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

Summary & key facts

This multi-site, randomized, double-blind phase 3 trial tested MDMA-assisted therapy (MDMA-AT) versus placebo with the same therapy in 104 people with moderate to severe PTSD. Blinded assessors found larger average reductions in PTSD symptoms and in functional impairment for the MDMA-AT group than for the placebo group. The MDMA group had more severe treatment-emergent side effects, but there were no deaths or serious adverse events. The authors report that the results suggest MDMA-AT reduced PTSD symptoms and improved functioning and was generally well tolerated.

Key facts:

• Study type: multi-site, randomized, double-blind, confirmatory phase 3 trial with blinded independent assessors.
• Participants: 104 total; 53 were randomized to MDMA-assisted therapy (MDMA-AT) and 51 to placebo with identical therapy.
• PTSD severity mix: 26.9% (28/104) had moderate PTSD and 73.1% (76/104) had severe PTSD.
• Primary outcome (CAPS-5, a clinician-rated PTSD severity score): least-squares mean change was -23.7 (95% CI -26.94 to -20.44) for MDMA-AT versus -14.8 (95% CI -18.28 to -11.28) for placebo with therapy (P < 0.001). Reported effect size d =
• Key secondary outcome (SDS, a functional impairment score): least-squares mean change was -3.3 (95% CI -4.03 to -2.60) for MDMA-AT versus -2.1 (95% CI -2.89 to -1.33) for placebo with therapy (P = 0.03). Reported effect size d = 0.4.
• Safety: seven participants had severe treatment-emergent adverse events (MDMA-AT 5/53 = 9.4%; placebo 2/51 = 3.9%). There were no deaths or serious treatment-emergent adverse events reported.
• Participant diversity: 26.9% (28/104) identified as Hispanic/Latino, and 33.7% (35/104) identified as a race or ethnicity other than White.
• Study identifier: ClinicalTrials.gov NCT04077437.

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 . Results from the phase 3 placebo-controlled MAPP2 trial show that MDMA-assisted therapy reduces post-traumatic stress disorder (PTSD) symptoms and functional impairment in a diverse population with moderate to severe PTSD.

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Alternative medicine Internal medicine MDMA Medicine Pathology Placebo Psychiatry Randomized controlled trial