MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

• DOI: 10.1176/appi.focus.23021011
• Publication Date: 2023-07-14T07:05:36Z
• Authors: Jennifer M. Mitchell; Michael Bogenschutz; Alia Lilienstein; Charlotte Harrison; Sarah Kleiman; Kelly Parker-Guil...; Marcela Ot’alora G; Wael Garas; Casey Paleos; Ingmar Gorman; Christopher Nicholas; Michael Mithoefer; Shannon Carlin; Bruce Poulter; Ann Mithoefer; Sylvestre Quevedo; Gregory Wells; Sukhpreet S. Klaire; Bessel van der Kolk; Keren Tzarfaty; Revital Amiaz; Ray Worthy; Scott Shannon; Joshua D. Woolley; Cole Marta; Yevgeniy Gelfand; Emma Hapke; Simon Amar; Yair Wallach; Randall Brown; Scott Hamilton; Julie B. Wang; Allison Coker; Rebecca Matthews; Alberdina de Boer; Berra Yazar-Klosi...; Amy Emerson; Rick Doblin
• Keywords: Adult; Male; 6.6 Psychological and behavioural; Drug-Related Side Effects and Adverse Reactions; 4-methylenedioxyamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Clinical Trials and Supportive Activities; Immunology; Medical and Health Sciences; Article; Stress Disorders, Post-Traumatic; Substance Misuse; 03 medical and health sciences; 0302 clinical medicine; Double-Blind Method; Clinical Research; Behavioral and Social Science; Humans; N-Methyl-3; 10. No inequality; Stress Disorders; Depression; Evaluation of treatments and therapeutic interventions; Middle Aged; Post-Traumatic Stress Disorder (PTSD); Anxiety Disorders; Combined Modality Therapy; Brain Disorders; 3. Good health; Mental Health; Good Health and Well Being; Treatment Outcome; 6.1 Pharmaceuticals; Post-Traumatic; Mental health; Female; Patient Safety

AbstractPost-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.