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

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.