Can Weight Loss Drugs Help the Addiction Crisis?

Repurposing Popular Diabetes, Weight Loss Drugs May Help Combat Alcohol Use Disorder

BY PETER MANZA, NIAAA

The recent buzz around a class of weight loss medications known as glucagon-like peptide–1 (GLP–1) receptor agonists is undeniable. GLP-1 receptor agonists mimic the GLP-1 hormone—which is released primarily in the gut and makes you feel fuller on far less food. The original purpose of these drugs was to aid glucose regulation, but the appeal of these drugs, which include semaglutide (the active ingredient in Ozempic, Wegovy, and Rybelsus), now extends beyond their ability to treat diabetes and help people shed pounds. Basic research, case reports, and patient anecdotes suggest that GLP-1 receptor agonists may also curb alcohol consumption.

Exciting, yes, but “we don’t want to celebrate victory without the actual rigorous science,” said Lorenzo Leggio, clinical director of NIDA and joint NIDA/NIAAA senior investigator in the NIDA Translational Addiction Medicine Branch.

Curbing cravings

Leggio and his colleagues, as well as other independent researchers, first recognized GLP-1 as a promising target for addiction nearly a decade ago. For example, in a series of studies, the Leggio team observed that GLP-1 receptor agonism reduced alcohol consumption in mice, and that genetic variants affecting GLP-1 receptor function influence a person’s risk for alcohol use disorder (AUD) (PMID: 26080318).

Support grew as other research teams found similar results. For example, research led by Leggio and Mehdi Farokhnia, staff scientist at the NIDA/NIAAA Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, explored the effects of semaglutide on excessive alcohol drinking in both mouse and rat models (PMID: 37192005). Farokhnia and Leggio collaborated with NIDA/NIAAA Stadtman Investigator Leandro Vendruscolo, NIAAA Director George Koob, and researchers from Scripps Research Institute (La Jolla, Calif.) on that project. Later, another group of scientists in Oklahoma published case reports of people taking GLP-1 receptor agonists for weight loss who also had a significant improvement in their AUD symptoms (PMID: 38019594).

What makes GLP-1 receptor agonists so effective at reducing craving for food is probably what makes them successful at lowering the urge to drink, according to Farokhnia.

“There are a lot of [similarities] between alcohol craving and food-seeking behavior,” Farokhnia explained, noting the common mechanisms between the two types of craving (PMID: 33536884). The GLP-1 system plays a crucial role not only in the experience of reward after eating or drinking, but also in moderating stress, “and both reward and stress are heavily involved in alcohol use,” he added.

Preliminary evidence is promising. Leggio and Farokhnia emphasize, however, that it is premature to hail these medications as the next major advancement in addiction medicine. To date, only one randomized controlled trial—the gold standard for testing a medication’s efficacy—of GLP-1 receptor agonists for AUD has been conducted. In that study, the primary endpoint was not met because exenatide, a GLP-1 receptor agonist, compared with placebo did not significantly reduce heavy drinking days in people with AUD (PMID: 36066977). Secondary analyses of that clinical trial suggested that people with comorbid obesity were successful in reducing alcohol consumption on exenatide compared with placebo, but leaner participants were not.

“This suggests that people with comorbid obesity and alcohol use disorder may benefit from these drugs,” Leggio said, also speculating that exenatide may not be the best compound for this purpose and emphasizing that researchers are now very interested in semaglutide.

Are they safe?

Researchers also aim to understand the safety profile of GLP-1 receptor agonists in people with AUD, who often have comorbid health problems that could elevate their risk for side effects.

“These are pretty safe drugs overall,” Farokhnia said, citing extensive evidence from GLP-1 trials for diabetes and obesity. “But they are not without risks. For example, though rare, there is a risk of pancreatitis because the pancreas also has GLP-1 receptors and people with AUD are already at higher risk of pancreatitis” (PMID: 37796527).

Scientists are also closely monitoring whether these drugs dampen motivation for rewards more broadly. If patients lose desire in other aspects of their lives beyond food and alcohol, it could increase their risk for developing mental health conditions such as anhedonia (the inability to feel pleasure), according to Farokhnia. Although more data are needed, a recent electronic medical records-based analysis is promising in showing no association between semaglutide prescriptions and risk of suicide (PMID: 38182782).

These considerations prompted Leggio, Farokhnia, and other GLP-1 addiction researchers around the globe to publish a commentary urging physicians to not put the cart before the horse when it comes to prescribing GLP-1 receptor agonists to curb alcohol use (PMID: 38001271).

Currently, there are three FDA-approved medications for treating AUD, but they do not work for everyone. Compounding the issue, many people do not know about these options or have access to adequate care. Thus, the researchers conveyed enthusiasm for the potential of GLP-1 receptor agonists to aid in addiction treatment.

“We know from clinical practice that we need a large menu of options to find the right fit for each patient,” Leggio said.

Peter Manza, a research fellow at NIAAA, is studying how chronic drug use changes brain function and how the brain recovers after people enter treatment for substance use disorders. Watch Manza speak about his work in this recent segment of the NIH SciBites video series.