Effects of tirzepatide on brain dopaminergic function in alcohol use disorder: protocol for a randomized, double-blind, crossover PET/MRI study

Abstract Background Alcohol use disorder (AUD) is a leading cause of preventable morbidity and mortality, yet currently approved pharmacotherapies have only modest efficacy. Emerging preclinical, clinical, and pharmacoepidemiologic evidence suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may reduce alcohol consumption by modulating dopamine brain reward pathways and brain–body communication. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, has demonstrated substantial metabolic benefits, but its effects on human brain function and dopamine neurotransmission in AUD remain unknown. Methods This single-center, phase 1b, randomized, double-blind, placebo-controlled crossover trial comprises a PET reproducibility study in healthy volunteers and a mechanistic study enrolling 44 healthy volunteers and 44 individuals with mild-to-moderate AUD. Participants receive tirzepatide and placebo in randomized sequence. Simultaneous PET/MRI will quantify dopamine D1 receptor availability (with [11 C]NNC-112), dopamine D2/D3 receptor availability and methylphenidate-induced dopamine release using [11 C]raclopride; resting-state functional connectivity, and functional responses to alcohol- and food- cues. Behavioral assessments include measures of alcohol craving and consumption, food craving, mood, cognition, sleep, locomotor activity, and withdrawal symptoms. Discussion This study is the first to evaluate the effects of tirzepatide on human dopaminergic neurotransmission in AUD using integrated PET/MRI. We hypothesize that tirzepatide will modulate striatal dopamine signaling and normalize corticostriatal reward and executive-control networks, with associated reductions in alcohol craving and consumption. By integrating molecular and functional neuroimaging with behavioral phenotyping, this study will provide mechanistic evidence on how dual GIP/GLP-1 receptor agonism influences addiction-related brain circuits and will inform the development of incretin-based therapies for AUD. Trial registration ClinicalTrials.gov: NCT07559500.