Navigating dose-effect complexities and challenges in cannabinoid therapy for aging-related neurobiological changes.

Growing evidence shows that brain aging is a time-dependent process, with very complex underlying mechanisms at molecular and cellular levels. The endocannabinoid system has emerged as a key regulator of brain homeostasis during aging, interfacing with neuroinflammation, neurogenesis, and blood-brain barrier integrity. However, the neurological impact of exogenous cannabinoids in the aging brain remains incompletely defined and often polarized between neuroprotective and neurodisruptive interpretations. This is a narrative review that critically synthesizes preclinical and clinical evidence on the age-dependent effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), with particular emphasis on dose, route of administration, and pharmacokinetic constraints imposed by aging. Available data indicate that THC exhibits a dual, dose-dependent profile, with low-dose exposure engaging adaptive or potentially neuroprotective mechanisms, whereas moderate to high doses, especially following parenteral administration, are associated with glial activation, neuroinflammatory signaling, and functional impairment. In contrast, CBD demonstrates a seemingly favorable neurological profile in aging models, characterized by anti-neuroinflammatory, antioxidant, and neuroprotective effects, largely independent of CB1R activation. Our findings support the idea that THC and THC predominant therapies may exert a dual effect in the aging brain of experimental models. A similar duality appears to emerge for CBD, particularly with respect to developmental effects, despite insufficient evidence. Collectively, these findings underscore the need for age-adapted, cannabinoid-specific dosing strategies and integrative experimental frameworks to accurately define the therapeutic potential and limitations of cannabinoids in age-associated neurological disorders.