{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:35:32Z","timestamp":1760146532425,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["K01-DA046561","R01-AA030923","R01-AA026514"],"award-info":[{"award-number":["K01-DA046561","R01-AA030923","R01-AA026514"]}]},{"name":"National Institute on Drug Abuse (NIDA)","award":["K01-DA046561","R01-AA030923","R01-AA026514"],"award-info":[{"award-number":["K01-DA046561","R01-AA030923","R01-AA026514"]}]},{"name":"National Institute on Alcohol Abuse and Alcoholism (NIAAA)","award":["K01-DA046561","R01-AA030923","R01-AA026514"],"award-info":[{"award-number":["K01-DA046561","R01-AA030923","R01-AA026514"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Substance use disorders (SUDs), including cocaine use disorder (CUD), have significant negative health risks and impose a substantial social burden, yet effective treatments are limited. Pregnenolone, a neuroactive steroid precursor, has been shown to reduce alcohol craving and normalize stress biology in individuals with CUD, but its clinical utility has been questioned due to limited data on bioavailability and the stability of blood levels in humans. Thus, this pilot study aimed to determine whether twice-daily oral pregnenolone (PREG) at 300 mg\/day and 500 mg\/day versus placebo in week two of PREG administration led to stable increased plasma pregnenolone levels in individuals with CUD. Seven treatment-seeking individuals with CUD, enrolled in an eight-week double-blind clinical trial, were randomized to receive placebo (n = 2) or pregnenolone at 300 mg\/day (n = 3) or 500 mg\/day (n = 2). For the first two weeks of the eight-week trial, participants were admitted to an inpatient Clinical Neuroscience Research Unit for repeated serial sampling of plasma pregnenolone concentrations over a 32.5 h period in week two of their inpatient stay while taking their assigned study drug under observation. Pregnenolone levels showed a significant main effect of the medication group (p = 0.039), with sustained higher levels in the 300 mg (p = 0.018) and 500 mg (p = 0.035) groups compared to placebo, and no significant difference between the two pregnenolone dosing groups. Moreover, correlation analyses showed that after observed study medication dosing on repeated sampling day 1, levels of pregnenolone were highly associated across time, with strong, positive correlations between time of dosing and 2 h (r = 0.80, p = 0.031), 4 h (r = 0.80, p = 0.031), 6 h (r = 0.86, p = 0.013), and 8 h post-dosing (r = 0.97, p &lt; 0.001). These findings from this pilot study suggest that chronic twice-daily\/\u201cbis in die\u201d (b.i.d.) oral administration of pregnenolone at both 300 mg\/day and 500 mg\/day achieved stable and reliable elevated plasma pregnenolone levels over 32.5 h in individuals with CUD, thereby supporting the good bioavailability of pregnenolone in these samples. These data indicate that twice-daily chronic dosing may overcome any potential concerns of poor bioavailability and rapid metabolism of pregnenolone in humans, and support further clinical investigations into pregnenolone\u2019s role in the treatment of cocaine use disorders.<\/jats:p>","DOI":"10.3390\/life14111483","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T08:06:32Z","timestamp":1731571592000},"page":"1483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Stability and Reliability of Repeated Plasma Pregnenolone Levels After Oral Pregnenolone Dosing in Individuals with Cocaine Use Disorder: Pilot Findings"],"prefix":"10.3390","volume":"14","author":[{"given":"Huaze","family":"Gao","sequence":"first","affiliation":[{"name":"The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6637-0010","authenticated-orcid":false,"given":"Zachary","family":"Magin","sequence":"additional","affiliation":[{"name":"The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nia","family":"Fogelman","sequence":"additional","affiliation":[{"name":"The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajita","family":"Sinha","sequence":"additional","affiliation":[{"name":"The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo A.","family":"Angarita","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Research Unit, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT 06519, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6752-2223","authenticated-orcid":false,"given":"Verica","family":"Milivojevic","sequence":"additional","affiliation":[{"name":"The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,14]]},"reference":[{"key":"ref_1","unstructured":"SAMSHA (2024). Key Substance Use and Mental Health Indicators in the United States: Results from the 2023 National Survey on Drug Use and Health, Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration."},{"key":"ref_2","first-page":"825","article-title":"Complications of cocaine addiction","volume":"59","author":"Karila","year":"2009","journal-title":"Rev. Prat."},{"key":"ref_3","first-page":"155","article-title":"Chronic diseases and conditions related to alcohol use","volume":"35","author":"Shield","year":"2013","journal-title":"Alcohol Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1080\/19371918.2013.758987","article-title":"The impact of alcohol on society: A brief overview","volume":"28","author":"Moss","year":"2013","journal-title":"Soc. Work. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1177\/0022427898035003004","article-title":"The Influence of Crack Cocaine on Robbery, Burglary, and Homicide Rates: A Cross-City, Longitudinal Analysis","volume":"35","author":"Baumer","year":"1998","journal-title":"J. Res. Crime Delinq."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"463","DOI":"10.31887\/DCNS.2006.8.4\/amorrow","article-title":"Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior","volume":"8","author":"Morrow","year":"2006","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108299","DOI":"10.1016\/j.pharmthera.2022.108299","article-title":"Neurosteroids (allopregnanolone) and alcohol use disorder: From mechanisms to potential pharmacotherapy","volume":"240","author":"Gatta","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1111\/j.1530-0277.2010.01300.x","article-title":"Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats","volume":"34","author":"Besheer","year":"2010","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.drugalcdep.2008.03.021","article-title":"Ethanol intake patterns in female mice: Influence of allopregnanolone and the inhibition of its synthesis","volume":"97","author":"Ford","year":"2008","journal-title":"Drug Alcohol Depend."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1111\/j.1530-0277.2008.00718.x","article-title":"Inhibition of 5alpha-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL\/6J mice","volume":"32","author":"Ford","year":"2008","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.pnpbp.2007.01.022","article-title":"Intrahippocampal allopregnanolone decreases voluntary chronic alcohol consumption in non-selected rats","volume":"31","author":"Darbra","year":"2007","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Milivojevic, V., Charron, L., Fogelman, N., Hermes, G., and Sinha, R. (2022). Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder. Biomolecules, 12.","DOI":"10.3390\/biom12111593"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s00213-022-06278-3","article-title":"Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder","volume":"240","author":"Milivojevic","year":"2023","journal-title":"Psychopharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1001\/jamapsychiatry.2022.1240","article-title":"Association of Drug Cues and Craving with Drug Use and Relapse: A Systematic Review and Meta-analysis","volume":"79","author":"Vafaie","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jsbmb.2015.09.030","article-title":"Neurosteroids and potential therapeutics: Focus on pregnenolone","volume":"160","author":"Vallee","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ejphar.2010.05.033","article-title":"Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration","volume":"641","author":"Ducharme","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-2952(94)00258-N","article-title":"Pregneolone-from Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABAA receptor","volume":"49","author":"Roberts","year":"1995","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.biopsych.2012.12.008","article-title":"Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits","volume":"73","author":"Sripada","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"ref_19","unstructured":"First, M.B., Williams, J.B.W., Karg, R.S., and Spitzer, R.L. (2015). Structured Clinical Interview for DSM-5\u2014Research Version (SCID-5 for DSM-5, Research Version; SCID-5-RV), American Psychiatric Association."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1038\/npp.2009.26","article-title":"Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia","volume":"34","author":"Marx","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_21","unstructured":"Wickham, H. (2024, September 05). ggplot2: Elegant Graphics for Data Analysis. Available online: https:\/\/ggplot2.tidyverse.org."},{"key":"ref_22","unstructured":"Wickham, H., Fran\u00e7ois, R., Henry, L., M\u00fcller, K., and Vaughan, D. (2024, September 05). dplyr: A Grammar of Data Manipulation. Available online: https:\/\/dplyr.tidyverse.org."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting Linear Mixed-Effects Models Using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J. Stat. Softw."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1080\/00031305.1980.10483031","article-title":"Population Marginal Means in the Linear Model: An Alternative to Least Squares Means","volume":"34","author":"Searle","year":"1980","journal-title":"Am. Stat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1111\/j.1399-6576.1994.tb03987.x","article-title":"Pharmacokinetics and pharmacodynamics of eltanolone (pregnanolone), a new steroid intravenous anaesthetic, in humans","volume":"38","author":"Carl","year":"1994","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1007\/s00213-014-3673-4","article-title":"Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia","volume":"231","author":"Marx","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1038\/npp.2014.138","article-title":"A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression","volume":"39","author":"Brown","year":"2014","journal-title":"Neuropsychopharmacology"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/11\/1483\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:32:15Z","timestamp":1760113935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/14\/11\/1483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,14]]},"references-count":27,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["life14111483"],"URL":"https:\/\/doi.org\/10.3390\/life14111483","relation":{},"ISSN":["2075-1729"],"issn-type":[{"type":"electronic","value":"2075-1729"}],"subject":[],"published":{"date-parts":[[2024,11,14]]}}}