Safety and efficacy of methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in post-traumatic stress disorder : An overview of systematic reviews and meta-analyses

Objective:
To critically evaluate published and unpublished systematic reviews and meta-analyses on the safety and efficacy of methylenedioxymethamphetamine-assisted psychotherapy for post-traumatic stress disorder.
Methods:
Six bibliometric databases and grey literature were searched from inception to 9 May 2024 for systematic reviews on the safety and efficacy of methylenedioxymethamphetamine (MDMA)-assisted psychotherapy compared to psychotherapy alone among adults with post-traumatic stress disorder. Quality assessment using the AMSTAR-2 tool was conducted independently by two investigators.
Results:
Fourteen systematic reviews comprising 20 primary studies involving up to 353 participants were included. All reviews included studies of one-to-three sessions of 50–125 mg MDMA-assisted psychotherapy (some with supplemental dosage) compared to either 25–40 mg of MDMA or inactive placebo with psychotherapy. Four were deemed high quality. Meta-analyses reported substantial benefits of MDMA-assisted psychotherapy in improving post-traumatic stress disorder symptoms (standardised mean difference, 0.8–1.3), response rate (relative risk, 1.3–3.5) and remission rate (relative risk, 2.3–2.9) compared to psychotherapy alone. However, for reviews that assessed the certainty of evidence, the evidence was rated as low to very low certainty due to high risk of bias, indirectness and imprecision. There was moderate-quality evidence that MDMA-assisted psychotherapy was associated with an increased odd of transient adverse events. However, reviews noted reliance on spontaneous rather than systematic adverse event reporting, discrepancies between adverse events reported in published studies and clinical trial registries, and a lack of long-term safety data.
Conclusion:
Four high-quality systematic reviews suggest low to very low certainty evidence for efficacy outcomes and moderate to very low quality evidence for safety outcomes.