The Cannabis plant produces cannabinoids in their acidic form —as anyone who has tasted a freshly pruned bud can attest. In recent years, doctors and patients have become very interested in THC Acid, which is said to be non-psychoactive while exerting anti-seizure effects and other medical benefits. Two isomers of THC Acid  have been identified —THCA-A and THCA-B.

Cannabis primarily biosynthesizes THCA-A, and this isomer has been the focus of most pharmacological studies,” Dr. John McPartland and pharmacologists from New Zealand note in a paper published in Cannabis and Cannabinoid Research. “Conversely, THCA-B has greater stability and crystalizes more readily.”  THCA-B is the molecule used in computer modeling studies of cannabinoid receptors.

Chemical Structures (from left) of THC, THCA-A, and THCA-B

Researchers investigating THCA’s mechanism of action are hindered by how readily it transforms into neutral THC by loss of a carboxyl group (COOH). This decarboxylation occurs not just when THCA is smoked or baked,  but even at room temperature. McPartland et al report that the THCA standard provided them by Cayman Chemical —supposedly 100% pure— turned out to be 2% THC.

Dr. Guillermo Moreno-Sanz, a researcher at UC Irvine School of Medicine, had previously published  a paper in Cannabis and Cannabinoid Research (and given a talk to the Society of Cannabis Clinicians) contending that THCA  is non-psychoactive because it does not cross the blood-brain barrier. Moreno-Sanz concluded, citing two studies, that THCA exerts its effects by binding, albeit weakly, to CB1 and CB2 receptors in peripheral areas of the body.

McPartland, a scientist and doctor of osteopathy affiliated with GW Pharmaceuticals and the University of Vermont’s Faculty of Medicine, did not understand how THCA could exert anti-seizure effects if it didn’t enter the brain. He reviewed the literature and found —in addition to the two studies cited by Moreno-Sanz that showed weak binding of THCA at CB1 and CB2— two studies that showed no binding at all.

To resolve the discrepancy, Michelle Glass and colleagues at the University of Auckland conducted gold-standard studies to measure the rates at which THCA-A actually binds to and activates CB1 and CB2 receptors in vitro. Affinity measurements involve tagging the receptors with a radioactive synthetic agonist (tritiated CP55,940). Glass found that adding THCA-A dislodged only a minuscule amount of  the synthetic agonist; but adding THC dislodged a large amount. Specifically, the binding affinity of THC was  62 times greater than THCA-A  at the CB1 receptor, and 125 times greater at the CB2 receptor.

The investigators cited by Moreno-Sanz who found that THCA-A bound to and activated CB1 and CB2, did not assess the purity of their THCA-A reagent by chromatography,  whereas the investigators who found no binding or effect used HPLC to confirm what they were testing.

McPartland et al conclude that “THCA-A has little affinity or efficacy at CB1 or CB2.” Clinical effects attributed to THCA-A are evidently effects of THC!

McPartland discussed with Dr. Raphael Mechoulam the difficulty of studying the pharmacology of THCA-A. Mechoulam confirmed that it was almost impossible to work with: “How can anybody do an experiment if the compound likes to convert into something else just by sitting around, and the ‘something else’ has all kinds of activities?” Mechoulam called THCA-A “a diabolical molecule” from the researchers’ point of view.


The authors hypothesize that THCA products that are widely used and reportedly efficacious may contain THCA-B, “which demonstrates greater thermal stability than THCA-A, so it may be worth investigating.”

Cayman Chemical does not (yet) sell a standard for THCA-B.. —Fred Gardner