Phytocannabinoids in Central Nervous System Disorders and Frameworks for Cellular Stress Adaptation: A Comprehensive Review

Abstract Background Central nervous system (CNS) disorders arise from many initiating factors, yet they repeatedly culminate in shared cellular stress-response programs. We organize this phenomenon by defining a comprehensive stress adaptation network as a set of coupled sensing and eff ector loops spanning oxidative–mitochondrial control, neuroimmune regulation, excitability regulation, and proteostasis maintenance. Methods We review how two major phytocannabinoids, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), modulate these adaptive modules. CBD is non-intoxicating and acts as a pleiotropic modulator that shapes stress-linked signaling through diverse molecular targets, including cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), and various non-cannabinoid receptors, whereas THC is an intoxicating partial agonist at CB1/CB2, with neurobehavioral effects that depend strongly on state and dose. Results Clinical evidence is strongest for purifi ed CBD in epilepsy and for standardized formulations of purified THC and CBD combinations in multiple sclerosis (MS) spasticity, while evidence in other neurodegenerative and sleepdisorders remains preliminary. Across these four adaptive domains, cannabinoids can alter redox tone, glial stateprograms, circuit stability, and autophagy or unfolded protein response (UPR) signaling. However, many mechanisticclaims are based mainly on preclinical systems and may vary with exposure, cell type, and disease stage. Conclusion We highlight translational priorities that include standardized chemotypes and formulations, exposure–response biomarkers, cell-type-specific biomarkers and functional endpoints, and trial designs that separate symptomatic effects from disease modification. Graphical Abstract