The Endocannabinoid System Explained: An Ultimate Guide

The endocannabinoid system is integral to human and animal health. This system, also known as the ECS, has signaling compounds and cannabinoid receptors in virtually every tissue in the body. In particular, these receptors are located in the immune system and nervous system. What does this vital system do? The endocannabinoid system is responsible for the balancing of the different actions of the body. It is constantly helping to maintain homeostasis, an equilibrium between opposing actions in the body.

Any endocannabinoid system review is incomplete without an understanding of how this network influences everyday functions such as mood and appetite. The ECS uses endocannabinoid signaling compounds that help to achieve this modulation of the human body.

Endocannabinoids act as neurotransmitters. Neurotransmitters are released by one cell to give instructions to another. This results in biological actions throughout the mind and body. The overall effect of these messages describes the tone of the endocannabinoid system. This tone, or the total action of the ECS, will fluctuate in response to the various states of the body and mind.

What Does the Endocannabinoid System Do?

In short, the endocannabinoid system maintains an overview of bodily functions. It responds to dysregulation or overactivity by adjusting its tone. The goal of these shifts is to help bring the body/mind back into homeostasis.


Homeostasis refers to a state of internal balance in the face of the ever-changing environmental influences of life. An example of an element that needs to be modulated in order to maintain homeostasis is temperature. Homeostasis is also relevant in regards to the topic of cellular functions such as oxidative stress. In homeostasis, everything tends to run efficiently, meaning that unwanted symptoms of body and mind are not as prevalent.

CECD and the Endocannabinoid System Explained

When the endocannabinoid system tone is modulated causing either an increase in activity or a reduction, homeostasis can no longer be maintained. This system helps to manage chronic pain, arthritis, autoimmune disorders, fatigue, mood disorders, and inflammation. The major mode of action of the ECS is through its cannabinoid compounds and receptors. When their functioning is irregular, it creates a condition known as clinical endocannabinoid deficiency (CECD). CECD can lead to a host of issues that seem to come from nowhere.

If the endocannabinoid tone is lost, then the body is in a state of CECD. Diet, lifestyle, and disease can all contribute to this deficiency. Cannabis plants also contain phytocannabinoids, plant-based compounds, that can interact with the ECS and help to maintain its tone.


The prefix “endo” indicates that these cannabinoids are native to the human system. They are produced within both the body and mind. These native signaling compounds are utilized by nearly every cell of the body.

Neurotransmitters each have a specific effect on a cell based upon the cell type and environmental factors. These chemical signalers interact with cannabinoid receptors that can be found on the surface of cells. The two most relevant cannabinoid receptors are CB1 and CB2 although others are known. There are 5 receptors that are considered endocannabinoids, but only 2-AG and AEA are well known.

A cell (cell 1) will release one of these endocannabinoids in order to communicate with a nearby cell (cell 2) whose functioning is creating an impact on the first cell (cell 1). Think about someone who is excited and making noise while you are trying to sleep. Asking them to continue their activity but lowering their voice would be akin to the message from cell 1 indicating that cell 2 should modify its behavior. If the message is received then the functioning of both parties runs in a smooth manner. If this system fails to operate properly problems in the overall functioning and health of the body may arise.

Cannabinoid Receptors

Receptors take in the input carried by neurotransmitters like endocannabinoids. Each cell contains DNA chains made of a specific sequence of components. This sequence dictates our individual genes and the genes which direct the production of various types of proteins.

Each type of proteins carries out a specific function. Receptors are a specific type of protein, and they are present in the membranes of cells. This receptor is exposed to both the outside environment and the inside of the cell. The portion of the receptor that outside responds to specific stimuli. The inside portion of the receptor encourages an action inside the cell in response to the outside environment. Of particular interest are the inputs provided by agonists. Neurotransmitters are chemical agonists meaning they bind to and activate a receptor to produce a specific response.

There are two major cannabinoid receptors, CB1 and CB2, along with a few others that are worthy of note.

CB1 Receptor

CB1 receptors are located throughout the entire body but are concentrated mainly in the brain and nervous system. It has been shown that certain phytocannabinoids from hemp can bind to this receptor mimicking the effects of our internal endocannabinoids. As research focused on decoding the effects of cannabis grew, it was discovered that over half of the receptors in our brain are cannabinoid receptors!

CB1 receptors modulate the core processes of cells. Specifically, CB1 reduces the activity of these functions and as these core processes are relevant to many types of cells this same mechanism can be used throughout the system to create varied effects. CB1 activation causes a high presence of calcium ions in nerve cells (neurons). These ions prevent the “firing” of the neuron. This can take on dramatically different effects depending on the location of the cell with the affected CB1 receptor.

CB2 Receptor

The immune system is home to the most CB2 receptors. These receptors are 44% identical to CB1 receptors. CB2 functioning changes in many different immune disorders. This relation to immune functioning makes it a prime candidate for therapeutic targeting.

CB2 also targets the core functions of different cells. In immune cells, CB2 modulates the creation of chemokines. Chemokines are released by immune cells (B cells) and their major function is to activate T-cells. T-cells are white blood cells that play a major role in immune function. CB2 also modifies the number of chemokines needed to encourage T-cells to act.

Other Cannabinoid Receptors

The other three receptors to be examined are GPR-55, PPAR, and TRPV1. GPR-55 receptors are thought to play a role in the soreness associated with immune cell activation. PPARs play a role in cancer and immune functioning. Endocannabinoids utilize these receptors to modify cellular gene expression. TRPV1 receptors are important in the modulation of pain perception. They are located on nerve cells spread throughout the PNS (peripheral nervous system). Endocannabinoids compete with painful stimulus for a spot on the TRPV1 receptor.

Review of the Various Endocannabinoids

AEA  | Anandamide

Anandamide, or N-arachidonoyl ethanolamide, was discovered in 1991. Ananda means “bliss” in Sanskrit, and the name was a nod to the fact that science had uncovered an internal cannabis compound. AEA acts as a partial agonist of CB1 receptors so they increase receptor activity. It is also a weak agonist of CB2 receptors. Despite its affinity for CB1 receptors, AEA is about 40% as potent as the 2-AG endocannabinoid.


2-Arachidonoyl Glycerol was discovered after AEA so it is not as well known. 2-AG is a full agonist of both CB1 and CB2 receptors although it has a greater affinity for CB2. Due to its relation to CB2, 2-AG is known for its part in the modulation of the immune system.

Endocannabinoid Misfits

Over the years three other indigenous compounds have been shown to display a significant amount of interaction with cannabinoid receptors.

In the year 2000, N-Arachidonoyl Dopamine, also known as NADA, was discovered to be an agonist of both CB1 and TRPV1 receptors. This neurotransmitter is 40x more attracted to CB1 than to CB2. The body primarily uses NADA to create TRPV1 receptor activation as it competes with painful stimulus for access to these receptors. The structure of NADA contains dopamine and arachidonic acid. Arachidonic acid is found in all endocannabinoids. NADA is the most potent endogenous CB1 agonist.

Noladin Ether goes by either 2-AGE or 2-Arachidonyl glyceryl ether. It was discovered in 2001 and as its name suggests it is similar in structure to 2-AG. It is important to note that even the slightest difference in structure changes the effect of a molecule. 2-AGE is an agonist for both cannabinoid receptor types. However, its affinity for CB1 receptors is 10x stronger than its attraction to CB2. Overall, it acts as a standard agonist of CB1; and it reduces the activity of CB2 receptors by competing with stronger CB2 agonists. 2-AGE also interacts with the PPAR receptors.

Virodhamine, or O-arachidonoyl ethanolamine, was discovered in 2002. Virodha in Sanskrit means “hindrance.” This endocannabinoid has a similar structure to AEA and binds at the same rate as other endocannabinoids. It gets the name hindrance from the fact that it produces a much weaker effect than other endocannabinoids and competes with other transmitters for a spot. This is a mechanism used by the ECS to limit the effects of stronger internal cannabinoids.

The Endocannabinoid System and Human Health

The total functioning of the ECS is far too complex to be discussed in just one article. All of the details in this article describe the basic functions of the components of this network. Just imagine that all of the receptor activations lead to a wave of effects in the cells and therefore the body. Ultimately the overall actions of these cells create a crescendo of impacts. All of these impacts together are the expression of the ECS tone.

Using this information, be sure to choose a lifestyle that best serves the balance of the endocannabinoid system and its related functions. It is enough to realize that the ECS is vital in maintaining homeostasis and fighting disease. Cannabinoid compounds present novel ways to access this powerful internal network.


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