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Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 37 patients with blood sampling and acquisition of psychometrics \u2013 at baseline, 24\u2009h after administration of psilocybin (25\u2009mg) or placebo (mannitol), and one month after treatment. As the primary endpoints (duration of abstinence and mean alcohol use) in this trial were not reached, our investigation included secondary psychometrics that differed significantly between groups: Beck\u2019s Depression Inventory and Beck\u2019s Hopelessness Scale. The epigenome-wide association study (EWAS) identified one CpG site in\n                    <jats:italic>TLE4<\/jats:italic>\n                    (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene\n                    <jats:italic>RASGRP4<\/jats:italic>\n                    (\n                    <jats:italic>pFDR<\/jats:italic>\n                    \u2009=\u20093.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) uncovered promoter-associated methylation changes in\n                    <jats:italic>HTR2A<\/jats:italic>\n                    and\n                    <jats:italic>TNF<\/jats:italic>\n                    . Interestingly, several of the reported analyses point to immunomodulatory actions of psilocybin. While the findings of this pilot study are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-03961-3","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T13:06:24Z","timestamp":1779800784000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenome-wide association study of psilocybin-induced methylome changes in alcohol use disorder"],"prefix":"10.1038","volume":"16","author":[{"given":"Marvin M.","family":"Urban","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7457-374X","authenticated-orcid":false,"given":"Lea","family":"Zillich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie M.","family":"Rieser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-1971","authenticated-orcid":false,"given":"Marcus","family":"Herdener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2151-4521","authenticated-orcid":false,"given":"Rainer","family":"Spanagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9053-6164","authenticated-orcid":false,"given":"Franz X.","family":"Vollenweider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0413-7672","authenticated-orcid":false,"given":"Katrin H.","family":"Preller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5103-0731","authenticated-orcid":false,"given":"Marcus W.","family":"Meinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"3961_CR1","volume-title":"Global Status Report on Alcohol and Health 2018","author":"World Health Organization","year":"2018","unstructured":"World Health Organization Global Status Report on Alcohol and Health 2018. 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