'Beyond Weight Loss': Emerging Studies Show How GLP-1 Receptor Agonists May Impact Addiction Behaviors

The last time slot of the last full day of American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition doesn't sound like the best time slot for drawing a crowd––especially when the society meets in Las Vegas, where even the presenter says "there are so many more fun things you could be doing right now."

Still, Marina Trefethen, PharmD, BCPP proved it can be done as long as you present on the right topic. Trefethen certainly found that: breaking down studies on the effects GLP-1 receptor agonists (GLP-1s) have on substance use and addiction behaviors, which she did before a packed room.

Trefethen, a board-certified mental health clinical pharmacist at the White River Junction Veterans Affairs Medical Center in Vermont, began by outlining the toll substance use disorders (SUDs) of all kinds have. "Substance use disorders have a profound impact on individuals' lives, not just the individual with the disorder, but those [close to] them and society as a whole," she said. Productivity reductions, quality-of-life impacts come second to lives lost. "Substance use disorders are associated with increased risk of mortality [and] medical and psychiatric comorbidities," Trefethen said.

The impact to the health care system is also extreme. "There was a study looking at employer-sponsored insurance ... [to] see how much it costs to treat substance use disorders per enrollee," Trefethen said, "and they found the annual cost per enrollee was just over $15,000. Total medical cost was just over $35 million." This includes inpatient services, outpatient services, and prescription medications.

According to national survey data cited by Trefethen, approximately 17% of the US population reports having a substance use disorder, with no significant change in those numbers since 2021. Furthermore, about 20% of survey respondents reported binge drinking (5 or more drinks for males, 4 or more for females) on 5 or more days out of the 30 days before they took the survey.

Pharmacologic options are limited for many SUDs. Naltrexone is approved for AUD and opioid use disorder (OUD); varenicline, buproprion SR, and nicotine replacements are approved for nicotine use disorder; acamprosate and disulfiram are approved for AUD; and buprenorphine and methadone are approved for OUD. "[For] cocaine use disorder and cannabis use disorder, there are no FDA-approved medications," Trefethen said, underscoring the unmet medical need that has driven interest in repurposing existing therapies.

The Neurobiology of Addiction

Trefethen detailed the dopamine theory of addiction, outlining how addictive substances hijack the mesolimbic dopamine pathway that connects the ventral tegmental area (VTA) to the nucleus accumbens, producing dopamine levels far greater than those seen with natural stimuli.

"Substance use disorders are more than just a habit," Trefethen said. As use becomes more chronic, "we start to see these changes in the brain. Decision-making starts to be impaired, so that despite harmful consequences, the use becomes compulsive."

Understanding these changes in the brain can inform the development of SUD treatment. "When we're looking at pharmacotherapy for substance use disorders, especially for continuous disorder and alcohol use disorder, we're targeting this mesolimbic pathway. ... We want to keep this nice, steady flow of dopamine to attenuate those cravings and those urges to use the substance," Trefethen said.

GLP-1 receptors are expressed in many of the same brain regions involved in reward processing, including the VTA, nucleus accumbens, amygdala, and hippocampus. Activation of these receptors is thought to reduce cravings and dampen conditioned responses, which has accounted for the success of these drugs in patients seeking to lose weight. The next question is whether those same results can be seen when the cravings and conditioned responses relate to illicit drugs rather than food.

Studies in rodent populations provided early support for this hypothesis. Mice and rats showed a decrease in addiction behaviors for alcohol, nicotine, amphetamines, and cocaine while on GLP-1 receptor agonists. The exception, Trefethen said, was in opioids, where the efficacy was more limited compared to other substances.

Results in human trials were less consistent regarding the effects of GLP-1s in SUDs, but with one notable exception.

How GLP-1s Affect Alcohol Use Disorder

One of the earliest randomized, placebo-controlled trials (NCT03232112) evaluated exenatide in patients with AUD. Though the trial arm did not show results superior to placebo, subgroup analysis revealed meaningful reductions in heavy drinking days and alcohol intake among patients with a body mass index (BMI) of 30 or higher.

"In that particular group, they saw a 45% reduction in heavy drinking days compared to 15% reduction in the placebo group. They saw a greater reduction in alcohol intake with over 2200 grams of alcohol [reduction] compared to 378 grams of alcohol in the placebo group," Trefethen said. "This study set the stage for future studies," and a BMI of 30 or greater became part of the inclusion criteria for new studies of GLP-1s in AUD.

The improvement was borne out in the brain scans conducted as part of this study. "They saw a statistically significant reduction in alcohol care reactivity in the treatment group compared to placebo. [Looking] at the dopamine transporter, they saw [a] reduction in transporter availability in the xenotype group compared to placebo," she said.

Subsequent analyses, including one looking at social media posts from people taking semaglutide or tirzepatide, found that many users reported reduced alcohol cravings or consumption, fewer drinking and binge-drinking days, and lower scores on the Alcohol Use Disorders Identification Test (AUDIT) after beginning GLP-1 therapy. Patients also reported fewer effects from alcohol on drinking days.

A more recent, randomized clinical trial looked at patients with AUD who were not actively seeking treatment, but who were taking semaglutide for weight loss. Over 9 weeks, patients reported a reduction in heavy drinking days, drinks per drinking day, and weekly cravings. They also reported a reduction in cigarette use. "These significant findings [were] independent of their BMI," Trefethen said.

What Does This Mean for Pharmacists?

Trefethen stressed to her audience that GLP-1 receptor agonists are not approved treatments for SUDs. Further trials will be needed before their use can be expanded into this indication, and the most promising patient population will be those with AUD as opposed to other SUDs.

She also stressed that medication alone is not enough to prevent relapse. "Substance use disorders are complex, chronic conditions. Medications are only one tool out of the big picture," Trefethen said, "one tool out of many. ... If you want to really optimize outcomes, you want to make sure that they're engaging in a multimodal treatment approach."

Trefethen also said that many patients who begin GLP-1 therapies discontinue because of the side effects, especially GI-related adverse events. She recommended that pharmacists check serum framing at baseline and body weight and BMI at baseline and at each visit. Patients should be closely monitored for pancreatitis, especially if they use alcohol, and for dehydration and GI side effects. "If you want to optimize outcomes, you want to make sure that they're tolerating these medications," she said.

Most of all, she said, "We have strong association data ... but we need more studies. We need more data."

REFERENCES

Zimmerman K, Trefethen M. "Beyond weight loss: GLP-1 Receptor Agonist Effects on Substance Use and Addictive Behaviors." Presented at: American Society of Health-System Pharmacists Midyear 2025 Clinical Meeting and Exposition; December 7-10, 2025; Las Vegas, Nevada.