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

This pooled analysis (n=105; s=6) of MAPS’ Phase II trials finds significant improvements (Cohen’s d=0.8) and no significant adverse effects with MDMA-assisted therapy for PTSD. This analysis has been done to support starting the Phase III trials (which have taken place).

Abstract of MDMA-assisted psychotherapy for treatment of PTSD

“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.”

Authors: Michael C. Mithoefer, Allison A. Feduccia, Lisa Jerome, Anne Mithoefer, Mark Wagner, Zach Walsh, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson & Rick Doblin

Notes on MDMA-assisted psychotherapy for treatment of PTSD

β take: This article has been retracted (Aug '24). The main reason is that it includes data from at least one patient who had been abused by the (unlicenced) therapist in the MAPS' sponsored Phase II trial. In a reaction to the retraction, the authors argue that excluding the data wouldn't change the headline findings (they have appealed to retraction).

This article showed that between all the disparate Phase II trials, the effects of MDMA-assisted therapy were significant. Another (also retracted) study by the same research group showed that these effects were durable up to 12 months later.

The cost-effectiveness of MDMA-assisted psychotherapy is further analyzed in Marseille et al (2020) and is based on the outcomes of the current paper.

This paper is also discussed in a press release by MAPS and in an article on Psychedelic Support.

Summary of MDMA-assisted psychotherapy for treatment of PTSD

Posttraumatic stress disorder (PTSD) is a prevalent mental health condition that lacks sufficient treatment options. PTSD is a serious debilitating disorder with a lifetime prevalence estimated at nearly 4% globally and over 8% in the USA. It can have profound negative consequences for individuals with PTSD, including obesity, hypertension, and suicidality.

Treatments for PTSD include psychotherapies and medications. However, most individuals with PTSD do not respond adequately to current treatments, and many individuals with PTSD require long-term use of medications to maintain effectiveness.

The combination of psychotherapy with pharmacotherapy using 3,4-methylenedioxymethamphetamine (MDMA) is a promising approach to the treatment of PTSD. MDMA was first synthesized in 1912 by Merck, but it was not until the early 1970s that MDMA was first used in combination with psychotherapy.

Six phase 2 randomized trials of MDMA-assisted psychotherapy for treatment of PTSD were conducted from 2004 to 2017, and all demonstrated acceptable safety and promising efficacy results. MDMA doses were selected based on tolerability and subjective effects reported in several prior phase 1 studies. Two phase 3 trials started in 2018 with Breakthrough Therapy Designation.

The authors pooled data from six phase 2 trials to determine the optimal design of phase 3 trials for MDMA-assisted psychotherapy among individuals with PTSD from a range of causes.

Materials & Methods