Could New Weight-Loss Drugs like Ozempic Treat Addiction?

Could New Weight-Loss Drugs like Ozempic Treat Addiction?

Some users of Ozempic, the popular diabetes drug that can help people eat less and lose weight, have been noticing a welcome side effect. An increasing number of people who use these injections to help control their food cravings say other cravings disappear as well—including ones for nicotine, alcohol, gambling, skin picking and other compulsive behaviors.

The abundance of anecdotal reports has made researchers wonder whether Ozempic and similar weight-loss drugs can serve as a basis for antiaddiction treatments. “It does make a lot of sense,” says Lorenzo Leggio, an addiction researcher at the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.* Ozempic, one of the brand names for the drug semaglutide, targets a hormone that tells the body when it is full and, through mechanisms that are not fully understood, weakens the brain’s association between food and pleasure. Addiction seems to use similar brain pathways whether it’s linked to drugs or alcohol, and animal studies suggest such drugs can help treat it.

But data from human trials are still scarce. Novo Nordisk, which makes Ozempic, and Eli Lilly, which makes a similar medication called Mounjaro and is developing the weight-loss drug candidate retatrutide, nicknamed “triple G,” both declined to comment on their respective drugs’ potential to treat addiction and said they are not currently running or planning trials to investigate such treatment. So Leggio and other addiction researchers are starting their own studies to directly test whether these drugs, and newer generations of them, will be as safe and effective for treating drug and alcohol addiction as they are for facilitating weight loss. The researchers also want to examine ways to help scientists find out if and how the drugs affect the brain. “People [taking these weight-loss drugs] who may benefit say it’s changing their life, but we don’t hear from people who don’t benefit,” Leggio says. “We need the human studies to be done.”

How Do the New Weight-Loss Drugs Impact Addictions?

Semaglutide, which was initially developed as a diabetes treatment, is a type of agonist—a substance that binds to specific receptors in the body and prompts a reaction. The drug triggers the pancreas to release a hormone called glucagonlike peptide–1 (GLP-1), which the organ normally produces in response to food. As GLP-1 levels increase, the body registers that it has had enough to eat and reduces hunger cravings as a result. GLP-1 levels can be disrupted in people who are overweight or have diabetes, which causes the body to consume more than it needs instead of recognizing that it is full. By raising hormone levels, semaglutide and similar GLP-1 agonists restore the correct hormone balance, although their effect seems to end if people stop taking the drugs.

Recent evidence suggests that GLP-1 acts on other organ systems as well, including the brain. It’s still unclear whether the hormone made in the pancreas enters the brain or if the effect is linked to GLP-1 made in the brain. Either way, the hormone seems to affect the brain’s reward pathways and to lower the dopamine levels that make food pleasurable. Dopamine—often called the “feel-good” hormone—also plays a major role in addiction.

Semaglutide’s story becomes even more complicated in drug addiction. Addictive drugs such as cocaine and opioids are generally thought to “hijack” the brain’s natural reward pathways, says Heath Schmidt, a neuropharmacologist at the University of Pennsylvania. Over time, the brain needs more and more dopamine to function, leading to addiction.

Previous research has found that activating GLP-1 receptors in rats’ brain causes the animals to eat less of a high-sugar chow, which they would normally prefer over a less delicious but healthier bland meal when given the option. This suggests that GLP-1 makes unhealthy food less rewarding. Schmidt’s team found the same to be true with cocaine: rats that received a GLP-1 agonist took less cocaine when it was offered. The researchers are now repeating the experiments in rats addicted to opioids or fentanyl. Several other studies have shown that GLP-1 agonists cause rats to drink less alcohol and produce less dopamine when they do drink, suggesting that the activity is no longer as pleasurable.

Patricia Sue Grigson, an addiction researcher at Pennsylvania State University, has an alternative explanation: drug seeking is driven not only by pleasurable rewards but also by fear of the bad feelings and physical side effects associated with withdrawal. In this scenario, the brain sees the drug as a physiological need—much like the need for food—and GLP-1 agonists, such as semaglutide, “short-circuit” that association.

Grigson’s team is running a clinical trial of a GLP-1 agonist in people receiving treatment for opioid use disorder in a rehabilitation center. As part of the trial, participants taking the medication receive messages throughout the day asking them about their cravings and their mood. The results are expected in a few months. If they indicate improvements in cravings, Grigson says, her team plans to test the drug in a larger group of people who are using opioids but are not in long-term care. It could be used similarly to a medication such as naloxone, which is currently available to treat opioid use disorder. “We’re desperate to find something that will give people some relief from their cravings,” she says.

Testing Semaglutide for Addiction

Grigson’s trial is one of several underway that directly test whether GLP-1 agonists are as effective for addiction in humans as they are in animals. The largest human trial completed so far tested exenatide, an earlier GLP-1 agonist drug that is no longer widely used, in 127 people with alcohol use disorder. People who received exenatide—which works similarly to semaglutide—displayed less activity in the brain’s reward centers when shown pictures of alcohol, suggesting that they were less drawn to it. But only participants with obesity ended up drinking significantly less than their peers who received a placebo.

“The results were complex,” says Anders Fink-Jensen, a psychiatrist at the University of Copenhagen and senior author of that study. He is unsure why alcohol consumption would only be lowered in people with obesity. But if the study’s initial results prove true, that would suggest that the anecdotal reports of “cures” of addictions could be “skewed,” Fink-Jensen says, considering that most people who are prescribed a GLP-1 agonist are overweight to begin with.

Fink-Jensen’s group is planning to repeat the study exclusively in people with a body mass index (BMI) of more than 30 to determine if the drug is effective at curbing addiction specifically in people with obesity. Leggio and W. Kyle Simmons, a pharmacologist at Oklahoma State University, are also running parallel trials to test semaglutide in people with a range of BMIs to see whether the drug has an effect on alcohol, nicotine and cannabis use over time.

Safety Concerns for Patients with Addiction

GLP-1 agonists have proven to be safe in the general population, but common side effects such as nausea could dissuade people from taking the drugs. And more information is needed on the drugs’ safety in people who are recovering from and may also have other health conditions, says Christian Hendershot, a psychiatrist at the University of North Carolina at Chapel Hill who is testing semaglutide on alcohol and nicotine addictions. For example, GLP-1 agonists could be problematic in people who are malnourished from opioid or methamphetamine use, he explains.

Another concern is whether semaglutide might simply be too good at dampening pleasure and reward pathways. In her study on opioid use recovery, Grigson is closely monitoring participants’ moods and emotions for signs of decreased happiness and motivation in general. Simmons says his team screens participants for depression and suicidal thoughts throughout the trial for the same reason. Animal evidence so far suggests that GLP-1 agonists don’t affect overall mood, but the medications might work differently in people who already have mood disorders. Even if such a side effect turns out to be rare, Simmons says, the popularity of Ozempic and similar drugs means that a large number of people could be affected.

Simmons says it’s too early to say whether people recovering from addiction would need to take an GLP-1 agonist for the rest of their lives, like people with diabetes do, or whether these drugs could be short-term treatments that curb cravings long enough for people to make lifestyle changes to stay sober. People who stop taking semaglutide for weight loss quickly gain the weight back, and study animals that stop taking it return to alcohol and drug use, but “I don’t think we know enough yet” in humans, Simmons says.

Although he is hopeful about the drugs’ promise as a treatment for addiction, Hendershot cautions providers against prescribing GLP-1 agonists primarily for drug or alcohol use. The Food and Drug Administration has not approved them for this purpose, but Hendershot says he has already seen some such prescriptions being made. “The anecdotal data has outpaced the science,” he says. “It will be some time before we have the trials that are necessary to support using these medications off-label.”

*Editor’s Note (7/13/23): This sentence was edited after posting to better clarify Lorenzo Leggio’s affiliations.

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