(41) Semaglutide as a Potential Breakthrough in Treatment of Alcohol Use Disorder

Background & Introduction: Alcohol Use Disorder (AUD) is a chronic, relapsing medical condition that significantly contributes to mortality and morbidity. Although it accounts for 4% of the global disease burden, very limited pharmacotherapeutic treatments are currently available. Recently, several preclinical and early human studies have provided some evidence supporting the beneficial effects of Semaglutide, a GLP-1 RA (Glucagon like peptide-1 receptor agonist), in the reduction of alcohol consumption and alcohol-related behaviors. Preclinical studies on animals have indicated that semaglutide can reduce alcohol intake and prevent relapse like drinking by modulating the reward center (Nucleus accumbens), a brain region identified as the key region implicated in the development of addictive behaviors [7,8].

Methods: The purpose of this review was to map literature published on the impact of semaglutide on alcohol consumption and alcohol-related behaviors as well as to assess evidence available regarding the safety of using semaglutide in AUD. A systematic literature search was conducted to identify all the articles addressing the key concepts of AUD and the use of Semaglutide available in the literature. A comprehensive search was conducted in May 2024 using MEDLINE-indexed database platforms of PubMed, Ovid MEDLINE, Cochrane CENTRAL, PsychINFO, and Embase. Further resources within Elsevier, EBSCO, Web of Science, and Google Scholar were navigated for relevant research. We used both medical subject heading (MesH) terms and text-word terms that combine terms related to Alcohol Use disorder and Semaglutide. Due to limited hits, no restrictions were placed on the publication date and language of the search. Grey literature was searched and reviewed from ClinicalTrials.gov, WHO’s International Clinical Trials Registry Platform. In addition, we also screened the reference and citation lists of relevant articles. An additional search of PubMed and Embase (up to June 2024) was conducted to retrieve new articles.
Preclinical studies eliciting the efficacy of semaglutide in animals were also included in the literature search.

Results: Six human studies reviewed demonstrated a positive impact of Semaglutide on reducing alcohol consumption and related behaviors. A retrospective analysis of 83,825 individuals with obesity showed a 50%-56% lower risk of alcohol use disorder (AUD) incidence and recurrence in the Semaglutide group over 12 months compared to other anti-obesity medications[1]. Similar outcomes were observed in an analysis of 598,803 patients with Type 2 diabetes over a 3-year follow-up [1]. A nationwide study further confirmed this, showing a reduced risk of alcohol-related events with Semaglutide (HR = 0.46, 95% CI: 0.24–0.86) compared to Dipeptidyl Peptidase-4 (DPP-4) inhibitors[2]. Social media analysis of 812 posts from Semaglutide users reported 28.5% decreased alcohol interest, 10.4% reduced cravings, 31% less alcohol consumption, and 10.8% abstinence initiation[3]. Another analysis of 1,580 alcohol-related posts from 962 Semaglutide or Tirzepatide users showed 71.7% reporting reduced cravings and negative alcohol effects[4]. Additionally, as part of the same study, a remote survey of 153 participants with obesity using Semaglutide or Tirzepatide, corroborated similar findings, with the Tirzepatide group showing a greater reduction in odds of binge drinking than the Semaglutide group4. Similar improvement in AUD symptoms was observed in a case series of six patients treated with Semaglutide, all showed improvements in AUD symptoms, as evidenced by lower AUDIT(Alcohol Use Disorder Identification Test) scores (a mean decrease of 9.5 points, P < .001)[5].
No significant safety concerns were reported, except for the patient with a history of regular alcohol use who developed exocrine pancreatic insufficiency after three years of Semaglutide use for obesity[6].
Research on animal models supported the findings reported in human studies [7,8].

Conclusion & Discussion: The findings across all the studies, consistently indicated that semaglutide might be a promising treatment for AUD. Wium-Anderson et al. reported a significant reduction in alcohol-related events compared to DPP-4 inhibitors, while Quoddo et al. found Tirzepatide to be even more effective in reducing binge drinking [2,4]. Both medications also reduced the stimulative and sedative effects of alcohol intoxication. Furthermore, semaglutide showed a stronger association with reducing recurrent AUD in patients with obesity than those with type 2 diabetes (HR of 0.53 vs. 0.74)[1].
The case of exocrine pancreatic insufficiency observed in a patient treated with semaglutide for obesity raises concerns regarding the potential interaction between semaglutide, alcohol consumption, and pancreatic function[6].
The findings from these studies were limited to populations with diabetes and obesity, and thus may not be generalizable to AUD due to the disorder’s heterogeneity in severity, demographics, and comorbidities. Furthermore, the dosing regimens used for diabetes and obesity may not be optimal for AUD treatment. The reliance on self-reported data from social media studies introduces potential selection bias. These limitations underscore the need for robust evidence from randomized controlled trials to validate the efficacy and safety of semaglutide in AUD populations.

References: 1. Wang, W., Volkow, N. D., Berger, N. A., Davis, P. B., Kaelber, D. C., & Xu, R. (2024). Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-48780-6
2. Ida Kim Wium‐Andersen, Marie Kim Wium‐Andersen, Anders Fink‐Jensen, Jørgen Rungby, Martin Balslev Jørgensen, & Osler, M. (2022). Use of GLP‐1 receptor agonists and subsequent risk of alcohol‐related events. A nationwide register‐based cohort and self‐controlled case series study. Basic & Clinical Pharmacology & Toxicology, 131(5), 372–379. https://doi.org/10.1111/bcpt.13776
3. Bremmer, M. P., & Hendershot, C. S. (2023). Social media as pharmacovigilance: The potential for patient reports to inform clinical research on glucagon-like peptide 1 (GLP-1) receptor agonists for substance use disorders. Journal of Studies on Alcohol and Drugs. https://doi.org/10.15288/jsad.23-00318
4. Quddos, F., Hubshman, Z., Tegge, A. N., Sane, D. C., Martı́E., Kablinger, A. S., Gatchalian, K. M., Kelly, A. L., DiFeliceantonio, A. G., & Bickel, W. K. (2023). Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity. Scientific Reports, 13(1). https://doi.org/10.1038/s41598-023-48267-2
5. Richards, J. R., Dorand, M. F., Royal, K., Mnajjed, L., Paszkowiak, M., & Simmons, W. K. (2023). Significant Decrease in Alcohol Use Disorder Symptoms Secondary to Semaglutide Therapy for Weight Loss: A Case Series. The Journal of Clinical Psychiatry, 85(1), 50515. https://doi.org/10.4088/JCP.23m15068
6. Junior, Eloi, N., Aurélio, M., & Freire, S. (2024). Exocrine Pancreatic Insufficiency During the Use of Semaglutide: A Case Report. Curēus. https://doi.org/10.7759/cureus.55549
7. Chuong, V., Farokhnia, M., Khom, S., Pince, C. L., Elvig, S. K., Vlkolinsky, R., Marchette, R. C. N., Koob, G. F., Roberto, M., Vendruscolo, L. F., & Leggio, L. (2023). The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. JCI Insight. https://doi.org/10.1172/jci.insight.170671
8. Fink-Jensen, A., Wortwein,G.,Klausen, M. K.,Holst, J.J.,Hartmann, B., Thomsen, M., Ptito, M., Beierschmitt, A., &Palmour, R.M. (2024). Effect of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide on alcohol consumption in alcohol-preferring male vervet monkeys. Psychopharmacology/Psychopharmacologia. https://doi.org/10.1007/s00213-024-06637-2