Can You Pass the Acid Test? Critical Review and Novel Therapeutic Perspectives of Δ9-Tetrahydrocannabinolic Acid A

Abstract

Δ⁹-tetrahydrocannabinolic acid A (THCA-A) is the acidic precursor of Δ⁹-tetrahydrocannabinol (THC), the main psychoactive compound found in Cannabis sativa. THCA-A is biosynthesized and accumulated in glandular trichomes present on flowers and leaves, where it serves protective functions and can represent up to 90% of the total THC contained in the plant. THCA-A slowly decarboxylates to form THC during storage and fermentation and can further degrade to cannabinol. Decarboxylation also occurs rapidly during baking of edibles, smoking, or vaporizing, the most common ways in which the general population consumes Cannabis. Contrary to THC, THCA-A does not elicit psychoactive effects in humans and, perhaps for this reason, its pharmacological value is often neglected. In fact, many studies use the term "THCA" to refer indistinctly to several acid derivatives of THC. Despite this perception, many in vitro studies seem to indicate that THCA-A interacts with a number of molecular targets and displays a robust pharmacological profile that includes potential anti-inflammatory, immunomodulatory, neuroprotective, and antineoplastic properties. Moreover, the few in vivo studies performed with THCA-A indicate that this compound exerts pharmacological actions in rodents, likely by engaging type-1 cannabinoid (CB1) receptors. Although these findings may seem counterintuitive due to the lack of cannabinoid-related psychoactivity, a careful perusal of the available literature yields a plausible explanation to this conundrum and points toward novel therapeutic perspectives for raw, unheated Cannabis preparations in humans.

Keywords: THC; THC-COOH; THCA-A.

FIG. 1.

Synthetic and metabolic routes for THCA-A. THCA-A (1) is produced by THCA synthase from its precursor, CBGA, and stored in Cannabis glandular trichomes. THCA-A decarboxylates to form THC, which can further degrade to cannabinol. Other acid derivatives found in the plant are THCA-B (2), the minor isomer of THCA-A, and the carboxylic derivative of THC (4). Conversion of THCA-A into THC does not occur in vivo. Rather, both compounds undergo similar metabolic pathways, transforming first into the 11-hydroxyl intermediate and further oxidizing to the 11-carboxylic metabolites (THCA-A-COOH and 3). CBGA, cannabigerolic acid; THC, tetrahydrocannabinol; THCA-A, tetrahydrocannabinolic acid A.