MDMA Safety Across Contexts: Pharmaceutical Trials and Real-World Ecstasy Compared Side by Side

Background. Safety is a property of a drug, in a population, in a context. Pharmaceutical MDMA (midomafetamine) given in a monitored psychotherapy trial, and material sold as ecstasy or MDMA outside that setting, are different exposures. This preprint compares those contexts side by side. It does not produce one pooled safety number. Methods. This is a rapid computational evidence synthesis: registry mining, pharmacovigilance counts, open-access identification, and a structured map of retrieved reviews. It is not a finished AMSTAR-2 umbrella of every MDMA review and not a dual-reviewer meta-analysis of the primary literature. PubMed on 24 October 2026 returned 183 review records (metadata retrieved) and 3,496 primary-query records (counted, not screened). ClinicalTrials.gov and openFDA were queried under pre-specified rules. Public FDA, ICER, ONS, AIHW, EDRS and CanTEST documents were extracted where a text layer or cell was present. Trial risk ratios use the Mantel–Haenszel method. Recreational counts are never entered into those pools. Retracted papers are excluded. Results. Two parallel phase 3 trials had posted one-to-one results. Serious adverse events were 0/46 versus 2/44 and 0/53 versus 0/51; the log risk ratio was not estimable. Suicidal ideation was 21/46 versus 21/44 and 18/53 versus 21/51 (risk ratio 0.891, 95% CI 0.639 to 1.241). Palpitations risk ratio 1.232 (0.478 to 3.179), DerSimonian–Laird I² = 62.4%. Systolic pressure of at least 140 mm Hg occurred in 67/99 versus 21/95 (risk ratio 3.062, 2.050 to 4.573); at least 180 mm Hg in 6/99 versus 0/95. Discontinuation risk ratio 0.320 (0.121 to 0.845). openFDA chemical-name reports (1,932 in a snapshot of 20,692,690; 1,830 serious-flagged) signalled serotonin syndrome (reporting odds ratio 56.919), rhabdomyolysis (15.027), seizure (6.531) and suicidal ideation (12.314), and did not signal hyponatraemia or the hyperthermia/pyrexia group. These reports are not incidence. England and Wales registered 78 ecstasy/MDMA mentions in 2024, 38 without other drugs; rates were not calculated. A CanTEST count detected MDMA in 178 of 227 samples expected to be MDMA. A second pass saved the TGA media release of 3 February 2023: from 1 July 2023, authorised psychiatrists may prescribe MDMA for PTSD (Schedule 8 for that use; Schedule 9 otherwise). EUDA pages were not retrieved (HTTP 403; archive HTTP 429). Eleven open-access reviews were partially appraised and were not given AMSTAR-2 summary scores. Two Basel phase 1 crossovers were extracted and were not pooled with the phase 3 risk ratios. Conclusions. Monitored-trial safety and real-world ecstasy safety are different questions. The record contains the preprint (PDF and Markdown) and the analysis code and outputs (MIT licence for the code). If you or someone else is in crisis, call Lifeline on 13 11 14 (Australia) or local emergency services.