Abstract            Volume:14  Issue-5  Year-2026         Original Research Articles

Online ISSN : 2347 - 3215 Issues : 12 per year Publisher : Excellent Publishers Email : editorijcret@gmail.com

Few areas of contemporary pharmacology have evolved as rapidly as the cannabinoid field. The cloning of cannabinoid receptors CB1 and CB2 in the early 1990s, the discovery of anandamide and 2-arachidonoylglycerol as endogenous ligands, and the characterization of the biosynthetic and degradative enzymes diacylglycerol lipase, N-acyl phosphatidylethanolamine phospholipase D, fatty acid amide hydrolase, and monoacylglycerol lipase have collectively defined the endocannabinoid system (ECS) as a pervasive lipid-signalling network modulating synaptic transmission, immune function, energy homeostasis, and pain. Cryo-electron microscopy structures of agonist-bound CB1 and CB2 receptor–G-protein complexes published since 2016 have illuminated activation conformations, biased agonism, and allosteric pockets, opening new avenues for selective drug design. The non-psychoactive phytocannabinoid cannabidiol has been approved for Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex, validating phytocannabinoid pharmacology at the regulatory level. This review provides an in-depth account of cannabinoid pharmacology with a focus on molecular mechanisms: receptor structure and signalling, endocannabinoid biosynthesis and turnover, the pleiotropic targets of cannabidiol, retrograde synaptic signalling, biased agonism, and allosteric modulation. Therapeutic applications in epilepsy, multiple sclerosis spasticity, chronic pain, chemotherapy-induced nausea, neurodegenerative and psychiatric disorders, and inflammation are reviewed alongside pharmacokinetics, drug–drug interactions, and adverse effects. Newer insights into the endocannabidiome, gut–brain endocannabinoid signalling, genetic polymorphisms of FAAH and CNR1, cannabinoid–microbiome interactions, and the role of CB2 in neuroinflammation are highlighted, and the contemporary drug-development pipeline of peripheral CB1 antagonists, selective CB2 agonists, MAGL/FAAH inhibitors, allosteric modulators, and cannabinoid nanoformulations is discussed.

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