The Mapping of Physiological Conversion Pathways from the Major Acidic Cannabinoids

The acidic cannabinoids tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabigerolic acid (CBGA) serve as primary precursors in cannabis phytochemistry. They undergo physiological conversion through decarboxylation, isomerization, degradation, and hepatic metabolism, yielding diverse neutral cannabinoids and phase I/II metabolites. Key Conversion PathwaysTHCA → Primarily converts to Δ9-THC (with minor Δ8-THC, Δ10-THC, THCV if varin precursors present, CBN via oxidation, and traces of CBL/CBT).Active metabolites include 11-OH-THC (psychoactive), various hydroxy-THC forms, and oxidated derivatives; inactive ones feature THC-COOH (primary urinary marker), glucuronides, and carboxy analogs. CBDA → Yields CBD (with traces of CBDV, CBE, CBT-C).Active metabolites encompass 7-OH-CBD (major, equipotent to CBD), other positional hydroxy-CBDs, and oxidated forms; inactive ones include 7-COOH-CBD (dominant circulating metabolite), glucuronides, and carboxy variants. CBGA → Produces CBG (with traces of CBGV, CBC, CBGM, CBCV).Active metabolites involve positional hydroxy-CBGs (e.g., 6-OH-CBG) and related CBC hydroxy forms; inactive ones feature 6-COOH-CBG, glucuronides, and carboxy analogs. Hepatic cytochrome P450 enzymes (e.g., CYP2C9, CYP3A4) drive hydroxylation and oxidation, followed by glucuronidation for excretion. Minor pathways include epoxidation, cyclization, and side-chain modifications, often speculative or trace. As the second in a three-part series on cannabis dietary inputs, this review maps these conversion cascades, highlighting implications for endocannabinoid system (ECS) modulation and physiological outcomes from whole-plant consumption. Integration with companion works on hemp seed nutrition and ECS mechanisms positions acidic cannabinoids as key contributors to homeostasis, warranting targeted clinical investigation.