Investigation of the effects of the glucagon-like peptide 1 receptor agonist semaglutide on cue-induced alcohol craving, striatal activation and dopamine function: a randomized-controlled longitudinal neuroimaging study

• Applicants: Professor Dr. Patrick Bach; Professor Dr. Gerhard Gründer
• Subject Area: Biological Psychiatry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577065715

Alcohol use disorder (AUD) is a leading cause for disability and death worldwide. Available treatments help only a minority of patients. In the search for new treatments the “brain-gut-axis” and the incretin hormone glucagon-like peptide 1 (GLP-1) recently received increasing attention, due to the promising effects in animal models of alcohol use disorder. It has been shown that the GLP-1 agonist semaglutide reduces alcohol use and relapse risk in animal models and reduces the severity and frequency of alcohol use in humans treated with semaglutide for their obesity. Based on the urgent need to identify novel targets and effective mechanisms for pharmacological treatments for alcohol use disorder and considering the promising animal data on GLP-1 agonists and observational data from patients with obesity, we aim to investigate the effects of the GLP-1 receptor agonist semaglutide on central neurocircuits and disease processes in the brain that underlie craving, relapse propensity and exacerbated alcohol use, to determine the neurobiological pathways underlying semaglutide’s effects and assess its potential for treating AUD. By applying an innovative combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) assessment alongside clinical and biomarker assessments in a randomized controlled longitudinal study design over 9 weeks with two study groups, we will determine the effects of semaglutide, compared to an active control condition, on cue-induced alcohol craving, cue-induced brain activation and dopamine release in the brain’s reward system that can be considered as core neuro-molecular processes underlying the development and maintenance of addictive behaviors. To this end, N=42 patients with alcohol use disorder, aged between 20 and 40 years, will be enrolled in a randomized controlled longitudinal study over nine weeks and receive either semaglutide or an active comparator treatment. Patients will participate in a first visit at baseline with a simultaneous combined [18F]-Desmethoxyfallypride PET and fMRI scan and clinical assessments and a second visit after nine weeks, when steady plasma levels of semaglutide can be expected, with again a simultaneous PET and fMRI scan. In parallel, alcohol craving and alcohol use will be assessed repeatedly during the nine-week study period. Through these means we will determine semaglutide’s effects on cue-induced alcohol craving and alcohol use, as well as on cue-induced brain activation (fMRI), dopamine D2/3 receptor availability (PET), and alcohol cue-induced dopamine release (PET) in the brain reward system and uncover the pathways through which semaglutide acts on addictive behavior and to determine its potential for treating AUD.

• DFG Programme: Research Grants