Audio long read: Will blockbuster obesity drugs revolutionize addiction treatment?

0:01This is an audio long read from Nature. In this episode, will blockbuster obesity drugs revolutionise addiction treatment? Written by Ailey Dolgin and read by me, Benjamin Thompson.

0:16Last April, neuroscientist Sue Grigson received an email from a man detailing his years-long struggle to kick addiction. First to opioids and then to the very medication meant to help him quit. The man had stumbled on research by Grigson, suggesting that certain anti-obesity medications could help to reduce rats' addiction to drugs such as heroin and fentanyl. He decided to try quitting again, this time while taking semaglutide, the blockbuster GLP-1 drug better known as a Zempick. That's when he wrote to me, says Grigson, who works at Pennsylvania State University College of Medicine in Hershey.

0:59He said that he was drug and alcohol-free for the first time in his adult life. Stories like this have been spreading fast in the past few years, through online forums, weight loss clinics and news headlines. They describe people taking diabetes and weight loss drugs such as semaglutide, also marketed as Uyghur V, and tezepatide, sold as Munjaro or ZepBound, who find themselves suddenly able to shake long-standing addictions to cigarettes, alcohol and other drugs. And now, clinical data are starting to back them up. Earlier this year, a team led by Christian Hendershot, a psychologist now at the University of Southern California in Los Angeles, reported in a landmark randomised trial that weekly injections of semaglutide cut alcohol consumption, a key demonstration that GLP-1 drugs can alter addictive behaviour in people with a substance use disorder.

1:59More than a dozen randomised clinical studies testing GLP-1 drugs for addiction are now underway worldwide, with some results expected in the next few months. Neuroscientists, meanwhile, are working out how the weight loss drugs suppress addiction by acting on hormone receptors in brain regions that control craving, reward, and motivation. They are finding that GLP-1 therapies help to blunt urges for alcohol, opioids, nicotine, and cocaine through some of the same brain pathways that also quell hunger cues and overeating. At the end of the day, the neurobiological system that is activated by rewarding substances, food, sex, drugs, rock and roll, it's the same system, says Roger McIntyre, a psychopharmacologist at the University of Toronto in Canada.

2:52And some researchers are testing whether, by influencing reward-related brain circuits, the drugs might help with dementia and depression as well. The research is still in its early stages, scientists warn. We first need to find out if it's efficacious and safe, says W. Kyle Simmons, a neuroimaging specialist at Oklahoma State University in Tulsa, who is leading a GLP-1 trial for alcohol reduction. But some researchers and physicians are excited. No truly new class of addiction medicine has won approval from regulators in decades, says Elisabeth Jörlogholm, an addiction biologist at the University of Gothenburg in Sweden.

3:36If GLP-1 drugs prove effective in bigger trials, she says, quote, it's a revolution, end quote. It took some years for the current buzz around GLP-1 drugs in addiction medicine to build. Researchers originally developed them to control blood sugar in people with type 2 diabetes by mimicking the hormone GLP-1. Soon it became clear that the drugs could curb appetite and promote weight loss too. They act on hormone receptors located in the pancreas and gut, where they help to regulate blood sugar and signal fullness, but also in key regions of the brain that control reward and motivation, dialing down the urge for tasty, calorie-laden food.

4:23By the early 2010s, Jörlok Holm was wondering whether the drugs could blunt other urges. She published a trio of papers showing that they could dampen cravings in rats and mice hooked on alcohol, nicotine and stimulants such as amphetamine and cocaine. Her team also showed that GLP-1 therapy could reduce animal behaviours that resemble relapse, which is when people return to drugs after a period of abstinence. Yet her findings barely registered among addiction researchers, she says, and pharmaceutical companies showed no interest either. I was quite alone for a long time, says Jörlokholm. But Lorenzo Leggio, a physician scientist at the US National Institutes of Health in Baltimore, Maryland, noticed the work.

5:15He had also been following clues that GLP-1 might influence addictive behaviour, and in 2015 joined forces with Jörlöckholm to uncover the first evidence of a connection between the hormone and alcohol dependence in humans. The team found that a common variant of the GLP-1 receptor gene was linked to heavier drinking. Using post-mortem human brain tissue, Leggio's lab later showed that people with alcohol use disorder have elevated levels of GLP-1 receptors in key reward-related regions of the brain. Leggio suspects that this reflects an adaptive response. Alcohol dampens the body's GLP-1 production and so the brain boosts expression of the hormone's receptors to preserve sensitivity to it in circuits that govern reward and motivation.

6:09These results, together with a growing number of animal studies, solidified GLP-1's connection to addictive behaviour. Yet it was not until May 2023 that the story spilled into the public eye. The Atlantic magazine published an article about people taking semaglutide who said their urge to smoke or drink had faded. Did scientists accidentally invent an anti-addiction drug it was headlined? Quote, that was definitely a turning point, says Leggio, who suddenly found himself getting calls from journalists. The first few rigorous trials, however, had largely disappointing results. A 2022 study in Denmark, led by psychiatrist Anders Fink Jensen at the University of Copenhagen, found that weekly treatment with exenatide, a first-generation GLP-1 compound used since 2005 to treat diabetes but never approved for weight loss, did not substantially reduce the number of heavy drinking days in people diagnosed with alcohol dependence.

7:17A 2023 trial in Switzerland likewise found that dulaglutide, another older GLP-1 drug, did not help people to quit smoking. But other results suggested that the drugs might have an effect. In a trial involving 20 people with opioid use disorder, led by Grigson and psychologist Scott Bunce, also at Pennsylvania State University, treatment with liraglutide, another first-generation GLP-1 drug, reduced opioid craving by roughly 40%. And when Fink Jensen's team used functional magnetic resonance imaging, or fMRI, to look at the brains of people taking exenatide in their clinical trial, they saw muted activity in reward-related regions when the participants viewed images of alcoholic drinks.

8:09But the first-generation drugs tested in these preliminary studies are much less potent than agents such as semaglutide or tizepatide. These second-generation compounds bind more tightly to the GLP-1 receptor, stay active in the body for longer, and have shown greater benefits across a range of health conditions. So could these latest drugs change the behaviour of people struggling with substance misuse? That's what researchers are now examining in a raft of clinical trials with hotly anticipated results. Fink Jensen and his colleagues have already tested whether the high dose of semaglutide approved for weight loss can cut alcohol intake in 108 people with alcohol use disorder and obesity in a clinical trial that wrapped up earlier this year.

8:59He says the results should be published in early 2026. In the United States, meanwhile, Leggio and Simmons are each leading independent but coordinated randomized trials testing injected semaglutide in moderate to heavy drinkers, who meet the diagnostic criteria for problematic alcohol use. Leggio's trial will involve 52 people and test the high-dose Ouigavi form of the drug, whereas Simmons's trial, involving 80 people, is testing the lower-dose Azempic, typically prescribed for diabetes. And psychologist Joseph Schacht at the University of Colorado Anschutz Medical Campus in Aurora has been running his own alcohol trial with the oral version of semaglutide, marketed as ribelsis.

9:47By coordinating their efforts, the three teams hope to tease apart how differences in dose and delivery affect outcomes. Schacht says that the pills, although less potent than injections, could be more appealing to people with alcohol addiction, many of whom also have a history of using injectable drugs such as fentanyl. They can be gun-shy around needles because that is a cue related to injection drug use, he says. In all of these trials of semaglutide for alcohol dependence, the research teams are also using fMRI to capture before and after snapshots of the brain to show how the drug alters responses to alcohol-related prompts, such as drinks or photos.

10:32This could reveal whether and how the drug disrupts the brain's drive for alcohol, the reward-seeking sense of wanting that fuels addiction. The imaging results might also show brain activity patterns that are more common in people who benefit from GLP-1 therapy than in those who don't. It may give us a better understanding for whom the drug works best, Simmons says. Researchers are already piecing together a picture of how GLP-1 drugs act on the brain's reward system. They know from animal models that rewarding substances, alcohol, nicotine, opioids, food, activate similar neural circuitry. This links deep brain structures such as the ventral tegmental area, where neurons that synthesize the neurotransmitter dopamine originate, to the nucleus accumbens, where dopamine signals arrive and register as pleasure.

11:28Normally, every sip, puff or hit sends a jolt of rewarding dopamine through this circuit, teaching the brain to want more and reinforcing addictive behaviour. GLP-1 receptors sit on neurons throughout this network and, when triggered, are thought to reduce the flow of dopamine and other chemical messages to make rewarding experiences feel less compelling. When drugs such as semaglutide mimic GLP-1, they blunt the dopamine response and the compulsion to repeat the addictive behaviour fades away. Stress responses come into play as well, animal studies show. When drugs activate GLP-1 receptors in brain regions such as the amygdala, they help to mute the surge of stress hormones that accompany anxiety, withdrawal and craving.

12:18This dual action, calming both the urge and the unease, could help to explain why the therapies seem to reduce not only consumption but also relapse, at least in rodents. In the case of alcohol, the drugs probably also curb intake by acting in the guts and through pathways that govern appetite and satiety. But in the brain, studies suggest that the drugs work in strikingly consistent ways. It may vary a bit by substance use disorders, says Simmons, but it's likely to be a universal mechanism. And that's exactly what excites addiction researchers. Existing drug therapies tend to tackle just one addiction because they target the same receptors or neurotransmitters as the substances being misused.

13:05And even the best therapies achieve only modest, short-lived success. By acting on shared circuits that underlie reward and motivation, GLP-1 therapies could, in theory, tackle any source of addiction and even help people who misuse more than one substance at a time, says Heath Schmidt, a neuropharmacologist at the University of Pennsylvania School of Nursing in Philadelphia. We've never seen this before, he says. The link between GLP-1 and reward is helping to inspire interest in treating disorders well beyond addiction. That's because the same brain circuits that underpin reward processing also support learning, memory, motivation and decision-making, all core elements of human cognition.

13:51That overlap has inspired some psychiatrists and neurologists to explore GLP-1 drugs as potential treatments for a range of cognitive and neuropsychiatric conditions. These include Alzheimer's disease and mood disorders such as depression, which often bring lingering problems with focus and memory that current antidepressants scarcely address. However, the results of clinical trials have so far been somewhat discouraging. Last month, Novo Nordisk, the Danish drug giant behind semaglutide, reported that the oral version of the drug failed to slow cognitive decline in people with Alzheimer's disease in two large phase 3 clinical trials.

14:34That setback came weeks after McIntyre and Rodrigo Mansour, a psychiatrist at Toronto Western Hospital in Canada, published data from a randomised trial of semaglutide in 72 people with depression. After 16 weeks, the therapy did not significantly improve overall cognitive performance, the team found, but it did sharpen aspects of attention and memory. Mansour remains optimistic that the drug strategy holds promise for treating mood disorders. It's filling the gaps by helping with things that antidepressants are not typically as good at, he says. When it comes to treating substance misuse, researchers say they are still a long way from winning regulatory approval for any of these drugs.

15:20They first need clear, reproducible evidence from large, randomised trials that show reductions in consumption big enough to improve people's lives. Shifts in brain activity or craving aren't sufficient. Another hurdle, specialists say, is ensuring that the drug's effects on weight and appetite don't complicate addiction treatment. Many people who use illicit substances already have erratic diets because of their lifestyles or drug-induced appetite changes, and there are concerns that GLP-1 therapy could lead to unwanted weight loss, malnutrition or frailty. To minimise these risks, clinical trials of GLP-1 drugs for addiction generally require participants to be overweight or living with obesity.

16:06And researchers will need to assess whether people return to addictive behaviours when they stop taking the drug. But the big pharmaceutical companies are now wading into this field. Novo Nordisk is testing whether semaglutide, alone or in combination with other therapies, can reduce liver damage and alcohol use in people with alcohol-related liver disease. Eli Lilly, the Indiana-based manufacturer of Tezepatide, has likewise launched a trial involving 300 people with alcohol use disorder. This will test one of the company's experimental weight loss agents, which, like Tezepatide, targets an extra hormone pathway alongside GLP-1.

16:49Meanwhile, the groundswell of anecdotal success stories continues. Social media is filled with testimonials from people who say the drugs have helped them to kick not just nicotine and opioids, but also compulsive behaviours such as shopping, gambling and even nail-biting. Such stories should be viewed with caution, researchers say. People might change their habits because they lost weight, for instance, rather than because of the drugs themselves. But for scientists such as Grigson, who was deeply moved by the email from the man freed of drug dependence, these reports helped to give her science urgency.

17:27Earlier this year, she and Bunce launched a 200-person trial of semaglutide for opioid use disorder, the largest academic study of its kind in the addiction field. People are feeling hopeful, and that's a good thing, Grigson says. To read more of Nature's long-form journalism, head over to nature.com slash news.