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Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-Methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD, known as \u201ccandyflipping.\u201d The present study investigated whether the co-administration of MDMA can be used to augment acute subjective effects of LSD. We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100\u2009mg) and LSD (100\u2009\u00b5g) with MDMA and LSD administration alone and placebo. Outcome measures included subjective, autonomic, and endocrine effects and pharmacokinetics. MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD\u2009+\u2009MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (C\n                      <jats:sub>max<\/jats:sub>\n                      and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD\u2009+\u2009MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone. Both MDMA alone and the LSD\u2009+\u2009MDMA combination increased oxytocin levels more than LSD alone. Overall, the co-administration of MDMA (100\u2009mg) did not improve acute effects or the safety profile of LSD (100\u2009\u00b5g). The combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy. Trial registration: ClinicalTrials.gov identifier: NCT04516902.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41386-023-01609-0","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T12:04:45Z","timestamp":1685534685000},"page":"1840-1848","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants"],"prefix":"10.1038","volume":"48","author":[{"given":"Isabelle","family":"Straumann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3143-1519","authenticated-orcid":false,"given":"Friederike","family":"Holze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Klaiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Wey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-3932","authenticated-orcid":false,"given":"Urs","family":"Duthaler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8598-0535","authenticated-orcid":false,"given":"Nimmy","family":"Varghese","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"}]}],"member":"297","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"1609_CR1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.biopsych.2022.08.025","volume":"93","author":"F Holze","year":"2023","unstructured":"Holze F, Gasser P, Muller F, Dolder PC, Liechti ME. 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The other authors declare no competing interests. Knowhow and data associated with this work and owned by the University Hospital Basel were licensed by Mind Medicine, Inc. Mind Medicine, Inc., had no role in planning or conducting the present study or the present publication.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}