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

This double-blind, active placebo-controlled study (n=95) finds that psilocybin (2x, 25-40mg/70kg) significantly reduced the number of heavy drinking days (10% versus 24% in the placebo group) in the 32-week follow-up period. The trial is the first to test psilocybin for alcoholism (alcohol use disorder, AUD) in a double-blind study.

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, 5 (5.3%) were Black, 16 (16.8%) 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.“

Authors: Michael P. Bogenschutz, Stephen Ross, Snehal Bhatt, Tara Baron, Alyssa A. Forcehimes, Eugene Laska, Sarah E. Mennenga, Kelley O’Donnell, Lindsey T. Owens, Samantha Podrebarac, John Rotrosen, J. Scott Tonigan & Lindsay Worth

Summary

Psilocybin and other classic psy-chedelics appear to enhance plasticity at multiple levels, including neuronal structure, neural networks, cognition, affect, and behavior. However, some clinically relevant effects may be independent of serotonin 2A receptor activation.

Alcohol use disorder is a promising target for treatment with psychedelics. A recent study demonstrated that moderately high doses of psilocybin were well tolerated by participants with alcohol dependence, and large reductions in drinking were observed over a 32-week follow-up period.

Participants

Participants were recruited at the University of New Mexico and New York University using advertisements in local media. They were aged 25 to 65 years, had a diagnosis of alcohol dependence, and had at least 4 heavy drinking days during the 30 days prior to screening.

Overview

Participants were randomly assigned to receive psilocybin or diphenhydramine and received up to $560 for completing assessments. They were not reimbursed for attending therapy and medication sessions.

Psychotherapeutic Elements of Treatment

All participants received 12 psychotherapy sessions, including motivational interviewing and cognitive behavioral therapy for AUD, as well as material designed to help them manage the psychoactive effects of the study medication.

Dosage of Study Medication

Participants took a single opaque capsule of unvarying appearance and weight containing 25 mg or 50 mg of psilocybin or diphenhydramine. The dose was increased if there were no dose-limiting adverse events and if the participant agreed to the increase.

Administration of Study Medication

Participants were administered medication at 9 AM and required to stay in the session room with the therapists for at least 8 hours.

Drinking Outcomes

The primary outcome was the percentage of heavy drinking days (PHDD), and secondary outcomes included percentage of drinking days (PDD), mean drinks per day (DPD), and reduction in World Health Organization (WHO) risk level (by 1, 2, or 3 levels).

Safety and Blinding Integrity

Blood pressure and heart rate were assessed during the first 6 hours of each medication session. Adverse events were solicited at each postscreening assessment.

Sample Size and Power

The study was originally designed to randomize 180 participants, but due to COVID-19, enrollment was halted at 95 randomized participants.

Subjective Effects and Efficacy

A multivariate repeated-measures analysis of variance was used to evaluate the effects of treatment on continuous drinking outcomes (PHDD, PDD, and DPD). Significant multivariate treatment effects were decomposed with univariate repeated-measures F tests within each drinking dimension.

Treatment contrasts were obtained using 2 statistics, and effects of treatment on problems related to drinking were compared using univariate mixed models for repeated measures and generalized linear models.

Safety Outcomes

Blood pressure and heart rate treatment contrasts were based on mixed models for repeated measures, and adverse events were coded according to the Medical Dictionary for Regulatory Activities.

Participants

95 participants were randomized to psilocybin or diphenhydramine, and the mean age was 45.8 years. The mean percentage of days consumed alcohol was 74.9%, including heavy consumption on 52.7% of days, and consuming a mean of 7.1 standard drinks per drinking day.

Treatment Exposure and Retention

Participants in the nonmedication therapy sessions completed a mean of 11.75 (0.76) sessions and 11.47 (1.20) sessions, respectively. Of 95 participants randomized, 93 received at least 1 dose of medication, and 43 received a second double-blind medication session.

Valid drinking outcome data were obtained for 717 of 744 months (96.4%) of the 93 participants receiving treatment, with missing data being due to telephone visits, insufficient hair samples, and other reasons.

Blinding Integrity

Participants correctly guessed their treatment assignment in 93.6% of the first sessions and 94.7% of the second sessions. The mean (SD) certainty was 90.6%.

Acute Effects Cardiovascular Effects

Psilocybin administration was associated with increased blood pressure and heart rate, but no symptoms were reported.

Subjective Effects

The mean MEQ scores for session 1 were 0.59 (0.24) in participants treated with psilocybin and 0.10 (0.13) in those receiving diphenhydramine.

Changes in Drinking Prior to Randomization

In both treatment groups, PHDD, PDD, and DPD decreased between screening and week 4, and PHDD decreased by a mean of 32.37 (95% CI, 23.68-41.07; Hedges g, 1.08; 95% CI, 0.741.47).

Continuous Drinking Outcomes

The primary outcome analysis demonstrated that participants who received psilocybin had lower 3-dimensional drinking outcomes than those who received diphenhydramine.

Dichotomous Drinking Outcomes and Problems Related To Drinking

Participants who received psilocybin were more likely to have no heavy drinking days and a 2-level reduction in WHO risk level during weeks 5 to 36 than those receiving diphenhydramine. They also showed moderate to large reductions in several categories of drinking-related problems at week 24 and/or week 36.

Safety

A total of 204 adverse events were reported in the 32 weeks following the first administration of study medication. Three serious adverse events were reported, all in the diphenhydramine group.

Treatment-emergent adverse events occurring within 48 hours of study drug administration were common and included headaches, anxiety and nausea. Two participants received diazepam for anxiety, which resolved within 45 minutes and 210 minutes, respectively.

Discussion

Psilocybin treatment was associated with improved drinking outcomes in this randomized clinical trial of psilocybin-assisted psychotherapy treatment for AUD. Adverse events were mostly mild and self-limiting, consistent with other recent trials evaluating the effects of psilocybin in various conditions.

Strengths

This trial had methodological strengths that enhance confidence in its findings. It included a large sample size, rigorous assessment, and high retention rates over a 32-week period of double-blind follow-up.

Limitations

Several limitations of the study warrant discussion, including the fact that diphenhydramine was ineffective in maintaining the blind after drug administration, that EtG samples were available for only 53.8% of treated participants, and that the study did not have adequate power to evaluate effects in subgroups.