A comprehensive systematic review and meta-analysis of 13 studies found that MDMA-assisted psychotherapy (MDMA-AP) is associated with increased odds of side effects compared to control conditions. In Phase 2 trials, MDMA-AP roughly doubled the odds of any side effect during medication sessions and in the following week. In Phase 3 trials, the odds of any adverse event during treatment were about 3.5 times higher with MDMA-AP than with placebo-assisted psychotherapy. Most side effects were transient and mild or moderate. However, the evidence had very low to moderate certainty, most trials had high risk of bias, and none adequately followed CONSORT Harms 2022 reporting guidelines, highlighting the need for further safety research.
A new tool, the MDMA-Assisted Psychotherapy Side Effects Tool (M-SET), was developed to systematically capture side effects during MDMA-assisted psychotherapy. Experts in MDMA-AP and neuropsychopharmacology participated in a two-round online Delphi process to refine a list of 165 items across four questionnaires covering screening, baseline, medication session days, and follow-up. The tool aims to improve safety monitoring and build a more robust evidence base on the tolerability of MDMA-AP for research and clinical use.