Journal Article

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Amiaz, Revital, van der Kolk, Bessel, Kleiman, Sarah, Doblin, Rick, Yazar-Klosinski, Berra, Paleos, Casey, Garas, Wael, Gorman, Ingmar, Carlin, Shannon, Wells, Gregory, Wang, Julie B., Coker, Allison, Shannon, Scott, Hapke, Emma, Gelfand, Yevgeniy, Mithoefer, Ann, Brown, Randall, Tzarfaty, Keren, Lilienstein, Alia, Mitchell, Jennifer M., Harrison, Charlotte, Ot’alora G., Marcela, Woolley, Joshua D., Hamilton, Scott, Klaire, Sukhpreet S., Marta, Cole, Matthews, Rebecca, Mithoefer, Michael, Nicholas, Christopher, Parker-Guilbert, Kelly, Poulter, Bruce, Bogenschutz, Michael, Quevedo, Sylvestre, Worthy, Ray, Wallach, Yair, de Boer, Alberdina, Emerson, Amy, Amar, Simon

2021

Overview

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants ( n  = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo ( P  < 0.0001, d  = 0.91) and to significantly decrease the SDS total score ( P  = 0.0116, d  = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Results from a phase 3, double-blind, randomized, placebo-controlled trial demonstrate that MDMA-assisted therapy is safe and effective in treating severe post-traumatic stress disorder.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/153 / 692/308/2779/109/1942 / Adult / Adverse events / Attenuation / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Children / Clinical trials / Combined Modality Therapy / Double-Blind Method / Double-blind studies / Drug abuse / Drug-Related Side Effects and Adverse Reactions - epidemiology / Drug-Related Side Effects and Adverse Reactions - pathology / Ecstasy / Ecstasy (Drug) / Female / Humans / Infectious Diseases / Male / MDMA / Mental disorders / Mental health / Metabolic Diseases / Middle Aged / Molecular Medicine / N-Methyl-3,4-methylenedioxyamphetamine - administration & dosage / N-Methyl-3,4-methylenedioxyamphetamine - adverse effects / Neurosciences / Placebos / Post traumatic stress disorder / Prolongation / Psychological stress / Public health / Signs and symptoms / Stress Disorders, Post-Traumatic - drug therapy / Stress Disorders, Post-Traumatic - epidemiology / Stress Disorders, Post-Traumatic - pathology / Substance use / Testing / Therapy / Trauma / Treatment Outcome