Post-traumatic stress disorder (PTSD) is a serious neuropsychiatric condition affecting approximately 5% of the US population each year¹. Managing PTSD is particularly complicated in individuals experiencing the dissociative subtype of PTSD, recurrent exposure to trauma and comorbidities, such as mood disorders and alcohol and substance use disorders^2,3,4. Together, these factors are associated with symptom exacerbation, treatment resistance and treatment discontinuation^3,5. Trauma-focused psychotherapies are the gold standard treatment for PTSD. However, many individuals have persisting symptomology, and dropout rates are high^6,7,8. Although the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are FDA approved for treating PTSD, 35–47% of individuals do not respond to treatment⁹. More effective, therapeutic interventions are needed to address the immense individual, societal and economic burdens of PTSD^10,11.

Mounting evidence supports substituted phenethylamine 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) as a treatment for PTSD^12,13. MDMA, an entactogen that promotes monoamine reuptake inhibition and release (primarily by inducing conformational change of pre-synaptic transporters^14,15,16,17), effectively modulates fear memory reconsolidation, enhances fear extinction and promotes openness and prosocial behavior^{18,19,20,21,22}. Several phase 2 trials indicated that MDMA-AT has an acceptable risk–benefit profile in individuals with PTSD¹³. A pivotal phase 3 study (MAPP1) showed that MDMA-AT was generally well tolerated and met the trial’s primary and secondary endpoints of reduced PTSD symptom severity and decreased functional impairment¹².

Due to disparities in trauma exposure, gender-diverse and transgender individuals, ethnoracial minorities, first responders, military personnel, veterans and victims of chronic sexual abuse have a disproportionately higher risk of developing PTSD^{2,23,24,25,26,27,28}. However, these diverse populations are historically underrepresented in clinical trials²⁹. Here we report the results of MAPP2, the second, confirmatory phase 3 study that extends the findings of MAPP1 (refs. ^12,30) in an ethnoracially diverse population with moderate to severe PTSD (Supplementary Table 1).

Demographics and baseline characteristics

Participants were recruited from 21 August 2020 to 18 May 2022 (last participant visit on 2 November 2022). Overall, 324 individuals were screened, and 121 were enrolled. Of these, 17 individuals did not meet enrollment confirmation after initiation of preparation therapy, and 104 were confirmed for randomization: 53 were assigned to MDMA-AT and 51 to placebo with therapy (Fig. 1). Ninety-four participants completed the study, and nine discontinued (n = 1 MDMA-AT; n = 8 placebo with therapy) (Fig. 1 and Supplementary Table 3).

CONSORT diagram, indicating participant numbers and disposition throughout the course of the trial. Endpoint assessments (T1, T2, T3 and T4) of CAPS-5 and SDS were conducted after each experimental session. ^aThe number of individuals after an initial phone screening who gave informed consent. ^bOther reasons for exclusion could include withdrawal of consent, adverse event or death, discontinuation of treatment by investigator, lack of therapeutic rapport and illness or lost to follow-up. ^cOne participant in the placebo with therapy group completed the study but had missing item-level data on the final CAPS-5 assessment, and the final assessment was not included in the analysis of the de jure estimand. AE, adverse event; ITT, intention to treat; mITT, modified intention to treat; T, time of endpoint assessment; T1, baseline; T2, after experimental session 1; T3, after experimental session 2; T4, 6–8 weeks after experimental session 3 (18 weeks after baseline).

Baseline characteristics were generally similar between groups (Table 1). In total, 74 of 104 (71.2%) participants were assigned female sex at birth, with a higher proportion in the placebo with therapy group (42/51, 82.4%) than the MDMA-AT group (32/53, 60.4%). Participants were ethnically and racially diverse: 35 of 104 (33.7%) participants identified their race as other than White, and 28 of 104 (26.9%) identified their ethnicity as Hispanic/Latino. The mean (s.d.) duration of PTSD was 16.2 (13.3) years. The mean (s.d.) Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score at baseline was 39.0 (6.6) and was similar between groups. Overall, 28 of 104 (26.9%) and 76 of 104 (73.1%) participants had moderate and severe PTSD, respectively; the dissociative subtype was present in 24 of 104 (23.1%) participants.

Primary outcomes

MDMA-AT significantly attenuated PTSD symptomology versus placebo with therapy, as measured by a reduction in CAPS-5 total severity score from baseline to 18 weeks. Mixed models for repeated measures (MMRM) analysis of the de jure estimand showed a least squares (LS) mean (95% confidence interval (CI)) change of −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy (treatment difference: −8.9 (−13.70, −4.12), P < 0.001; Fig. 2a)