Biochemical Role of the Endocannabinoid System in the Pathophysiology of Attention Deficit Hyperactivity Disorder: A Narrative Review and Future Directions.

The endocannabinoid system (ECS) is a lipid-derived signaling network composed of cannabinoid receptors, endogenous ligands, and metabolic enzymes. Through its widespread neuromodulatory functions, the ECS regulates dopaminergic, noradrenergic, and glutamatergic pathways that are critical for attention and behavioral control. Emerging evidence indicates that dysregulation of ECS components may contribute to the pathophysiology of attention deficit hyperactivity disorder (ADHD). This review synthesizes current biochemical evidence on ECS involvement in ADHD pathophysiology, with a focus on receptor signaling, ligand levels, and enzyme activity. By evaluating emerging molecular targets and highlighting gaps in mechanistic knowledge, it aims to guide future studies toward novel therapeutic strategies. A total of 11 preclinical and 2 clinical studies evaluating ECS-related biochemical alterations in ADHD were included. Preclinical research demonstrates alterations in ECS components linked to hyperactivity and impaired cognitive regulation. Although clinical research in this area remains limited, preliminary results are promising, supporting ECS-targeted approaches as novel therapeutic strategies for ADHD. Overall, current evidence suggests that dysregulation of the endocannabinoid system contributes to ADHD pathophysiology. Clarifying ECS-related biochemical mechanisms in ADHD may identify novel molecular targets, while advancing translational efforts toward ECS-based therapeutic strategies.