MDMA-assisted psychotherapy for treatment of post-traumatic stress disorder: a systematic review with meta-analysis

This systematic review (2021) entails a meta-analysis of the current literature on MDMA-assisted therapy for the treatment of PTSD. It was found that MDMA significantly reduced CAPS scores and is generally safe and well-tolerated although side effects such as headache and nausea are commonly reported.


“This article discusses current literature on the use of 3,4-methylenedioxymethamphetamine (MDMA) assisted psychotherapy in the treatment of post-traumatic stress disorder (PTSD). MDMA, the intended active ingredient in illicit Ecstasy or Molly products, is a psychedelic that causes an elevated mood, feeling of bonding, and increased energy. In MDMA assisted psychotherapy, patients are subjected to 2 or 3 multi hour sessions of therapy with a team of psychiatrists. The dosing of MDMA is used to allow the therapist to probe the underlying trauma without causing emotional distress. The use of MDMA-assisted psychotherapy treatment reduced patient’s Clinician-Administered PTSD Scale (CAPS) scores from baseline more than control psychotherapy [-22.03 (95%CI -38.53 to -5.52)] but with high statistical heterogeneity. MDMA-assisted psychotherapy enhanced the achievement of clinically significant reductions in CAPS scores [RR 3.65 (95%CI 2.39 to 5.57)] and CAPS score reductions sufficient to no longer meet the definition of PTSD [RR 2.10 (95%CI 1.37 to 3.21)] with no detected statistical heterogeneity. While therapy was generally safe and well tolerated, bruxism, anxiety, jitteriness, headache, and nausea are commonly reported. While MDMA assisted psychotherapy has been shown to be an effective therapy for PTSD patients with a reasonable safety profile, use of unregulated MDMA or use in the absence of a strongly controlled psychotherapeutic environment has considerable risks.”

Authors: Kimberley W. Smith, Dakota J. Sicignano, Adrian V. Hernandez & Michael White



MDMA assisted psychotherapy reduced patients’ Clinician-Administered PTSD Scale (CAPS) scores from baseline more than control psychotherapy, but with high statistical heterogeneity. MDMA assisted psychotherapy was generally safe and well tolerated, but use of unregulated MDMA has considerable risks.

Posttraumatic stress disorder (PTSD) is a debilitating mental health disorder characterized by avoidance, hypervigilance and flashbacks. It can be further confounded by comorbid anxiety, depression, substance abuse, and suicidal ideation and actions. MDMA can increase energy, elevate mood, increase bonding with strangers, and provide a psychedelic effect. It is also a substance of abuse and the active ingredient sought by purchasers of Ecstasy and Molly, although many of these illicit products contain a variable amount of MDMA and adulterants. The Drug Enforcement Agency designated MDMA as a Schedule I drug, but several clinical studies showed promise. In 2017, the Food and Drug Administration granted breakthrough therapy designation to MDMA assisted psychotherapy. There are two common outcome scales for PTSD, the Clinician-Administered PTSD Scale (CAPS) and the Severity of Symptoms Scale for PTSD (SSSPTSD). MDMA assisted psychotherapy may have a place in therapy.

Sertraline and paroxetine are the only two FDA approved treatment options for PTSD, and fluoxetine and venlafaxine are recommended by American Psychological Association’s and Veterans Administration Department of Defense PTSD guidelines. Sertraline was assessed in four Phase III trials of similar design in patients with severe PTSD. Paroxetine was assessed in three 12-week Phase III clinical trials in PTSD patients. No sex-based differences in efficacy were found. Fluoxetine was assessed in two trials in patients with severe PTSD (CAPS scores above 45 units) and the change in CAPS score was the primary outcome. Both trials reported statistically significant decreased in CAPS scores, but 47% of participants withdrew during the study. MDMA assisted psychotherapy was assessed in one randomized double-blind, placebo-controlled trial in patients with severe PTSD. Venlafaxine ER showed significantly greater reduction in the 17-item Clinician-Administered PTSD Scale (CAPS-SX17) score verses placebo, and no significant difference in withdrawal rates between placebo and venlafaxine group was reported.

We used meta-analysis to compare the effects of MDMA vs. control on CAPS scores, percentage of people receiving a clinically significant CAPS score reduction, and percent of people no longer meeting the CAPS score criteria for PTSD at the follow-up period.

All trials were randomized and double-blinded, and most had 6 to 90 subjects. One trial used the SSSPTSD scale, while the others used the more commonly used and better validated CAPS-IV or CAPS-V scales.

All of the trials had specific safeguards to minimize the adverse effects of MDMA therapy. They used moderate 50-75mg MDMA doses and did not allow a second subsequent MDMA dose to be administered.

Figures 2 and 3 show that patients receiving MDMA-assisted psychotherapy had greater reductions in CAPS scores than control, and that more patients no longer met the CAPS criteria for PTSD at follow-up in the MDMA-assisted psychotherapy group vs. control. Statistical heterogeneity was not detected in either of these analyses. There were several possible sources of heterogeneity, including baseline CAPS score, active control trial, time from last experimental session to assessment of MDMA’s impact on the primary endpoint, and follow-up time. The initial MDMA doses in placebo controlled trials varied from high 125mg to variable 80mg to 120mg, but there were not major differences in CAPS score reductions in trials with moderate and high dose MDMA-assisted psychotherapy arms vs. control. All placebo or active controlled trials allowed a second subsequent MDMA or placebo dose to be given part way through each assisted psychotherapy session to maintain the MDMA effects. However, in only 22 out of 23 MDMA sessions was a supplemental dose accepted, raising questions about the adequacy of blinding. There was not enough data to assess the possible causes of statistical heterogeneity. Low dose MDMA sessions did not reduce CAPS-IV scores more than placebo sessions did in the placebo-controlled trials.

Mitchell et al.20 found that people with the dissociative subtype of PTSD had similar symptom reductions to those with non-dissociative PTSD, even with a history of alcohol use disorder, substance use disorder, or severe childhood trauma.

In several trials, participants who originally received placebo or low dose MDMA were offered the ability to receive open label high dose MDMA assisted psychotherapy. These participants showed clinically meaningful reductions in CAPS-IV score after MDMA therapy was used, which averaged 48% lower than baseline.

Jerome et al. assessed four Phase II studies, including 12-month posttreatment follow-up analyses from these trials, along with two unpublished Phase II studies, and found that MDMA assisted psychotherapy reduced CAPS-IV scores from baseline to 1 to 2 months after the last active MDMA session.

Safety of MDMA Assisted Psychotherapy

In a pooled analysis of trials, the safety of MDMA-assisted psychotherapy was assessed but not statistically analyzed. The adverse events were predominantly mild to moderate in severity, and there was one patient receiving high dose MDMA that experienced ventricular extrasystoles. Mitchell et al. found increases in anxiety, dizziness, jaw clenching, lack of appetite, and nausea in the MDMA group versus the placebo group. Additionally, 37% of MDMA participants reported suicidal ideation at baseline. The results of a questionnaire sent to participants in the constituent Phase II trials showed that most people did not report adverse events from MDMA assisted psychotherapy. Participants receiving MDMA assisted psychotherapy reported improved feelings of well-being, less excess vigilance, fewer nightmares, less avoidance, less anxiety, and improved sleep.

MDMA Place in Therapy and Future Directions

The VA DoD guidelines for systematic review specifies that trauma focused psychotherapy is preferable to pharmacotherapy for patients with PTSD. MDMA is being used in patients who were not sufficiently responsive to unenhanced trauma focused psychotherapy and would likely be tried before SSRI or venlafaxine therapy.

The trials assessing MDMA assisted psychotherapy yielded consistent directions of effect that were superior to that of psychotherapy alone, but the sample sizes were small and statistical heterogeneity was high. Additionally, the patients in the available trials had more severe PTSD than those in future studies.


MDMA-assisted psychotherapy is a novel experimental therapy that only takes two or three sessions and may reduce PTSD symptoms for a year or more. However, the literature base is hampered by small sample sizes and a lack of direct comparisons to other drugs in treatment of PTSD.

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Meta-Analysis Literature Review