A Phase 2 trial published in the American Journal of Psychiatry found oral semaglutide reduced heavy drinking and alcohol-related harm in adults with alcohol use disorder.
Written By: Chikkula Pavan Kumar, PharmD
Reviewed By: Pharmacally Editorial Team
Oral semaglutide reduced heavy alcohol consumption and alcohol-related harm in adults seeking treatment for moderate-to-severe alcohol use disorder (AUD) in a Phase 2 randomized, double-blind, placebo-controlled clinical trial (NCT05892432) led by Joseph P. Schacht, Ph.D., and colleagues at the University of Colorado School of Medicine. Published in the American Journal of Psychiatry, the investigator-initiated study was conducted under an FDA Investigational New Drug (IND) exemption. Although the trial did not meet its primary endpoint of reducing laboratory-based alcohol cue-induced craving, investigators observed consistent improvements across several clinically important secondary outcomes, supporting further clinical development of semaglutide for AUD.
GLP-1 Receptor Agonists Expand Beyond Metabolic Disease
Alcohol use disorder remains a major public health challenge, with only three FDA-approved medications currently available and overall treatment effectiveness remaining modest.
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist widely used for type 2 diabetes and obesity. In addition to regulating appetite and glucose metabolism, GLP-1 receptors are expressed in brain regions involved in reward processing and motivation. Preclinical studies have suggested that activating these pathways may reduce alcohol reward, craving, and excessive alcohol consumption, making GLP-1 receptor agonists promising candidates for AUD treatment.
Phase 2 Trial Design
The investigator-initiated study enrolled 50 treatment-seeking adults aged 21 years or older with moderate-to-severe AUD and overweight or obesity between November 2023 and October 2025 at a U.S. academic center.
Participants were randomized 1:1 to receive oral semaglutide 3 mg once daily for four weeks followed by 7 mg once daily for an additional four weeks, or matching placebo. During the 8-week treatment period, investigators evaluated alcohol craving, drinking behavior, alcohol-related consequences, cannabis use, and safety.
Primary Endpoint Not Met
The primary endpoint was laboratory-based alcohol cue-induced craving at Week 6.
Semaglutide did not improve this endpoint compared with placebo (b = −0.614; 95% CI, −3.563 to 2.335; p=0.68).
Heavy Drinking Declined During Treatment
Despite missing the primary endpoint, oral semaglutide produced clinically meaningful improvements across several prespecified and exploratory outcomes.
During the final four weeks of treatment, participants receiving semaglutide experienced fewer heavy drinking days than those receiving placebo (b = −0.580; 95% CI, −1.012 to −0.148; p=0.008). The reduction in drinks consumed per calendar day approached statistical significance (b = −1.166; 95% CI, −2.368 to 0.035; p=0.057).
Treatment also reduced drinks consumed per drinking day (b = −1.177; 95% CI, −2.307 to −0.047; p=0.041).
Across the entire 8-week treatment period, participants receiving semaglutide continued to show fewer heavy drinking days (b = −1.065; p=0.035) and fewer drinks per drinking day (b = −0.946; p=0.049), indicating sustained reductions in alcohol consumption.
Improvements Extended Beyond Alcohol Intake
Benefits extended beyond drinking behavior.
Naturalistic alcohol craving, assessed using the Penn Alcohol Craving Scale, declined compared with placebo (b = −2.195; 95% CI, −4.174 to −0.216; p=0.030). Scores on the Alcohol Craving Questionnaire-Short Form also improved (p=0.027), although laboratory-based visual analogue craving scores remained unchanged.
Investigators also observed greater reductions in alcohol-related negative consequences measured by the PROMIS Alcohol Scale (b = −4.618; 95% CI, −8.651 to −0.585; p=0.025).
In addition, 81.0% of participants treated with semaglutide reduced their World Health Organization (WHO) Risk Drinking Level by at least one category compared with 53.8% of participants receiving placebo (p=0.045), reflecting clinically meaningful reductions in harmful alcohol use.
Exploratory Findings Suggest Broader Effects
Among participants who used cannabis at baseline, treatment reduced cannabis use days during the study (b = −1.434; 95% CI, −2.568 to −0.301; p=0.014).
Although this was an exploratory endpoint, the finding suggests that GLP-1 receptor agonists may influence reward-related behaviors beyond alcohol consumption. Larger studies will be needed to confirm this observation.
Safety Profile Remained Consistent
Treatment completion reached 94%, and medication adherence remained high throughout the study.
Most adverse events were mild and consistent with the established safety profile of semaglutide. One participant discontinued treatment because of a probable drug-related maculopapular rash. One serious adverse event, myocardial infarction, occurred in the placebo group after treatment had ended.
No new safety signals were identified during the trial.
Investigators Support Further Clinical Development
The investigators concluded that although oral semaglutide did not reduce laboratory-based alcohol cue-induced craving, its consistent improvements in heavy drinking, real-world alcohol craving, alcohol-related consequences, and risk drinking levels provide further evidence that GLP-1 receptor agonists may offer a new pharmacological approach for alcohol use disorder.
They noted that larger and longer Phase 3 studies are needed to confirm efficacy, establish the optimal treatment duration and dosage, and determine whether semaglutide can provide durable reductions in harmful alcohol use.
What This Means for Patients
Only three FDA-approved medications are currently available for alcohol use disorder, and their overall effectiveness remains modest.
This Phase 2 study suggests that oral semaglutide may help people reduce heavy drinking, lessen alcohol cravings outside the laboratory, and decrease alcohol-related harm without introducing major safety concerns. While additional Phase 3 studies are required before semaglutide could become a routine treatment for AUD, these findings represent an encouraging step toward expanding therapeutic options for people living with alcohol dependence.
Reference
Oral Semaglutide for Alcohol Use Disorder: A Randomized Clinical Trial
About the Writer
Chikkula Pavan Kumar (LinkedIn), PharmD is a Doctor of Pharmacy with a keen interest in clinical pharmacy, pharmacovigilance, and evidence-based practice. In his words, he is passionate about patient safety and translating complex medical information into clear, research-driven communication.