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Heart rate variability (HRV), a marker of autonomic nervous system responsiveness to stressors, may mediate alcohol's impact on the cardiovascular system. While pregnenolone (PREG) has been shown to normalize heart rate and blood pressure in individuals with AUD, its effects on sympathetic and parasympathetic components of HRV and related alcohol craving are not known.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty\u2010five treatment\u2010seeking individuals with AUD were randomized to placebo (<jats:italic>n<\/jats:italic>\u2009=\u200921) or daily pregnenolone at 300\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200918) or 500\u2009mg (<jats:italic>n<\/jats:italic>\u2009=\u200916), in a double\u2010blind, 8\u2010week pilot clinical trial. In week 2, participants underwent three randomized, counterbalanced 5\u2010minute personalized guided imagery provocations (stress, alcohol, and neutral\/relaxing cues) on separate days. HRV indices were assessed during each session and analyzed using linear mixed\u2010effects models (LMEs), including association between HRV indices and anxiety and alcohol craving.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A medication group \u00d7 condition interaction was found for parasympathetic, high\u2010frequency (HF) (<jats:italic>p<\/jats:italic>\u2009=\u20090.028) and sympathetic\/parasympathetic, low\u2010frequency\/high\u2010frequency (LF\/HF) ratio (<jats:italic>p<\/jats:italic>\u2009=\u20090.017) indices of HRV. Placebo had higher HF during alcohol cue (<jats:italic>p<\/jats:italic>\u2009=\u20090.011), while 500\u2009mg PREG demonstrated lower HF in response to stress (<jats:italic>p<\/jats:italic>\u2009=\u20090.050) and alcohol cues (<jats:italic>p<\/jats:italic>\u2009=\u20090.047). Placebo showed lower LF\/HF ratio during stress (<jats:italic>p<\/jats:italic>\u2009=\u20090.006) and alcohol cue (<jats:italic>p<\/jats:italic>\u2009=\u20090.001), while the PREG groups showed no changes. Overall, the LF\/HF response to alcohol cue was significantly lower in placebo compared to the 300\u2009mg PREG (<jats:italic>p<\/jats:italic>\u2009=\u20090.012) and 500\u2009mg PREG (<jats:italic>p<\/jats:italic>\u2009=\u20090.037) groups. Lastly, HF was found to predict alcohol craving regardless of PREG doses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We found a normalization of autonomic response in PREG groups. These findings suggest that PREG holds therapeutic potential for enhancing autonomic function in AUD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15529","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T02:09:22Z","timestamp":1736388562000},"page":"619-628","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pregnenolone effects on parasympathetic response to stress and alcohol cue provocation in treatment\u2010seeking individuals with alcohol use disorder"],"prefix":"10.1111","volume":"49","author":[{"given":"Huaze","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Psychiatry, The Yale Stress Center Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajita","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, The Yale Stress Center Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8754-7479","authenticated-orcid":false,"given":"Stephanie","family":"Wemm","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, The Yale Stress Center Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6752-2223","authenticated-orcid":false,"given":"Verica","family":"Milivojevic","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, The Yale Stress Center Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/nutraceuticals4020015"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(89)90408-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v067.i01"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2010.01300.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2007.04.005"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2017.01.044"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.4065\/77.1.45"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386525-0.00036-6"},{"key":"e_1_2_8_10_1","volume-title":"Structured clinical interview for Dsm\u20105\u2014research version (Scid\u20105 for Dsm\u20105, research version; 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