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Review
. 2025 Jan 1;182(1):54-78.
doi: 10.1176/appi.ajp.20230682.

Psilocybin: From Psychiatric Pariah to Perceived Panacea

Gregory A Fonzo  1 , Aaron S Wolfgang  1 , Bryan R Barksdale  1 , John H Krystal  1 , Linda L Carpenter  1 , Nina V Kraguljac  1 , Adrienne Grzenda  1 , William M McDonald  1 , Alik S Widge  1 , Carolyn I Rodriguez  1 , Charles B Nemeroff  1
Affiliations
Review

Psilocybin: From Psychiatric Pariah to Perceived Panacea

Gregory A Fonzo et al. Am J Psychiatry. .

Abstract

Objective: The authors critically examine the evidence base for psilocybin administered with psychological support/therapy (PST) in the treatment of psychiatric disorders and offer practical recommendations to guide future research endeavors.

Methods: PubMed was searched for English-language articles from January 1998 to November 2023, using the search term "psilocybin." A total of 1,449 articles were identified and screened through titles and abstracts. Of these, 21 unique open-label or randomized controlled trials (RCTs) were identified that examine psilocybin for the treatment of obsessive-compulsive and related disorders (N=2), anxiety/depression associated with a cancer diagnosis (N=5), major depressive disorder (MDD; N=8), substance use disorders (N=4), anorexia (N=1), and demoralization (i.e., hopelessness, helplessness, and poor coping) in AIDS survivors (N=1).

Results: The most developed evidence base is for the treatment of MDD (three double-blind RCTs with positive signals spanning a range of severities). However, the evidence is tempered by threats to internal and external validity, including unsuccessful blinding, small samples, large variability in dosing and PST procedures, limited sample diversity, and possibly large expectancy effects. Knowledge of mechanisms of action and predictors of response is currently limited.

Conclusions: The evidence is currently insufficient to recommend psilocybin with PST as a psychiatric treatment. Additional rigorously designed clinical trials are needed to definitively establish efficacy in larger and more diverse samples, address dosing considerations, improve blinding, and provide information on mechanisms of action and moderators of clinical response. Head-to-head comparisons with other evidence-based treatments will better inform the potential future role of psilocybin with PST in the treatment of major psychiatric disorders.

Keywords: Anxiety; Depression; Psilocybin; Psychiatric Disorders; Psychological Support/Therapy.

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Conflict of interest statement

Dr. Fonzo has served as a consultant for SynapseBio AI and Alto Neuroscience; he has received research support from the Brain and Behavior Research Foundation, the One Mind Baszucki Brain Research Fund, and the SEAL Future Foundation; he is named as an inventor on a patent application related to the treatment of depression; and he is a stockholder in Alto Neuroscience. Dr. Krystal serves on the editorial board of Biological Psychiatry; he is co-founder of Freedom Biosciences; he has served on scientific advisory boards for Biohaven Pharmaceuticals, BioXcel Therapeutics (clinical advisory board), Cerevel Therapeutics, Delix Therapeutics, Eisai, EpiVario, Jazz Pharmaceuticals, Neumora Therapeutics, Neurocrine Biosciences, Novartis, PsychoGenics, Takeda, Tempero Bio, and Terran Biosciences; he has received in-kind research support (medications) from AstraZeneca, Cerevel, Novartis; he has served as a consultant for Aptinyx, Biogen Idec MA, Bionomics, Boehringer Ingelheim International, Epiodyne, EpiVario, Janssen Research & Development, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Spring Care, and Sunovion Pharmaceuticals; he is named on patents related to various mental disorders, including schizophrenia, depression, suicidal ideation, addiction, and gambling and gaming disorders; and he holds stock or stock options in Biohaven Pharmaceuticals, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, EpiVario, Freedom Biosciences, Neumora Therapeutics, Response Pharmaceuticals, Rest Therapeutics, Spring Health, Tempero Bio, Terran Biosciences, and Tetricus. Dr. Carpenter has received research support from Janssen, Neuronetics, Neurolief, and Nexstim, and she has served as a consultant for Janssen, Magnus Medical, MAPS Public Benefit Corp, Motif Neurotech, Neuronetics, Neurolief, Otsuka, and Sage Therapeutics. Dr. McDonald and Dr. Rodriguez are Deputy Editors for the American Journal of Psychiatry; the Editors’ disclosures appear in the April 2024 issue of the Journal. Dr. Grzenda serves on the Editorial Board of the Journal (statistical editor) and has served as a consultant for the American Psychiatric Association. Dr. Widge has received research support from the Minnesota Medical Discovery Team on Addictions and the MnDRIVE Brain Conditions Initiative. Dr. Nemeroff has served as a consultant for AbbVie, ANeuroTech (division of Anima BV), BioXcel Therapeutics, Clexio, EMA Wellness, EmbarkNeuro, Engrail Therapeutics, Galen Mental Health, GoodCap Pharmaceuticals, Intra-Cellular Therapies, Relmada Therapeutics, Sage, Senseye, Signant Health, and Silo Pharma; he is a stockholder in Corcept Therapeutics, EMA Wellness, Galen Mental Health, Precisement Health, Relmada Therapeutics, and Seattle Genetics; he has served on scientific advisory boards for ANeuroTech, the Brain and Behavior Research Foundation, the Laureate Institute for Brain Research, Sage, Signant Health, and Skyland Trail and on the board of directors for Lucy Scientific Discovery; and he is named on patents related to psychiatric treatment.

Figures

Figure 1.
Figure 1.
PRISMA Diagram of Literature Search and Inclusion/Exclusion of Studies
See this image and copyright information in PMC

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