Glucagon-like peptide receptor agonists (GLP-1RAs) like Novo Nordisk’s semaglutide (Ozempic, Wegovy) and Eli Lilly’s tirzepatide (Mounjaro, Zepbound) have dominated headlines for their blockbuster sales earned through use to treat diabetes and obesity.
As the hype around them intensifies, the candidates are being investigated in other indications beyond metabolic disorders, with trials underway for cardiovascular, neurodegenerative, and respiratory diseases. Now, these drugs are being investigated for a new and unexpected application: opioid use disorder (OUD).
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Last month, Eli Lilly CEO Dave Ricks alluded to its plans for expanding the scope of tirzepatide during his remarks at the 2025 JP Morgan healthcare conference: “We’ve talked about starting studies this year in a number of dependencies — alcohol, tobacco seems pretty straightforward. What about opioids and others? I think we should do that and see if something’s there because that’s such a huge public health problem.”
The opioid addiction market across the eight major countries—Australia, Canada, France, Germany, Italy, Spain, the UK, and the US—is set to grow at a compound annual growth rate (CAGR) of 1.8% from $2bn in 2023 to $2.4bn in 2033, according to a GlobalData report.
While Novo Nordisk has stated to this news service that it is not currently conducting dedicated studies in substance use disorders, Eli Lilly and other academic institutions are moving forward. “We are following the science on incretins and will initiate studies on our incretin pipeline to evaluate potential treatments for other conditions in the near future,” states a Lilly spokesperson.
As traditional treatments struggle with high relapse rates, stigma, and low adoption, researchers are looking at how new approaches could reshape the landscape of opioid addiction therapy.
The opioid crisis
Opioid-related overdoses claim over 100,000 lives annually in the US, with fentanyl driving the majority of deaths, as per the Centers for Disease Control and Prevention.
While medications such as methadone, buprenorphine, and naltrexone are FDA-approved for treating opioid use disorder, they remain underutilised, says Rong Xu, PhD, professor at Case Western Reserve University and an expert in addiction research.
A study from the CDC and National Institutes of Health (NIH) found that only 20% of eligible patients received these treatments in 2021.
Beyond access barriers, these approved drugs have notable drawbacks. Methadone and buprenorphine, for example, are themselves opioids, leading to concerns about replacing one addiction with another. Additionally, fentanyl users often struggle with these treatments due to severe withdrawal symptoms, making them less effective.
Xu explains that GLP-1RAs don’t carry this risk of addiction, making them a good alternative for opioid treatment or substance use disorders. This is a sentiment also on the radar of scientists researching alcohol use disorder (AUD).
How GLP-1RAs could help address opioid addiction
GLP-1RAs, originally developed for treating diabetes, work by stimulating insulin secretion and suppressing glucagon release, thereby helping regulate blood sugar. However, these drugs also act on the brain’s reward system, an area deeply involved in addiction.
Sue Grigson, PhD, chair of the Penn State College of Medicine’s Department of Neural and Behavioral Sciences says preclinical research has suggested that GLP-1RAs may reduce drug-seeking behaviour across various substances, including opioids, alcohol, and nicotine. The GLP-1 receptors in the brain’s mesolimbic system – the same system involved in motivation and reward – appear to modulate cravings and compulsive behaviours.
Grigson was involved in collecting preclinical data from animal models, which indicate that these drugs may help prevent relapse, a major challenge in opioid addiction, says Grigson (Douton et al; Behav Pharmacol. 2021 Jun 1;32(4):265–277). “GLP-1RAs reduced all three roads to relapse in animals: the exposure to drug-related cues, exposure to the drug itself, or exposure to stress,” she states.
Following this preclinical work, Grigson and her team received a grant from the NIH to conduct a Phase I study in humans. The three-week study (NCT04199728), conducted at the Caron Treatment Centers in Pennsylvania, enrolled 20 participants undergoing residential treatment for OUD. Half received Novo Nordisk’s Saxenda (liraglutide) while the other half were given a placebo, with all participants having the option to take buprenorphine.
The results showed a 40% reduction in opioid cravings among those taking Saxenda, an effect that was evident even at the lowest dose.
“That was important because if a person comes into treatment, we don’t want to have to wait a week, or even a few days for it to be effective. It was effective initially, right away with the first dose. It was effective in the afternoon and evening – times of high risk and high relapse,” explains Grigson.
These findings led to a larger, NIH-funded Phase II study (NCT06548490) led by Grigson. The study will recruit 200 participants across three sites and evaluate semaglutide, as a potential treatment. The primary endpoint is opioid abstinence in individuals receiving standard medications such as buprenorphine or methadone, measured through urine tests and self-reported data over 12 weeks.
Challenges with studying GLP-1RAs for opioid addiction
While the early data is promising, several obstacles must be addressed before GLP-1RAs can be considered a viable treatment for OUD. Xu notes that recruiting participants for addiction research is particularly challenging. Patients may drop out of trials due to unstable living conditions, relapses, or logistical barriers.
Additionally, assessing opioid use reduction is complex, relying on self-reporting and urine tests, both of which have limitations.
During the ongoing Phase II trial with semaglutide, Grigson says patients will be monitored closely, but in the outpatient setting weekly. Additionally, the study will use an “ecological momentary assessment”—a method to gather behavioural data.
“We’re going to be able to ping them with a set of questions on their phone a few times a day periodically to get a sense of an assessment of their craving, their stress, their affect and things like that,” adds Grigson.
Similar to any pharmaceutical drug, GLP-1RAs come with their own set of toxicities and can cause gastrointestinal side effects, including nausea and vomiting, which could be particularly problematic in a vulnerable population. Moreover, these drugs induce weight loss, which raises concerns about their use in individuals who are not overweight.
“In this patient population, we have cut-offs where participants will be taken off the GLP-1RA if they are losing weight at a dangerous level”, Grigson notes.
Moreover, viewing semaglutide as a “miracle drug” for opioid and alcohol use disorders is a false idea, says Gary Malone, the medical director at Greenhouse Treatment Center, an American Addiction Centers’ facility.
“While it certainly shows some promise in mildly reducing cravings, it is also associated with a number of worrying side effects, including pancreatic cysts, pancreatic cancer, low blood sugar, muscle cramps, and cognitive slowing,” he says.
The future of GLP-1RAs in addiction treatment
Despite these challenges, Grigson remains cautiously optimistic about the field generating enough data to secure FDA approval for using these drugs to treat substance use disorders. However, she notes that addiction treatment is unlikely to be a one-size-fits-all approach. Some formulations may work better for certain individuals, and refinements will be necessary to minimise gastrointestinal side effects. She adds the pharmaceutical industry is already exploring next-generation formulations of GLP-1RAs with fewer side effects.
Malone says there should be caution instead of rushing to treat semaglutide like a magic cure and that the disease of addiction is multifaceted: “Comprehensive treatment must address the psychosocial issues common to those with substance use disorders, including trauma, mood disorders, and maladaptive coping mechanisms.”
Non-opioid pain medications are also an option. Vertex Pharmaceuticals’ non-opioid pain med Journavx (suzetrigine) secured FDA approval last month (January 2025), potentially reducing the need for opioids for chronic pain sufferers in the first place.
Additionally, psychedelic-assisted therapy and novel neuropeptide-based treatments are also being investigated in addiction medicine. GLP-1RAs will need to demonstrate clear advantages over these emerging therapies to gain a foothold in addiction treatment.
