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GLP1 Receptor Agonists: Investigational Insights into Addiction-Related Models
Substance use disorders, including alcohol, nicotine, opioid, and stimulant use remain a major global health concern. Conventional pharmacotherapies have shown limited long-term success. Recently, glucagon-like peptide-1 (GLP1), an incretin hormone involved in glucose metabolism and appetite regulation, has drawn attention in academic and preclinical research for its possible role in modulating reward pathways.
GLP1 receptor agonists (GLP1RAs), approved for metabolic conditions such as type 2 diabetes and obesity, have demonstrated intriguing effects in animal and non-human primate models of substance use. In rodent studies, GLP1RAs were associated with reduced alcohol intake, cocaine and amphetamine self-administration, and decreased nicotine-seeking behavior. Similar findings were observed in non-human primates with long-term alcohol exposure treated with exenatide or liraglutide.
These findings are believed to involve GLP1 receptors expressed in brain regions that regulate reward and motivation, including the nucleus accumbens and ventral tegmental area. Evidence suggests that stimulation of these receptors may modulate dopamine signaling, thereby affecting behavioral responses to addictive stimuli. Additional pathways, such as stress regulation and synaptic plasticity in regions like the amygdala and hippocampus, may also be involved.
While preclinical results are promising, clinical data remain limited. Two early-phase human studies have examined GLP1RAs in substance use contexts one randomized trial using exenatide in individuals with alcohol use disorder (AUD), and another small study exploring nicotine craving. Initial observations suggest possible reductions in alcohol consumption and improvements in withdrawal symptoms, though these findings are preliminary and require further validation
Large-scale retrospective cohort data have also reported associations between GLP1RA use and lower incidence of substance use disorders, including alcohol, opioids, stimulants, and cannabis, in individuals prescribed these agents for metabolic indications. These associations were observed even among patients not enrolled in substance use interventions, suggesting a possible indirect effect on reward modulation. However, such findings should be interpreted with caution due to confounding variables inherent to observational research.
The interface between metabolic signaling and addictive behaviors is increasingly recognized as an area of scientific interest. Investigators have proposed that GLP1RAs may benefit individuals managing both metabolic and behavioral health conditions. Nevertheless, the exact neural mechanisms and the consistency of these effects across different types and stages of substance use (e.g., initiation, relapse, withdrawal) remain under active investigation.
Future research will benefit from well-designed Phase II/III trials focused on specific addiction types, using standardized dosing protocols and incorporating biomarker endpoints. Differences in brain bioavailability and receptor signaling pathways (e.g., cAMP vs -arrestin) among liraglutide, semaglutide, and exenatide may also influence outcomes and merit further comparison.
In summary, GLP1RAs represent a compelling but still investigational class of compounds in addiction-related research. Preclinical studies have consistently demonstrated behavioral effects across several substance types, and early human research suggests possible benefit. Nonetheless, additional clinical trials are necessary to determine safety, efficacy, and appropriate context of use.
Citations
Klausen MK et al. The role of glucagon-like peptide-1 (GLP-1) in addictive disorders. Br J Pharmacol. 2022;179(4):625–641.
JCI Insight. Semaglutide reduces binge-like alcohol drinking in mice. 2023;8(6):e170671.
Pharmacological Research. GLP‑1 and substance use disorders: an emerging pharmacotherapeutic target. 2024.
Drug Alcohol Depend. Potential role of GLP‑1 receptor agonists in substance use disorders. 2024.
News-Medical. Are GLP-1 Drugs the Future of Alcohol Addiction Treatment? Mar 2025.
Financial Times. Weight-loss drugs show promise in tackling substance use disorders. Dec 2024.
Disclaimer
This article is intended for informational and educational purposes only. The compounds referenced are sold for laboratory research use only and are not approved by the FDA for the treatment or prevention of any disease or condition. The content should not be interpreted as medical advice or an endorsement of therapeutic use. All discussion of findings relates to research settings only.
