When the diabetes treatments known as GLP-1 analogs reached the market in 2005, doctors advised patients taking the drugs that they might lose a small amount of weight. Talk about an understatement. Obese people can drop more than 15% of their body weight, studies have found, and two of the medications are now approved by the U.S. Food and Drug Administration (FDA) for weight reduction. A surge in demand for the drugs as slimming treatments has led to shortages. “This class of drugs is exploding in popularity,” says clinical psychologist Joseph Schacht of the University of Colorado School of Medicine.
But patient reports and animal studies have yielded tantalizing signs that the drugs may spur another unexpected and welcome effect: fighting addiction. Most early trials were disappointing, but they used less potent versions of the drugs. Now, at least nine phase 2 clinical trials are underway or being planned to test whether the more powerful compound semaglutide and its chemical cousins can help patients curb their use of cigarettes, alcohol, opioids, or cocaine. Hopes are high. Semaglutide (sold under the trade names Wegovy, Ozempic, and Rybelsus) “is truly the most exciting drug for the last few decades,” says neuropharmacologist Leandro Vendruscolo of the U.S. National Institute on Drug Abuse.
If the results of the new trials are positive, addiction science could have its own “Prozac moment,” says clinical neuroscientist W. Kyle Simmons of the Oklahoma State University Center for Health Sciences. In the 1980s, that drug brought a sea change to psychiatry, becoming part of popular culture and leading to the wider use of antidepressants.
Scientists have long been searching for new addiction drugs. Although FDA has approved several, including three for patients with alcohol use disorder, these medicines only work for a small percentage of people who try them. And the pharmaceutical industry has not delivered new compounds, in part because companies believe patients won’t stick with treatments, making their development a poor investment, says clinical neuroscientist Lara Ray of the University of California, Los Angeles. The last “new” drug treatment for alcohol use disorder received FDA approval in 2006—and it was an injectable version of a drug, naltrexone, that had been available since the 1980s.
So when patients taking GLP-1 analogs for diabetes or weight loss reported that their hankering for substances such as alcohol and nicotine declined, researchers and doctors in the addiction field perked up. “You usually don’t hear people say that a drug makes them less interested in drinking,” Schacht says.
Researchers are still probing how GLP-1 analogs might pull off that feat. The drugs replicate the effects of the hormone glucagon-like peptide-1; by prodding its receptors in the pancreas, they stimulate release of insulin and trigger other beneficial responses, which explains how they help people with diabetes. But several structures in the brain also produce GLP-1 or carry receptors for the hormone—including brain areas that are involved in our reward pathways, which drive us to pursue pleasurable activities, such as eating tasty food or hanging out with friends. Addiction involves “hijacking of the reward pathways in the brain,” says behavioral neuroscientist Patricia Grigson of the Pennsylvania State University College of Medicine. Researchers think GLP-1 analogs spur weight loss in part by quelling activity of this system, and the same mechanism could explain why people who take the medications report they are less motivated to drink and smoke.
Studies in rodents and primates have supported that mechanism and confirmed the drugs diminish the desire for substances such as alcohol, fentanyl, nicotine, and heroin. Clinical psychiatrist Anders Fink-Jensen of the University of Copenhagen and colleagues even demonstrated that the drugs work in an incorrigible group of drinkers, the monkeys living on the islands of St. Kitts and Nevis in the Caribbean. These rowdy primates are notorious for heavy consumption of alcoholic drinks, which they often swipe from tourists.
So far, however, only two clinical trials have suggested the drugs can curb addiction. In one, a team led by Luba Yammine, a clinician and researcher at the University of Texas Health Science Center at Houston, found in 2021 that 46% of patients who wore nicotine patches and received weekly injections of exenatide, a first-generation GLP-1 analog, stopped smoking, versus 27% of people who relied only on the patches. “That’s pretty good in the world of smoking cessation research,” Yammine says. A second preliminary trial for binge eating was also positive.
Four other clinical trials came up empty. Fink-Jensen and colleagues performed one of these studies on 127 patients with alcohol use disorder. During the 6-month trial, all of the participants went through behavioral therapy to encourage them to drink less, and 62 patients received weekly injections of exenatide. Yet both groups cut their alcohol consumption and the number of days on which they drank heavily by about the same amount, the researchers revealed last year. “That was a surprise for us,” Fink-Jensen says. A trial for cocaine consumption was also negative—as were additional studies on smoking and binge eating. But those trials, even the successful ones, all used older GLP-1 analogs, Fink-Jensen notes. Semaglutide binds more tightly to the GLP-1 receptor and induces greater weight loss than previous drugs. So Fink-Jensen and other researchers have launched new trials, almost all of which use semaglutide, that they hope will reveal greater capabilities against addiction, help identify which patients are most likely to benefit, and clarify how the drugs work.
To try to nail down whether GLP-1 analogs quell cravings, Schacht and colleagues will ask participants with alcohol use disorder to watch as a research technician pours a brimming glass of their favorite drink. After raising the glass and sniffing the aroma, the patients will then rate their motivation to imbibe. Participants in two other studies headed by clinical psychologist Christian Hendershot of the University of North Carolina School of Medicine will actually be given the opportunity to smoke or drink alcohol in the lab. But they will try to abstain for as long as possible, earning an increasing amount of cash the longer they hold out. Offering participants the chance to indulge to gauge their cravings is advantageous, he says, because it “can improve sensitivity for detecting medication effects.”
The current trials are also deploying techniques that measure brain activity, including electroencephalography and functional MRI (fMRI), to look for clues to the drugs’ mechanisms. So far, only one published study—the clinical trial of exenatide by Fink-Jensen and colleagues—has collected those data for patients receiving GLP-1 agonists as addiction treatments. The researchers used fMRI to determine the activity of three brain structures in the reward system while patients viewed photographs of alcoholic drinks. The results were inconclusive. Compared with participants who took a placebo, patients on exenatide showed less activity in one structure—the ventral striatum—but activity in two other regions didn’t change. Researchers hope the new work will provide more clarity about the drugs’ effects on brain circuits.
If GLP-1 analogs prove effective in the current phase 2 trials, access to the medications, which can cost more than $12,000 per year, could become a concern. Because of high costs and other barriers, patients with substance use disorders often can’t access current addiction treatments, says psychologist Katie Witkiewitz of the University of New Mexico. “I don’t want [semaglutide] to be a medication that is only available to people who are wealthy.”
In the United States, insurance might help if the drugs gain FDA approval as addiction treatments. That would require pharmaceutical companies to present data from larger, phase 3 trials. In the meantime, doctors could still prescribe the drugs off-label. But because insurance plans usually won’t cover off-label prescriptions, patients would have to foot the bill themselves.
Researchers and doctors also fret about potential side effects—and not just the gastrointestinal problems such as nausea and vomiting the drugs typically cause. Ray worries they might work so well that they crush patients’ enjoyment of life, a condition called anhedonia that has been linked to depression, suicide, and relapse. And if patients are going to be on GLP-1 analogs for years, new problems could emerge. The once-weekly version of semaglutide that is so popular for weight loss only reached the market in 2021, notes molecular neuroendocrinologist Giles Yeo of the University of Cambridge. “We need a better idea of long-term safety,” he says.
Doctors would face a further hurdle if the drugs gained approval for addiction treatment: determining how to work them into treatment programs. They won’t be the cure-alls that some popular articles imply, researchers warn. They might be more like Prozac and other antidepressants, which only work for a fraction of patients. But even that would be a boon, Ray says. “You can help a lot of people even if only one in five responds.”
