Abstract
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.
Highlights
A total of 345 participants were assessed for eligibility, 131 were enrolled, 91 were confirmed for randomization (United States, n = 77; Canada, n = 9; Israel, n = 5), and 46 were randomized to MDMA and 44 to placebo (Fig. 1)
Six participants in the MDMA group and 13 participants in the placebo group had the dissociative subtype according to CAPS-5 score
We demonstrate that three doses of MDMA given in conjunction with manualized therapy over the course of 18 weeks results in a significant and robust attenuation of Post-traumatic stress disorder (PTSD) symptoms and functional impairment as assessed using the CAPS-5 and SDS, respectively
Summary
The primary objective of this trial was to evaluate the efficacy and safety of MDMA-assisted therapy for PTSD compared with placebo with therapy, based on comparison of CAPS-5 total severity score at baseline with that at 18 weeks after baseline. The CAPS-5 is a semi-structured interview that assesses the index history of DSM-5-defined traumatic event exposure, including the most distressing event, to produce a diagnostic score (presence versus absence) and a PTSD total severity score. The CAPS5 is scored on a scale from 0 to 80, with moderate PTSD defined from a rationally derived severity range of 23–34 The secondary objective of this trial was to evaluate the efficacy of MDMA-assisted therapy for PTSD compared with placebo with therapy in clinician-rated functional impairment, as measured by the mean change in SDS total scores from baseline to 18 weeks after baseline. Exploratory outcome measures included the BDI-II, the Alcohol Use Disorders Identification Test (AUDIT), the Drug Use Disorders Identification Test (DUDIT) and the Adverse Childhood Experiences (ACE) Questionnaire
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