Cannabinoid Biosynthesis: A Closer Look at How THC and CBD are Created

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The dynamics of how cannabis works in medicinal and psychoactive ways have become more clear as researchers gain additional insight into what makes cannabis so special. It is known that cannabinoids hold the key to much of the plant’s operations, and while there is still much to learn about the biosynthesis of cannabinoids, scientists now have a solid grasp on how they are formed within the plant and how some of them affect the human body.

Cannabinoids are synthesized through a common pathway in trichomes and are most prevalent in capitate-stalked trichomes, the largest of the three types of glandular trichomes. Trichomes look like tiny shiny hairs and are found on the surface of cannabis buds. Beyond where cannabinoids develop, they also produce the terpenes and flavonoids that make cannabis so distinctive.

The Biosynthesis of Cannabinoids Within Cannabis

During flowering, cannabinoids are formed through enzymatic biosynthesis in the glandular trichomes. To achieve this, precursor—or parent—compounds are needed.

The first precursor compound, Geranyl diphosphate (GPP), is generated via the mevalonate-dependent isoprenoid (MEP) pathway. GPP is a parent compound to all cannabinoids and monoterpenes.

Olivetolic acid (OA) and/or Divarinic Acid (DA) are produced through fatty acid biosynthesis from hexanoyl-CoA and butyl-CoA, respectively. OA is the other parent compound to pentyl (5-carbon) cannabinoid acids like CBGA, THCA, CBCA and CBDA. DA is the other parent compound to propyl (3-carbon) cannabinoid acids like CBGVA, THCVA, CBCVA and CBDVA. Both pentyl and propyl cannabinoid acids share the common parent of Geranyl diphosphate (GPP) – CBGA and CBGVA can be thought of as half-siblings.

Once those precursor compounds are formed, they get converted into cannabinoids when specific enzymes act as catalysts. This transforms both the precursor compounds into the mother cannabinoids and the mother cannabinoids into other cannabinoids. The enzyme cannabigerolic acid synthase (CBGAS) will convert GPP and OA into CBGA, and/or GPP and DA into CBGVA, forming the first “mother” cannabinoid. Similarly, the enzymes THCAS, CBDAS, and CBCAS will convert CBGA and CBGVA into other cannabinoids:

Most of the cannabinoids in fresh cannabis flower are in their acid forms through the enzymatic biosynthesis process explained above. Additional changes in cannabinoids can happen only when exposed to things like heat, radiation, oxidation, decarboxylation and isomerization.

The Final Step: Decarboxylation 

Cannabis decarboxylation is when acidic cannabinoids are exposed to heat and their molecular structure changes as they are converted into their neutral forms. When decarboxylated, the acids lose one carboxyl group (-COOH) as carbon dioxide while retaining one hydrogen atom.

Decarboxylation is key to activating the psychoactive and potentially therapeutic compounds found in cannabis like THC and CBD. For example: THCA converts to D9THC, CBGA converts to CBG, CBGVA to CBGV, THCVA to THCV, etc. When smoking cannabis, the heat from the fire prompts decarboxylation. For things like edibles or tinctures, compounds are activated via heat prior to being incorporated into the products.

There can also be breakdowns through oxidation. Neutral cannabinoids can degrade into other cannabinoids, like D9THC into CBN. Similarly, with isomerization, cannabinoids can also be transformed into other isomers of that cannabinoid. The best example is probably CBD conversion into D8THC.

The Need for Cannabinoid Research

While much is known about the importance of CBGA and CBGVA in the creation of all other cannabinoids at the molecular level, the need for increased clinical trial based research continues to be paramount. Some cannabinoids, like the propyl cannabinoids (aka the varins) and CBC, are not widely produced, so understanding their potential therapeutic effects is sadly limited.