Cannabinoids Innies and Outies – Endogenous vs Exogenous Cannabinoids

The cannabis community has enjoyed a couple of recent positive write-ups in mainstream media due to some interesting studies being released. Although there are increasing numbers of valuable and impactful studies on the positive effect of cannabinoids, the two chosen for this article are particularly noteworthy and helpful in demonstrating a few points. The first study shows how plant-derived cannabinoids, especially CBDA and CBGA, may block the access to human cells that the COVID virus requires to infect a person successfully.

The second study shows how cannabinoids made by the body (endocannabinoids) stimulate the Endocannabinoid System (ECS) and produce the effect known as ‘runner’s high’, which was previously believed to be solely the work of the hormone endorphin, which is released by the body during exercise. These two studies have combined the idea to create an article that addresses endocannabinoids vs exogenous or exo-cannabinoids.

Endocannabinoid System (ECS)

The discovery of the Endocannabinoid System was pieced together in the 80s and 90s, with the first endogenous cannabinoid (endocannabinoid) only discovered in 1992. Not all medical degrees include the ECS in their teachings and those that do often don’t consider the effects of the exogenous or plant-derived cannabinoids in their courses. The ECS consists of the commonly-known CB1 and CB2 receptors. These receptors on their own do very little and need a binding partner to be functional.

These binding partners – think of a key and lock system, but each receptor (lock) has multiple ‘keys’ – are found naturally and are produced by the body. ECS in humans is linked to homeostasis, the balancing/monitoring/control of multiple biological systems working in concert. Endocannabinoids are synthesised from lipids/fats and can direct certain cell types to utilise carbohydrate (sugar) metabolism or lipid (fat) metabolism (1). These two types of metabolism are associated with high energy output and slow energy output, respectively.

Receptors

CB1 is one of the most abundant receptors of the class known as G-protein-coupled receptors in the human nervous system. It is found in the brain and other tissues, including peripheral nerve terminals such as eyes and testicles. It can bind THC, resulting in the multiple effects associated with cannabis consumption.

CB2 receptor is less abundant than CB1 and also found in the central nervous system. However, unlike CB1, CB2 is found in immune cells and is often associated with the hypersensitive response (inflammation) and neural signalling.

Endocannabinoids

There is a suite of endogenous compounds that act or may act on the receptors above, and the most well-known is probably that which was the first discovered – anandamide. Before describing this, it should be noted that fatty acids can vary in length, which makes for different body functions.

Animo acids are literally the components of all the proteins made by the body. Endocannabinoids appear to be fatty acids bound to amino acids, making the number of variations exceptionally high. This means there are hundreds of endocannabinoids, and many have no explicit or known function at this time.

Anandamide is a fatty acid-derived compound with neurotransmitter capabilities found in almost all tissue types (2). Anandamide can mediate both CB1 and CB2, although it is not particularly abundant in the human body. It is found in other plants and animals and can play a role in a wide range of functions from working memory to the implantation stage of pregnancy and much more (3).

The second discovered endocannabinoid was 2-AG (2-Arachidonoylglycerol), but unlike anandamide, 2-AG is highly abundant in the body, especially in the central nervous system. Neural protection has been shown in mice studies, with brain trauma causing increased levels of 2-AG at the site of injury, which leads to a reduction in swelling and less cell death at the injured area compared to the control studies (4).

Exogenous cannabinoids

To buck the trend and stay on track, this article will not discuss THC at length but will instead give a brief overview of CBDA CBGA and their decarboxylated cousins CBD and CBG.

CBD and CBDA

Produced by the decarboxylation of CBDA, CBD shows independent functional properties to both CB1 and CB2 receptors, with the most well-known mechanism being CB1 antagonistic action (blocker) against THC. CBD’s other properties include anti-inflammatory, neuroprotectant, sedation, and pain relief.

CBDA is less understood than CBD but seems to have an affinity for another type of G-protein-coupled receptor known as 5-HT1A (AKA the serotonin 1A receptor). CBD can also interact with 5-HT1A but to a much lesser extent. CBDA may have antiemetic properties but doesn’t have a high interaction rate with the CB receptors. Therefore its ability to act upon the body may not directly involve the ECS (5).

CBG and CBGA

CBG has been implicated in various receptors, particularly a class known as Transient Receptor Potential channels of subtype Vanilloid (TRPV). Involved in many functions, CBG can influence receptors affecting pain, inflammation, depression and even some cancers. CBG is also implicated in 5-HT1A and CB1 activity, and studies show it has potential as a superbug resistance compound, having effectively inhibited anandamide uptake in MSRA.

CBGA is often called ‘the grandmother of the cannabinoids’ as it is the precursor to THC, CBD and CBG. Not much is known about its function and interaction so far. However, it has been implemented in anti-inflammatory responses and has antiemetic and anti-convulsion properties in rodent studies (6,7).

Exercise High – a Result of Endocannabinoids

Commonly-recited immediate benefits from exercise include a euphoria-like sensation, often with a calm or zen-like mentality. This was previously associated with endorphin release. Although this exercise high is achieved by the body naturally, it is not a result of opioid signalling as would be the case if endogenous endorphins were the active constituent.

It appears running itself stimulates the ECS, and as a result, endocannabinoids are now a leading candidate to explain the sensation of exercise high. The term ‘runner’s high’ could be replaced with ‘exercise high’ – running is merely an easy to control means of estimating and measuring output.

After this information is learned, the likeness in body sensation between cannabis-induced body high and exercise high is not too dissimilar. Although there is no science involved in this statement, it is the author’s experience that these sensations are relatively alike. Other more credible observations exist, such as running/exercise and specific doses/ratios of cannabinoids having been shown to reduce anxiety in humans.

When testing the theory that endogenous opioids are not the cause of runner’s high, the authors of the study used opioid receptor blockers to gauge if runner’s high was still achieved. Both the euphoric sensation and the reduced anxiety were still experienced when opioid receptor blockers were used and would indicate that exercise-induced high was more likely resulting from stimulation of the ECS (8).

Cannabinoids and COVID-19

An exciting study in January 2022 showed how the acidic forms of CBD and CBG (CBDA and CBGA) could prevent COVID-19 from entering human epithelial cells. The study went on to suggest that simple oral ingestion would be an effective way to help the body prevent COVID infection, and, while the mechanism of action here is not fully understood, it would appear that the surface (spike) proteins on the virus require a specific binding site which the exo-cannabinoids seem to block (9). This would indicate that those who regularly take CBDA or CBGA are better protected from COVID infections than those who don’t.

However, in biology, there are always exceptions to the rule. The intake method, the dose, and the current health status of individuals are just some of the variables that must be considered in this.

Conclusion

Because the exact mode of action remains somewhat elusive, both endocannabinoids and exogenous cannabinoids, such as those derived from the cannabis plant, play essential roles in our well-being. As our understanding is still in its infancy, it would not be surprising if several more breakthrough studies were pushed into mainstream media. There is also a suite of phytochemicals, such as other cannabinoids, terpenoids and flavonoids, all of which remain relatively under-studied and may play essential roles in our body’s regulation.

Although of different origin, endocannabinoids and plant-derived cannabinoids seem to have the ability to influence a range of processes in the body, and the presence of some endocannabinoids already in the body will likely determine some of the roles associated with the entourage effect. This will take a fair bit of research to understand further, as the isolated components may function differently without other components. Therefore their full functionality may only be revealed in the presence of the other phytochemicals.

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References

ESC

1)10.1016/j.biopsych.2015.07.028

2) https://doi.org/10.1016%2FS0024-3205%2899%2900281-7

3) https://doi.org/10.1038/nm0104-19

Cannabinoids

5) Ethan B. Russo and Jahan Marcu, Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. In: David Kendall and Stephen P.H. Alexander, editors, Advances in Pharmacology, Vol. 80, Burlington: Academic Press, 2017, pp. 67-134.

6) Anderson et al. (2021) Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy, British Journal of Pharmacology, 178, 4826-4841

7) Bolognini et al. (2012) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation, British Journal of Pharmacology, 168, 1456-1470

Runners High

8) https://doi.org/10.1016/j.psyneuen.2021.105173

COVID

9) J Nat Prod. 2022 Jan 28;85(1):176-184. doi: 10.1021/acs.jnatprod.1c00946. Epub 2022 Jan 10.