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

Abstract

Importance: Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown.

Objective: To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy.

Design, setting, and participants: In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD.

Interventions: Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy.

Main outcomes and measures: The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance.

Results: A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin.

Conclusions and relevance: Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD.

Trial registration: ClinicalTrials.gov Identifier: NCT02061293.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bogenschutz reported grants from the Heffter Research Institute, Carey and Claudia Turnbull, Efrem Nulman, MD, Rodrigo Niño, and Cody Swift during the conduct of the study and the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the Heffter Research Institute, Mind Medicine, Inc, Tilray Canada, the Multidisciplinary Association for Psychedelic Studies (MAPS), B. More, Inc, the Turnbull Family Foundation, the Fournier Family Foundation, Dr Bronner’s Family Foundation, and the Riverstyx Foundation as well as personal fees from the Heffter Research Institute, Ajna Labs LLC, Beckley Psytech Limited, Journey Colab, and Bright Minds Biosciences outside the submitted work; Dr Bogenschutz also reports being listed as inventor in a provisional patent application related to this work, filed by his employer (New York University Grossman School of Medicine), for which Dr Bogenschutz has formally waived all rights and has no prospect of financial gain; moreover, Dr Bogenschutz’s employer has licensed the commercial rights to the data from the study described in this manuscript to B.More, Inc, for a nominal sum, and Dr Bogenschutz has no financial stake in this agreement. Dr Ross reported grants from Heffter Research Institute during the conduct of the study and from Usona Institute and Reset Pharmaceutical outside the submitted work; in addition, Dr Ross had a patent for N420838US and for N419987US, both issued by Reset Pharmaceuticals. Dr Forcehimes reported personal fees from New York University Grossman School of Medicine during the conduct of the study. Dr Mennenga reported grants from Ceruvia Lifesciences outside the submitted work. Dr O’Donnell reported personal fees from MAPS-Public Benefit Corporation and Polaris Insight Center outside the submitted work. Dr Rotrosen reported having served as a principal investigator or a coinvestigator on studies for which support in the form of donated or discounted medication, smartphone apps, and/or funds has been or is provided by Alkermes, Inc (vivitrol, extended-release injectable naltrexone), Indivior, Inc (formerly Reckitt-Benckiser; suboxone, buprenorphine/naloxone combination), Braeburn Pharmaceuticals, Inc (extended-release injectable buprenorphine), Pear Therapeutics (smartphone apps ReSET and ReSET-O), CHESS Health (Connections smartphone app), and Data Cubed (smartphone apps SOAR and mSAPPORT), directed to either New York University, or to National Institute on Drug Abuse, or to National Institute on Drug Abuse’s contractor Emmes, Inc; served in a nonpaid capacity as a member of an Alkermes study steering committee, as a nonpaid scientific advisor to Mind-Medicine, Inc, as principal investigator on RD-i15-00461 (National Institute on Drug Abuse Clinical Trials Network: New York Node), which is an umbrella grant that supports numerous studies, as a member on each of 2 doctoral dissertation committees at the University of Oslo, Norway, and as a nonpaid chair of the data and safety monitoring board for the OPTIMA trial conducted by CRISM, the Canadian addiction treatment clinical trials network; and currently serves as Chair of the data and safety monitoring board for the US Department of Veterans Affairs Cooperative Studies Program 2014. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Effects of Treatment on Continuous Drinking Outcomes

Mean (SE) estimates for screening (84 days prior to screening), weeks 1-4 (28 days prior to first double-blind medication session; covariate in the model), and eight 28-day bins following the first double-blind medication session (shaded area: weeks 5-8, 9-12, 13-16, 17-20, 21-24, 25-28, 29-32, and 33-36). Arrows represent double-blind medication sessions 1 and 2.