The Interaction of Stomach Acid, Blood pH, and Liver Metabolism with Acidic Cannabinoids: Partial Decarboxylation, Metabolic Transformation, and Physiological Implications

Acidic cannabinoids (e.g., THCA, CBDA) are the dominant phytoconstituents in Cannabis Sativa and serve as precursors to neutral forms (THC, CBD) via decarboxylation. This is the third work in an integrated series exploring how dietary cannabis inputs interact with the Endocannabinoid System (ECS) pathways. This paper examines the role of physiological environments—specifically stomach acidity, blood pH, and hepatic metabolism—in determining the fate and bioavailability of ingested acidic cannabinoids.[Approach & Findings] Integrating organic chemistry and pharmacokinetics, the study confirms that gastric conditions (pH 1.5–3.5, 37°C) induce a minor, diet-dependent partial decarboxylation ($\leq 5-10\%$) due to the low activation energy at physiological temperature and poor solubility. Upon absorption, systemic blood pH (7.35–7.45) stabilizes the acidic cannabinoids, which exist primarily as non-decarboxylating carboxylate anions (>99% ionized). The hepatic first-pass metabolism then primarily processes the compounds through CYP and UGT enzymes, leading to conjugated metabolites (e.g., THCA-glucuronide) rather than extensive decarboxylation.[Microbiome & Implication] Crucially, the gut microbiome is identified as a secondary modulator, utilizing microbial decarboxylases and $\beta$-glucuronidases to potentially recycle cannabinoids via enterohepatic circulation, thus impacting systemic exposure and therapeutic effects. This comprehensive analysis integrates chemical kinetics and physiological variables, showing that acidic cannabinoids are delivered largely intact to modulate the ECS directly (e.g., THCA activating TRPA1; CBDA inhibiting FAAH).[Conclusion] The minor in vivo conversion rate means the therapeutic potential of ingested acidic cannabinoids is shaped more by direct ECS interaction and microbial/metabolic processing than by thermal decarboxylation.