A phase II randomized clinical trial found that low-dose semaglutide may reduce alcohol consumption and craving in adults with alcohol use disorder, suggesting potential new treatment applications for the glucagon-like peptide-1 receptor agonist class of medications.
In the 9-week trial, published in JAMA Psychiatry, researchers used a hybrid design that combined clinical outpatient and human laboratory components to evaluate semaglutide's effects. Participants receiving semaglutide showed significant reductions in laboratory alcohol self-administration and certain drinking outcomes compared with those receiving placebo.
The study involved 48 nontreatment-seeking adults with alcohol use disorder (AUD) who were predominantly female (71%) and a mean age of 39.9 years. Participants received weekly subcutaneous injections of either semaglutide or placebo. The semaglutide group received escalating doses: 0.25 mg/week for 4 weeks, followed by 0.5 mg/week for 4 weeks, and 1 mg for the final week.
The results showed medium to large effect sizes for reduced alcohol consumption during laboratory self-administration tasks. The medication also led to lower peak breath alcohol concentration. Notably, these effect sizes were larger than those typically observed with U.S. Food and Drug Administration (FDA)-approved AUD medications, including naltrexone.
"These findings provide initial prospective evidence that low-dose semaglutide can reduce craving and some drinking outcomes, justifying larger clinical trials to evaluate [glucagon-like peptide-1 receptor agonists] (GLP-1 RAs) for [AUD]," wrote study author Christian S. Hendershot, PhD, of the Department of Population and Public Health Sciences and Institute for Addiction Science at the Keck School of Medicine at the University of Southern California, and colleagues.
Weekly outcomes revealed that while semaglutide did not affect average drinks per calendar day, the treatment significantly reduced drinks per drinking day and weekly alcohol craving.
An unexpected finding emerged in a subsample of participants who reported cigarette use. The semaglutide group showed greater reductions in cigarettes per day compared with placebo.
The study's timing was particularly relevant given recent increases in alcohol-related mortality.
"An estimated 178 000 U.S. deaths per year are alcohol attributable, with further increases in rates of alcohol-related disease projected," the researchers noted.
Less than 2% of individuals with AUD receive pharmacotherapy, representing one of the largest known health care treatment gaps. Currently, only three medications are FDA-approved for AUD: disulfiram, naltrexone, and acamprosate.
Safety outcomes were consistent with semaglutide's known profile. Participants treated with semaglutide experienced expected adverse effects, primarily mild in severity, and no serious adverse events or treatment-related discontinuations were reported. The semaglutide group showed an average 5% weight loss compared with 0.18% in the placebo group.
The researchers emphasized that this study used only the two lowest clinical doses of semaglutide, whereas doses for weight reduction can reach 2.4 mg/week. They suggested higher doses may have greater effects, though safety profiles would require careful evaluation.
Study limitations included the modest sample size, short-term treatment duration, and moderate AUD severity level of participants. The researchers called for larger trials prioritizing FDA-accepted efficacy endpoints to fully evaluate GLP-1 RAs as potential AUD treatments.
The research was supported by the National Institute on Alcohol Abuse and Alcoholism and conducted at the University of North Carolina-Chapel Hill School of Medicine between September 2022 and February 2024.
Full disclosures can be found in the study.
