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Novel pharmacotherapeutic interventions for CUD, such as those that target the endocannabinoid (eCB) system, must be developed in a manner consistent with these sex differences. The present pilot study sought to prospectively assess sex differences in cannabis withdrawal in a small sample of adults with moderate\u2010to\u2010severe CUD and to determine if withdrawal was associated with peripheral eCB and eCB congener tone. Men and women (<jats:italic>n<\/jats:italic>\u00a0=\u20095\/sex) completed 2\u2009weeks of study participation separated by 1\u2009month; in the latter week, participants abstained from cannabis use. Each week, participants attended in\u2010person laboratory visits during which blood was drawn repeatedly to assess plasma eCB and eCB congener tone. Participants also completed multiple daily ambulatory assessments to assess cannabis use and withdrawal symptoms. As anticipated, women reported a greater increase in withdrawal symptoms during the abstinent week [\u0394\u2009=\u20099.4 (SE\u2009=\u20091.1); <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001] than men [\u0394\u2009=\u20091.2 (SE\u2009=\u20091.2); <jats:italic>p<\/jats:italic>\u00a0=\u00a00.35]. Sex differences in levels of the eCB <jats:italic>N<\/jats:italic>\u2010arachidonoylethanolamide (AEA), as well as the eCB congeners stearoylethanolamide (SEA) and linoleylethanolamide (LEA), were evident during abstinence at the morning time point only (<jats:italic>p<\/jats:italic>'s\u2009&lt;\u00a00.05). LEA was associated with withdrawal symptom expression in both sexes [\u03b2\u2009=\u20090.16 (SE\u2009=\u20090.09)] and palmitoylethanolamide (PEA) [\u03b2\u2009=\u20090.22 (SE\u2009=\u20090.13)] and 2\u2010arachidonoylglycerol (2\u2010AG) [\u03b2\u2009=\u20090.32 (SE\u2009=\u20090.15)] were associated with withdrawal symptoms in women only. Pharmacotherapeutic development for CUD should consider evident sex differences in eCB and eCB congener tone during abstinence and their associations with cannabis withdrawal, as eCB\u2010based interventions may produce differential effects by sex.<\/jats:p>","DOI":"10.1111\/adb.13337","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T08:42:49Z","timestamp":1694594569000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-4933","authenticated-orcid":false,"given":"Erin L.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-1579","authenticated-orcid":false,"given":"Nathaniel L.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Sempio","sequence":"additional","affiliation":[{"name":"iC42 Clinical Research and Development, Department of Anesthesiology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Christians","sequence":"additional","affiliation":[{"name":"iC42 Clinical Research and Development, Department of Anesthesiology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jost","family":"Klawitter","sequence":"additional","affiliation":[{"name":"iC42 Clinical Research and Development, Department of Anesthesiology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Institute of Cognitive Science University of Colorado Boulder  Boulder Colorado USA"},{"name":"Department of Psychiatry University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee L.","family":"McRae\u2010Clark","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Psychiatry and Behavioral Sciences Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Ralph H. 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