03. Semaglutide for Alcohol Use Disorder: New RCT Data

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Alcohol Use Disorder: Unmet Treatment Needs

Alcohol use disorder (AUD) is one of the most prevalent psychiatric conditions. An estimated 29 million US residents had AUD in 2023. Of these, only about 2% received pharmacological treatment.

The US Food and Drug Administration (FDA) has approved three medications for AUD:

• Disulfiram
• Acamprosate
• Naltrexone

However, none of these approved medications is broadly effective or widely prescribed. There’s a clear need for new pharmacological treatments for AUD.

GLP-1 Agonists: A Promising Candidate

One very promising candidate is glucagon-like peptide 1 (GLP-1) receptor agonists. These medications work by:

• Activating GLP-1 receptors in the pancreas and GI tract
• Enhancing glucose-dependent insulin secretion
• Reducing glucagon secretion

GLP-1 receptor agonists are FDA-approved for diabetes and obesity treatment. Interestingly, anecdotal evidence suggests patients taking these for diabetes or obesity may reduce their alcohol intake.

Semaglutide Study Design and Outcome Measures

The study by Dr. Hendershot and colleagues provides more convincing evidence regarding the efficacy and safety of GLP-1 receptor agonists for AUD. They conducted a randomized, double-blind, placebo-controlled clinical trial (RCT) on Semaglutide (a long-acting GLP-1 receptor agonist), using FDA-approved doses of 0.25 and 0.5 mg.

The study was innovative in implementing two types of outcome measures:

1. Standard weekly data on alcohol intake over a 9-week outpatient trial
2. Observed voluntary alcohol intake during a 2-hour human laboratory session, in which participants had free access to their preferred alcoholic beverage

Results: Reduced Heavy Drinking Days

Study results showed a robust benefit from Semaglutide. This is notable given that participants were not seeking treatment for AUD and were not provided any psychosocial treatment to accompany their medication.

Semaglutide significantly reduced:

• The number of drinks per drinking day
• The number of days with heavy drinking (defined as ≥4 drinks for women, ≥5 for men)
• Self-reported alcohol craving

There was no significant effect on number of drinking days, suggesting that Semaglutide might not produce complete abstinence.

In the laboratory session, Semaglutide:

• Reduced alcohol intake by about 2 standard drinks (26g of alcohol)
• Led to a 57% reduction in average breath alcohol concentration

Adverse Events Match GLP-1 Profile

Semaglutide was well tolerated. Adverse events were largely those expected from a GLP-1 receptor agonist:

• Decreased appetite
• GI symptoms
• Headache

There were no serious adverse events. No participant withdrew because of an adverse event and there were no medication interactions with alcohol. As expected, participants taking Semaglutide lost about 5% of their body weight. ****

Study Limitations Affect Generalizability

These findings are promising but may not generalize to all patients. The study excluded participants with:

• Severe medical or psychiatric comorbidities
• Other substance use disorders (except for tobacco and cannabis)

But in real practice, many patients with heavy drinking also have comorbidities like liver disease or depression. Semaglutide may therefore be best suited initially for patients with mild AUD. Also, some patients may be deterred by the need for weekly subcutaneous injections.

Clinical Recommendations for Semaglutide Use

Semaglutide is a promising new treatment for AUD. It has shown efficacy and tolerability in both phase 1 and phase 2 RCTs.

I would recommend considering semaglutide for patients with AUD who haven’t responded to adequate trials of currently approved treatments—after careful screening for clinically relevant comorbidities.

Abstract

Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial

Christian S. Hendershot, Ph.D.; Michael P. Bremmer, MA; Michael B. Paladino, BS; et al.

Importance Preclinical, observational, and pharmacoepidemiology evidence indicates that glucagon-like peptide 1 receptor agonists (GLP-1RAs) may reduce alcohol intake. Randomized trials are needed to determine the clinical significance of these findings.

Objective: To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD).

Design, Setting, and Participants This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non–treatment-seeking participants with AUD were randomized.

Intervention  Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits.

Main Outcomes and Measures  The primary outcome was laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week). Secondary and exploratory outcomes, including prospective changes in alcohol consumption and craving, were assessed at outpatient visits.

Results Forty-eight participants (34 [71%] female; mean [SD] age, 39.9 [10.6] years) were randomized. Low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration task, with evidence of medium to large effect sizes for grams of alcohol consumed (β, −0.48; 95% CI, −0.85 to −0.11; P = .01) and peak breath alcohol concentration (β, −0.46; 95% CI, −0.87 to −0.06; P = .03). Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day (β, −0.41; 95% CI, −0.73 to −0.09; P = .04) and weekly alcohol craving (β, −0.39; 95% CI, −0.73 to −0.06; P = .01), also predicting greater reductions in heavy drinking over time relative to placebo (β, 0.84; 95% CI, 0.71 to 0.99; P = .04). A significant treatment-by-time interaction indicated that semaglutide treatment predicted greater relative reductions in cigarettes per day in a subsample of individuals with current cigarette use (β, −0.10; 95% CI, −0.16 to −0.03; P = .005).

Conclusions and Relevance: These findings provide initial prospective evidence that low-dose semaglutide can reduce craving and some drinking outcomes, justifying larger clinical trials to evaluate GLP-1RAs for alcohol use disorder.

Trial Registration ClinicalTrials.gov Identifier: NCT05520775

Reference

Hendershot CS, Bremmer MP, Paladino MB, et al. Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025;82(4):395–405.