The CB1 receptor: linking impulsivity and substance use disorder

The cannabinoid receptor type 1 (CB1R) is the most widely expressed G protein-coupled receptor in the brain, with high concentrations in the basal ganglia, hippocampus, and cerebellum. Predominantly localized in presynaptic terminals, CB1R modulates synaptic transmission through retrograde endocannabinoid signaling. Its expression follows an ontogenetic trajectory, with region- and age-specific patterns that are particularly dynamic during adolescence. This developmental window is characterized by marked neuroplasticity and heightened impulsivity, a trait closely associated with increased vulnerability to substance use disorders (SUDs). While the prefrontal cortex has traditionally been viewed as the primary locus of self-control, growing evidence supports a broader regulatory network involving CB1R-rich subcortical structures. In particular, the hippocampus and cerebellum contribute to the modulation of impulsive behavior through their connectivity with prefrontal and limbic circuits. CB1R signaling in these regions influences decision-making, reward sensitivity, and response inhibition-all processes critical to the emergence of impulsive traits and drug-seeking behavior. This review integrates preclinical and clinical evidence to propose a distributed CB1R-regulated neurocircuit that underlies impulsivity and mediates risk for SUDs. We highlight adolescence as a critical period during which CB1R ontogeny may transiently unbalance inhibitory control systems, creating a neurobiological substrate for risky behaviors. Furthermore, we identify key knowledge gaps, including the underexplored ontogeny of CB1R in the cerebellum and its functional implications in addiction vulnerability. Understanding the dynamic role of CB1R across development and brain regions offers a more comprehensive model of impulsivity and its pathological escalation into substance use. This perspective may inform translational strategies targeting the endocannabinoid system for early prevention.