GLP-1 Agonists Show Promise in Treating Alcohol and Substance Use Disorders
Key Clinical Summary
- GLP-1 receptor agonists (GLP-1RAs), currently used for type 2 diabetes and obesity, may reduce alcohol and substance use.
- Preclinical and early clinical data indicate reductions in cravings and substance-seeking behaviors.
- Ongoing trials are investigating GLP-1RAs, dual agonists (e.g., tirzepatide), and their role in treating addiction comorbidities.
A review published in the Journal of the Endocrine Society by researchers from the National Institutes of Health and international collaborators highlights the emerging potential of GLP-1 receptor agonists (GLP-1RAs) as pharmacotherapies for alcohol and substance use disorders (ASUDs). These agents, initially developed for type 2 diabetes mellitus and obesity, have demonstrated effects on reward pathways implicated in addiction, opening new avenues for treating these chronic conditions.
Study Findings
The review summarizes preclinical, clinical, and pharmacoepidemiologic evidence showing that GLP-1RAs—such as exenatide, liraglutide, semaglutide, and dulaglutide—reduce substance intake and related behaviors across alcohol, nicotine, opioid, and stimulant use models.
Alcohol and Nicotine
In rodents and non-human primates, GLP-1RAs reduced alcohol intake, dopamine release, and craving behaviors. Human studies echoed these findings:
- A Danish national cohort linked GLP-1RA use to reduced alcohol-related events.
- A randomized trial of semaglutide demonstrated lower drinks per drinking day and decreased cravings in individuals with alcohol use disorder (AUD).
- Exenatide also lowered cigarette consumption in participants who smoked compared to placebo.
Opioid and Stimulant Use
Several GLP-1RAs decreased heroin, oxycodone, and fentanyl self-administration in animal models, with epidemiologic data suggesting reduced opioid overdose risk among human GLP-1RA users. In cocaine use, GLP-1 signaling in the brain’s reward circuits attenuated drug-seeking behavior, though human trials remain limited.
Mechanistic Insights
As illustrated in Figure 1, GLP-1RAs modulate reward, stress, satiety, and inflammation pathways through central and peripheral GLP-1 receptors located in regions such as the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). This multi-system activity may underlie their potential in treating ASUDs.
Clinical Implications
The findings suggest that GLP-1RAs could address both metabolic and addictive disorders, particularly in patients with comorbid obesity or diabetes—populations frequently encountered in endocrinology and primary care settings.
Given their established safety in metabolic conditions and preliminary success in addiction-related outcomes, these agents could fill a major treatment gap where pharmacologic options remain scarce.
However, clinicians must weigh benefits against side effects such as gastrointestinal disturbances and the potential for muscle mass loss, especially in malnourished patients with ASUDs. Ongoing randomized controlled trials (RCTs) are expected to clarify optimal dosing, safety, and combination strategies with existing behavioral and pharmacologic interventions.
Expert Commentary
“GLP-1RAs have the potential to help people with polysubstance use, as well as those with medical comorbidities—phenotypes that are more the norm than exception in addiction medicine. “,” wrote Lorenzo Leggio, MD, of the National Institute on Drug Abuse (NIDA), part of the Intramural Research Program at the National Institute of Health in Baltimore, MD.
He emphasized that while preclinical evidence is promising, “RCTs are critically needed to investigate the safety and efficacy of GLP-1RAs in patients with ASUDs.”
GLP-1 receptor agonists, long used in metabolic medicine, may potentially redefine the pharmacologic landscape of addiction treatment. As multiple RCTs progress globally, clinicians should monitor emerging data to guide potential off-label or future approved use in managing alcohol and substance use disorders.
Reference
