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

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 −58.78, −35.02), 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. International Prospective Register of Systematic Reviews: CRD42019109132 available online at www.crd.york.ac.uk/prospero.