2. Academic Validation
  3. Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodents

Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodents

  • EBioMedicine. 2026 Feb:124:106119. doi: 10.1016/j.ebiom.2025.106119.
Christian E Edvardsson 1,  Louise Adermark 1,  Sam Gottlieb 2,  Safana Alfreji 1,  Thaynnam A Emous 3,  Yomna Gouda 1,  Annika Thorsell 4,  Milica Vujičić 5,  Cajsa Aranäs 1,  Anna Benrick 6,  Ingrid Wernstedt Asterholm 5,  Marcelo F Lopez 2,  Howard C Becker 2,  Elisabet Jerlhag 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 2 Charleston Alcohol Research Center, Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, USA.
  • 3 Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Psychobiology, Paulista School of Medicine (EPM), Federal University of São Paulo (UNIFESP), Sao Paulo, Brazil.
  • 4 Proteomics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 5 Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 6 Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; School of Health Sciences, University of Skövde, Skövde, Sweden.
  • 7 Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: [email protected].
PMID: 41506148 DOI: 10.1016/j.ebiom.2025.106119
Abstract

Background: Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry.

Methods: Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioural assays (locomotor activity and conditioned place preference), alcohol intake paradigms (intermittent access two-bottle choice, drinking in the dark and the alcohol deprivation effect), and molecular analyses (microdialysis, electrophysiology and proteomics) in rodents.

Findings: First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release (P < 0.001). Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption (P < 0.001), prevented binge (P < 0.01) and relapse-like drinking (P < 0.001), and maintained efficacy during repeated administration (P < 0.001). Finally, tirzepatide induced sustained synaptic depression in the lateral septum (P < 0.05) and further altered histone regulatory proteins in this region (P < 0.05), suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight (P < 0.001), adipose tissue mass (P < 0.01), hepatic triglycerides (P < 0.01) and circulating pro-inflammatory cytokines (P < 0.05).

Interpretation: Together, our findings suggest tirzepatide modulates alcohol-related behaviours through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatide's established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications.

Funding: The study is supported by grants from the Swedish Research Council (2023-2600, 2020-00559, 2020-01463, 2024-03054), LUA/ALF (723941 & 1005347) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), National Institutes of Health (NIH) (P50 AA010761 & U01 AA014095), U.S. Department of Veterans Affairs Office of Research and Development (BLR&D I01BX000813 & IK6BX006299), Herbert & Karin Jacobssons Foundation (2024-Forskning-225), Adlerbertska Research Foundation (2024-791), Wilhelm & Martina Lundgren's Research Foundation (2024-SA-4698), Åke Wibergs Foundation (M24-0216), Swedish Diabetes Foundation (DIA 2024-898) and Mary von Sydow Foundation (2024-36 & 2024-185). Thaynnam A Emous held an international internship scholarship from the São Paulo Research Foundation (FAPESP), Process Number #2023/18470-5, while conducting research at the University of Gothenburg.

Keywords

Addiction; Alcohol; Dopamine; Ethanol; GIP; GLP-1; Reward.

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