GLP-1 receptor agonists (GLP-1RAs) are multi-system modulators currently being investigated for their potential in treating alcohol use disorder (AUD). While originally developed for metabolic disorders, serendipitous clinical observations and pre-clinical data suggest these agents may modulate both central reward processing and peripheral physiological pathways. This dual mechanism positions GLP-1RAs as a promising candidate to bridge neuropsychiatric and metabolic health in addiction medicine. However, their application in AUD remains in the early stage of clinical validation. Critical questions persist regarding long-term efficacy, optimal dosing/tolerability compared to metabolic populations and the maintenance of clinical benefits (e.g. drinking reduction and abstinence) after discontinuation. The pharmacological targeting of glucagon-like peptide-1 (GLP-1), through mimetic peptides (e.g. exenatide) and specific receptor agonists (RAs) (e.g. semaglutide) has emerged as therapeutic approach for metabolic disorders. Increasingly, the therapeutic potential of GLP-1RAs in psychiatry has attracted considerable attention 1 because of the convergence of biological and behavioral mechanisms in both metabolic and addiction disorders. Specifically, both conditions involve dysregulation of the mesolimbic dopamine system and shared homeostatic signaling pathways that govern rewarding behaviors 2. Recently, in clinical trials the dual RA tirzepatide (glucose-dependent insulinotropic polypeptide and GLP-1), has demonstrated superior efficacy in promoting weight loss compared to semaglutide 3. Consequently, several next-generation dual RAs are currently being evaluated in ongoing clinical studies to determine whether these metabolic advantages translate into improved outcomes in addiction medicine. Alcohol use disorder (AUD) is characterized by complex neuroadaptations within reward and executive control circuitry, however, it is increasingly recognized as a systemic pathology involving complex metabolic and inflammatory disturbances 4. Although still premature, GLP-1RAs provide an opportunity to address this multi-organ pathophysiology by modulating interconnected central (rewarding) and peripheral (homeostatic) systems 5. Historically, severe chronic heavy drinking was associated with a malnourished phenotype. In the modern clinical landscape, however, there is a surging prevalence of metabolic syndrome among individuals with AUD 6, 7. Chronic alcohol use significantly disrupts glucose metabolism and increases insulin resistance 8. GLP-1RAs restore metabolic homeostasis by improving insulin sensitivity and reducing oxidative stress 9. GLP-1RAs not only improve systemic metabolic markers, but also regulate hepatic and pancreatic enzymes 10, therefore, protecting critical metabolic organs compromised in individuals who consume alcohol heavily. A key peripheral-brain axis mechanism is the GLP-1RAs impact on gastric motility 11. GLP-1RAs delay gastric emptying by reducing stomach and small intestine motility and enhancing satiety signals via vagal afferents to the brainstem and hypothalamus 12. Although this action contributes to reduced caloric intake and glycemic control in metabolic patients, it has significant implications for AUD treatment. By delaying gastric emptying, GLP-1RAs slow alcohol transit to the small intestine, the primary site of absorption, thereby moderating peak blood alcohol concentrations. This mechanism may attenuate the acute intoxicating effects and reduce the reinforcing stimulation that fuels craving. Moreover, the enhanced vagal signaling associated with slowed gastric emptying indirectly dampens alcohol-seeking behavior by influencing brain regions governing reward, mood and impulse control 13. Additionally, alcohol provides substantial calories (7 kcal/g), often contributing to weight gain and central adiposity, particularly when consumed with sugary mixers. GLP-1RAs offer a dual benefit by reducing alcohol intake through reward pathway modulation and enhancing motivation to improve associated health outcomes, such as weight and metabolic parameters, in individuals potentially less inclined to prioritize drinking modification. Much of the current understanding regarding GLP-1RAs use in addiction medicine stems from retrospective analyses of real-world data. These include large-scale cohort studies demonstrating reduced incidence and recurrence of AUD 14, as well as significant associations with improved outcomes in tobacco 15 and cannabis 16. Furthermore, dissemination of GLP-1RAs effects on AUD has been significantly amplified by news media and social media, often outpacing peer-reviewed scientific publications. To date, only a limited number of RCTs have directly tested GLP-1-based therapies for AUD. A 26-week RCT investigating extended-release exenatide found no significant reduction in alcohol consumption compared to placebo 17 and a 9-week RCT involving semaglutide demonstrated a significant reduction in alcohol self-administration and craving within a controlled laboratory setting 18. Although the evidence landscape is rapidly changing with numerous new RCTs underway, these prospective trials are essential for establishing efficacy, safety, and protocols for prolonged use. The dual efficacy of GLP-1 RAs in managing alcohol cravings and promoting weight loss enhances their social desirability. Given the high prevalence of metabolic comorbidities among patients with AUD, the prospect of weight management may serve as a significant motivator for treatment adherence. Adherence metrics from metabolic populations, however, may not generalize to AUD cohorts because of differences in motivation, comorbidities and required dosing strategies. The definition of a goal achieved in AUD is inherently complex, differing significantly from the straightforward targets used in metabolic disease. Consequently, extrapolation from metabolic studies is limited, and critical questions remain regarding long-term safety, discontinuation effects and risk of reoccurrence following cessation. A critical clinical concern for chronic disorders like AUD is medication discontinuation. Although dose-escalation protocols for GLP-1RAs derived from type 2 diabetes and obesity management exist to optimize effect and minimize adverse events, no guidance exists on discontinuation/tapering in the context of addictive disorders. This is salient because discontinuation in metabolic populations often results in substantial weight regain, suggesting that GLP-1RAs may need to be considered a chronic therapy 19. Currently, there are no published data on: (1) how many patients with AUD sustain GLP-1RA therapy after achieving abstinence or reduced heavy drinking; (2) the required role of adjunct psychotherapy alongside pharmacotherapy in the recovery process; and (3) whether drinking reductions or other clinical benefits are sustained without ongoing medication. The development of GLP-1RAs treatments for addiction, however, represents a paradigm shift in public health and pharmaceutical engagement. For the first time in decades, the pharmaceutical industry is demonstrating renewed interest in developing medications for addiction, an area that has seen limited innovation since the approval of extended-release naltrexone in 2006. This renewed interest is partially driven by a shift in regulatory standards. Historically, the United States Food and Drug Administration required addiction treatments to demonstrate abstinence. Today, reductions in use are accepted as meaningful clinical outcomes, aligning treatment development with attainable patient goals 20. This change opens the door for more feasible therapeutic strategies that reflect the spectrum of recovery. GLP-1RAs, being well-characterized and widely used, offer a scientifically grounded, scalable and potentially transformative tool to meet patients where they are motivated to reduce use and improve health, even if not ready for full abstinence. In summary, the GLP-1RA research is a potent reminder that we must discard the historical segregation of primary care, endocrine-metabolic and neuropsychiatric medicine. As multi-system modulators, GLP-1RAs represent a promising class of therapeutics that allow for the treatment of AUD as a complex, multi-organ pathology rather than an isolated neurological deficit. However, realizing the clinical potential of these agents requires addressing significant research maturity gaps through rigorous clinical trials to establish clinical validity, long-term efficacy and safety in diverse patient populations. Carolina L. Haass-Koffler: Conceptualization (lead); writing—original draft (lead); writing—review and editing (lead). The funding sources were not involved in writing or the decision to submit this manuscript for publication. OpenAI. (2024). ChatGPT (May 5 version) Large language model was used solely for proofreading assistance. All content was conceptualized, reviewed and finalized by the author. C.L.H.K. holds two patents for the development of negative allosteric modulators targeting the stress system and one patent application on the development of a compound for noradrenergic blockade. All is unrelated to this work. C.L.H.K. is also a Site PI in Ely Lilly, Apollo and Altimmune-sponsored clinical trials on GLP-1 dual agonists with no financial interest (shares, consultancy, employment, paid lectures).
Carolina L. Haass‐Koffler (Thu,) studied this question.