Abstract

Substance use disorders (SUDs) represent a major global public health challenge, and currently available pharmacological treatments remain only moderately effective. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the treatment of obesity and type 2 diabetes, have recently attracted attention as potential therapeutic agents in addiction medicine due to their effects on reward-related neural pathways. The aim of this review was to evaluate the efficacy and safety of GLP-1RAs in adults with substance use disorders. A total of nine studies met the inclusion criteria and were included in the qualitative analysis. The available evidence suggests that semaglutide and exenatide may reduce alcohol consumption, decrease craving, and support the maintenance of nicotine abstinence, while also contributing to weight control. In contrast, clinical data regarding stimulant use disorders remain limited. Across the analysed studies, GLP-1RAs demonstrated a favourable safety profile. The most commonly reported adverse effects were mild gastrointestinal symptoms, and no significant neuropsychiatric safety concerns were identified. Overall, GLP-1RAs may represent a promising adjunctive approach in the treatment of substance use disorders. However, potential plateau effects and rebound phenomena after treatment discontinuation suggest that long-term therapeutic strategies may be required. Further large-scale randomized clinical trials are needed to confirm these findings and to determine the optimal role of GLP-1RAs in addiction treatment.

Study at a Glance

Study Snapshot: Key Statistics

Full Study Facts

What the Researchers Actually Did

Gwałt and colleagues conducted a PRISMA-compliant systematic review of published clinical evidence evaluating GLP-1 receptor agonists in adults with substance use disorders. They searched PubMed/MEDLINE, Scopus, and Web of Science through March 3, 2026, supplementing automated retrieval with manual reference screening of identified systematic reviews and meta-analyses. Eligibility was structured around the PICOS framework: included studies required pharmacological administration of a GLP-1RA or dual agonist, adult participants with problematic substance use or a formal SUD diagnosis, and direct empirical measurement of addiction-relevant outcomes, such as consumption quantity, validated craving scores, days of abstinence, fMRI cue-reactivity, or addiction-related hospitalization rates. Preclinical studies, non-SUD obesity/diabetes trials without addiction-specific endpoints, and publications evaluating only endogenous GLP-1 changes were excluded. Six investigators independently conducted study selection. Risk of bias was assessed with Cochrane RoB 2 for RCTs and ROBINS-I for observational studies.

Nine studies met inclusion criteria: four original RCTs, four secondary or post-hoc analyses of existing RCT data, and one large retrospective cohort using the TriNetX electronic health record database. Because design heterogeneity precluded meta-analytic pooling, the authors conducted a qualitative synthesis organized by substance category: alcohol use disorder (AUD), nicotine use disorder (NUD), and stimulant use disorder (StUD). The review did not perform a formal GRADE assessment of the overall evidence, though it noted that most RCTs carried a moderate risk of bias driven primarily by participant attrition, and the observational study was limited by residual confounding inherent to retrospective analyses.

Key Findings: Primary Outcomes

• Alcohol self-administration (semaglutide): In a Phase II RCT enrolling adults with moderate AUD over nine weeks, semaglutide produced a statistically significant reduction in laboratory-based alcohol self-administration (g-ETOH, p=0.01) and in peak breath alcohol concentration (peak BrAC, p=0.03).
• Alcohol craving (semaglutide): The same trial reported a significant attenuation of alcohol cravings on the Penn Alcohol Craving Scale (PACS, p=0.01).
• Heavy drinking days (exenatide ER): A 26-week RCT of extended-release exenatide as adjunctive therapy to standard of care demonstrated a reduction in heavy drinking days.
• Phosphatidylethanol (exenatide ER, post-hoc): A secondary analysis of the exenatide RCT cohort found significant reductions in blood PEth concentrations, a direct biomarker of alcohol consumption, alongside favourable shifts in pro-inflammatory and metabolic marker profiles.
• AUD risk (real-world cohort): A retrospective TriNetX database analysis found that patients prescribed semaglutide had a significantly lower risk of both incident AUD diagnoses and AUD recurrence.
• AUD risk (meta-analysis cited in review): A meta-analysis of observational studies found that GLP-1RA use in patients with obesity and type 2 diabetes was associated with a statistically significant 28% reduction in the risk of an AUD diagnosis compared to other therapeutic interventions.

Key Findings: Secondary Outcomes and Subgroup Analyses

Nicotine Use Disorder

• Abstinence rates: A pilot double-blind RCT integrating once-weekly exenatide into a regimen of nicotine replacement patches and behavioural counselling significantly enhanced biologically verified 7-day abstinence rates at week 6, and reduced post-cessation weight gain.
• Treatment response predictors: A secondary analysis of that trial identified heterogeneous therapeutic response to exenatide, moderated by baseline body mass index, depressive symptomatology, and CHRNA5 receptor genotype, suggesting that personalized treatment selection may be feasible.
• Long-term cardiovascular safety (dulaglutide): A 52-week follow-up of patients receiving dulaglutide alongside varenicline identified no cardiovascular safety signals, specifically regarding systolic blood pressure reductions, among participants maintaining abstinence.
• Cross-substance effect: Participants receiving semaglutide in the AUD trial demonstrated a significant reduction in daily cigarette consumption (p=0.005), suggesting that anti-addictive effects may extend across substance classes simultaneously.

Stimulant Use Disorder

• Cocaine (exenatide, crossover, n=13): Individuals with cocaine use disorder who received a single dose of exenatide three hours before a testing session showed a measurable reduction in subjective ratings of euphoria and drug-seeking intent, translating into a significant decrease in cocaine infusions selected during an operant self-administration paradigm. This represents the sole clinical data point for stimulant use disorders in this review.

Opioid Use Disorder (referenced in discussion)

• The review’s discussion cites a systematic review of EHRs indicating that semaglutide initiation significantly reduced intoxication episodes and the risk of fatal overdose in patients with opioid use disorders; however, no original OUD study was included among the nine qualifying studies.

Adverse Events and Safety Profile

Across all nine appraised studies, the administration of GLP-1RAs in patients with SUD was characterized by a consistently favourable tolerability profile. The most frequently reported adverse events were gastrointestinal, primarily manifesting as mild nausea and, less frequently, emesis. These symptoms were typically transient and resolved during the initial titration phase.

No significant neuropsychiatric adverse events were identified. Specifically, no evidence of treatment-induced major depressive disorder or suicidal ideation was detected across the analysed studies. The authors frame the absence of neuropsychiatric signal as particularly clinically meaningful, given the high prevalence of comorbid psychiatric conditions in the SUD population, where such signals would constitute a substantial barrier to adoption.

One cautionary finding: the 52-week dulaglutide follow-up in smokers found that participants maintaining abstinence showed a significant increase in systolic blood pressure after dulaglutide discontinuation at week 52, which the authors interpret as consistent with a post-discontinuation rebound phenomenon rather than a direct drug toxicity signal.

Statistical Approach and Rigor

This review is a qualitative synthesis only. No pooled effect sizes, weighted means, or meta-analytic calculations were performed by the review authors. Risk of bias was formally assessed using Cochrane RoB 2 for RCTs and ROBINS-I for observational studies, with most studies rated at moderate risk of bias due to attrition (RCTs) or residual confounding (observational data). No formal GRADE evidence quality assessment was conducted. The inclusion of four secondary or post-hoc analyses derived from the same underlying RCT datasets introduces the possibility that shared-sample findings are overrepresented in the evidence base. The smallest study informing conclusions about stimulant use disorders enrolled only 13 participants, a sample size that affords negligible statistical power for subgroup inference. The review’s reliance on individual study p-values rather than pooled effect estimates limits quantitative precision and precludes dose-response inference.

Clinical Takeaway

For the clinician managing patients with alcohol or nicotine use disorders who are already on or being considered for GLP-1 receptor agonist therapy, this review provides a coherent, if preliminary, signal: semaglutide and exenatide show statistically significant reductions in alcohol consumption, craving, and nicotine relapse across multiple study designs. The safety profile is reassuring, with no neuropsychiatric signals, which distinguishes GLP-1RAs from agents such as varenicline that carry labeling warnings in certain populations. However, the evidence does not yet support prescribing GLP-1RAs as primary addiction pharmacotherapy, and the possibility of rebound phenomena after discontinuation argues against time-limited courses. Clinicians should treat these data as hypothesis-strengthening rather than practice-defining, and patients with comorbid metabolic disease and SUD represent the most defensible population in whom adjunctive use might be considered off-label today.

Why This Matters Clinically

Substance use disorders impose a staggering global burden, and the current pharmacological toolkit is limited in both breadth and effectiveness. Naltrexone for AUD and varenicline for NUD represent the standard, yet real-world adherence to both agents is persistently suboptimal, driven in part by adverse event profiles. GLP-1 receptor agonists occupy an unusual pharmacological niche: they are already approved, widely prescribed, and carry a well-characterized safety record from metabolic indications. If their apparent anti-addictive effects are confirmed at scale, the clinical benefit would be additive for patients who carry the common clinical phenotype of comorbid obesity, type 2 diabetes, and substance use disorder. The dual metabolic and addiction-modifying profile described in this review would address two high-mortality comorbidities with a single agent class, reducing polypharmacy burden and potentially improving overall adherence. That said, clinicians must resist the narrative compression that often follows promising early-phase data in addiction medicine.