‘New Hope’ for Alcohol Use Disorder Treatment

Evidence is mounting that new therapies already used to treat gut diseases, type 2 diabetes, and obesity may help people with alcohol use disorder (AUD).

Glucagon-like peptide 1 (GLP-1) receptor agonists, first used to treat diabetes and now widely used for weight loss, and fecal microbiota transplants (FMTs), used to treat diseases such as recurrent Clostridioides difficile infection, are advancing in clinical trials as potential options for treating AUD.

AUD Affects 28.9 Million People in the United States

In 2023, 28.9 million people aged 12 years or older in the United States had AUD (10.2% of the people in this age group). The US Food and Drug Administration (FDA) has approved three medical therapies: Acamprosate, naltrexone, and disulfiram to help keep people with the disorder from returning to heavy drinking. Acamprosate’s mechanism of action is not clear, but it is thought to modulate and normalize alcohol-related changes in brain activity, thereby reducing withdrawal symptoms. Naltrexone blocks opioid receptors to reduce alcohol cravings. Disulfiram causes a toxic physical reaction when mixed with alcohol.

Some with AUD also benefit from behavioral therapies and support groups such as Alcoholics Anonymous. But for others, nothing has worked, and that’s part of the reason Lorenzo Leggio, MD, PhD, a scientist in the field of alcohol addiction with the National Institutes of Health, told Medscape Medical News that this is the “most exciting moment” for AUD treatment in his more than two decades of research in this area.

GLP-1 Agonists Showing Consistent Results

GLP-1 receptor agonists work by modulating the brain’s reward pathways, including the areas that regulate cravings and motivation.

“By dampening the reward signals associated with alcohol consumption, GLP-1 agonists may reduce cravings and heavy drinking episodes,” Fares Qeadan, PhD, MS, associate professor of biostatistics in the Department of Public Health Sciences at Loyola University Chicago, Chicago, told Medscape Medical News.

“The unique aspect of GLP-1 agonists is their ability to target both metabolic and reward systems in the brain,” he said. While naltrexone or acamprosate blocks the effects of alcohol or reduces withdrawal symptoms, “GLP-1 agonists approach addiction through a broader mechanism, potentially addressing underlying factors that contribute to cravings and compulsive behaviors,” he said.

As part of a study published in October in Addiction, Qeadan’s team found that people with AUD who were prescribed GLP-1 agonists had a 50% lower rate of severe intoxication than those who were not prescribed those medications.

“While this is observational and not yet definitive, it highlights the potential of these drugs to complement existing treatments for AUD,” he said.

Another study, a nationwide cohort study published last month in JAMA Psychiatry, found that using the GLP-1 receptor agonists semaglutide and liraglutide was linked to a lower risk for AUD-related hospitalizations than traditional AUD medications.

A systematic review, published last month in eClinical Medicine, concluded that though there is little high-quality evidence demonstrating the effect of GLP-1 receptor agonists on alcohol use, “Subgroup analysis from two [randomized, controlled trials] and supporting data from four observational studies suggest that GLP-1 [receptor agonists] may reduce alcohol consumption and improve outcomes in some individuals.”

Studying individual differences in response may have implications for personalized medicine, Qeadan said, as treatments could be tailored to those most likely to benefit, such as people with both metabolic dysfunction and AUD.

“These medications may offer hope for patients who struggle with addiction and have not responded to traditional therapies,” Qeadan said.

Exploring FMT as AUD Treatment

FMT is also a new research focus for treating AUD. Jasmohan Bajaj, MD, a gastroenterologist and liver specialist at Virginia Commonwealth University Medical Center in Richmond, Virginia, is leading the Intestinal Microbiota Transplant in Alcohol-Associated Liver Disease (IMPACT) trial.

AUD has been linked with gut microbial alterations that worsen with cirrhosis. Research has shown that alcohol consumption changes the diversity of bacteria and can lead to bacterial overgrowth and progression of alcohol-associated liver disease.

FMT has been effective in rebalancing gut bacteria by transferring healthy stool from screened donors into patients who have developed an overgrowth of harmful bacteria. In the IMPACT trial, participants, who have not previously received traditional treatment for AUD or for whom treatment has not worked, are randomized either to the oral treatment capsule, which contains freeze-dried stool from a donor with healthy gut bacteria, or placebo.

The trial, sponsored by the National Institutes of Health, is halfway through its target enrollment of 80.

In a previous smaller, placebo-controlled phase 1 study, also led by Bajaj and published in Hepatology, 9 of the 10 volunteers who had severe AUD and cirrhosis experienced fewer alcohol cravings and had lower consumption after 15 days. Only three of the placebo participants saw similar improvements. Those who received the microbiota transplant also had fewer AUD-related events over 6 months.

Bajaj said that if trials show FMT is safe and effective, he envisions the treatment as one tool in a multidisciplinary, integrated clinic that would include a hepatologist and mental health clinicians.

One benefit of the FMT treatment approach is it is given once or twice only, rather than administered regularly.

Current Treatments Work, But More are Needed

Leggio, who is clinical director of the National Institute on Drug Abuse Intramural Research Program, said, “We know that alcohol use disorder, and addiction in general, is a brain disease. We also know that the brain does not work in isolation. The brain is constantly interacting with the rest of the body, including with the gut.”

Leggio said it’s important to note that the three FDA-approved medications do work for alcohol addiction. He said they work as well as selective serotonin reuptake inhibitors for depression and beta-blockers for chronic heart failure.

But there are only three, and they don’t work for everyone, he noted. Those are among the reasons developing new treatments is important. New treatments could be used as an alternative or in combination with already approved treatments.

FMT is in “the very early stages” of trials testing its use for AUD, Leggio noted, adding that the studies by Bajaj’s team are among the very few addressing gut dysbiosis in AUD, and all have involved small numbers of patients. “It’s promising. It’s intriguing. It’s exciting. But we are just at the beginning.”

Results Consistent Across Species, Labs

GLP-1 agonists are further along in trials but still not ready for prescribing for AUD, Leggio noted. The positive results have been consistent across species, different labs, and different research teams around the world.

Researchers have also explored through electronic health record emulation trials whether people already taking GLP-1 agonists for diabetes or obesity drink less alcohol compared with matched cohorts not taking GLP-1s. “They consistently show that the people who are on GLP-1s drink less,” he said.

“[Emulation trials] don’t replace the need for randomized controlled trials, Leggio noted. Leggio’s team is currently working on a randomized, placebo-controlled, double-blinded trial studying GLP-1s in relation to AUD.

New Directions 20-Year Highlight

This whole line of research represents “new hope” and has many implications, Leggio said. “I have been in this business for 20-plus years, and I think this is themost exciting moment when we have a very promising target in GLP-1s.”

Regardless of efficacy, he said, the focus on GLP-1 agonists and FMT for AUD has people talking more about addiction and the brain-body connection rather than assuming AUD is a result of poor choices and “bad behavior.”

The momentum of new treatments could also lead to patients and physicians having conversations about existing treatments.

“Hopefully, this momentum will help us destigmatize addiction, and by destigmatizing addiction, there will be an uptick in use of currently approved medications,” Leggio said.

Qeadan, Bajaj, and Leggio reported no relevant financial relationships.

Marcia Frellick is a freelance journalist based in Chicago. She has previously written for the Chicago Tribune, Science News, Northwestern Magazine, and Nurse.com and was an editor at the Chicago Sun-Times, The Cincinnati Enquirer, and St. Cloud (Minn.) Times. Follow her on X@MLfrellick.