(132) Breaking the Cycle: GLP-1/GIP Agonist Treatment and Alcohol Use Disorder

Background & Introduction: Emerging research suggests glucagon-like peptide-1 (GLP-1) agonists hold significant promise as a groundbreaking treatment for alcohol use disorder (AUD) (1, 2). Yet, the role of dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonists remains uncertain. Only one observational study has examined this, which found that social media posts for patients on a GLP-1/GIP agonist (tirzepatide) noted a reduction in alcohol cravings (1).
The mechanisms for GLP-1 agonists and reduced alcohol use are well-described in the literature. GLP-1 agonists directly activate receptors in the nucleus tractus solitarius, reducing the excitability of dopaminergic neurons. GABAnergic neurons and glutamine receptors are also targeted and may play an important role. Additional research suggests interaction with the hypothalamic-pituitary-adrenal axis, reducing stress-induced relapse behaviors. GLP-1 agonists also slow gastric emptying, which increases gastric metabolism of alcohol, thus decreasing rates of systemic alcohol absorption. The mechanisms of GIP agonists and alcohol use are infrequently described but thought to have significant overlap with the mechanisms of GLP-1 agonists (1). When compared to glycemic control and weight loss, dual GLP-1/GIP agonists (tirzepatide) have been shown to be more effective than GLP-1 agonists (semaglutide) (3). Whether dual GLP-1/GIP agonists are superior for alcohol use disorder is unknown.

Case Description: A woman in her 50’s with a history of severe AUD and obesity class I was managed in an ambulatory care setting. Before treatment, she consumed 20-40 standard drinks of alcohol daily. She was started on intramuscular (IM) naltrexone with a significant reduction in drinking to 4-8 drinks per day. Acamprosate was subsequently added without further reduction in drinking. Despite consistent adherence to her medications, counseling, and lifestyle modifications, she reported continued cravings and was unsuccessful in further alcohol reduction over a six-month period. One week before her monthly IM naltrexone injections, she needed to supplement her regimen with naltrexone 50 mg PO daily, otherwise she would return to drinking 20 drinks per day during that period.
Given her difficulty with sustained weight loss and concerns about metabolic health, tirzepatide, a dual GLP-1/GIP agonist, was initiated at a low dose (2.5 mg subcutaneously weekly) for weight management. Over the subsequent three months, the patient experienced a substantial reduction in alcohol cravings, particularly nighttime urges. She was able to reduce her quantity to less than four drinks per day with the addition of low-dose tirzepatide. She also no longer needed oral naltrexone shortly before her IM naltrexone dose. She attributed her alcohol reduction to improved satiety, reduced stress, and mild nausea with alcohol consumption. Her weight was reduced by 7 kg and her BMI decreased from 32 to 29.
She reported no adverse effects apart from mild nausea, which limited dose titration to only 2.5 mg weekly (the target dose for obesity is 15 mg). The patient maintained adherence to her naltrexone regimen and continued psychosocial therapy, which, combined with tirzepatide, appeared to synergistically improve her alcohol use.

Conclusion & Discussion: This case demonstrates the potential benefits of tirzepatide, a dual GLP-1/GIP receptor agonist, for treatment of AUD in a patient with concomitant obesity. This patient experienced alcohol reduction attributed to enhanced satiety, improved ability to resist alcohol-related cues, and reduced stress.
In addition to direct clinical outcomes, there are compelling personal and social reasons to consider utilizing these agents in patients with AUD. Some patients may have high motivation to address their underlying obesity, but may not be ready to reduce alcohol use. Yet, GLP-1/GIP receptor agonists may achieve both health benefits. Moreover, FDA-approved medications for AUD are difficult to access due to patient-perceived stigma and low prescribing rates in primary care. As GLP-1s and GLP-1/GIP receptor agonists continue to grow in popularity for obesity treatment and other indications, they may offer a less stigmatizing treatment option. Further research is needed to clarify their efficacy, risks, and optimal dosing for patients with alcohol use disorder. Cost-effectiveness research is also necessary.
For now, it seems reasonable to consider prioritizing these agents for FDA-approved indications when there is a concurrent alcohol use disorder.

References: (1) Lähteenvuo M, Tiihonen J, Solismaa A, Tanskanen A, Mittendorfer-Rutz E, Taipale H. Repurposing Semaglutide and Liraglutide for Alcohol Use Disorder. JAMA Psychiatry. 2025;82(1):94–98.
(2) Bruns Vi N, Tressler EH, Vendruscolo LF, Leggio L, Farokhnia M. IUPHAR review - Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target. Pharmacol Res. 2024 Sep;207:107312.
(3) Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., ... & Rubino, D. M. (2021). Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine, 384(11), 989-1002.
(4) Eberly LA, Yang L, Essien UR, et al. Racial, Ethnic, and Socioeconomic Inequities in Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Diabetes in the US. JAMA Health Forum. 2021;2(12):e214182.
(5) Le P, Rich JJ, Bernstein EY, Glass J, Gasoyan H, Back SE, Bui TC, Gina Ayers, Rothberg MB. Disparities in Treatment for Alcohol Use Disorder Among All of Us Participants. Am J Psychiatry. 2024 Nov 1;181(11):973-987.