Neuropharmacology of Cannabinoids: A Comprehensive Review of Preclinical and Clinical Evidence for Hemp-Derived Extracts and Active Compounds

Cannabis sativa contains more than 120 phytocannabinoids, with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the best characterized. This review synthesizes preclinical and clinical evidence on hemp-derived extracts, cannabinoids, and active compounds. THC primarily acts as a partial agonist at cannabinoid receptor type 1 (CB1) and type 2 (CB2), producing psychoactive, appetite-stimulating, antiemetic, and analgesic effects. CBD is non-intoxicating and has a multimodal profile involving CB1 negative allosteric modulation, CB2 inverse agonism or antagonism, inhibition of anandamide inactivation, and activity at 5-HT1A receptors, transient receptor potential channels, GPR55, and peroxisome proliferator-activated receptor gamma. Preclinical models of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, epilepsy, and pain support anti-inflammatory, antioxidant, anti-excitotoxic, and glial-modulating mechanisms, but clinical translation remains uneven. The strongest evidence supports FDA-approved cannabidiol for Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex, and THC-based agents for refractory chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Moderate-certainty evidence supports nabiximols for multiple sclerosis spasticity and small benefits in selected chronic neuropathic pain populations. Evidence remains insufficient or negative for acute pain, insomnia, most psychiatric disorders, and many promoted indications. Key risks include cannabis use disorder, cognitive and psychiatric effects, cardiovascular events, sedation, high-dose CBD hepatotoxicity, and drug interactions. Rigorous, long-term, product-standardized trials are needed.