MDMA-Assisted Therapy Randomized Controlled Trial Incremental Effects Systematic Review and Meta-Analysis
Nicholas C. Borgogna, D. Drew Whittington, Tyler Owen, Dan Petrovitch, Jacob Vaughn, Cara Struble, Louis A. Pagano, Stephen L. Aita, Benjamin D. Hill
medRxiv Preprint Server May 5, 2026 preprint DOI: 10.64898/2026.05.05.26352468 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Randomized |
|---|---|
| Sample size | 295 |
| Population | Participants in MDMA-AT randomized controlled trials |
| Intervention | MDMA-assisted therapy |
| Topics | MDMA |
| Key findings | MDMA-AT demonstrated a significant moderate-to-large incremental reduction in psychopathology relative to controls (g = 1.03, 95% CI [0.46, 1.60]), but heterogeneity was high and harm reporting quality was low. |
Abstract
Mental illness poses a substantial global burden, yet existing psychotherapies and psychopharmacologies often produce limited outcomes. Psychedelic-assisted therapies have re-emerged as potential transdiagnostic interventions. In particular, 3,4-methylenedioxymethamphetamine–assisted therapy (MDMA-AT) has generated interest for its rapid psychological effects and potential to enhance psychotherapy outcomes. However, the incremental efficacy of MDMA-AT relative to control interventions across transdiagnostic outcomes remains unclear. Further, there have been emerging concerns regarding harm reporting quality in MDMA-AT clinical trials. We conducted a systematic review and meta-analysis of MDMA-AT randomized controlled trials. Eleven publications representing eight controlled trials with 10 analyzed subgroups (n = 295 participants) were included in meta-analyses. Two additional secondary publications were included for harm reporting syntheses (k = 13 total). Across 114 extracted effect sizes, MDMA-AT demonstrated a significant moderate-to-large incremental reduction in psychopathology relative to controls (g = 1.03, 95% CI [0.46, 1.60]), though heterogeneity was high (I² = 76%). Incremental effects were larger versus inert placebos (g = 1.27) than active controls (g = 0.75). Symptom-specific analyses indicated strong incremental effects for trauma reduction (g=1.46 [95% CI: 0.67, 2.25]) and smaller non-significant effects for depression (g=0.51 [95% CI: −0.06, 1.08]). Harm reporting quality synthesis showed only 23% of publications met high-quality reporting standards. Overall, MDMA-AT demonstrates potential transdiagnostic efficacy, but small samples, confounding factors, and mediocre harm reporting highlight the need for larger more transparent clinical trials.
Comparable studies
Other systematic reviews and meta-analyses on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A review of the acute subjective effects of MDMA/ecstasy | 2006 | Systematic review | |
| Adverse events in clinical treatments with serotonergic psychedelics and MDMA: A mixed-methods systematic review Patients in clinical trials with MDMA or serotonergic psychedelics | 2022 | Systematic review | n = 598 |
| Treating posttraumatic stress disorder with MDMA-assisted psychotherapy: A preliminary meta-analysis and comparison to prolonged exposure therapy Patients with PTSD | 2016 | Meta-analysis | |
| The neuropsychology of ecstasy (MDMA) use: a quantitative review MDMA users | 2007 | Meta-analysis | |
| Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review | 2022 | Systematic review |