MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials
A pooled analysis of six randomised, double‑blind phase 2 trials found MDMA‑assisted psychotherapy produced large, clinically meaningful reductions in PTSD symptoms versus control (MMRM mean difference −22.0; Cohen’s d = 0.8) with higher remission rates (54.2% vs 22.6%) and acceptable tolerability, providing the rationale and design basis for phase 3 trials and FDA Breakthrough Therapy designation.
Authors
- Rick Doblin
- Berra Yazar-Klosinski
- Michael Mithoefer
Published
Abstract
Background
Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.
Methods
Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session.
Results
After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.
Conclusions
MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment. Trial registration ClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
Research Summary of 'MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials'
Introduction
Posttraumatic stress disorder (PTSD) is a common, disabling condition associated with intrusive memories, negative changes in mood and cognition, hyperarousal, avoidance and substantial reductions in quality of life. Existing trauma-focused psychotherapies are first-line treatments but are often inaccessible or ineffective for many patients, and only two drugs (sertraline and paroxetine) are FDA-approved for PTSD; pharmacotherapies more broadly fail to produce adequate response in an estimated 40–60% of patients. The resulting unmet need has prompted investigation of novel approaches that combine pharmacological agents with psychotherapy. Mithoefer and colleagues evaluate pooled data from six Phase II randomized, double-blind trials of MDMA-assisted psychotherapy conducted between 2004 and 2017 to inform the design of Phase III trials. Specifically, the investigators sought to define how many MDMA sessions are needed for clinically meaningful benefit, to explore dose and baseline predictors of outcome, to characterise essential safety parameters, and to identify trial-design features that minimise bias and improve blinding across diverse sites and participant groups.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
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- APA Citation
Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2019). MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology, 236(9), 2735-2745. https://doi.org/10.1007/s00213-019-05249-5
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