Oral semaglutide was associated with significant reductions in heavy drinking and other alcohol-related outcomes in adults with moderate-to-severe alcohol use disorder (AUD). 

A phase 2 randomized controlled trial of the drug did not meet its primary endpoint of significantly reducing laboratory-based alcohol cue-induced craving at 6 weeks, but did significantly reduce heavy drinking days compared with placebo, a key secondary endpoint. 

Semaglutide was also associated with significant reductions in naturalistic alcohol craving and alcohol-related consequences. Among participants who used cannabis, it also significantly reduced cannabis use days. Significantly more participants receiving semaglutide vs placebo experienced a reduction in WHO risk-drinking level by at least one level.

The drug was generally well tolerated, with most adverse events classified as mild. Treatment adherence and retention were high, with 94% of participants completing the 8-week trial.

“This study suggests oral semaglutide may help reduce heavy and harmful drinking, even in people who are not trying to quit alcohol entirely,” lead study author Joseph Schacht, PhD, associate professor in the Department of Psychiatry, University of Colorado School of Medicine in Aurora, said in a release.

“It could represent a new treatment option for AUD, particularly for those who have not benefited from existing medications,” Schacht added.

The findings were published online on July 29 in The American Journal of Psychiatry.

A Significant Unmet Need

There are currently only three medications approved by the FDA for the treatment of AUD. These are disulfiram, naltrexone, and acamprosate. Although many patients do not respond to these treatments, no other medications have been approved for this indication in nearly 20 years, “highlighting a significant unmet medical need,” Schacht said.

GLP-1 receptor agonists are FDA-approved for other indications, including weight management and type 2 diabetes, but a growing body of preclinical, observational, and clinical research suggests they may also reduce alcohol consumption.

As previously reported by Medscape Medical News, a study published in April in The Lancet showed that once weekly injections of semaglutide were associated with reduced alcohol consumption in adults with AUD and comorbid obesity. 

The current investigators noted that an oral formulation may be more acceptable to patients than an injectable medication, potentially broadening access to treatment.

The phase 2 double-blind, randomized, parallel-arm trial included 50 adults with moderate-to-severe AUD (mean age, 51.1 years; 56% women; mean BMI, 31.4; mean drinks/week, ≥ 28 for men and ≥ 21 for women) who sought to reduce or stop their drinking. 

About half of the participants (n = 26) were randomly assigned to receive oral semaglutide at 3 mg/day for 4 weeks, followed by 7 mg/day for an additional 4 weeks. The other participants received a matching placebo for 8 weeks.

The primary outcome was laboratory-based alcohol cue-induced craving at week 6, assessed using a visual analog scale (VAS). The two preregistered key secondary outcomes were heavy drinking days and drinks per calendar day during the final 4 weeks of treatment.

‘Promising Evidence’

Results showed that the group receiving semaglutide did not have a greater reduction in VAS score for alcohol craving or in drinks per calendar day than the group receiving placebo. 

However, the semaglutide group had significantly reduced heavy drinking days during the last 4 weeks of treatment (P = .008) and during the entire treatment period (P = .035) compared with the placebo group, as well as reduced drinks per drinking day during the same two timepoints (P = .04 and.049, respectively).

They also had greater reductions in alcohol craving outside the laboratory, as measured by the Penn Alcohol Craving Scale (P = .03), and alcohol-related consequences, as measured on the Patient-Reported Outcomes Measurement Information System (P = .025).

In addition, significantly more participants in the semaglutide group than in the placebo group had a reduction of at least one level on the World Health Organization risk drinking scale (81.0% vs 53.8%; P = .045).

Exploratory analysis among the 11 participants who reported using cannabis prior to the start of the study showed reduced cannabis use days in those who received semaglutide vs those who received placebo (P = .01).

Overall, although the active treatment did not meet the study’s primary outcome, its effect on several other outcomes — both in the laboratory and in the environment — “provides promising evidence of its potential efficacy for AUD,” the investigators noted. 

Larger phase 3 trials will need to determine which measures of alcohol consumption are most appropriate for assessing efficacy, as well as the optimal dose and duration of semaglutide treatment, the researchers said. Despite these unanswered questions, they concluded that “efforts to repurpose semaglutide for AUD should continue apace.”

The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the National Center for Advancing Translational Sciences, the Hewit Family Foundation, and an anonymous family donor. Disclosure information for Schacht is available in the original study publication. The other investigators reported having no relevant financial disclosures.