Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for posttraumatic stress disorder: A systematic review and meta-analysis of clinical and functional outcomes

Abstract

• MDMA-AT was associated with reductions in PTSD symptom severity and improvements in dissociative symptoms and global functioning; however, the high risk of bias, substantial heterogeneity, and very low certainty of evidence limit the robustness of synthesised findings and their clinical interpretability. • Key clinical domains remain unexplored; no published RCTs have evaluated cognition or specific functional outcomes (work, social functioning, quality of life) following MDMA-AT for PTSD. • Large, well-powered RCTs, with active controls and ≥12-month follow-up are needed to establish the efficacy MDMA-AT and classic psychedelic-AT for PTSD, complex PTSD, and other trauma-related disorders. Posttraumatic stress disorder (PTSD) is a chronic and disabling condition and identifying beneficial therapies is timely and important. We aimed to estimate the efficacy of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) compared with control on clinical and functional outcomes in PTSD. A PRISMA-compliant search (PROSPERO CRD42022353261) up to August 14, 2025, covered nine databases and manual searches to identify randomised controlled trials (RCTs). Methodological quality was assessed using the Cochrane Risk of Bias tool (RoB2), and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Of 1035 records identified, 14 studies met inclusion criteria for qualitative synthesis; eight trials provided sufficient data for quantitative synthesis ( k = 24). Random-effects meta-analyses indicated that MDMA-AT was associated with reductions in PTSD symptom severity ( n = 298, k = 9, SMD = -1.19, 95 % CI [-1.95, -0.42]; I² = 68.8 %, τ 2 = 1.02), dissociative symptoms ( n = 148, k = 5, SMD = -0.37, 95 % CI [-0.70, -0.04]; I ² = 0.0 %, τ 2 = 0), and may improve functioning ( n = 227, k = 4, SMD = -0.83, 95 % CI [-1.47, -0.19]; I² = 61.2 %, τ 2 = 0.27). No clear evidence of benefit was observed for depressive symptoms. Most studies showed a high risk of bias in the measurement of the outcome, and some concerns due to deviations from the intended intervention; the overall certainty of the evidence was very low. The number of trials remains limited, with considerable heterogeneity in certain outcomes, small sample sizes, and the absence of active controls in most studies, which likely compromised blinding integrity. Current findings suggest that MDMA-AT may warrant further investigation as a potential treatment for PTSD; however, larger, higher-quality RCTs with active controls and long-term follow-up are needed to determine its efficacy.