Adverse event reporting and management in psilocybin therapy clinical trials: A systematic review to guide clinical and research protocol development

Oct 25, 2025Progress in neuro-psychopharmacology & biological psychiatry

Reporting and managing side effects in psilocybin therapy trials to improve clinical and research guidelines

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Psychedelic Science on OpenScience ↗PubMed ↗DOI ↗

Abstract

A total of 42 studies involving 1,068 participants reported on adverse events related to psilocybin use.

Common adverse events included headache, nausea, and temporary increases in blood pressure.
These adverse events usually resolved without medical intervention.
Serious adverse events were rare and mostly occurred in participants with existing depressive disorders.
High risk of bias was noted in all studies due to concerns about blinding.
Overall, psilocybin may have a favorable safety profile when used in controlled environments.

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Psilocybin, a psychedelic prodrug, has gained renewed interest for its potential to treat various psychiatric disorders, including depression, anxiety, and substance use disorders. While promising, concerns remain regarding its safety profile and the management of potential adverse events (AEs). This systematic review aimed to evaluate the incidence, nature, and severity of adverse events and serious adverse events (SAEs) associated with psilocybin use across diverse clinical populations. A comprehensive search was conducted across MEDLINE, Embase, and APA PsycInfo via the OVID platform, from database inception to June 5, 2024. A total of 42 clinical studies (N = 1068 participants) met inclusion criteria, all of which reported on AEs and/or SAEs following psilocybin administration. All studies were deemed to have a high risk of bias due to concerns regarding blinding. We synthesized information on common, uncommon, and SAEs, instances of suicidal ideation, methods of measuring AEs, and AEs requiring medical intervention. Reported AEs included headache, transient increases in blood pressure, and nausea, which typically resolved on their own. In rare instances, medical intervention was required. SAEs were reported infrequently in 2 of 42 studies and were limited to participants with underlying depressive disorders (e.g., suicidal behaviour, hospitalization). Overall, psilocybin appears to have a favourable safety profile when administered in controlled settings. Based on our findings, we provide an outline of commonly reported AEs, uncommon AEs, SAEs, and considerations for future clinical and research protocols.