in
pharmacological
sciences
Exclusion reason:
Wrong study
design;
Lessons to be learned
from early psychedelic
therapy in Denmark
Erritzoe, D.;
Richards, W. A.
2017
Nordic Journal of
Psychiatry
Exclusion reason:
Wrong study
design;
Experiments of
psychodysleptics in
Sainte-Anne in the 1960s
Edel Y.
2017
Annales Medico-
Psychologiques
Exclusion reason:
Wrong study
design;

334
Should addiction
researchers be interested
in psychedelic science?
Bright, Stephen;
Williams,
Martin;
Caldicott, David
2017
Drug and Alcohol
Review
Exclusion reason:
Wrong study
design;
It's time to take
psilocybin seriously as a
possible treatment for
substance use disorders.
Bogenschutz,
Michael P
2017
The American journal
of drug and alcohol
abuse
Exclusion reason:
Wrong study
design
Qualitative and
Quantitative Features of
Music Reported to
Support Peak Mystical
Experiences during
Psychedelic Therapy
Sessions
Barrett, F. S.;
Robbins, H.;
Smooke, D.;
Brown, J. L.;
Griffiths, R. R.
2017
Frontiers in
Psychology
Exclusion reason:
Wrong study
design;
The Safety and Efficacy of
Psilocybin in Participants
With Treatment Resistant
Depression
NCT03775200
2018
The Safety and
Efficacy of Psilocybin
in Participants With
Treatment Resistant
Depression
Exclusion reason:
No clinical
outcome(s)
measured;
Clinical, Neurocognitive,
and Emotional Effects of
Psilocybin in Depressed
Patients - Proof of
Concept
NCT03715127
2018
Phase II, Randomized,
Double Blind, Placebo
Controlled, Parallel
Group, Single Center
Study of Psilocybin
Efficacy in Major
Depression
Exclusion reason:
No clinical
outcome(s)
measured;
Psilocybin - Induced
Neuroplasticity in the
Treatment of Major
Depressive Disorder
NCT03554174
2018
Psilocybin - Induced
Neuroplasticity in the
Treatment of Major
Depressive Disorder
Exclusion reason:
No clinical
outcome(s)
measured;
Assessing psilocybin as a
treatment for depression
EUCTR2017-
000219-18-GB
2018
Psilocybin vs.
escitalopram for major
depressive disorder:
comparative
mechanisms -
Psilodep-RCT
Exclusion reason:
No clinical
outcome(s)
measured;

335
Psilocybin improves
cognitive control and
downregulates parietal
cortex in treatment-
seeking smokers
McKenna M.;
Fedota J.;
Garcia-Romeu
A.; Johnson M.;
Griffiths R.; Stein
E.
2018
Biological Psychiatry
Exclusion reason:
No clinical
outcome(s)
measured;
Lysergic acid
diethylamide and
psilocybin for the
management of patients
with persistent pain: a
potential role?.
Whelan, Andy;
Johnson, Mark I
2018
Pain management
Exclusion reason:
Wrong study
design;
Therapeutic use of classic
psychedelics to treat
cancer-related psychiatric
distress.
Ross, Stephen
2018
International review of
psychiatry (Abingdon,
England)
Exclusion reason:
Wrong study
design;
Psilocybin vs
Escitalopram for Major
Depressive Disorder:
comparative Mechanisms
NCT03429075
2018
Psilocybin vs
Escitalopram for Major
Depressive Disorder:
comparative
Mechanisms
Exclusion reason:
No clinical
outcome(s)
measured;
Psychedelic drugs in the
treatment of anxiety,
depression and addiction.
Kvam, Tor-
Morten;
Stewart, Lowan
H; Andreassen,
Ole A
2018
Tidsskrift for den
Norske laegeforening :
tidsskrift for praktisk
medicin, ny raekke
Exclusion reason:
Wrong study
design;
The therapeutic potential
of ayahuasca and other
serotonergic
hallucinogens in the
treatment of social
anxiety.
dos Santos,
Rafael G; Osorio,
Flavia L; Crippa,
Jose Alexandre
S; Bouso, Jose
Carlos; Hallak,
Jaime E. C
2018
Social anxiety
disorder: Recognition,
diagnosis and
management.
Exclusion reason:
Wrong study
design;
Therapeutic Applications
of Classic Hallucinogens.
Bogenschutz,
Michael P; Ross,
Stephen
2018
Current topics in
behavioral
neurosciences
Exclusion reason:
Wrong study
design;

336
Death anxiety
interventions in patients
with advanced cancer: A
systematic review
Grossman C.H.;
Brooker J.;
Michael N.;
Kissane D.
2018
Palliative Medicine
Exclusion reason:
Wrong study
design;
Efficacy, tolerability, and
safety of serotonergic
psychedelics for the
management of mood,
anxiety, and substance-
use disorders: a
systematic review of
systematic reviews.
Dos Santos,
Rafael G; Bouso,
Jose Carlos;
Alcazar-
Corcoles, Miguel
Angel; Hallak,
Jaime E C
2018
Expert review of
clinical pharmacology
Exclusion reason:
Wrong study
design;
Natural speech algorithm
applied to baseline
interview data can
predict which patients
will respond to psilocybin
for treatment-resistant
depression.
Carrillo,
Facundo;
Sigman,
Mariano;
Fernandez
Slezak, Diego;
Ashton, Philip;
Fitzgerald, Lily;
Stroud, Jack;
Nutt, David J;
Carhart-Harris,
Robin L
2018
Journal of affective
disorders
Exclusion reason:
Wrong study
design;
Psychedelics and related
drugs: therapeutic
possibilities, mechanisms
and regulation
Curran H.V.;
Nutt D.; de Wit
H.
2018
Psychopharmacology
Exclusion reason:
Wrong study
design;
Psychedelic-assisted
psychotherapy: A
paradigm shift in
psychiatric research and
development
Schenberg E.E.
2018
Frontiers in
Pharmacology
Exclusion reason:
Wrong study
design;
Novel psychotherapeutics
- a cautiously optimistic
focus on Hallucinogens.
Sherwood,
Alexander M;
Prisinzano,
Thomas E
2018
Expert review of
clinical pharmacology
Exclusion reason:
Wrong study
design;

337
Psychiatry & the
psychedelic drugs. Past,
present & future.
Rucker, James J
H; Iliff, Jonathan;
Nutt, David J
2018
Neuropharmacology
Exclusion reason:
Wrong study
design;
Serotonergic
hallucinogens in the
treatment of anxiety and
depression in patients
suffering from a life-
threatening disease: A
systematic review.
Reiche, Simon;
Hermle, Leo;
Gutwinski,
Stefan;
Jungaberle,
Henrik; Gasser,
Peter; Majic,
Tomislav
2018
Progress in neuro-
psychopharmacology
& biological psychiatry
Exclusion reason:
Wrong study
design;
Renaissance of
serotonergic
hallucinogens in
psychiatry
Quednow B.
2018
European Psychiatry
Exclusion reason:
Wrong study
design;
Psilocybin:
Antidepressive, anxiolytic
and antiaddictive effects
Machado C.;
Monteiro L.;
Fragoeiro C.;
Almeida B.
2018
European Psychiatry
Exclusion reason:
Wrong study
design;
Serotonin, psychedelics
and psychiatry
Carhart-Harris
R.L.
2018
World Psychiatry
Exclusion reason:
Wrong study
design;
Psychedelics and
Personality.
Aixala, Marc;
Dos Santos,
Rafael G; Hallak,
Jaime E C;
Bouso, Jose
Carlos
2018
ACS chemical
neuroscience
Exclusion reason:
Wrong study
design;
In Patients With Major
Depressive Disorder,
Psilocybin Administration
is Associated With
Reduced Amygdala
Response to Negative
Affective Stimuli and
Normalization of Cortical
Glutamate One Week
After Psilocybin, and
Improved Cognitive
Flexibility One and Four
Weeks After Psilocybin
Barrett, F.
2019
Neuropsychopharmac
ology
Exclusion reason:
Wrong study
design;

338
Clinical and Mechanistic
Effects of Psilocybin in
Alcohol Addicted Patients
NCT04141501
2019
Phase II, Randomized,
Double Blind, Placebo
Controlled, Parallel
Group, Single Center
Study of Psilocybin
Efficacy and
Mechanism in Alcohol
Use Disorder
Exclusion reason:
Wrong study
design;
Psilocybin-assisted
psychotherapy for the
treatment of depression
and anxiety associated
with life-threatening
illness
ACTRN12619001
225101
2019
Exclusion reason:
Wrong study
design;
P.839 Modelling the
acute temporal dynamics
of psilocybin
psychoactive effects;
relation to brain
serotonin 2a receptor
levels
Stenbaek D.;
Madsen M.K.;
Ozenne B.;
Kristiansen S.;
Burmester D.;
Erritzoe D.;
Knudsen G.M.;
Fisher P.M.
2019
European
Neuropsychopharmac
ology
Exclusion reason:
Wrong patient
population;
The Role of Self-
Compassion in Psilocybin-
Assisted Motivational
Enhancement Therapy to
Treat Alcohol
Dependence: A
Randomized Controlled
Trial
Agin-Liebes,
Gabrielle
2020
ProQuest Dissertations
and Theses
Exclusion reason:
Duplicate
Prediction of patient's
response to psylocybin
treatment for depression
using gradient boosting
machine learning based
on baseline fMRI data
Copa, Debora;
Pallavicini, Carla;
Zanutto, Silvano;
Tagliazucchi,
Enzo
2020
ASN Neuro
Exclusion reason:
Not english
language;

339
Automatic Quantification
of Language Features
Following Psilocybin
Administration: A Pilot
Study
Bradley E.R.;
Anderson B.T.;
Trope A.;
Danforth A.;
Daroff R.;
Stauffer C.;
Dilley J.; Mitchell
J.; Woolley J.D.
2020
Psychosomatic
Medicine
Exclusion reason:
Full text
unavailable;
Me, myself, bye: regional
alterations in glutamate
and the experience of
ego dissolution with
psilocybin.
Mason, N L;
Kuypers, K P C;
Muller, F;
Reckweg, J; Tse,
D H Y; Toennes,
S W; Hutten, N R
P W; Jansen, J F
A; Stiers, P;
Feilding, A;
Ramaekers, J G
2020
Neuropsychopharmac
ology : official
publication of the
American College of
Neuropsychopharmac
ology
Exclusion reason:
Wrong patient
population;
Pilot Trial of Visual
Healing(R) in Psilocybin-
assisted Therapy for
Alcohol Use Disorder
NCT04410913
2020
Pilot Trial of Visual
Healing(R), a Nature-
themed Virtual
Immersive Experience,
to Optimize Set and
Setting in Psilocybin-
assisted Therapy for
Alcohol Use Disorder
Exclusion reason:
Wrong study
design;
A Two-Year Observational
Follow-up Study of
Subjects With Major
Depressive Disorder
Following a Randomized,
Double-Blind Single-Dose
of Psilocybin or Niacin-
Control
NCT04353921
2020
A Two-Year
Observational Follow-
up Study of Subjects
With Major Depressive
Disorder Following a
Randomized, Double-
Blind Single-Dose of
Psilocybin or Niacin-
Control
Exclusion reason:
Wrong study
design;

340
Psilocybin Treatment of
Major Depressive
Disorder With Co-
occurring Alcohol Use
Disorder
NCT04620759
2020
Psilocybin Treatment
of Major Depressive
Disorder With Co-
occurring Alcohol Use
Disorder
Exclusion reason:
Wrong study
design;
A Trial of Psilocybin in
Clinical Depression
Resistant to Standard
Treatments
EUCTR2018-
003573-97-GB
2020
A randomised, placebo
controlled trial of
psilocybin in
treatment resistant
depression: a
feasibility study -
Psilocybin TRD
Feasibility RCT
Exclusion reason:
Wrong study
design;
Psilocybin-assisted group
therapy: A new hope for
demoralization
Hendricks P.S.
2020
EClinicalMedicine
Exclusion reason:
Wrong study
design;
Effectiveness of
psilocybin on depression:
A qualitative study
Al-Naggar,
Redhwan
Ahmed;
Alshaikhli,
Hisham; Erlam,
Gwen
2021
Electronic Journal of
General Medicine
Exclusion reason:
Wrong study
design
Effects of Psilocybin-
Assisted Therapy on
Major Depressive
Disorder: A Randomized
Clinical Trial (Nov,
10.1001/jamapsychiatry.
2020.3285, 2020)
Davis, AK;
Barrett, FS; May,
DG
2021
JAMA PSYCHIATRY
Exclusion reason:
Duplicate
Psilocybin for Depression.
Reply.
Carhart-Harris,
Robin; Blemings,
Allan; Nutt,
David J
2021
The New England
journal of medicine
Exclusion reason:
Corrigendum to
previous study;
Psilocybin for Depression
Carhart-Harris,
R; Blemings, A;
Nutt, DJ
2021
NEW ENGLAND
JOURNAL OF
MEDICINE
Exclusion reason:
Corrigendum to
previous study;

341
Effects of Psilocybin-
Assisted Therapy on
Major Depressive
Disorder: A Randomized
Clinical Trial.
Davis, Alan K;
Barrett,
Frederick S;
May, Darrick G;
Cosimano, Mary
P; Sepeda,
Nathan D;
Johnson,
Matthew W;
Finan, Patrick H;
Griffiths, Roland
R
2021
JAMA psychiatry
Exclusion reason:
Duplicate;
Errors in a Response Rate
and in Effect Sizes in
Study of Psilocybin-
Assisted Therapy for
Major Depressive
Disorder.
Davis, Alan K;
Griffiths, Roland
R
2021
JAMA psychiatry
Exclusion reason:
Corrigendum to
previous study;

342
Appendix C: Supporting Documents, Behavioural Investigations of Psilocybin in Non-human
Animals
Appendix C.1: Protocol: Scoping Review: Mapping Psilocybin Animal Research
October 25, 2019
Team Members:
Ron Shore, PhD Student, School of Kinesiology & Health Studies, Queen’s University, Kingston,
ON
Nigel Barnim, Undergraduate Psychology Student, Queen’s University
Katrina Dobson, MSc Student, Research School of Behavioural and Cognitive Neurosciences,
University of Groningen
Sandra McKeown, MLS, Health Sciences Librarian, Queen’s University
Dr. Eric Dumont (supervisor), Department of Biomedical and Molecular Sciences, Queen’s
University
Dr. Craig Goldie (supervisor), Department of Medicine, Queen’s University
Objective:
To determine the effects of psilocybin in animal studies across behavioural task clusters
and neurological measures and to chart:
1. What studies have been done.
2. What behavioural tests have been used.
3. What neurological measures have been implemented.
4. What dosing modalities have been used.
Further, we wish to assess the quality of research to date in line with the ARRIVE animal
research quality guidelines (Kilkenny, Browne, Cuthill, Emerson, & Altman, 2010) and to
indicate areas for future research.

343
Through librarian-conducted literature searches and defined inclusion criteria, the
relevant number of internationally published, peer-reviewed academic articles in addition to
grey area literature will be identified, and the findings charted to identify the current state of
psilocybin animal study research.
Stages of Scoping Review
A scoping review methodology was selected given the heterogeneous and emergent nature
of the application of psilocybin in animal research. Following the methodological framework
proposed by Arksey & O’Malley (2005) and further discussed by Levac, Colquhoun, & O’Brien
(2010), this scoping review has 6 specific stages.
1. Development and formulation of research question
2. Identifcation of relevant studies
3. Study selection
4. Charting the data
5. Collating, summarizing and reporting results
6. Consultation with relevant stakeholders
Research Question:
What are the neurological and behavioural effects of psilocybin administered in non-
human animal studies?
Preparation / preliminary work:

344
Reviewers (NB , KD & RS) will complete multiple preliminary reviews, literature research,
scan abstracts for keywords, pilot inclusion criteria, pilot data extraction tool, and research
background and history of psilocybin in animal models prior to conducting the actual scoping
review. Reviewers will also familiarize themselves with scoping review methodology, existing
reviews, and ARRIVE guidelines (see citations).
Literature Searches / Methodology:
A librarian from Queen’s Bracken Health Sciences Library (SM) will conduct a preliminary
search using MEDLINE, Embase and PsycINFO. A final search for the purpose of this scoping
review will include electronic databases, grey literature sources and the reference lists of
identified key studies to identify possible for inclusion. Bibliographic data, study and species
characteristics as well as other indicators will be collected and analyzed using a data extraction
tool developed by the research team.
Key extraction fields / data extraction tool:
Table 2. Psilocybin Scoping Review Data Extraction Tool Summary Table
Study Characteristics
Intervention
Characteristics
Research Orientation
Implications
citation
drug(s) administered
Domain of research (behavioural
vs. neurological)
research
question
year of publication
dose
outcomes measured
conclusions
source/country of origin
route of administration
Statistical significance
limitations
journal type
schedule of administration
Effect size
future research
sample size
quality (ARRIVE
guidelines)
follow-up

345
Table 2. Psilocybin Scoping Review Data Extraction Tool Summary Table
Study Characteristics
Intervention
Characteristics
Research Orientation
Implications
study design
tests used
methodology
animals used
Review Process:
Screening/Identifying Relevant Studies:
Librarian (SM) to complete literature search with agreed upon keywords, filtering out
for duplication.
Study Selection:
Two reviewers (NB & KD) to review each article abstract using Covidence (Cochrane)
software. All disagreements in study reviewing will be resolved through finding consensus
through discussion among the two reviewers. Articles must meet inclusion criteria to be
selected.
Inclusion Criteria: animal studies, psilocybin, mammals
Exclusion Criteria: duplication, comparative study with no baseline control, competitive
study, review article, not specific to neurological and/or behavioural effects
# included =
# excluded =
# duplicates=
# studies selected =

346
Charting the Data:
Reviewers to read entirety of selected studies and extract data using original data
extraction tool designed in Microsoft Excel. Reviewers to cross-check for homogenous process
quality control. Data entered from selected studies in agreed upon categories.
Collating/Summarizing Data:
Data to be summarized using standardized methodology. Key findings to be highlighted,
and both practice and patient variables to be summarized. Indications for future research to
also be identified.
Consultation with Relevant Stakeholders:
Draft results to be shared and reviewed by relevant stakeholders, including all team
members and associated biostatistician, and recognized experts in the field of psilocybin and
animal research, as well as individuals with scoping review research experience.
Results Mapping / Knowledge Distribution and Reporting:
Data from the scoping review will be mapped in at least the following manners:
1. clusters of behavioural tests and neurological measures
2. dosing modalities used
3. quality assessment of research conducted
4. chart time distribution of publication dates
5. compare and contrast disciplines of research and program aims/objectives

347
Additional Findings:
1. Gaps in literature to be identified
2. Indications for areas of future research
3. Interpretation of Key Findings
4. Indications for future animal trials
Authorship:
Scoping review authorship to include all team members. Publication to be sought within
relevant academic journals. Opportunities to present as poster/paper or as conference
presentation to be sought. Protocol to be published on Prospero.
Appendix C.2: Search Strategy: Behavioural Investigations of Psilocybin in Animals
Initial searches executed Oct 28 2019
Search methods
A comprehensive search approach was employed to locate published studies and conference
materials. A preliminary search was conducted in Ovid Embase using a combination of
keywords and subject headings, followed by an analysis of relevant citations to identify other
relevant keywords and subject headings. The optimized Ovid Embase search strategy was then
adapted for Ovid MEDLINE, Ovid EBM Reviews – Cochrane Central Register of Controlled Trials,
Ovid PsycINFO, Web of Science Core Collection, and BIOSIS Previews. All databases were
searched from inception up to February 2021. No publication date limits were applied. The

348
complete search strategies for all databases are presented in Appendices. The reference lists of
all eligible studies were screened to identify any additional studies.
Embase 510
Ovid MEDLINE 254
Ovid EBM Reviews - Cochrane Central Register of Controlled Trials 9
PsycINFO 117
Web of Science 162
BIOSIS Previews 693
Database(s): Embase Classic+Embase 1947 to 2019 October 25
Search Strategy:
#
Searches
Results
1
psilocybine/
1676
2
psilocybin*.mp.
1792
3
indocybin.mp.
4
4
psilocibin*.mp.
9
5
psilotsibin.mp.
0
6
teonanacatl.mp.
7
7
psilocin.mp.
468
8
baeocystin.mp.
30

349
9
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
1980
10
exp animal experiment/
2475333
11
exp experimental animal/
679538
12
exp animal model/
1324678
13
animal/
1929167
14
exp "sponge (Porifera)"/
7079
15
exp placozoa/
196
16
exp mesozoa/
21
17
coelenterate/
3738
18
Bilateria/
211
19
Coelomata/
16
20
Pseudocoelomata/
3
21
exp protostomia/
670345
22
exp ambulacraria/
16135
23
chordata/
1435
24
exp cephalochordata/
542
25
exp hyperotreti/
533
26
exp urochordata/
4486
27
vertebrate/
26642
28
exp fish/
224583

350
29
tetrapod/
457
30
exp amphibia/
73349
31
amniote/
317
32
exp sauropsid/
309380
33
exp reptile/
50414
34
mammal/
93265
35
"calf (mammal)"/
2285
36
exp monotreme/
744
37
therian/
55
38
exp marsupial/
10740
39
placental mammal/
189
40
exp afrotheria/
3847
41
boreoeutheria/
18
42
exp laurasiatheria/
912181
43
exp xenarthra/
1739
44
euarchontoglires/
36
45
dermoptera/
40
46
exp glires/
3948872
47
exp scandentia/
1017
48
primate/
30089

351
49
exp prosimian/
3227
50
haplorhini/
31892
51
exp tarsiiform/
235
52
simian/
285
53
exp platyrrhini/
9343
54
catarrhini/
118
55
exp cercopithecidae/
72326
56
ape/
5313
57
exp hylobatidae/
711
58
hominid/
5721
59
exp orangutan/
541
60
homo neanderthalensis/
1038
61
exp gorilla/
2983
62
exp chimpanzee/
12004
63
(animal or animals or pisces or fish or fishes or catfish or catfishes or sheatfish
or silurus or arius or heteropneustes or clarias or gariepinus or fathead
minnow or fathead minnows or pimephales or promelas or cichlidae or trout
or trouts or char or chars or salvelinus or salmo or oncorhynchus or guppy or
guppies or millionfish or poecilia or goldfish or goldfishes or carassius or
auratus or mullet or mullets or mugil or curema or shark or sharks or cod or
8088061

352
cods or gadus or morhua or carp or carps or cyprinus or carpio or killifish or
eel or eels or anguilla or zander or sander or lucioperca or stizostedion or
turbot or turbots or psetta or flatfish or flatfishes or plaice or pleuronectes or
platessa or tilapia or tilapias or oreochromis or sarotherodon or common sole
or dover sole or solea or zebrafish or zebrafishes or danio or rerio or seabass
or dicentrarchus or labrax or morone or lamprey or lampreys or petromyzon
or pumpkinseed or pumpkinseeds or lepomis or gibbosus or herring or clupea
or harengus or amphibia or amphibian or amphibians or anura or salientia or
frog or frogs or rana or toad or toads or bufo or xenopus or laevis or bombina
or epidalea or calamita or salamander or salamanders or newt or newts or
triturus or reptilia or reptile or reptiles or bearded dragon or pogona or
vitticeps or iguana or iguanas or lizard or lizards or anguis fragilis or turtle or
turtles or snakes or snake or aves or bird or birds or quail or quails or coturnix
or bobwhite or colinus or virginianus or poultry or poultries or fowl or fowls or
chicken or chickens or gallus or zebra finch or taeniopygia or guttata or canary
or canaries or serinus or canaria or parakeet or parakeets or grasskeet or
parrot or parrots or psittacine or psittacines or shelduck or tadorna or goose
or geese or branta or leucopsis or woodlark or lullula or flycatcher or ficedula
or hypoleuca or dove or doves or geopelia or cuneata or duck or ducks or
greylag or graylag or anser or harrier or circus pygargus or red knot or great
knot or calidris or canutus or godwit or limosa or lapponica or meleagris or
gallopavo or jackdaw or corvus or monedula or ruff or philomachus or pugnax

353
or lapwing or peewit or plover or vanellus or swan or cygnus or columbianus
or bewickii or gull or chroicocephalus or ridibundus or albifrons or great tit or
parus or aythya or fuligula or streptopelia or risoria or spoonbill or platalea or
leucorodia or blackbird or turdus or merula or blue tit or cyanistes or pigeon
or pigeons or columba or pintail or anas or starling or sturnus or owl or athene
noctua or pochard or ferina or cockatiel or nymphicus or hollandicus or skylark
or alauda or tern or sterna or teal or crecca or oystercatcher or haematopus or
ostralegus or shrew or shrews or sorex or araneus or crocidura or russula or
european mole or talpa or chiroptera or bat or bats or eptesicus or serotinus
or myotis or dasycneme or daubentonii or pipistrelle or pipistrellus or cat or
cats or felis or catus or feline or dog or dogs or canis or canine or canines or
otter or otters or lutra or badger or badgers or meles or fitchew or fitch or
foumart or foulmart or ferrets or ferret or polecat or polecats or mustela or
putorius or weasel or weasels or fox or foxes or vulpes or common seal or
phoca or vitulina or grey seal or halichoerus or horse or horses or equus or
equine or equidae or donkey or donkeys or mule or mules or pig or pigs or
swine or swines or hog or hogs or boar or boars or porcine or piglet or piglets
or sus or scrofa or llama or llamas or lama or glama or deer or deers or cervus
or elaphus or cow or cows or bos taurus or bos indicus or bovine or bull or
bulls or cattle or bison or bisons or sheep or sheeps or ovis aries or ovine or
lamb or lambs or mouflon or mouflons or goat or goats or capra or caprine or
chamois or rupicapra or leporidae or lagomorpha or lagomorph or rabbit or

354
rabbits or oryctolagus or cuniculus or laprine or hares or lepus or rodentia or
rodent or rodents or murinae or mouse or mice or mus or musculus or murine
or woodmouse or apodemus or rat or rats or rattus or norvegicus or guinea
pig or guinea pigs or cavia or porcellus or hamster or hamsters or
mesocricetus or cricetulus or cricetus or gerbil or gerbils or jird or jirds or
meriones or unguiculatus or jerboa or jerboas or jaculus or chinchilla or
chinchillas or beaver or beavers or castor fiber or castor canadensis or
sciuridae or squirrel or squirrels or sciurus or chipmunk or chipmunks or
marmot or marmots or marmota or suslik or susliks or spermophilus or
cynomys or cottonrat or cottonrats or sigmodon or vole or voles or microtus
or myodes or glareolus or primate or primates or prosimian or prosimians or
lemur or lemurs or lemuridae or loris or bush baby or bush babies or
bushbaby or bushbabies or galago or galagos or anthropoidea or anthropoids
or simian or simians or monkey or monkeys or marmoset or marmosets or
callithrix or cebuella or tamarin or tamarins or saguinus or leontopithecus or
squirrel monkey or squirrel monkeys or saimiri or night monkey or night
monkeys or owl monkey or owl monkeys or douroucoulis or aotus or spider
monkey or spider monkeys or ateles or baboon or baboons or papio or rhesus
monkey or macaque or macaca or mulatta or cynomolgus or fascicularis or
green monkey or green monkeys or chlorocebus or vervet or vervets or
pygerythrus or hominoidea or ape or apes or hylobatidae or gibbon or gibbons
or siamang or siamangs or nomascus or symphalangus or hominidae or

355
orangutan or orangutans or pongo or chimpanzee or chimpanzees or pan
troglodytes or bonobo or bonobos or pan paniscus or gorilla or gorillas or
troglodytes).mp. [mp=title, abstract, heading word, drug trade name, original
title, device manufacturer, drug manufacturer, device trade name, keyword,
floating subheading word, candidate term word]
64
nonhuman/
5999019
65
human versus animal comparison/
18107
66
human versus nonhuman data/
1979
67
nonhuman*.mp.
6005349
68
non human*.mp.
19848
69
or/10-68
10291268
70
9 and 69
643
71
limit 70 to editorial
12
72
limit 70 to "review"
121
73
70 not (71 or 72)
510
Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed
Citations, Daily and Versions(R) 1946 to October 24, 2019
Search Strategy: (Used for Cochrane CENTRAL as well)
#
Searches
Results
1
Psilocybin/
687

356
2
psilocybin*.mp.
952
3
indocybin.mp.
1
4
psilocibin*.mp.
7
5
psilotsibin.mp.
0
6
teonanacatl.mp.
3
7
psilocin.mp.
183
8
baeocystin.mp.
20
9
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
992
10
exp Animal Experimentation/
9204
11
exp models, animal/
548939
12
exp Animal Population Groups/
1159640
13
exp Chordata, Nonvertebrate/
5819
14
exp Amphibians/
107366
15
exp Birds/
218464
16
exp Fishes/
184024
17
exp Reptiles/
38951
18
Hyraxes/
146
19
exp Insectivora/
4899
20
exp Marsupialia/
10112
21
exp Monotremata/
668

357
22
exp Proboscidea Mammal/
2111
23
exp Xenarthra/
1602
24
Eutheria/
46
25
Mammals/
29233
26
Vertebrates/
11387
27
Chordata/
576
28
exp Artiodactyla/
673890
29
exp Carnivora/
461474
30
exp Cetacea/
8874
31
Chiroptera/
9171
32
exp Lagomorpha/
338140
33
exp Perissodactyla/
70588
34
exp Rodentia/
3161163
35
exp Scandentia/
1142
36
exp Sirenia/
319
37
Primates/
11880
38
exp Strepsirhini/
2515
39
Haplorhini/
46512
40
exp Platyrrhini/
13744
41
exp Tarsii/
77

358
42
Catarrhini/
93
43
exp Cercopithecidae/
121236
44
exp Hylobatidae/
945
45
Hominidae/
8112
46
Gorilla gorilla/
1898
47
Neanderthals/
633
48
Pan paniscus/
541
49
Pan troglodytes/
9321
50
exp Pongo/
1258
51
Animals/
6500190
52
(animal or animals or pisces or fish or fishes or catfish or catfishes or sheatfish
or silurus or arius or heteropneustes or clarias or gariepinus or fathead minnow
or fathead minnows or pimephales or promelas or cichlidae or trout or trouts
or char or chars or salvelinus or salmo or oncorhynchus or guppy or guppies or
millionfish or poecilia or goldfish or goldfishes or carassius or auratus or mullet
or mullets or mugil or curema or shark or sharks or cod or cods or gadus or
morhua or carp or carps or cyprinus or carpio or killifish or eel or eels or
anguilla or zander or sander or lucioperca or stizostedion or turbot or turbots or
psetta or flatfish or flatfishes or plaice or pleuronectes or platessa or tilapia or
tilapias or oreochromis or sarotherodon or common sole or dover sole or solea
or zebrafish or zebrafishes or danio or rerio or seabass or dicentrarchus or
7288178

359
labrax or morone or lamprey or lampreys or petromyzon or pumpkinseed or
pumpkinseeds or lepomis or gibbosus or herring or clupea or harengus or
amphibia or amphibian or amphibians or anura or salientia or frog or frogs or
rana or toad or toads or bufo or xenopus or laevis or bombina or epidalea or
calamita or salamander or salamanders or newt or newts or triturus or reptilia
or reptile or reptiles or bearded dragon or pogona or vitticeps or iguana or
iguanas or lizard or lizards or anguis fragilis or turtle or turtles or snakes or
snake or aves or bird or birds or quail or quails or coturnix or bobwhite or
colinus or virginianus or poultry or poultries or fowl or fowls or chicken or
chickens or gallus or zebra finch or taeniopygia or guttata or canary or canaries
or serinus or canaria or parakeet or parakeets or grasskeet or parrot or parrots
or psittacine or psittacines or shelduck or tadorna or goose or geese or branta
or leucopsis or woodlark or lullula or flycatcher or ficedula or hypoleuca or dove
or doves or geopelia or cuneata or duck or ducks or greylag or graylag or anser
or harrier or circus pygargus or red knot or great knot or calidris or canutus or
godwit or limosa or lapponica or meleagris or gallopavo or jackdaw or corvus or
monedula or ruff or philomachus or pugnax or lapwing or peewit or plover or
vanellus or swan or cygnus or columbianus or bewickii or gull or
chroicocephalus or ridibundus or albifrons or great tit or parus or aythya or
fuligula or streptopelia or risoria or spoonbill or platalea or leucorodia or
blackbird or turdus or merula or blue tit or cyanistes or pigeon or pigeons or
columba or pintail or anas or starling or sturnus or owl or athene noctua or

360
pochard or ferina or cockatiel or nymphicus or hollandicus or skylark or alauda
or tern or sterna or teal or crecca or oystercatcher or haematopus or ostralegus
or shrew or shrews or sorex or araneus or crocidura or russula or european
mole or talpa or chiroptera or bat or bats or eptesicus or serotinus or myotis or
dasycneme or daubentonii or pipistrelle or pipistrellus or cat or cats or felis or
catus or feline or dog or dogs or canis or canine or canines or otter or otters or
lutra or badger or badgers or meles or fitchew or fitch or foumart or foulmart
or ferrets or ferret or polecat or polecats or mustela or putorius or weasel or
weasels or fox or foxes or vulpes or common seal or phoca or vitulina or grey
seal or halichoerus or horse or horses or equus or equine or equidae or donkey
or donkeys or mule or mules or pig or pigs or swine or swines or hog or hogs or
boar or boars or porcine or piglet or piglets or sus or scrofa or llama or llamas
or lama or glama or deer or deers or cervus or elaphus or cow or cows or bos
taurus or bos indicus or bovine or bull or bulls or cattle or bison or bisons or
sheep or sheeps or ovis aries or ovine or lamb or lambs or mouflon or mouflons
or goat or goats or capra or caprine or chamois or rupicapra or leporidae or
lagomorpha or lagomorph or rabbit or rabbits or oryctolagus or cuniculus or
laprine or hares or lepus or rodentia or rodent or rodents or murinae or mouse
or mice or mus or musculus or murine or woodmouse or apodemus or rat or
rats or rattus or norvegicus or guinea pig or guinea pigs or cavia or porcellus or
hamster or hamsters or mesocricetus or cricetulus or cricetus or gerbil or
gerbils or jird or jirds or meriones or unguiculatus or jerboa or jerboas or

361
jaculus or chinchilla or chinchillas or beaver or beavers or castor fiber or castor
canadensis or sciuridae or squirrel or squirrels or sciurus or chipmunk or
chipmunks or marmot or marmots or marmota or suslik or susliks or
spermophilus or cynomys or cottonrat or cottonrats or sigmodon or vole or
voles or microtus or myodes or glareolus or primate or primates or prosimian
or prosimians or lemur or lemurs or lemuridae or loris or bush baby or bush
babies or bushbaby or bushbabies or galago or galagos or anthropoidea or
anthropoids or simian or simians or monkey or monkeys or marmoset or
marmosets or callithrix or cebuella or tamarin or tamarins or saguinus or
leontopithecus or squirrel monkey or squirrel monkeys or saimiri or night
monkey or night monkeys or owl monkey or owl monkeys or douroucoulis or
aotus or spider monkey or spider monkeys or ateles or baboon or baboons or
papio or rhesus monkey or macaque or macaca or mulatta or cynomolgus or
fascicularis or green monkey or green monkeys or chlorocebus or vervet or
vervets or pygerythrus or hominoidea or ape or apes or hylobatidae or gibbon
or gibbons or siamang or siamangs or nomascus or symphalangus or hominidae
or orangutan or orangutans or pongo or chimpanzee or chimpanzees or pan
troglodytes or bonobo or bonobos or pan paniscus or gorilla or gorillas or
troglodytes).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, floating sub-heading word, keyword heading word,
organism supplementary concept word, protocol supplementary concept word,
rare disease supplementary concept word, unique identifier, synonyms]

362
55
nonhuman*.mp.
17013
54
non human*.mp.
13927
55
or/10-54
7295497
56
9 and 55
254
Database(s): PsycINFO 1806 to October Week 2 2019
Search Strategy:
#
Searches
Results
1
Psilocybin/
209
2
psilocybin*.mp.
506
3
indocybin.mp.
0
4
psilocibin*.mp.
2
5
psilotsibin.mp.
0
6
teonanacatl.mp.
0
7
psilocin.mp.
35
8
baeocystin.mp.
2
9
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
516
10
animal models/
32226
11
exp Animals/
343015

363
12
(animal or animals or pisces or fish or fishes or catfish or catfishes or sheatfish or
silurus or arius or heteropneustes or clarias or gariepinus or fathead minnow or
fathead minnows or pimephales or promelas or cichlidae or trout or trouts or
char or chars or salvelinus or salmo or oncorhynchus or guppy or guppies or
millionfish or poecilia or goldfish or goldfishes or carassius or auratus or mullet
or mullets or mugil or curema or shark or sharks or cod or cods or gadus or
morhua or carp or carps or cyprinus or carpio or killifish or eel or eels or anguilla
or zander or sander or lucioperca or stizostedion or turbot or turbots or psetta or
flatfish or flatfishes or plaice or pleuronectes or platessa or tilapia or tilapias or
oreochromis or sarotherodon or common sole or dover sole or solea or zebrafish
or zebrafishes or danio or rerio or seabass or dicentrarchus or labrax or morone
or lamprey or lampreys or petromyzon or pumpkinseed or pumpkinseeds or
lepomis or gibbosus or herring or clupea or harengus or amphibia or amphibian
or amphibians or anura or salientia or frog or frogs or rana or toad or toads or
bufo or xenopus or laevis or bombina or epidalea or calamita or salamander or
salamanders or newt or newts or triturus or reptilia or reptile or reptiles or
bearded dragon or pogona or vitticeps or iguana or iguanas or lizard or lizards or
anguis fragilis or turtle or turtles or snakes or snake or aves or bird or birds or
quail or quails or coturnix or bobwhite or colinus or virginianus or poultry or
poultries or fowl or fowls or chicken or chickens or gallus or zebra finch or
taeniopygia or guttata or canary or canaries or serinus or canaria or parakeet or
parakeets or grasskeet or parrot or parrots or psittacine or psittacines or
502557

364
shelduck or tadorna or goose or geese or branta or leucopsis or woodlark or
lullula or flycatcher or ficedula or hypoleuca or dove or doves or geopelia or
cuneata or duck or ducks or greylag or graylag or anser or harrier or circus
pygargus or red knot or great knot or calidris or canutus or godwit or limosa or
lapponica or meleagris or gallopavo or jackdaw or corvus or monedula or ruff or
philomachus or pugnax or lapwing or peewit or plover or vanellus or swan or
cygnus or columbianus or bewickii or gull or chroicocephalus or ridibundus or
albifrons or great tit or parus or aythya or fuligula or streptopelia or risoria or
spoonbill or platalea or leucorodia or blackbird or turdus or merula or blue tit or
cyanistes or pigeon or pigeons or columba or pintail or anas or starling or sturnus
or owl or athene noctua or pochard or ferina or cockatiel or nymphicus or
hollandicus or skylark or alauda or tern or sterna or teal or crecca or
oystercatcher or haematopus or ostralegus or shrew or shrews or sorex or
araneus or crocidura or russula or european mole or talpa or chiroptera or bat or
bats or eptesicus or serotinus or myotis or dasycneme or daubentonii or
pipistrelle or pipistrellus or cat or cats or felis or catus or feline or dog or dogs or
canis or canine or canines or otter or otters or lutra or badger or badgers or
meles or fitchew or fitch or foumart or foulmart or ferrets or ferret or polecat or
polecats or mustela or putorius or weasel or weasels or fox or foxes or vulpes or
common seal or phoca or vitulina or grey seal or halichoerus or horse or horses
or equus or equine or equidae or donkey or donkeys or mule or mules or pig or
pigs or swine or swines or hog or hogs or boar or boars or porcine or piglet or

365
piglets or sus or scrofa or llama or llamas or lama or glama or deer or deers or
cervus or elaphus or cow or cows or bos taurus or bos indicus or bovine or bull or
bulls or cattle or bison or bisons or sheep or sheeps or ovis aries or ovine or lamb
or lambs or mouflon or mouflons or goat or goats or capra or caprine or chamois
or rupicapra or leporidae or lagomorpha or lagomorph or rabbit or rabbits or
oryctolagus or cuniculus or laprine or hares or lepus or rodentia or rodent or
rodents or murinae or mouse or mice or mus or musculus or murine or
woodmouse or apodemus or rat or rats or rattus or norvegicus or guinea pig or
guinea pigs or cavia or porcellus or hamster or hamsters or mesocricetus or
cricetulus or cricetus or gerbil or gerbils or jird or jirds or meriones or
unguiculatus or jerboa or jerboas or jaculus or chinchilla or chinchillas or beaver
or beavers or castor fiber or castor canadensis or sciuridae or squirrel or squirrels
or sciurus or chipmunk or chipmunks or marmot or marmots or marmota or
suslik or susliks or spermophilus or cynomys or cottonrat or cottonrats or
sigmodon or vole or voles or microtus or myodes or glareolus or primate or
primates or prosimian or prosimians or lemur or lemurs or lemuridae or loris or
bush baby or bush babies or bushbaby or bushbabies or galago or galagos or
anthropoidea or anthropoids or simian or simians or monkey or monkeys or
marmoset or marmosets or callithrix or cebuella or tamarin or tamarins or
saguinus or leontopithecus or squirrel monkey or squirrel monkeys or saimiri or
night monkey or night monkeys or owl monkey or owl monkeys or douroucoulis
or aotus or spider monkey or spider monkeys or ateles or baboon or baboons or

366
papio or rhesus monkey or macaque or macaca or mulatta or cynomolgus or
fascicularis or green monkey or green monkeys or chlorocebus or vervet or
vervets or pygerythrus or hominoidea or ape or apes or hylobatidae or gibbon or
gibbons or siamang or siamangs or nomascus or symphalangus or hominidae or
orangutan or orangutans or pongo or chimpanzee or chimpanzees or pan
troglodytes or bonobo or bonobos or pan paniscus or gorilla or gorillas or
troglodytes).mp. [mp=title, abstract, heading word, table of contents, key
concepts, original title, tests & measures, mesh]
13
nonhuman*.mp.
12391
14
non human*.mp.
4498
15
10 or 11 or 12 or 13 or 14
508257
16
9 and 15
117
Web of Science (used for BIOSIS Previews as well)
TOPIC: (psilocybin* or indocybin or psilocibin* or psilotsibin or teonanacatl or psilocin or
baeocystin) AND TOPIC: ((mammal or mammals or nonhuman or non-human or non-humans or
nonhumans or animal or animals or pisces or fish or fishes or catfish or catfishes or sheatfish or
silurus or arius or heteropneustes or clarias or gariepinus or fathead minnow or fathead
minnows or pimephales or promelas or cichlidae or trout or trouts or char or chars or salvelinus
or salmo or oncorhynchus or guppy or guppies or millionfish or poecilia or goldfish or goldfishes
or carassius or auratus or mullet or mullets or mugil or curema or shark or sharks or cod or cods
or gadus or morhua or carp or carps or cyprinus or carpio or killifish or eel or eels or anguilla or

367
zander or sander or lucioperca or stizostedion or turbot or turbots or psetta or flatfish or
flatfishes or plaice or pleuronectes or platessa or tilapia or tilapias or oreochromis or
sarotherodon or common sole or dover sole or solea or zebrafish or zebrafishes or danio or
rerio or seabass or dicentrarchus or labrax or morone or lamprey or lampreys or petromyzon or
pumpkinseed or pumpkinseeds or lepomis or gibbosus or herring or clupea or harengus or
amphibia or amphibian or amphibians or anura or salientia or frog or frogs or rana or toad or
toads or bufo or xenopus or laevis or bombina or epidalea or calamita or salamander or
salamanders or newt or newts or triturus or reptilia or reptile or reptiles or bearded dragon or
pogona or vitticeps or iguana or iguanas or lizard or lizards or anguis fragilis or turtle or turtles
or snakes or snake or aves or bird or birds or quail or quails or coturnix or bobwhite or colinus
or virginianus or poultry or poultries or fowl or fowls or chicken or chickens or gallus or zebra
finch or taeniopygia or guttata or canary or canaries or serinus or canaria or parakeet or
parakeets or grasskeet or parrot or parrots or psittacine or psittacines or shelduck or tadorna or
goose or geese or branta or leucopsis or woodlark or lullula or flycatcher or ficedula or
hypoleuca or dove or doves or geopelia or cuneata or duck or ducks or greylag or graylag or
anser or harrier or circus pygargus or red knot or great knot or calidris or canutus or godwit or
limosa or lapponica or meleagris or gallopavo or jackdaw or corvus or monedula or ruff or
philomachus or pugnax or lapwing or peewit or plover or vanellus or swan or cygnus or
columbianus or bewickii or gull or chroicocephalus or ridibundus or albifrons or great tit or
parus or aythya or fuligula or streptopelia or risoria or spoonbill or platalea or leucorodia or
blackbird or turdus or merula or blue tit or cyanistes or pigeon or pigeons or columba or pintail
or anas or starling or sturnus or owl or athene noctua or pochard or ferina or cockatiel or

368
nymphicus or hollandicus or skylark or alauda or tern or sterna or teal or crecca or
oystercatcher or haematopus or ostralegus or shrew or shrews or sorex or araneus or crocidura
or russula or european mole or talpa or chiroptera or bat or bats or eptesicus or serotinus or
myotis or dasycneme or daubentonii or pipistrelle or pipistrellus or cat or cats or felis or catus
or feline or dog or dogs or canis or canine or canines or otter or otters or lutra or badger or
badgers or meles or fitchew or fitch or foumart or foulmart or ferrets or ferret or polecat or
polecats or mustela or putorius or weasel or weasels or fox or foxes or vulpes or common seal
or phoca or vitulina or grey seal or halichoerus or horse or horses or equus or equine or
equidae or donkey or donkeys or mule or mules or pig or pigs or swine or swines or hog or hogs
or boar or boars or porcine or piglet or piglets or sus or scrofa or llama or llamas or lama or
glama or deer or deers or cervus or elaphus or cow or cows or bos taurus or bos indicus or
bovine or bull or bulls or cattle or bison or bisons or sheep or sheeps or ovis aries or ovine or
lamb or lambs or mouflon or mouflons or goat or goats or capra or caprine or chamois or
rupicapra or leporidae or lagomorpha or lagomorph or rabbit or rabbits or oryctolagus or
cuniculus or laprine or hares or lepus or rodentia or rodent or rodents or murinae or mouse or
mice or mus or musculus or murine or woodmouse or apodemus or rat or rats or rattus or
norvegicus or guinea pig or guinea pigs or cavia or porcellus or hamster or hamsters or
mesocricetus or cricetulus or cricetus or gerbil or gerbils or jird or jirds or meriones or
unguiculatus or jerboa or jerboas or jaculus or chinchilla or chinchillas or beaver or beavers or
castor fiber or castor canadensis or sciuridae or squirrel or squirrels or sciurus or chipmunk or
chipmunks or marmot or marmots or marmota or suslik or susliks or spermophilus or cynomys
or cottonrat or cottonrats or sigmodon or vole or voles or microtus or myodes or glareolus or

369
primate or primates or prosimian or prosimians or lemur or lemurs or lemuridae or loris or bush
baby or bush babies or bushbaby or bushbabies or galago or galagos or anthropoidea or
anthropoids or simian or simians or monkey or monkeys or marmoset or marmosets or
callithrix or cebuella or tamarin or tamarins or saguinus or leontopithecus or squirrel monkey or
squirrel monkeys or saimiri or night monkey or night monkeys or owl monkey or owl monkeys
or douroucoulis or aotus or spider monkey or spider monkeys or ateles or baboon or baboons
or papio or rhesus monkey or macaque or macaca or mulatta or cynomolgus or fascicularis or
green monkey or green monkeys or chlorocebus or vervet or vervets or pygerythrus or
hominoidea or ape or apes or hylobatidae or gibbon or gibbons or siamang or siamangs or
nomascus or symphalangus or hominidae or orangutan or orangutans or pongo or chimpanzee
or chimpanzees or pan troglodytes or bonobo or bonobos or pan paniscus or gorilla or gorillas
or troglodytes))
Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years
Appendix C.3:Behavioural Investigations of Psilocybin In Non-human Animals: List of Included
and Excluded Studies
Included Studies by Date
Title
Authors
Year
Journal
Behavioral and electrographic effects of
intraventricular injection of bulbocapnine and
other substances in freely moving monkeys.
In: Some biological aspects of schizophrenic
behavior
Wada, Juhn A.
1962
Ann New York Acad Sci

370
Dephosphorylation of psilocybin in the intact
mouse
Horita, A.; Weber,
L. J.
1962
Toxicol and Appl Pharmacol
Simultaneous studies of blood sugar,
serotonin metabolism, behaviourial changes
and EEG of the wake rabbit after the
administration of mescaline and psilocybin
Steiner, J. E.;
Sulman, F. G.
1963
Harokeach Haivri
Inhibition of isolation-induced attack
behavior of mice by drugs.
Uyeno, E T
1966
Journal of pharmaceutical
sciences
Psilocin: effects on behaviour and brain
serotonin in mice.
Collins, R L; Ordy, J
M; Samorajski, T
1966
Nature
Effects of mescaltne and psilocybin on
dominance behavior of the rat
Uyeno E.T.
1967
Archives internationales de
pharmacodynamie et de
therapie
Studies on the effects of drugs on
performance of a delayed discrimination
Roberts, M. H. T.;
Bradley, P. B.
1967
Physiol Behav
The Effects of Psilocybin Cent Stim Upon the
Visual Pathways of Baboons
Bert, J.; Ayats, H.;
Bermond, F.
1968
Vagtborg, Harold (Edited by).
Use of Nonhuman Primates
in Drug Evaluation. A
Symposium. Xii + 640p. Illus.
University of Texas Press:
Austin, Tex., U.S.A. And
London, England
Behavioural effects of some morphine
antagonists and hallucinogens in the rat.
Schneider, C
1968
Nature

371
A STUDY OF THE ROLE OF NORADRENALINE
NOREPINEPHRINE IN BEHAVIORAL CHANGES
PRODUCED IN THE RAT BY
PSYCHOTOMIMETIC DRUGS LYSERGIC-ACID DI
ETHYLAMIDE PSILOCYBIN DITRAN RESERPINE
ALPHA METHYL TYROSINE METHYL ESTER
HYDRO CHLORIDE METAB
Sugrue, M. F.
1969
British Journal of
Pharmacology
ALTERATION OF A LEARNED RESPONSE OF
THE SQUIRREL MONKEY BY HALLUCINOGENS
2 5 DI METHOXY-4-ETHYL AMPHETAMINE 2 5
DI METHOXY-4-METHYL AMPHETAMINE
PSILOCYBIN 4 METHOXY-N N-DIMETHYL
TRYPTAMINE N N DI METHYL TRYPTAMINE 6
HYDROXY-N N-DIMETHYL TRYPTAMINE CENT
STIM
Uyeno, E. T.
1969
International Journal of
Neuropharmacology
Effects of psilocybin, dimethyltryptamine,
mescaline and various lysergic acid
derivatives on the EEG and on photically
induced epilepsy in the baboon (Papio papio).
Meldrum, B S;
Naquet, R
1971
Electroencephalography and
clinical neurophysiology
Relative potency of amphetamine derivatives
and N,N-dimethyltryptamines.
Uyeno, E T
1971
Psychopharmacologia

372
PART 2 THE EFFECTS OF SOME
HALLUCINOGENS ON AGGRESSIVENESS OF
MICE AND RATS
Kostowski, W.;
Rewerski, W.;
Piechocki, T.
1972
Pharmacology (Basel)
EFFECTS OF AMPHETAMINE LSD PSILOCYBIN
AND 2 5 DI METHOXY-4-METHYL
AMPHETAMINE ON SCHEDULE CONTROLLED
BEHAVIOR IN THE RAT
Marquis, W. J.;
Tilson, H. A.; Rech,
R. H.
1973
Federation Proceedings
The effects of psilocybin on EEG and
behaviour in monkeys.
Horibe, M
1974
Activitas nervosa superior
COMPARISON OF DISCRIMINATIVE STIMULUS
PROPERTIES OF DELTA9-THC AND PSILOCYBIN
IN RATS
GREENBERG, I;
KUHN, D; APPEL, JB
1975
PHARMACOLOGY
BIOCHEMISTRY AND
BEHAVIOR
Adaptive changes in behavior after repeated
administration of various psychoactive drugs.
Rech, R H; Tilson, H
A; Marquis, W J
1975
Advances in biochemical
psychopharmacology
An animal behavior model for studying the
actions of LSD and related hallucinogens.
Jacobs, B L;
Trulson, M E; Stern,
W C
1976
Science (New York, N.Y.)
DRUG INDUCED SUPPRESSION SPECIFICITY
DUE TO DRUG EMPLOYED AS
UNCONDITIONED STIMULI
Cameron, O. G.;
Appel, J. B.
1976
Pharmacology Biochemistry
and Behavior
Comparative effects of hallucinogenic drugs
on rotational behavior in rats with unilateral
6-hydroxydopamine lesions.
Trulson, M E; Stark,
A D; Jacobs, B L
1977
European journal of
pharmacology
Serotonin and sexual behaviour in female
rats. Effects of hallucinogenic
indolealkylamines and phenylethylamines
Everitt B.J.; Fuxe K.
1977
Neuroscience Letters

373
Comparative effects of hallucinogenic drugs
on behavior of the cat.
Jacobs, B L;
Trulson, M E; Stark,
A D; Christoph, G R
1977
Communications in
psychopharmacology
Behavioral effects of LSD in the cat: proposal
of an animal behavior model for studying the
actions of hallucinogenic drugs.
Jacobs, B L;
Trulson, M E; Stern,
W C
1977
Brain research
Psilocybin: biphasic dose-response effects on
the acoustic startle reflex in the rat.
Davis, M; Walters, J
K
1977
Pharmacology, biochemistry,
and behavior
Psychoactivity of normacromerine in animals.
Bourn, W M; Keller,
W J; Bonfiglio, J F
1978
Life sciences
Evaluation of psychotropic drugs with a
modified open field test
Cunha J.M.; Masur
J.
1978
Pharmacology
The effects of lysergic acid diethylamide and
mescaline-derived hallucinogens on sensory-
integrative function: tactile startle.
Geyer, M A;
Petersen, L R; Rose,
G J; Horwitt, D D;
Light, R K; Adams, L
M; Zook, J A;
Hawkins, R L;
Mandell, A J
1978
The Journal of pharmacology
and experimental
therapeutics
The identification of LSD-like hallucinogens
using the chronic spinal dog.
Martin, W R;
Vaupel, D B;
Nozaki, M; Bright, L
D
1978
Drug and alcohol
dependence
EFFECTS OF MESCALINE AND PSILOCIN ON
ACQUISITION, CONSOLIDATION, AND
PERFORMANCE OF LIGHT-DARK
DISCRIMINATION IN 2 INBRED STRAINS OF
MICE
Castellano, C.
1978
Psychopharmacology
Screening hallucinogenic drugs. II. Systematic
study of two behavioral tests
Calil H.M.
1978
Psychopharmacology
PSILOCYBIN NEURO-PSYCHO-
PHARMACOLOGY IN RABBITS
Guest, J.; Consroe,
P.
1979
Research Communications in
Psychology Psychiatry and
Behavior

374
Severe aggression in rats induced by
mescaline but not other hallucinogens.
Sbordone, R J;
Wingard, J A;
Gorelick, D A;
Elliott, M L
1979
Psychopharmacology
THE INHIBITION OF FOOD INTAKE IN THE DOG
BY LSD MESCALINE PSILOCIN D
AMPHETAMINE AND PHENYL ISO
PROPYLAMINE DERIVATIVES
Vaupel, D. B.;
Mozaki, M.;
Martin, W. R.;
Bright, L. D.;
Morton, E. C.
1979
Life Sciences
A characteristic effect of hallucinogens on
investigatory responding in rats.
Geyer, M A; Light,
R K; Rose, G J;
Petersen, L R;
Horwitt, D D;
Adams, L M;
Hawkins, R L
1979
Psychopharmacology
Comparisons of mescal bean alkaloids with
mescaline, DELTA9-THC and other
psychotogens
Bourn W.M.; Keller
W.J.; Bonfiglio J.F.
1979
Life Sciences
GROSS BEHAVIORAL AND PHYSIOLOGICAL
EFFECTS OF HALLUCINOGENS IN CONSCIOUS
RESTRAINED MONKEYS MACACA-
FASCICULARIS
Wilson, M. C.;
Bedford, J. A.;
Davis, W. M.
1981
Research Communications in
Substances of Abuse
STRUCTURE ACTIVITY RELATIONSHIPS
AMONG HALLUCINOGENIC TRYPTAMINE
DERIVATIVES EVALUATED BY SCHEDULE
CONTROLLED BEHAVIOR
Harris, R. A.;
Homfeld, E.;
Campaigne, E.
1981
Journal of Pharmacy and
Pharmacology
Induction of 5-hydroxytryptamine (5HT)-
dependent myoclonus in guinea pigs by
indole-containing, but not by piperazine-
containing, 5HT-agonists suggests multiple
cerebral 5HT receptors
Jenner P.;
Luscombe G.;
Marsden C.D.
1981
British Journal of
Pharmacology

375
Dissociations between the effects of
hallucinogenic drugs on behavior and raphe
unit activity in freely moving cats.
Trulson, M E;
Heym, J; Jacobs, B L
1981
Brain research
PSILOCYBIN AS A DISCRIMINATIVE STIMULUS
- LACK OF SPECIFICITY IN AN ANIMAL
BEHAVIOR MODEL FOR HALLUCINOGENS
KOERNER, J; APPEL,
JB
1982
PSYCHOPHARMACOLOGY
DOSE DEPENDENT BEHAVIORAL-CHANGES
INDUCED BY PSILOCYBIN IN SELECTED
MEMBERS OF A PRIMATE SOCIAL COLONY
Sink, C. A.;
Beluhan, L. J.;
Schlemmer, R. F.;
Heinze, W. J.;
Davis, J. M.
1983
Federation Proceedings
Differential effects of hallucinogenic drugs on
the activity of serotonin-containing neurons
in the nucleus centralis superior and nucleus
raphe pallidus in freely moving cats.
Trulson, M E;
Preussler, D W;
Trulson, V M
1984
The Journal of pharmacology
and experimental
therapeutics
5-Hydroxytryptamine (5-HT)-dependent
myoclonus in guinea pigs is induced through
brainstem 5-HT-1 receptors
Luscombe G.;
Jenner P.; Marsden
C.D.
1984
Neuroscience Letters
A primate model for the study of
hallucinogens
Schlemmer Jr. R.F.;
Davis J.M.
1986
Pharmacology Biochemistry
and Behavior
Comparison of stimulants and hallucinogens
on shuttle avoidance in rats
Davis W.M.;
Hatoum H.T.
1987
General Pharmacology:
Vascular System

376
3,4-
methylenedioxymethapmhetamine(MDMA)
and 4-OH-dimethyltryptamine (psilocin)
interaction in rats: Behavioral study on
prepulse inhibition of acoustic startle reaction
and on locomotion
Palenicek, T.;
Bubenikova, V.;
Votava, M.
2005
Behavioural Pharmacology
Effects of Psilocybe argentipes on marble-
burying behavior in mice.
Matsushima,
Yoshihiro; Shirota,
Osamu; Kikura-
Hanajiri, Ruri;
Goda, Yukihiro;
Eguchi, Fumio
2009
Bioscience, biotechnology,
and biochemistry
Acute toxicity of Psilocybe cubensis (Ear.)
Sing., Strophariaceae, aqueous extract in
mice
Kirsten, T. B.;
Bernardi, M. M.
2010
Revista Brasileira De
Farmacognosia-Brazilian
Journal of Pharmacognosy
Differential contributions of serotonin
receptors to the behavioral effects of
indoleamine hallucinogens in mice.
Halberstadt, Adam
L; Koedood,
Liselore; Powell,
Susan B; Geyer,
Mark A
2011
Journal of
psychopharmacology
(Oxford, England)
THE EFFECT OF TRYPTAMINE
HALLUCINOGENS ON QUANTITATIVE EEG
AND BEHAVIOR IN RATS
Filip, Tyls; Tomas,
Palenicek;
Michaela,
Fujakova; Anna,
Kubesova; Martin,
Brunovsky;
Vladimir, Krajca;
Jiri, Horacek
2011
Behavioural Pharmacology
Comparison of sensorimotor gating and
quantitative EEG in serotonergic models of
psychosis in the rat
Tyls, F.; Palenicek,
T.; Fujakova, M.;
Kaderabek, L.;
Novakova, P.;
Kubesova, A.;
Horacek, J.
2013
European
Neuropsychopharmacology
Effects of psilocybin on hippocampal
neurogenesis and extinction of trace fear
conditioning.
Catlow, Briony J;
Song, Shijie;
Paredes, Daniel A;
Kirstein, Cheryl L;
Sanchez-Ramos,
Juan
2013
Experimental brain research

377
The impact of serotonin system modulation
on behavior and quantitative EEG in an
animal model of psychosis induced by psilocin
Tyls, F.; Palenicek,
T.; Novakova, P.;
Kaderabek, L.;
Fujakova, M.;
Kubesova, A.;
Horacek, J.
2014
European
Neuropsychopharmacology
The effect of psilocin on memory acquisition,
retrieval, and consolidation in the rat.
Rambousek, Lukas;
Palenicek, Tomas;
Vales, Karel;
Stuchlik, Ales
2014
Frontiers in behavioral
neuroscience
Research on acute toxicity and the behavioral
effects of methanolic extract from psilocybin
mushrooms and psilocin in mice.
Zhuk, Olga; Jasicka-
Misiak, Izabela;
Poliwoda, Anna;
Kazakova,
Anastasia;
Godovan, Vladlena
V; Halama, Marek;
Wieczorek, Piotr P
2015
Toxins
Effect of psilocin on extracellular dopamine
and serotonin levels in the mesoaccumbens
and mesocortical pathway in awake rats.
Sakashita, Yuichi;
Abe, Kenji; Katagiri,
Nobuyuki; Kambe,
Toshie; Saitoh,
Toshiaki;
Utsunomiya, Iku;
Horiguchi, Yoshie;
Taguchi, Kyoji
2015
Biological & pharmaceutical
bulletin
Sex differences and serotonergic mechanisms
in the behavioural effects of psilocin.
Tyls, Filip;
Palenicek, Tomas;
Kaderabek, Lukas;
Lipski, Michaela;
Kubesova, Anna;
Horacek, Jiri
2016
Behavioural pharmacology
Psilocin and ketamine microdosing: effects of
subchronic intermittent microdoses in the
elevated plus-maze in male Wistar rats.
Horsley, Rachel R;
Palenicek, Tomas;
Kolin, Jan; Vales,
Karel
2018
Behavioural pharmacology

378
Alteration of Depressive-like Behaviors by
Psilocybe cubensis Alkaloid Extract in Mice:
the Role of Glutamate Pathway
Mahmoudi, E.;
Faizi, M.;
Hajiaghaee, R.;
Razmi, A.
2018
Research Journal of
Pharmacognosy
Harnessing psilocybin: Synaptic mechanisms
underlying the antidepressant response
Thompson S.
2019
Neuropsychopharmacology
The polypharmacological profile of psilocybin
and potential behavioural effects of very low
doses
Kiilerich, K.; Speth,
N.; Lorenz, J.;
Casado-Sainz, A.;
Shalgunov, V.;
Lange, D.; Xiong,
M.; Herth, M. M.;
Overgaard, A.;
Hansen, H. D.;
Palner, M.
2019
European
Neuropsychopharmacology
Psilocybin lacks antidepressant-like effect in
the Flinders Sensitive Line rat.
Jefsen, Oskar;
Hojgaard,
Kristoffer;
Christiansen, Sofie
Laage; Elfving,
Betina; Nutt, David
John; Wegener,
Gregers; Muller,
Heidi Kaastrup
2019
Acta neuropsychiatrica
Effects of acute and repeated treatment with
serotonin 5-HT2A receptor agonist
hallucinogens on intracranial self-stimulation
in rats.
Sakloth, Farhana;
Leggett, Elizabeth;
Moerke, Megan J;
Townsend, E
Andrew; Banks,
Matthew L; Negus,
S Stevens
2019
Experimental and clinical
psychopharmacology
The Effects of Psilocybin on Binge-Like
Feeding Behaviour in Rats
Hurley, S.; Gilmour,
G.; Soula, A.;
Medhurst, L.;
Hickey, M.;
Whelan, T.;
Selimbeyoglu, A.
2020
Neuropsychopharmacology

379
Effects of a single dose of psilocybin on
behaviour, brain 5-HT2A receptor occupancy
and gene expression in the pig.
Donovan, Lene
Lundgaard;
Johansen, Jens
Vilstrup; Ros, Nidia
Fernandez; Jaberi,
Elham; Linnet,
Kristian; Johansen,
Sys Stybe; Ozenne,
Brice; Issazadeh-
Navikas, Shohreh;
Hansen, Hanne
Demant; Knudsen,
Gitte Moos
2020
European
Neuropsychopharmacology
Psychedelics, but Not Ketamine, Produce
Persistent Antidepressant-like Effects in a
Rodent Experimental System for the Study of
Depression.
Hibicke, Meghan;
Landry, Alexus N;
Kramer, Hannah M;
Talman, Zoe K;
Nichols, Charles D
2020
ACS chemical neuroscience
One Dose of Psilocybin in Late Adolescence
Mitigates Deleterious Effects of
Developmental Stress on Cognition and
Behavioral Despair in Adult Female Rats
Hibicke, M.;
Nichols, C.
2020
Faseb Journal
Harnessing Psilocybin: Antidepressant-Like
Behavioral and Synaptic Actions of Psilocybin
are Independent of 5-HT2R Activation in Mice
Hesselgrave, N.;
Troppoli, T.; Wulff,
A.; Cole, A.;
Thompson, S.
2020
Neuropsychopharmacology
Psilocybin and Ketamine Acutely Promote
Wakefulness, Suppress REM Sleep but
Differentially Modulate High Frequency EEG
Oscillatory Power in Wistar Kyoto Rats - a
Preliminary Analysis
Thomas, C.;
Gilmour, G.;
Medhurst, L.;
Soula, A.; Hickey,
M.; Hurley, S.;
Whelan, T.;
Selimbeyoglu, A.
2020
Neuropsychopharmacology

380
Psilocybin, After Only a Single Treatment, has
Persistent Antidepressant-Like Effects in a Rat
Experimental System for the Study of Mood
Disorders
Nichols, C.; Hibicke,
M.
2020
Neuropsychopharmacology
Low Doses of Psilocybin and Ketamine
Enhance Motivation and Attention in Poor
Performing Rats: Evidence for an
Antidepressant Property.
Higgins, Guy A;
Carroll, Nicole K;
Brown, Matt;
MacMillan, Cam;
Silenieks, Leo B;
Thevarkunnel,
Sandy; Izhakova,
Julia;
Magomedova, Lilia;
DeLannoy, Ines;
Sellers, Edward M
2021
Frontiers in pharmacology
A Complex Impact of Systemically
Administered 5-HT2A Receptor Ligands on
Conditioned Fear.
Hagsater, Sven
Melker; Pettersson,
Robert; Pettersson,
Christopher;
Atanasovski,
Daniela; Naslund,
Jakob; Eriksson,
Elias
2021
The international journal of
neuropsychopharmacology
Investigation of the Structure-Activity
Relationships of Psilocybin Analogues
Klein A.K.; Chatha
M.; Laskowski L.J.;
Anderson E.I.;
Brandt S.D.;
Chapman S.J.;
McCorvy J.D.;
Halberstadt A.L.
2021
ACS Pharmacology and
Translational Science
Harnessing psilocybin: antidepressant-like
behavioral and synaptic actions of psilocybin
are independent of 5-HT2R activation in mice.
Hesselgrave,
Natalie; Troppoli,
Timothy A; Wulff,
Andreas B; Cole,
Anthony B;
Thompson, Scott M
2021
Proceedings of the National
Academy of Sciences of the
United States of America
List of Excluded Studies by Date, BIPA
Title
Authors
Pub
Year
Journal
Notes

381
Pharmacology of psilocybin, a drug
from psilocybe mexicana heim
Weidmann H.;
Taeschler M.;
Konzett H.
1958
Experientia
Exclusion reason: not
available in English;
The effect of the action of
psilocybin on the rabbit brain
Monnier M.
1959
Experientia
Exclusion reason: not
available in English
Studies on psilocybin and related
compounds. I. Communication.
Structure/activity relationship of
oxyindole-derivatives with regard
to their effect on the knee jerk of
spinal cats.
WEIDMANN,
H; CERLETTI, A
1960
Helvetica physiologica et
pharmacologica acta
Exclusion reason: No
behaviour measured
The relationship between the
metabolic fate and
pharmacological actions of
serotonin, bufotenine and
psilocybin
Gessner, P. K.;
Khairallah, P.
A.; McIsaac, W.
M.; Page, L. H.
1960
Jour Pharmacol and Exptl
Therap
Exclusion reason: No
behaviour measured
EFFECT OF PSILOCYBIN UPON
SYSTEMIC, PULMONARY, AND
CORONARY CIRCULATION OF
INTACT DOG
MAXWELL,
GM;
KNEEBONE,
GM; ELLIOTT,
RB
1962
ARCHIVES INTERNATIONALES
DE PHARMACODYNAMIE ET
DE THERAPIE
Exclusion reason:
Unavailable within
timeframe of study
DEPHOSPHORYLATION OF
PSILOCYBIN IN INTACT MOUSE
HORITA, A;
WEBER, LJ
1962
TOXICOLOGY AND APPLIED
PHARMACOLOGY
Exclusion reason: No
behaviour measured
FATE OF PSILOCIN IN RAT
KALBERER, F;
RUTSCHMANN,
J; KREIS, W
1962
BIOCHEMICAL
PHARMACOLOGY
Exclusion reason: No
behavioural/neurological
outcome

382
EFFECTS OF LSD-25, PSILOCYBIN,
AND PSILOCIN ON TEMPORAL
LOBE EEG PATTERNS AND
LEARNED BEHAVIOR IN CAT
ADEY, WR;
BELL, FR;
DENNIS, BJ
1962
NEUROLOGY
Exclusion reason:
Unavailable within
timeframe of study
Effects of LSD-25, psiolocybin, and
psilocin on temporal lobe EEG
patterns and learned behavior in
the cat.
ADEY, W R;
BELL, F R;
DENNIS, B J
1962
Neurology
Exclusion reason: Could
not be found after ILLs
Search for experimental
equivalents of hallucinogenic
activity. Effects of hallucinogens on
rectal temperature in rabbit and on
morphine effects in mouse
Jacob J.; Lafille
C.; Loiseau G.;
Echinard-Garin
P.; Barthelemy
C.
1962
Exclusion reason: Could
not be found after ILLs
The effect of psilocybin upon the
systemic, pulmonary and coronary
circulation of the intact dog
Maxwell G.M.;
Kneebone
G.M.; Elliott
R.B.
1962
Archives internationales de
pharmacodynamie et de
therapie
Exclusion reason: No
behaviour measured
The late of Psilocin in the rat
Kalberer, F.;
Kreis, W.;
Rutschmann, J.
1962
Biochem Pharmacol
Exclusion reason: No
behaviour measured
SIMULTANEOUS STUDIES OF
BLOOD SUGAR, BEHAVIOURAL
CHANGES AND EEG ON WAKE
RABBIT AFTER ADMININISTRATION
OF PSILOCYBIN
STEINER, JE;
SULMAN, FG
1963
ARCHIVES INTERNATIONALES
DE PHARMACODYNAMIE ET
DE THERAPIE
Exclusion reason:
Unavailable within
timeframe of study

383
SIMULTANEOUS STUDIES OF
BLOOD SUGAR, BEHAVIOURAL
CHANGES AND EEG ON WAKE
RABBIT AFTER ADMININISTRATION
OF PSILOCYBIN
Steiner, J. E.;
Sulman, F. G.
1963
Archives Internationales De
Pharmacodynamie Et De
Therapie
Exclusion reason: Could
not be found after ILLs
Some biochemical studies on
psilocybin and psilocin
Horita, A.
1963
Jour Neuropsychiat
Exclusion reason: No
behaviour measured
PSYCHOTOMIMETICS--A
NEUROPHARMACOLOGICAL
STUDY.
CURTIS, D R
1963
Proceedings of the Australian
Association of Neurologists
Exclusion reason: not
original research
PHARMACOLOGICAL DETECTION
and CHARACTERIZATION of
HALLUCINOGENS. I.
HYPERTHERMIZING ACTIVITIES in
THE RABBIT
Jacob J.; Lafille
C.
1963
Archives internationales de
pharmacodynamie et de
therapie
Exclusion reason: not
available in English
An electrographic study of psilxcin
and 4-methyl-alpha-methyl
tryptamine (mp-809)
Brodey J.F.;
Steiner W.G.;
Himwich H.E.
1963
Exclusion reason: No
behaviour measured
Research on the pharmacological
characterization and
differentiation of hallucinogenic
drugs (indole derivatives and
mescaline, nalorphine, central
anticholinergics, and
phencyclidine).
Jacob, J; Lafille,
C; Loiseau, G;
Echinard-
Garin, P;
Barthelemy, C
1964
L'Encephale: Revue de
psychiatrie clinique
biologique et therapeutique
Exclusion reason: not
available in English
DISINHIBITION OF CONDITIONED
BEHAVIOR BY CEREBRAL SYNAPTIC
INHIBITORS
Halasz, M. F.;
Marrazzi, A. S.
1965
Pharmacologist
Exclusion reason: No
behaviour measured

384
The effects of tryptamine and
alpha-methyl-tryptamine on the
general and coronary
haemodynamics and metabolism
of the dog
Maxwell, G.
M.; Burnell, R.
H.; Kneebone,
G. M.
1965
Arch Int Pharmacodyn
Therap
Exclusion reason: No
behaviour measured
EFFECTS OF STRESS AND
PSYCHOTROPIC DRUGS ON RAT
LIVER TRYPTOPHAN PYRROLASE.
NOMURA, J
1965
Endocrinology
Exclusion reason: No
behaviour measured
The influence of hallucinogenic
drugs upon in vivo brain levels of
adenine nucleotides,
phosphocreatine and inorganic
phosphate in the rat.
Lewis, J J;
Ritchie, A P;
van Petten, G R
1965
British journal of
pharmacology and
chemotherapy
Exclusion reason: No
behaviour measured
PSILOCIN - EFFECTS ON
BEHAVIOUR AND BRAIN
SEROTONIN IN MICE
COLLINS, RL;
ORDY, JM;
SAMORAJS.T
1966
NATURE
Exclusion reason:
duplicate
EFFECT OF PSILOCYBINE ON
VISUAL EVOKED POTENTIALS IN A
CERCOPITHECINAE PAPIO PAPIO
BERMOND, F;
BERT, J; AYATS,
J
1966
COMPTES RENDUS DES
SEANCES DE LA SOCIETE DE
BIOLOGIE ET DE SES FILIALES
Exclusion reason: not
available in English
Inhibition of isolation-induced
attack behavior of mice by drugs.
Uyeno, E T
1966
Proceedings of the Western
Pharmacology Society
Exclusion reason: not
original research

385
The modification of the EEG in the
reserpinized rabbit caused by
psychoanaleptics and the
precursors of biogenic amines Ger.,
and Engl. summ.
Nakajima, H.;
Thuillier, J.
1966
Med Pharmacol Exp
Exclusion reason: No
behaviour measured
Eeg effects of psychoanaleptics
and biogenic amine precursors in
reserpinized rabbits
Kakajirna H.;
Thuillier J.
1966
Exclusion reason: No
behaviour measured
EFFECT OF PSILOCYBINE ON
VISUAL EVOKED POTENTIALS IN A
CERCOPITHECINAE PAPIO PAPIO
Bermond, F.;
Bert, J.; Ayats,
J.
1966
Comptes Rendus Des
Seances De La Societe De
Biologie Et De Ses Filiales
Exclusion reason: not
available in English
Effect of certain
psychopharmacologic substances
on S35-methionine cytoplasm
incorporation (cyrillic)
Petkov V.;
Shoumkov G.;
Koushev V.
1966
Savremenna Medicina
Exclusion reason: No
behaviour measured
EFFECTS OF CHLORPROMAZINE
AND PSILOCIN ON PREGNANCY OF
C57BL/10 MICE AND THEIR
OFFSPRING AT BIRTH
ROLSTEN, C
1967
ANATOMICAL RECORD
Exclusion reason:
Unavailable within
timeframe of study
EFFECTS OF MESCALINE AND
PSILOCYBIN ON DOMINANCE
BEHAVIOR OF RAT
UYENO, ET
1967
ARCHIVES INTERNATIONALES
DE PHARMACODYNAMIE ET
DE THERAPIE
Exclusion reason:
Unavailable within
timeframe of study;

386
EFFECT OF PSILOCYBIN ON EYE
MOVEMENTS AND ON
ELECTRORETINOGRAM IN A
CERCOPITHECINAE PAPIO PAPIO
BERMOND, F;
BERT, J; AYATS,
H
1967
COMPTES RENDUS DES
SEANCES DE LA SOCIETE DE
BIOLOGIE ET DE SES FILIALES
Exclusion reason: not
available in English
EFFECTS OF CHLORPROMAZINE
AND PSILOCIN ON PREGNANCY OF
C57BL/10 MICE AND THEIR
OFFSPRING AT BIRTH
Rolsten, C.
1967
Anatomical Record
Exclusion reason: No
behaviour measured
Hallucinogens and dominance
behavior of the rat.
Uyeno, E T
1967
Proceedings of the Western
Pharmacology Society
Exclusion reason: not
original research
A possible correlation between
drug-induced hallucinations in man
and a behavioural response in
mice.
Corne, S J;
Pickering, R W
1967
Psychopharmacologia
Exclusion reason:
Competitive
Inhibitory effects of lysergic acid
derivatives and reserpine on 5-HT
binding to nerve ending particles.
Marchbanks, R
M
1967
Biochemical pharmacology
Exclusion reason: No
behaviour measured
EFFECT OF MONO AMINO OXIDASE
INHIBITORS ON EXPERIMENTAL
PSYCHOSES FOLLOWING THE
ADMINISTRATION OF PSILOCYBIN
Vojtechovsky,
M.; Hort, V.;
Safratove, V.
1968
Activitas Nervosa Superior
Exclusion reason: Could
not be found after ILLs

387
TRYPTAMINE RECEPTORS IN DOG
SPINAL CORD AND THEIR
RELATIONSHIP TO THE AGONISTIC
ACTIONS OF LYSERGIC-ACID DI
ETHYLAMIDE LIKE PSYCHOTOGENS
Martin, W. R.;
Eades, C. G.
1968
Pharmacologist
Exclusion reason: No
behaviour measured
DIFFERENTIATION OF INST
ELECTRO ENCEPHALOGRAM
DEACTIVATION NICOTINE CENT
STIM LYSERGIC-ACID DI
ETHYLAMIDE CENT STIM
PSILOCYBIN CENT STIM RABBIT
Kakolewski, J.
W.
1968
Physiology and Behavior
Exclusion reason: No
behaviour measured
Interactions of norepinephrine
with subcellular fractions of rat
brain. L characteristics of
norepinephrine uptake
Herblin W.F.;
O'Brien R.D.
1968
Brain Research
Exclusion reason: No
behaviour measured
Autoradiographic studies on the
distribution of psychoactive drugs
in the rat brain: III. 14C psilocin.
Hopf, A;
Eckert, H
1969
Psychopharmacologia
Exclusion reason: No
behaviour measured
EFFECTS OF PSILOCYBIN,
DIMETHYLTRYPTAMINE AND
VARIOUS LYSERGIC ACID
DERIVATIVES ON PHOTICALLY-
INDUCED EPILEPSY IN BABOON
(PAPIO-PAPIO)
MELDRUM, BS;
NAQUET, R
1970
BRITISH JOURNAL OF
PHARMACOLOGY
Exclusion reason:
duplicate

388
EFFECT OF LSD-25 AND PSILOCYBIN
ON NOREPINEPHRINE AND 3H-
NOREPINEPHRINE METABOLITES IN
RAT BRAIN
GOLDSTEI.ML;
LOVELL, RA;
BOGGAN, WO
1970
FEDERATION PROCEEDINGS
Exclusion reason:
Unavailable within
timeframe of study
ACTION OF SOME NEURO DRUGS
AND PSYCHO PHARMACA DRUGS
ON MEMBRANE ATPASE AND
ACETYL CHOLIN ESTERASE OF
CORTICAL SYNAPTOSOMES
Waser, P. G.;
Schaub, E.
1970
Heilbronn, Edith and Anders
Winter
Exclusion reason: No
behaviour measured
EFFECTS OF PSILOCYBIN,
DIMETHYLTRYPTAMINE AND
VARIOUS LYSERGIC ACID
DERIVATIVES ON PHOTICALLY-
INDUCED EPILEPSY IN BABOON
(PAPIO-PAPIO)
Meldrum, B. S.;
Naquet, R.
1970
British Journal of
Pharmacology
Exclusion reason:
duplicate
The action of tryptamine on the
dog spinal cord and its relationship
to the agonistic actions of LSD-like
psychotogens.
Martin, W R;
Eades, C G
1970
Psychopharmacologia
Exclusion reason:
Competitive;
EFFECT OF LSD-25 AND PSILOCYBIN
ON NOREPINEPHRINE AND 3H-
NOREPINEPHRINE METABOLITES IN
RAT BRAIN
Goldstei.Ml,;
Lovell, R. A.;
Boggan, W. O.
1970
Federation Proceedings
Exclusion reason: No
behaviour measured
EFFECTS OF HALLUCINOGENS ON
RAT BRAIN MONO AMINE OXIDASE
ACTIVITY
Collins, B. J.;
Lovell, R. A.;
Boggan, W. O.;
1970
Pharmacologist
Exclusion reason: No
behaviour measured

389
Freedman, D.
X.
PSYCHOTOMIMETIC DRUGS AND
BRAIN 5 HYDROXY TRYPTAMINE
METABOLISM
Freedman, D.
X.; Gottlieb, R.;
Lovell, R. A.
1970
Biochemical Pharmacology
Exclusion reason: No
behaviour measured
EFFECTS OF PSILOCYBIN,
DIMETHYLTRYPTAMINE,
MESCALINE AND VARIOUS
LYSERGIC ACID DERIVATIVES ON
EEG AND ON PHOTICALLY
INDUCED EPILEPSY IN BABOON
(PAPIO-PAPIO)
MELDRUM, BS;
NAQUET, R
1971
ELECTROENCEPHALOGRAPHY
AND CLINICAL
NEUROPHYSIOLOGY
Exclusion reason:
duplicate
THE ACTION OF SOME NEURO
PHARMACOLOGICAL AND PSYCHO
PHARMACOLOGICAL AGENTS ON
THE MEMBRANE ATPASE OF
CORTICAL SYNAPTOSOMES
Waser, P. G.;
Schaub, E.
1971
Clementi, F. And B. Ceccarelli
Exclusion reason: No
behaviour measured
EFFECT OF PSYCHOTOMIMETIC
DRUGS ON THE CYCLIC 3 5 AMP
SYSTEM OF RAT BRAIN
Uzunov, P.;
Weiss, B.
1971
Pharmacologist
Exclusion reason: No
behaviour measured
Effects of psilocybin,
dimethytaryptamine, mescaline
and various lysergic acid derivates
on the eeg and on photically
induced epilepsy in the baboon
(papio papio)
Meldrum B.S.;
Naquet R.
1971
Exclusion reason:
duplicate

390
Stimulation of [14C]serotonin
synthesis from [ 14C]tryptophan by
mescaline in rat pineal organ
cultures
Shein H.M.;
Wilson S.; Larin
F.; Wurtman
R.J.
1971
Life Sciences
Exclusion reason:
duplicate
Effects of psychoactive agents on
the conditioning of the
microcirculation in the rat.
Kato, L; Gozsy,
B; Ban, T A;
Sterlin, C
1971
Conditional reflex
Exclusion reason: No
behaviour measured
Hallucinogenic drugs of the
indolealkylamine type and central
monoamine neurons.
Anden, N E;
Corrodi, H;
Fuxe, K
1971
The Journal of pharmacology
and experimental
therapeutics
Exclusion reason: No
non-drug control
Stimulation of 14clerotonin
synthesis from 14chryptophan by
mescaline in rat pineal organ
cultures
Shein H.M.;
Wilson S.; Larin
F.; Wurtman
R.J.
1971
Life Sciences
Exclusion reason: No
behaviour measured
EFFECTS OF SEROTONIN 5
HYDROXY TRYPTAMINE AND SOME
RELATED INDOLE COMPOUNDS IN
A MAMMALIAN SYMPATHETIC
GANGLION
Haefely, W.
1972
Experientia (Basel)
Exclusion reason: No
behaviour measured
THE EFFECTS OF VARIOUS ERGOT
DERIVATIVES ON THE ELECTRO
ENCEPHALOGRAM AND PHOTO
SENSITIVITY IN PAPIO-PAPIO
Balzano, E.;
Meldrum, B. S.;
Naquet, R.;
Vuillon-
Cacciuttolo, G.
1972
Electroencephalography and
Clinical Neurophysiology
Exclusion reason: No
psilocybin/psilocin

391
EFFECTS OF LSD, PSILOCYBIN,
HARMALINE AND AMPHETAMINE
ON BODY-TEMPERATURE OF PARA-
CHLOROPHENYLALANINE
PRETREATED RATS
LADEFOGED, O
1973
ARCHIVES INTERNATIONALES
DE PHARMACODYNAMIE ET
DE THERAPIE
Exclusion reason:
Unavailable within
timeframe of study
EFFECTS OF AMPHETAMINE (A),
LSD, PSILOCYBIN (P), AND DOM ON
SCHEDULE-CONTROLLED
BEHAVIOR IN RAT
MARQUIS, WJ;
TILSON, HA;
RECH, RH
1973
FEDERATION PROCEEDINGS
Exclusion reason:
Unavailable within
timeframe of study;;
The effects of d-amphetamine, 2,5-
dimethoxy-4-methyl-amphetamine
(DOM), and psilocybin on fixed-
interval responding in the rat.
Tilson, Hugh A;
Marquis,
William J;
Rech, R. H
1973
Proceedings of the Annual
Convention of the American
Psychological Association
Exclusion reason: Could
not be found after ILLs
The effects of LSD, psilocybin,
harmaline and amphetamine on
the body temperature of para-
chlorophenylalanine pretreated
rats.
Ladefoged, O
1973
Archives internationales de
pharmacodynamie et de
therapie
Exclusion reason: No
behaviour measured
EFFECT OF LSD, PSILOCYBIN,
HARMALINE AND AMPHETAMINE
ON BODY-TEMPERATURE OF PARA-
CHLOROPHENYLALANINE
PRETREATED RABBITS
LADEFOGED, O
1974
ARCHIVES INTERNATIONALES
DE PHARMACODYNAMIE ET
DE THERAPIE
Exclusion reason:
duplicate
EFFECTS OF PSILOCYBIN ON EEG
AND BEHAVIOR IN MONKEYS
HORIBE, M
1974
ACTIVITAS NERVOSA
SUPERIOR
Exclusion reason:
Unavailable within
timeframe of study

392
EFFECTS OF LSD MESCALINE AND
PSILOCYBIN ON SYMPATHETIC
PREGANGLIONIC NEURONS
McCloskey, K.
L.; Franz, D. N.
1974
Pharmacologist
Exclusion reason: No
behaviour measured
DIFFERENT EFFECTS OF PSILOCYBIN
ON THE ELECTRO
ENCEPHALOGRAM OF VARIOUS
TYPES OF EPILEPSY
Kolarik, J.
1974
Electroencephalography and
Clinical Neurophysiology
Exclusion reason: No
behaviour measured
Distribution patterns of -sup-1-sup-
4-psilocybin in the brains of various
animals.
Hopf, A;
Eckert, H
1974
Activitas Nervosa Superior
Exclusion reason: No
behaviour measured
A comparison of psychotomimetic
drug effects on rat brain
norepinephrine metabolism.
Stolk, J M;
Barchas, J D;
Goldstein, M;
Boggan, W;
Freedman, D X
1974
The Journal of pharmacology
and experimental
therapeutics
Exclusion reason: No
behaviour measured
The possible role of tryptamine in
brain function and its relationship
to the actions of LSD-like
hallucinogens.
Martin, W R;
Sloan, J W
1974
The Mount Sinai journal of
medicine, New York
Exclusion reason: No
psilocybin/psilocin
The effect of LSD, psilocybin,
harmaline and amphetamine on
the body temperature of para-
chlorophenylalanine pretreated
rabbits.
Ladefoged, O
1974
Archives internationales de
pharmacodynamie et de
therapie
Exclusion reason: No
behaviour measured

393
CORTICAL AND OR SUBCORTICAL
EFFECTS AS A FUNCTION OF
HALLUCINOGENIC DRUG
STRUCTURE
Goldman, H.;
Fischer, R.
1974
Pharmacologist
Exclusion reason: No
psilocybin/psilocin;
The effects of 5-hydroxytryptamine
and some related compounds on
the cat superior cervical ganglion in
situ.
Haefely, W
1974
Naunyn-Schmiedeberg's
archives of pharmacology
Exclusion reason: No
behaviour measured
Comparison of the discriminative
stimulus properties of delta9-THC
and psilocybin in rats.
Greenberg, I;
Kuhn, D;
Appel, J B
1975
Pharmacology, biochemistry,
and behavior
Exclusion reason: Drug
discrimination
The dopamine receptor:
differential binding of d LSD and
related agents to agonist and
antagonist states
Creese I.; Burt
D.R.; Snyder
S.H.
1975
Life Sciences
Exclusion reason: No
behaviour measured
Serotonin sensitive adenylate
cyclase activity in immature rat
brain
Von Hungen K.;
Roberts S.; Hill
D.F.
1975
Brain Research
Exclusion reason: No
behaviour measured
Interactions between lysergic acid
diethylamide and dopamine-
sensitive adenylate cyclase systems
in rat brain.
Hungen, K V;
Roberts, S; Hill,
D F
1975
Brain research
Exclusion reason: No
behaviour measured
Hallucinogenic indoleamines:
Preferential action upon
presynaptic serotonin receptors.
Aghajanian, G
K; Hailgler, H J
1975
Psychopharmacology
communications
Exclusion reason: No
behaviour measured
DISCRIMINATIVE RESPONSE
CONTROL BY PSYCHO MOTOR
STIMULANTS
Silverman, P.
B.; Ho, B. T.
1976
Psychopharmacology
Communications
Exclusion reason: Drug
discrimination

394
THE BABOON PAPIO-PAPIO
HUMAN EPILEPSY MODEL
PHARMACOLOGICAL ASPECTS
Balzamo, E.
1976
Stal
Exclusion reason: Could
not be found after ILLs
DRUGS AND PONTO GENICULO
OCCIPITAL WAVES IN THE LATERAL
GENICULATE BODY OF THE
CURARIZED CAT PART 2 PONTO
GENICULO OCCIPITAL WAVE
ACTIVITY AND BRAIN 5 HYDROXY
TRYPTAMINE
Ruch-
Monachon, M.
A.; Jalfre, M.;
Haefely, W.
1976
Archives Internationales De
Pharmacodynamie Et De
Therapie
Exclusion reason: No
behaviour measured
Binding interactions of lysergic acid
diethylamide and related agents
with dopamine receptors in the
brain
Burt D.R.;
Creese I.;
Snyder S.H.
1976
Molecular Pharmacology
Exclusion reason: No
behaviour measured
PSILOCYBIN - BIPHASIC DOSE-
RESPONSE EFFECTS ON ACOUSTIC
STARTLE REFLEX IN RAT
DAVIS, M;
WALTERS, JK
1977
PHARMACOLOGY
BIOCHEMISTRY AND
BEHAVIOR
Exclusion reason:
duplicate
Effect of indole hallucinogens,
mescaline and DMPEA on rat
plasma prolactin
Meltzer H.Y.;
Fessler R.G.;
Simonovic M.;
Fang V.S.
1977
Federation Proceedings
Exclusion reason: No
behaviour measured
EFFECTS OF MESCALINE AND
PSILOCIN ON ACQUISITION,
CONSOLIDATION, AND
PERFORMANCE OF LIGHT-DARK
DISCRIMINATION IN 2 INBRED
STRAINS OF MICE
CASTELLANO, C
1978
PSYCHOPHARMACOLOGY
Exclusion reason:
duplicate
;

395
LSD-LIKE HALLUCINOGENS IN DOG
- VALIDATION STUDIES WITH
MESCALINE (MES), PSILOCIN (PSI)
AND DIMETHYLTRYPTAMINE
(DMT)
VAUPEL, DB;
MARTIN, WR
1978
FEDERATION PROCEEDINGS
Exclusion reason: Drug
discrimination
LSD-like hallucinogens in the dog:
validation studies with mescaline
(MES), psilocin (PSI) and
dimethyltryptamine (DMT)
Vaupel D.B.;
Martin W.R.
1978
Federation Proceedings
Exclusion reason: not
original research
STIMULUS PROPERTIES OF
COMMONALITY WITH OTHER
HALLUCINOGENS 2 5 DI METHOXY-
4-METHYL AMPHETAMINE
Silverman, P.
B.; Ho, B. T.
1978
Psychopharmacology
Exclusion reason: Could
not be found after ILLs
EFFECTS OF PSYCHO DYSLEPTICS
ON AGGRESSIVE BEHAVIOR OF
ANIMALS
Uyeno, E. T.
1978
Valzelli, Luigi
Exclusion reason: not
original research
Defining the histamine H2-receptor
in brain: the interaction with LSD.
Green, J P;
Weinstein, H;
Maayani, S
1978
NIDA research monograph
Exclusion reason: No
behaviour measured
LSD and related drugs as DA
antagonists: Receptor-mediated
effects on the synthesis and
turnover of DA.
Persson, Sven-
Ake
1978
Life Sciences
Exclusion reason: No
behaviour measured
LSD AND RELATED DRUGS AS
DOPAMINE ANTAGONISTS
RECEPTOR MEDIATED EFFECTS ON
THE SYNTHESIS AND TURNOVER OF
DOPAMINE
Persson, S. A.
1978
Life Sciences
Exclusion reason: No
behaviour measured

396
HIGH AFFINITY TRITIATED
SEROTONIN BINDING TO CAUDATE
INHIBITION BY HALLUCINOGENS
AND SEROTONINERGIC DRUGS
Whitaker, P.
M.; Seeman, P.
1978
Psychopharmacology
Exclusion reason: No
behaviour measured
Selective labeling of serotonin
receptors by d-[3H]lysergic acid
diethylamide in calf caudate
Whitaker P.M.;
Seeman P.
1978
Proceedings of the National
Academy of Sciences of the
United States of America
Exclusion reason: No
behaviour measured
Stimulation of rat prolactin
secretion by indolealkylamine
hallucinogens.
Meltzer, H Y;
Fessler, R G;
Simonovic, M;
Fang, V S
1978
Psychopharmacology
Exclusion reason: No
behaviour measured
Stimulation of adenylate cyclase
activity in monkey anterior limbic
cortex by serotonin
Ahn H.S.;
Makman M.H.
1978
Brain Research
Exclusion reason: No
behaviour measured
INHIBITION OF FOOD-INTAKE IN
THE DOG BY LSD, MESCALINE,
PSILOCIN, D-AMPHETAMINE AND
PHENYLISOPROPYLAMINE
DERIVATIVES
VAUPEL, DB;
NOZAKI, M;
MARTIN, WR;
BRIGHT, LD;
MORTON, EC
1979
LIFE SCIENCES
Exclusion reason:
duplicate
COMPARISONS OF THE EFFECTS OF
MESCAL BEAN ALKALOIDS WITH
MESCALINE, N,N-
DIMETHYLTRYPTAMINE (DMT),
PSILOCYBIN, AMPHETAMINE,
DELTA-9-
TETRAHYDROCANNABINOL (THC),
AND PENTOBARBITAL IN RATS
BOURN, WM;
KELLER, WJ;
BONFIGLIO, JF
1979
FEDERATION PROCEEDINGS
Exclusion reason:
Unavailable within
timeframe of study

397
PSILOCYBIN NEURO-PSYCHO-
PHARMACOLOGY IN RABBITS
GUEST, J;
CONSROE, P
1979
RESEARCH
COMMUNICATIONS IN
PSYCHOLOGY PSYCHIATRY
AND BEHAVIOR
Exclusion reason:
Unavailable within
timeframe of study
COMPARISONS OF THE EFFECTS OF
MESCAL BEAN ALKALOIDS WITH
MESCALINE, N,N-
DIMETHYLTRYPTAMINE (DMT),
PSILOCYBIN, AMPHETAMINE,
DELTA-9-
TETRAHYDROCANNABINOL (THC),
AND PENTOBARBITAL IN RATS
Bourn, W. M.;
Keller, W. J.;
Bonfiglio, J. F.
1979
Federation Proceedings
Exclusion reason: not
original research
EXPERIENCE OF INDUCED VISUAL
HALLUCINATIONS DEPENDS ON
PRE TREATMENT ELECTRO
ENCEPHALOGRAM SPECTRA
Koukkou, M.;
Lehmann, D.
1979
Neuroscience Letters
Exclusion reason: No
mammals
HALLUCINOGENS ANTAGONIZE
HISTAMINE H-1 RECEPTORS OF
CULTURED MOUSE NEURO
BLASTOMA CELLS
Fredrickson, P.
A.; Richelson,
E.
1979
European Journal of
Pharmacology
Exclusion reason: No
behaviour measured
Shape change of blood platelets: A
model for cerebral 5-
hydroxytryptamine receptors?
Graf M.;
Pletscher A.
1979
British Journal of
Pharmacology
Exclusion reason: No
behaviour measured
INCREASE OF CYCLIC GMP IN
BLOOD PLATELETS BY BIOGENIC
AMINES A RECEPTOR MEDIATED
EFFECT
Laubscher, A.;
Pletscher, A.
1980
Journal of Pharmacy and
Pharmacology
Exclusion reason: No
behaviour measured

398
Pharmacological characteristics of
tetrahydrocannabinol seizure
susceptible rabbits
Consroe P.;
Fish B.S.
1980
Federation Proceedings
Exclusion reason: Could
not be found after ILLs
Hallucinogenic agents as
discriminative stimuli: A
correlation with serotonin receptor
affinities
Glennon R.A.;
Young R.;
Rosecrans J.A.;
Kallman M.J.
1980
Psychopharmacology
Exclusion reason: Drug
discrimination
Serotonin receptors in
hippocampus and frontal cortex
Seeman P.;
Westman K.;
Coscina D.;
Warsh J.J.
1980
European Journal of
Pharmacology
Exclusion reason: No
behaviour measured
Hallucinogens potentiate
responses to serotonin and
norepinephrine in the facial motor
nucleus.
McCall, R B;
Aghajanian, G
K
1980
Life sciences
Exclusion reason: No
behaviour measured
ELECTRO ENCEPHALOGRAPHIC
EFFECTS OF HALLUCINOGENS AND
CANNABINOIDS USING SLEEP
WAKING BEHAVIOR AS A BASELINE
Fairchild, M.
D.; Jenden, D.
J.; Mickey, M.
R.; Yale, C.
1980
Pharmacology Biochemistry
and Behavior
Exclusion reason: No
behaviour measured
5 HYDROXY TRYPTAMINE
DEPENDENT MYO CLONUS IN
GUINEA-PIGS IS INDUCED BY 5
HYDROXY TRYPTAMINE AGONISTS
CONTAINING AN INDOLE NUCLEUS
BUT NOT BY THOSE POSSESSING A
PIPERAZINE MOIETY
Luscombe, G.;
Jenner, P.;
Marsden, C. D.
1981
Neuroscience Letters
Exclusion reason: not
original research

399
5HT dependent myoclonus in
guinea pigs is induced by 5HT
agonists containing an indole
nucleus, but not by those
possessing a piperazine moiety
Luscombe G.;
Jenner P.;
Marsden C.D.
1981
Neuroscience Letters
Exclusion reason: not
original research
Structure-activity relationships
among hallucinogenic tryptamine
derivatives evaluated by schedule-
controlled behaviour
Adron Harris
R.; Homfeld E.;
Campaigne E.
1981
Journal of Pharmacy and
Pharmacology
Exclusion reason:
duplicate
Psilocybin as a discriminative
stimulus: lack of specificity in an
animal behavior model for
'hallucinogens'.
Koerner, J;
Appel, J B
1982
Psychopharmacology
Exclusion reason: Drug
discrimination
Depolarizing responses recorded
from nodose ganglion cells of the
rabbit evoked by 5-
hydroxytryptamine and other
substances
Wallis D.I.;
Stansfeld C.E.;
Nash H.L.
1982
Neuropharmacology
Exclusion reason: No
behaviour measured
Nerve terminal effects of
indoleamine psychotomimetics on
5-hydroxytryptamine.
Halaris, A E
1982
Neuroscience and
biobehavioral reviews
Exclusion reason: No
behaviour measured
DOSE DEPENDENT BEHAVIORAL-
CHANGES INDUCED BY PSILOCYBIN
IN SELECTED MEMBERS OF A
PRIMATE SOCIAL COLONY
SINK, CA;
BELUHAN, LJ;
SCHLEMMER,
RF; HEINZE,
WJ; DAVIS, JM
1983
FEDERATION PROCEEDINGS
Exclusion reason:
Unavailable within
timeframe of study

400
DIFFERENTIAL EFFECTS OF
INDOLEAMINE HALLUCINOGENS
ON SEROTONIN CONTAINING
NEURONS IN THE NUCLEUS
CENTRALIS SUPERIOR AND
NUCLEUS RAPHE PALLIDUS IN
FREELY MOVING CATS
Trulson, V. M.;
Trulson, M. E.
1983
Federation Proceedings
Exclusion reason: No
behaviour measured
INTERACTION OF 5 HYDROXY
TRYPTAMINE AGONISTS WITH
GUINEA-PIG BRAIN STEM 5
HYDROXY TRYPTAMINE
RECEPTORS AND THE INDUCTION
OF MYO CLONUS
Jenner, P.;
Luscombe, G.;
Marsden, C. D.
1983
British Journal of
Pharmacology
Exclusion reason: No
behaviour measured
Inhibition of synaptosomal
neurotransmitter uptake by
hallucinogens
Whipple M.R.;
Reinecke M.G.;
Gage F.H.
1983
Journal of Neurochemistry
Exclusion reason: No
behaviour measured
Correlation of [3H]5-
hydroxytryptamine (5HT) binding
to brain stem preparations and the
production and prevention of
myoclonus in guinea pig by 5HT
agonists and antagonists
Luscombe G.;
Jenner P.;
Marsden C.D.
1984
European Journal of
Pharmacology
Exclusion reason: No
behaviour measured
Pharmacological characterization
of solubilized 5-HT1 serotonin
binding sites from bovine brain
Allgren R.L.;
Kyncl M.M.A.;
Ciaranello R.D.
1985
Brain Research
Exclusion reason: No
behaviour measured

401
RELATIONSHIP OF CENTRAL
NERVOUS SYSTEM
TRYPTAMINERGIC PROCESSES AND
THE ACTION OF LSD-LIKE
HALLUCINOGENS
Martin, W. R.;
Sloan, J. W.
1986
Pharmacology Biochemistry
and Behavior
Exclusion reason: not
original research
Relationship of CNS tryptaminergic
processes and the action of LSD-
like hallucinogens.
Martin, W R;
Sloan, J W
1986
Pharmacology, biochemistry,
and behavior
Exclusion reason: No
non-drug control
Differences in the stimulus
properties of 3,4-
methylenedioxyamphetamine and
3,4-
methylenedioxymethamphetamine
in animals trained to discriminate
hallucinogens from saline.
Callahan, P M;
Appel, J B
1988
The Journal of pharmacology
and experimental
therapeutics
Exclusion reason: No
non-drug control
DIFFERENTIAL INTERACTIONS OF
INDOLEALKYLAMINES WITH 5
HYDROXYTRYPTAMINE RECEPTOR
SUBTYPES
McKenna, D. J.;
Repke, D. B.;
Lo, L.;
Peroutka, S. J.
1990
Neuropharmacology
Exclusion reason: No
behaviour measured
Lysergic acid diethylamide (LSD)
administration selectively
downregulates serotonin2
receptors in rat brain.
Buckholtz, N S;
Zhou, D F;
Freedman, D X;
Potter, W Z
1990
Neuropsychopharmacology :
official publication of the
American College of
Neuropsychopharmacology
Exclusion reason: No
behaviour measured
Effect of ring fluorination on the
pharmacology of hallucinogenic
tryptamines.
Blair, J B;
Kurrasch-
Orbaugh, D;
Marona-
2000
Journal of medicinal
chemistry
Exclusion reason: No
psilocybin/psilocin

402
Lewicka, D;
Cumbay, M G;
Watts, V J;
Barker, E L;
Nichols, D E
The effect of Psilocybe cubensis
extract on hippocampal neurons in
vitro.
Moldavan, M
G;
Grodzinskaya,
A A; Solomko,
E F; Lomberh,
M L; Wasser, S
P; Storozhuk, V
M
2001
Fiziolohichnyi zhurnal (Kiev,
Ukraine : 1994)
Exclusion reason: No
behaviour measured
5-HT2A receptor-stimulated
phosphoinositide hydrolysis in the
stimulus effects of hallucinogens.
Rabin, Richard
A; Regina,
Meredith;
Doat, Mireille;
Winter, J C
2002
Pharmacology, biochemistry,
and behavior
Exclusion reason: No
behaviour measured
The indoleamine hallucinogens,
psilocin and 5MeODMT, increase
prepulse inhibition in mice: role of
5 - HT1A and 5 - HT2A receptors
Powell, S. B.;
Risbrough, V.
B.; Lehmann-
Masten, V. D.;
Krebs-
Thomson, K.;
Hen, R.;
Gingrich, J. A.;
Geyer, M. A.
2003
Society for Neuroscience
Abstract Viewer and Itinerary
Planner
Exclusion reason: Could
not be found after ILLs

403
Cognitive and psychopathological
aspects of the 5-HT2A model of
experimental psychosis
Hasler, F.;
Dobricki, M.;
Grimber, U.;
Vollenweider,
F. X.
2003
Journal of
Psychopharmacology
Exclusion reason: Human
trial
Serotonin 5-hydroxytryptamine2A
receptor-coupled phospholipase C
and phospholipase A2 signaling
pathways have different receptor
reserves
Kurrasch-
Orbaugh D.M.;
Watts V.J.;
Barker E.L.;
Nichols D.E.
2003
Journal of Pharmacology and
Experimental Therapeutics
Exclusion reason: No
behaviour measured
The influence of psilocin and
phenylethylamine on the energy
metabolism in the rat heart
Machoy-
Mokrzynska A.;
Safranow K.;
Borowiak K.S.;
Majdanik S.;
Dziedziejko V.;
Bialecka M.;
Chlubek D.
2003
Acta Toxicologica
Exclusion reason: No
behaviour measured
Transient reinforcing effects of
phenylisopropylamine and
indolealkylamine hallucinogens in
rhesus monkeys.
Fantegrossi, W
E; Woods, J H;
Winger, G
2004
Behavioural pharmacology
Exclusion reason: Drug
discrimination;
Effects of systemic psilocin on
serotonin release in rat brain
Katagiri, N.;
Abe, K.;
Yamaguchi, M.;
Saitoh, T.;
Horiguchi, Y.;
Utsunomiya, I.;
2006
Journal of Pharmacological
Sciences
Exclusion reason: No
behaviour measured

404
Hoshi, K.;
Taguchi, K.
Modeling of psychotic-like
behavior: Comparison of MK-801
with psilocin, LSD, mescaline and
2C-B models. behavioral study on
prepulse inhibition of acoustic
startle and on locomotion
Palenicek, T.;
Bubenikova,
V.; Horacek, J.
2006
Schizophrenia Research
Exclusion reason: No
non-drug control
Hallucinogens recruit specific
cortical 5-HT(2A) receptor-
mediated signaling pathways to
affect behavior.
Gonzalez-
Maeso, Javier;
Weisstaub,
Noelia V; Zhou,
Mingming;
Chan, Pokman;
Ivic, Lidija; Ang,
Rosalind; Lira,
Alena; Bradley-
Moore, Maria;
Ge, Yongchao;
Zhou, Qiang;
Sealfon, Stuart
C; Gingrich, Jay
A
2007
Neuron
Exclusion reason: No
psilocybin/psilocin

405
CONCENTRATION OF SELECTED
MICROELEMENTS IN BLOOD
SERUM OF RATS EXPOSED TO THE
ACTION OF PSILOCIN AND
PHENYLETHYLAMINE
Majdanik,
Slawomir;
Borowiak,
Krzysztof;
Brzezinska,
Maria;
Machoy-
Mokrzynska,
Anna
2007
Roczniki Pomorskiej
Akademii Medycznej w
Szczecinie
Exclusion reason: No
behaviour measured
Influence of Assays Conditions to
Glucuronidation Activity in Vitro:
Psilocin Study
Manevski,
Nenad;
Kurkela, Mika;
Hoglund,
Camilla;
Mauriala,
Timo; Court,
Michael H.; Yli-
Kauhaluoma,
Jari; Finel,
Moshe
2010
Drug Metabolism Reviews
Exclusion reason: No
behaviour measured
A comparision of the effects of two
hallucinogens, psilocin and
meskaline, in quantitative EEG and
in senzorimotor information
processing in the animal model of
psychosis
2011
Psychiatrie
Exclusion reason:
Unavailable within
timeframe of study

406
A comparision of the effects of two
hallucinogens, psilocin and
meskaline, in quantitative EEG and
in senzorimotor information
processing in the animal model of
psychosis
Palenieek T.;
Fujakova M.;
Tyls F.;
Kubesova A.;
Brunovsky M.;
Horacek J.
2011
Psychiatrie
Exclusion reason: not
available in English
Quantitative EEG in animal models
of psychosis: the impact of
behaviour
Palenicek, T.;
Fujakova, M.;
Tyls, E.;
Brunovsky, M.;
Kubesova, A.;
Horacek, J.;
Krajca, V.
2011
European
Neuropsychopharmacology
Exclusion reason: No
behaviour measured
Development of a discrete trials
task to assess serotonergic
modulation of interval timing in
mice
Halberstadt
A.L.; Young
J.W.; Geyer
M.A.
2011
Neuropsychopharmacology
Exclusion reason: No
psilocybin/psilocin
Determining the pharmacokinetics
of psilocin in rat plasma using
ultra-performance liquid
chromatography coupled with a
photodiode array detector after
orally administering an extract of
Gymnopilus spectabilis.
Chen, Jianbo;
Li, Meijia; Yan,
Xitao; Wu,
Enqi; Zhu,
Hongmei; Lee,
Kwan Jun; Chu,
Van Men;
Zhan, Lifeng;
Lee, Wonjae;
Kang, Jong
Seong
2011
Journal of chromatography.
B, Analytical technologies in
the biomedical and life
sciences
Exclusion reason: No
behaviour measured

407
A comparison of
electroencephalographic activity in
serotonergic and gultamatergic
models of psychosis
Tyls F.;
Palenicek T.;
Fujakova M.;
Kubesova A.;
Brunovsky M.;
Horacek J.;
Krajca V.
2012
International Journal of
Neuropsychopharmacology
Exclusion reason: No
behaviour measured
Flavone Glycoside Antagonizes
Psilocybin-Induced Toxicity by
Reducing Oxidative Stress in Rats
Model
Huang, Hong-
yan; Huang,
Zhe; Li, Yu-bai
2012
Journal of China Medical
University
Exclusion reason: No
behaviour measured
Neurovascular and neuroimaging
effects of the hallucinogenic
serotonin receptor agonist psilocin
in the rat brain.
Spain, Aisling;
Howarth,
Clare;
Khrapitchev,
Alexandre A;
Sharp, Trevor;
Sibson, Nicola
R; Martin,
Chris
2015
Neuropharmacology
Exclusion reason: No
behaviour measured
Quantitative EEG study of
serotonergic hallucinogens in rats-
the relationship of brain activity
and behavior
Vejmola C.;
Tyls F.;
Kaderabek L.;
Lipski M.;
Palenicek T.
2016
European
Neuropsychopharmacology
Exclusion reason: No
behaviour measured
Psilocybin-induced psychosis in
humans and in rats - translational
quantitative EEG study
Tyls, F.;
Vejmola, C.;
Viktorinova,
2016
European
Neuropsychopharmacology
Exclusion reason: No
behaviour measured

408
M.; Kaderabek,
L.; Palenicek, T.
Fully Automated System to Explore
the Differential Effects of
Psychedelic and Non-Psychedelic
Serotonin 2 A (5-HT2A) Receptor
Agonists on Behavioral Tolerance
Revenga,
Mario de la
Fuente; Shah,
Urjita;
Gonzalez-
Maeso, Javier
2018
Neuropsychopharmacology
Exclusion reason: No
psilocybin/psilocin
Psilocybin modulated expression of
plasticityrelated genes and
proteins in rat prefrontal cortex
and hippocampus
Jefsen O.;
Hojgaard K.;
Elfving B.;
Wegener G.;
Muller H.K.
2018
Acta Neuropsychiatrica
Exclusion reason: No
behaviour measured
Sex differences in serotonergic and
dopaminergic mediation of LSD
discrimination in rats.
Herr, Keli A
2018
Dissertation Abstracts
International: Section B: The
Sciences and Engineering
Exclusion reason: Drug
discrimination
EEG correlates of the serotonergic
hallucinogens as a parameter of
assessing translational validity of
the serotonergic model of
psychosis in rats
Vejmola C.;
Tyls F.; Lipski
M.; Palenicek
T.
2018
Clinical EEG and
Neuroscience
Exclusion reason: No
behaviour measured
Time course of quantitative EEG
changes in an animal model of
psilocin-induced psychosis
Tyls F.;
Vejmola C.;
Piorecka V.;
Koudelka V.;
2018
Clinical EEG and
Neuroscience
Exclusion reason: No
behaviour measured

409
Novak T.;
Palenicek T.
Functional connectivity embedding
for electrophysiological models of
induced psychosis
Koudelka V.;
Tyls F.;
Vejmola C.;
Brunovsky M.;
Palenicek T.;
Horacek J.
2018
Clinical EEG and
Neuroscience
Exclusion reason: No
behaviour measured
Significant probability mapping on
animal EEG
Piorecka V.;
Tyls F.; Krajca
V.; Palenicek T.
2018
Clinical EEG and
Neuroscience
Exclusion reason: No
behaviour measured
P.228 The polypharmacological
profile of psilocybin and potential
behavioural effects of very low
doses
Kiilerich K.;
Speth N.;
Lorenz J.;
Casado-Sainz
A.; Shalgunov
V.; Lange D.;
Xiong M.;
Herth M.M.;
Overgaard A.;
Hansen H.D.;
Palner M.
2019
European
Neuropsychopharmacology
Exclusion reason:
duplicate
Psychedelics Improve the Mental
Health of Rats
Hibicke,
Meghan;
Landry, Alexus
N.; Talman,
Zoe K.; Nichols,
Charles
2019
Faseb Journal
Exclusion reason:
duplicate

410
Psilocybin-Assisted Treatment of
Major Depressive Disorder: Results
From a Randomized Trial
Griffiths,
Roland;
Barrett,
Frederick;
Darrick, May;
Johnson,
Matthew;
Mary,
Cosimano;
Patrick, Finan;
Alan, Davis
2019
Neuropsychopharmacology
Exclusion reason: Human
study
EEG correlates of the effect of
psychedelics in rat - Spectral maps
and coherence
Vejmola C.;
Tyls F.;
Kaderabek L.;
Piorecka V.;
Palenicek T.
2019
Neuropsychobiology
Exclusion reason: No
behaviour measured
The effect of psilocybin on
plasticity-related genes and
proteins in the rat brain
Jefsen, O.;
Hojgaard, K.;
Elfving, B.;
Wegener, G.;
Muller, H. K.
2019
European Psychiatry
Exclusion reason: No
behaviour measured
The MATLAB toolbox for animal 3D
brain mapping and significant
probability mapping
Piorecka V.;
Tyls F.;
Vejmola C.;
Piorecky M.;
Palenicek T.;
Krajca V.
2019
Neuropsychobiology
Exclusion reason: No
behaviour measured

411
The effect of psilocybin on EEG
activity: Comparison of recent
human findings with animal data
Palenicek T.;
Tyls F.;
Viktorinova M.;
Androvicova
R.; Brunovsky
M.; Horacek J.
2020
Clinical EEG and
Neuroscience
Exclusion reason: No
behavioural/neurological
outcome
Correlation between the potency
of hallucinogens in the mouse
head-twitch response assay and
their behavioral and subjective
effects in other species.
Halberstadt,
Adam L;
Chatha,
Muhammad;
Klein, Adam K;
Wallach, Jason;
Brandt, Simon
D
2020
Neuropharmacology
Exclusion reason: No
psilocybin/psilocin
Psilocybin and LSD have no long-
lasting effects in an animal model
of alcohol relapse.
Meinhardt,
Marcus W;
Gungor, Cansu;
Skorodumov,
Ivan; Mertens,
Lea J;
Spanagel,
Rainer
2020
Neuropsychopharmacology :
official publication of the
American College of
Neuropsychopharmacology
Exclusion reason:
Competitive
Sustained Reductions in Headache
Burden After the Limited
Administration of low Dose
Psilocybin in Migraine and Cluster
Headache: Results From Two
Preliminary Studies
Schindler,
Emmanuelle
2020
Neuropsychopharmacology
Exclusion reason: Human
study

412
What Does the Sucrose Preference
Test Tell Us About Reward
Behavior? An Analysis of Licking
Behavior in the SPT
Wulff,
Andreas;
Thompson,
Scott
2020
Neuropsychopharmacology
Exclusion reason: No
non-drug control
Automated detection of the head-
twitch response using wavelet
scalograms and a deep
convolutional neural network
Halberstadt, A.
L.
2020
Sci Rep
Exclusion reason: wrong
study design
The blue of mushrooms: Psilocybin
serves as building block for
protective oligomers
Anonymous.
2020
Deutsche Apotheker Zeitung
Exclusion reason: Could
not be found after ILLs;
Transcriptional regulation in the
rat prefrontal cortex and
hippocampus after a single
administration of psilocybin.
Jefsen, Oskar
Hougaard;
Elfving, Betina;
Wegener,
Gregers;
Muller, Heidi
Kaastrup
2020
Journal of
psychopharmacology
(Oxford, England)
Exclusion reason: No
behaviour measured
Synthesis and Biological Evaluation
of Tryptamines Found in
Hallucinogenic Mushrooms:
Norbaeocystin, Baeocystin,
Norpsilocin, and Aeruginascin.
Sherwood,
Alexander M;
Halberstadt,
Adam L; Klein,
Adam K;
McCorvy, John
D; Kaylo, Kristi
W; Kargbo,
Robert B;
Meisenheimer,
Poncho
2020
Journal of natural products
Exclusion reason: No
behaviour measured

413
Integrity and Segregation of
Macroscale Cerebral Functional
Networks Correlate With Plasma
Psilocin Level and Psychedelic
Experience
Knudsen, Gitte;
Madsen,
Martin K.;
Stenbaek, Dea
S.; Arvidsson,
Albin; Armand,
Sophia;
Marstrand-
Joergensen,
Maja;
Johansen, Sys
S.; Linnet,
Kristian;
Ozenne, Brice;
Fisher, Patrick
2020
Neuropsychopharmacology
Exclusion reason: Human
study
Examining the Acute Effect of
Psilocybin in Treatment-Resistant
Obsessive Compulsive Disorder
Kelmendi,
Benjamin;
Adams,
Thomas;
Depalmer,
Giuliana;
Kichuk,
Stephen; Forte,
Jennifer;
Grazioplene,
Rachael;
Pittenger,
Christopher
2020
Neuropsychopharmacology
Exclusion reason: Human
study

414
Chemoenzymatic Synthesis of 5-
Methylpsilocybin: A Tryptamine
with Potential Psychedelic Activity.
Fricke, Janis;
Sherwood,
Alexander M;
Halberstadt,
Adam L;
Kargbo, Robert
B; Hoffmeister,
Dirk
2021
Journal of natural products
Exclusion reason: No
psilocybin/psilocin
Structure-Activity Relationship
Analysis of Psychedelics in a Rat
Model of Asthma Reveals the Anti-
Inflammatory Pharmacophore
Flanagan,
Thomas W.;
Billac, Gerald
B.; Landry,
Alexus N.;
Sebastian,
Melaine N.;
Nichols,
Charles D.;
Cormier,
Stephania A.
2021
ACS Pharmacology and
Translational Science
Exclusion reason: No
behaviour measured
Investigating the role of 5-HT2A and
5-HT2C receptor activation in the
effects of psilocybin, DOI, and
citalopram on marble burying in
mice.
Odland, Anna
U; Kristensen,
Jesper L;
Andreasen,
Jesper T
2021
Behavioural brain research
Exclusion reason: No
non-drug control

415
Psilocybin exerts distinct effects on
resting state networks associated
with serotonin and dopamine in
mice.
Grandjean,
Joanes;
Buehlmann,
David; Buerge,
Michaela;
Sigrist, Hannes;
Seifritz, Erich;
Vollenweider,
Franz X; Pryce,
Christopher R;
Rudin, Markus
2021
NeuroImage
Exclusion reason: No
behaviour measured
Discriminative stimulus effects of
substituted tryptamines in rats
Gatch M.B.;
Hoch A.;
Carbonaro
T.M.
2021
ACS Pharmacology and
Translational Science
Exclusion reason: Drug
discrimination
Effects of a single dose of
psilocybin on behaviour, brain 5-
HT2A receptor occupancy and gene
expression in the pig.
Donovan, Lene
Lundgaard;
Johansen, Jens
Vilstrup; Ros,
Nidia
Fernandez;
Jaberi, Elham;
Linnet,
Kristian;
Johansen, Sys
Stybe; Ozenne,
Brice;
Issazadeh-
Navikas,
2021
European
neuropsychopharmacology :
the journal of the European
College of
Neuropsychopharmacology
Exclusion reason: No
behaviour measured

416
Shohreh;
Hansen, Hanne
Demant;
Knudsen, Gitte
Moos
Transcriptional regulation in the
rat prefrontal cortex and
hippocampus after a single
administration of psilocybin.
Jefsen, Oskar
Hougaard;
Elfving, Betina;
Wegener,
Gregers;
Muller, Heidi
Kaastrup
2021
Journal of
psychopharmacology
(Oxford, England)
Exclusion reason: No
behaviour measured
Preclinical screening for
antidepressant activity - shifting
focus away from the Forced Swim
Test to the use of translational
biomarkers
Sewell, Fiona;
Waterson, Ian;
Jones, David;
Tricklebank,
Mark David;
Ragan, Ian
2021
Regulatory Toxicology and
Pharmacology
Exclusion reason: No
psilocybin/psilocin
A Single Dose of Psilocybin
Increases Synaptic Density and
Decreases 5-HT2A Receptor Density
in the Pig Brain.
Raval, Nakul
Ravi; Johansen,
Annette;
Donovan, Lene
Lundgaard;
Ros, Nidia
Fernandez;
Ozenne, Brice;
2021
International journal of
molecular sciences
Exclusion reason: No
behaviour measured

417
Hansen, Hanne
Demant;
Knudsen, Gitte
Moos
List of Excluded Studies (Full-text Review): BIPA
Number
Source
Reason for exclusion post
full-text review
1.
Adey, W. R., Bell, F. R. & Dennis, B. J. Effects of LSD-25, psilocybin,
and psilocin on temporal lobe EEG patterns and learned
behavior in the cat. Neurology. 12, 591-602 (1962).
Could not be found after
ILLs (inter-library loans).
2.
Adron Harris, R., Homfeld, E. & Campaigne, E. Structure-activity
relationships among hallucinogenic tryptamine derivatives
evaluated by schedule-controlled behaviour. J. Pharm.
Pharmacol. 33, 320–322 (1981).
Duplicate
3.
Aghajanian, G. K. & Hailgler, H. J. Hallucinogenic indoleamines:
preferential action upon presynaptic serotonin receptors.
Psychopharmacol. Commun. 1, 619–629 (1975).
No behavior measured –
“new criterion”
4.
Ahn, H. S. & Makman, M. H. Stimulation of adenylate cyclase activity
in monkey anterior limbic cortex by serotonin. Brain Res. 153,
636
No behavior measured –
“new criterion”
5.
Allgren, R. L., Kyncl, M. M. A. & Ciaranello, R. D. Pharmacological
characterization of solubilized 5-HT1 serotonin binding sites
from bovine brain. Brain Res. 348, 77–85 (1985).
No behavior measured –
“new criterion”
6.
Anden, N. E., Corrodi, H. & Fuxe, K. Hallucinogenic drugs of the
indolealkylamine type and central monoamine neurons. J.
Pharmacol. Exp. Ther. 179, 236–249 (1971).
No non-drug conrol
7.
Balzamo, E. The baboon Papio papio human epilepsy model
pharmacological aspects. Stal 1, 317–323 (1976).
Could not be found after
ILLs
8.
Balzano, E., Meldrum, B. S., Naquet, R. & Vuillon-Cacciuttolo, G. The
effects of various ergot derivatives on the electro
encephalogram and photo-sensitivity in Papio papio.
Electroencephalogr. Clin. Neurophysiol. 32, 578 (1972).
No psilocybin/psilocin
9.
Bermond, F., Bert, J. & Ayats, J. Effects of psilocybine on visual
evoked potentials in a cercopithecinae Papio papio. C. R.
Seances Soc. Biol. Fil. 160, 2405–2409 (1966).
Not available in English
10.
Blair, J. B. et al. Effect of ring fluorination on the pharmacology of
hallucinogenic tryptamines. J. Med. Chem. 43, 4701–4710
(2000).
No psilocybin/psilocin
11.
Bourn, W. ., Keller, W. J. & Bonfiglio, J. F. Comparisons of the effects
of mescal bean alkaloids with mescaline, N,N-
Dimethyltryptamine (DMT), psilocybin, amphetamine, delta-
9-tetrahydrocannabinol (THC), and pentobarbital in rats. Fed.
Proc. 38, 590 (1979).
Not original research
(source study)

418
12.
Brodey, J. F., Steiner, W. G. & Himwich, H. E. An electrographic study
of psilixcin and 4-methyl-alpha-methyl-tryptamine (MP-809).
J. Pharmacol. Exp. Ther. 140, 8–18 (1963).
No behavior measured –
“new criterion”
13.
Buckholtz, N. S., Zhou, D., Freedman, D. X. & Potter, W. Z. Lysergic
acid diethylamide (LSD) administration selectively
downregulates serotonin2 receptors in rat brain.
Neuropsychopharmacology 3, 137–148 (1990).
No behavior measured –
“new criterion”
14.
Burt, D. R., Creese, I. & Snyder, S. H. Binding interactions of lysergic
acid diethylamide and related agents with dopamine
receptors in the brain. Mol. Pharmacol. 12, 631–638 (1976).
No behavior measured –
“new criterion”
15.
Callahan, P. M. & Appel, J. B. Differences in the stimulus properties of
3,4-Methylenedioxyamphetamine and 3,4-
Methylenedioxymethamphetamine in animals trained to
discriminate hallucinogens from saline. J. Pharmacol. Exp.
Ther. 246, 866–870 (1988).
No non-drug control
16.
Chen, J. et al. Determining the pharmacokinetics of psilocin in rat
plasma using ultra-performance liquid chromatography
coupled with a photodiode array detector after orally
administering an extract of Gymnopilus spectabilis. J.
Chromatogr. B Anal. Technol. Biomed. Life Sci. 879, 2669–
2672 (2011).
No behavior measured –
“new criterion”
17.
Collins, B. J., Lovell, R. A., Boggan, W. O. & Freedman, D. X. Effects of
hallucinogens on rat brain monoamine oxidase activity.
Pharmacologist 12, 256 (1970).
No behavior measured –
“new criterion”
18.
Consroe, P. & Fish, B. S. Pharmacological characteristics of
tetrahydrocannabinol seizure susceptible rabbits. Fed. Proc.
39, 3065 (1980).
Could not be found after
ILLs
19.
Corne, S. J. & Pickering, R. W. A possible correlation between drug-
induced hallucinations in man and a behavioural response in
mice. Psychopharmacologia 11, 65–78 (1967).
Competitive
20.
Creese, I., Burt, D. R. & Snyder, S. H. The dopamine receptor:
differential binding of d-LSD and related agents to agonist
and antagonist states. Life Sci. 17, 1715–1720 (1975).
No behavior measured –
“new criterion”
21.
Curtis, D. R. Psychotomimetics - a neuropharmacological study. Proc.
Aust. Assoc. Neurol. 1, 43–45 (1963).
Not original research
(source study)
22.
Fairchild, M. D., Jenden, D. J., Mickey, M. R. & Yale, C. EEG effects of
hallucinogens and cannabinoids using sleep-waking behavior
as baseline. Pharmacol. Biochem. Behav. 12, 99–105 (1980).
No behavior measured –
“new criterion”
23.
Fantegrossi, W. E., Woods, J. H. & Winger, G. Transient reinforcing
effects of phenylisopropylamine and indolealkylamine
hallucinogens in rhesus monkeys. Behav. Pharmacol. 15,
149–157 (2004).
Drug discrimination
24.
Fredrickson, P. A. & Richelson, E. Hallucinogens antagonize histamine
H-1 receptors of cultured mouse neuro blastoma cells. Eur. J.
Pharmacol. 56, 261–264 (1979).
No behavior measured –
“new criterion”
25.
Freedman, D. X., Gottlieb, R. & Lovell, R. A. Psychotomimetic drugs
and brain 5-hydroxytryptamine metabolism. Biochem.
Pharmacol. 19, 1181–1188 (1970).
No behavior measured –
“new criterion”
26.
Gessner, P. K., Khairallah, P. A., McIsaac, W. M. & Page, I. H. The
relationship between the metabolic fate and pharmacological
actions of serotonin, bufotenine and psilocybin. J. Pharmacol.
Exp. Ther. 130, 126–133 (1960).
No behavior measured –
“new criterion”

419
27.
Glennon, R. A., Young, R., Rosecrans, J. A. & Kallman, M. J.
Hallucinogenic agents as discriminative stimuli: A correlation
with serotonin receptor affinities. Psychopharmacology
(Berl). 68, 155–158 (1980).
Drug discrimination
28.
Goldman, H. & Fischer, H. Cortical and/or subcortical effects as a
function of hallucinogenic drug structure. Pharmacologist 16,
237 (1974).
No psilocybin/psilocin
29.
Goldstein, M. L., Lovell, R. A., Boggan, W. O. & Freedman, D. X. Effect
of LSD-25 and psilocybin on norepinephrine and 3H-
norepinephrine metabolites in rat brain. Fed. Proc. 29, A650
(1970).
No behavior measured –
“new criterion”
30.
González-Maeso, J. et al. Hallucinogens Recruit Specific Cortical 5-
HT2A Receptor-Mediated Signaling Pathways to Affect
Behavior. Neuron 53, 439–452 (2007).
No psilocybin/psilocin
31.
Graf, M. & Pietscher, A. Shape change of blood platelets: a model for
cerebral 5-hydroxytryptamine receptors? Br. J. Pharmacol.
65, 601–608 (1979).
No behavior measured –
“new criterion”
32.
Green, J. P., Weingartner, H. & Maayani, S. Defining the histamine
H2-receptor in brain: the interaction with LSD. NIDA Res.
Monogr. 38–59 (1978).
No behavior measured –
“new criterion”
33.
Greenberg, I., Kuhn, D. & Appel, J. B. Comparison of the
discriminative stimulus properties of clonidine and
amphetamine in rats. Pharmacol. Biochem. Behav. 3, 931–
934 (1975).
Drug discrimination
34.
Haefely, W. The effects of 5-hydroxytryptamine and some related
compounds on the cat superior cervical ganglion in situ.
Naunyn. Schmiedebergs. Arch. Pharmacol. 281, 145–165
(1974).
No behavior measured –
“new criterion”
35.
Haefely, W. Effects of serotonin (5-HT) and some related indole
compounds in a mammalian sympathetic ganglion. Exp. 27,
1112 (1972).
No behavior measured –
“new criterion”
36.
Halaris, A. E. Nerve terminal effects of indoleamine
psychotomimetics on 5-hydroxytryptamine. Neurosci.
Biobehav. Rev. 6, 483–487 (1982).
No behavior measured –
“new criterion”
37.
Halasz, M. F. & Marrazzi, A. S. Disinhibition of conditioned behavior
by cerebral synaptic inhibitors. Pharmacologist 7, 173 (1965).
No behavior measured –
“new criterion”
38.
Halberstadt, A. L., Young, J. W. & Geyer, M. A. Development of a
discrete trials task to assess serotonergic modulation of
interval timing in mice. Neuropsychopharmacology. 36,
S210–S211 (2011).
No psilocybin/psilocin
39.
Hasler, F., Dobricki, M., Grimber, U. & Vollenweider, F. X. Cognitive
and psychopathological aspects of the 5-HT2A model of
experimental psychosis. J. Psychopharmacol. 17, A44 (2003).
No mammals
40.
Herblin, W. F. & O’Brien, R. D. Interactions of norepinephrine with
subcellular fractions of rat brain I. Characteristics of
norepinephrine uptake. Brain Res. 8, 298–309 (1968).
No behavior measured –
“new criterion”
41.
Herr, K. A. Sex differences in serotonergic and dopaminergic
mediation of LSD discrimination in rats. Diss. Abstr. Int. Sect.
B Sci. Eng. 79, No-Specified (2018).
Drug discrimination
42.
Hopf, A. & Eckert, H. Distribution patterns of 14-C-psilocin in the
brains of various animals. Act. Nerve Super. 16, 64–66 (1974).
No behavior measured –
“new criterion”

420
43.
Hopf, A. & Eckert, H. Autoradiographic studies on the distribution of
psychoactive drugs in the rat brain. Psychopharmacologia 16,
201–222 (1969).
No behavior measured –
“new criterion”
44.
Horita, A. Some biochemical studies on psilocybin and psilocin. J.
Neuropsychiatry 4, 270–273 (1963).
No behavior measured –
“new criterion”
45.
Huang, H., Huange, Z. & Li, Y. Flavone glycoside antagonizes
psilocybin-induced toxicity by reducing oxidative stress in rat
models. J. China Med. Univ. 41, 48–51 (2012).
No behavior measured –
“new criterion”
46.
Hungen, K. V., Roberts, S. & Hill, D. F. Interactions between lysergic
acid diethylamide and dopamine sensitive adenylate cyclase
systems in rat brain. Brain Res. 94, 57–66 (1975).
No behavior measured –
“new criterion”
47.
Jacob, J. & Lafille, C. Pharmacological detection and characterization
of hallucinogens. I. Hyperthermizing activities in the rabbit.
Arch. Int. Pharmacodyn. Ther. 145, 528–545 (1963).
Not available in English
48.
Jacob, J., Lafille, C., Loiseau, G., Echinard-Garin, P. & Barthelemy, C.
Search for experimental equivalents of hallucinogenic
activity. Effects of hallucinogens on rectal temperature in
rabbit and on morphine effects in mouse. 7, 296–304 (1962).
Could not be found after
ILLS
49.
Jacob, J., Lafille, C., Loiseau, G., Echinard-Garin, P. & Barthelemy, C.
Research on the pharmacological characterization and
differentiation of hallucinogenic drugs (indole derivatives and
mescaline, nalorphine, central anticholinergics, and
phencyclidine). L’Encephale Rev. Psychiatr. Clin. Biol. Ther.
53, 520–535 (1964).
Not available in English
50.
Jefsen, O., Hojgaard, K., Elfving, B., Wegener, G. & Muller, H. K. The
effect of psilocybin on plasticity-related genes and proteins in
the rat brain. Eur. Psychiatry 56, S166 (2019).
No behavior measured –
“new criterion”
51.
Jefsen, O., Hojgaard, K., Elfving, B., Wegener, G. & Muller, H. K.
Psilocybin modulated expression of plasticity related genes
and proteins in rat prefrontal cortex and hippocampus. Acta
Neuropschiatrica 30, 13–14 (2018).
No behavior measured –
“new criterion”
52.
Jenner, P., Luscombe, G. & Marsden, C. D. Interaction of 5-HT
agonists with guinea-pig brain stem 5-HT receptors and the
induction of myoclonus. Br. J. Pharmacol. 80, 667P (1983).
No behavior measured –
“new criterion”
53.
Kakajima, H. & Thuillier, J. EEG effects of psychoanaleptics and
biogenic amine precursors in reserpinized rabbits. 14, 161–
168 (1966).
No behavior measured –
“new criterion”
54.
Kakolewski, J. W. Differentiation of EEG ‘deactivation’. Physiol.
Behav. 3, 503–506 (1968).
No behavior measured –
“new criterion”
55.
Kalberer, F., Kreis, W. & Rutschmann, J. The fate of psilocin in the rat.
Biochem. Pharmacol. 11, 261–269 (1962).
No behavior measured –
“new criterion”
56.
Katagiri, N. et al. Effects of systemic psilocin on serotonin release in
rat brain. J. Pharmacol. Sci. 100, 141P (2006).
No behavior measured –
“new criterion”
57.
Kato, L., Gözsy, B., Ban, T. A. & Sterlin, C. Effects of psychoactive
agents on the conditioning of the microcirculation in the rat.
Cond. Reflex 6, 67–77 (1971).
No behavior measured –
“new criterion”

421
58.
Koerner, J. & Appel, J. B. Psilocybin as a discriminative stimulus: Lack
of specificity in an animal behavior model for ‘hallucinogens’.
Psychopharmacology (Berl). 76, 130–135 (1982).
Drug discrimination
59.
Kolarik, J. Different effects of psilocybin on the
electroencephalogram of various types of epilepsy.
Electroencephalogr. Clin. Neurophysiol. 36, 80 (1974).
No behavior measured –
“new criterion”
60.
Koudelka, V. et al. Functional connectivity embedding for
electrophysiological models of induced psychosis. Clin. EEG
Neurosci. 49, NP20–NP21 (2018).
No behavior measured –
“new criterion”
61.
Koukkou, M. & Lehmann, D. Experience of induced visual
hallucinations depends on pre-treatment EEG spectra.
Neurosci. Lett. S190 (1979).
No mammals
62.
Kurrasch-Orbaugh, D., Watts, V. J., Barker, E. L. & Nichols, D. E.
Serotonin 5-hydroxytryptamine2A receptor-coupled
phospholipase C and phospholipase A2 signalling pathways
have different receptor reserves. J. Pharmacol. Exp. Ther.
304, 229–237 (2003).
No behavior measured –
“new criterion”
63.
Ladefoged, O. The effects of LSD, psilocybin, harmaline and
amphetamine on the body temperature of para
chlorophenylalanine pretreated rats. Archives Internationales
de Pharmacodynamie et de Therapie vol. 204 326–332
(1973).
No behavior measured –
“new criterion”
64.
Ladefoged, O. The effect of LSD, psilocybin, harmaline and
amphetamine on the body temperature of para-
chlorophenylalanine pretreated rabbits. Arch. Int.
Pharmacodyn. Ther. 208, 251–254 (1974).
No behavior measured –
“new criterion”
65.
Laubscher, A. & Pletscher, A. Increase of cyclic GMP in blood
platelets by biogenic amines a receptor mediated effect. J.
Pharm. Pharmacol. 32, 601–602 (1980).
No behavior measured –
“new criterion”
66.
Lewis, J. J., Ritchie, A. P. & Van Petten, G. R. The influence of
hallucinogenic drugs upon in vivo brain levels of adenine
nucleotides, phosphocreatine and inorganic phosphate in the
rat. Br. J. Pharmacol. Chemother. 25, 631–637 (1965).
No behavior measured –
“new criterion”
67.
Luscombe, G., Jenner, P. & Mardsen, C. D. 5HT dependent myoclonus
in guinea pigs is induced by 5HT agonists containing an indole
nucleus, but not by those possessing a piperazine moiety.
Neurosci. Lett. 24, S23 (1981).
No behavior measured –
“new criterion”
68.
Luscombe, G., Jenner, P. & Mardsen, C. D. 5 hydroxytryptamine
dependent myoclonus in guinea-pigs is induced by 5
hydroxytryptamine agonists containing an indole nucleus but
not by those possessing a piperazine moiety. Neurosci. Lett.
S23 (1981).
Not original research
(source study)
69.
Luscombe, G., Jenner, P. & Marsden, C. D. University Department of
Neurology, Institute of Psychiatry and King’s College Hospital
Medical School, Denmark Hill, London SE5, U.K. Eur. J.
Pharmacol. 104, 235–244 (1984).
Not original research
(source study)
70.
Machoy-Mokrzynska, A. et al. The influence of psilocin and
phenylethylamine on the energy metabolism in the rat heart.
Acta Toxicol. 11, 13–19 (2003).
No behavior measured –
“new criterion”
71.
Majdanik, S., Borowiak, K., Brzezinska, M. & Machoy-Mokrzynska, A.
Concentration of selected microelements in blood serum or
rats exposed to the action of psilocin and phenylethylamine.
Rocz. Pomor. Akad. Med. w Szczecinie 53, 153–158 (2007).
No behavior measured –
“new criterion”

422
72.
Manevski, N. et al. Influence of assays conditions to glucuronidation
activity in vitro: psilocin study. Drug Metab. Rev. 42, 64
(2010).
No behavior measured –
“new criterion”
73.
Marchbanks, R. M. Inhibitory effects of lysergic acid derivatives and
reserpine on 5-HT binding to nerve ending particles.
Biochem. Pharmacol. 16, 1971–1979 (1967).
No behavior measured –
“new criterion”
74.
Martin, W. R. & Eades, C. G. The action of tryptamine on the dog
spinal cord and its relationship to the agonistic actions of
LSD-like psychotogens. Psychopharmacologia 17, 242–257
(1970).
Competitive
75.
Martin, W. R. & Sloan, J. W. Relationship of CNS tryptaminergic
processes and the action of LSD-like hallucinogens.
Pharmacol. Biochem. Behav. 24, 393–399 (1986).
No non-drug control
76.
Martin, W. R. & Eades, C. G. Tryptamine receptors in dog spinal cord
and their relationship to the agonistic actions of lysergic-acid
diethylamide like psychotogens. Pharmacologist 10, 196
(1968).
No behavior measured –
“new criterion”
77.
Martin, W. R. & Sloan, J. W. The possible role of tryptamine in brain
function and its relationship to the actions of LSD-like
hallucinogens. Mt. Sinai J. Med. 41, 276–282 (1974).
No psilocybin/psilocin
78.
Martin, W. R. & Sloan, J. W. Relationship of central nervous system
tryptaminergic processes and the action of LSD-like
hallucinogens. Pharmacol. Biochem. Behav. 24, 393–400
(1986).
Not original research
(source study)
79.
Maxwell, G. M., Burnell, R. H. & Kneebone, G. M. The effects of
tryptamine and alpha-methyl-tryptamine on the general and
coronary haemodynamics and metabolism of the dog. Arch
Int Pharmacodyn Ther. 153, 79–86 (1965).
No behavior measured –
“new criterion”
80.
Maxwell, G. M., Kneebone, G. M. & Elliot, R. B. The effect of
psilocybin upon the systemic, pulmonary and coronary
circulation of the intact dog. Arch. Int. Pharmacodyn. Ther.
137, 108–115 (1962).
No behavior measured –
“new criterion”
81.
McCall, R. B. & Aghajanian, G. K. Hallucinogens potentiate responses
to serotonin and norepinephrine in the facial motor nucleus.
Life Sci. 26, 1149–1156 (1980).
No behavior measured –
“new criterion”
82.
McCloskey, K. L. & Franz, D. N. Effects of LSD mescaline and
psilocybin on sympathetic preganglioinic neurons.
Pharmacologist 16, 237 (1974).
No behavior measured –
“new criterion”
83.
McKenna, D. J., Repke, D. B., Lo, L. & Peroutka, S. J. Differential
interactions of indolealkylamines with 5-hydroxytryptamine
receptor subtypes. Neuropharmacology 29, 193–198 (1990).
No behavior measured –
“new criterion”
84.
Meldrum, B. S. & Naquet, R. Effects of psilocybin,
dimethyltryptamine, mescaline and various lysergic acid
derivatives on the EEG and on photically induced epilepsy in
the baboon (Papio papio). Electroencephalogr. Clin.
Neurophysiol. 31, 563–572 (1971).
Duplicate
85.
Meldrum, B. S. & Naquet, R. Effects of psilocybin,
dimethyltryptamine and various lysergic acid derivatives on
photically-induced epilepsy in baboon (Papio papio). Br. J.
Pharmacol. 40, 144–145 (1970).
Duplicate
86.
Meltzer, H. Y., Fessler, R. G., Simonovic, M. & Fang, V. S. Stimulation
of rat prolactin secretion by indolealkylamine hallucinogens.
Psychopharmacology (Berl). 56, 255–259 (1978).
No behavior measured –
“new criterion”

423
87.
Meltzer, H. Y., Fessler, R. G., Simonovic, M. & Fang, V. S. Effect of
indole hallucinogens, mesacline and DMPEA on rat plasma
protein. Fed. Proc. 36, (1977).
No behavior measured –
“new criterion”
88.
Moldavan, M. G. et al. The effect of psilocybe cubensis extract on
hippocampal neurons in vitro. Fiziol. Zh. 47, 15–23 (2001).
No behavior measured –
“new criterion”
89.
Monnier, M. The effect of the action of psilocybin on the rabbit
brain. Experentia 15, 321–323 (1959).
Not available in English
90.
Nakajima, H. & Thuillier, J. Changes in the EEG in the reserpinized
rabbit caused by psychoanaleptics and the precursors of
biogenic amines. Med Pharmacol Exp Int J Exp Med 14, 161–
168 (1966).
No behavior measured –
“new criterion”
91.
Nomura, J. Effects of stress and psychotropic drugs on rat liver
tryptophan pyrrolase. Endocrinology 76, 1190–1194 (1965).
No behavior measured –
“new criterion”
92.
Palenicek, T., Bubenikova, V. & Horacek, J. Modelling of psychotic-
like behavior: comparison of MK-801 with psilocin, LSD,
mescaline and 2C-B models.
No non-drug control
93.
Palenicek, T. et al. Quantitative EEG in animal models of psychosis:
the impact of behaviour. Eur. Neuropsychopharmacol. 21,
S317–S3
No behavior measured –
“new criterion”
94.
Palenicek, T. et al. A comparison of the effects of two hallucinogens,
psilocin and meskaline, in quantitative EEG and in
sensorimotor information
Not available in English
95.
Persson, S. A. LSD and related drugs as dopamine antagonists
receptor mediated effects on the synthesis and turnover of
dopamine. Life Sci. 23, 523–526 (1978).
No behavior measured –
“new criterion”
96.
Persson, S.-A. LSD and related drugs as DA antagonists: receptor-
mediated effects on teh synthesis and turnover of DA. Life
Sci. 23, 523–526 (1978).
No behavior measured –
“new criterion”
97.
Petkov, V., Shoumkov, G. & Koushev, V. Effect of certain
psychopharmacologic substances on S35-methionine
cytoplasm incorporation (cyrillic). Savrem. Med. 17, 461–470
(1966).
No behavior measured –
“new criterion”
98.
Piorecka, V., Tyls, F., Krajca, V. & Palenicek, T. Significant probability
mapping on animal EEG. Clin. EEG Neurosci. 49, NP22 (2018).
No behavior measured –
“new criterion”
99.
Piorecka, V. et al. The MATLAB toolbox for animal 3D brain mapping
and significant probability mapping. Neuropsychobiology 77,
149–150 (2019).
No behavior measured –
“new criterion”
100.
Powell, S. B. et al. The indoleamine hallucinogens, psilocin and
5MeODMT, increase prepulse inhibition in mice: rol eof 5-
HT1A and 5-HT2A receptors. Soc. Neurosci. Abstract No. 315.7
(2003).
Could not be found after
ILLs
101.
Rabin, R. A., Regina, M., Doat, M. & Winter, J. C. 5-HT2A receptor-
stimulated phosphoinositide hydrolysis in the stimulus
effects of hallucinogens. Pharmacol. Biochem. Behav. 72, 29–
37 (2002).
No behavior measured –
“new criterion”
102.
Rolsten, C. Effects of chlorpromazine and psilocin on pregnancy of
C57BL/10 mice and their offspring at birth. Anat. Rec. 157,
311 (1967).
No behavior measured –
“new criterion”
103.
Ruch-Monachon, M. A., Jalfre, M. & Haefely, W. Drugs and PGO
waves in the lateral geniculate body of the curarized cat. II.
PGO wave activity and brain 5-hydroxytryptamine. Arch Int
Pharmacodyn Ther 219, 269–286 (1976).
No behavior measured –
“new criterion”

424
104.
Seeman, P., Westman, K., Coscina, D. & Warsh, J. J. Serotonin
receptors in hippocampus and frontal cortex. Eur. J.
Pharmacol. 66, 179–191 (1980).
No behavior measured –
“new criterion”
105.
Shein, H. M., Wilson, S., Larin, F. & Wurtman, R. J. Stimulation of
[14C] serotonin synthesis from [14C] tryptophan by
mescaline in rat pineal organ cultures. Life Sci. 10, 273–282
(1971).
No behavior measured –
“new criterion”
106.
Shein, H. M., Wilson, S., Larin, F. & Wurtman, R. J. Stimulation of 14C
serotonin synthesis from 14C tryptophan by mescaline in rat
pineal organ cultures. Life Sci. 10, 273–282 (1971).
Duplicate
107.
Silverman, P. B. & Ho, B. T. Stimulus properties of commonality with
other hallucinogens 2,5-dimethoxy-4-methyl amphetamine.
Psychopharmacology (Berl). 58, 10 (1978).
Could not be found after
ILLs
108.
Silverman, P. B. & Ho, B. T. Discriminative response control by
psychomotor stimulants. Psychopharmacol. Commun. 2,
331–337 (1976).
Drug discrimination
109.
Spain, A. et al. Neurovascular and neuroimaging effects of the
hallucinogenic serotonin receptor agonist psilocin in the rat
brain. Neuropharmacology 99, 210–220 (2015).
No behavior measured –
“new criterion”
110.
Steiner, J. E. & Sulman, F. G. Simultaneous studies of blood sugar,
behavioural changes and EEG on wake rabbit after
administration of psilocybin. Arch. Int. Pharmacodyn. Ther.
145, 301 (1963).
Could not be found after
ILLs
111.
Stolk, J. M., Barchas, J. D., Goldstein, M., Boggan, W. & Freedman, D.
X. A comparison of psychotomimetic drug effects on rat brain
norepinephrine metabolism. J. Pharmacol. Exp. Ther. 189,
42–50 (1974).
No behavior measured –
“new criterion”
112.
Tilson, H. A., Marquis, W. J. & Rech, R. H. The effects of d-
amphetamine, 2,5-dimethoxy-4-methyl-amphetamine
(DOM), and psilocybin on fixed-interval responding in the rat.
Proc. Annu. Conv. Am. Pyschological Assoc. 1007–1008
(1973).
Could not be found after
ILLs
113.
Trulson, V. M. & Trulson, M. E. Differential effects of indoleamine
hallucinogens on serotonin containing neurons in the nucleus
centralis superior and nucleus raphe pallidus in freely moving
cats. Fed. Proc. 42, 5036 (1983).
No behavior measured –
“new criterion”
114.
Tyls, F. et al. A comparison of electroencephalographic activity in
serotonergic and glutamatergic models of psychosis. Int. J.
Neuropsychopharmacol. 15, 211 (2012).
No behavior measured –
“new criterion”
115.
Tyls, F. et al. Time course of quantitative EEG changes in an animal
model of psilocin-induced psychosis. Clin. EEG Neurosci. 49,
NP
No behavior measured –
“new criterion”
116.
Tyls, F., Vejmola, C., Viktorinova, M., Kaderabek, L. & Palenicek, T.
Psilocybin-induced psychosis in humans and in rats −
translational quantitative EEG study. Eur.
Neuropsychopharmacol. 26, S257–S258 (2016).
No behavior measured –
“new criterion”
117.
Uyeno, E. T. Inhibition of isolation-induced attack behavior of mice by
drugs. Proc. West. Pharmacol. Soc. 9, (1966).
Not original research
(source study)
118.
Uyeno, E. T. Hallucinogens and dominance behavior in the rat. Proc.
West. Pharmacol. Soc. 10, (1967).
Not original research
(source study)
119.
Uyeno, E. T. Effects of psycho dysleptics on aggressive behavior of
animals. Mod. Probl. Pharmacopsych. 13, 103–113 (1978).
Not original research
(source study)

425
120.
Uzunov, P. & Weiss, B. Effect of pyschotomimetic drugs on the cyclic
3 5 AMP system of rat brain. Pharmacologist 13, 257 (1971).
No behavior measured –
“new criterion”
121.
Vaupel, D. B. & Martin, W. R. LSD-like hallucinogens in the dog:
validation studies with mescaline (MES), psilocin (PSI) and
dimethyltryptamine (DMT). Fed. Proc. 37, (1978).
Not original research
(source study)
122.
Vejmola, C., Tylš, F., Kadeřábek, L., Lipski, M. & Páleníček, T.
Quantitative EEG study of serotonergic hallucinogens in rats
− the relationship of brain activity and behavior. Eur.
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No behavior measured –
“new criterion”
123.
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No behavior measured –
“new criterion”
124.
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No behavior measured –
“new criterion”
125.
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Could not be found after
ILLs
126.
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No behavior measured –
“new criterion”
127.
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No behavior measured –
“new criterion”
128.
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No behavior measured –
“new criterion”
129.
Waser, P. G. & Schaub, E. Action of some neuro drugs and psycho
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No behavior measured –
“new criterion”
130.
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No behavior measured –
“new criterion”
131.
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Not available in English
132.
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No behavior measured –
“new criterion”
133.
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No behavior measured –
“new criterion”
134.
Whitaker, P. M. & Seeman, P. Selective labeling of serotonin
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No behavior measured –
“new criterion”

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