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

Ninety participants were randomised and received study treatment; three in the MDMA arm and four in the placebo arm withdrew, leaving 82 participants with complete baseline and termination AUDIT/DUDIT data used in these analyses. The analysed sample was predominantly female (64.6%), White (80.3%), non-Hispanic or Latino (92.7%), with mean age 41.4 (SD 12.22). Baseline clinical measures indicated severe PTSD (mean CAPS-5 43.8 (6.00)), severe depression (mean BDI-II 32.3 (13.01)), and significant functional impairment on the adapted Sheehan Disability Scale (mean 7.06 (1.89)). At baseline, 21 (25.61%) reported past alcohol use disorder only, 14 (17.07%) reported past substance use disorders, and 2 placebo participants reported current mild cannabis use disorder. Overall, 69 (84.2%) had AUDIT ≥ 1 and 48 (58.5%) had DUDIT ≥ 1 at baseline, and there were no statistically significant baseline differences between treatment arms on demographic variables or AUDIT/DUDIT scores. With respect to primary comparisons, MDMA-AT was associated with a greater reduction in AUDIT scores from baseline to study termination than Placebo+Therapy: mean change Δ = -1.02 (SD 3.52) for MDMA-AT versus Δ = 0.40 (SD 2.70) for placebo, yielding F(80, 1) = 4.20, p = 0.0436, and Hedge's g = 0.45 (reported as the effect size). This effect corresponds to a small-to-moderate standardised effect size. However, when models adjusted for baseline AUDIT values the between-group difference in AUDIT change scores was no longer statistically significant (p = 0.52). There were no significant between-group differences in DUDIT change scores. Correlational analyses found no significant linear relationship between AUDIT change scores and baseline or change scores for CAPS-5, BDI-II, or SDS in the overall sample. Within the MDMA-AT group only, AUDIT change scores were positively correlated with baseline CAPS-5 (r = 0.32, p = 0.04), suggesting greater baseline PTSD severity was associated with larger reductions in AUDIT. The extracted text also states that there was no evidence of increased substance use, abuse, dependence, or increased MDMA use during and two months following treatment, though detailed incidence data are not provided in the extracted text.

Nicholas and colleagues interpret these exploratory findings as suggesting that MDMA-AT for severe PTSD was associated with a statistically significant decrease in hazardous alcohol use as measured by AUDIT change scores, and that the MDMA-AT protocol did not increase risk of illicit drug use in the short term. The authors caution that the AUDIT effect was no longer significant after adjustment for baseline scores, and note there were no baseline differences between groups, indicating the result should be considered preliminary. The investigators emphasise key limitations that constrain interpretation: the trial enrolled few or no participants with current diagnosable alcohol use disorder despite allowing mild cases, and other active substance use disorders were excluded, producing a restricted distribution of AUDIT and DUDIT scores that limits sensitivity to detect change or to examine diagnostic cut-offs and factor-level changes (consumption, consequences, dependence). Heterogeneity in types of substances used and low baseline severity of drug use may explain the lack of a detectable DUDIT effect. The authors also describe the exploratory nature of the analysis. In terms of implications, the discussion notes that long-term follow-up is under way and will report AUDIT/DUDIT changes and self-reported MDMA craving and use at least 12 months post-trial. The authors position these results alongside previous Phase 2 follow-up data that suggested limited abuse potential of MDMA when administered in controlled clinical settings with careful eligibility screening and therapeutic support. They suggest that, given the observed reductions in alcohol-related screening scores and prior open-label findings in primary alcohol use disorder, further investigation of MDMA-AT as an integrated treatment for co-occurring PTSD and alcohol use disorder, or for alcohol use disorder alone, may be warranted.