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The present study investigated the acute response to single doses of LSD (100\u2009\u03bcg) after daily administration of paroxetine (10\u2009mg for 7\u2009days, followed by 20\u2009mg for 35\u2009days) or placebo (42\u2009days) using a randomized, double\u2010blind, cross\u2010over design in 23 healthy participants. Paroxetine did not alter pleasant subjective effects of LSD but significantly reduced \u201cbad drug effect,\u201d \u201canxiety,\u201d and \u201cnausea.\u201d No differences in autonomic effects or QTc interval after LSD administration were found between both conditions. The strong cytochrome P450 2D6 (CYP2D6) inhibitor paroxetine led to higher maximal concentrations and total exposures of LSD (geometric mean ratios of 1.4 and 1.5, respectively) indicating relevant involvement of CYP2D6 in its metabolism. The extent of this inhibition was nominally highest in genetic CYP2D6 normal metabolizers and lowest in poor metabolizers. The present findings suggest that add\u2010on treatment with LSD to an SSRI is well\u2010tolerated. The pharmacokinetic and pharmacodynamic interactions indicate that no dose adjustment of LSD seems necessary in the presence of an SSRI that inhibits CYP2D6. For SSRIs that do not relevantly inhibit CYP2D6, a dose increase of LSD might be appropriate, but due to lacking data and potential other pharmacokinetic interactions with these compounds, no definitive dose recommendation can be made.<\/jats:p>","DOI":"10.1002\/cpt.3618","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:35:09Z","timestamp":1741757709000},"page":"1784-1792","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Acute Effects and Pharmacokinetics of <scp>LSD<\/scp> after Paroxetine or Placebo Pre\u2010Administration in a Randomized, Double\u2010Blind, Cross\u2010Over Phase I Trial"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5308-7945","authenticated-orcid":false,"given":"Anna M.","family":"Becker","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Toxicology Department of Biomedicine Department of Clinical 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