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In this review, we contextualize the emergence of MDMA\u2010assisted psychotherapy (MDMA\u2010AT) within 20th century psychiatry and trace its journey from assisting with military interrogation, through prohibition and to clinical use. We outline three core domains of MDMA's subjective effects\u2014prosocial behaviour, reduced threat perception and euphoria\u2014and explore how each may relate to its therapeutic efficacy and abuse liability. Drawing from clinical, behavioural, and pharmacological studies, we highlight the central role of 5\u2010HT (serotonin) in mediating the effects of MDMA, while identifying key gaps in our understanding of its mechanism of action. We also assess how preclinical models capture therapeutic\u2010relevant processes, discuss the limitations of existing data (including sex biases and an assumed role for therapeutic alliance) and suggest strategies to unravel the neurobiological basis of MDMA's therapeutic effects. Clarifying these mechanisms will be critical for optimizing future clinical protocols, mitigating risks and guiding the clinical development of safer, mechanistically informed MDMA\u2010like therapeutic agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LINKED ARTICLES<\/jats:title>\n                    <jats:p>\n                      This article is part of a themed issue Emerging Therapeutic Opportunities for Psychedelic and Related Drugs. To view the other articles in this section visit\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v183.14\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v183.14\/issuetoc<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70225","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:12:11Z","timestamp":1761109931000},"page":"3950-3969","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["History, pharmacology and therapeutic mechanisms of 3,4\u2010methylenedioxymethamphetamine (MDMA)"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4670-851X","authenticated-orcid":false,"given":"Austen B.","family":"Casey","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris D.","family":"Heifets","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Stanford University School of Medicine  Stanford California USA"},{"name":"Department of Psychiatry and Behavioral Sciences Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/psymed.2023.0049"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.16149"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16182"},{"key":"e_1_2_11_6_1","unstructured":"Alles G. 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