GLP-1 Receptor Agonists and Research to Treat Overeating and Substance Use Disorders
- 1Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida 32610
- 2Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- 3NIDA/NIAAA, National Institutes of Health Intramural Research Program, Baltimore, Maryland 21224
- 4Diabetes, Obesity and Complications Therapeutic Area, Eli Lilly and Company, Indianapolis, Indiana 46285
- 5Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32304
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Author contributions: J.G., M.R.H., L.L., E.O., and L.R. wrote the paper.
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists have revolutionized the therapeutic landscape of diabetes and obesity, yet their therapeutic potential extends significantly further. Research using human data and animal models indicates that systemically administered GLP-1R agonists access receptors in the periphery and in the brain. The latter site of action underlies the apparent efficacy of GLP-1R agonists to treat pathological consummatory behaviors that lead not only to obesity but also to binge-type eating disorders, alcohol use disorder, and other substance use disorders. This article provides an overview of basic science research, human clinical data, and real-world observations relevant to these topics and presented in a symposium at the 2025 Annual Meeting of the Society for Neuroscience.
Introduction
The persistent rise in rates of diet-related obesity and type 2 diabetes mellitus (T2DM) contributes to an increase in negative health comorbidities that reduce quality of life and increase the economic burden of healthcare (Finkelstein et al., 2009, 2010). Similar problems are associated with the increased incidence of binge-type eating disorders and increased use of alcohol and certain other drugs with addictive potential. Despite decades of research detailing physiological and behavioral mechanisms that contribute to the pathophysiology of obesity, eating disorders, and drug addictions, effective cures remain elusive. Optimal therapeutic management of these diseases involves behavioral modifications alongside treatment with pharmaceutical and hormone mimetics (Drucker et al., 2011; Sadry and Drucker, 2013).
Glucagon-like peptide-1 receptor (GLP-1R) agonists are one such hormonal mimetic. GLP-1R agonists such as exenatide, liraglutide, semaglutide, and tirzepatide (the latter being a dual agonist for GLP-1R and glucose-dependent insulinotropic polypeptide receptor) are now widely used in the treatment of T2DM and obesity (Hayes et al., 2014; Tella and Rendell, 2015). These drugs also are receiving considerable attention for their potential to treat binge-related eating disorders and substance use disorders. As reviewed in this article (Fig. 1), GLP-1R agonists are under increasing investigation in preclinical and early clinical exploratory trials to examine their efficacy in treating additional systemic diseases and other health challenges, including eating disorders and substance use disorders (Zhang et al., 2020; Herman and Schmidt, 2024; Merkel et al., 2024; Zheng et al., 2024; Freet et al., 2025).
Overview of the initial development of GLP-1R agonist drugs to treat type 2 diabetes and emerging evidence that these drugs also have utility to treat overeating, alcohol use disorder, and other substance use disorders.
The endogenous GLP-1 system
Endogenous GLP-1 is a cleavage product of the peptide precursor preproglucagon, encoded by the glucagon gene. GLP-1 is produced both in intestinal enteroendocrine L-cells, which are the primary source of circulating GLP-1, and in neurons within the olfactory bulb and the medulla of the caudal brainstem. GLP-1–producing neurons in the olfactory bulb are local interneurons whose axons remain confined to the bulb (Thiebaud et al., 2019). Brainstem GLP-1–producing neurons are located within the caudal nucleus of the solitary tract and the intermediate reticular nucleus. Axons arising from these brainstem neurons innervate a large number of subcortical regions that express GLP-1R (Fig. 2), including discrete nuclei within the pons, midbrain, thalamus, hypothalamus, amygdala, and ventral striatum (Gu et al., 2013; Pyke et al., 2014; Trapp and Cork, 2015; Holt et al., 2019; Farkas et al., 2021; Randolph et al., 2024). Accumulating evidence indicates that GLP-1 reduces food intake and body weight by engaging both peripheral and central GLP-1R signaling pathways. Activating either of these pathways is sufficient to reduce food intake, and reduced intake after engagement of one pathway does not depend on engagement of the other (Brierley et al., 2021).
Schematic depicting the endogenous GLP-1 neural projection system in the rat brain [figure created using BioRender.com, adapted and modified from Gu et al. (2013) and also based on data reported by Randolph et al. (2024)]. The cell bodies of GLP-1–producing neurons are positioned within the nucleus tractus solitarius (NTS) and intermediate reticular nucleus (IRt) of the caudal brainstem, depicted on the left side of the schematic. Axons arising from these neurons project to the spinal cord (SC) and to many subcortical brain regions, as indicated by arrows (line thickness for each arrow roughly represents relative GLP-1 axonal projection density). GLP-1Rs are expressed centrally in subcortical regions that receive axonal input from GLP-1 neurons, as well as in the cerebral cortex and hippocampus. AMB, nucleus ambiguous; ARC, arcuate nucleus of the hypothalamus; AVPV, anteroventral periventricular nucleus of the hypothalamus; BST, bed nucleus of the stria terminalis; CEA, central nucleus of the amygdala; DMH, dorsomedial nucleus of the hypothalamus; DMX, dorsal motor nucleus of the vagus; IPN, interpeduncular nucleus; LC, locus ceruleus; LHA, lateral hypothalamic area; MEPO, median preoptic nucleus; MPN, medial preoptic nucleus; MS, medial septal nucleus; NAc, nucleus accumbens; NDB, nucleus of the diagonal band of Broca; PAG, periaqueductal gray; PF, parafascicular nucleus; PBN, parabrachial nucleus; PS, parastrial nucleus; PVH, paraventricular nucleus of the hypothalamus; PV, periventricular hypothalamic nucleus; PVT, paraventricular thalamic nucleus; RH, rhomboid nucleus; SC, spinal cord; SFO, subfornical organ; SN, substantia nigra; SO, supraoptic nucleus of the hypothalamus; TMv, ventral tuberomammillary nucleus; VTA, ventral tegmental area.
Endogenous GLP-1 released in the intestine (and potentially other peripheral tissues) is quickly degraded in the blood by the enzyme dipeptidyl peptidase IV (for review, see Deacon, 2019). Thus, circulating GLP-1 is unlikely to engage central GLP-1Rs, with the possible exception of those in the hindbrain area postrema and other circumventricular regions that lack a blood–brain barrier (Ørskov et al., 1996; Daniels and Mietlicki-Baase, 2019; Trapp and Brierley, 2022). GLP-1Rs in the brain are instead exposed to GLP-1 released centrally from the axon terminals of caudal brainstem neurons. Principal among the brain regions mediating the food intake and body-weight–suppressive effects of GLP-1R–mediated signaling are the nucleus of the solitary tract and adjacent area postrema (Hayes et al., 2009, 2011; Huang et al., 2024), with additional actions in other regions of the brainstem, several hypothalamic nuclei, mesolimbic pathways related to reward processing, and other distributed regions (Dossat et al., 2011; Alhadeff et al., 2012, 2014; Mietlicki-Baase et al., 2014; Richard et al., 2014; Secher et al., 2014; Hsu et al., 2015; López-Ferreras et al., 2018, 2019). Collectively, these brain regions comprise the central neural circuits that underlie not only food intake and energy-balance control but also behavioral reinforcement and reward.
GLP-1 receptor agonists
GLP-1R agonists are now being investigated as potential pharmacotherapies for an ever-growing number of diseases affecting the CNS, including cognitive impairments, neurodegeneration, and substance use disorders (Zheng et al., 2024). GLP-1R agonists in current clinical use access at least a subset of central GLP-1Rs, including those expressed in circumventricular organs that lie outside the blood–brain barrier (e.g., in the area postrema, subfornical organ, and median eminence) and those expressed in some additional hindbrain and hypothalamic nuclei positioned in close anatomical proximity to those circumventricular organs (Gabery et al., 2020). The goal of achieving greater brain bioavailability of these agents must be balanced with strategies to minimize negative side effects.
In 2017, nausea and emesis were the principal reported side effects of existing GLP-1 therapeutics (Bettge et al., 2017). Nausea and emetic responses to GLP-1R agonists appear to arise largely from drug effects in the area postrema (Huang et al., 2024). The area postrema is a circumventricular organ that forms one component of the dorsal vagal complex, a hindbrain region that also includes the nucleus tractus solitarius and dorsal motor nucleus of the vagus. A recent report from GlaxoSmithKline based on real-world evidence indicates that gastrointestinal malaise during treatment with GLP-1R agonists was the top reason for patients to discontinue the drug (Sikirica et al., 2017). These aversive drug effects reduce dose tolerance in ∼15% of patients taking GLP-1R agonists and lead to complete attrition in an additional ∼6–10% of patients (O’Neil et al., 2018; Capehorn et al., 2020; Trujillo, 2020). Thus, >20% of patients with obesity or diabetes cannot benefit from existing FDA-approved GLP-1 therapeutics. Unfortunately, the desired effect of GLP-1R agonists to reduce food intake by increasing satiation/satiety requires circuits within the hindbrain dorsal vagal complex that also underlie undesired GLP-1R agonist–induced side effects of nausea and malaise (Grill and Hayes, 2012; Huang et al., 2024). A challenge will be to attenuate GLP-1R agonist–induced nausea/emesis while preserving the desired effects of GLP-1R agonists to reduce food intake, body weight, and/or substance use disorders (discussed further, below). Meeting this challenge will promote better patient compliance and therapeutic tolerability of future types of GLP-1R agonists with enhanced central bioavailability.
Beyond obesity and diabetes
GLP-1R agonists were originally developed to treat T2DM by mimicking the effect of endogenous GLP-1, which binds to GLP-1Rs in the pancreas to enhance the ability of glucose to promote insulin release (Holst and Ørskov, 2004). It was later discovered that GLP-1R agonists can treat obesity by reducing food intake, an effect that has been linked to GLP-1R agonist modulation of neural signaling in the mesolimbic reward system [for recent reviews of animal research and clinical data, see Eren-Yazicioglu et al. (2021) and Badulescu et al. (2024)]. This discovery led researchers and clinicians to examine whether GLP-1R agonists could be repurposed to treat substance use disorders (Egecioglu et al., 2013; Shirazi et al., 2013; Skibicka, 2013; Hayes and Schmidt, 2016; Hernandez and Schmidt, 2019; Jerlhag, 2019; Eren-Yazicioglu et al., 2021). Neural pathways involved in processing reward, motivation, and elements of wanting and liking are often implicated as contributing factors in excessive food intake, binge-type eating disorders, bulimia nervosa, and substance use disorders. Indeed, existing GLP-1R agonists appear to reduce the hedonic value of food and drugs by directly and indirectly reducing dopamine transmission in the mesolimbic reward system (Skibicka, 2013; Mietlicki-Baase et al., 2014; Fortin and Roitman, 2017; Merkel et al., 2024; Edvardsson et al., 2025). GLP-1–producing brainstem neurons project directly to the ventral tegmental area and nucleus accumbens, as well as to other brain regions that provide synaptic input to these mesolimbic nuclei (Skibicka, 2013; Randolph et al., 2024; Fig. 2). Direct infusion of GLP-1R agonists into these reward-related brain regions in rodent models reduces intake of highly palatable foods, apparently without disrupting homeostatic factors that drive intake of nutritious but less palatable foods (Schick et al., 2003; Dossat et al., 2011; Alhadeff et al., 2012; Mietlicki-Baase et al., 2013; Richard et al., 2015). The mesolimbic reward system and related brain circuits also are thought to underlie the reinforcing effects of binge eating and addictive drug use (Hayes and Schmidt, 2016; Balantekin et al., 2024), promoting disorder-related harmful behaviors in some individuals that are clinically resistant to treatment. The following sections overview the current status of basic science research, clinical trials, and real-world evidence supporting the use of GLP-1R agonists as a potential therapeutic approach to some of these disorders.
GLP-1R Agonists in Binge Eating Disorder and Bulimia Nervosa
GLP-1R agonists have emerged as promising candidates for treating binge-type eating disorders in clinical populations, particularly binge eating disorder and binge eating associated with bulimia nervosa (Aoun et al., 2024; Kałas et al., 2025). The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision distinguishes binge eating disorder as different from bulimia nervosa based on the presence or absence of purging after a binge eating episode (American Psychiatric Association, 2022).
Preclinical evidence
The available evidence suggests that GLP-1R agonists modulate appetite and may reduce compulsive eating behaviors through centrally mediated mechanisms involving hypothalamic and mesolimbic pathways (Balantekin et al., 2024). GLP-1R agonists act in these and other brain regions to regulate homeostatic and hedonic (i.e., pleasure-driven) eating by promoting satiety and reducing food reward (Dickson et al., 2012; Balantekin et al., 2024; Huang et al., 2024). For example, in addition to engaging reward-related mechanisms by dampening dopaminergic signaling in the mesolimbic reward pathway, GLP-1R agonists stimulate pro-satiety POMC/CART neurons and inhibit orexigenic NPY/AgRP neurons in the hypothalamic arcuate nucleus and reduce the meal size by engaging neural circuits in the hindbrain dorsal vagal complex. Thus, their dual action helps reduce both physiological hunger and the hedonic appeal of food (Balantekin et al., 2024).
Studies with animal models designed to mimic key features of binge eating disorder demonstrate that binge-like eating downregulates GLP-1 expression in the brain, especially in the NTS, even as peripheral levels of circulating GLP-1 increase. This central disruption is associated with reduced satiety signaling and enhanced reward-driven feeding (Mukherjee et al., 2022). Overall, preclinical data support the hypothesis that GLP-1R agonists can normalize binge-like eating behaviors by acting on both satiety and reward mechanisms. These findings provide a strong biological rationale for ongoing clinical trials exploring GLP-1R agonists as potential treatments for binge eating disorder, with potential relevance for the binge-type eating associated with bulimia nervosa. However, no current animal models effectively capture the purging aspect of bulimia nervosa.
Clinical trial evidence
Liraglutide is the most extensively studied GLP-1R agonist for the treatment of eating disorders. A 17 week pilot randomized controlled trial enrolled 27 overweight or obese adults with binge eating disorder who received liraglutide (3.0 mg/d) or placebo. While both groups experienced reductions in binge episodes, those receiving liraglutide achieved significantly greater weight loss (∼5.2 vs <1%; Allison et al., 2023). Similarly, Robert et al. (2015) conducted a 12 week open-label trial in 44 nondiabetic participants characterized with subclinical binge eating. Compared with the baseline, liraglutide (1.8 mg/d), combined with lifestyle counseling, significantly reduced binge eating symptoms, with a higher transition rate to “nonbinge” status and improved metabolic markers (i.e., body mass index, waist circumference, and fasting blood levels of glucose and cholesterol; Robert et al., 2015). A larger randomized controlled trial evaluated liraglutide (3.0 mg/d) as an adjunct to intensive behavioral therapy in 150 participants with obesity (Chao et al., 2019; Wadden et al., 2019). After 24 weeks of treatment, subjects in the liraglutide group had greater reductions in binge behaviors and eating disorder psychopathology compared with subjects receiving only intensive behavioral therapy. However, the benefits of liraglutide were not sustained after 52 weeks of treatment. Thus, while this GLP-1R agonist may accelerate short-term improvements, its long-term efficacy beyond that of behavioral interventions alone remains uncertain (Chao et al., 2019; Wadden et al., 2019).
The therapeutic efficacy of a different GLP-1R agonist, dulaglutide, was examined in a 12 week open-label controlled trial involving 60 adults with both T2DM and binge eating disorder. Compared with the sulfonylurea medication gliclazide (used to stimulate pancreatic insulin production), dulaglutide led to greater reductions in binge severity, body weight, body mass index, body fat, and HbA1c (a marker of persistently elevated blood sugar), underscoring its dual efficacy in managing both metabolic and behavioral symptoms (Da Porto et al., 2020). The ongoing SEMASEARCH trial (NCT05897398) is expected to provide preliminary insights into the ability of semaglutide to reduce binge eating symptoms.
Overall, the existing body of clinical evidence supports the therapeutic potential of GLP-1R agonists in binge eating disorder and possibly binge eating behavior in bulimia nervosa. The pharmacological mechanisms of action of GLP-1R agonists, coupled with clinical and real-world data (reviewed below), promise potential benefits for binge reduction and metabolic improvement. However, while the pilot trials summarized above have generated promising results, critical gaps remain. These include the following. (1) Limited generalizability: Most clinical studies to date have focused on individuals with binge eating disorder and comorbid obesity, with no completed randomized controlled trials evaluating the effects of GLP-1R agonists in normal-weight individuals, or in those with bulimia nervosa. (2) Short follow-up durations: Existing trials are limited both by small sample sizes and short follow-up durations. Long-term sustainability of treatment effects remains unclear, given the still-open question of whether the central effects of these medications are subject to tachyphylaxis. (3) Safety concerns: Risk of restrictive eating disorders, especially in vulnerable patients, necessitates vigilant monitoring. (4) Lack of large-scale, high-quality real–world studies: Robust pharmacoepidemiologic analyses using causal inference frameworks are needed to assess treatment heterogeneity, long-term effectiveness, and safety in routine practice. Future research should prioritize large, multisite randomized controlled trials and longitudinal observational studies to delineate the efficacy, safety, generalizability, and patient-centered outcomes of GLP-1R agonists across diverse patient populations. Integration with behavioral therapies, individualized treatment plans, and ongoing psychosocial support will be essential to optimize benefits and mitigate risks.
Observational and real-world evidence
Robust real-world evidence of the therapeutic efficacy of GLP-1R agonists for eating disorders is limited. However, small observational studies and case reports have offered early support for their effectiveness. For example, a retrospective health chart review compared outcomes in 48 patients with binge eating disorder who were treated off-label with semaglutide alone, with traditional medications (e.g., lisdexamfetamine, topiramate), or with a combination of these drugs. Semaglutide monotherapy produced the most substantial reductions in binge symptoms, with no added benefit from combination regimens—suggesting potential superiority of this GLP-1R agonist compared with existing pharmacotherapies (Richards et al., 2023). Furthermore, a case report described clinical improvements following initiation of liraglutide treatment, including a sustained remission of binge-purge behavior in a patient with long-standing bulimia nervosa (Innocent et al., 2025). While interesting, these results are quite preliminary. Large-scale data from high-quality, real-world studies are critically needed to evaluate the effectiveness of GLP-1R agonists in managing binge eating and other eating disorders in routine clinical settings.
GLP-1R Agonists in Alcohol Use Disorder and Other Substance Use Disorders
Beyond their promise of limiting excessive food intake by individuals with diet-induced obesity and those suffering from binge eating disorder and bulimia nervosa, GLP-1R agonists have emerged as promising candidates for the treatment of alcohol use disorder and other substance use disorders. While underlying mechanisms of action are not yet fully understood, the existing literature suggests that GLP-1R agonists may reduce reward-driven overconsumption of food, alcohol, and other addictive drugs by modulating neural activity in caudal brainstem, hypothalamic, and mesolimbic pathways (Skibicka, 2013; Richard et al., 2015; Hayes and Schmidt, 2016; Eren-Yazicioglu et al., 2021). As reviewed below, additional mechanisms linked to satiation and stress-related processes may also contribute to the effects of these drugs.
Preclinical evidence
The role of GLP-1R agonists in modulating alcohol- and drug-seeking behaviors has been investigated for over a decade, well before these medications gained popularity in the public domain. Multiple studies have provided consistent evidence that GLP-1R agonists (including exenatide, dulaglutide, liraglutide, semaglutide, and others) reduce alcohol intake and motivation for alcohol in mice, rats, and nonhuman primates. These results come from independent laboratories using a variety of paradigms and procedures, such as continuous and intermittent access to alcohol in a two-bottle choice procedure, drinking-in-the-dark binge–like drinking, alcohol-induced conditioned place preference, and operant self-administration of alcohol (for review, see Bruns Vi et al., 2024).
Similar results have been observed with other addictive substances. For instance, GLP-1R agonists have been shown to reduce cue- and drug-induced reinstatement of heroin seeking, intravenous heroin self-administration, as well as fentanyl self-administration and reinstatement of fentanyl seeking (Bruns Vi et al., 2024). Data collected in rodent models demonstrate that GLP-1R agonists reduce the ability of nicotine to increase dopamine release in the nucleus accumbens while concurrently reducing nicotine-induced conditioned place preference, hyperlocomotion, and locomotor sensitization. Additionally, GLP-1R agonists facilitate the extinction of intravenous nicotine self-administration and block reinstatement of nicotine seeking (Bruns Vi et al., 2024). Similarly, GLP-1R agonists reduce cocaine self-administration, cocaine-induced locomotion and dopamine release, drug- and cue-induced reinstatement of cocaine seeking, and cocaine-induced conditioned place preference in both mice and rats (Bruns Vi et al., 2024).
Collectively, a wide body of preclinical studies across mice, rats, and nonhuman primates converges on a consistent conclusion: GLP-1R agonists reduce behaviors associated with seeking and consuming alcohol and other addictive drugs in experimental models in which these behaviors resemble human phenotypic features of alcohol use disorder and other substance use disorders. Nevertheless, several questions remain open. While most studies have reported significant effects of GLP-1R agonist treatment, some findings have been negative. For example, Bornebusch and colleagues reported that administration of exendin-4 did not reduce intravenous self-administration of remifentanil (an opioid analgesic that is chemically related to fentanyl) during phases of acquisition, extinction, or reacquisition following extinction (Bornebusch et al., 2019). Such negative results are critically important, as they can inform future translational research aimed at identifying predictors of treatment response (or nonresponse) to GLP-1R agonists in the context of AUD and SUD. Revealing potential sex differences in responses to GLP-1R agonists in clinical populations should also be a focus, given that early preclinical research assessing GLP-1R agonist effects on drug seeking and intake was predominantly conducted in male rodents. More recent studies have included both male and female animals, and while most report no sex differences in the effects of GLP-1R agonists on alcohol- and drug-related outcomes, there are notable exceptions. For instance, one study found that exendin-4 suppressed alcohol self-administration and reinstatement in male mice, but not in females (Díaz-Megido and Thomsen, 2023). Future preclinical work should thoroughly investigate the conditions under which males and females exhibit different responses to GLP-1R agonists.
Clinical trial evidence
While several randomized controlled trials are currently underway, only a limited number have been completed and published. The available results regarding therapeutic efficacy of GLP-1R agonists for substance use disorders are modestly promising, though somewhat mixed. Focusing on alcohol use disorder, the first completed and published randomized controlled trial tested exenatide and found no significant difference between exenatide and placebo on the predefined primary outcome: reduction in alcohol consumption (Klausen et al., 2022). However, neuroimaging studies included in this clinical trial indicated that exenatide reduced dopamine transporter availability and reactivity to alcohol cues. A secondary analysis of this randomized controlled trial revealed more nuanced results: while there were no differences between exenatide- and placebo-treated participants who were overweight and while placebo outperformed exenatide in normal-weight individuals, exenatide was superior to placebo in reducing alcohol consumption among participants with obesity (body mass index >30 kg/m2).
More promising findings come from a recently published randomized controlled trial (Hendershot et al., 2025) demonstrating that low-dose semaglutide reduced alcohol self-administration in a laboratory setting among people with alcohol use disorder but not seeking treatment. Semaglutide also reduced the number of drinks consumed per drinking day and reduced self-reported levels of craving in participants’ real-world daily lives. Furthermore, a secondary analysis in the subgroup of participants who smoked cigarettes showed that semaglutide was associated with a reduction in the number of cigarettes smoked per day.
Regarding research on tobacco use disorder, one completed randomized controlled trial evaluated exenatide as an adjunct to nicotine patch therapy. Compared with placebo or nicotine replacement therapy alone, exenatide promoted smoking abstinence, reduced nicotine craving, reduced withdrawal symptoms, and attenuated postcessation weight gain (Yammine et al., 2021). Subsequent secondary analyses suggested stronger effects in specific subgroups, including heavy smokers, individuals with normal blood glucose levels and/or normal body weight, those with minimal depressive symptoms, and individuals carrying a particular nicotinic acetylcholine receptor genotype (Yammine et al., 2025).
Another completed randomized controlled trial tested dulaglutide as an adjunct to varenicline and behavioral counseling. While dulaglutide did not increase abstinence from smoking compared with placebo, it did prevent postcessation weight gain and significantly reduced levels of HbA1c, the latter reflecting a chronic reduction in blood sugar (Lengsfeld et al., 2023). In a predefined secondary analysis of participants who smoked and also consumed alcohol, dulaglutide was found to reduce alcohol consumption. Notably, the changes in alcohol intake were not correlated with smoking status (Probst et al., 2023).
A small, double-blind, placebo-controlled study in individuals with cocaine use disorder found no significant effect of a single 5 μg dose of exenatide on cocaine self-administration or on related outcomes such as euphoria and drug wanting (Angarita et al., 2021). Importantly, the small sample size and the use of only a one-time administration of GLP-1R agonist limit the ability to draw definitive conclusions from this study.
While findings from these completed randomized controlled trials are promising, larger and longer trials are needed to confirm the efficacy of GLP-1R agonists in individuals with alcohol use disorder and other substance use disorders. Future research should also address key open questions regarding optimal dosing, treatment duration, and the identification of potential responders versus nonresponders (Leggio et al., 2023). In this regard, several additional clinical trials testing GLP-1R agonists or dual agonists are ongoing in the addiction field, including single-site randomized controlled trials in people with alcohol use disorder. These trials are testing subcutaneous (NCT05895643, NCT06015893, NCT05891587) or oral (NCT05892432) semaglutide or tirzepatide (NCT06994338). Other ongoing single-site randomized controlled trials are focusing on people with alcohol use disorder and comorbidities, specifically schizophrenia (NCT06939088), alcohol-associated liver disease (NCT06546384), and testing positive for human immunodeficiency virus (NCT07040592). One multisite randomized controlled trial is evaluating pemvidutide, a dual GLP-1R/glucagonR agonist (NCT06987513) in people with alcohol use disorder. Another multisite randomized controlled trial is evaluating semaglutide alone or in combination with cagrilintide (a synthetic amylin analog being investigated for body weight management) on alcohol-associated liver disease and other alcohol use disorder-related outcomes (NCT06409130). With regard to tobacco use disorder, ongoing single-site randomized controlled trials are evaluating the effects of GLP-1R agonists on smoking cessation and craving (NCT06924697, NCT06015893, NCT06986993, NCT06173778); furthermore, a multisite randomized trial testing tirzepatide for smoking cessation will start soon (U01DA064384). In the opioid field, a recent pilot randomized controlled trial using liraglutide was completed (NCT04199728; results not available yet), and other studies are ongoing, including a single-site pilot randomized controlled trial (NCT06639464) and multisite randomized controlled trials with semaglutide (NCT06548490) and tirzepatide (NCT06651177). Finally, ongoing studies in people with cocaine use disorders are underway, including a single-site randomized controlled trial testing exenatide (NCT06252623) and a single-site randomized controlled trial testing semaglutide in people with cocaine use disorder who also test positive for human immunodeficiency virus (NCT06691243).
Observational and real-world evidence
Recent case reports and case series (Richards et al., 2023; Yammine et al., 2023; Romeo, 2025), along with observational studies analyzing social media posts (Quddos et al., 2023; Arillotta et al., 2024; Bremmer and Hendershot, 2024), have revealed that individuals taking GLP-1R agonists or tirzepatide for diabetes and/or obesity report reduced cravings and use of alcohol, nicotine, or other addictive substances. Although observational, these studies provide preliminary human evidence supporting the potential role of GLP-1R agonists in the treatment of alcohol use disorder and other substance use disorders. Pharmacoepidemiological studies offer more robust evidence. These studies leverage electronic medical records and apply advanced computational approaches such as propensity score-matching and trial emulation to assess the association between GLP-1R agonist prescriptions (for diabetes and/or obesity) and improved alcohol- or drug-related clinical outcomes. With regard to alcohol, these studies indicate that GLP-1R agonist use is associated with a reduced incidence of new-onset alcohol use disorder, lower recurrence rates in individuals with prior alcohol use disorder, and a decreased incidence of alcohol-related events such as intoxication, hospitalization, and total alcohol consumption (Wium-Andersen et al., 2022; Wang et al., 2024a; Farokhnia et al., 2025; Lähteenvuo et al., 2025). Notably, these findings have been replicated using electronic health records from multiple datasets across the United States, Denmark, and Finland. Other pharmacoepidemiological studies have identified associations between GLP-1R agonist use and reduced incidence of opioid overdose (Wang et al., 2024d; Qeadan et al., 2025), tobacco use disorder (Wang et al., 2024b), and cannabis use disorder (Wang et al., 2024c). Importantly, while most of these studies were designed to examine substance use outcomes specifically, a large-scale, hypothesis-free study conducted using US Veterans Affairs healthcare system electronic medical records assessed the safety and effectiveness of GLP-1R agonists across 175 different health outcomes. Even in this broad analysis, GLP-1R agonist use was significantly associated with beneficial neuropsychiatric effects, including a reduced risk of several substance use disorders, i.e., alcohol, cannabis, opioid, and stimulant use disorders (Xie et al., 2025).
Biomarker Data on the Effectiveness of GLP-1R Agonists to Treat Substance Use Disorders
As reviewed above, there is growing preclinical and early clinical evidence to support the potential utility of GLP-1R agonists for treating substance use disorders. However, no studies to date have systematically examined the effects of these drugs on established peripheral biomarkers of substance use, which can provide critical objective measures that complement self-reported reductions in substance use during and after treatment. Relevant biomarkers for assessing different substance use disorders and available data investigating effects of GLP-1R agonists on these biomarkers are summarized below.
Alcohol use disorder
Urine or blood-based biomarkers such as phosphatidylethanol, ethyl glucuronide, ethyl sulfate, carbohydrate-deficient transferrin, and gamma glutamyl transferase are commonly used to objectively assess ongoing alcohol consumption and heavy drinking patterns (Wurst et al., 2015). A secondary analysis of a randomized control trial of the GLP-1R agonist exenatide versus placebo in 30 participants with alcohol use disorder showed a significant reduction in phosphatidylethanol in exenatide-treated subjects at Week 26 (−0.9 µmol/L; 95% CI −1.6 to −0.1; p = 0.03; Jensen et al., 2025). However, no significant differences in phosphatidylethanol were observed at earlier assessment timepoints (i.e., Weeks 4, 12, or 20), suggesting a delayed effect of exenatide on alcohol drinking outcomes. It is unclear whether the delayed effect on alcohol use was due to a cumulative pharmacological impact on reward-driven behavior following sustained exenatide dosing and/or due to gradual lifestyle adjustments facilitated by reduced alcohol cravings. While informative, the small sample size and relatively high dropout rates seen in the study limit the ability to draw broader generalizations regarding exenatide efficacy in alcohol use disorder, highlighting the need for larger-scale studies to validate these early observations. Forthcoming clinical trials have begun to incorporate several additional peripheral biomarkers of quantitative use such as phosphatidylethanol alongside traditional behavioral and self-reported outcomes during treatment for alcohol use disorder.
Tobacco, opioid, and stimulant use disorders
Cotinine, a primary metabolite of nicotine with a half-life of ∼16–18 h, remains the gold-standard biomarker for verifying recent tobacco exposure and quantifying reductions in smoking behavior (Benowitz et al., 2002, 2009). Urine drug screens detecting specific metabolites, alongside confirmatory blood and hair analyses, provide robust measures of recent or chronic use (Verstraete, 2004). A systematic integration of biomarkers across planned studies will be essential to supplement and validate the robust real-world and clinical trial data emerging on the use of GLP-1R agonists for these disorders.
Ongoing Clinical Trial Landscape and Future Directions
Overall, initial findings from pilot human studies and observational cohorts suggest that GLP-1R agonists may be effective for treating alcohol and other substance use disorders, but the clinical trial landscape is still developing and larger randomized controlled trials are needed (Leggio et al., 2023). Future trials would benefit from additive measures such as investigating dose–response relationships that determine the optimal therapeutic window for people with alcohol use disorder and other substance use disorders, enrolling larger sample sizes to replicate initial findings and improve generalizability, and incorporating biomarkers to validate self-reports and other clinical findings. Furthermore, long-term follow-ups will be essential to assess the durability of treatment effects, the potential for tachyphylaxis, and to evaluate therapeutic potential across several use disorder-related outcomes, including reduction in or prevention of alcohol/drug use (Petrie and Mayo, 2025). Results from human studies indicate that the efficacy of GLP-1R agonists to reduce food intake and body weight requires continued drug administration (Abdullah Bin Ahmed, 2024; Wu et al., 2025), which may also be true if these therapeutic drugs are used for long-term treatment of binge eating and substance use disorders. It will be critical to discover whether concurrent behavioral modification therapy can reduce the chance of relapse after dose tapering or complete discontinuation of GLP-1R agonist treatment. Additional basic science questions regarding the cellular, physiological, and molecular mechanisms that mediate effects of GLP-1R agonists on food intake, energy balance, and drug reward remain underinvestigated. Continued research using animal models will be critically important for improving knowledge in these domains and therefore inform precision medicine-oriented clinical work with patients. Such work comprises an essential step for leveraging the next generation of GLP-1R agonist–based pharmacotherapies in clinical populations, given the need for upfront identification of potential responders versus nonresponders to these treatments.
In conclusion, accumulated evidence from animal studies, clinical trials, and real-world data support the promise of GLP-1R agonists for treating overeating, binge eating, alcohol use disorder, and other substance use disorders. Continued research is needed to address potential sex differences in these effects, to examine therapeutic efficacy in larger and more diverse cohorts, and to include rigorous biomarker data as objective measures of substance use during treatment. It also will be critical to address potential tachyphylaxis during chronic GLP-1R agonist treatment and to determine whether concurrent behavioral modification therapy increases the likelihood that pharmacological treatment can be tapered or discontinued.
Footnotes
- Received May 28, 2025.
- Revision received August 6, 2025.
- Accepted August 10, 2025.
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For work included in this article and for preparation of the article, J.G. was supported by the National Institutes of Health (NIH) Grants DK133465, AG089445, and MD019614; M.R.H. was supported by NIH Grant DK112812; L.L. was supported by the NIH Intramural Research Program (NIDA and NIAAA); L.R. was supported by NIH Grants MH059911 and DK100685. This work also was supported by the Intramural Research Program of NIH. The contributions of the NIH author (L.L.) were made as part of his official duties as an NIH federal employee, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services.
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M.R.H receives research funding from Boehringer Ingelheim, Eli Lilly and Company, Pfizer, Gila Therapeutics, and Coronation Bio, which was not used in support of work reported in this article. M.R.H. is a founding scientist of Coronation Bio, conducting research unrelated to that reviewed in this article. E.O. is an employee of Eli Lilly and Company. All other authors report no biomedical financial interests or other potential conflicts of interest.
- Correspondence should be addressed to Linda Rinaman at lrinaman{at}psy.fsu.edu.
- Copyright © 2025 the authors
