MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial

Abstract

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 .

Fig. 1. CONSORT diagram.

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).

Fig. 2. Measures of efficacy in the MDMA-AT and placebo with therapy groups.

a, LS mean change (±s.e.m.) in CAPS-5 total severity score from baseline to after session 3 (primary outcome) for placebo with therapy (n = 50) versus MDMA-AT (n = 53, P < 0.001, Cohen’s d = 0.7). b, LS mean change (±s.e.m.) in SDS total score from baseline to after session 3 (key secondary outcome) for placebo with therapy (n = 50) versus MDMA-AT (n = 53, P = 0.03, Cohen’s d = 0.4). Source data

Fig. 3. Treatment response and remission in the MDMA-AT (n = 53) and placebo with therapy (n = 50) groups.

A ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful. Responders (≥10-point reduction from baseline), loss of diagnosis (≥10-point reduction from baseline and no longer meeting PTSD diagnostic criteria) and remission (loss of diagnosis and CAPS-5 total severity score of 11 or less) were tracked in both groups as a percentage of participants. Non-responders were defined as any CAPS-5 total severity score change <10-point reduction from baseline. Source data