Opioid Use Disorder (OUD) remains a major public health crisis, with high risks of relapse, overdose, and mortality. Traditional treatments—such as methadone, buprenorphine, and naltrexone—are effective but limited by access barriers, stigma, and adherence issues. A recent systematic review (Au et al., 2025) evaluated whether GLP-1 receptor agonists (GLP-1 RAs)—widely used in diabetes and obesity management—could be repurposed as a novel therapeutic strategy for OUD. Summarized below are the key findings.

Human Data

• A large retrospective cohort study (503,747 individuals with OUD, with or without comorbid diabetes or obesity) found:
• GLP-1/GIP agonist use was associated with ~40% lower risk of opioid overdose (aIRR = 0.60, 95% CI [0.43, 0.83]).
• Effects were consistent across subgroups with OUD alone, OUD with diabetes, and OUD with obesity.
• No randomized controlled trials (RCTs) have yet been completed. Several are underway, with results expected around 2027.

Animal Data

• Exenatide (Ex-4): Reduced oxycodone and fentanyl self-administration and attenuated drug-seeking behaviors when administered systemically or directly into the nucleus accumbens.
• Liraglutide: Consistently decreased heroin and fentanyl seeking and self-administration in rodent models, with effects seen in both high and low drug-taking animals.
• Effects appeared dose- and time-dependent, highlighting the need for careful pharmacologic optimization.

Mechanistic Insights

• GLP-1 receptors are expressed in reward-related brain regions, including the ventral tegmental area (VTA) and nucleus accumbens.
• Agonism may reduce dopaminergic activity and modulate GABAergic pathways, thereby decreasing reinforcement from opioids.
• Dual GLP-1/GIP agonists may offer additive effects via insulinotropic and weight-loss mechanisms, potentially further reducing drug-seeking.

Clinical Relevance for Practitioners

• Potential Benefit: GLP-1 RAs may complement existing OUD treatments by reducing craving, relapse, and overdose risk.
• Current Limitation: Human evidence is preliminary, with only observational data available. No RCTs have yet confirmed efficacy for OUD.
• Safety & Practicality: GLP-1 RAs are already widely prescribed for diabetes and obesity, with known tolerability and safety profiles - this could accelerate repurposing if efficacy is confirmed.
• Future Direction: Ongoing clinical trials (NCT06651177, NCT06639464, NCT06548490) will provide critical insight into dosing, safety, and real-world effectiveness in OUD populations.

Takeaway for Clinicians
Although GLP-1 RAs are not yet approved for OUD, emerging evidence suggests they may modulate opioid-related behaviors via central reward pathways. Pending results from ongoing trials, these agents could offer a novel adjunctive strategy, especially for patients with comorbid metabolic conditions.

Reference:

Au HCT et al. Acta Neuropsychiatrica. 2025;37:e85. Epub ahead of print. Abstract