Opioid cravings were reduced by anti-obesity drug in small study

DENVER — The GLP-1 medication liraglutide significantly reduced opioid cravings in a small analysis presented on Saturday. It is the first randomized controlled trial to test anti-obesity drugs against opioid addiction, which kills around 80,000 people in the U.S. each year.

Among 20 patients for opioid use disorder, those on liraglutide experienced a 40% reduction in opioid cravings over the three-week study, with this effect evident at even the lowest liraglutide dose, according to data presented here at the American Association for the Advancement of Science conference.

Among patients already on buprenorphine, a medication approved by the FDA to treat opioid use disorder, those also on liraglutide were more likely to report zero cravings than the placebo group. This effect became statistically significant from the tenth day of the study onward, as patients were titrated to increasingly higher doses of liraglutide. “It suggests there’s an additive effect of these two medications,” said Andrew Saxon, an addiction psychiatrist at the University of Washington who was not involved with this study, potentially because liraglutide and buprenorphine target different mechanisms.

For the most part, there were no notable differences in side effects between patients on liraglutide and those on placebo, suggesting that this GLP-1 drug is safe in patients with opioid use disorder. Gastrointestinal distress, however, was twice as common in the liraglutide group and largely responsible for the study’s high dropout rate, with only nine patients completing the three-week trial.

However, Scott Bunce, a clinical psychologist at Penn State and one of the trial’s principal investigators, noted that patients who received both liraglutide and buprenorphine had lower GI distress and dropout rates than participants on liraglutide alone, suggesting that the combination approach could alleviate some of these issues. Furthermore, the finding that cravings were significantly reduced at the lowest liraglutide dose suggests that many of these side effects could be mitigated by maintaining a low dose, although this merits further study.

The study was conducted at the Caron Treatment Center in Wernersville, Pa., and funded by the National Institute on Drug Abuse, a donor family, and the pharma company Novo Nordisk, which sells liraglutide as Victoza for diabetes and Saxenda for obesity. The patients were all residential, having just undergone medication-assisted withdrawal.

About 80% of participants were white men, and everyone received a notification on their phones four times a day to assess self-reported cravings. “That allowed us to ask people how much they’re craving in the moment — not yesterday, not last week,” said Patricia Grigson, director of the Penn State Addiction Center for Translation and the trial’s other PI.

This clinical trial is the culmination of seven years of animal studies in Grigson’s lab, showing that GLP-1s target three roads to relapse — environmental cues, stress, and the drug itself — as STAT has previously reported. While the FDA has approved three drugs for treating opioid addiction, a recent study from the Centers for Disease Control and Prevention and National Institutes of Health estimated that only 20% of patients received these medications in 2021.

Beyond low uptake, these drugs are associated with significant relapse rates (around 50%), don’t work as well in patients who have used fentanyl, and, in the case of buprenorphine and methadone, are sometimes stigmatized as opioids replacing opioids. GLP-1s could thus be a promising alternative or, at the very least, an adjunct to existing treatments, Grigson and Bunce said.

However, the small sample size, limited participant diversity, and relatively short trial means that “we have to be very cautious about interpreting these preliminary results,” said Heath Schmidt, a neuropharmacologist at the University of Pennsylvania who was not involved with this study. An added limitation is that studying patients in a residential treatment facility might not be representative: “That’s very different than being at home or on the street, where you’re around a lot of cues that promote relapse and craving,” Schmidt added. Moreover, people in a treatment facility are likely a highly motivated subset of patients, more inclined toward treatment.

But perhaps the most significant limitation of these data is the high dropout rate, which not only limits interpretation of the results but also highlights a potential barrier of using GLP-1s to treat drug addiction. “Nausea is one of the first withdrawal symptoms — and this patient population is severely anxious and fearful about withdrawal,” said Saxon. “So they could interpret nausea as ‘I’m getting into withdrawal, and I’ve got to get away from it, however I can.’ ”

Despite these limitations, Christian Hendershot, a University of North Carolina at Chapel Hill psychologist who has been studying GLP-1s for alcohol use disorder and was not involved with the study, emphasized the importance of this data as a proof of concept and a stepping stone toward larger trials. “The reason these initial findings are nice is that they looked at this question in a really controlled environment,” said Hendershot. “We know that craving predicts relapses in many cases, so having established that reduction, the next question is whether drugs like liraglutide suppress craving and relapse in the natural environment.”

Grigson and Bunce similarly emphasize the preliminary nature of their findings and the need for follow-up studies. They are planning a randomized controlled trial in 200 people on methadone or buprenorphine, half receiving semaglutide and half receiving placebo — across three outpatient sites in Pennsylvania, New York, and Maryland.

“With one person dying every five minutes and people dying around the world due to opioid exposure, we feel a sense of urgency,” Grigson said. “I feel very hopeful; there may be a new treatment for opioid use disorder.”

Clarification: Participants using liraglutide experienced a 40% reduction in opioid cravings in the study (as the researchers showed in a slide), not 30% reduction (as stated in the presentation).

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