The Endocannabinoid System

The Endocannabinoid System

The Endocannabinoid System. How does CBD work?

CBD is one of many phytocannabinoids that act on a number of receptor systems in humans, including the opioid, serotonergic, and cannabinoid systems. 1. The way in which CBD and other cannabinoids work within the human body is highly complex and not fully understood. This article concentrates on the Endocannabinoid System (eCS). Firstly, here is the simplified version.

CBD and the Endocannabinoid System – the simplified story

Research on how phytocannabinoids work within the body has grown in recent years but the exact mechanism of action within the Endocannabinoid System (eCS) is still not fully understood. At 600 million years old, the eCS is thought to be one of the oldest body systems present in every animal species, except insects. It is an extensive and complex signalling system that seems to play a significant role in health and disease. 2.

The eCS works to maintain homeostasis (internal balance)

The eCS is a stress/harm regulation network and works to restore homeostasis (internal balance) within the body. This vital physiological system is regulated by a wide range of factors, including diet, sleep, exercise, stress, and phytocannabinoids. It is upregulated and downregulated (increase or decrease in the number of receptors) continuously, as required. The eCS communicates with all other body systems and is involved in a number of regulatory functions in both health and disease, including pain, perception, mood, memory, and reward (as shown in Figure 1). 2.. 3.

The Endocannabinoid System: Major sites and associated functions of the cannabinoid receptors in the human body. 3.

Figure 1: Major sites and associated functions of the cannabinoid receptors in the human body. 3.

What is the Endocannabinoid System?

The eCS (Figure 2) consists of at least 2 cannabinoid receptors [CB1 and CB2], endocannabinoids that bind to those receptors [anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the 2 most important], and the enzymes that biosynthesise (build up) and degrade (break down) those endocannabinoids [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] 1. Cannabinoid receptor 1 (CB1) is the most abundant receptor found in neurons (nerve cells) in the brain and central nervous system, as well as non-neuronal cells, such as adipocytes (fat cells) and hepatocytes (liver cells), and in musculoskeletal tissues. 1., 5.  Cannabinoid receptor 2 (CB2) is mainly found in cells of the immune system, but can also be found in the central nervous system. 4, 6. 

The eCS regulates vital processes in the body

Endocannabinoids, anandamide and 2-AG, are released from cell membranes on demand, and are broken down after they activate the CB1 or CB2 receptors. Through these and more complex mechanisms, the eCS regulates a number of vital bodily processes that include embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis (programmed cell death) and carcinogenesis (formation of cancer cells), pain and emotional memory, appetite and metabolism. 5.

The Human Endocannabinoid System 4.

Figure 2: The Human Endocannabinoid System 4.

How the Endocannabinoid System Works

Endocannabinoids function as neuromodulators, and are associated with the increased consumption and storage of energy, as well as restoring homeostasis (internal balance) following stress, as shown in Figure 3. When the concentrations of endocannabinoids change and become unbalanced, illness and disease occur. Chronic pain, anxiety and mood disorders, and obesity have been linked to changes in the circulating endocannabinoids within the body. 7. CBD and other phytocannabinoids are thought to work by both substituting endocannabinoids and also helping to ‘kick-start’ the eCS when it is not functioning properly. Therefore, CBD has the potential to help the body to heal itself.

CBD has the potential to help alleviate diseases and disorders

Scientific research has shown that CBD products have the potential to help alleviate a number of diseases and disorders, including epilepsy, mood disorders, chronic pain, anti-inflammatory and neurodegenerative diseases, but further research is required to discover conclusive results. Differences in individual physiology make this difficult, and means that CBD and other cannabinoids affect people differently. As such, people find CBD products to be more or less effective than others so it’s important to find the dose most effective for you.

Schematic representing the sources and targets of the endocannabinoid system. 7.

Figure 3: Schematic representing, on the left side, the stimuli and potential sources of endocannabinoids that are present in the circulation and, on the right side, the potential targets of endocannabinoids, together with the cannabinoid receptor subtype that is involved. 7.

If you are satisfied with the simpler explanation of how CBD and the eCS work, you can move on to the next section here. The following section describes CBD and THC within the eCS in more scientific detail.

CBD and THC and the eCS – the more complicated story

The way in which different cannabinoids interact with the CB1 and CB2 receptors and the varying physiological reactions that occur are highly complex. Not only do different cannabinoids cause different reactions when they bind with CB1 or CB2 receptors, the effects can differ, and sometimes be contradicting, depending on the location in the body. 8.  

THC interacts with CB1 and CB2 receptors

THC is the primary cannabinoid that causes the intoxicating effects of Cannabis sativa. It interacts with CB1 and CB2 receptors in a similar way to the endocannabinoids anandamide (AEA) and 2-AG. (See Figure 1). THC is a CB1 and CB2 agonist, which means that it binds to the receptor and activates it to produce a biological response. THC activates the CB1 receptors, which inhibits the release of neurotransmitters such as gamma-aminobutyric acid and glutamate. However, THC has also been observed to occasionally increase the release of acetylcholine, dopamine and glutamate in various regions of the brain in rats. 4.

These actions result in varying effects within the body and appear to be dependent on whether the THC use is acute (single dose at one time) or chronic (multiple doses over time). Studies have shown that the acute administration of THC causes CB1 to be more sensitive to cannabinoids and stimulates the synthesis of AEA, while chronic, high dosing of THC causes a predictable desensitisation and downregulation of CB1 and CB2 receptors, which increases drug tolerance. 6.  Therefore, the effects of THC upon the eCS fluctuate between increased efficiency and suppression, dependent on dosage, and this likely differs amongst individuals. THC as a CB2 agonist is the target of emerging research due to its potential analgesic, anti-inflammatory, and immune-modulating properties. 9.

CBD indirectly modifies the receptors’ ability to bind endocannabinoids

In contrast, CBD does not share the intoxicating effects of THC and does not directly affect either CB receptor, but instead modifies the receptors’ ability to bind endocannabinoids. 9. CBD acts as a CB1 inverse agonist (i.e., causes a biological action opposite to an agonist), or even antagonist (i.e., blocks the action of an agonist), which weakens the action of THC.  There is also evidence that CBD interacts with CB2 receptors as an inverse agonist, which reduces pro-inflammatory responses such as cytokine release and immune cell response, and results in the reduction of clinical pro-inflammatory markers. 4.  In other words, CBD appears to act as an anti-inflammatory.

Adding CBD to THC has also been shown to enhance CB1 action in some parts of the brain, and causes an increase in neuron cell survival and neurogenesis; the opposite effect of THC. CBD has also been shown to inhibit the cellular uptake and breakdown of AEA 6.  and enhances the activity of anandamide, the endogenous cannabinoid. CBD is also thought to interact with several other receptors out with the eCS, such as the μ-receptor and serotonin (5-HT) receptors. 9. Several other cannabinoids interact with enzymes of the eCS. For example, cannabidivarin and cannabidiolic acid inhibit an enzyme that synthesises 2-AG, and cannabigerol and cannabichromene reduce the uptake of anandamide into cells. 6.

Cannabis and its many constituents work, in part, by ‘‘kick-starting’’ the eCS system

It has been suggested that rather than simply substituting for AEA and 2-AG, Cannabis and its many constituents work, in part, by ‘‘kick-starting’’ the eCS system. A dysfunctional eCS has been associated with a number of health conditions, including obesity, migraine, fibromyalgia, irritable bowel syndrome, depressive illnesses, schizophrenia, multiple sclerosis, Huntington’s, Parkinson’s, anorexia and chronic motion sickness. 6. It has been proposed that these conditions represent ‘‘clinical endocannabinoid deficiency syndromes’’ and could be corrected via at least three molecular mechanisms: 1. increasing endocannabinoid biosynthesis; 2. decreasing endocannabinoid degradation; 3. increasing or decreasing receptor density or function. 10. Phytocannabinoids therefore have the potential to improve these conditions, but further, more targeted research is required.

NEXT: “Cannabinoid Extraction from Cannabis sativa


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3. Romero, P., Peris, A., Vergara, K. and Matus, J.T., 2020. Comprehending and improving cannabis specialized metabolism in the systems biology era. Plant Science, 298, p.110571.

4. Nahtigal, I. & Blake, Alexia & Hand, A. & Florentinus-Mefailoski, A. & Hashemi, Haleh & Friedberg, Jeremy. (2016). The pharmacological properties of cannabis. Cannabis: Medical Aspects. 9. 481-491.

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6. McPartland, J.M., Guy, G.W. and Di Marzo, V., 2014. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PloS one, 9(3), p.e89566.

7. Hillard, C.J., 2018. Circulating endocannabinoids: from whence do they come and where are they going?. Neuropsychopharmacology, 43(1), pp.155-172.

8. Silote, G.P., Sartim, A., Sales, A., Eskelund, A., Guimarães, F.S., Wegener, G. and Joca, S., 2019. Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms. Journal of chemical neuroanatomy, 98, pp.104-116.

9. Chin, G.S., Page, R.L. and Bainbridge, J., 2020. The Pharmacodynamics, Pharmacokinetics, and Potential Drug Interactions of Cannabinoids. In Cannabis in Medicine (pp. 49-61). Springer, Cham.

10. Russo, E.B., 2008. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?. Neuro endocrinology letters, 29(2), pp.192-200.

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