Researchers see promise in semaglutide drugs, which may tap into the brain’s reward circuits
A class of powerful drugs can dramatically change people’s body weight. But one of the drugs’ most alluring jobs may happen in a spot that’s harder to see: the brain.
Some people taking drugs such as Wegovy and Ozempic, two brand names for the drug semaglutide, have reported surprising — and welcome — side effects: Their constant thoughts about food quiet; their desire for alcohol diminishes; their need for nicotine dissipates.
These reports point to the possibility that these drugs, approved by the U.S. Food and Drug Administration for type 2 diabetes and obesity, may be repurposed as desperately needed treatments for substance use disorders.
That hope sounds like a long shot. But the idea has merit, some researchers think, and that conclusion isn’t based solely on anecdotes. Semaglutide’s potential to reduce a person’s drive for alcohol, tobacco and even opioids comes as no surprise to some addiction researchers, who have been studying earlier cousins of semaglutide for their role in reward-seeking.
“It’s safe to say that the degree of clinical and anecdotal evidence that’s come out recently is fairly unprecedented,” says Christian Hendershot, a clinical psychologist at the University of North Carolina School of Medicine in Chapel Hill. “So that’s a reason for some optimism and for really wanting to move this area of clinical research forward.”
Hendershot and others are quick to point out that more studies, particularly on large numbers of people, need to be done. What’s more, there are existing medicines that have been proven to help with addictions. But the potential of semaglutide and its relatives as addiction treatments, he says, is real.
Semaglutide and related drugs change addictive behaviors in mice and rats
One recent study on the potential for semaglutide to curb addiction looked at rats and mice that had already developed excessive alcohol drinking behavior. The experiments were designed to mimic binge drinking and alcohol dependency in people. Rodents that were subsequently dosed with semaglutide drank less alcohol than rodents that weren’t, addiction physician-scientist Lorenzo Leggio and colleagues reported online May 16 in JCI Insight. Similar results were published June 7 in eBioMedicine by researchers at the University of Gothenburg in Sweden.
Mice on semaglutide also drank less sweet nonalcoholic liquids and unsweetened calorie-rich liquids. That general dampening of consumption wasn’t a surprise, “because this medication is approved already for obesity, for its ability to reduce appetite and food intake,” says Leggio, of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism in Baltimore.
Parts of the brain that help drive eating behavior, such as the nucleus accumbens, overlap extensively with the drive to use alcohol or drugs, Leggio says.
These drugs could also help curb opioid addictions, says behavioral neuroscientist Patricia “Sue” Grigson of Penn State College of Medicine. Brianna Evans, a researcher in Grigson’s lab, and colleagues found that liraglutide, a close relative of semaglutide, reduced heroin seeking in certain tests of male rats. Those results were published in 2022 in Brain Research Bulletin.
A preliminary study by the same researchers may help explain why — patterns of brain activity change.
Usually, when a rat is looking for a drug, nerve cells in two areas of its brain are active: the outer layer of the nucleus accumbens, which is involved with rewards, and the locus coeruleus, which is involved with withdrawal. That’s not the case for rats on liraglutide that were seeking fentanyl. In these rats, liraglutide seemed to reduce activity in both brain regions, the researchers found. The team expects to present these unpublished results in November at the annual meeting of the Society for Neuroscience in Washington, D.C.
Several human trials are underway — and researchers are “very, very cautiously optimistic”
Grigson and her colleagues have nearly finished a clinical trial of liraglutide in people being treated for opioid use disorder at the Caron Treatment Center in Wernersville, Pa. The study is small: Only nine people have completed it, and 16 people are partially done. And the study was short, with participants receiving liraglutide for just 19 days. The results are still blinded, so neither the researchers nor participants know who got liraglutide, or whether it showed an effect.
Other trials are also underway. Hendershot is involved in two trials with semaglutide: one for smokers and one for heavy drinkers. And Leggio is embarking on a clinical trial assessing alcohol use as well.
He and other addiction researchers feel collectively energized, Leggio says. “In my professional life so far, I don’t recall any time like this time,” where scientists have had such intriguing and potentially promising ways to influence addictions.
Although he sees the promise, he’s also been working in the field of addiction long enough to know that some ideas just don’t pan out. “This will not be the first time that we were feeling strongly about something, and we were not correct,” Leggio says. “If we already knew that semaglutide worked, there would be no reason to do the clinical trials.”
That idea is echoed by Andrew Saxon, an addiction psychiatrist and neuroscientist at the University of Washington School of Medicine in Seattle. The potential for this family of drugs to help with substance use disorders is plausible, says Saxon, whose work hasn’t been focused on semaglutide and drugs like it.
“There’s encouraging information there,” he says. That said, “I do think that we’ve been repeatedly disappointed by medications that look great in animal studies but don’t pan out that well in humans.” Overall, he’s “very, very cautiously optimistic,” he says. “But we need to do the studies.”
What’s next?
One of the powerful aspects of these drugs is that they seem to affect lots of different parts of the body, the brain included. That’s because the drugs are designed to mimic the hormone GLP-1. As a result, the drugs can affect the many nerve cells in the brain that respond to GLP-1, either directly or indirectly, Grigson says.
While researchers have some clues about how GLP-1 and its copycats work, scientists don’t know the full details of how nerve cells, and the brain networks they form, are affected. There are still lots of basic questions, including whether semaglutide and its relatives get directly into the brain or exert their effects from other parts of the body.
If the drugs do work to reduce addictions, they, like any medication, won’t be useful for everyone. Side effects include nausea, digestive trouble and headaches. And while some people are happy to have weight loss as a side effect, some aren’t. People who are underweight, for instance, might not want to take this class of drugs.
This buzzy moment may be overpromising, but researchers won’t know for sure where else the drugs might shine — and where they fall short — until a lot more work is done. Nigel Greig, a neuroscientist who focuses on drug development, is studying drugs that mimic GLP-1 as a possible treatment for Parkinson’s disease. There are hints that the drugs can influence inflammation in the brain, and perhaps stave off brain decline.
Like other researchers, he’s circumspect. “Certain classes of drugs pop up. And when they pop up at the right time, they can do anything and everything,” says Greig, of the National Institute on Aging in Baltimore. “In the end, they won’t do as much as people hope, like every class of drugs. But they do look very intriguing.”