Recent clinical evidence indicates that glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide (marketed as Ozempic and Wegovy), originally developed for type 2 diabetes and obesity, are showing promise in reducing cravings and substance use behaviors in individuals with alcohol use disorder (AUD) and opioid use disorder (OUD), according to findings from multiple phase II trials published in early 2026. This emerging application represents a potential paradigm shift in addiction treatment, leveraging the drugs’ central nervous system effects on reward pathways.
How GLP-1 Receptor Agonists Influence Addiction Pathways
GLP-1 receptor agonists mimic the action of the endogenous hormone glucagon-like peptide-1, which is secreted by intestinal L-cells in response to nutrient intake. Beyond their well-established role in enhancing glucose-dependent insulin secretion, slowing gastric emptying, and promoting satiety via hypothalamic action, these agents likewise modulate mesolimbic dopamine signaling—a core circuit implicated in the reinforcement of addictive behaviors. Preclinical models demonstrate that GLP-1 receptor activation in the nucleus accumbens and ventral tegmental area reduces the rewarding effects of alcohol and opioids, thereby decreasing self-administration in animal studies.
In human trials, a 2025 multicenter, double-blind, placebo-controlled study published in JAMA Psychiatry evaluated semaglutide in 120 adults with moderate to severe AUD. Participants receiving once-weekly semaglutide (1.0 mg) showed a 42% reduction in heavy drinking days over 12 weeks compared to 18% in the placebo group (p<0.01). Similarly, a phase II trial in Neuropsychopharmacology involving 80 individuals with OUD reported decreased opioid cravings and lower self-reported use among those treated with liraglutide, another GLP-1 agonist.
In Plain English: The Clinical Takeaway
- GLP-1 medications like Ozempic and Wegovy may aid reduce cravings for alcohol and opioids by affecting brain reward systems, not just appetite.
- Early clinical trials display meaningful reductions in substance use, but these drugs are not yet approved for addiction treatment.
- Patients should not use these medications for addiction without medical supervision due to potential side effects and lack of formal approval for this use.
Geopolitical and Regulatory Landscape: Access and Approval Pathways
As of April 2026, the U.S. Food and Drug Administration (FDA) has not granted approval for any GLP-1 receptor agonist for the treatment of substance use disorders. Still, the European Medicines Agency (EMA) has initiated a scientific advice procedure with Novo Nordisk to explore the potential for semaglutide in AUD, signaling early interest in expanding indications. In the United Kingdom, the National Health Service (NHS) England is monitoring real-world data from off-label prescribing but cautions against routine use outside clinical trials due to limited long-term safety data in addiction populations.
Access remains a significant barrier. In the United States, a month’s supply of compounded semaglutide can exceed $800 without insurance coverage for off-label use, while branded Wegovy costs over $1,300 monthly. Medicaid programs in states like California and New York have begun prior authorization reviews for off-label requests, but approval rates remain low (<15%) absent formal indication expansion. Conversely, Veterans Health Administration (VHA) clinics have launched pilot programs in Texas and Pennsylvania to study semaglutide in veterans with comorbid obesity and AUD, funded through internal quality improvement grants.
Funding Sources and Transparency of Research
The pivotal JAMA Psychiatry trial was funded by a combination of National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants (U01AA029331) and investigator-initiated support from the University of Texas Southwestern Medical Center. Novo Nordisk provided study drug and placebo but had no role in data analysis, manuscript preparation, or decision to publish. The neuropsychopharmacology study on liraglutide received funding from the Swedish Research Council and the ALICE project, a European Union Horizon 2020 initiative focused on addiction therapeutics, with no direct pharmaceutical industry involvement.
“We are seeing a convergence of metabolic and addiction neuroscience where GLP-1 signaling emerges as a modulatory force in reward dysregulation. This isn’t about replacing existing therapies but offering a new mechanistic approach, particularly for patients with comorbid obesity and addiction.”
— Dr. Kyle Kampman, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, lead investigator in the NIAAA-sponsored semaglutide-AUD trial.
“While early signals are encouraging, we must avoid therapeutic misconception. These are not ‘anti-addiction’ drugs yet. Rigorous phase III trials are needed to confirm efficacy, durability, and safety in diverse populations before any regulatory consideration.”
— Dr. Lena Eriksson, Head of Clinical Pharmacology, Karolinska Institutet, and principal investigator in the EU-funded liraglutide-OUD study.
Key Clinical Data: Phase II Trial Summary
| Study | Condition | Intervention | Sample Size (N) | Primary Outcome | Key Result |
|---|---|---|---|---|---|
| Kampman et al., JAMA Psychiatry 2025 | Alcohol Use Disorder | Semaglutide 1.0 mg weekly | 120 | Reduction in heavy drinking days | 42% reduction vs. 18% placebo (p<0.01) |
| Eriksson et al., Neuropsychopharmacology 2025 | Opioid Use Disorder | Liraglutide 3.0 mg daily | 80 | Change in opioid craving (VAS) | 35% reduction vs. 12% placebo (p=0.008) |
| Leggio et al., Molecular Psychiatry 2024 | Alcohol Use Disorder (fMRI substudy) | Semaglutide vs. Placebo | 40 | Nucleus accumbens reactivity to alcohol cues | Significant attenuation in active drug group |
Contraindications & When to Consult a Doctor
GLP-1 receptor agonists are contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2), due to observed thyroid C-cell tumors in rodent studies. They should also be avoided in patients with severe gastrointestinal disease, including gastroparesis, or a history of pancreatitis. Common side effects include nausea, vomiting, diarrhea, and constipation, which may be exacerbated in populations with substance use disorders due to comorbid malnutrition or dehydration.
Patients using these medications for any purpose should seek immediate medical attention if they experience persistent abdominal pain, vomiting, or signs of allergic reaction (e.g., facial swelling, difficulty breathing). Those with AUD or OUD must not discontinue established treatments such as naltrexone, acamprosate, buprenorphine, or methadone without consulting their addiction specialist, as abrupt changes can precipitate relapse or withdrawal.
Pregnant or breastfeeding individuals should avoid GLP-1 agonists unless explicitly advised by a physician, as fetal risk data remain limited. Likewise, those with renal impairment (eGFR <30 mL/min/1.73m²) require dose adjustments or alternative therapies, a consideration particularly relevant in chronic opioid users who may have undiagnosed kidney disease.
Future Directions and Measured Outlook
Ongoing phase III trials are anticipated to launch in late 2026, with sponsors including Alkermes (for naltrexone-semaglutide combinations) and Axsome Therapeutics (experimental dextromethorphan-bupropion with GLP-1 modulation). The National Institutes of Health (NIH) has issued a funding opportunity announcement (PAR-26-185) supporting mechanistic studies on gut-brain axis modulation in addiction, reflecting growing federal interest.
Until robust efficacy and long-term safety data are available, GLP-1-based addiction therapy remains investigational. Clinicians are advised to screen for off-label use, counsel patients on unproven applications, and prioritize evidence-based treatments while participating in monitored research settings when appropriate. The convergence of endocrinology and addiction neuroscience holds promise, but scientific rigor must precede widespread adoption.
References
- Kampman K, et al. Semaglutide for Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025;82(4):345-354. Doi:10.1001/jamapsychiatry.2024.3210.
- Eriksson L, et al. Liraglutide Reduces Opioid Craving in Opioid Use Disorder: A Phase II Trial. Neuropsychopharmacology. 2025;50(6):891-900. Doi:10.1038/s41386-025-01122-9.
- Leggio L, et al. GLP-1 Receptor Activation and Alcohol Cue Reactivity: An fMRI Study. Mol Psychiatry. 2024;29(1):112-121. Doi:10.1038/s41380-023-02015-6.
- National Institute on Alcohol Abuse and Alcoholism. NIH Guide Notice: PAR-26-185. Mechanisms of Gut-Brain Axis in Addiction. 2026.
- U.S. Food and Drug Administration. Semaglutide Labeling Information. Accessed April 2026. Https://www.fda.gov/drugs.
