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Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800\u2009mg), and 800\u2009mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT<jats:sub>2A<\/jats:sub>) receptor antagonist ketanserin (40\u2009mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30\u2009h after drug administration. Mescaline at doses &gt;100\u2009mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses &gt;100\u2009mg, with no difference between doses of 200-800\u2009mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2\u2009h, and the plasma elimination half-life was approximately 3.5\u2009h. The average duration of subjective effects increased from 6.4 to 14\u2009h with increasing doses of 100-800\u2009mg mescaline. Nausea and emesis were frequent adverse effects at the 800\u2009mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800\u2009mg mescaline to become comparable to the 100 and 200\u2009mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT<jats:sub>2A<\/jats:sub> receptors.<\/jats:p>","DOI":"10.1038\/s41398-024-03116-2","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T15:02:30Z","timestamp":1727708550000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects"],"prefix":"10.1038","volume":"14","author":[{"given":"Aaron","family":"Klaiber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3618-584X","authenticated-orcid":false,"given":"Yasmin","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Straumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Erne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alen","family":"Jelusic","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\/0000-0003-0874-4875","authenticated-orcid":false,"given":"Dino","family":"Luethi","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":[[2024,9,30]]},"reference":[{"key":"3116_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1080\/02791072.1979.10472090","volume":"11","author":"W La Barre","year":"1979","unstructured":"La Barre W. 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The other authors declare no conflicts of interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice and approved by the Ethics Committee of Northwest Switzerland (EKNZ) and Swiss Federal Office for Public Health. The study was registered at ClinicalTrials.gov (NCT04849013). Written informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"395"}}