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Phase 2 and 3 trials typically administered a first dose of MDMA followed by a second \u201cbooster\u201d dose 1.5\u20132.5\u2009h later, to extend the acute effect duration. However, the risks and benefits of the booster dose have not been systematically investigated. In this double-blind, randomized, placebo-controlled, cross-over study, we compared 120\u2009mg MDMA followed by a 60\u2009mg booster dose or placebo after 2\u2009h, and placebo followed by placebo. The primary outcome was the overall duration of any subjective drug effects, measured by a Visual Analog Scale. Secondary outcomes included additional subjective effects, adverse effects, vital signs, and plasma concentrations of MDMA, oxytocin, and neurophysin I. Twenty-five healthy volunteers were included, and twenty-three (12 male, 11 female) completed all dosing sessions. The booster dose of MDMA prolonged the acute subjective effects of MDMA compared with the single dose (mean\u2009\u00b1\u2009SD, 5.6\u2009\u00b1\u20091.8\u2009h\n                    <jats:italic>vs<\/jats:italic>\n                    . 4.6\u2009\u00b1\u20091.2\u2009h,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001), while no differences in subjective or autonomic peak effects were observed. Acute (0\u20139\u2009h) and subacute (up to 3 days) adverse effects were more common after both MDMA conditions than placebo. These results indicate that acute MDMA effects can be prolonged by using a booster dose, as intended in clinical trials of MDMA-AT. Whether this translates into clinical benefit remains to be investigated.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-04148-6","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:26:49Z","timestamp":1780543609000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparison of acute effects of 3,4-methylenedioxymethamphetamine (MDMA) with and without a supplemental booster dose in healthy participants: a double-blind, randomized, placebo-controlled, crossover study"],"prefix":"10.1038","volume":"16","author":[{"given":"M\u00e9lusine","family":"Humbert-Droz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5308-7945","authenticated-orcid":false,"given":"Anna M.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7040-1041","authenticated-orcid":false,"given":"Jan","family":"Valenta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Rudin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0874-4875","authenticated-orcid":false,"given":"Dino","family":"Luethi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Vukalovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9341-3669","authenticated-orcid":false,"given":"Anne","family":"Eckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1765-9659","authenticated-orcid":false,"given":"Matthias E.","family":"Liechti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-1080","authenticated-orcid":false,"given":"Lorenz","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"4148_CR1","doi-asserted-by":"publisher","first-page":"e36476","DOI":"10.1371\/journal.pone.0036476","volume":"7","author":"CM Hysek","year":"2012","unstructured":"Hysek CM, Simmler LD, Nicola V, Vischer N, Donzelli M, Kr\u00e4henb\u00fchl S, et al. 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