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.
Level 1 - systematic review of randomized trials
Pooled analysis of six randomized controlled trials.
PubMed 31065731 · doi:10.1007/s00213-019-05249-5
What was done
The authors conducted a pooled analysis of participant-level data from six randomized, double-blind, controlled phase 2 trials across five sites (April 2004 to February 2017). Participants with PTSD received active MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) during two or three 8-hour manualized psychotherapy sessions spaced one month apart. Drug sessions were embedded within three 90-minute preparatory sessions and three to four integration sessions per experimental drug session. The primary outcome was change in Clinician-Administered PTSD Scale (CAPS-IV) total score from baseline after two blinded sessions.
What was found
After two experimental sessions, the active MDMA group showed significantly greater reductions in CAPS-IV total scores from baseline than the control group (MMRM estimated mean difference [SE] -22.0 [5.17], P < 0.001; between-group Cohen's d = 0.8). Additionally, 54.2% of participants in the active group no longer met CAPS-IV diagnostic criteria for PTSD versus 22.6% in the control group. Beck Depression Inventory-II (BDI-II) score reductions trended toward a significant difference favoring active MDMA (MMRM estimated mean difference [SE] -6.0 [3.03], P = 0.053). Expected reactions were more frequent in the active group during sessions and up to 7 days post-treatment, with no major tolerability issues reported.
Why it matters
This pooled dataset provided the core effect size and safety parameters used to design phase 3 clinical trials, leading directly to the FDA granting Breakthrough Therapy designation for MDMA-assisted psychotherapy for PTSD.
Limits
The total sample across six trials is relatively small (n = 103) with an unbalanced control group (n = 31). Control arms pooled inactive placebo with low active doses (0–40 mg). Distinct psychoactive effects create a high risk of functional unblinding among participants and therapists. The publication is indexed as a retracted publication in PubMed. Numeric adverse event rates and long-term durability are not detailed in the abstract.
Cited by
- supports In a phase two study of MDMA-assisted therapy for severe PTSD, approximately two-thirds of participants no longer met diagnostic criteria for PTSD at the primary endpoint and at one-year follow-up.