Gambling Disorder as a Behaviorally Driven Systemic Medical Condition: From Reward Circuitry to Multi-System...

Historically framed as a behavioral addiction, gambling disorder (GD) has had its somatic dimension neglected by standard clinical evaluation. This is a narrative, hypothesis-generating review focusing on the somatic aspects of GD. Cross-sectional and prospective evidence increasingly shows a somatic phenotype distributed across four axes: cardiovascular (hypertension, angina, stroke, acute stress-induced cardiac events), metabolic (obesity, type 2 diabetes, chronic liver disease), sleep-related (insomnia, poor sleep quality, daytime sleepiness), and-as an emerging and insufficiently characterized dimension-neurological (clustering with seizures and frontal lobe epilepsy). Three candidate biological systems may translate this exposure into multi-system physiology: (i) a hyperreactive mesostriatal reward circuit hypothesized to sustain a behavioral cluster of smoking, hazardous alcohol use, low physical activity, and unhealthy diet; (ii) an integrated stress response postulated to shift from acute hyperreactivity to chronic basal cortisol blunting and reduced vagal tone; and (iii) putative alterations in peripheral neurotrophic signaling and frontal-callosal structure, marked by elevated peripheral brain-derived neurotrophic factor and by frontal-callosal white-matter alterations-with cumulative allostatic load serving as a conceptual integrating frame. We propose that GD can be a behaviorally driven systemic medical condition, warranting internal medicine involvement alongside addiction psychiatry. Within this framework, glucagon-like peptide-1 receptor agonists emerge as an exploratory therapeutic hypothesis warranting dedicated evaluation in GD, given their action on the mesolimbic reward substrate and phase 3 evidence in adjacent cardiometabolic, hepatic, and sleep conditions.