Using diabetes drugs that target GLP-1 receptors to treat alcohol use disorder: a review and combined analysis

Alcohol misuse and alcohol use disorder (AUD) pose a significant global health challenge, characterized by impaired control over alcohol use, compulsive consumption, and negative affect during withdrawal, which contribute to relapse [1]. AUD is a serious cause of mortality and morbidity, with more than 400 million people around the world affected by their inability to manage their alcohol consumption [2, 3]. There are also many disabilities and medical conditions causally associated with alcohol, with more prevalent conditions (such as cardiovascular diseases, liver disorders, malignancies, and other related conditions) contributing to a significant amount of alcohol-associated morbidity [4].

The treatment of AUD includes psychosocial and pharmacological interventions [5]. Psychosocial treatments are the cornerstone of AUD management, though pharmacological options are also beneficial [6]. To date, only a limited number of medications (disulfiram, acamprosate, and naltrexone) have been approved for the treatment of AUD by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A fourth medication, nalmefene, is currently approved by the EMA but not by the FDA [7, 8]. Although the aforementioned medications demonstrate some efficacy, their number is limited, and not all patients respond to them. Therefore, expanding the range of available pharmacotherapies is essential to better support individuals with AUD [9]. There is a critical need to identify new molecular targets to expand the range of treatment options for AUD. Although current therapies benefit some individuals, relapse rates remain high, with most studies reporting rates exceeding 70% within one year, underscoring the necessity for more effective interventions [10, 11].

Endogenous glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone synthesized by intestinal L cells in response to nutrient intake, as well as in the nucleus tractus solitarius of the medulla oblongata [12, 13]. GLP-1 stimulates insulin secretion, inhibits glucagon release, and, perhaps most notably, suppresses appetite and reduces food intake [14]. Although GLP-1 receptor agonists (GLP-1RAs) were initially developed for the management of diabetes and weight loss, their therapeutic applications have since broadened considerably to encompass a range of cardiovascular, renal, and metabolic disorders [15–17]. Preliminary investigations have also suggested the potential therapeutic benefits of this drug class in the treatment of AUD [18]. These agents appear to modulate brain regions implicated in addiction, thereby reducing alcohol cravings and consumption, particularly among individuals with obesity [19, 20]. Given that alcohol and drug abuse activate the same reward pathways involved in food intake, it is plausible that appetite-regulating peptides, such as GLP-1, exert their effects on brain regions associated with reward and addiction [20, 21]. Their efficacy in treating both AUD and metabolic disorders, including obesity and type 2 diabetes mellitus (T2DM), offers a compelling additional clinical rationale for their use [22, 23].

GLP-1 and its receptor agonists appear to modulate brain regions implicated in addiction, particularly the mesolimbic reward system, which also plays a central role in the regulation of food and substance use. These agents are believed to suppress presynaptic dopamine release and dampen postsynaptic reward signaling at mesolimbic synapses, thereby diminishing the reinforcing effects of alcohol consumption. Given the substantial overlap between the neural circuits governing appetite and those involved in addictive behaviors, it is plausible that appetite-regulating peptides such as GLP-1 contribute to reduced alcohol cravings and intake, an effect that has been especially evident in individuals with obesity.

Despite encouraging preclinical findings and limited clinical evidence, the therapeutic impact of GLP-1RAs on AUD remains unclear. Given their ability to modulate reward pathways shared by both food and substance use (particularly the mesolimbic dopamine system), GLP-1RAs may offer a novel approach to reducing alcohol cravings and consumption. However, the clinical efficacy of GLP-1RAs in AUD has yet to be clearly established. To the best of our knowledge, this study represents the first meta-analysis specifically designed to systematically evaluate the clinical effects of GLP-1RAs on AUD and alcohol-related hospitalization.

This systematic review and meta-analysis evaluated the association between GLP-1RA use and the risk of AUD in adults with obesity or T2DM. We restricted the scope to ICD-10–defined outcomes and analyzed AUD diagnoses and alcohol-related hospitalization separately. Across three observational cohort studies, GLP-1RA exposure was associated with a 28% lower risk of AUD diagnosis. Between-study heterogeneity was substantial, reflecting variability in design and comparator groups. Because only three cohorts were available, no formal meta-regression was performed. Observed heterogeneity likely reflects differences in comparator drugs (DPP-4 inhibitors vs. no GLP-1RA), baseline risk, and follow-up duration rather than a single identifiable source. It may also arise from the inclusion of the Adeniran et al. [27] cohort, which involved patients who had undergone Roux-en-Y gastric bypass (RYGB), a bariatric procedure known to carry a higher risk of AUD and alcohol-related complications [31, 32]. These findings align with emerging research on GLP-1RAs as novel pharmacotherapies for AUD, a condition with limited effective treatments [33]. For alcohol-related hospitalization, pooling two cohorts suggested a possible protective effect, but this did not reach statistical significance. The trend warrants further investigation, as even modest reductions in hospitalization could have important clinical and economic implications if confirmed in larger datasets. The observed reduction in AUD risk is particularly noteworthy given the global burden of AUD, which affects an estimated 280 million people and is associated with high morbidity and mortality [34].

These findings are supported by previous evidence from randomized controlled trials, although results remain mixed. One trial found that exenatide had no overall benefit on alcohol consumption in individuals with AUD, except in participants with obesity [23]. Another study, using dulaglutide, reported a medium-to-large effect size for reducing alcohol use in people with obesity, although no benefit was seen in heavy drinkers [35]. These different outcomes may reflect variations in GLP-1RA agent, treatment duration, underlying conditions, and baseline alcohol consumption.

Because the hospitalization outcome included only two studies and showed high heterogeneity, these findings should be interpreted cautiously.

In addition to our included studies, there were more original studies excluded from our meta-analysis due to methodological differences and a lack of appropriate data, which provide additional support for GLP-1RAs’ role in reducing alcohol consumption. In a 26-week Randomized Controlled Trial (RCT), Klausen et al. [23] evaluated exenatide in individuals with AUD. While the overall reduction in heavy drinking days did not reach significance, exploratory analyses showed notable reductions in alcohol intake among participants with obesity. In contrast, exenatide appeared to worsen drinking outcomes in lean individuals, suggesting that body weight may influence treatment response. Neuroimaging data from the same study indicated reduced alcohol cue reactivity in reward-related brain regions and decreased dopamine transporter availability, offering a plausible neurobiological mechanism for these effects [23].

In the study by Jensen et al. [36], alcohol consumption was measured using the biomarker phosphatidylethanol (PEth). A significant reduction in PEth levels was observed at week 26 in the exenatide group compared to placebo, though no differences emerged earlier. This delayed effect may relate to exenatide’s pharmacokinetics or the time needed to influence compulsive drinking behaviors [37]. Moreover, O’Farrell et al. [38] suggested that obese patients treated with liraglutide or Semaglutide showed a marked reduction in self-reported alcohol intake after 3–6 months, particularly among high consumers. Weight loss was also observed, with a modest correlation between alcohol reduction and weight change, suggesting GLP-1RAs may simultaneously target both alcohol use and obesity.

Other original studies, such as those included in a recent systematic review, reported benefits with Semaglutide and dulaglutide [39]. For example, Probst et al. conducted a secondary analysis of an RCT using dulaglutide in smokers with AUD, finding trends toward reduced alcohol use, but data limitations precluded inclusion in our meta-analysis [35]. Case series, such as Richards et al., also reported decreased AUD symptoms based on alcohol use disorder identification test score in patients receiving Semaglutide for weight loss, further corroborating the potential of GLP-1RAs across formulations [40]. Together, these findings illustrate the consistency of alcohol-reducing effects across real-world, biomarker-based, and neuroimaging-supported studies, despite heterogeneity in design and outcome measures.

The efficacy of GLP-1RAs in AUD likely stems from their modulation of the brain’s reward circuitry, as evidenced by preclinical and clinical data [41, 42]. GLP-1 receptors are expressed in reward-related regions, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA), where they influence dopaminergic signaling [43]. Preclinical studies in rodent models demonstrate that GLP-1RAs, including exenatide, liraglutide, and semaglutide, attenuate alcohol-induced dopamine release in the NAc, reducing the reinforcing properties of alcohol [44]. For instance, a study found that semaglutide modulates central GABA neurotransmission, which is implicated in alcohol withdrawal and craving [45]. In an experimental study conducted on African vervet monkeys, administration of liraglutide and exenatide led to a significant reduction in alcohol intake without any signs of emesis [46]. Similarly, another preclinical investigation examined the effects of semaglutide on voluntary alcohol consumption in non-human primates and demonstrated a marked decrease in alcohol intake, with no evidence of emetic responses [47]. Although these animal models (such as those employing chronic intermittent ethanol exposure paradigms) provide compelling mechanistic insights, extrapolation to human populations should be approached with caution, given interspecies physiological and behavioral differences. Additionally, GLP-1RAs promote satiety and delay gastric emptying, potentially decreasing the drive for alcohol as part of broader ingestive behavior changes [41]. Also, in alcohol-dependent rodents, administration of GLP-1R agonists mitigated signs of alcohol withdrawal and associated anxiety-like behavior [48]. This dual effect on both positive and negative reinforcement mechanisms suggests that GLP-1RAs may reduce alcohol use through multiple neurobiological pathways. Genetic studies further support a biological link through the gut-brain axis, identifying associations between GLP-1 receptor gene variants and AUD [49].

The primary strength of this meta-analysis lies in its novelty and methodological rigor. While previous studies have provided systematic or narrative reviews examining the relationship between GLP-1RAs and alcohol use, this work represents the first quantitative meta-analysis to synthesize effect estimates across observational cohorts. The analysis was conducted in strict accordance with PRISMA guidelines and employed a random-effects model to account for interstudy heterogeneity. By utilizing HRs as the effect measure, we ensured greater comparability among studies and enhanced the robustness and stability of the pooled estimate for the association between GLP-1RAs and AUD. However, we acknowledge that our research may have some limitations. First, the small number of included studies may affect the overall quality of our pooled analysis; however, this reflects the early stage of research in this field. Notably, most studies were published very recently (2024–2025), highlighting the novelty of this topic and the emerging nature of GLP-1 research in this context. The absence of RCTs among the included studies is a notable limitation, as observational and retrospective designs may be more susceptible to confounding, selection bias, and variability in data quality. This limitation highlights the inherent difficulties of performing a meta-analysis that relies exclusively on retrospective cohorts. High heterogeneity suggests variability in study populations or methodologies, which may partly stem from differences in study design, follow-up duration, and outcome assessment. Although we sought to further elucidate the sources of heterogeneity, subgroup analyses based on sex, BMI, or other covariates could not be performed because too few studies and insufficient data were available. Additionally, different studies use various measurement criteria for reporting their outcomes, which hinders our ability to conduct optimal analysis. Moreover, each study used different time frames for follow-up, which adds to the heterogeneity of our results and makes it impossible to assess the long-term outcomes. Future RCTs should test various GLP-1RAs across broader AUD populations, standardize outcomes, and explore body weight’s moderating role. Long-term studies on relapse prevention and combination therapies (e.g., with naltrexone) are also critical.

This meta-analysis suggests that GLP-1RAs, beyond their metabolic benefits, are associated with reduced risks of AUD. These effects are likely mediated through modulation of the brain’s reward system and gut–brain axis. The benefits were more pronounced when compared to no treatment, and findings remained robust across sensitivity analyses. While heterogeneity and limited study numbers warrant caution, these results highlight GLP-1RAs as promising candidates for AUD management. Further large-scale, long-term trials are needed to confirm these effects.