The Effects of MDMA-Assisted Therapy on Alcohol and Substance Use in a Phase 3 Trial for Treatment of Severe PTSD

This trial (n=90) assessed patterns of alcohol and substance use in patients receiving MDMA-assisted therapy. MDMA was associated with a significant reduction in Alcohol Use Disorder Identification Test (AUDIT) scores when compared to placebo. Changes in Drug Use Disorder Identification Test (DUDIT) scores did not significantly differ between groups.

Abstract

“Background Post-traumatic stress disorder (PTSD) is commonly associated with alcohol and substance use disorders (ASUD). A randomized, placebo-controlled, phase 3 trial demonstrated the safety and efficacy of MDMA-assisted therapy (MDMA-AT) for the treatment of severe PTSD. This analysis explores patterns of alcohol and substance use in patients receiving MDMA-AT compared to placebo plus therapy (Placebo+Therapy).

Methods Adult participants with severe PTSD (n = 90) were randomized to three blinded trauma-focused therapy sessions with either MDMA-AT or Placebo+Therapy. Eligible participants met DSM-5 criteria for severe PTSD and could meet criteria for mild (current) or moderate (early remission) alcohol or cannabis use disorder; other SUDs were excluded. The current analyses examined outcomes on standardized measures of hazardous alcohol (i.e., Alcohol Use Disorder Identification Test; AUDIT) and drug (i.e., Drug Use Disorder Identification Test; DUDIT) use at baseline prior to randomization and at study termination.

Results There were no treatment group differences in AUDIT or DUDIT scores at baseline. Compared to Placebo+therapy, MDMA-AT was associated with a significantly greater reduction (improvement) in mean (SD) AUDIT change scores (Δ = -1.02 (3.52) as compared to placebo (Δ = 0.40 (2.70), F (80, 1) = 4.20, p = 0.0436; Hedge’s g=.45). Changes in DUDIT scores were not significantly different between treatment groups.

Conclusions MDMA-AT for severe PTSD may also lead to subclinical improvements in alcohol use. MDMA-AT does not appear to increase risk of illicit drug use. These data provide preliminary evidence to support the development of MDMA-AT as an integrated treatment for co-occurring PTSD and ASUD.”

Authors: Christopher R. Nicholas, Julie B. Wang, Allison Coker, Jennifer Mitchell, Sukhpreet Klaire, Berra Yazar-Klosinki, Amy Emerson & Rick Doblin

Author Highlights

• A randomized, placebo-controlled, phase 3 trial demonstrated the safety and efficacy of MDMA-assisted therapy (MDMA-AT) for the treatment of severe post-traumatic stress disorder (PTSD)

• Participants met DSM-5 criteria for severe PTSD and were permitted to have current mild or moderate (early remission) alcohol or cannabis use disorder

• Outcomes on standardized measures of hazardous alcohol (i.e., Alcohol Use Disorder Identification Test; AUDIT) and drug (i.e., Drug Use Disorder Identification Test; DUDIT) use at baseline prior to randomization and at study termination were examined

• Compared to Placebo+Therapy, MDMA-AT was associated with greater decreases on the AUDIT and no differential changes on the DUDIT

• MDMA-AT was not associated with increased risk for illicit substance use and may show beneficial effects on alcohol consumption and risk for hazardous use

Summary

MDMA was used to treat severe PTSD in a clinical trial sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) non-profit organization. The authors would like to express appreciation to all the participants and research staff who made this work possible.

Post-traumatic stress disorder is often associated with alcohol and substance use disorders. MDMA-assisted therapy may be an effective treatment for PTSD.

Adult participants with severe PTSD who also had a substance use disorder were randomized to receive three blinded trauma-focused therapy sessions with either MDMA-AT or Placebo+Therapy. MDMA-AT was associated with a significantly greater reduction in mean (SD) AUDIT change scores than Placebo+Therapy.

Post-traumatic stress disorder (PTSD) is strongly associated with the co-occurrence of alcohol and substance use disorders (ASUDs), and the impact of PTSD and ASUDs on health, psychosocial functioning, and service utilization is compounded when these conditions are comorbid. In a multi-site, randomized, placebo-controlled, Phase 3 trial, 3,4-Methylenedioxymethamphetamine (MDMA) in combination with therapy was found to be efficacious and safe, and to have a substantial decrease in symptoms associated with severe PTSD.

A two-arm, randomized, double-blind, placebo-controlled study of MDMA-assisted therapy for PTSD was conducted across 15 study sites in the US, Canada, and Israel. Participants were recruited from the community who provisionally met criteria for PTSD and who had a CAPS-5 Total Severity Score of 35 or greater at baseline. They were also assessed for psychiatric disorders and ASUDs in the last 12 months.

Following safety and eligibility screening, participants received 3 90-minute preparatory therapy sessions and were randomized to MDMA-AT or Placebo+Therapy for 3 8-hour experimental sessions. They received a divided-dose of MDMA or placebo, with an initial dose followed by a supplemental dose 1.5-2 hours later. The present analysis examined outcome measures related to alcohol and substance use. The Alcohol Use Identification Test (AUDIT) and Drug Use Identification Test (DUDIT) were used as screening instruments.

The AUDIT and DUDIT are 11-item self-report measures designed to identify the patterns of substance use and drug-related problems. They are not diagnostic assessments, but have demonstrated validity as screening measures across various populations. Descriptive analyses were performed on all demographic, baseline, and outcome variables. Student’s t-tests were used to compare between-group change scores for AUDIT and DUDIT, and models were used to examine treatment group differences in AUDIT and DUDIT scores.

Participants were recruited from 7 November 2018 to 26 May 2020 and were randomized to receive MDMA or Placebo. 82 participants completed both baseline and study termination assessments. Participants were mostly female, White, non-Hispanic or Latino, and had a mean age of 41.4 years. The mean CAPS-5 total severity score was 43.8 (6.00), mean BDI-II score was 32.3 (13.01), and mean modified SDS score was 7.06 (1.89).

The MDMA-AT group had a greater statistically significant reduction in AUDIT scores than Placebo+Therapy, but the difference was not statistically significant after adjusting for baseline AUDIT. The mean AUDIT scores for MDMA group were 4.09 (4.16), Placebo+Therapy group were 2.80 (3.18), and the mean DUDIT scores for MDMA group were 2.70 (3.1) at baseline and 1.33 (3.14) at study termination. There were no statistically significant correlations between AUDIT change scores and baseline scores for CAPS-5, BDI-II, and SDS.

The current analyses found that MDMA-AT was associated with a statistically significant decrease in alcohol use among Phase 3 study participants with severe PTSD and no incidence of current AUD. The reduction in alcohol use was independent of depression and functional impairment but positively associated with baseline PTSD severity. The lack of group differences in DUDIT change scores may be related to the absence of current SUD diagnosis at baseline and potential heterogeneity in the type of substance use reported.

MDMA-AT treatment did not increase risk of substance use, abuse, or dependence, or increased MDMA use during and 2 months following treatment. Long-term follow-up data will be collected from these Phase 3 participants and will include changes in AUDIT and DUDIT as well as self-reported MDMA craving and use post study. References Beck, Steer, Brown, G. K., and Berman, A. T. 2005. The Beck Depression Inventory-II and the Drug Use Disorders Identification Test-II.

A review of the psychometric properties of the Drug Use Disorders Identification Test, AUDIT-C, and USAUDIT for screening in the United States, as well as a systemic review of the self-medication hypothesis in the context of comorbid PTSD and substance use disorders, is presented.

MDMA-assisted psychotherapy for treatment of post-traumatic stress disorder: a longitudinal pooled analysis of six phase 2 trials. 2020. Posttraumatic stress disorder and co-occurring substance use disorders: Advances in assessment and treatment. Clinical Psychology: Science and Practice, 19(3), 283.

The Columbia-Suicide Severity Rating Scale, the Alcohol Use Disorders Identification Test, and the Najavits, L.M. and Hien, D. 2013 instruments were developed to assess the comorbidity of substance use disorder and PTSD, and to assess the utility of the instruments in clinical practice.

Tate, Norman, McQuaid, and Brown (2007) compared substance-dependent veterans with and without trauma history for health problems and drafted the paper.

Conflict of Interest: The authors received salary support from MAPS PBC, BY-K and RD received salary support from MAPS, and CRN received funding from MAPS PBC during the conduct of the current study and other studies.

A randomized, placebo-controlled, phase 3 trial of MDMA-assisted therapy (MDMA-AT) for the treatment of severe post-traumatic stress disorder (PTSD) demonstrated that MDMA-AT was associated with greater decreases on the AUDIT and no differential changes on the DUDIT.