A preliminary, phase 2 clinical trial has shown the potential benefit of a class of popular medications so far approved for control of diabetes and obesity to help reduce alcohol consumption and craving in individuals with alcohol use disorder (AUD).

The drug, injected weekly at low dosages for 9 weeks in the newly reported trial, is semaglutide (marketed as Ozempic and Wegovy). It is an agonist, or stimulator, of the GLP-1 receptor, a key regulator of blood sugar levels, appetite, and other metabolic processes. AUD, notes the Mayo Clinic, is “a pattern of alcohol use that involves problems controlling your drinking, being preoccupied with alcohol or continuing to use alcohol even when it causes problems. It also involves having to drink more to get the same effect or having withdrawal symptoms when you rapidly decrease or stop drinking.”

There is a great unmet need for new medicines to treat alcohol-related problems. In the U.S., an estimated 178,000 deaths per year are attributed to alcohol consumption, and 2.6 million deaths annually worldwide. Excess alcohol consumption is clearly linked to health problems, including many of the major public health threats facing Americans: heart and liver diseases and cancer among them.

In the U.S., 29% of adults meet conditions for an AUD diagnosis over their lifetime and an estimated 11% in the most recent year. Yet less than 10% of those with AUD report past-year treatment, of whom less than 2% have taken medicines for it. Only three drugs have ever received FDA approval for AUD—disulfiram, naltrexone, and acamprosate—and their limited use for AUD is traced to factors including stigma and poor public awareness of their potential benefit.

Rapidly increasing prescription rates of long-acting GLP-1 agonist medicines like semaglutide have been accompanied by frequent informal reports of reduced alcohol intake and craving by patients. And there are many reports from experiments in animals and in lab settings not involving human patients that these medications reduce voluntary alcohol consumption and perhaps also help to reduce the reinforcement provided by, among other things, activation of the brain’s reward system.

The newly reported randomized clinical trial was motivated by these factors and one other—the fact that substantial numbers of patients have obtained prescriptions for semaglutide and similar medications to help reduce heavy drinking. Such “off-label” use, i.e., made in the absence of an FDA approval for this indication, in itself is reason for carefully conducted, evidence-based clinical trials, say the researchers, who reported results in JAMA Psychiatry.

The team, led by Christian S. Hendershot, Ph.D., of the Keck School of Medicine and Institute for Addiction Science at the University of Southern California, and which included Sherry A. McKee, Ph.D., a 2004 BBRF Young Investigator, recruited 48 participants at the University of North Carolina, Chapel Hill, for their phase 2 trial (such trials are typically small and are geared to determine if there is strong reason to test a therapy in a larger population—typically at much greater expense and effort).

71% of the participants were female; the total group was about 40 years old on average, and had, within the year prior to the trial, met criteria for AUD, and reported that during the past month they had consumed more than 7 (women) or 14 (men) drinks in at least 1 week, including 2 or more episodes of heavy drinking (4 or more drinks for women and 5 or more for men). About half of the participants had a body mass index (BMI) of 30 or more, the medical definition of obesity; none were underweight (a factor in taking GLP-1 agonist drugs, which cause weight loss). Important to the trial, none of those enrolled were actively seeking treatment for their drinking or attempting to reduce their drinking.

Half the participants received a weekly injection of semaglutide, first at the very low dose of 0.25 mg, then after 4 weeks at 0.5 mg, and finally at 1 mg in the 9th and final week of the trial (the typical maximum dose for weight loss is 2.4mg/week). The other 24 participants received a weekly placebo injection.

The trial involved 2 phases. One involved laboratory tests trying to gauge each participant’s voluntary alcohol consumption and ability to delay drinking. Prior to the start of injections and also between the 8th and 9th weeks of the trial, participants were presented (in a lab setting) with their preferred drink and could elect to delay consumption for up to 50 minutes in exchange for a monetary reward. After that, they were instructed to consume at their preferred pace over 2 hours. The amount of alcohol consumed as well as breath alcohol concentration at different points were measured by investigators.

The other phase of the trial was based on self-reports by each participant of alcohol consumption during the time between weekly visits to the clinic, recorded week by week over the 9 weeks. Daily logs were compiled, enabling researchers to analyze data on the number of total days alcohol was consumed and not consumed; the total and average number of drinks per calendar day and per “drinking” day; the number of heavy drinking days, and self-reported measures of craving. Participants who were smokers (27%) also recorded number of cigarettes smoked per day (GLP-1 drugs are also thought to help reduce smoking and the craving for nicotine).

Results were encouraging. Relative to those in the placebo group, those treated with semaglutide took significantly fewer drinks on days they consumed alcohol, and reported greater reductions in heavy drinking days during the trial. They also had significantly lower levels of weekly alcohol craving throughout the trial.  There was also evidence that among a subgroup of smokers, those receiving semaglutide had a greater reduction in cigarettes per day than those receiving placebo.

In data comparing results from weeks 1-4 and 5-8 (with semaglutide dose doubling from 0.25mg/week to 0.5mg/week over that interval) a clear dose-sensitivity was seen in most measures: the beneficial impacts of the medication (measured by “effect size”) were greater at the higher dose.

The observed magnitude of medication effects on heavy drinking, said the team, while preliminary, is promising especially considering the effect sizes observed for FDA-approved AUD treatments, and are also notable in that they were obtained at the two lowest doses of semaglutide used clinically. “When participants completed both pre- and post-treatment alcohol self- administration sessions, we observed greater reductions in the medication group. This is a key aspect of this study because this is an objective (rather than self-report) measure of alcohol consumption,” Dr. Hendershot explained.

In addition to noting the treatment was safe and well-tolerated in the trial, the team also highlighted the fact that these results were seen in a group, albeit small, that had not been seeking treatment to reduce their drinking. The number of individuals with AUD in the general population receiving GLP-1-based medications is believed to greatly exceed the number who receive FDA-approved drug treatments for AUD. “This presents an ideal scenario” to test the viability of “medication repurposing,” the team said. Evidence from this trial that semaglutide had minimal effects on number of drinking vs. abstinence days, and with its largest effect seen in reducing quantity of alcohol consumed and number of days of heavy drinking, suggest the possibility of its use in people who do not seek to abstain entirely from alcohol or prevent relapse after stopping drinking, but rather in those who seek to reduce alcohol consumption and patterns of heavy or binge drinking.

The current trial, by design, was small and had a short duration. Much larger and longer controlled clinical trials involving both individuals with moderate AUD (as in this trial) and those with severe AUD, are called for, the team said. These future trials might also test the efficacy of multiple GLP-1-based medications already approved by the FDA for various purposes, and which have thus passed the “safety test,” in persons with problematic alcohol consumption.