Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder

Ninety‑five participants were randomised (49 to psilocybin, 46 to diphenhydramine); 93 received at least one dose and were included in the primary analyses. The mean (SD) age was 46 (12) years and 44.2% were female. Valid drinking‑outcome data were obtained for 717 of 744 follow‑up months (96.4%) across the 93 treated participants. Attendance at psychotherapy sessions was high and similar between groups (mean [SD] completed sessions 11.75 [0.76] for psilocybin vs 11.47 [1.20] for diphenhydramine). EtG confirmation at week 24 was available for 50 of 93 participants (53.8%). The prespecified primary outcome, PHDD during the 32‑week double‑blind period (weeks 5 to 36), was lower in the psilocybin group: 9.7% versus 23.6% in the diphenhydramine group, a mean difference of 13.9% (95% CI, 3.0%–24.7%; F1,86 = 6.43; P = .01). The authors also report that mean daily alcohol consumption was lower in the psilocybin group. In relative terms, PHDD in the psilocybin arm was 41% of that observed in the diphenhydramine arm over the observation period. Exploratory analyses of secondary continuous outcomes (PDD and DPD) similarly favoured psilocybin in multivariate tests. For dichotomous outcomes, participants receiving psilocybin were more likely to have no heavy drinking days and to achieve a 2‑level reduction in WHO risk level during weeks 5 to 36; these differences persisted in the final month of follow‑up (weeks 33 to 36), when abstinence and 1‑ and 3‑level WHO reductions were also more common in the psilocybin group. Numbers needed to treat ranged from 4.0 to 8.2 and odds ratios from 2.03 to 4.74 for these outcomes. Drinking‑related problems were reduced to a greater extent in the psilocybin group: mean (SD) total problems score at week 36 was 6.59 (8.80) for psilocybin versus 13.00 (10.48) for diphenhydramine (mean difference 6.4; 95% CI, 2.22–10.60; Hedges g = 0.67; P = .003). Regarding subjective drug effects and blinding, MEQ scores differed by group (psilocybin produced higher MEQ scores), and both participants and therapists overwhelmingly guessed treatment assignment correctly (participants guessed correctly in 93.6% of first sessions and 94.7% of second sessions; therapists guessed correctly in 92.4% and 97.4%, respectively), with high reported certainty. Safety data showed no serious adverse events among participants who received psilocybin. Three serious adverse events occurred, all in the diphenhydramine group: two psychiatric hospital admissions for suicidal ideation during binge drinking and one hospitalisation for Mallory‑Weiss tear from severe vomiting. Treatment‑emergent events within 48 hours of drug administration included headache (reported in 21 of 48 psilocybin recipients [43.8%] vs 2 of 45 diphenhydramine recipients [4.4%]), and higher rates of anxiety and nausea with psilocybin. Two psilocybin‑assigned participants received diazepam 10 mg during a session for anxiety; one participant experienced brief passive suicidal ideation during a session that resolved without sequelae. No persistent psychosis or hallucinogen persisting perception disorder was observed. Among the 14 participants who reported total abstinence at week 24 and had EtG results, all had negative EtG, providing some objective corroboration of self‑report.

Bogenschutz and colleagues interpret their findings as evidence that psilocybin, administered with manualised psychotherapy, was associated with substantially improved drinking outcomes over 32 weeks of double‑blind follow‑up compared with active placebo plus the same psychotherapy. The primary outcome showed a clinically meaningful reduction in percentage of heavy drinking days, and exploratory analyses found consistent between‑group effects across several secondary drinking measures. The authors place these results in the context of older LSD trials and recent open‑label psilocybin work, noting consistency with prior signals of efficacy. Safety observations are described as mostly mild and self‑limited, aligning with reports from other recent psilocybin trials; however, the authors emphasise that these safety findings arise from a tightly controlled research environment with careful screening, two trained therapists including a psychiatrist present during sessions, and provision for acute medical and psychiatric management, and therefore cannot be generalised to other settings. The trial's strengths include what the authors describe as the largest sample of any published psilocybin trial to date, rigorous assessment, high retention over 32 weeks, and use of manualised psychotherapeutic procedures drawn from empirically supported addiction treatments. Several limitations are acknowledged. Blinding was not maintained—participants and therapists usually identified treatment assignment—which could have introduced expectancy bias. Objective EtG corroboration was available for only 53.8% of participants. The enrolment stopped early because of the COVID‑19 suspension, leaving a smaller sample than planned and limiting power for subgroup analyses (for example by sex, race/ethnicity or psychiatric comorbidity) and for investigation of mechanisms, dosing optimisation, or predictors of response. The sample had lower drinking intensity at screening than many AUD pharmacotherapy trials, limiting generalisability to more severely affected populations. The two‑group design does not permit separation of medication effects from psychotherapy effects or their interaction, and the study provides no data on durability beyond the 32‑week double‑blind observation period. The authors conclude that further studies are needed to address these open questions and to expand understanding of psilocybin‑assisted treatment for AUD.

In this randomised clinical trial, psilocybin administered alongside manualised psychotherapy was associated with robust and sustained reductions in drinking over a 32‑week double‑blind period, exceeding the reductions observed with active placebo plus the same psychotherapy. The authors state these results support further research into psilocybin‑assisted treatment for adults with alcohol use disorder.