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How is Cannabidiol made in hemp?

Cannabidiol in hemp

The amount of cannabidiol (CBD) or tetrahydrocannabinol (THC) a cannabis product contains is vitally important both for health and for legal reasons. For CBD oil producers to supply a product high in Cannabidiol (CBD) and only trace levels of THC, they must ensure that they have chosen cannabis plants with good CBD genetics. In this article we are going to explore just what that means by tracing back just where CBD and THC come from, and the mechanisms by which they are formed.

hemp oil on rocks

Hemp or cannabis?

Hemp is no different from the cannabis plant, it is just a term which encompasses certain strains of cannabis plants. Hemp plants are just cannabis strains which produce very low levels of THC, and as a result can be grown legally in many countries around the world. Due to the low levels of THC (tetrahydrocannabinol) in hemp, other cannabinoids such as CBD (cannabidiol) and CBDa (Cannabidiolic acid) are in high concentrations - consequently giving the plant amazing medical properties.

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The importance of genetics

The genetics of the cannabis plant used is very important for both regulatory and manufacturing purposes equally. As hemp farmers have to make sure that THC levels in the plant are kept very low, it is essential that they keep track of their genetics strains and make sure that they are growing plants with good genes for CBDa synthase.  Similarly CBD (cannabidiol) manufacturers also need to make sure that they are sourcing or growing botanical raw material with good genetics for their CBD (cannabidiol) and CBDa production, and bad genetics for THCa and THC production. This is so that there is a very low chance of contamination of their CBD (cannabidiol) products with THC, thus preventing any psychoactive side effects in their products.   

But why is a plant either abundant in THC or CBD?

It’s all down to the genetic detail that governs whether a cannabis plant will produce the psychoactive molecule THC or not. This is because these genetics decide which enzymes will be expressed and whether active forms of the enzyme are expressed. The integral enzyme involved in the production of CBDa (Cannabidiolic acid) is called CBDa synthase. It is the key piece of ‘plant machinery’ which creates the magical molecule of CBDa, which eventually turns into CBD (cannabidiol).  

The precursor of CBDa (Cannabidiolic acid) is CBGa (Cannabigerolic acid). CBGa (Cannabigerolic acid) is formed by a reaction between the precursors geranyl pyrophosphate and olivetolic acid, and catalyzed by the enzyme CBGa (Cannabigerolic acid) synthase. CBDa (Cannabidiolic acid) synthase then takes a proton from the terminal methyl group of CBGa (Cannabigerolic acid).  

After the proton is eliminated, there is stereoselective ring closure to form CBDa (Cannabidiolic acid). In the language of chemistry, this reaction is a stereospecific oxidative cyclization of the geranyl group of CBGa (Cannabigerolic acid). CBDa synthase is very similar to the enzyme THCa (Tetrahydrocannabinolic acid) synthase (83.9% identity in a 544-amino acid overlap), which catalyses the production of THCa from CBGa. In the reaction for the production of THCa (Tetrahydrocannabinolic acid), a proton is removed from the hydroxyl group of the substrate.

Only a difference in a small number of amino acid residues modulates the other surrounding molecules. Interestingly, the similarity in the enzymes CBDa synthase and THCa (Tetrahydrocannabinolic acid) synthase demonstrates that they are both derived from a common ancestor, and a similar enzyme is also present in the Humulus genus (hops) which another member of the Cannabaceae. These reactions occur in the trichomes, which are most densely located on the flowers of the plants. Trichomes are the ‘cannabinoid microfactories’ of the cannabis plant. The two types of trichomes which produce cannabinoids are the capitate sessile and capitate stalked trichomes. The essential oils produced by these trichomes (which contain the cannabinoids and terpenes) are housed in the resin head with a waxy cuticle.

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What is the relationship between CBDa (Cannabidiolic acid) and THCa (Tetrahydrocannabinolic acid)?

In the cannabis plant, the genes encoding for CBDa synthase and THCa synthase are codominant. Henceforth the ratio of CBDa:THCa in the trichomes is determined by the how much of each respective molecules enzyme is expressed, and the catalytic efficiencies of the respective enzymes (how good they are at transforming CBGa).  The key regulators are the single nucleotide polymorphisms (SNPs) and where they are located. SNPs in the active site of CBDa synthase can lead to the reduced efficiency of the enzyme and limit the production of CBDa.

When the DNA of hemp (high in CBDa) and street cannabis (high in THCa) were compared, it was discovered that the DNA of street cannabis had many SNPs in the CBDa synthase region. Whereas the genetic region for CBDa synthase in the hemp DNA had very few SNPs. As a result hemp produces very little THCa, and consequently products derived from hemp are not psychoactive! 

cannabis genome