Cannabigerol and the Endocannabinoid System, By Fred Delisio

Let’s move on to a base Cannabinoid (the Building Block for the dominant Cannabinoids THC, CBD and CBC, through enzymatic action with Cannabigerolic acid, or CBGa).

Note: this is an article that delves into the chemistry and science of Cannabis and Cannabinoid production, and as such, tends to be, well, very chemistry-oriented. I’ve tried to explain/define terms as best I can, but there are some terms that are not able to be put more simply. What this means is, get out your dictionaries, folks!

CBD is such a misunderstood Cannabinoid, as it is not psychoactive, but is responsible for the “weight-behind-the-eyes” feeling (as it reduces ocular pressure) which is often misunderstood/associated with a feeling of psychoactivity, where there is none, although it definitely modifies/modulates the effects of other Cannabinoids.

Cannabinoid production starts with an enzyme that causes geranyl pyrophosphate and olivetolic acid to combine and form CBGa. CBGa is then converted to either CBG, THCa, CBDa or CBCa by four separate synthase (an enzyme that catalyzes the linking together of two molecules), FAD dependent dehydrogenase enzymes. There is no enzymatic conversion of CBDa or CBD to THCa or THC.

For THCVa, CBDVa and CBCVa, there is a similar process that is based on CBGVa from divarinolic acid instead of olivetolic acid. Since it is such an important building-block for Cannabinoids, let’s discuss Olivitol/Olivetolic acid a bit. The cannabis plant internally produces olivetolic acid (OLA), which the plant utilizes to biosynthesize the tetrahydrocannabinol (THC).

THCv Production

Unlike THC, cannabidiol (CBD), and cannabichromene (CBC), THCV doesn’t begin as cannabigerolic acid (CBGa). Instead of combining with olivetolic acid to create CBGa, geranyl pyrophosphate joins with divarinolic acid, which has two fewer carbon atoms. The result is cannabigerovarin acid (CBGVa). Once CBGVa is created, the process continues exactly the same as it would for THC. CBGVa is broken down to tetrahydrocannabivarin carboxylic acid (THCVa) by the enzyme THCV synthase. At that point, THCVa can be decarboxylated with heat or UV light to create THCV.

Specific enzymes in the plant break CBGa down into these three Cannabinoids. When the acids are exposed to UV light or heat they are transformed into THC and CBD. In most strains, CBGa is immediately converted to either THCa or CBDa. Because of this, more THC means less CBG and CBD proportionally because of how these compounds are synthesized.

How Cannabinoids Interact With the Endocannabinoid System

Whenever there are deviations from homeostasis (cellular balance) in the body’s functions, the endocannabinoid system responds accordingly by synthesizing endocannabinoids, acting as neurotransmitters.

When the body creates neurotransmitters for the endocannabinoid system, they are picked up by specialized cannabinoid receptors, which sit on the surface of cells. These receptors are found distributed in varying densities throughout the body, in various locations including: organs and glands, connective tissue, the immune system and the brain

Specific endocannabinoids fit into these, either perfectly, or imperfectly, which either activates or blocks effects to varying degrees, to communicate to the endocannabinoid system to interact with these receptors and transmit information about changing conditions to trigger a response, which helps the body achieve homeostasis, or balance, within the body.

The endocannabinoid systems receptor sites include CB1 and CB2 receptor variants, which respond differently to various cannabinoids. CB1 receptors are most prevalent in the central nervous system and bring about benefits in these areas:

Modulation of stress and anxiety
Decreasing nausea
Increased appetite
Balancing the immune system
Inhibition of tumors

CB2 receptors are found primarily on cells in the immune system to fight inflammation and damage to tissue. Some cells contain both types of receptors, each providing different functions.

The two major endocannabinoids are 2-arachidonoylglycerol (2-AG) and Anandamide (AEA).

2-AG is an agonist of both CB1 and CB2 receptors. This means that it binds with, and fits well inside, both receptors to activate them to stimulate a physiological response.

Anandamide is considered a partial agonist of both receptors, because, while it binds with and activates the receptors, it doesn’t fit as well inside them, so it doesn’t trigger as strong of a physiological response.

Once the function that had deviated from homeostasis returns to a balanced state and the endocannabinoids are no longer needed, metabolic enzymes break down and degrade them.

Fatty acid amide hydrolase (FAAH) degrades Anandamide, and monoacylglycerol lipase (MAGL) breaks down 2-AG. By ridding the body of the endocannabinoids once they are no longer needed, the endocannabinoid system “turns off” the molecular signals and ends whatever physiological activity it had stimulated.

How the Endocannabinoid System Preserves and Protects Health

Since discovering the endocannabinoid system and its components, we’ve worked to better understand how the endocannabinoid system may be used therapeutically to:

Promote general health
Decrease pain
Fight cancer
Prevent neurodegenerative diseases

The endocannabinoid system works to ensure that the body’s immune and central nervous systems are functioning correctly. Finding ways to modulate the endocannabinoid systems activity has the ability to treat disparate set of chronic diseases and disorders.

One example is that stimulation of cannabinoid receptors may help in the deletion of past traumatic memories and provide clinical benefits in age-related diseases associated with brain inflammation. This list also includes conditions like Parkinson’s, multiple sclerosis, and cancer.

The extinction of aversive memories is vitally important to the progress of PTSD patients to their reaction to those with chronic anxiety. By allowing patients to forget painful memories, they can reset their stress and anxiety to specific experiences and respond in a more positive reaction.

Controlling Appetite & Weight

Cannabis has a well-known ability to increase appetite. However, because endocannabinoids are used internally for appetite control, inverse agonists to the CB1 receptor can be used to combat obesity by shutting off the body’s desire for food. The opposite can be accomplished by stimulating appetite in those suffering from wasting syndrome and allowing them to gain weight.

Finally, endocannabinoids also regulate metabolism to help control the transfer of energy through cells, ensuring optimal use of the food we do take in.

Anxiety

The natural cycle of anxiety and physical response cannot be shut off due to constant exposure to stressors. Because cannabinoids affect the body’s glandular response to stress to regulate and buffer response, the endocannabinoid system can assist in the way in which humans process long term stress and other persistent anxiety triggers.

Immune Function & Inflammation

Additionally, endocannabinoids promote proper immune function to allow for a greater overall wellness. The role they play in immune homeostasis prevents ‘spontaneous activation of immune cell function’, helping to prevent inflammation and possibly even resulting neurological diseases.

Cannabis Phytocannabinoids and how they react with the Endocannabinoid System

As we learn more about the endocannabinoid system, we are also exploring the role that cannabis-derived phytocannabinoids like Tetrahydrocannabinol (THC), Cannabidiol (CBD) Cannabinol (CBN), and other phytocannabinoids can play in supporting the system.

Phytocannabinoids mimic the behavior of endocannabinoids and interact with the cannabinoid receptors to augment the endocannabinoid system. As the cannabinoids interact with the cannabinoid receptors, they stimulate various physiological responses.

THC, the well-recognized psychoactive compound found in cannabis, activates receptors and elicits a chemical response. It is considered an agonist of both CB1 and CB2 receptors because it directly binds to the receptors and activates them.
THC favors CB1 receptors because it fits very well inside them and is able to stimulate a strong reaction.

When THC reacts with CB1 receptors, this is what causes the “high” feeling from Cannabis. THC also directly activates CB2 receptors, but is considered a partial agonist and therefore doesn’t elicit such a strong response.

Because it doesn’t fit perfectly into both CB1 and CB2 receptors, CBD causes chemical changes by blocking receptors. It has a low affinity for both CB1 and CB2 receptors, and instead acts as an indirect antagonist of agonists. This means that CBD does not activate the receptors, but prevents other chemical messengers like THC from binding to them.

As we continue to learn more about the endocannabinoid system, we also learn about the potential for the scope of active compounds from cannabis (like THC, CBD, CBC and CBN) to be used therapeutically.

Supplementing the Endocannabinoid System with Cannabis Phytocannabinoids

One theory about how the endocannabinoid system relates to our overall health is endocannabinoid deficiency syndrome, which postulates that in some people the body does not generate enough endocannabinoids. In addition, we’ve found that the endocannabinoid system’s ability to create sufficient amounts of endocannabinoids that our bodies need tends to degrade over time as we age. By supplementing the endocannabinoid system with phytocannabinoids, and specifically CBG/CBGa because of the base nature of this phytocannabinoid, we theorize this can augment/stimulate the body’s production of endocannabinoids. This could be one of the root causes of many autoimmune disorders, including migraines, fibromyalgia, and IBS.

By modulating the endocannabinoid system, several diseases and conditions could possibly be treated, including:

Pain
Inflammation
Multiple sclerosis
Anorexia
Epilepsy
Cancer
Glaucoma
Increased Appetite
Obesity
Schizophrenia
Cardiovascular disorders
Parkinson’s disease
Huntington’s disease
Alzheimer’s disease
Tourette’s syndrome

One of the main obstacles to the acceptance and use of cannabis and its active phytocannabinoids in medicine is the problem of abuse for its psychoactivity.
However, this issue does not arise in a number of possible approaches to the regulation of the endocannabinoid system:

When an antagonist to the CB1 receptor is applied

When production or transportation of endocannabinoids is altered

When a non-psychoactive agonist to the CB2 receptor, like THCa, CBD or CBG, is used for therapeutic results.

Phytocannabinoids, like THCa, CBD and CBG from Cannabis Sativa, obviously affect the endocannabinoid system, however, it has also been shown that non-psychoactive substances from Cannabis terpenes and flavonoids, are picked up by receptors in our endocannabinoid systems.

Because small doses of phytocannabinoids can encourage the body to create more naturally occurring endocannabinoids and their receptors, it may be possible to bolster the sensitivity of our native systems with regular cannabinoid supplements, and in particularly CBGa, being a precursor to other phytocannabinoids.

Ongoing research adds to our understanding of the impact of the endocannabinoid system on our health, and, how supplementing our natural endocannabinoid production with plant-based phytocannabinoids may play a significant role in improving our overall health.

Extensive studies show great potential for using this vital system to the benefit of health and well-being of humans, so it is imperative that we keep working towards changing public perception in the hope that this research can benefit all people around the globe.

Written and Published By Fred Delisio In Weed World Magazine Issue 135

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