Psilocybin-assisted therapy for relapse prevention in alcohol use disorder: a phase 2 randomized clinical trial

Background Despite the promising therapeutic effects of psilocybin, its efficacy in preventing relapse after withdrawal treatment for alcohol use disorder (AUD) remains unknown. This study aims to assess whether a single dose of psilocybin combined with brief psychotherapy could reduce relapse rates and alcohol use in AUD patients. Methods This single-center, double-blind, randomized clinical trial was conducted in Switzerland. We recruited participants with AUD between June 8, 2020, and August 16, 2023 who completed withdrawal treatment within six weeks prior to enrollment. Participants were randomized (1:1) to receive either a single oral dose of psilocybin (25 mg) or placebo (mannitol), combined with brief psychotherapy. The primary outcomes were abstinence and mean alcohol use at 4-week follow-up. Participants completed the timeline followback to assess daily alcohol use. The trial is registered on ClinicalTrials.gov (NCT04141501). Findings We included 37 participants who completed the 4-week follow-up (female:male = 14:23; psilocybin = 18, placebo = 19) in the analysis. There were no significant differences between groups in abstinence duration (p = 0.55, psilocybin mean = 16.80 days, 95% CI: 14.31-19.29; placebo mean = 13.80 days, 95% CI: 10.97-16.63; Cohen's d = 0.151) or mean alcohol use per day (p = 0.51, psilocybin: median = 0.48 standard alcohol units, range: 0-3.99, placebo: median = 0.54 standard alcohol units, range: 0-5.96; Cohen's d = 0.11) at 4-week or 6month follow-up (abstinence: Cohen's d = 0.10, alcohol use: Cohen's d = 0.075). Participants in both groups reported reduced craving and temptation to drink alcohol after the dosing visit, with an additional reduction observed in the psilocybin group. Thirteen adverse events occurred in the psilocybin and seven in the placebo group. One serious adverse event occurred in the psilocybin and four in the placebo group, all related to inpatient withdrawal treatments. Interpretation A single dose of psilocybin combined with five psychotherapy sessions may not be sufficient to reduce relapse rates and alcohol use in severely affected AUD patients following withdrawal treatment. However, given the limited sample size of our study, larger trials are needed in the future to confirm these findings. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).