What is the Endocannabinoid System?

The endocannabinoid system is a lipid signalling system that research has shown to have appeared early in the evolution of vertebrates and possesses important regulatory functions throughout the bodies of same.

Two of the main components of the ECS are the cannabinoid receptors CB1 found in the brain and many peripheral tissues, and CB2, primarily found in immune cells.

The ECS is also known as “the body’s own cannabinoid system” and is involved in multiple physiological processes including pain-sensation, appetite, memory and mood as well as mediating the psychoactive and therapeutic effects of cannabis.

What is the ECS Made up of?

Cannabinoid receptors present on the surface of cells

Endocannabinoids, small molecules that activate cannabinoid receptors

Metabolic enzymes, synthesize and degrade the endocannabinoids

Cannabinoid Receptors

There are 2 primary endocannabinoid receptors: CB1 which was first cloned in 1990 and CB2 which was cloned in 1993. CB1 receptors are mainly found in the human brain and nervous system but can also be found in our peripheral organs and tissues.

Cannabinoid receptors are located in the cell membrane and are activated by cannabinoids. Certain endocannabinoids, phytocannabinoids (plant derived) and synthesised cannabinoids “fit” cannabinoid receptors in the ECS which is analogous to a key fitting a lock. When cannabinoids bind to these receptors in the body they all produce a diverse range of physiological effects.

CB1 and CB2 receptors take part in the regulation of many biological functions including but not limited to immune system functions, memory and learning, appetite and pain management.

Fig. 1 Cannabinoid receptor locations in the human body

Cannabinoid Receptors in the human body

Endocannabinoids

Endocannabinoids are molecules that, similar to the plant cannabinoid THC, bind to and activate cannabinoid receptors. Endocannabinoids are produced by natural processes in the cells of the human body whereas THC is a phytocannabinoid (plant derived cannabinoid) produced in the cannabis plant.

The cannabinoid receptors CB1 and CB2 are targeted by the endocannabinoid ligand (binding molecule), Anandamide, along with its mimetic phytocannabinoid, THC.

Anandamide Molecular Structure

Another primary endocannabinoid is 2-Arachidonoylglycerol (2-AG) which has been found to be active at both of these cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD.

2-Arachidonoylglycerol (2-AG)-Molecular Structure

Endocannabinoids act as synaptic “circuit breakers” and have been shown to regulate multiple physiological and pathological conditions e.g. inflammation, addictive behaviour, analgesia, cancer, epilepsy, regulation of food intake and others.

The primary endocannabinoids, anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol, bind primarily to CB1 and CB2 receptors, but can also bind to the vanilloid receptor and in doing so produce a wide range of effects as they function as agonists, antagonists and partial antagonists.

Metabolic Enzymes

The 2 metabolic enzymes FAAH and MAGI are involved in breaking down the endocannabinoids in our body. FAAH breaks down anandamide, and MAGL breaks down 2-AG.

These enzymes rapidly destroy endocannabinoids once they have been used. These enzymes ensure that endocannabinoids are processed when they’re needed, but for no longer than is required. Because of this, endocannabinoids stand apart from many molecular signals in the human body, for example, classical neurotransmitters or hormones.

Functions of the Endocannabinoid System

It has been widely reported that the endocannabinoid system may have a role in or an effect on the following:

Sleep

An increase in endocannabinoid signalling within the central nervous system promotes sleep-inducing effects.

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Learning and Memory

The endocannabinoid system (ECS) plays a central role in the regulation of learning and memory processes. This is likely attributable to the regulation of neural transmission by the ECS.

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Appetite

Evidence suggests that the ECS has a central role in the modulation of both homeostatic and hedonic aspects of food intake and appetite.

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Signalling and synaptic function

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors in the central nervous system, endocannabinoids can regulate several neural functions and behaviours.

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Energy balance and metabolism

Within the past 2 decades, the ECS has been identified as a lipid signalling system heavily involved in the regulation of energy balance. This occurs as the ECS exerts a regulatory control on every element related to the search, intake, the metabolism and the storage of calories

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Stress response

Studies have shown that endocannabinoids are synthesised during periods of stress and that anandamide and 2-AG divergently regulate the HPA axis response to stress.

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Anxiety / Stress, Fear memory and habituation

The participation of the endocannabinoid system in fear and anxiety has been reported and researched extensively. Research in this area has lead to novel therapeutic approaches.

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Multiple sclerosis and other neurodegenerative diseases

Cannabinoid compounds and their interaction with the endocannabinoid system along with the associated neuronal stimulation have opened up new avenues of research into potential treatments for multiple sclerosis and other neurodegenerative diseases.

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Immune function

In the following article, the author has reviewed the possible mechanisms of the regulation of the immune response by endocannabinoids.

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Analgesia

In pain research, the endocannabinoid that has been examined more than others is palmitoylethanolamide. This endocannabinoid has been examined for its analgesic actions with regard to multiple pain indications and it has been reported to be safe and effective in this area.

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Cannabinoids and how they interact with the Endocannabinoid System

Cannabinoids deliver chemical messages for the endocannabinoid system. They activate the cannabinoid receptors and cause biological responses through lipid signalling. There are multiple variations of cannabinoids but there are two overall categories to which they belong: endogenous or exogenous.

Endogenous cannabinoids:

Also known as endocannabinoids, these are generated within the human body. They react with the ECS and have been shown to regulate multiple physiological and pathological conditions.

Exogenous cannabinoids:

These originate externally to the body. The cannabinoids found in plants such as marijuana, including tetrahydrocannabinol (THC) and cannabidiol (CBD), are exogenous cannabinoids. These also interact with cannabinoid receptors to result in both physical and psychological effects in the body. Cannabinoids found in the cannabis plant are also known as phytocannabinoids.

What are Phytocannabinoids?

Phytocannabinoids are cannabinoids that occur naturally in the cannabis plant. “Phyto” is the greek word for “plant”. Several hundred compounds have been found in in the cannabis plant and of those, many have been identified as cannabinoids. The most high-profile of these are CBD, THC and CBN.

CBD (Cannabidiol)

CBD is thought to be the most abundant cannabinoid in the cannabis plant, contributing up to 40% of cannabis resin. Unlike some other phytocannabinoids, CBD has been shown to be non-psychoactive and may actually have a reducing effect on the psychoactive effects of cannabinoids like THC. It has been reported that CBD may have the potential for medicinal treatments in many areas.

CBD Molecular Structure

THC (Delta-9-tetrahydrocannabinol [Δ9-THC])

Delta-9-tetrahydrocannabinol (Δ9-THC) is the primary psychoactive agent in the cannabis plant. It is one of many compounds found in the resin secreted by glands of the marijuana plant. THC produces psychoactive effects on the human brain and is the “high” causing agent in cannabis. It has also been reported that THC may have the potential for medicinal treatments in several areas.

THC Molecular Structure

CBN (Cannabinol)

CBN is a phytocannabinoid that is created through the degradation / oxidation of THC. It has been shown to have little to no psychoactive effects and one of the primary benefits of this cannabinoid is sedation. Comparisons have been made to the effects of CBN and existing pharmaceutical sedatives such as diazepam. Some studies have shown that doses of CDN can have the same effect as twice the dose of diazepam.

CBN Molecular Structure

Phytocannabinoids Interacting with the ECS

Phytocannabinoids can interact with the ECS receptors in the body of vertebrates as antagonists and in doing so can alter the events triggered at those receptors. It has been postulated that such interactions can result in beneficial effects within the body.

Fig. 2 Endocannabinoid System: Cannabinoids and Receptors

Endocannabinoid System: Cannabinoids and Receptors Diagram

Definitions

Lipid signalling: Broadly defined as the process by which the interior components of a cell respond to a signal external to the cell, allowing the cell to respond to their local environment.

Cannabinoid Receptors: These are cell-membrane receptors that are activated by ligands. Each receptor responds to different cannabinoids, but some cannabinoids interact with both.

Ligands: In biochemistry and pharmacology, a ligand is a substance that, once it forms a complex with a biomolecule, serves a biological purpose.

Agonist: A cannabinoid that causes a receptor to react in the same manner as it would to a naturally occurring neurotransmitter or hormone.

Antagonist: A cannabinoid that prevents a receptor from binding to a naturally occurring compound and therefore diminishes or modifies the resulting event or reaction.