The endocannabinoid system (ECS) is universally found in Phylum Chordates. There are three subphyla of Chordates, and humans fall into the subphylum known as vertebrata – meaning they have a backbone. 

The human ECS is an intricate lipid signaling system that regulates homeostatic and physiological functions such as the modulation of pain and inflammation. 

The human ECS is comprised of receptors known as CB1R and CB2R. 

CB1R’s are primarily located on nerve cells in the brain and spinal cord, while CB2R’s are found on immune cells. There is some carryover, but in the interest of simplicity, this characterization will suffice. 

These receptors are activated by endocannabinoids, which are endogenous metabolites (produced in the body) that bind to receptors. 

These molecules are derived from arachidonic acid, anandamide and 2-arachidonoyglycerol. 

They’re existence and effects are relatively shot-lived due to their degradation by two well-characterized enzymes, the fatty acid amide hydrolase and monoacylglycerol lipase. 

Phytocannabinoid Biosynthesis

Phytocannabinoids are terpenophenolic compounds produced from fatty acids and isoprenoids precursors as part of the secondary metabolism of cannabis.

 The secondary metabolism of plants refers to pathways and small molecule products of metabolism that are not necessarily required for the survival of the organism.

In the context of C. Sativa L., the secondary metabolism would be the pathways that lead to the formation of the small molecule products known as phytocannabinoids.

The cannabis plant produces many small molecules, but in the interest of brevity, we will focus on the main and most prevalent molecules. These include:

  • (THC) D-9 tertrahydrocannabidiol 
  • (CBD) Cannabidiol 
  • (CBN) Cannabinol 
  • (CBG) Cannabigerol
  • (CBC) Cannabichromene

The formation of these complex molecules begins with the short-chain fatty acid known as hexanoic acid.

There are several enzymes that play a vital role in the biosynthesis of cannabinoids.

These enzymes are as follows:

  • Acyl Activating Enzyme 1 (AAE1)
  • Olivetol Synthase (OLS)
  • Olivetolic Acid Cyclase (OAC)
  • Cannabigerolic Acid Synthase (CBGAS)
  • Tetrahydrocannabinolic Acid Synthase (THCAS)
  • Cannabidiolic Acid Synthase (CBDAS)
  • Cannabichromenic Acid Synthase (CBCAS)

The exact chemical reactions through which these enzymes create phytocannabinoids can be difficult to understand, but what is important is that AAE1, OLS, and OAC operate on hexanoic acid and byproducts to form CBGAS.

CBGAS is the enzyme responsible for the production of cannabigerolic acid (CBGA).

The monoterpene moiety of CBGA is stereoselectively cyclized by the three different enzymes, meaning that a single steroisomer is formed, even though more than one is possible.

These enzymes are:

  • Tetrahydrocannabinolic Acid Synthase (THCAS)
  • Cannabidiolic Acid Synthase (CBDAS)
  • Cannabichromenic Acid Synthase (CBCAS)

In other words, three separate enzymes work upon CBGA to produce THC-acid, CBD-acid, and CBC-acid.

Phytocannabinoids and the Human ECS

Phytocannabinoids approximate the endocannabinoids we produce naturally. When we ingest them, in their decarboxylated form, they activate the receptors in our ECS – either CB1R or CB2R.

D-9 tertrahydrocannabidiol is a potent activator of the CB1R, while the non-psychoactive CBD is a very low affinity CB1 ligand.

What this means is that CB1R’s, located in the brain and spinal cord, are highly sensitive to THC, and have less tendency to form chemical bonds with CBD molecules.

However, CBD molecules will act as a direct blockade of CB1R’s which exerts a measure of control over some of the side effects of THC, including anxiety, dysphoria, panic reactions and euphoria. In addition, it also appears to improve the therapeutic activity of THC.

In this way, CBD behaves somewhat like a non-competitive receptor antagonist. This means that it binds to the same cell as THC, but not the same site on the cell. In so doing, it prevents the activation of the receptor by THC. This is in contrast to competitive receptor antagonists which would bind to the same receptor site as THC.

This is why some people say that THC and CBD are most effective when used together, because CBD attenuates some of the less favourable effects of THC, and can make regular dosing more tolerable.

Despite being a low affinity CB1 ligand, CBD does behave as a CB2R inverse agonist. This is significant insofar as there is evidence that CB2R inverse agonism can inhibit immune cell migration and reduce clinical signs of inflammation. This could be the explanation for why CBD has such potent anti-inflammatory properties.