The Endocannabinoid System

Expression of the endocannabinoid system (ECS) throughout the human body

What is the Endocannabinoid System?

The endocannabinoid system (ECS) can be found in almost every part of our body, but especially the nervous system and immune system. A healthy endocannabinoid system enables homeostasis. This simply means the ECS balances our cells and organs – it’s the Yin and Yang of the body.

What Does the Endocannabinoid System Do?

In order to maintain this balance, the endocannabinoid system (ECS) regulates physical and emotional processes like appetite and mood. It does this with substances called endocannabinoids, which are neurotransmitters. Simply put, neurotransmitters are “chemical commands” that one cell releases to tell another cell what to do, creating a specific biological response.

The net effect of these commands is called endocannabinoid tone. Tonic systems in the body have resting activity, so cannabinoid receptors are constantly activated by a low level of anandamide production. Because the system has a resting activity of greater than 0, that means that its activity can be turned down! This is how the ECS is able to control regulation; if it wasn’t able to decrease its activity from the baseline, then it wouldn’t be able to promote balance when a process needs to be reduced slightly.

When was the endocannabinoid system discovered?

Do I have an endocannabinoid system? All mammals have an endocannabinoid system (ECS). Its discovery has been a 40 year journey, and more is uncovered every day. Researchers discovered the endocannabinoid system while attempting to pinpoint exactly how THC produces its effects; THC is the compound found in cannabis which causes the psychoactive effects (the high) associated with marijuana.

What they have learned over the years is that the endocannabinoid system, ECS for short, is a signaling system that allows our cells and organs to communicate with each other in order to balance overall activity and energy consumption. This results in what we call homeostasis: a healthy state of balance within our body.

What is homeostasis? Homeostasis is internalbalance or stability amid changing external conditions. The term homeostasis is very broad. It refers to general organism-level factors, like body temperature, which are affected by the external environment. Homeostasis also refers to specific cellular factors like oxidative stress, which are affected by the activity levels of other cells in the immediate microscopic vicinity.

The endocannabinoid system – a complex, scaled communication network – maintains homeostasis and balance across the different systems of our body.

What Are Endocannabinoids?

Endocannabinoids are chemical messengers. The word endocannabinoid means “cannabinoid produced inside”; it refers to cannabinoids that are produced inside our bodies. Endocannabinoids are signalling molecules used by almost all of our cells. Chemical signals are released by one cell in order to produce some effect in a nearby cell, like when you use a remote control to turn on the TV.

Every chemical signal has a predictable and consistent effect depending on cell-type and chemical environment, just like the power button on your remote turns the TV on, but doesn’t affect the volume or the menu because there are different buttons – neurotransmitters – for those actions. Hormones like estrogen, and neurotransmitters such as dopamine and serotonin, are all common examples of chemical signals or messengers.

The process of cellular communication involves chemical signals and the receptors which they act on. In the ECS, there are 5 relatively well-known endocannabinoids, although 2-AG and anandamide are the most well-known. Specifically, a cell releases endocannabinoids to alter the activity levels of a nearby cell which is affecting it in some way.

To think of this relationship, imagine a teacher giving information to her students. If she’s going too fast, the students will ask her to slow down. If the teacher and her students were cells in our body, the endocannabinoid system would be the students’ ability to ask the teacher to slow down. If this ability is hampered in some way, then problems with the students’ understanding will occur. Similarly, when the ECS fails to allow cells to communicate, health problems arise.

What is endocannabinoid deficiency?

When the ECS becomes overactive or underactive, endocannabinoid tone can no longer promote homeostasis. Without the ECS to maintain balance, systems of the body begin to malfunction. This condition is called Clinical Endocannabinoid Deficiency (CECD).

CECD leads to many common health problems that seem to arise without cause.

Endocannabinoid system deficiency Symptoms Can Include:

  • Chronic pain
  • Arthritis Fatigue Inflammation
  • Autoimmune disorders
  • Depression and other mood disorders

What causes Clinical  Endocannabinoid Deficiency?

CECD occurs when your body loses the ability to maintain a healthy endocannabinoid tone. This can be caused by dietary and lifestyle factors, or other disorders. Cannabis plants produce compounds called phytocannabinoids, which interact with our endocannabinoid system to promote balance and maintain a healthy endocannabinoid tone.

Below is an overview of the endocannabinoids that have been discovered so far, and what we know about their activities and responsibilities.

Anandamide (N-Arachidonoyl Ethanolamide)

What is Anandamide?Anandamide, also known as AEA , was the first endocannabinoid discovered back in 1991. The word  anandamide comes from the sanskrit word for bliss: “ananda”.

Anandamide is a partial agonist of CB1 receptors, which are found in the central nervous system. It’s a weaker agonist of CB2 receptors, which are found in the periphery and immune system.

What Is An Agonist?

An agonist is any chemical compound which activates a given receptor. In the case of anandamide, it binds to and activates CB1 and CB2 cannabinoid receptors. However, it
only partially activates them. It’s about 40% as potent as 2-AG at cannabinoid CB1 receptors.


2-AG, or 2-arachidonoyl glycerol, is another major endocannabinoid in addition to anandamide. It was discovered after anandamide so it’s less-commonly known, but 2-AG’s role is equally important. Unlike anandamide, 2-AG is a full agonist of CB1 and CB2 receptors. For some context, 2-AG is strongly associated with the feeling of a “runner’s high,” the sense of euphoria reported by athletes following intense workouts.

Virodhamine (O-Arachidonoyl Ethanolamine)

In 2002, another endogenous compound with activity at cannabinoid receptors was discovered: virodhamine. It has the same chemical formula as anandamide, but its effects are slightly diminished. By binding to cannabinoid receptors at the same rate as the other endocannabinoids, but producing a significantly smaller effect, virodhamine reduces the overallactivation of cannabinoid receptors.

Researchers believe this is just one of the many regulatory mechanisms innate within the endocannabinoid system: virodhamine limits the effects of the stronger endocannabinoids in a process called competitive antagonization.

Noladin Ether

2-Arachidonyl glyceryl ether, 2-AGE, or simply noladin ether, is an endocannabinoid that was discovered in 2001 by a team led by Raphael Mechoulam, the scientist who discovered THC and many other phytocannabinoids (plant-derived cannabinoids).

Structurally, 2-AGE is almost identical to 2-AG. Similar to the relationship between anandamide and virodhamine, 2-AG and 2-AGE have nearly identical chemical formulas, but are arranged in a slightly different manner, producing slightly different effects. 2-AGE is an agonist of both cannabinoid receptors, although it has ten times the affinity (attraction) for CB1 receptors compared to CB2. For this reason, it acts as an agonist at CB1 receptors, but has the net effect of reducing the activity of CB2 receptors, by competing for spots at the receptor with stronger agonists.

In addition to the classic CB1 and CB2 cannabinoid receptors, 2-AGE also binds to the PPAR receptor, which controls how genes get expressed in brain cells.

N Arachidonoyl Dopamine (NADA)

In 2000, NADA was discovered as an cb1 receptor agonist and TRPV1 receptors, but not of CB2. It is 40 times more attracted to CB1 than CB2, and it’s the body’s primary endogenous TRPV1 agonist. 

TRPV1 Receptor Location

TRPV 1 receptors are located on sensory nerves and they react to chemicals that are painful to touch. NADA competes with these painful chemicals for a spot at the pain receptor, but it doesn’t cause a pain response. NADA protects us from chemical pain by blocking the receptors where the pain would be registered.

NADA is the combination of arachidonic acid, found in all endocannabinoids, with dopamine, one of the brain’s primary neurotransmitters. It is the strongest endogenous CB1 agonist, and it can also be applied as a dietary supplement.

What Are Cannabinoid Receptors?

Receptors receive. In biological organisms like humans and cannabis plants, long chains of DNA (deoxyribonucleic acid) are included in every single cell. DNA is shaped like a twisting ladder, but instead of 10 or 20 rungs, the DNA ladder in eachofyourindividualcellshas about 3,000,000,000 (billion) “rungs”, or base pairs.

Why Do We Have Cannabinoid Receptors?

The order of these base pairs determines our genes, and our genes work by getting turned into one of over 50,000 different proteins which each have a distinct and important purpose. Proteins  are the “machines” which carry out all of the different processes within our cells. They are classified by their purpose. Receptors  are a class of proteins which become embedded in cell membranes: they’re called  membrane-bound proteins. This is key to their function, because part of the receptor is exposed to the outside of the cell, while the rest resides within the cell.

The part of the receptor which is positioned outsideof the cell responds to environmental stimuli, such as heat, light, or a certain chemicals (remember chemical messengers?). The part of the receptor extending insidethe cell then produces an effect within the cell based on the external stimuli. Each different receptor is receptive to a unique stimulus, called an agonist.

What Are CB1 and CB2 Receptors?

Cannabinoid Receptors CB1 

Where are CB1 Receptors Found?Cannabinoid receptor type 1 (CB1) are found in the brain and central nervous system of all mammals. This receptor was first discovered as researchers sought to decode the effects of THC, the main psychoactive ingredient in marijuana. It was found that Δ9-THC potently binds to CB1 receptors, and thus mimics the effects of the endogenous cannabinoids. Although it was only recently discovered, the importance of CB1 in the central nervous system is demonstrated by the fact that there are more CB1 receptors than all other receptors, combined: more than half of all receptors in your brain are cannabinoid receptors.

When activated, CB1 receptors drastically reduce the activity of important cellular processes that are required for the core functionality of cells. Importantly, these core processes are repeated in many different types of cells, so the endocannabinoid system is able to use the same mechanismto control the activity of drastically different types of cells.

The core function of neurons is to produce an action potential, the scientific term for when a neuron “fires”. CB1 activation causes an influx of calcium ions into the neuron, which temporarily prevents the formation of such an action potential; CB1 activation preventsthe neuron from firing. This can have many different effects depending on the region of the brain which is being inhibited by CB1 activation.

CB2 Cannabinoid Receptors

Cannabinoid receptors type 2(CB2) are primarily concentrated in the immune system of mammals as opposed to the concentration of CB1 receptors  in the CNS. CB2 receptors are only 44% identical to CB1 receptors, but they have nearly the same cellular purpose, the primary differences being the type of cell which expresses them and the specific compounds which activate them.

Similar to CB1 in the brain, CB2 is one of the most abundant receptors in immune tissue. Furthermore, CB2 activity is impacted in many disorders of immune origin. Researchers believe this correlation is responsible for at least some of the therapeutic properties of the phytocannabinoids whichinteract with CB2 receptors. As a cannabinoid receptor, CB2 inhibits the activity of fundamental processes which many different kinds of cells use to carry out their core function. The core functionality of immune cells (B cells) is to recognize specific chemical markers of injury or infection – called antigens – and activate “soldier”   or “doctor” cells (T cells) by releasing chemical messengers known as chemokines.

CB2 activation reduces the ability of B cells to produce chemokines. It also raises the threshold amount of chemokines required to “activate” the T cells, which create inflammation and can subsequently harm healthy tissue if not properly balanced and regulated by processes like CB2 activation.

GPR-55 (Orphan G-protein coupled receptor 55)

Another receptor, the ultimate function of which is not entirely clear, but the existence of which has been known for decades, is the GPR-55 receptor.    It is found throughout all tissues, and it appears to have a role in mediating “soreness”, or pain caused by the activation of immune cells. Aches and pains associated by a workout or a moderate cold/flu are not actually caused by these things.

Rather, the immune response to muscle damage or an infection like the flu causes the release of compounds which activate pain receptors on sensory nerves. It is thought that GPR-55 is one  of these receptors, and cannabinoids regulate pain by competing with the painful immune chemicals for a spot activating a GPR-55 receptor.

Other receptors

In addition to CB1, CB2, and GPR-55, other kinds of receptors respond to and interact with endocannabinoids and plant cannabinoids. The discovery of additional receptors that operate within the endocannabinoid system continuously expands our understanding of how the ECS works.

Peroxisome Proliferator-activated receptors  (PPARs) control the expression of genes depending on cell-type. They are implicated in cancer growth and activation of immune cells. Endocannabinoids interact with PPARs to modulate the expression of certain genes based on the requirements ofthe cell’s environment.

Transient  receptor  potential  vanilloid type 1 receptors  (TRPV1)  are found on sensory nerves throughout the peripheral nervous system. TRPV 1 receptors recognize both high temperatures as well as chemicals that “burn”, like the primary compound responsible for the taste of chili peppers: capsaicin.

They are an instrumental part of human pain perception, and endocannabinoid regulation of TRPV1 is a negative feedback mechanism whichmaintains the sensitivity of this receptor by competing with painful stimuli for spots at TRPV1 receptors, a process called competitive antagonization.

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