An Agathokakological Tale of Δ9-THC: Exploration of Possible Biological Targets

Abstract

∆9-Tetrahydrocannabinol (∆9-THC), the active phytocannabinoid in cannabis, is virtual-ly an adjunct to the endogenous endocannabinoid signaling system. By interacting with G-protein-coupled receptors CB1 and CB2, ∆9-THC affects peripheral and central circulation by lowering sympathetic activity, altering gene expression, cell proliferation, and differentiation, decreasing leukocyte migration, modulating neurotransmitter release, thereby modulating cardiovascular func-tioning, tumorigenesis, immune responses, behavioral and locomotory activities. ∆9-THC effectively suppresses chemotherapy-induced vomiting, retards malignant tumor growth, inhibits metasta-sis, and promotes apoptosis. Other mechanisms involved are targeting cell cycle at the G2-M phase in human breast cancer, downregulation of E2F transcription factor 1 (E2F1) in human glioblasto-ma multiforme, and stimulation of ER stress-induced autophagy. ∆9-THC also plays a role in ame-liorating neuroinflammation, excitotoxicity, neuroplasticity, trauma, and stroke and is associated with reliving childhood epilepsy, brain trauma, and neurodegenerative diseases. ∆9-THC via CB1 receptors affects nociception, emotion, memory, and reduces neuronal excitability and excitotoxici-ty in epilepsy. It also increases renal blood flow, reduces intraocular pressure via a sympathetic pathway, and modulates hormonal release, thereby decreasing the reproductive function and increasing glucose metabolism. Versatile medical marijuana has stimulated abundant research demon-strating substantial therapeutic promise, suggesting the possibilities of first-in-class drugs in diverse therapeutic segments. This review represents the current pharmacological status of the phyto-cannabinoid, ∆9-THC, and synthetic analogs in cancer, cardiovascular, and neurodegenerative disor-ders.