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Epigenetic regulation of the oxytocin and oxytocin receptor (OXTR) gene is altered in several mental disorders and influences social behaviour, often depending on the underlying sex. Evidence suggests that altered promoter methylation could result in oxytocin and OXTR expression differences, thereby possibly influencing drug craving and relapse risk. It is unclear whether promoter methylation changes throughout alcohol withdrawal and is linked to craving and withdrawal symptoms. In this exploratory study, we investigated the effect of 2\u2010week alcohol withdrawal therapy in 99 males on methylation levels (oxytocin and OXTR) compared with 31 healthy controls. We found significantly higher mean methylation values of the OXTR gene in controls than patients across withdrawal (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Regarding oxytocin, we found no differences in mean methylation in healthy controls compared with patients. Across withdrawal, mean methylation decreased in both genes. Fitting a mixed linear model, craving and withdrawal symptoms were associated with changes in methylation levels of the oxytocin gene (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), which was also true for the OXTR gene when considering age and smoking as additional covariates. Our study is the first to report an association between AUD, oxytocin and OXTR gene methylation. Methylation of the OXTR gene is reduced in AUD compared with healthy controls, with OT gene methylation linked to craving and withdrawal severity. Our results suggest that investigations of oxytocin as a therapeutic agent need to consider epigenetic regulation of its receptor and gene as a mechanism that could influence oxytocin's effect on craving and withdrawal symptoms.<\/jats:p>","DOI":"10.1111\/adb.70060","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:14:12Z","timestamp":1752502452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Oxytocin and Oxytocin Gene Receptor Methylation During Withdrawal Therapy in Males With Alcohol Use Disorder"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-8867","authenticated-orcid":false,"given":"Phileas\u00a0J.","family":"Proskynitopoulos","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa\u00a0F.","family":"Haarmeyer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Bleich","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helge","family":"Frieling","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School  Hannover Germany"},{"name":"Laboratory for Molecular Neuroscience Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hillemacher","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy Paracelsus Medical University  Nuremberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Glahn","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1685-9843","authenticated-orcid":false,"given":"Mathias","family":"Rhein","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Social Psychiatry and Psychotherapy Hannover Medical School  Hannover Germany"},{"name":"Laboratory for Molecular Neuroscience Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(16)00104-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.2.629"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2014.00031"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2015.08.013"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.06.009"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12362"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2017.07.021"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2017.257"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2012.01958.x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2019.01.003"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2022.06.011"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2015.04.003"},{"issue":"4","key":"e_1_2_10_14_1","first-page":"142","article-title":"Sex\u2010Specific Differences in Oxytocin Receptor Expression and Function for Parental Behavior","volume":"1","author":"Mitre M.","year":"2017","journal-title":"Gend Genome"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2023.106076"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03701"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12945"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2013.00083"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2020.07.033"},{"issue":"3","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","DOI":"10.1002\/brb3.2425","article-title":"Associations Between Alcohol Use and Peripheral, Genetic, and Epigenetic Markers of Oxytocin in a General Sample of Young and Older Adults","volume":"12","author":"Rung J. 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