Modulation of the Incretin Axis (GLP-1/GIP) in Behavioral Compulsions: A New Neuropsychopharmacology Frontier

Background Behavioral compulsions unrelated to substance use, including compulsive buying disorder and compulsive sexual behavior disorder, share core neurobiological mechanisms with addictions, particularly mesolimbic dopaminergic dysregulation and impaired prefrontal inhibitory control. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert central effects on reward circuitry, and tirzepatide, a dual GLP-1/GIP receptor agonist, may enhance these effects through combined dopaminergic modulation and synaptic plasticity mechanisms involving intracellular signaling pathways. Objective To review the role of the GLP-1/GIP axis, with emphasis on tirzepatide, in modulating non-alimentary behavioral compulsions, integrating neurobiological and clinical evidence, and to present two illustrative case reports. Methods Narrative review of PubMed/MEDLINE-indexed literature, including preclinical, clinical, and real-world evidence through 2026. Two original cases are presented: one involving compulsive buying and one compulsive sexual behavior, both treated with tirzepatide without changes in psychopharmacological or psychotherapeutic management. Results GLP-1RAs modulate mesolimbic circuits, reducing reward salience and behavioral urgency. Preclinical studies show decreased reward-seeking and relapse. Human data demonstrate electrophysiological modulation of the nucleus accumbens following tirzepatide exposure. Clinically, a obese female patient reported reduced compulsive buying after four weeks, while a male patient undergoing psychoanalytic therapy exhibited decreased intrusive sexual thoughts and improved impulse control. However, potential risks include compulsive symptom substitution, reduced hedonic tone, and behavioral instability with nonstandard dosing. Conclusions Tirzepatide may represent a novel transdiagnostic approach to behavioral compulsions, though controlled studies are needed to confirm efficacy and safety.