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The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects

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Classic psychedelics produce altered states of consciousness that individuals often interpret as meaningful experiences. Across a number of human studies, when the participant-rated intensity of the overall drug effects are statistically controlled for, certain subjective effects predict therapeutic and other desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects. We propose that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.
Left panel shows data from a study (N = 15) of psilocybin on cigarette smoking cessation (replotted from Garcia et al. 22 ). Smoking craving data are change scores from pretreatment to the 6-month follow-up. Mystical experience data for each participant are the mean total score on the 43-item version of the Mystical Experience Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of each of 2 or 3 psilocybin sessions. The middle panel shows data from a study (N = 24) of psilocybin on depression (adapted from Davis et al. 9 ). Depression was measured with GRID-Hamilton Depression Rating Scale and expressed as change scores from pretreatment to 4 weeks after the second psilocybin session. Mystical experience data for each participant are the highest of two total scores on the 30-item Mystical Experience Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of each of two psilocybin sessions. The right panel shows data from a study of (N = 50) of individuals with a life-threatening cancer diagnosis who received either a very low dose or a moderately high dose of psilocybin (Griffiths et al. 5 ). Mystical experience data for each participant are the total score on the 30-item Mystical Experience Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of the first psilocybin session. Anxiety was measured with the Hamilton Anxiety Rating Scale and expressed as a change score from baseline to 5 weeks postsession. More details regarding these images can be found in the citations above describing the original studies.
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The Subjective Eects of Psychedelics Are Necessary for Their
Enduring Therapeutic Eects
David B. Yaden and Roland R. Griths*
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ABSTRACT: Classic psychedelics produce altered states of
consciousness that individuals often interpret as meaningful
experiences. Across a number of human studies, when the
participant-rated intensity of the overall drug eects are statistically
controlled for, certain subjective eects predict therapeutic and
other desirable outcomes. Underlying neurobiological mechanisms
are likely necessary but not sucient to confer full and enduring
benecial eects. We propose that the subjective eects of
psychedelics are necessary for their enduring benecial eects
and that these subjective eects account for the majority of their
benet.
INTRODUCTION
The classic psychedelics are a structurally diverse group of
compounds that are partial agonists at 5-HT2A serotonin
receptors and produce a unique prole of subjective eects.
1
These compounds include tryptamines such as psilocybin (the
main psychoactive constituent in psychedelic mushrooms),
N,N-dimethyltryptamine (DMT, an ingredient of the plant
admixture ayahuasca), phenethlyamines such as mescaline
(from peyote and other cacti), and the ergotamines (such as
lysergic acid diethylamide, LSD). Pharmacological blocking of
the 5-HT2A receptor blocks many subjective and other major
eects of psychedelics in humans and infrahuman animals.
2
These classic psychedelics have low toxicity and limited
abuse liability,
3
and several recent studies have investigated
their treatment potential for mood and substance use
disorders.
49
While favorable outcomes have been observed
when psychedelics are taken under supportive conditions,
questions remain regarding their mechanisms of action. Here
we argue that some subjective eects occasioned by moderate
to high doses of psychedelics in humans are necessary for their
full and enduring therapeutic and otherwise benecial
outcomes. In this article, subjective eects refer to rst-person
experience, which is empirically measured by self-report data.
Our view is neatly captured by the thought experiment (which
we elaborate on later in this piece): would psychedelics confer
their therapeutic benets if they were administrated to
someone who was under heavy sedation? We suspect the
answer is no.
Our position contrasts the idea that subjective eects of
psychedelics may be irrelevant to their therapeutic eects. The
position that subjective eects are irrelevant to therapeutic
eects is probably true of many pharmacological treatments.
Suggestive evidence supporting this position include studies in
which psychedelics have been shown to produce positive
eects in a rodent model of depression.
10
Although we cannot
completely discount the possibility of subjective drug eects in
rodents, it seems unlikely that rodents would have experiences
similar to those to which humans attribute deep personal
meaning and positive, therapeutically relevant mood and
behavioral change after taking a psychedelic. From this
perspective, the subjective experiences elicited by psychedelic
substances are merely epiphenomena of the underlying
neurobiological mechanisms which convey the benecial
eects. For example, psychedelics promote structural and
functional neural plasticity in the prefrontal cortex through 5-
HT2A receptor-mediated mechanisms,
11
or, to cite another
example of a neurobiological model that may not require
subjective experience, it is observed that the antidepressant
eects of psychedelics are associated with brain network
reorganization.
12
While these and other neurobiological
mechanisms could plausibly account for some of the
therapeutic actions of psychedelics, none rule out an essential
mediating role of subjective eects in humans.
Special Issue: Psychedelics
Received: November 12, 2020
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SUBJECTIVE EFFECTS OF PSYCHEDELICS
Naturally occurring psychedelics have been used for millennia
in some cultures in religious and healing rituals, with an
emphasis on the subjective experiences that they produce.
13
The importance of acute subjective eects in therapeutic
outcomes has been also been documented in qualitative
interview studies of patients treated with psychedelics in
contemporary settings.
14,15
There is a great deal of historical,
anecdotal, and qualitative data supporting the value of the
subjective eects of psychedelics.
The meaning and signicance attributed to psychedelic
experiences has been well established in laboratory settings.
Psilocybin administration studies have repeatedly shown that
participants frequently rate their psychedelic experiences as
among the most meaningful of their entire lives
5,6,8,1619
and
they are sometimes compared to the birth of a rst-born child
or death of a parent. Due to their salience, such experiences
may serve as narrative inection pointsin ones life that
could provide an impetus for changing ones identication with
certain patterns of thoughts, feelings, and behaviors.
Several subjective features of psychedelic experiences are
measurable through psychometric survey instruments. Building
on the foundational scholarship of William James, Walter
Stace, Walter Pahnke, and others,
20
the Mystical Experience
Questionnaire (MEQ) was developed and subsequently
revised and psychometrically validated to provide a self-report
measure of the acute eects of psilocybin.
21
This scale includes
four subscales: 1, an authoritative sense of unity or connected-
ness accompanied by feelings of reverence; 2, positively
valenced feelings such as love or peace; 3, alterations to the
sense of both time and space; and 4, diculty with putting the
experience into words. The MEQ likely taps several dierent
cognitive and aective processes that ongoing psychometric
studies are further delineating.
Scores on questionnaires assessing mystical-type experiences
arepredictiveofbenecial outcomes from psychedelics
administered in experimental contexts (Figure 1). An initial
double-blind study from Johns Hopkins showed that 61% of 36
psychedelic naı
̈
ve participants met a priori criteria for having a
completemystical experience at the end of the psilocybin
session day compared to 11% after methylphenidate.
16
Two
months after sessions, participants attributed signicantly
greater positive changes in attitudes about life and self, positive
mood, positive behaviors, and positive social eects to
experiences during the psilocybin than methylphenidate
sessions. Importantly, correlation and regression analyses
indicated a central role of the mystical experience assessed
on the session day, but not the intensity of the psilocybin
experience, in predicting the high ratings of personal meaning
assessed at 14 months.
17
For instance, r-values of 0.61 were
found between mystical experience scores immediately after
psilocybin sessions and the follow-up ratings of the personal
meaning of the experience after controlling for three dierent
measures of the intensity of the drug eect. A systematic
replication of the rst study in 18 healthy participants showed
that mystical experience on session days and positive ratings on
follow-up increased as an orderly function of psilocybin dose.
18
A further extension of this research explored the role of
psilocybin-occasioned mystical experience in combination with
meditation on enduring changes in trait measures of prosocial
attitudes and behaviors.
19
In that randomized double-blind
study, 50 participants received moderate-high doses of
psilocybin on each of two sessions while 25 received a low
placebo-like dose on both sessions. Overall, 61% of those
receiving moderate-high doses of psilocybin had complete
mystical experiences in contrast to 4% for those receiving the
low placebo-like dose with the same levels of psychological
support. Hierarchical regression analysis showed that mystical
experience (MEQ scores) on session days contributed
Figure 1. Left panel shows data from a study (N= 15) of psilocybin on cigarette smoking cessation (replotted from Garcia et al.
22
). Smoking
craving data are change scores from pretreatment to the 6-month follow-up. Mystical experience data for each participant are the mean total score
on the 43-item version of the Mystical Experience Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of
each of 2 or 3 psilocybin sessions. The middle panel shows data from a study (N= 24) of psilocybin on depression (adapted from Davis et al.
9
).
Depression was measured with GRID-Hamilton Depression Rating Scale and expressed as change scores from pretreatment to 4 weeks after the
second psilocybin session. Mystical experience data for each participant are the highest of two total scores on the 30-item Mystical Experience
Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of each of two psilocybin sessions. The right panel
shows data from a study of (N= 50) of individuals with a life-threatening cancer diagnosis who received either a very low dose or a moderately high
dose of psilocybin (Griths et al.
5
). Mystical experience data for each participant are the total score on the 30-item Mystical Experience
Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of the rst psilocybin session. Anxiety was measured
with the Hamilton Anxiety Rating Scale and expressed as a change score from baseline to 5 weeks postsession. More details regarding these images
can be found in the citations above describing the original studies.
ACS Pharmacology & Translational Science pubs.acs.org/ptsci Viewpoint
https://dx.doi.org/10.1021/acsptsci.0c00194
ACS Pharmacol. Transl. Sci. XXXX, XXX, XXXXXX
B
signicantly (improving the r-square of a model that included
only spiritual practices by 0.54) to predicting a composite
measure of positive outcomes such as positive attitudes about
life, self, mood, and behavior at 6 months.
Mystical-type experience scores on psilocybin session days
are also predictive of treatment success at long-term follow-up
in clinical studies (see Figure 1). Two double-blind crossover
studies showed that psilocybin produced substantial and
enduring decreases in symptoms of anxiety and depression
among patients with a life-threatening cancer diagnosis.
5,6
In
the rst of these studies,
5
mean percentage of maximum total
possible score on the MEQ was signicantly higher
immediately after a moderate psilocybin dose (64%) than
after a low placebo-like dose (27%). These scores after the rst
session were signicantly correlated with most of the enduring
changes in therapeutic outcome measured 5 weeks later. For
most measures, this relationship continued to be signicant
when the intensity of overall psilocybin eect was controlled
for in a partial correlation analysis, suggesting that mystical-
type experience per se has an important role apart from overall
intensity of drug eect. Furthermore, a statistical mediation
analysis suggested that mystical-type experience was a mediator
in positive therapeutic response. The results of the second of
these studies
6
were very similar, with correlation analysis
controlling for the intensity of drug eect and a mediation
analysis suggesting that mystical experience was a mediator of
therapeutic eects. Open-label pilot studies of psilocybin in the
treatment of substance dependence and depression have
reported data consistent with these ndings. In a smoking
cessation study, 9 of 15 participants (60%) had a complete
mystical experience during one or more psilocybin ses-
sion(s).
22
Results showed signicant correlations between
mean MEQ total scores assessed on session days and change
from baseline in smoking craving scores (r=0.65) and urine
cotinine (r=0.56) at the 6-month follow-up. Further, those
participants who showed stronger mystical experiences on
psilocybin sessions were more likely to be successful in
biologically assessed smoking abstinence. In a psilocybin study
in 20 patients with treatment-resistant depression, a measure
assessing oceanic boundlessness (a construct related to
mystical experience) on session days correlated with
reductions in depression and was a signicantly better
predictor than subjective measures assessing visual or auditory
alterations.
23
Finally, in a psilocybin study in 24 patients with
major depressive disorder there was a moderate correlation (r
=0.41) between peak postsession mystical experience ratings
and decreases in depression, but no such correlation with
postsession challenging experience ratings, thus again suggest-
ing some specicity to mystical-type experiences.
9
In addition to mystical-type experiences, meaningful insights
and belief changes are also frequently cited as fundamentally
important to enduring positive outcomes in anecdotal
descriptions of psychedelic treatments. For example, in a
study of successful smoking cessation after psilocybin treat-
ment, participants reported gaining vivid insights into self-
identity and reasons for smoking along with strengthened
belief that they had the ability remain abstinent.
8,15
In a
double-blind study comparing psilocybin and dextromethor-
phan, psychological or personal insight rated after sessions
increased as a function of psilocybin dose and was identied as
an important domain associated with motivation to use
psilocybin.
24
Although experiences of insight may sometimes
overlap with mystical-type experience, a statistical path analysis
of cross-sectional survey data suggests that insightful and
mystical experiences independently mediate positive therapeu-
tic outcomes on depression, anxiety, and substance use after
psychedelics.
2527
A prospective survey study that assessed
respondents before and after taking a psychedelic in a
noncontrolled, naturalistic manner showed that a measure of
emotional breakthrough,likely related to psychological
insight, predicted well-being 2 weeks later after controlling
for mystical and challenging types of experiences.
23
A recent
open label study of psilocybin in depression (N= 24) showed
a strong correlation (r= 0.60) between ratings of psychological
insight the day after the session and decreases in depression 4
weeks later.
9
PROPOSAL FOR A CRITICAL TEST OF THE
RELEVANCE OF SUBJECTIVE EFFECTS
Although preliminary, the foregoing experimental observations
make a case that some subjective eects occasioned by
moderate to high doses of psychedelics play a key role in their
enduring benecial eects. It is our contention that the only
denitive study to disprove the importance of such subjective
eects would be one in which a psychedelic was administered
to individuals who were rendered fully unconscious (e.g., via
deep anesthesia) and who subsequently reported no memory
for a psychedelic-like experience. Although we think it to be
highly unlikely, if full and lasting therapeutic ecacy remained
under these conditions, we would concede that the subjective
eects are irrelevant.
CONCLUSION
Based on the results from experimental studies of moderate to
high dose psychedelics we believe that the case for subjective
eects playing a major role in enduring benecial eects is
compelling. Across a number of studies, when the intensity of
thesubjectivepsychedeliceect is controlled, certain
subjective eects predict desirable outcomes. Underlying
neurobiological-based mechanisms are undoubtedly necessary
but likely not sucient to confer full benecial eects. In the
nonsubjective anesthesia test that we describe, we would not
be surprised to see some therapeutic eects but that they
would be of lower magnitude and/or more transient. We
suspect that the proportion of the long-term benecial
outcomes that are mediated through subjective eects is
substantial, accounting for the majority of the lasting benecial
eects of psychedelics. For an alternative perspective, please
see a companion Viewpoint in this issue.
28
AUTHOR INFORMATION
Corresponding Author
Roland R. Griths Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205, United States; Center
for Psychedelic and Consciousness Research and Department
of Neuroscience, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21224, United States;
Phone: 410-550-0034; Email: rgri@jhmi.edu
Author
David B. Yaden Department of Psychiatry and Behavioral
Sciences, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205, United States; Center for
Psychedelic and Consciousness Research, Johns Hopkins
ACS Pharmacology & Translational Science pubs.acs.org/ptsci Viewpoint
https://dx.doi.org/10.1021/acsptsci.0c00194
ACS Pharmacol. Transl. Sci. XXXX, XXX, XXXXXX
C
University School of Medicine, Baltimore, Maryland 21224,
United States; orcid.org/0000-0002-9604-6227
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsptsci.0c00194
Notes
Dr. Griths reports grants from the Riverstyx Foundation, a
crowdsourced funding campaign organized by Tim Ferris, and
National Institute on Drug Abuse (grant R01DA03889) for
research support outside of submitted the work; personal fees
from the Heter Research Institute (HRI) to cover travel costs
as member of the board of directors of HRI outside the
submitted work; and is site principal investigator for a multisite
trial of psilocybin-facilitated treatment of major depressive
disorder, which is sponsored by the Usona Institute.
The authors declare no competing nancial interest(s).
ACKNOWLEDGMENTS
We thank Chris Letheby (University of Western Australia),
Albert Garcia-Romeu (Johns Hopkins University School of
Medicine), Brian D. Earp (Yale University), Derek E.
Anderson (Boston University), and Chaz Firestone (Johns
Hopkins University) for their helpful comments and
suggestions. Support for Drs. D. Yaden and Griths through
the Johns Hopkins Center for Psychedelic and Consciousness
Research was provided by Tim Ferriss, Matt Mullenweg, Blake
Mycoskie, Craig Nerenberg, and the Steven and Alexandra
Cohen Foundation.
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... Finally, our third main hypothesis stated that the intensity of past mystical and ego-dissolution experiences caused by psychedelics will mediate the expected effects of psychedelics use on emotionality and self-consciousness. This is in line with reported evidence that the intensity of the subjective effects of psychedelics predicted long-term psychological outcomes in singledose studies (Griffiths et al., 2016;Lyvers and Meester, 2012;Yaden and Griffiths, 2021). ...
... To what extent acute subjective effects are necessary to observe lasting psychological changes induced by psychedelics is one of the key research questions in the psychedelics research field (Olson, 2021;Yaden and Griffiths, 2021). Our third main finding, namely that the effects of psychedelic experiences on emotional reactivity and self-consciousness are mediated by the reported intensity of ego-dissolution and the mystical aspects of psychedelic experiences, supports the view that subjective effects are indeed important. ...
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Background: Psychedelics are able to acutely alter emotional reactivity and self-consciousness. However, whether the regular naturalistic use of psychedelics can be linked to more persistent trait-level changes in these domains remains an open question. Aim: To test the hypotheses that (1) using psychedelics is related to higher positive and lower negative emotional reactivity; and (2) an adaptive pattern of self-consciousness, including diminished public self-consciousness and rumination, and increased reflection and self-awareness; and (3) these relations are mediated by the intensity of past ego-dissolution and mystical experiences. Method: An online survey including questions about the history of psychoactive substance use; questionnaires measuring trait levels of emotional reactivity and self-consciousness; questionnaires for retrospective assessment of ego-dissolution and mystical experiences. Data collected from 2516 participants (1661 psychedelics users) were analyzed using robust linear regression and mediation analysis. Results: A higher number of lifetime uses of psychedelics predicted greater positive and lower negative emotional reactivity; also, in the domain of self-consciousness, it predicted greater reflection and internal state awareness, and reduced rumination tendency and public self-consciousness. Finally, the intensity of past mystical and ego-dissolution experiences mediated almost all the observed relationships between the lifetime number of psychedelics uses and psychological variables. Conclusions: Lifetime psychedelics use predicts an adaptive pattern of trait-level emotional reactivity and self-consciousness. Ego-dissolution and mystical experiences are essential in understanding the long-lasting psychological effects of psychedelics use. Our findings might potentially explain previous observations of increased well-being in psychedelics users.
... On the other hand, some researchers have suggested that the subjective effects of psychedelics may be "necessary for their full and enduring therapeutic effects". 2 According to this contrary view, certain cognitive and affective shifts from the subjective effects of psychedelics account for a large degree of the size and longevity of their beneficial effects. Such changes may involve, for example, explicit adoption of alternative conceptual frameworks through which to view and interpret one's experiences, motivations, and social relationships 3 . ...
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Evidence suggests that psychedelics bring about their therapeutic outcomes in part through the subjective or qualitative effects they engender and how the individual interprets the resulting experiences. However, psychedelics are contraindicated for individuals who have been diagnosed with certain mental illnesses, on the grounds that these subjective effects may be disturbing or otherwise counter-therapeutic. Substantial resources are therefore currently being devoted to creating psychedelic substances that produce many of the same biological changes as psychedelics, but without their characteristic subjective effects. In this article, we consider ethical issues arising from the prospect of such potential 'non-subjective' psychedelics. We are broadly supportive of efforts to produce such substances for both scientific and clinical reasons. However, we argue that such non-subjective psychedelics should be reserved for those special cases in which the subjective effects of psychedelics are specifically contraindicated, whereas classic psychedelics that affect subjective experience should be considered the default and standard of care. After reviewing evidence regarding the subjective effects of psychedelics, we raise a number of ethical concerns around the prospect of withholding such typically positive, meaningful, and therapeutic experiences from most patients.
... Accordingly, MDMA, a quasi-psychedelic drug (Nichols, 1986) whose models of clinical application closely match those of classic psychedelics, is expected to become the first FDA-approved drug for which the administration protocol mandates a psychotherapeutic frame (Emerson and Cooper, 2021;Servick, 2021). Although some actors in the field are seeking to develop drugs that replicate the putatively therapeutic neuropharmacology of classic psychedelics while eliminating their subjective effects (Dong et al., 2021)-and thereby the need for supportive therapy (Yakowicz, 2021)-the potential efficacy of this approach remains speculative (Yaden and Griffiths, 2020;Olson, 2021). In fact, it may be more likely that the widely touted increases in neuroplasticity induced by some psychedelics reflect a pluripotent state that requires therapeutic framing to bring about enduring beneficial outcomes (Vollenweider and Kometer, 2010;Carhart-Harris et al., 2018a;Dölen, 2021;Lepow et al., 2021). ...
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The current standard of care in most uses of psychedelic medicines for the treatment of psychiatric indications includes the provision of a supportive therapeutic context before, during, and after drug administration. A diversity of psychedelic-assisted psychotherapy (PAP) models has been created to meet this need. The current article briefly reviews the strengths and limitations of these models, which are divided into basic support models and EBT-inclusive therapy models. It then discusses several shortcomings both types of models share, including a lack of adequate attention to embodied and relational elements of treatment, and insufficient attention to ethical concerns. The article then introduces the EMBARK model, a transdiagnostic, trans-drug framework for the provision of supportive psychotherapy in PAP clinical trials and the training of study therapists. EMBARK was designed to overcome challenges that prior models have had in conceptualizing therapeutic change in psychedelic treatment, incorporating elements of non-psychedelic evidence-based therapies, incorporating therapists’ prior skills and clinical orientations, delimiting therapist interventions for research standardization, and determining specific factors that contribute to treatment outcomes. The article explains EMBARK’s six clinical domains, which represent parallel conceptualizations of how therapists may support therapeutic benefit in PAP treatment, and its four care cornerstones, which reflect therapists’ broad ethical responsibility to participants. The article describes how these elements of the model come together to structure and inform therapeutic interventions during preparation, medicine, and integration sessions. Additionally, the article will discuss how EMBARK therapist training is organized and conducted. Finally, it will demonstrate the broad applicability of EMBARK by describing several current and upcoming PAP clinical trials that have adopted it as the therapeutic frame.
... Classic psychedelics (e.g., psilocybin and LSD; Nichols, 2016) can occasion effects spanning self-dissolution, the experience of intense emotions, distortion of sensory awareness, and even a sense of death and rebirth (Griffiths et al., 2006(Griffiths et al., , 2018Johnson et al., 2008;Cook, 2014;Hendricks et al., 2015;Carhart-Harris et al., 2016;Richards, 2016;Yaden and Griffiths, 2020). Such experiences often result in a lasting sense of improved life quality (Griffiths et al., 2006(Griffiths et al., , 2018Carhart-Harris et al., 2016). ...
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In this study, we describe the development and initial validation of two psychometric scales for measuring psychedelic integration. Psychedelic integration refers to the post-acute period of time following psychedelic drug administration. We created the Integration Engagement Scale (IES) to capture positive behavioral engagement with integration and the Experienced Integration Scale (EIS) to capture internal aspects of feeling integrated. These scales were developed to measure post-acute psychedelic administration dynamics in order to inform the creation of enhanced integration support and to help refine a general conceptual understanding of the construct of psychedelic integration. The scales are brief and face valid instruments designed for practical use in applied and research settings. Scale items were generated and refined using the Iterative Process Model of scale development, with input from psychedelics experts and clinicians. Content validity, internal structure, and reliability were assessed via expert surveys, content validity analysis, cognitive interviewing, convergent validity analysis, exploratory factor analysis, and confirmatory factor analysis. The data indicates the scales are valid and reliable measurements of the behavioral and experiential forms of Psychedelic Integration.
... Though some researchers regard the description of these experiences as mystical to be unscientific this description does not imply a supernatural explanation for these phenomena. Several studies have demonstrated dose-dependent relationships between psychedelics and measures of mystical qualities of the experience, with greater mystical qualities being correlated with better long-term outcomes (Yaden and Griffiths, 2020). Davis et al., (2020b) found that in a sample of 24 adults undergoing psilocybin-assisted psychotherapy for MDD, there was a moderate correlation (r = 0.41, p < 0.5) between changes in GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at 4 weeks and peak MEQ-30 score. ...
... As the families are differentiated via structure, they are proposed to have different binding affinities at both primary (5-HT 2A ) and secondary sites, resulting in differing in levels of potency, effect duration and likely subjective effect profiles (Leth-Petersen et al. 2014;Halberstadt et al. 2020), the latter of which is closely tied to outcomes in classical counterparts. Namely, experiential facets such loss of oneself and sentiments of unity and harmony have repeatedly been shown to drive positive psychological markers in studies employing healthy and clinical populaces (Roseman et al. 2018;Yaden and Griffiths 2020). Concerning this aspect, data-driven approaches using machine learning (ML) have proven themselves to be particularly sensitive in demonstrating structural-experiential alignment of psychedelics regarding the semantic content of these experiences (Zamberlan et al. 2018;Martial et al. 2019). ...
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Background Novel psychedelics (NPs) are an expanding set of compounds, presenting new challenges for drug policy and opportunities for clinical research. Unlike their classical derivatives, little is known regarding their use profiles or their subjective effects. Aims The purpose of this study was to compile usage patterns and adverse event rates for individual NPs belonging to each of three main psychedelic structural families. Targeting the most widely used representatives for each class, we expanded on their phenomenological distinctions. Methods A two-part survey was employed. We investigated the prevalence of novel phenethylamines, tryptamine and lysergamides in NP users ( N = 1180), contrasting the type and incidence of adverse events (AEs) using a set of logistic regressions. Honing in on 2–4-Bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) (48.6%), 1-propionyl-lysergic acid diethylamide (1P-LSD) (34.2%) and 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) (23.1%), we examined their phenomenological separability using a gradient boosting (XGBoost) supervised classifier. Results Novel phenethylamines had the highest prevalence of use (61.5%) seconded by tryptamines (43.8%) and lysergamides (42.9%). Usage patterns were identified for 32 different compounds, demonstrating variable dosages, durations and a common oral route of administration. Compared to phenethylamines, the odds for tryptamines and lysergamides users were significantly less for overall physical AEs. No significant differences in overall psychological AEs were found. Overall model area under the curve (AUC) stood at 0.79 with sensitivity (50.0%) and specificity (60.0%) for 2C-B ranking lowest. Conclusion NP classes may hold distinct AE rates and phenomenology, the latter potentially clouded by the subjective nature of these experiences. Further targeted research is warranted.
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Mystical experiences frequently precede decreases in human suffering or increased functioning. Therapies that include the ingestion of psychoactive substances in supportive environments often lead to improvements that correlate with the magnitude of the mystical experiences generated. A close look at these phenomena from a philosophy of science perspective might put empiricists in a quandary. Arguments with critics of the import of these mystical experiences, prohibitionists, or others who are apprehensive about psychedelic-assisted treatments, might prove awkward or difficult given the tacit assertion that the mystical genuinely exists. The assumption might even dampen theorizing in ways that remain outside of theorists' awareness. The predicament might lack the epistemic humility ideal for good science as well. Nevertheless, abandoning the construct of mystical experiences would require ignoring compelling, replicated empirical work. We argue that a version of philosophical fictionalism that draws on research in logic and linguistics can help investigators engage in this discourse without implying a belief in the mystical. Comparable approaches have proven helpful in mathematics and empiricism more broadly. Mystical fictionalism could help theorists view reports of mystical experiences as true even if the mystical fails to be veridical. The approach creates an expressive advantage that could assist researchers and theorists eager to refine our understanding of mystical experiences and improve psychedelic-assisted treatments. Mystical fictionalism might also inspire novel looks at correlates of mystical experiences that might serve as mediators of their effects, potentially generating models with comparable explanatory power that sidestep the need for a fictionalist approach.
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Altered states of consciousness (ASC) provide an opportunity for researchers to study the neurophysiological basis of changes in phenomenal experience. Δ9-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis, however whether the effects of THC include ASC features that are shared with other ASC induction mechanisms, such as classical psychedelics, has not been systematically addressed. We used survey (11D-ASC; State Mindfulness), self-report, and natural language processing (NLP) to assess 7.5 and 15 mg oral THC, relative to placebo, in 25 healthy, infrequent cannabis users. THC dose-dependently increased measures of ASC including Insightfulness, and increased ratings of mindfulness and mind-wandering. THC also increased language entropy as previously reported for LSD. Future studies may seek to determine whether reports of increased mindfulness or insight after THC are primarily representative of a psychotomimetic state (i.e., delusional thinking) or conversely, reflect an enhancement of conscious awareness that may be validated empirically.
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Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past two decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (e.g., cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.
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RationaleAlthough both psilocybin and dextromethorphan (DXM) produce psychedelic-like subjective effects, rates of non-medical use of psilocybin are consistently greater than DXM.Objective New data are presented from a study of psilocybin and DXM relevant to understanding the features of psilocybin subjective effects that may account for its higher rates of non-medical use.Methods Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use.ResultsHigh doses of both drugs produced similar time courses and increases in participant ratings of peak overall drug effect strength. Nine subjective effect domains are proposed to be related to the reinforcing effects of psilocybin: liking, visual effects, positive mood, insight, positive social effects, increased awareness of beauty (both visual and music), awe/amazement, meaningfulness, and mystical experience. For most ratings, (1) psilocybin and DXM both produced effects significantly greater than placebo; (2) psilocybin showed dose-related increases; 3, DXM was never significantly higher than psilocybin; (4) the two highest psilocybin doses were significantly greater than DXM. These differences were consistent with two measures of desire to take the drug condition again.Conclusions This analysis provides new information about domains of psilocybin subjective effects proposed to be related to its reinforcing effects (alternatively described as the “motivation” to use). Observed differences on these domains between psilocybin and DXM are consistent with the relative rates of non-medical use of psilocybin and DXM.
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Psilocybin shows efficacy to alleviate depression in human clinical trials for six or more months after only one or two treatments. Another hallucinogenic drug, esketamine, has recently been U.S. Food and Drug Administration (FDA)-approved as a rapid-acting antidepressant. The mechanistic basis for the antidepressant effects of psilocybin and ketamine appear to be conserved. The efficacy of these two medications has not, however, been directly compared either clinically or preclinically. Further, whether or not a profound subjective existential experience is necessary for psilocybin to have antidepressant effects is unknown. To address these questions, we tested psilocybin, lysergic acid diethylamide (LSD), and ketamine in a rat model for depression. As in humans, a single administration of psilocybin or LSD produced persistent antidepressant-like effects in our model. In contrast, ketamine produced only a transient antidepressant-like effect. Our results indicate that classic psychedelics may have therapeutic efficacy that is more persistent than that of ketamine, and also suggest that a subjective existential experience may not be necessary for therapeutic effects.
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Background Observational data and preliminary studies suggest serotonin 2A agonist psychedelics may hold potential in treating a variety of substance use disorders (SUDs), including opioid use disorder (OUD).AimsThe study aim was to describe and analyze self-reported cases in which naturalistic psychedelic use was followed by cessation or reduction in other substance use.Methods An anonymous online survey of individuals reporting cessation or reduction in cannabis, opioid, or stimulant use following psychedelic use in non-clinical settings.ResultsFour hundred forty-four respondents, mostly in the USA (67%) completed the survey. Participants reported 4.5 years of problematic substance use on average before the psychedelic experience to which they attributed a reduction in drug consumption, with 79% meeting retrospective criteria for severe SUD. Most reported taking a moderate or high dose of LSD (43%) or psilocybin-containing mushrooms (29%), followed by significant reduction in drug consumption. Before the psychedelic experience 96% met SUD criteria, whereas only 27% met SUD criteria afterward. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced substance misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with greater reduction in drug consumption.Conclusions While these cross-sectional and self-report methods cannot determine whether psychedelics caused changes in drug use, results suggest the potential that psychedelics cause reductions in problematic substance use, and support additional clinical research on psychedelic-assisted treatment for SUD.
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Background: Meta-analysis of randomized studies using lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) showed large, significant effects for LSD efficacy compared to control conditions. Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders. Aims: To supplement clinical studies, reports of psychedelic use in naturalistic settings can provide further data regarding potential effects of psychedelics on alcohol use. Methods: An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in nonclinical settings. Results: 343 respondents, mostly White (89%), males (78%), in the USA (60%) completed the survey. Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption, with 72% meeting retrospective criteria for severe AUD. Most reported taking a moderate or high dose of LSD (38%) or psilocybin (36%), followed by significant reduction in alcohol consumption. After the psychedelic experience 83% no longer met AUD criteria. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress. Conclusions: Although results cannot demonstrate causality, they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use, supporting further investigation of psychedelic-assisted treatment for AUD.
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Background: Recent pilot trials suggest feasibility and potential efficacy of psychedelic-facilitated addiction treatment interventions. Fifteen participants completed a psilocybin-facilitated smoking cessation pilot study between 2009 and 2015. Aims: The aims of this study were as follows: (1) to identify perceived mechanisms of change leading to smoking cessation in the pilot study; (2) to identify key themes in participant experiences and long-term outcomes to better understand the therapeutic process. Methods: Participants were invited to a retrospective follow-up interview an average of 30 months after initial psilocybin sessions. Semi-structured interviews were conducted with 12 of the 15 participants. Data were analysed using thematic analysis. Results: Participants reported gaining vivid insights into self-identity and reasons for smoking from their psilocybin sessions. Experiences of interconnectedness, awe, and curiosity persisted beyond the duration of acute drug effects. Participants emphasised that the content of psilocybin experiences overshadowed any short-term withdrawal symptoms. Preparatory counselling, strong rapport with the study team, and a sense of momentum once engaged in the study treatment were perceived as vital additional factors in achieving abstinence. In addition, participants reported a range of persisting positive changes beyond smoking cessation, including increased aesthetic appreciation, altruism, and pro-social behaviour. Conclusions: The findings highlight the value of qualitative research in the psychopharmacological investigation of psychedelics. They describe perceived connections between drug- and non-drug factors, and provide suggestions for future research trial design and clinical applications.
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Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
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Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.
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Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective: To investigate the effect of psilocybin therapy in patients with MDD. Design, Setting, and Participants: This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. Main Outcomes and Measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.2; 95% CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 3.0; 95% CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9-4.2; P < .001). In the overall sample, 16 participants (67%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). Conclusions and Relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. Trial Registration: ClinicalTrials.gov Identifier: NCT03181529
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Prior research has shown that acute subjective psychedelic effects are associated with both spontaneous and intended changes in depression and anxiety. Psychedelics are also theorized to produce increases in psychological flexibility, which could explain decreases in depression and anxiety following a psychedelic experience. Therefore, the present cross-sectional survey study sought to examine whether psychological flexibility mediated the relationship between acute psychedelic experiences and spontaneous or intended changes in depression and anxiety among a large international sample of people who reported having used a psychedelic (n=985; male=71.6%; Caucasian/white=84.1%; Mage=32.2, SD=12.6). A regression analysis showed that acute effects (i.e., mystical and insightful effects) were significantly associated with decreases in depression/anxiety following a psychedelic experience. A path analysis revealed that, while controlling for age and sex, increases in psychological flexibility fully mediated the effect of mystical and insightful experiences on decreases in depression and anxiety following a psychedelic experience. This suggests that psychological flexibility may be an important mediator of the therapeutic effects of psychedelic drugs. Future prospective experimental studies should examine the effect of psychedelic drug administration on psychological flexibility in order to gain a better understanding of the psychological processes that predict therapeutic effects of psychedelics.
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The purpose of this paper is to provide an integrative review and offer novel insights regarding human research with classic psychedelics (classic hallucinogens), which are serotonin 2A receptor (5-HT2AR) agonists such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Classic psychedelics have been administered as sacraments since ancient times. They were of prominent interest within psychiatry and neuroscience in the 1950s to 1960s, and during this time contributed to the emergence of the field of molecular neuroscience. Promising results were reported for treatment of both end-of-life psychological distress and addiction, and classic psychedelics served as tools for studying the neurobiological bases of psychological disorders. Moreover, classic psychedelics were shown to occasion mystical experiences, which are subjective experiences reported throughout different cultures and religions involving a strong sense of unity, among other characteristics. However, the recreational use of classic psychedelics and their association with the counterculture prompted an end to human research with classic psychedelics in the early 1970s. We provide the most comprehensive review of epidemiological studies of classic psychedelics to date. Notable among these are a number of studies that have suggested the possibility that nonmedical naturalistic (non-laboratory) use of classic psychedelics is associated with positive mental health and prosocial outcomes, although it is clear that some individuals are harmed by classic psychedelics in non-supervised settings. We then review recent therapeutic studies suggesting efficacy in treating psychological distress associated with life-threatening diseases, treating depression, and treating nicotine and alcohol addictions. We also describe the construct of mystical experience, and provide a comprehensive review of modern studies investigating classic psychedelic-occasioned mystical experiences and their consequences. These studies have shown classic psychedelics to fairly reliably occasion mystical experiences. Moreover, classic-psychedelic-occasioned mystical experiences are associated with improved psychological outcomes in both healthy volunteer and patient populations. Finally, we review neuroimaging studies that suggest neurobiological mechanisms of classic psychedelics. These studies have also broadened our understanding of the brain, the serotonin system, and the neurobiological basis of consciousness. Overall, these various lines of research suggest that classic psychedelics might hold strong potential as therapeutics, and as tools for experimentally investigating mystical experiences and behavioral-brain function more generally.