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The revival of psilocybin between scientific
excitement, evidence of efficacy, and real-world
challenges
Mauro Scala
1,2
, Chiara Fabbri
1
, Paolo Fusar-Poli
3,4,5,6
, Giorgio Di Lorenzo
7,8
,
Maria Ferrara
9
, Andrea Amerio
10,11
, Laura Fusar-Poli
4
, Anna Pichiecchio
4,12
,
Carlo Asteggiano
12
, Marco Menchetti
1
, Diana De Ronchi
1
,
MNESYS - Mood and Psychosis Sub-Project (Spoke 5)
#
, Giuseppe Fanelli
1,13
and
Alessandro Serretti
14,15
1
Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy;
2
Health
Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain;
3
Early Psychosis: Interventions and Clinical-
detection (EPIC) Lab, Department of Psychosis Studies, King’s College London, London, United Kingdom;
4
Depart-
ment of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy;
5
OASIS Service, South London and Maudsley
NHS Foundation Trust, London, United Kingdom;
6
Department of Psychiatry and Psychotherapy, University Hospi-
tal, Ludwig-Maximilian-University, Munich, Germany;
7
Department of Systems Medicine, Tor Vergata University of
Rome, Rome, Italy;
8
IRCCS Fondazione Santa Lucia, Rome, Italy;
9
Institute of Psychiatry, Department of Neurosci-
ence and Rehabilitation, University of Ferrara, Ferrara, Italy;
10
Health Research Institute Hospital 12 de Octubre
(imas12), Madrid, Spain;
11
IRCCS Ospedale Policlinico San Martino, Genoa, Italy;
12
Advanced Imaging and Artificial
Intelligence Center, Department of Neuroradiology, IRCCS Mondino Foundation, Pavia, Italy;
13
Department of
Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour,
Nijmegen, The Netherlands;
14
Department of Medicine and Surgery, Kore University of Enna, Italy and
15
Oasi
Research Institute-IRCCS, Troina, Italy
Abstract
The revival of psilocybin in psychopharmacological research heralds a potential paradigm shift
for treating mood and anxiety disorders, and other psychiatric conditions beyond the psychotic
spectrum. This critical review evaluates current evidence on psilocybin’s efficacy, juxtaposing
potential benefits with the practical aspects of psychedelic-assisted psychotherapy (PAP) and
the methodological constraints of existing research.
An electronic literature search was conducted using PubMed/MEDLINE, selecting studies
published up to December 2023 that explored the clinical use of psilocybin in mood and anxiety
disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and substance use
disorder. Despite promising preliminary results suggesting psilocybin’s efficacy in alleviating
depression and anxiety, as well as obsessions, compulsions, and addictive behaviors, significant
evidence gaps persist. These include evaluating the efficacy of psilocybin compared to standard
antidepressants or anxiolytic molecules and identifying patient subpopulations that might
benefit most from PAP. Concerns about psilocybin’s safety, long-term efficacy, and optimal
dosage remain unclear due to previous trials’limitations. Real-world implementation faces
challenges, including infrastructural requirements, personnel training, and unresolved legal and
ethical issues. This paper argues for further research to substantiate the evidence base, empha-
sizing the need for larger studies that overcome current methodological limitations and explore
psilocybin’s full therapeutic potential. While psilocybin holds promise for psychiatry, its
successful translation from research to clinical practice demands more robust evidence on
efficacy, safety, and methodological rigor. In addition, other factors, such as cultural stigma and
legal/ethical issues, need to be successfully addressed to facilitate psilocybin’s implementation in
healthcare systems.
Introduction
The need for new treatments for psychiatric disorders is evidenced by increased research into
novel pharmacological approaches.
1-3
Standard antidepressant drugs are widely used in depres-
sive disorders but not without drawbacks. These include high nonresponse rates, the persistence
of some residual symptoms (e.g., cognitive and sleep disturbances), undesirable metabolic and
sexual side effects,
4-7
as well as the delayed onset of therapeutic effects.
8
Antidepressants are also
used to treat other psychiatric disorders including obsessive-compulsive disorder (OCD),
9
post-
traumatic stress disorder (PTSD),
10
and substance use disorder (SUD).
11
However, despite the
establishment of an appropriate treatment paradigm with current antidepressants, up to 60% of
patients with OCD continue to experience debilitating residual symptoms,
9
and less than 30% of
CNS Spectrums
www.cambridge.org/cns
Review
Cite this article: Scala M, Fabbri C, Fusar-Poli
P, Di Lorenzo G, Ferrara M, Amerio A, Fusar-
Poli L, Pichiecchio A, Asteggiano C, Menchetti
M, De Ronchi D, MNESYS - Mood and Psychosis
Sub-Project (Spoke 5), Fanelli G, and Serretti A
(2024). The revival of psilocybin between
scientific excitement, evidence of efficacy, and
real-world challenges. CNS Spectrums
https://doi.org/10.1017/S1092852924002268
Received: 24 May 2024
Accepted: 17 October 2024
Keywords:
rapid-acting antidepressants; psilocin;
pharmacotherapy; synaptic plasticity;
personality; cognitive flexibility
Corresponding author:
Giuseppe Fanelli;
Emails: giuseppe.fanelli5@unibo.it;
drgiuseppefanelli@gmail.com
#
MNESYS—Mood and Psychosis Sub-Project (Spoke
5) [Collaborative Author Group]: Luigi Grassi (Univer-
sity of Ferrara, Ferrara, Italy); Alessio Maria Monte-
leone and Silvana Galderisi (University of Campania,
Naples, Italy); Alessandro Bertolino (University of
Bari, Bari, Italy); Mirella Ruggeri and Sarah Tosato
(University of Verona, Verona, Italy); Valdo Ricca
(University of Florence, Florence, Italy); Gianluca
Serafini (University of Genoa, Genoa, Italy); Cinzia
Niolu (Tor Vergata University of Rome, Rome, Italy);
Pierluigi Politi (University of Pavia, Pavia, Italy).
© The Author(s), 2024. Published by Cambridge
University Press. This is an Open Access article,
distributed under the terms of the Creative
Commons Attribution licence (http://
creativecommons.org/licenses/by/4.0), which
permits unrestricted re-use, distribution and
reproduction, provided the original article is
properly cited.
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
patients with PTSD achieve clinical remission.
10
Standard antide-
pressants produce inconsistent improvements when treating
depression associated with SUD.
11
These challenges highlight the
need for novel, rapid-acting pharmacological approaches to possi-
bly overcome the limitations of standard antidepressants.
Within this context, psychedelics have received much attention
over the past few years. Although researchers started to explore the
effects of psychedelics in the 1950s,
12
psilocybin only recently was
granted the status of breakthrough therapy by the Food and Drug
Administration (FDA) for treatment-resistant depression (TRD).
13
The latter was not an endorsement for clinical use, but an invitation
to provide further evidence on which clinical decisions can be
based. The principal reason for this caution can be identified in
previous trials’methodological issues that have contributed to
classifying psilocybin as a drug of abuse with no medical value
over the past 50 years.
14
Furthermore, the psychoactive effects of
psilocybin, including disturbances of consciousness, mood, per-
ception, and thought, left this drug for recreational use rather than
a potential psychopharmacological treatment.
15
Indeed, the histor-
ical primary use of psilocybin in ancient indigenous rituals
intended to induce mystical experiences and a simultaneous altered
state of consciousness, thus allowing for better processing of
unconscious memories.
16
More recently, these effects were found to be closely dependent
on plasma psilocin levels (i.e., psilocybin’s active metabolite) and
serotonin 5HT
2A
receptor occupancy rates,
17
which increases gluta-
mate tone, thus leading to more active synaptic plasticity.
18
Despite
these compelling pharmacodynamic properties, a 2016 survey
revealed conflicting opinions among clinicians regarding the possi-
ble use of psilocybin for therapeutic purposes. Only 43% of the
participants expressed support, while the majority of responders
perceived the use of hallucinogens as potentially hazardous.
19
However, recent brain imaging studies aimed at elucidating
psilocybin’s therapeutic mechanisms showed significant changes
in brain connectivity.
20,21
Functional magnetic resonance imaging
(fMRI) and perfusion studies conducted before and after treatment
showed decreased activation and reduced cerebral blood flow in the
amygdala,
22
as well as variations in prefrontal-limbic functional
connectivity.
23,24
Psilocybin also decreases brain modularity, cor-
relating with clinical outcomes, unlike the selective serotonin reup-
take inhibitor (SSRI) escitalopram.
25,26
Electrophysiology studies
also revealed that psilocybin reduces alpha, beta, and delta band
activity in both healthy and depressed individuals, while an
increase in theta power correlates with depressive symptoms
improvement in major depressive disorder (MDD).
27,28
Preliminary literature provides converging evidence about the
potential therapeutic efficacy of psilocybin after one or two admin-
istrations, particularly in mood disorders.
29
Psilocybin might also
represent a treatment alternative for depression and anxiety
comorbid with life-threatening cancers –conditions often resistant
to other psychopharmacological therapies –
30
as demonstrated in
some randomized, crossover trials, despite their small sample
sizes.
31-33
However, these clinical trials showed several limitations
that require careful consideration when drawing conclusions about
efficacy. Moreover, only one randomized clinical trial (RCT)
directly compared the efficacy of psilocybin with escitalopram
without demonstrating a significant difference between the two.
26
After these preliminary findings, Australia has recently become
the first country in the world to approve psilocybin for the treat-
ment of TRD, albeit with stringent regulatory oversight requiring
ethics committee approval for use in each patient.
34
Despite these
advancements and the ensuing enthusiasm, psilocybin has not been
approved for the treatment of depression or other mental disorders
(i.e., anxiety disorders, OCD, PTSD, and SUD) in other countries,
and its use in real-world clinical settings will have to face several
unresolved issues, which have not been frequently discussed in the
literature.
35-37
The present critical review aims to offer an evidence-informed
clinical opinion on the possible implementation of psilocybin-
based treatment strategies in psychiatric clinical settings, examin-
ing the shortcomings of previous studies that assessed the clinical
efficacy of psilocybin, as well as discussing the possible obstacles to
its use in real-world psychiatric practice. Some suggestions for the
potential use of psilocybin in clinical practice will also be made,
with particular attention to feasibility and acceptability. The psilo-
cybin’s unique strengths and innovative potential will also be
discussed.
Materials and methods
An electronic literature search was conducted using PubMed/
MEDLINE for English-language articles published from inception
to December 2023. We used the keyword “psilocybin”combined
with terms related to depressive disorders, bipolar depression,
anxiety disorders, OCD, PTSD, and SUD.
This critical review does not intend to systematically summarize
the extent of the effect of psilocybin, given the number of reviews
already available in the literature,
29,38
but rather to offer an expert
clinical opinion on the available evidence and possible future per-
spectives. Key aspects evaluated include its safety profile, addictive
potential, optimal dosing, and the altered states of consciousness
that may arise during psychedelic-induced mystical experiences.
Moreover, this review evaluates the uncertainty about the efficacy of
psilocybin independent of concomitant psychotherapy, as well as
the positioning of psilocybin-based therapy within treatment par-
adigms, its comparative efficacy versus standard antidepressants,
the appropriate infrastructure and personnel expertise for its safe
and effective implementation, and ethical and legal challenges
related to psilocybin use.
Results
Barriers to clinical implementation of psilocybin-based treatments,
along with psilocybin’s potential strengths and innovations, are
presented in Table 1 and described in the following paragraphs.
Safety profile and addictive potential
In evaluating the incorporation of psilocybin into clinical psychi-
atric practice, a thorough assessment of its safety profile and
addictive potential is imperative. In this section, we present the
safety warnings related to psilocybin use, providing an opinion on
the risk of adverse events when psilocybin is administered in
controlled settings.
Overall, the compound was well tolerated in most clinical trials.
8
The most common adverse events include nausea, headache, and
minimal reductions in cardiovascular parameters (such as basal
heart rate and blood pressure), with frequencies up to 33%, 67%,
and 76%, respectively, according to the available trials.
8
A mild
activation syndrome characterized by moderate anxiety or fear,
tremors, and emotional liability affects between 17 and 23.2% of
participants at the beginning of the treatment.
8
When this syn-
drome is accompanied by transient paranoid ideation, it is
2 M. Scala et al.
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
Table 1. Evidence-based strengths and challenges of potential use of psilocybin in real-world clinical practice
Strengths Challenges
PAP Short-term treatment with one or few sessions Unknown benefits of psilocybin without PAP
Limited/no risk of poor treatment adherence Operator-dependent approach
Rapid onset of action Patients’motivation
Alleged sustained therapeutic effect over time Need for strong therapeutic alliance
Possible implementation of different
psychotherapeutic approaches
Unclear optimal duration
Economic and human resources to train clinicians
Need for culturally adapted versions
Long duration of a PAP session
Unknown benefits in depressed patients with comorbid personality
disorders
Safety profile Dose-dependent AEs Transient and self-limiting fatigue, hypertension, tachycardia,
vomiting, insomnia, and psychological discomfort during PAP
Rare serious AEs Risk of serious AEs if simultaneous ingestion of alcohol and/or other
psychedelics
Rare “bad trips”Lack of a “rescue”drug
Low risk of HPPD Paucity of data about long-term safety profile
No sexual dysfunction, cognitive impairments, weight
gain, metabolic changes, or manic switch
No withdrawal symptoms
Low risk of serotonin toxicity
No risk of dependency and/or addiction
Dosing Possibility of adapting the dose (macro- or micro-dosing) Incomplete knowledge about dose–response therapeutic relationship
Lack of multi-arms RCTs
Unknown interactions with antidepressants and other psychotropic drugs
Lack of psilocin-level measures
Influence of subjective experiences
Mystical experience and
personality domains
Improvement in cognitive flexibility Possibility of being influenced by one’s thoughts
Rapid decrease in depressive ruminations Brainwash and inappropriate behaviors
Increase in empathy, self-acceptance, and social life Potentially unwanted personality changes
Effects in personality domains (neuroticism,
extroversion, and openness)
Trial confounders and
limitations
Stringent inclusion criteria
Small sample size
Risk of selection, performance, and detection biases
Short follow-up
No comparison with placebo or TAU
Open-label and crossover designs
Pilot and proof-of-concept studies
Single-dose protocols
Ethical challenges and
legal considerations
Appropriate delivery of informed consent
Recreational use
Self-medication use without medical support
Equitable access to PAP
Need of psychoeducation
Cultural and social stigma
Impossibility of patenting psilocybin
Abbreviations: AE, adverse event; HPPD, hallucinogen persisting perception disorder; PAP, psychedelic-assisted psychotherapy; RCT, randomized clinical trial; TAU, treatment as usual.
CNS Spectrums 3
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
colloquially referred to as a “bad trip”. Anxiety, mainly due to
psychological discomfort during psychedelic-assisted psychother-
apy (PAP), is generally acute and transient and improves with
therapists’reassurance.
39
Rates of fatigue and insomnia were found
to be above 5%.
8
A major concern is related to the risk of developing
hallucinogen-persisting perception disorder (HPPD), which
includes two major subtypes. HPPD I, also known as “benign
flashback”or “flashback type”, has a short-term, reversible, and
benign course.
40
In a study involving a small sample of male
patients with AIDS, one participant experienced a post-traumatic
stress flashback of a sexual assault two days after the PAP, which
may be attributed to HPPD I.
39
HPPD II, conversely, usually pre-
sents as recurrent, long-term, distressing, and pervasive perceptive
disturbances. It’s noteworthy that the Diagnostic and Statistical
Manual of Mental Disorders (DSM) does not differentiate between
HPPD I and II, and the issue is still controversial.
40
The common
symptomatology across both types of HPPD includes recurring
visual hallucinations (e.g., flashes and intensified color perception,
palinopsia, micropsia, and macropsia), false perceptions of move-
ment, recurrent synesthesia, dissociation, auras, depersonalization,
and derealization.
15
HPPD has mainly been associated with the use
of lysergic acid diethylamide (LSD).
40
However, it has also been
reported after recreational psilocybin use, often together with
alcohol and cannabis consumption.
15
Despite the limited occur-
rence of HPPD in clinical studies with therapeutic dosages of
psilocybin (10–25 mg), further controlled trials should better
explore the clinical implications. It is essential to understand
whether the potential occurrence of these transient or enduring
psychotic symptoms may represent an obstacle to the therapeutic
use of psilocybin.
Regarding possible serotonin toxicity, psilocybin shows a lower
risk compared to other psychedelics.
41
Both psychedelic effects and
serotonin syndrome are associated with an increase in 5-HT
2A
neurotransmission
42,43
that is responsible for transient serotonin-
related symptoms such as nausea, anxiety, hypertension, tachycar-
dia, visual deficits, motor incoordination, and mild tremors, even at
therapeutic doses. These symptoms usually subside within a few
hours and typically do not need hospitalization.
44
However, there is
a tipping point at which 5-HT
2A
receptor stimulation can occa-
sionally lead to severe intoxications, marked by symptoms such as
myoclonus, rigidity, severe hyperthermia, and impaired mental
status persisting beyond the psilocybin sessions. In such cases,
serotonin syndrome should be considered.
Overall, all the mentioned adverse events display a dose-
dependent relationship and can cause significant impairment when
combined with alcohol or other psychedelics during recreational use.
Despite the potential for adverse effects, clinical findings remain
encouraging. During trials, participants do not express a desire for
further PAP sessions or dose increases. Hence, despite psilocybin
being classified as a drug of abuse, the US Drug Enforcement
Administration (DEA) does not include it among the drugs that
can cause dependence and/or addiction.
45
Based on the evidence so
far, a high risk of physical addiction could be excluded. At most, in
uncontrolled settings, there is a potential for behavioral depen-
dence, where dopamine release would not be triggered by the drug
itself but by an external factor (i.e., the state of mind or the gesture
of assumption).
46
A potential limitation of psilocybin use in clinical settings is the
lack of a specific antagonist medication to counteract adverse
experiences. Benzodiazepines could be a viable solution in case of
mild activation or occasional insomnia after PAP, while low doses
of typical (i.e., haloperidol, perphenazine, or sulpiride) or atypical
antipsychotics (i.e., aripiprazole)
40
may be used if transient psy-
chotic symptoms occur.
In summary, patients treated with psilocybin generally experi-
ence mild and transient side effects, which can be partially allevi-
ated through psychological support provided during PAP. Long-
term side effects cannot be well quantified and evaluated at present,
given the current lack of well-powered studies. Therefore, we
suggest carefully considering the safety profile of psilocybin, but
also balancing the risks with the pros; for example, in medical and
research settings there is no risk of withdrawal symptoms for
psilocybin, and the drug has a sexually and metabolically safe
profile.
8
However, further research is needed to understand the
safety profile of psilocybin in naturalistic contexts.
Dosing
Establishing a safe and effective dose is fundamental for the medical
use of psilocybin. Whether higher dosing or micro-dosing has a
better therapeutic effect remains controversial, and the dose–
response relationship of psilocybin is still a debated issue. According
to two recent dose–response meta-analyses, the most effective dose
for depressive disorders appears to be between 24.68 mg/70 kg
47
and
35 mg/70 kg.
48
For TRD, the optimal dose is suggested to be higher,
with an effective dose of 40 mg/70 kg, whereas for anxiety lower
doses should be considered 22.78 mg/70 kg.
47
However, these
results were likely influenced by publication and reporting bias.
While higher dosages may be more effective in some groups of
patients, such as those with alcohol use disorders, they may be
responsible for more frequent adverse events such as dysphoria
and anxiety, particularly troublesome for patients with advanced
cancer.
49
Multi-arms studies testing psilocybin across various psy-
chiatric conditions could help to address this issue.
We suggest here some aspects that researchers and clinicians
should consider when tailoring psilocybin dose in clinical settings.
First, micro-dosing sessions should be considered before prescrib-
ing a macro-dose, considering the patient’s expected sensitivity to
adverse events. Second, measuring plasma psilocin levels, as is done
with current antidepressants,
50
may help optimize the dose.
17
However, it remains to be clarified whether administering another
antidepressant in combination therapy influences therapeutic
response, regardless of psilocybin’s blood levels.
51
Lastly, assessing
patients’genetic polymorphisms in psilocybin pharmacodynamic
targets might help to predict response.
52
Nonetheless, the intro-
spective and subjective experiences (i.e., significant changes in
perception, cognition, affect, volition, and somesthesia)
16
induced
by this compound may go beyond the dosage, pharmacokinetic,
and pharmacodynamic mechanisms, as discussed in the next par-
agraph.
Mystical experience and personality domains
During PAP, therapists aim to support patients to access an endur-
ing mystic state where they can reprocess unconscious memories.
Music and a supportive environment during PAP facilitate this
process, increasing psychological and cognitive flexibility, which is
the main mediator of psilocybin benefits in mood disorders.
53
During these processes, rigid thought patterns are loosened and
experiences of ego-dissolution and deep universal connections are
reported.
54
Within the phenomenon of ego-dissolution, patients
experience a profound disintegration of their perception of being a
separate self from their surroundings. Ego-dissolution involves the
breakdown of typical cognitive structures that contribute to
4 M. Scala et al.
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
individual consciousness, ultimately leading to a sense of loss of
personal identity, as well as a more fluid perception of subjective
experience.
55
However, under these conditions, there is a possibil-
ity of individuals being influenced in their thoughts, and there have
been occasional attempts to brainwash individuals.
56
One way to
prevent inappropriate behaviors during PAP sessions could be to
ensure the constant presence of at least two therapists per session.
Despite these negative occurrences, we emphasize that mystical
experiences appear relevant to decrease depressive ruminations
and increase empathy, self-acceptance, social life, and openness.
A single PAP session has indeed been found to decrease neuroti-
cism and increase both extroversion and openness when person-
ality was assessed using the Revised NEO Personality Inventory
(NEO-PI-R) at 3 months of follow-up.
57
While standard antide-
pressants can also slightly mitigate neuroticism in MDD, extrover-
sion and openness are specifically related to the effect of PAP.
58,59
These variations in personality domains, if durable, reshape the
patient’s interactions with the environment and may explain the
sustained effect of psilocybin over time only after a few sessions. On
the other hand, the possibility of long-lasting personality effects
may raise ethical issues.
32,57
We underline that the available studies
have a maximum follow-up duration of 12 months,
60
with only two
secondary analyses providing data on 4.5 years of follow-up,
61,62
This temporal limitation underscores the necessity for extended
longitudinal studies to comprehensively evaluate the durability of
psilocybin’s therapeutic benefits.
The relevance of these findings derives from the fact that they
overcome the traditional assumption that personality changes can
only occur slowly and gradually.
63
The effect of psilocybin appears
even more intriguing when considering the stability of personality
traits in healthy adults, as well as the greater rigidity of personality in
patients with psychiatric disorders
64
compared to the general pop-
ulation.
65
According to the above, we glimpse the potential benefits
of using the PAP paradigm in personality disorders, especially
considering that to date no drugs are specifically approved to treat
these conditions. However, we also underline that there is currently
no experimental evidence from clinical trials supporting this
hypothesis. Future research would help to bridge the gap between
psychopathology and neurobiology, by studying the possible link
between changes in psychopathological dimensions of personality
(assessed, for instance, with the NEO-PI-R or the Personality
Inventory for DSM-5 (PID-5)) and variations in specific functional
brain networks induced by psilocybin in neuroimaging studies.
Despite neuroplasticity phenomena mainly occurring in the pre-
frontal cortex, amygdala, and hippocampus,
66
the molecular mech-
anisms underlying these effects remain essentially unknown.
Psychedelic-assisted psychotherapy
According to the current trial protocols, psilocybin is typically
administered alongside a psychological support called PAP. The
only exception is a trial of psilocybin for OCD where no concom-
itant psychotherapy or psychosocial intervention was provided to
participants.
67
PAP includes three phases: preparation, psilocybin session, and
integration. During preparation, patients are given information
about the upcoming drug therapy session and guidance on how
to maximize benefits while minimizing adverse events. This
increases patients’expectations and suggestibility toward the treat-
ment, posing challenges in obtaining accurate informed consent.
Since the surrounding setting significantly influences the experi-
ence and the adverse events, PAP sessions are delivered in a calm
and relaxing environment with a preselected music program. If
future trials confirm the importance of these setting requirements,
this could limit widespread clinical application, as only a few
healthcare centers may be adapted in a feasible way, and provide
the personnel needed. In the weeks after treatment, psychotherapy
is used to integrate thoughts, unconscious memories, and other
psychopathological phenomena that arise during the sessions.
68
While cognitive-behavioral therapies (CBTs) have the strongest
evidence in PAP,
69
the unconscious processes during session and
integration phases are also related to psychodynamic theories.
Despite differences, PAP sessions contain elements of psychody-
namic treatment where unconscious material is revealed. In the
integration phase, patients report to nondirective therapists all
thoughts and perceptions previously arisen without exerting any
censorship or giving a conscious direction as if they were free
associations, an essential tool of psychoanalytical practices.
70
It is
indeed interesting to consider that elements from different psy-
chotherapeutic approaches merge into an innovative approach that
is, however, rooted in previous theories. PAP may offer another
potential advantage. Traditional psychotherapeutic interventions
often require multiple weekly sessions, sometimes lasting up to
12 months, to achieve a therapeutic effect.
71
Intriguingly, when
combined with psilocybin, enduring benefits over even 6 months
can be achieved after only one or two sessions, resulting in less time
consuming and potentially more cost-effective for the healthcare
systems. Additionally, the rapid onset of action (as early as 8hours
62
)
and the lack of a daily pill intake can improve treatment adherence.
However, PAP shows some potential challenges. First, the psy-
chological support hinders the quantification of psilocybin’s ben-
efit itself. Given the paucity of studies without psychotherapy, the
benefits of the drug itself remain to be demonstrated still if not
associated with psychotherapy. Second, PAP is an operator-
dependent approach, leading to significant heterogeneity and out-
come differences. Third, future studies should determine the opti-
mal psychotherapeutic approach in terms of intervention type and
session frequency, as well as the possible benefits of different
psychologically oriented interventions and settings. For instance,
depressed patients with comorbid borderline personality disorder
(BPD) were excluded from the majority of trials, while a study
showed the benefits of PAP in this group.
39
Possible integration of
PAP with specific CBT approaches (e.g., dialectical behavioral
therapy or DBT) may further improve outcomes in patients with
personality disorders. Furthermore, integrating PAP with specific
skills of the DBT modules (i.e., mindfulness, distress tolerance,
emotion regulation, and interpersonal effectiveness) might be ben-
eficial for all patients, providing them with tools to deal with
unpleasant memories or to face changes to achieve new goals in
their lives.
69
Undoubtedly, significant economic and human
resources are needed in the short term to train and certify clinicians
and to set the environment for preparatory and integrative sessions.
This may constitute a challenge in implementing PAP in develop-
ing countries or culturally diverse nations. Developing a culturally
adapted version of PAP is crucial for worldwide accessibility, as it
was investigated mostly in the United States (US) and Western
countries. Finally, yet importantly, as PAP sessions can last several
hours or even an entire workday, working shifts will have to
consider this aspect.
Evidence of efficacy, confounders, and limitations of clinical trials
The evidence previously presented should be interpreted consid-
ering that it derives from a mix of RCTs not always well-designed,
CNS Spectrums 5
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non-randomized studies, open-label trials, and pilot studies.
Details regarding the main findings and limitations of the available
studies investigating psilocybin use in psychiatric disorders are
summarized in Table 2.
Research on MDD, anxiety and depressive symptoms associated
with life-threatening cancer, and TRD showed the most robust
evidence, supported by a non-randomized study
72
and several
RCTs.
26,31-33,60,73-77
Open-label studies
25,39,57,78-81
and two follow-
up analyses
61,62
supported the overall positive findings of RCTs.
Among all the studies conducted, five were pilot studies.
25,31,39,72,80
Concerning the outcome, two trials reported no significant differ-
ence in the antidepressant effect between psilocybin and escitalo-
pram
26
or placebo,
72
whereas another one showed improvement in
depression only at month 6.
31
According to a recent meta-analysis,
which included three RCTs and three open-label studies, the use of
psilocybin (at doses ranging from 1 mg to 25 mg) to patients not
currently taking any other psychotropic medications resulted in
significant reductions in depressive symptoms.
38
However, these studies have significant limitations and do
not clearly provide conclusive evidence on the antidepressant
efficacy of psilocybin, particularly in the long term. Concerning
the recruitment phase, there are clear limitations such as small
sample sizes
25,31-33,39,57,60,72-74,77-81
with lack of diversity
among participants
32,33,39,57,60,72,75-79
and potential selection
biases.
26,31,39,72-74,76
These issues limit the generalizability of
findings and impede a comprehensive assessment of rare adverse
events, as well as the precise evaluation of the number needed to
harm, and the number needed to treat. One study only recruited
healthy subjects.
74
In terms of methodology, some studies showed
inconsistent application of correction for multiple testing,
26,74
no
consideration of confounding factors,
57,78
lack of randomization,
72
and relatively short-term follow-up periods were often
observed,
25,26,31-33,39,57,72-81
generally between one and 6 months
after one or two single active psilocybin treatments. Only one RCT
has a 12-month follow-up.
60
Furthermore, the intake of other
antidepressants during follow-up periods could confound results,
and it remains uncertain whether the maintenance of medium-
term therapeutic effect can be solely attributable to the PAP.
60
Only
two long-term 4.5-year follow-up studies are available, involving
4 and 14 patients, respectively.
61,62
One of these shows a sustained
reduction in demoralization,
62
while the other presents the clinical
response rates for depression and anxiety.
61
This lack of informa-
tion on long-term safety, tolerability, and efficacy represents an
important obstacle to the use of psilocybin in clinical practice, as
mood disorders are typically chronic and recurrent. In terms of
study design, the use of open-label
25,39,57,78-81
and crossover
designs,
31-33,74,80
as well as a single-dose protocol,
31,33,39,72-77
was
frequently noted. Blinding procedures were not consistently
robust,
26,32,60,72-76
and comparison with placebo or standard treat-
ments was lacking in many studies.
25,26,31-33,39,57,60,72,73,75-81
Poten-
tial detection bias was sometimes observed due to differences in
outcome measurement between the treatment and control
groups.
31,33
In some instances, control groups consisted of waiting
lists rather than active comparators,
60,73
and therapeutic settings
were sometimes not consistently provided.
74,76
Finally, in one RCT
not all questionnaires used for data collection were validated,
introducing an additional source of bias.
32
Evidence of efficacy for OCD,
67
body dysmorphic disorder
(BDD),
82
alcohol dependence,
83
and tobacco addiction
84,85
is
promising but limited due to the absence of RCTs. To address this
limitation, two RCTs assessing the effects of PAP in alcohol-
dependent volunteers
86
and smokers (NCT01943994) have been
conducted, albeit results have not been published yet. To date, no
study has investigated PAP treatment for PTSD. An open-label
pilot study of psilocybin for bipolar depression II (BDII)
(NCT05065294) is currently recruiting participants, while another
one (NCT04433845) with a single-dose design has been already
published.
87
Additionally, two qualitative analyses of follow-up
interviews
88
and web-survey
89
of anecdotal use of psilocybin in
individuals with putative BD reported that the drug was perceived
to be more helpful than harmful. However, it is important to note
several limitations of qualitative studies including self-reported
diagnosis, selection, recall bias, and reporting bias, which may
primarily emphasize positive experiences limiting the understand-
ing of negative ones.
Besides these intrinsic limitations of the study design, another
common limitation among available trials is the strict inclusion
criteria, which severely reduces the results’generalizability. Com-
mon exclusion criteria include a family history of psychotic and
bipolar disorders, current psychotic symptoms, concomitant anti-
depressant drugs during PAP, and active suicidal ideation or
intent.
32
The exclusion of patients with psychotic symptoms
and/or suicidal ideation aims to avoid the rare possibility of
inducing psychotomimetic adverse events and suicidal behavior
in patients with congruent ideation. However, excluding
depressed patients treated with other antidepressants may be
considered overly conservative, preventing a comprehensive
understanding of psilocybin’s safety and effects in combination
therapy, as well as the necessary tapering or washout periods to
avoid pharmacological interactions upon switching medications.
To the best of our knowledge, only two recent clinical trials
(NCT03429075 and NCT03912974) included two separate treat-
ment sessions with psilocybin and an SSRI. In the former, there
was no concomitant administration of the two drugs
26
;inthe
latter, psilocybin was administrated only on the last day of the
two-week escitalopram pretreatment period.
74
Consequently, the
relative efficacy of psilocybin in combination with another anti-
depressant has not yet been established in RCTs. Moreover, stan-
dard antidepressants typically show limited efficacy in reducing
suicidal ideation in the first phase of treatment.
90
In this regard,
one of the mentioned clinical trials compared psilocybin to the
SSRI escitalopram.
26
The study did not demonstrate the superi-
ority of psilocybin over escitalopram in reducing depressive symp-
toms, its primary outcome. Although secondary outcomes,
including suicidal ideation, clinical remission, other measures of
depressive symptoms, anxiety, and anhedonia, tended to favor
psilocybin, the analysis was not corrected for multiple compari-
sons. Therefore, drawing firm conclusions from these findings
may be questionable.
26
In terms of safety, psilocybin was better
tolerated than escitalopram,
26
although the latter contributed to
mitigating psilocybin-induced acute autonomic adverse events in
the study arm evaluating the response to psilocybin after pretreat-
ment with escitalopram.
74
Although this finding does not result
from a sustained and combined drug administration, it suggests
that combining psilocybin with a standard antidepressant may not
only be safe but also beneficial in terms of side effects. However,
this may not apply to all antidepressants, and potential interac-
tions should be considered carefully. For instance, since psilocin is
metabolized by the liver monoamine oxidase (MAO),
91
MAO
inhibitors may intensify the effects, and this combination should
be avoided. Conversely, a recent retrospective online survey found
that psilocybin’s effect was attenuated up to 3 months after dis-
continuing SSRIs or serotonin and norepinephrine reuptake
inhibitors (SNRIs).
92
This attenuation might be due to
6 M. Scala et al.
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
Table 2. Completed Clinical Trials and Secondary Analyses with Results Published in Peer-Reviewed Journals until December 2023
Reference Year
Trial registration
identifier
Sample size and
clinical
presentation Study design Main findings Limitations
Carhart-Harris
et al.
2021 NCT03429075 n 59
MDD
Randomized
double-blind
controlled trial
No difference in
antidepressant effect
between PSY 25 mg
and ESC by wk 6
QIDS-SR–16: 8.0 for PSY
vs. 6.0 for ESC
(p = 0.17)
- Possible selection bias
- Moderate depression at baseline
- Brief duration of escitalopram treatment
- Blinding effectiveness not assessed within
each treatment group
- No comparison with placebo
- Lack of correction for multiple compari-
sons for secondary outcomes
- Medium-term follow-up (6 mth)
- Follow-up data not fully collected
Davis et al. 2021 NCT03181529 n 24
MDD
Randomized,
waiting-list
controlled
clinical trial
Greater ↓of depressive
symptoms in GRID-
HDRS in the immediate
treatment group (PSY
20 mg/ and 30 mg/kg)
by wks 1 and 4 (SD 8.0
[7.1] and 8.5 [5.7])
compared to delayed
treatment group by
wks 5 and 8 (SD 23.8
[5.4] and 23.5 [6.0])
- Small sample size
- Possible selection bias
- Moderate depression at baseline
- Psychotherapy was delivered by facilita-
tors without formal clinical training
- Single-blinded
- Waiting list
- No comparison with placebo or TAU
- Possible attrition bias
- Short-term follow-up (1 mth)
Becker et al., 2022 NCT03912974 n 27
MDD
Randomized
double-blind
placebo-
controlled
crossover study
ESC (10–20 mg)
pretreatment (14 d)
reduced PSY (25 mg)
bad effects, AEs
(p = 0.004), fear
(p = 0.004), anxiety
(p < 0.05), and
autonomic AEs
(p < 0.02) compared
with placebo
pretreatment
- Crossover design
- Small sample size
- HS only
- Possible selection bias
- Brief duration of escitalopram treatment
- No therapeutic setting
- No correction for multiple testing
- No follow-up
Gukasyan et al. 2022 NA n 24
MDD
Randomized-
waiting-list
controlled
clinical trial
PSY 20 and 30 mg/70 kg 2
wks apart:
antidepressant
response rate of 75%
and remission of 58%
in GRID-HDRS by mth
12
- Small sample size
- Lack of diversity among participants
- Single-blinded
- Waiting list
- No comparison with placebo or TAU
- Lack of a long-term comparison group
- 33% of participants used other ADs during
follow-up
- Medium-term follow-up (12 mth)
von Rotz et al. 2023 NCT03715127 n 52
MDD
Randomized,
double-blind,
placebo-
controlled,
parallel-group
trial
Greater ↓of depressive
symptoms with PSY
(0.215 mg/kg)
compared with
placebo by d 14MADRS:
15.0 to 1.3 (Cohens’
d = 0.97, p = 0.0011) for
PSY
- Small sample size
- Lack of diversity among participants
- Single-dose protocol
- No comparison with TAU
- Short-term follow-up (2 wk)
Sloshower et al. 2023 NCT03554174 n 19
MDD
Placebo-
controlled,
within-subject,
fixed-order trial
No significant difference
in the improvement of
depression and anxiety
between PSY 0.3 mg/kg
compared with
placebo by wk 6
GRID-HDRS: Δ= 6.3–8.7,
Cohens’d = 1.02–2.27
for PSY vs. Δ= 4.4–5.8,
and Cohens’
d = 0.65–0.99 for
placebo
- Pilot study
- Small sample size
- Potential selection bias
- Lack of diversity among participants
- Lack of randomization
- Single-blinded
- Fixed-order design
- Single-dose protocol
- No comparison with TAU
- Short-term follow-up (16 wk)
CNS Spectrums 7
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Table 2. Continued
Reference Year
Trial registration
identifier
Sample size and
clinical
presentation Study design Main findings Limitations
Raison et al. 2023 NCT03866174 n 104
MDD
Randomized
double-blind
active placebo-
controlled
PSY 25 mg ↓depressive
symptoms by d 43
compared with niacin
MADRS: MD 12.3
[95% CI, 17.5 to
7.2]; p < 0.001)
- Lack of diversity among participants
- Potential selection bias
- Ineffective blinding
- Niacin as an active placebo may have
amplified the placebo response
- Single-dose protocol
- Facilitator adherence to psychological
support protocol not assessed
- No comparison with TAU
- Short-term follow-up (43-d)
Carhart-Harris
et al.
2016 ISRCTN14426797 n 12
TRD
Open-label
uncontrolled
study
PSY 10 and 25 mg 7 days
apart ↓depressive
symptoms by 1 wk and
mth 3
QIDS: mean change wk
1–11.8, 95% CI –9.15 to
14.35, p = 0.002,
Hedges’g = 3.1) and
mth 3–9.2, 95%
CI –5.69 to 12.71,
p = 0.003, Hedges’g=2
- Pilot study
- Open-label design
- Small sample size
- Within-group analyses only
- No comparison with placebo or TAU
- No enduring improvements after 3 mths
- Short-term follow-up (3 mth)
Carhart-Harris
et al.
2017 NA n 16
TRD
Open-label
uncontrolled
study
PSY 10 and 25 mg/70 kg 1
wk apart ↓depressive
symptoms by wk 5
QIDS-SR16: mean change
8 ± 5.1, t = 6.3,
p < 0.001
- Open-label design
- Small sample size
- Lack of diversity among participants
- No consideration of confounding factors
- No comparison with placebo or TAU
- Short-term follow-up (5 wk)
Carhart-Harris
et al.
2018 NA n 20
TRD
Open-label
uncontrolled
follow-up study
PSY 10 and 25 mg 7 d
apart ↓depressive
symptoms (BDI and
QIDS-SR16) by mth 3
and 6 (Cohen’s d = 1.5
and 1.4, p < 0.001)
- Open-label design
- Small sample size
- Lack of diversity among participants
- Variability in patients’assessment of cur-
rent depressive episode duration
- No comparison with placebo or TAU
- Medium-term follow-up (6 mth)
Erritzoe et al. 2018 NA n 20
TRD
Open-label
uncontrolled
study
PSY 10 and 25 mg 7 d
apart modulates
personality structure
(NEO-PI-R) by mth 3
↓neuroticism
(MD –5.7, p = 0.002,
Cohen’s d = 0.571)
↑extraversion (MD 6.5,
p = 0.001, Cohen’s
d = 0.716) and ↑
openness (MD 4.9,
p = 0.012, Cohen’s
d = 0.437)
- Open-label design
- Small sample size
- Lack of diversity among participants
- No consideration of confounding factors
- No comparison with placebo or TAU
- Short-term follow-up (3 mth)
Lyons et al. 2018 NA n 15
TRD
Open-label study PSY 10 and 25 mg 7 d
apart
↓pessimism bias (POFLE)
by wk 1[t(14 = 2.714,
p = 0.017; 95% CI
(0.21, 0.02), g = 0.7]
↓depressive symptoms
(BDI) by wk 1
[t
14
= 7.900, p < 0.001;
95% CI (16.17, 28.23),
g = 1.9]
- Pilot study
- Open-label and cross-sectional design
- Small sample size
- It is part of another open-label study
(Carhart-Harris et al., 2016)
- HS control group (n = 15), not exposed to
the same treatment procedures
- No comparison with placebo or TAU
- Uncertain improvement in cognitive
(pessimism) bias, as it may be an epiphe-
nomenon of the core effects of treatment
on depressive symptoms
- Short-term follow-up (1 wk)
8 M. Scala et al.
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Table 2. Continued
Reference Year
Trial registration
identifier
Sample size and
clinical
presentation Study design Main findings Limitations
Goodwin et al. 2022 NCT03775200 n 233
TRD
Randomized
double-blind,
dose-finding,
parallel-group,
clinical trial
PSY 25 mg, but not 10 mg,
reduced depression
more than a 1-mg dose
by 3 wk
MADRS MD between
PSY25 mg and PSY
1mgwas6.6
(p < 0.001)No
difference between
PSY 10 mg and 1 mg
MADRS MD between PSY
10 mg and PSY 1 mg
was 2.5 (p = 0.18)
- Dose–response study
- Lack of diversity among participants
- Moderate depression at baseline
- Incomplete blinding
- Single-dose protocol
- Variability in session monitors’back-
ground and education
- No comparison with placebo or TAU
- Short-term follow-up (12 wk)
Grob et al. 2011 NCT00302744 n 12
Cancer-related
anxiety and
depressive
symptoms
Randomized
double-blind
active placebo-
controlled
crossover study
PSY 0.2 mg/kg failed to
improve depressive
symptoms and anxiety
symptoms by wk 2
Depression (BDI)
decreased at mth 6
(t
7
= 2.71, p = 0.03)
Anxiety (STAI trait)
decreased at mth 1
(t
11
= 4.36, p = 0.001)
- Pilot study
- Crossover design
- Small sample size
- Potential selection bias
- Single-dose protocol
- No comparison with TAU
- No data of the between-group compari-
son
- Variability in posttreatment subject con-
tact
- Potential detection bias
- Medium-term follow-up (6 mth)
Griffiths et al. 2016 NCT00465595 n 51
Cancer-related
anxiety and
depressive
symptoms
Randomized
double-blind
crossover study
PSY 1 or 3 mg/70 kg vs. PSY
22 or 30 mg/70 kg 5 wks
apart
Depression (GRID-HDRS–
17): clinical response
rate of 78% and
treatment remission
65% 6 mths
Anxiety (HAM-A): clinical
response rates of 83%
and treatment remission
57% by 6 mths
- Crossover design
- Small sample size
- Lack of diversity among participants
- Not all questionnaires are validated
- No double-blind assessment after cross-
over
- No comparison with placebo or TAU
- Medium-term follow-up (6 mth)
Ross et al. 2016 NCT00957359 n 29
Cancer-related
anxiety and
depressive
symptoms
Randomized
double-blind
active placebo-
controlled
crossover study
PSY 0.3 mg/kg vs. niacin 7
wks apartDepression
(BDI): clinical response
rate of 83% by wk 7
Anxiety (HAD-A): clinical
response rate of 58%
by wk 7
- Crossover design
- Small sample size
- Lack of diversity among participants
- Possible detection bias in the control
group
- Single-dose protocol
- No comparison with TAU
- Medium-term follow-up (6.5 mth)
Agin-Liebes
et al.
2020 NA n 15
Cancer-related
anxiety and
depressive
symptoms
Long-term within-
subject follow-
up analysis of
Ross et al., 2016
PSY 0.3 mg/kg vs. niacin 7
wks apart
Depression (BDI): clinical
response rate of 79% at
4.5-yr follow-up
Anxiety (HADS): clinical
response rate of 57% at
4.5-yr follow-up
- Crossover design
- Small sample size
- Lack of diversity among participants
- Possible detection bias in the control
group
- Single-dose protocol
- No comparison with TAU
- Intake of other ADs during follow-up
- Potential reporting bias
Ross. et al. 2021 NA n 11
Cancer-related
anxiety and
depressive
symptoms
Follow-up analysis
ofRoss et al.,
2016
PSY 0.3 mg/kg vs. niacin 7
wks apart
↓in SI (BDI and BSI) by 8 h
[p < 0.001] and
sustained for 6.5 mths
[p < 0.001]
↓LoM (DS) by wk 2
[p = 0.005] and
sustained by mth 6.5
[p < 0.001], yr 3.2
[p < 0.001], and yr 4.5
[p < 0.001]
- Crossover design
- Small sample size
- Lack of diversity among participants
- Possible detection bias in the control
group
- Single-dose protocol
- No comparison with TAU
- The parent trial was not designed to
assess the antisuicidal effects of PSY
- underpowered analyses
- Only 4 patients completed 4.5-yr
follow-up
CNS Spectrums 9
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Table 2. Continued
Reference Year
Trial registration
identifier
Sample size and
clinical
presentation Study design Main findings Limitations
Agrawal et al. 2023 NA n 30
MDD associated
with cancer
Fixed-dose open-
label study
PSY 25 mg ↓depressive
symptoms by wk 8
MADRS: mean change
19.1 (95% CI, 22.3 to
16.0; p < 0.001)
by wk 8.
Antidepressant response
rate of 80% and
treatment remission of
50% by wk 8
- Open-label design
- Small sample size
- Single-dose protocol
- No comparison with placebo or TAU
- Short-term follow-up (8 wks)
Anderson et al. 2020 NCT02950467 n 18
AIDS-related
demoralization
Open-label
uncontrolled
study
PSY 0.3–0.36 mg/kg ↓
demoralization by
mth 3
DS-II: mean
difference 5.78
[SD 6.01], partial eta
squared = 0.47, 90% CI
0.21–0.60 by mth 3
- Pilot study
- Open-label design
- Small sample size
- Lack of diversity among participants
- Possible selection bias
- Single-dose protocol
- No comparison with placebo or TAU
- Short-term follow-up (3 mth)
Moreno et al. 2006 NA n 9
OCD
Modified double-
blind trial
PSY escalating dosage
sequence 1 wk apart
(25–100–200–300 μg/
kg) ↓OCD symptoms
(23%–100% decrease
in YBOCS score). No
significant effect of
dose (F = 2.25, df = 3,3;
p = .261) orinteraction
of time and dose
(F = 0.923, df = 9,45;
p = .515)
- Proof-of-concept study
- Pre/posttest design
- Small sample size
- Potential selection bias
- Lack of randomization
- The study was designed primarily to
assess safety and tolerability, but clinical
data were also collected.
- No comparison with placebo or TAU
- No comparison between groups
- Modified blinded procedures
- Only one participant with medium-term
follow-up (6 mth)
Schneier et al. 2023 NA n 12
BDD
Open-label
uncontrolled
study
PSY 25 mg ↓BDD
symptoms (BDD-
YBOCS) by wk 12
(p < 0.001, partial eta
squared = 0.54)
- Pilot study
- Open-label design
- Small sample size
- Limited diversity among participants
- Potential selection bias
- Single-dose protocol
- No comparison with placebo or TAU
- Lack of systematic assessment of non-
serious AEs
- Short-term follow-up (12-wk)
Bogenschutz
et al.
2015 NCT02061293 n 10
Alcohol
dependence
Open-label
uncontrolled
study
↓in percentage drinking
days (mean difference
SD = 27.2 (23.7), 95% CI
9.0–45.4, t
8
= 3.449,
p = 0.009) and heavy
drinking days (mean
difference SD = 26.0
(22.4), 95% CI 8.7–43.2,
t
8
= 3.477, p = 0.008)
during wks 5–12
- Proof-of-concept study
- Open-label design
- Small sample size
- Lack of biological verification of alcohol
use (only self-reported-only measures)
- No comparison with placebo or TAU
- Medium-term follow-up (36 wk)
Johnson et al. 2014 NA n 15
Tobacco
addiction
Open-label,
uncontrolled
study
After PSY 20 mg/70 kg at
wk 1, PSY 30 mg/70 at
wk 7 and 13; 80% of
participants showed
seven-day point
prevalence abstinence
at 6 mth
- Pilot study
- Open-label design
- Small sample size
- Lack of diversity among participants
- Self-selection bias
- No comparison with placebo or TAU
- Unable to differentiate effects of moder-
ate vs. high PSY doses
- Medium-term follow-up (6 mth)
Johnson et al. 2017 NA n 15
Tobacco
addiction
Long-term within-
subject follow-
up analysis of
Johnson et al.,
2014
After PSY 20 mg/70 kg at
wk 1, PSY 30 mg/70 at
wk 7, and 13, 67% of
the participants were
still abstinent at mth 12
(F 2,23 = 81.4, p < 0.001)
- Small sample size
- Lack of diversity among participants
- Self-selection bias
- Possible reporting bias
- No comparison with placebo or TAU
10 M. Scala et al.
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postsynaptic serotonergic receptor downregulation following
chronic antidepressant use.
93
Thus, regardless of the drug class,
attention should be paid to the duration of standard antidepres-
sant treatment: an acute administration may intensify the psyche-
delic effect and exacerbate adverse events, whereas a chronic
administration may decrease the therapeutic effects of psilocybin.
Another challenge is conducting high-quality trials with a
blinded control group treated with a psychoactive placebo that
mimics subjective experiences and potential adverse events during
PAP. Additionally, enhancing our understanding of how placebo
effects influence psilocybin’s antidepressant efficacy could be
achieved by using active comparators like ketamine, which induce
similar immediate antidepressant response rates (71% at 28 hours
for ketamine vs. 69% at 48 hours for psilocybin)
94
to assist with
blinding, whereas it typically does not produce the sustained anti-
depressant response of psilocybin (35% at week 1 for ketamine
vs. 71% at 1 month for psilocybin).
73,94,95
The difficulty of blinding
studies on psychedelics also includes the possibility that positive
results of psilocybin may have been enhanced by a nocebo effect in
the control group. To reduce the impact of the nocebo effect, it has
been recommended that in clinical trials, every patient randomized
should receive an effective dose of psilocybin after the primary
endpoint is assessed.
96
Furthermore, overcoming performance and
detection bias in future studies will be of valuable importance, given
the subjective effects induced by psilocybin and the self-rated scales
used to detect them. In this respect, excluding participants with
prior psychedelic exposure is essential to reduce expectancy bias, as
many patients included in clinical trials reported previous
psychedelic use.
Addressing these limitations will be essential for establishing the
efficacy and safety profile of psilocybin as a treatment for psychi-
atric disorders.
Ethical challenges and legal considerations
Despite the therapeutic potential, psilocybin remains a prohibited
and controlled substance in many countries. Nowadays, the legal
use of psilocybin is limited to a few countries such as Jamaica, and
the Netherlands, as well as in the context of research clinical trials.
As clinical studies yield promising results, the benefits and
popularity of this psychedelic are growing faster than the ethical
and legislative processes necessary for its proper use. An estimated
21 million people in the US use psilocybin, with some stating they
use it for recreational purposes and others for self-medication.
97
The pressing need for novel therapeutic options for treatment-
resistant psychiatric disorders is leading many patients to self-
administer this drug, rather than waiting for further evidence of
efficacy, legal medical, and protected access.
98
Social and cultural
stigma, arising from both recreational and therapeutic misuse,
presents another significant barrier to the potential use of psilocy-
bin in clinical practice.
An ethical issue that may arise if psilocybin is approved by
regulatory authorities for medical use is the need to standardize
access to PAP sessions. If the benefits of this drug extend beyond
psychiatry to conditions such as migraine headaches, organ trans-
plantation, cancer, and immune diseases,
68
ensuring fair access to
treatment will be crucial. Priority should likely be given to life-
threatening conditions initially (e.g., TRD with suicidal ideation
and cancer).
A final issue that may slow the approval of psilocybin for
medical use is the impossibility of patenting this drug since it is a
naturally occurring compound. Therefore, psilocybin is not attrac-
tive to pharmaceutical companies, and the high involvement of
institutional stakeholders is important.
Discussion
Despite the issues and challenges discussed above, there is increas-
ing evidence suggesting the therapeutic potential of psilocybin in
several conditions, characterized by a transdiagnostic profile with
internalizing symptoms and ruminations. In depression, common
ruminations include passive and negative thoughts about feelings
of guilt, inefficacy, negative topics, and self-criticism.
99
Ruminative
brooding was consistently linked to a more severe substance use
profile,
100
while ruminations about one’s obsessions can make
obsessions even more intrusive and ego-dystonic in OCD.
101
Psilocybin is typically administered for a few weeks, a consid-
erably shorter duration compared to treatment with SSRIs/SNRIs,
which can last several months or years to show and maintain
antidepressant effects.
102
Despite this more desirable shorter treat-
ment period, PAP needs a specific therapeutic setting, making its
Table 2. Continued
Reference Year
Trial registration
identifier
Sample size and
clinical
presentation Study design Main findings Limitations
Aaronson et al. 2023 NCT04433845 n 15
BD
Open-label
uncontrolled
study
PSY 25 mg ↓BDII
depression by wk 3 and
remission persisted by
wk 12.
MADRS: mean (SD)
change 24.00 (9.23),
Cohen d = 4.08, 95% CI,
29.11 to 18.89,
p < 0.001 by wk 3
- Open-label design
- Small sample size
- Possible selection bias
- Single-dose protocol
- No comparison with placebo or TAU
- Short-term follow-up (12 wk)
For some studies, some data is not available (i.e., p-value, effect size, SD, and MD).
Abbreviations: AE, adverse event; AIDS, acquired immune deficiency syndrome; BD, bipolar depression; BDD, body dysmorphic disorder; BDD-YBOCS, Yale Brown Obsessive Compulsive Scale
Modified for Body Dysmorphic Disorder; BDI, Beck Depression Inventory total score; BDII, bipolar depression II; BSI, Brief Symptom Inventory; CI, confidence interval; df, degrees of freedom; DS,
Demoralization Scale, DS-II, Demoralization Scale-II; ESC, escitalopram; F, F-statistic; GRID-HDRS, Grid-Hamilton Depression Rating Scale total score; HADS, Hospital Anxiety and Depression
Scale total score; HAM-A, Hamilton Anxiety Rating Scale total score; h, hour; HS, healthy subjects; MADRS, Montgomery-Asberg Depression Rating Scale total score; MD, mean deviation;
MDD, major depressive disorder; mth, month; N, sample size; NA, not available; NEO-PI-R, revised NEO Personality Inventory; OCD, obsessive-compulsive disorder; p, p-value; POFLE, Prediction
Of Future Life Events task; PSY, psilocybin; QIDS, Quick Inventory of Depressive Symptomatology total score; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Reported total score;
SD, standard deviation; STAI, State–Trait Anxiety Inventory total score; TAU, treatment as usual; TRD, treatment resistant depression; wk, week; YBOCS, Yale-Brown Obsessive Compulsive Scale;
yr, year.
CNS Spectrums 11
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
administration more complicated compared to standard antide-
pressants that are generally taken by patients at home.
In our opinion, the potential benefits of psilocybin may also be
considered with cautious optimism in other conditions, such as
autism spectrum disorder (ASD). LSD showed potential efficacy in
ASD during the “first wave”of psychedelic research.
103
Psilocybin’s
empathogenic effects may alleviate social anxiety, and depression,
as well as rigid cognitive and behavioral patterns associated with
ASD while increasing emotional empathy and sociability. Given
the significant impact of social withdrawal as an early manifesta-
tion in various neuropsychiatric disorders, and its trans-diagnostic
association with a decreased likelihood of short-term symptom
remission,
104
the use of psilocybin to engage directly with social
impairments presents a compelling therapeutic avenue. Addition-
ally, a recent preclinical research involving a rat model reported
that serotonin-modulating drugs such as psilocybin may be effec-
tive in ameliorating ASD-related cognitive deficits.
105
Based on the
evidence of psilocybin’s efficacy in ameliorating ego-dystonic
obsessions in OCD,
67
it may also be useful in reducing the pervasive
interests and repetitive behaviors in ASD, though obsessive and
compulsive-like symptoms in ASD differ from those in OCD and
present unique psychopathological experiences.
106
While these
effects are desirable in ASD, a potential challenge of PAP in this
population could be the risk of triggering aggressive behavior due
to the difficulties in interacting with therapists and communicating
the deeper consciousness contents.
107
Considering that psychotic
experiences are significantly higher in people with ASD compared
to neurotypical individuals, another risk of using PAP in the ASD
population may be related to the rare psychotic-like symptoms
potentially induced by psilocybin.
108
Therefore, a tailored PAP
protocol for neurodevelopmental disorders may involve micro-
dosing to minimize adverse events, and repeated sessions to facil-
itate the processing of unconscious material.
Nevertheless, before implementing psilocybin in the real world,
further evidence of its safety and efficacy is required to support
informed clinical decision-making. Future well-powered and
designed RCTs should randomize patients to receive PAP, standard
antidepressant drugs (i.e., SSRIs or SNRIs), and/or psychotherapy
(i.e., CBT). Standardized psychometric scales should be used to
assess symptom improvement/remission as the primary outcome.
To ensure the validity of results, the assessment should be con-
ducted at baseline, approximately 1 month after treatment initia-
tion (to compare the onset of action), and periodically up to 1 year
(to evaluate medium-term effects). Double-blinding procedures
should be maintained throughout the study duration and the
follow-up to eliminate potential detection biases. Considering that
the different time periods between PAPs may impact treatment
outcomes, RCTs should compare psilocybin effects when used with
various time intervals between dosing sessions, such as once a week
or once a month. Furthermore, RCTs may identify distinct sub-
populations responding optimally to psilocybin, SSRIs/SNRIs, or
CBT. By evaluating the impact of assignment to one of these three
treatment groups on the outcomes, we might be able to explore
whether these therapeutic pathways serve as the causal mediators
through which treatment effectiveness is achieved.
We need to further investigate dose optimization, the optimal
duration of washout periods to sustain the therapeutic effect
between PAP sessions, the ideal number of sessions, as well as
the most relevant elements and strategies of psychological inter-
vention. This will allow us to understand if it is possible to minimize
mild hallucinogenic effects and alterations in consciousness while
still benefiting from neuroplasticity mechanisms. If this is possible,
we would have a pure psychoplastogen agent.
109
However, it is
possible that the psychedelic experience is necessary to produce the
therapeutic benefits, and neuroplasticity itself can partly contrib-
ute.
110
Since mystic experiences may direct the effects of neuro-
plasticity toward a beneficial change, providing supporting
therapeutic settings seems necessary to obtain the full therapeutic
potential of psilocybin. Enrolled patients should be willing to
actively undergo this mystical experience, rather than passively
hoping that psilocybin will change their thoughts and behavioral
patterns. Therefore, patients’motivation for this treatment and the
therapeutic alliance with clinicians remain indispensable condi-
tions for ensuring the benefits of the treatment itself.
A major effort from the scientific community is pivotal to
strengthen boundaries, both legal and ethical, between the clinical
and recreational use of psilocybin. This entails the development of
appropriate ethical principles and guidelines, as well as legislative
measures to prevent the misuse of psychedelics. Learning from the
therapeutic use of ketamine, it is essential to carefully balance the
risks and benefits associated with psilocybin.
It is important to temper excessive media enthusiasm surround-
ing psilocybin and comprehensively assess its potential interactions
with other drugs, as well as the duration of its therapeutic effects.
Furthermore, exploring other possible mechanisms of action, such
as potential anti-inflammatory properties,
111
may provide addi-
tional support for benefits in various disorders, including depres-
sive
112
and anxiety disorders.
113
Conclusions
This review critically examined essential aspects related to the
implementation of psilocybin in real-world settings, extending
beyond its efficacy in treating major psychiatric disorders. While
further evidence of efficacy is needed for the treatment of OCD and
SUD, the use of psilocybin may present a potential alternative to
current antidepressants, improving depressive and anxiety symp-
toms with mild and transient side effects, as well as a shorter onset
of action and treatment duration. However, the integration of
psilocybin into clinical practice still faces significant challenges,
including the need for larger, well-powered RCTs to validate its
efficacy and safety in a comprehensive manner. These future
studies should also explore optimal dosing, treatment frequency,
and the integration of psychological therapies to maximize thera-
peutic benefits. Moreover, it is imperative to establish clear ethical
and legal frameworks to differentiate clinical use of psilocybin from
its recreational misuse. Advancing psilocybin research will there-
fore require a concerted effort to accumulate robust, evidence-
based data supporting its therapeutic application in psychiatry.
This endeavor will not only help delineate the precise therapeutic
niche of psilocybin but also potentially augment the armamentar-
ium of available psychiatric treatments.
Ethical considerations. Since this review included only published data, ethics
approval was not sought.
Funding and acknowledgments. This work was supported by #NEXTGEN-
ERATIONEU (NGEU) and funded by the Italian Ministry of University and
Research (MUR), National Recovery and Resilience Plan (NRRP), project
MNESYS (PE0000006)—a multiscale integrated approach to the study of the
nervous system in health and disease (DN. 1553, October 11, 2022).
Author contribution. Conceptualization: A.S., C.F., M.S., G.F.; Data curation:
A.S., C.F., M.S., G.F.; Funding acquisition: A.S., C.F., M.a.P.S.(.5.M., G.F.;
12 M. Scala et al.
https://doi.org/10.1017/S1092852924002268 Published online by Cambridge University Press
Investigation: A.S., C.F., M.S., G.F.; Methodology: A.S., C.F., M.S., G.F.; Project
administration: A.S., C.F., G.F.; Resources: A.S., C.F., M.S., G.F.; Software: A.S.,
G.F.; Supervision: A.S., A.A., A.P.,C.F., L.F., G.F.;Validation: A.S., A.A., A.P., C.F.,
L.F., M.S., G.F.; Writing –review & editing: A.S., A.A., A.P., C.A., C.F., G.D.L.,
D.D.R., M.a.P.S.(.5.M., L.F., M.M., M.F., M.S., P.F., G.F.; Writing –original draft:
A.A., A.P., L.F., M.S.; Visualization: C.F., M.S.; Formal analysis: M.S.
Competing interest. AS is or has been a consultant to or has received
honoraria or grants unrelated to the present work from Abbott, AbbVie,
Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli
Lilly, GlaxoSmithKline, InnovaPharma, Italfarmaco, Janssen, Lundbeck,
Naurex, Pfizer, Polifarma, Sanofi, Servier, and Taliaz. CF was a speaker for
Janssen. The other authors declare no potential conflicts of interest.
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