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We compared acute effects of 2C-B (10, 20, and 30\u2009mg), 125\u2009mg MDMA, and 25\u2009mg psilocybin in 24 healthy participants (12 women, 12 men) using a double-blind, randomized, placebo-controlled, crossover design. Outcome measures included acute subjective effects, autonomic effects, adverse effects, effects on emotional and cognitive empathy, plasma oxytocin and neurophysin I concentrations, and pharmacokinetics up to 9\u2009h. 2C-B produced dose-dependent subjective effects, with the 30\u2009mg dose exerting comparable \u201cany drug effects\u201d to MDMA but lower \u201cany drug effects\u201d than psilocybin. Only psilocybin induced \u201cbad drug effects\u201d and \u201canxiety\u201d compared with placebo. The 30\u2009mg dose of 2C-B induced psychedelic-type alterations of state of consciousness and increased emotional empathy similarly to MDMA. The average subjective effect duration of 30\u2009mg 2C-B was 4.9\u2009h and similar to MDMA (4.8\u2009h) and shorter than psilocybin (6.1\u2009h). MDMA produced the highest cardiovascular stimulation, followed by psilocybin and 2C-B. Only MDMA increased plasma oxytocin and neurophysin I concentrations. 2C-B exhibited dose-proportional pharmacokinetics, with a plasma elimination half-life of ~1.3\u2009h. The 30\u2009mg dose of 2C-B induced entactogenic and psychedelic effects similarly to MDMA and psilocybin, respectively. MDMA is more cardiostimulant than psilocybin and 2C-B. At the tested dose-level, psilocybin is more distressing than MDMA and 2C-B. These results may assist with dose-finding for future 2C-B research and provide a direct comparison with standard doses of the prototypical compounds MDMA and psilocybin. Trial registration: ClinicalTrials.gov identifier: NCT05523401.<\/jats:p>","DOI":"10.1038\/s41386-026-02428-9","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:43:10Z","timestamp":1777394590000},"page":"1511-1518","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Acute dose-dependent effects of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) compared with 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin in a double-blind, placebo-controlled study in healthy participants"],"prefix":"10.1038","volume":"51","author":[{"given":"Denis","family":"Arikci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joran","family":"Borgulya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2952-586X","authenticated-orcid":false,"given":"Isabelle","family":"Straumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5954-4446","authenticated-orcid":false,"given":"Patrick","family":"Vizeli","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3820-2671","authenticated-orcid":false,"given":"Jan","family":"Thomann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3069-9732","authenticated-orcid":false,"given":"Deborah","family":"Rudin","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\/0000-0003-3143-1519","authenticated-orcid":false,"given":"Friederike","family":"Holze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"2428_CR1","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/s41591-021-01336-3","volume":"27","author":"JM Mitchell","year":"2021","unstructured":"Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. 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