["Addiction, EarlyView. ", "\nAbstract\n\nBackground and aims\nCurrent medications for alcohol use disorders (AUD) are under‐used and of moderate benefit; new or improved treatments are much needed. Preclinical and small clinical studies indicate that pioglitazone, a thiazolidinedione agonist of the peroxisome proliferator‐activated receptor gamma, may reduce alcohol use. The primary purpose of this study was to evaluate, in a randomized trial, the effect of pioglitazone on alcohol use and craving in adults with AUD.\n\n\nDesign\nA double‐blind, placebo‐controlled randomized trial.\n\n\nSetting\nEnrollment occurred in the United States at two Veterans Affairs Health Care Centers (VAHCS) from July 2019 to March 2024.\n\n\nParticipants\nOne hundred eighty‐five Veteran men and women older than 18 years with at least a moderate AUD and current alcohol use.\n\n\nIntervention and comparator\nOral pioglitazone was given at dosages of 0 (placebo) (n = 92), or 45 mg (n = 93) over 14 weeks. All participants received Brief Behavioral Compliance Enhancement Treatment at each visit.\n\n\nMeasurements\nThe primary outcome measure was the number of heavy drinking days during week 14 as measured by the Timeline Follow Back (TLFB). Secondary measurements included the number of standard drinks consumed per week, the rate of no heavy drinking days over the last 8 weeks of the study, alcohol craving, anxiety, depression and post‐traumatic stress disorder symptoms. Exploratory outcome included change in alcohol use based on inflammation (C‐reactive protein) at baseline.\n\n\nFindings\nThere was no difference between groups on the primary outcome (pioglitazone mean = 2.43, placebo mean = 2.01, difference = 0.43, 95% confidence interval = −0.25 to 1.10, P = 0.22). No differences were found between groups in secondary alcohol use measures or a measure of craving. Participants with elevated inflammation at baseline treated with pioglitazone had a greater decrease in heavy drinking days over time compared with placebo (z = 2.21, P = 0.03). Pioglitazone was safe and well tolerated.\n\n\nConclusions\nPioglitazone administered to people with alcohol use disorder at a dose of 45 mg per day appears to be safe although there is no evidence that it is efficacious in reducing alcohol use, alcohol craving or any psychiatric measures.\n\n"]