This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was −3.3 (−4.03, −2.60) for MDMA-AT versus −2.1 (−2.89, −1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437.
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 disorders2,3,4. Together, these factors are associated with symptom exacerbation, treatment resistance and treatment discontinuation3,5. Trauma-focused psychotherapies are the gold standard treatment for PTSD. However, many individuals have persisting symptomology, and dropout rates are high6,7,8. 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 PTSD10,11.