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  • Writer's pictureTravis Cesarone

New THC function targets a critical enzyme

After centuries of research, periodically plagued with prohibitive laws, research continues to uncover new tools in cannabis’s pharmacological treasure chest. A small series of cannabinoids, for example, facilitate a recently discovered mechanism with broad applications. This newly found function of two THC isomers targets a critical enzyme known as autotaxin (ATX.)

The enzyme helps liberate the signaling agent, lysophosphatidic acid (LPA), which expresses throughout the body and contributes to various conditions. Cells within a glaucoma patient’s eye, the scarred tissue of pulmonary fibrosis, or cancerous growths express autotaxin. This enzyme helps convert lysophosphatidylcholine (LPC) into LPA. Autotaxin effectively strips the choline group from LPC.

What are autotaxin and LPA?

A study by researchers from the European Molecular Biology Laboratory (EMBL) published in Life Science Alliance elucidated Delta-9-THC, THCa, and Delta-6(a)(10a)-THC as partial autotaxin inhibitors. Autotaxin’s metabolic end-product, LPA, contributes to cancer growth when left unchecked by normal regulatory processes. In contrast, their precursor molecule, LPC, helps immune cells capable of destroying unwanted cells find and eat their target.

A drug that inhibits autotaxin previously failed a Phase III Clinical Trial. In contrast to cannabinoids, though, current synthetic ligands act as full inhibitors of autotaxin. Due to the enzyme’s importance in healthy cells, full autotaxin (ATX) blockers are not clinically applicable.

A full outline of effects induced by any substance, especially phytocompounds like cannabinoids, is required to develop the most efficient therapies. Effects from the community of compounds in a whole-cannabis product cannot be understood without each component’s complete list of properties.

Photo courtesy of Eymery, McCarthy, Hausmann, 2023. | Life Science Alliance

Testing THC and autotaxin

Initially, only first-stage studies will describe THC’s interactions with autotaxin. Researchers from EMBL conducted experiments in test tubes, using two forms of ATX cultivated and then extracted from human embryonic kidney cells. The researchers subsequently exposed LPC to the two ATX isoforms.

With confirmation that D9-THC and D6(a)10(a)-THC inhibit ATX beta and gamma by around 50-70%, further studies will test the reaction in humans. Drug developers can alternatively use formulations with whole-cannabis remedies containing THCa, which inhibits the enzyme by slightly less than 50%.

What about CBD and the ECS?

According to the new study, cannabidiol (CBD) inhibits ATX but with drastically less efficacy than even THCa. As it turns out, though, molecular modifications enhance CBD’s ability to bind to this critical human enzyme. CBD-DM is an artificial cannabinoid ester with two additional methyl groups that help the cannabinoid bind to autotaxin.

ATX binding does not depend on cannabinoid receptors, no matter the agonist’s bias. Endocannabinoids —2-AG and anandamide — cannot fit inside the enzyme’s complex folds. But the amino acid sequence of LPA receptors is only 18-20% similar to CB1 or CB2 receptors. Instead, THC and CBD can bind directly to the ATX enzyme due to their unique shape. The study authors even hypothesize that autotaxin helps transport THC throughout the bloodstream.

How do cannabinoids block ATX?

Molecules that sit in a bioactive target site are called ligands. Downstream effects depend on how a ligand sits in a receptor. Computer modeling determined the cannabinoid’s microscopic position inside the two ATX isoforms.

D6a(10a)-THC binds to the newly discovered target with slightly enhanced binding efficacy. Differences between the natural and artificial isomers are visible in the study’s generated in-silico models. A bridge consisting of a water molecule stretches across D6a(10a) and ATX. A similar structure appears, however, to bind D9-THC to the enzyme.

Both isomers of THC in the experiment comprise of five-carbon side chain that slides inside a pocket folded within autotaxin’s structure. And the inward position of the double-bond in the isomer’s third ring allows for slightly more stable binding to ATX. Although, partial inhibition is optimal.

B) Properties within THC-ATX binding. (C) D9-THC and ATX bound in superposition
B) Properties within THC-ATX binding. (C) D9-THC and ATX bound in superposition. Photo courtesy of Eymery, McCarthy, Hausmann, 2023.

What does LPA do?

ATX catalysis converts LPC into LPA, a signaling agent that binds to several associated receptors. THC blocks LPA-receptor activity by partially inhibiting its enzymatic metabolism. Complete depletion of LPA is deleterious, yet partial control of the signaling agent might treat several ailments.

The study surmises that smoking THC-dominant cannabis efficiently targets LPA and ATX in saliva; a medium that strongly expresses the enzyme and signaling agent. Autotaxin is also found in acute quantities in the eye, and LPA contributes to glaucoma. Notably, full ATX inhibitors work against cancer, as described earlier. Cannabinoid medicines might apply to several other diseases if THC isomers can gently inhibit this newly discovered critical cancer function.

Let us in the comments if you are surprised they found a new function of THC with widespread health implications.


  1. Eymery MC, McCarthy AA, Hausmann J. Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling. Life Sci Alliance. 2023;6(2):e202201595. Published 2023 Jan 9. doi:10.26508/lsa.202201595

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