Discussion
psychiatric, PTSD, comorbid personality disorders
CARDIOVASCULAR DISEASE
In this confirmatory phase 3 study of participants with moderate to severe PTSD, MDMA-AT significantly improved PTSD symptoms and functional impairment, as assessed by CAPS-5 and SDS, respectively, compared to placebo with therapy over 18 weeks. Notably, 45 of 52 (86.5%) participants treated with MDMA-AT achieved a clinically meaningful benefit, and 37 of 52 (71.2%) participants no longer met criteria for PTSD by study end. In a historic first, to our knowledge, for psychedelic treatment studies, participants who identified as ethnically or racially diverse encompassed approximately half of the study sample. These findings confirm and extend the results observed in MAPP1 (ref. Given the diverse population and degree of participant complexity, the replication of efficacy is particularly notable. In our study, 26.9% (28/104) of participants expressed moderate PTSD, whereas, in MAPP1, all participants expressed severe PTSDMDMA simultaneously induces prosocial feelings and softens responses to emotionally challenging and fearful stimuliConsistent with MAPP1, no new major safety issues were reported. Common TEAEs were similar to previous studies and consistent with expected effects of MDMAAlthough the sample sizes of the MAPP1 and MAPP2 phase 3 studies had 90% statistical power and were developed with guidance from the FDA to ensure adequate, rigorous testing of outcomes, these evaluations did not extend further than 2 months after therapy and were intended to support an acute treatment course. To support these studies, data from the ongoing follow-up of participants from phase 2 and 3 studies (ClinicalTrials.gov Identifier: Several limitations may impact the integration of MDMA-AT into clinical care, including the exclusion of participants with high suicide risk, comorbid personality disorders and underlying cardiovascular disease. Observed effect sizes for MDMA-AT (between-group, The notable effect seen in the placebo with therapy arm could suggest the standalone value of the manualized inner-directed therapy that was developed for use with MDMA. Additional head-to-head studies will need to be conducted to evaluate whether this form of manualized therapy provides greater value in the treatment of PTSD than the current first-line cognitive behavioral therapy and prolonged exposure therapy treatmentsAlthough treatment expectancy, per se, was not measured in this study, prospective treatment expectancy would likely have been high in both study arms, with random assignment expected to distribute this equally between groups. Although expectancy effects are a well-known issue in psychiatric clinical trials and are intertwined with the observation of treatment benefit during a trialThe therapists who participated in this study were required to complete the sponsor’s training program (see This confirmatory phase 3 trial showed consistent benefits of MDMA-AT in an ethnoracially diverse group of individuals with longstanding moderate to severe PTSD and numerous comorbidities. The dropout rate was low, and treatment was generally well tolerated. These findings represent the culmination of over two decades of research