A recent study published in Frontiers in Pharmacology highlights the potential of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) as innovative treatments for substance use disorders (SUDs), a major public health challenge marked by limited therapeutic options and high relapse rates.
Substance Use Disorders and GLP-1 Therapy
Originally developed for type 2 diabetes and obesity, GLP-1 RAs have gained attention for their broader effects beyond glucose control and appetite suppression. These drugs exhibit neuroprotective and anti-inflammatory properties in the central nervous system and modulate gut-related immune signaling, suggesting a possible role in addiction therapy.
Study Design and Methodology
Researchers conducted a comprehensive review of randomized controlled trials (RCTs), preclinical studies, and clinical trials with control groups across databases including PubMed, Web of Science, Scopus, Embase, Cochrane Central, and PsycINFO. After screening 2,869 records, 42 studies were included—six clinical trials and 36 preclinical studies, primarily involving rodent models.
Data were extracted on study characteristics, interventions, outcomes, and statistical methods. Study quality was assessed using the Cochrane Risk of Bias tool, and evidence was synthesized narratively due to heterogeneity in study design and outcomes.
Preclinical and Clinical Findings
Alcohol Use Disorder (AUD)
Preclinical models demonstrated that GLP-1 RAs like exendin-4, semaglutide, and liraglutide reduced relapse-like drinking behavior and overall alcohol consumption in rodents. Clinically, semaglutide lowered alcohol intake, though effects on heavy drinking days were inconsistent, and exenatide showed reductions primarily in participants with BMI over 30 kg/m².
Tobacco Use Disorder
Semaglutide reduced daily cigarette consumption in an RCT, while dulaglutide mitigated post-cessation weight gain. Preclinical studies with liraglutide and exenatide also decreased nicotine self-administration, reduced withdrawal symptoms, and improved abstinence rates.
Cocaine Use Disorder
Rodent studies indicated that exendin-4 and exenatide could suppress cocaine-seeking behavior and relapse, although clinical trials found no significant changes in self-reported craving or euphoria, highlighting a disconnect between metabolic and behavioral outcomes.
Opioid Use Disorder
Preclinical evidence showed liraglutide suppressed heroin self-administration and drug-induced reinstatement in high-intake rats. However, exendin-4 did not consistently reduce opioid self-administration or withdrawal symptoms in mice.
Implications and Future Directions
The study provides a comprehensive overview of GLP-1 RAs in SUD treatment. Preclinical results are consistently promising across multiple substances, while clinical evidence suggests potential benefits for nicotine and alcohol use disorders. Nonetheless, the current clinical data are limited, heterogeneous, and often underpowered for addiction-specific outcomes.
Most trials used GLP-1 RA dosing approved for metabolic conditions, leaving optimal dosing for addiction treatment uncertain. Researchers emphasize the need for larger, well-designed RCTs to confirm efficacy, identify responsive patient subgroups, and establish treatment protocols.
Conclusion: GLP-1 receptor agonists represent a novel therapeutic avenue in addiction medicine, bridging neuropsychiatric and metabolic domains, and offering hope for more effective interventions against substance use disorders.
