A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis

This systematic review and meta-analysis (2020) of MDMA-assisted therapy for PTSD, found that over four RCT’s (n=67), PTSD scores (CAPS-IV) were lower in the 75mg and 125mg groups (not 100mg), and depression scores (BDI) only in the 75mg group.


Rationale: Novel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.

Objective: To review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.

Methods: Systematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within 7 days of intervention.

Results: Four randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75 mg (MD -46.90; 95% (confidence intervals) CI -8.78, -5.02), 125 mg (MD -20.98; 95% CI -34.35, -7.61) but not 100 mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75 mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after 7 days.

Conclusion: These results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further.”

Authors: Benjamin J. G. Illingworth, Declan J. Lewis, Andrew T. Lambarth, Kate Stocking, James M. N. Duffy, Luke A. Jelen & James J. Rucker


This meta-analysis is less favorable than some/many of the reports around MDMA-assisted psychotherapy. One reason for this difference is that this study compared the intervention versus the other groups that did get (high quality) therapy, whereas usually the headline number is compared to the status quo (no improvement at all).

It should also be noted that this study (2020) predates the Phase III studies by MAPS which promise to show efficacy (and have larger samples sizes to do so).

The results of this meta-analysis suggest that the use of MDMA in conjunction with psychotherapy is associated with a significant decrease in CAPS-IV scores at greater than 3 weeks when compared to both active (except at 100 mg) and inactive placebo groups in the treatment of treatment-resistant PTSD. MDMA-assisted psychotherapy showed no significant decreases in BDI except for at 75 mg. Subjects in these trials experienced significant physical side effects from the intervention. These included nausea (58% of sessions), low mood (17% of sessions) and jaw clenching in session (30% of sessions) and also lack of appetite within 7 days of intervention (25% of sessions).

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