From laboratory models to small human trials, a new review explores whether popular metabolic drugs could help curb alcohol, nicotine, and drug use, while underscoring how much clinical testing still lies ahead.
The potential role of GLP-1 receptor agonists in substance use disorders – a systematic review. Image Credit: VectorMine / Shutterstock
In a recent study published in the journal Frontiers in Pharmacology, researchers examined the potential role of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in treating substance use disorders (SUDs).
Substance Use Disorders and Rationale for GLP-1-Based Therapies
SUDs represent a significant public health concern and are characterized by limited therapeutic efficacy and high relapse rates. GLP-1 RAs, initially developed for type 2 diabetes (T2D) and obesity, have emerged as promising candidates for treating addiction. Beyond their appetite-suppressing and glucose-lowering effects, GLP-1 RAs exert neuroprotective and anti-inflammatory actions in the central nervous system and gut-related immune-inflammatory signaling via GLP-1 receptors.
Study Scope and Objectives
In the present study, researchers systematically assessed the therapeutic potential of GLP-1 RAs in SUD treatment. First, a comprehensive search was conducted across the Web of Science, Scopus, PubMed, Cochrane Central Register, Embase, and PsycINFO databases to identify randomized controlled trials (RCTs), preclinical studies, and clinical trials with control groups. Following deduplication, titles and abstracts were screened, and full texts were reviewed.
Study Selection and Data Extraction
Relevant data were extracted from eligible studies, including study characteristics, sample details, intervention specifics, outcomes, and statistical methods. The Cochrane Risk of Bias tool was used to assess the quality of studies. Evidence from clinical and preclinical studies was narratively synthesized due to heterogeneity in study designs, interventions, and outcome measures.
Overview of Included Studies
The search strategy yielded 2,869 records. Of these, 41 studies met the inclusion criteria through database searching, and one additional eligible clinical study was identified through manual reference tracking, for a total of 42 included studies. Six were clinical studies, including pilot studies, secondary analyses, and RCTs, and the remaining were preclinical studies, mainly involving rodents.
Preclinical Models and Behavioral Paradigms
Preclinical studies used validated behavioral paradigms to evaluate substance-seeking behavior, including oral self-administration, intravenous administration, drug- and cue-induced reinstatement, conditioned place preference, and operant conditioning.
Clinical Focus and Substances Studied
Clinical studies mainly addressed nicotine and alcohol use disorders, assessing pharmacological effects on intake, craving, abstinence, and related neuroendocrine or metabolic parameters. Across studies, alcohol was the most frequently investigated substance, followed by cocaine, nicotine, and opioids.
GLP-1 Receptor Agonists Evaluated
GLP-1 RAs included liraglutide, dulaglutide, exendin-4, and semaglutide. Exendin-4 was assessed in cocaine and nicotine models. Liraglutide and semaglutide were predominantly studied in the context of opioid and alcohol use disorders. Dulaglutide was exclusively studied in clinical trials for alcohol-related outcomes and smoking cessation, with alcohol intake often assessed as a secondary outcome.
Outcomes Assessed Across Studies
Studies assessed a wide range of outcomes, comprising neurobiological, clinical, and behavioral domains. Neurobiological outcomes included changes in dopaminergic signaling, neuroinflammatory markers, circulating insulin and GLP-1 levels, and activation of reward-related brain regions.
Behavioral outcomes included substance intake, operant motivation, relapse-like reinstatement, and drug-seeking behavior. Clinical endpoints focused on craving intensity, daily substance use, weight changes, treatment tolerability, and abstinence duration.
Clinical Evidence in Alcohol Use Disorder
Two clinical studies primarily investigated the effects of GLP-1 RAs in alcohol use disorder (AUD). One trial examining semaglutide in individuals with AUD demonstrated lower alcohol intake, but reported inconsistent effects on heavy drinking days.
In another trial, no overall reduction in heavy drinking days was observed with exenatide. However, secondary analyses showed significant decreases among individuals with a body mass index (BMI) greater than 30 kg/m². In addition, a smoking-cessation trial of dulaglutide included a secondary analysis of alcohol outcomes, reporting reduced weekly alcohol intake, with weaker effects among heavier drinkers.
Preclinical Evidence in Alcohol Use Disorder
Preclinical studies also support the use of GLP-1 RAs in AUD treatment. Exendin-4 was reported to reduce relapse-like drinking behavior in mice, delaying the onset of renewed alcohol consumption and decreasing the number of drinking bouts.
Similarly, semaglutide led to reduced relapse-like drinking behaviors and alcohol consumption in rodents. Further, liraglutide treatment led to a significant reduction in alcohol consumption in rodents with high baseline alcohol intake.
Evidence in Tobacco Use Disorder
In one RCT examining GLP-1 RAs in tobacco use disorder, semaglutide treatment reduced daily cigarette smoking. Dulaglutide treatment resulted in a significant reduction in weight gain following smoking cessation.
A pilot study reported that a combination of exenatide and nicotine replacement therapy improved smoking abstinence rates, reduced withdrawal symptoms, and alleviated post-cessation weight gain. In a preclinical study, liraglutide significantly decreased nicotine self-administration and relapse behavior in rats and mitigated withdrawal-induced hyperphagia and associated weight gain.
Evidence in Cocaine Use Disorder
One clinical study found no differences in self-reported euphoria, craving, or cocaine infusions in individuals with cocaine use disorder treated with exenatide compared with placebo. However, exenatide reduced circulating insulin and GLP-1 levels, highlighting metabolic modulation.
Targeted injection of exendin-4 into the laterodorsal tegmental nucleus suppressed cocaine-seeking behavior in rats, without affecting body weight, food intake, or sucrose-seeking behavior. In another rodent study, exenatide led to a marked reduction in cocaine-primed reinstatement without impacting sucrose-seeking behavior.
Evidence in Opioid Use Disorder
Several preclinical investigations focused on opioid-related behaviors. Liraglutide treatment was reported to suppress heroin self-administration and drug-induced reinstatement in rats with high drug intake.
In contrast, one study showed that exendin-4 did not attenuate remifentanil self-administration or opioid withdrawal symptoms in mice.
Overall Conclusions and Future Directions
The study provided a comprehensive overview of evidence on GLP-1 RA use in the treatment of substance use disorders. Preclinical studies consistently support the efficacy of GLP-1 RAs across multiple SUDs.
Clinical studies suggest potential benefits, particularly in nicotine and alcohol use disorders. However, the clinical evidence base remains preliminary, heterogeneous, and limited in size, with several trials not primarily powered to detect addiction-related outcomes.
Most clinical trials used GLP-1 RA dosing regimens consistent with approved metabolic indications, and the optimal dosing strategies for addiction-specific outcomes remain uncertain. Larger, well-designed randomized controlled trials are warranted to clarify efficacy, confirm findings in adequately powered addiction-focused studies, identify responsive subgroups, and establish appropriate treatment protocols.
Overall, GLP-1 RAs represent a novel therapeutic strategy that bridges the neuropsychiatric and metabolic domains in addiction medicine.
Further Reading
Journal reference:
- Völker, K. M., Prechtl, B. L. H., Bormann, N. L., Choi, D. S. (2026). The potential role of GLP-1 receptor agonists in substance use disorders, a systematic review. Frontiers in Pharmacology, 16, 1702448. DOI: 10.3389/fphar.2025.1702448, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1702448/full
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