The Endocannabinoid System: Everything You Need To Know

The ECS (endocannabinoid system) is an intricate neuromodulatory system that plays a crucial role in regulating various functions, including growth and development, metabolism, learning and memory, hunger, reproduction, and anxiety, among many others. First discovered by researchers in the 1990s (researching the effects of THC – a cannabinoid), the ECS responds to various cannabinoids to stimulate, trigger, or regulate a number of bodily functions, thus crucial for one’s overall wellbeing. You don’t necessarily have to use cannabis or related products for your ECS system to be active. Here is a brief outline of how the ECS works and/or how it interacts with cannabis.

How Does The ECS Work?

The ECS is made up of 3 core components:
1. Endocannabinoids
2. Enzymes
3. Receptors

1. Endocannabinoids

Endogenous cannabinoids (endocannabinoids) are produced naturally in the body. They however are quite similar to cannabinoids. Endocannabinoids are classified into two:

I. Anandamide (AEA)
ii. Endocannabinoid receptors

I. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG)
Anandamide and 2-AG are crucial in regulating internal bodily processes and functions. The two endocannabinoids are, however, produced on demand depending on a number of factors. It is thus almost impossible to determine how much of these are present at any given moment.

ii. Endocannabinoid Receptors
Endocannabinoid receptors are present in virtually every part of the body. ECS receptors are critical in the central nervous system and respond to cannabinoids to tell the ECS what action to take. There are two subtypes of endocannabinoid receptors, namely:

a. CB1 receptors – are found in the central nervous system
b. CB2 receptors – located in the peripheral nervous system, e.g., immune cells

Although endocannabinoids can bind to either of the two receptors, the results mainly depend on where the receptor is located and to which it binds. An excellent example of this is when an endocannabinoid targets CB1 receptors in the spinal cord/never for pain relief. Other endocannabinoids may bind onto CB2 receptors inside immune cells to help trigger natural action against foreign materials or microbes that cause illnesses or autoimmune disorders. This mostly occurs when the body experiences inflammation as a way to fight off conditions such as arthritis, acne, and other conditions.

2. Enzymes
Enzymes play a vital role in breaking down endocannabinoids once their job is done. The enzymes responsible for this are:
- Amide hydrolase fatty acids - breaks down anandamide (AEA)
- Monoacylglycerol acid lipase – acts on2-AG

How Did It Come to Be Known as The Endocannabinoid (ECS) System?

1964
Professors Raphael Mechoulam and Yechiel Gaoni first discovered and isolated THC (tetrahydrocannabinol) from the cannabis plant, which they initially referred to as a cannabinoid. The word cannabinoid is derived from the very plant they were analyzing, the cannabis plant. For this reason, researchers named ECS after the plant that led to its discovery.

1988
Researcher William Devane and professor Allyn Howlett discovered a part of the brain (receptors) that responded to cannabis. These receptors particularly responded to cannabinoids from the cannabis Sativa plant, thus named them cannabinoid receptors.

1992
Lumir Hanus, an analytical chemist, while working with Willian Devane, discovered the presence of an endocannabinoid in the human brain. This confirmed theories about the existence of a biological system that regulated endogenous cannabinoids. This birthed the endogenous cannabinoid system. The term endogenous can be defined as originating from an organism. The term would be later shortened to the ECS, or endocannabinoid system, and has remained the same.

endocannaboid system

Endocannabinoids: Definition

Endocannabinoids (endogenous cannabinoids) are essentially naturally produced and transmitted in the body. They specifically bind onto CB1 and CB2 receptors in the immune system, the brain, and other parts of the body. Some of the best examples of endocannabinoids include virodhamine (OAE), anandamide, n-arachidonoyl dopamine (NADA), and 2-arachidonoylglycerol.

Endocannabinoids are unique in that they don’t work like other well-known neurotransmitters (norepinephrine, dopamine, serotonin, etc.) do. They, in fact, work in reverse. Dopamine, for example, is produced and stored in a presynaptic cell, from where it is released in response to stimuli. It thus has to cross a synapse to get to, and active the postsynaptic cell, causing one to feel motivated, happy or focused. Dopamine can also be defined as the brain’s reward system, commonly released in response to an achievement or anything like it.

Endocannabinoids are different in that; they are part of the cellular membrane and are manufactured on demand. As mentioned, endocannabinoids travel backward from the postsynaptic cell to the presynaptic cell. This thus makes it easier for the postsynaptic cell to monitor and regulate neurotransmitters coming to and from the presynaptic cell.

Anandamide: The Molecule of Bliss

Anandamide is one of the most commonly known and researched molecules in the endocannabinoid spectrum. One reason for this is that anandamide is responsible for mood elevation, motivation, and memory. Anandamide is manufactured in the part of the brain responsible for higher thoughts, mood, motivation, and memory. It was first discovered and isolated in the 1990s.

According to research, anandamide is effective in reducing depression, anxiety, formation of cancerous cells, and increasing neurogenesis in Alzheimer’s patients. Recent studies have also revealed that anandamide produces the ‘runners high’ that most people experience after an intense workout or exercise.

Researchers in Germany, 2015, examined the role various neurochemicals play in reducing pain and stress after exercise in mice. Although many believe endorphins to be responsible for the feeling of happiness and contentment, this isn’t the case. The researchers gathered that endorphin molecules are too big to pass through the blood-brain barrier and cannot be responsible for triggering the feeling of contentment and happiness after an exercise. From their observation, this phenomenon (bliss) could only happen due to anandamide activating cannabinoid receptors, thus contributing to reduced stress and pain after a strenuous workout or exercise.

Studies also show anandamide plays a considerable role in the lives of mother and child from conception to breastfeeding. A study conducted in 2009 on the same showed that anandamide levels were significantly higher in ovulating women, especially those that had used IVF (in-vitro fertilization) and ICSI (intracytoplasmic sperm injection) to get pregnant. From the study, the researchers concluded that higher amounts of plasma anandamide were required for successful pregnancy at ovulation and lower during implantation.

Reviewing the role of endocannabinoids on human reproduction, shows anandamide to be crucial in ensuring successful embryo implantation and healthy development of the fetus. A comprehensive review also points out that a malfunctioning endocannabinoid system or its receptors could lead to pregnancy complications.

in another study and review, anandamide and 2-AG endocannabinoid are shown to play a crucial role in prompting suckling response in newborns. In 2006, scientists discovered a correlation between baby mice being able to latch and suckle and endocannabinoids in their system. From the study, the mice pups had relatively high levels of endocannabinoids after birth, with the same replenished as they suckled their mother’s milk. Some mice pups were then given a CB1 receptor antagonist (preventing activation of CB1 receptors by 2-AG or anandamide), making them not want to latch and suckle instinctively.

From the study, it is evident that anandamide is crucial for our overall wellbeing. How can one ensure they are getting enough anandamide? You may ask. The answer lies with arachidonic acid, or AA. Arachidonic acid is an omega-6 fatty acid commonly found in animal foods and some grain and pasta dishes. AA is the primary building block for the synthesis of anandamide, hence required to ensure enough is manufactured. Creating and sticking to a well-balanced diet plan can thus improve your chances of getting enough arachidonic acid, thus healthy levels of anandamide.

Coincidentally, anandamide has an almost similar molecular structure as THC (tetrahydrocannabinol), the infamous cannabinoid known to produce the feeling of high. Both anandamide and THC have an almost comparable potency when activating CB1 receptors. The only significant difference between these two is that THC has psychoactive effects that can be mind-altering. For this reason, it cannot be used as a substitute for anandamide.

The 2-AG Endocannabinoid

Although found in the brain in much higher concentrations (170 times anandamide), 2-AG is one of the uncelebrated primary endocannabinoids present in the brain. 2-AG, unlike anandamide, binds to both CB1 and CB2 receptors. It is thus more effective and efficient in activating cannabinoid receptors compared to anandamide. It however plays a crucial role in activating the body’s immune response. According to research, 2-AG has been shown to inhibit the production of cytokines, the proteins responsible for triggering a natural immune response in the body.

That aside, 2-AG has been attributed to contain potent neuroprotective properties. Studies show that increased levels of 2-AG help protect brain cells from further damage, especially in cases of neurodegenerative conditions (Alzheimer’s, Parkinson’s disease, etc..) and other forms of brain injury. It is worth noting that 2-AG is a product of arachidonic acid, though it is manufactured using glycerol. Glycerol is commonly used in food production as a preservation agent, filler, or sweetener. It is also a key ingredient in the production of e-cigarette liquids. If your body is unable to produce some of these crucial endocannabinoids, then chances are you will suffer from a clinical endocannabinoid deficiency.

CB1 and CB2 Cannabinoid Receptors

The human body is not only perfectly capable of producing cannabinoids but also has receptors designed to recognize and respond to them. The receptors in question are CB1 and CB2.

1. CB1 Receptors
CB1 receptors are mainly found within the brain’s neurons or nerve cells, most commonly in the hippocampus, hypothalamus, and amygdala. These parts of the brain are known to regulate memory, emotion, and hormones. You can also find CB1 receptors in the thyroid glands, muscles, intestines, the central nervous system, and several other glands and organs.

Should CB1 receptors start to fail/malfunction, one can experience:
- Decreased brain function and energy
- Cognitive decline – common with age progression
- Irregular hormone production (irregular metabolism, heart rate, and digestion)
- Irregular food intake or appetite
- Fatty liver disease.

2. CB2 Receptors
CB2 receptors are mostly concentrated in immune cells, thymus, tonsils, and spleen, with a tiny amount in the brain. First discovered in 1993, CB2 receptors are responsible for, among other roles, regulating immune function by triggering/stopping immune response and inflammation. Any changes in the CB2 receptor’s function can lead to a wide range of health complications. These include autoimmune, psychiatric, neurodegenerative, cancerous, cardiovascular, and gastrointestinal conditions.

The endocannabinoid system is thus made up of endocannabinoids and CB1 and CB2 receptors.

CBD (Cannabidiol)

Is There an Endogenous Type of Cannabidiol?

The short answer is YES. While CBD might be a phytocannabinoids, the human body still produces endocannabinoids. Technically, the endocannabinoid produced in the human body isn’t exactly the same as phytocannabinoids but mimic the same. The human endocannabinoid system however responds to CBD the same way it engages with endocannabinoids. Introducing CBD into the bloodstream thus signals the ECS into action. The only two endocannabinoids that researchers and scientists have positively identified are 2-arachidonoylglycerol (2-AG) and anandamide.

CBD And THC: Similar Yet Very Different

Although products of the cannabis plant, and both cannabinoids, CBD and THC differ in their properties. They however are 2 out of the 113 cannabinoids identified from the cannabis plant and known to engage endocannabinoid receptors in the body, with varying effects.

For example, THC is the only cannabinoid known to trigger a sense of euphoria in users. Marijuana typically contains higher THC content than any other phytocannabinoids, which is why it is a controlled product today. Hemp (a variety of cannabis Sativa) is a variety that contains higher concentrations of CBD but relatively low THC levels at less than 0.03%. The hemp plant is thus the most preferred variant for producing CBD and related products. CBD oil derived from hemp may contain THC but at negligible levels. You thus do not have to worry about getting high from using hemp-derived CBD oil or related products.

CBD and THC have varying effects on the human body, with CBD considerably the most beneficial. CBD gummies and oils packs many potent properties that may come in handy in promoting good health. CBD oil is also legal to use in most countries, while marijuana isn’t.

How CBD Interacts with The Endocannabinoid System

CBD binds to both CB1 and CB2 receptors triggering an almost immediate response from the endocannabinoid system. Although many of the CB1 receptors are found in the brain and the nervous system, some of these can also be found in the gut. CB1 receptors in the gut are thus first to be activated when one swallows full-spectrum CBD. It is worth noting that CB2 receptors are mostly concentrated in the immune system.

CB1 receptors are naturally proteins. They bind to endocannabinoid molecules to detect CBD and moderate and facilitate information flow to and from the brain. This is why phytocannabinoids and endocannabinoids are known to regulate, among other functions, memory, mood, pain, and appetite.


Known Side Effects Of CBD

According to neurosciencenews.com (dedicated to neuroscience research), an unregulated increase in endocannabinoids in the brain can trigger inflammation of the cerebellum in mice. While this might be the case with mice, it isn’t with humans. In a study conducted on the effects of degradation inhibitors (which cause over-accumulation of endocannabinoids in the brain) in humans, it was evident that CBD doesn’t cause inflammation at all. The only notable concern was that manipulating the body’s endocannabinoids could trigger inflammation in mice, a rare occurrence in humans. CBD is thus safe to use, especially if you are an adult. You however might want to consult your doctor if looking to use CBD to help improve symptoms of a chronic condition.

How THC Interacts With The Endocannabinoid System
THC is the main compound responsible for getting users ‘high’. It is also one of the most abundant compounds in the cannabis Sativa plant. Tetrahydrocannabinol (THC) binds onto CB1 and CB2 Receptors, like endocannabinoids, to interact with the endocannabinoid system. The fact that THC can bind to both of these receptors is what makes it overpowering.

THC may trigger a range of desirable and undesirable effects once in the body. Researchers have noted that THC might be effective in reducing pain but could also stimulate increased appetite in the user. It is also infamous for triggering anxiety and paranoia among some users, a reason most people prefer to stay away from marijuana altogether. Naturally, THC can trigger undesired effects in the body. Nevertheless, researchers are looking for ways to produce synthetic THC to tap into its beneficial aspect while eliminating the euphoric properties.

How CBD (Cannabidiol) Interacts with The Endocannabinoid System
CBD is considered to pack more beneficial properties for the human body than THC. For starters, CBD won’t make you high, nor will it trigger paranoia. This is one of the reasons more and more people use CBD oil for improved health and wellness. That aside, experts are yet to uncover how CBD interacts with the endocannabinoid system. One this is, however for sure; it doesn’t bind onto CB1 and CB2 receptors like THC does.

Many researchers believe CBD works by maintaining enough endocannabinoids in the system. By preventing the breakdown of endocannabinoids, the body can respond more accurately to signals from CB1 and CB2 receptors. Some researchers are also of the idea that CBD binds to a receptor yet to be discovered. As researchers continue with their debate and scientists try to unravel the mystery around CBD, it is evident that it will help ease pain and nausea, improve appetite, and improve skin health, and digestion, among other conditions.

Endocannabinoid Deficiency: What You Need to Know

Clinical endocannabinoid deficiency (CECD) is a theoretical condition that some believe to be caused by low levels of endocannabinoids in the body. This causes the ECS to start malfunctioning, leading to a myriad of health conditions and complications. According to a journal published in Trusted Source in 2016, 10-year research suggests that CECD might be the reason some people have fibromyalgia, migraines, and irritable bowel syndrome. The main keyword and giveaway in all these conditions is that they do not have a clear underlying cause. In addition to this, the said conditions occur alongside each other and are resistant to treatment. If this is the case, targeting the endocannabinoid system might be the missing link scientists need to find a cure for most of these conditions. More research is, however, required to ascertain this.