CB2 Receptor: The Balancer Of The CB1 Receptor

Science has discovered that cannabinoid receptors in the human body, like the CB2 receptor, plays a role in the management of many physiological responses. Without curious minds wanting to understand the cannabis plant, we might never have known that our bodies make their own cannabinoids and cannabinoid receptors.

CB2 Receptor: The Highlights

  • The CB2 receptor is one of two main cannabinoid receptors which make up the endocannabinoid system (ECS), with the other being CB1.
  • The CB2 receptor is mainly found in the immune system, with the greatest concentration found in the spleen and the gastrointestinal system.
  • CBD has no binding affinity to the CB2 receptor, unlike THC. Therefore, stimulation of the CB2 receptor using phytocannabinoids occurs in the presence of THC, not CBD.
  • The endocannabinoid system is made up of endogenous cannabinoids (such as anandamide and 2-AG), cannabinoid receptors (such as CB1 and CB2) and enzymes which digest those cannabinoids.
  • The main objective of the endocannabinoid system is to restore and maintain homeostatic balance in the body and brain.

What Are Cannabinoid Receptors?

Cannabinoid receptors are integral parts of the endocannabinoid system and are G-coupled proteins which rest on the outside of certain cells. Their main function is to “receive” endogenous cannabinoids such as anandamide, whereby endogenous cannabinoids bind to the receptor’s binding site.

Once an endogenous cannabinoid has made contact with the binding site, it causes a cascade of events inside the cell. Depending on the cannabinoid receptor that is stimulated, and which cannabinoid has stimulated it, the final result of this cascade of events will vary.

In some circumstances, it will be the reduction of inflammation while in others, it will be an overall feeling of “bliss”.

Different cannabinoid receptors are located in different parts of the body. For example, the CB1 receptor is mainly located in the central nervous system and the peripheral nervous system. The CB2 receptor, on the other hand, is mainly found in immune cells and tissues.

When dysfunction of the ECS occurs, multiple different ailments can ensue. For example, in mice that are lacking CB2 receptors, there is an increased expression of the inflammatory phenotype.

What Is The Endocannabinoid System?

The Endocannabinoid System

The discovery of the endocannabinoid system began to unfold in 1992. It was first only a theory belonging to Raphael Mechoulam after the isolation of THC and CBD from the cannabis plant.

Upon the isolation of THC, Mechoulam hypothesized that there must be a naturally occurring receptor in the human body that openly receives THC. And if such a thing exists, then there must be endogenous cannabinoids!

This hypothesis led to the discovery of the first endogenous cannabinoid named anandamide. From this came multiple subsequent discoveries which finally led to the “mapping” of a human endocannabinoid system.

What’s more interesting is that it was discovered that the endocannabinoid system is not unique to humans. It is a system that permeates virtually all the living world and is found in the body of every mammal on earth.

The components of the ECS are endogenous cannabinoids themselves, cannabinoid receptors and the enzymes that breakdown endogenous cannabinoids. The system itself is not localized in the way the gastrointestinal system is.

Rather, it is located on different kinds of cells all over the body.

The role of the endocannabinoid system is to modulate the functions of the brain, endocrine, and immune tissues. It regulates the secretion of hormones, the inflammatory response and the body’s response to stressful stimuli.

It even modulates how different cells absorb and use energy, such as muscle tissues, adipose tissue, and the liver.

Where Can You Find The Cannabinoid Receptors?

As we mentioned, cannabinoid receptors can be found just about everywhere on the body. They are found on:

  • the skin
  • the tissues of the gastrointestinal system
  • in the brain
  • on the spinal cord
  • on the spleen and liver

And really just about anywhere else in the body. The joint work of cannabinoids and cannabinoid receptors can be likened to chemical signaling that takes place in the brain and body.

CB1 Receptor

The CB1 receptor is most commonly found in the central and peripheral nervous systems, as well as in the lungs, liver, and kidneys. They are concentrated in the brain, more specifically in the basal ganglia and the limbic system.

THC has a very strong binding affinity for the CB1 receptor, and it is this strong relationship that causes the psychoactive effect when THC is consumed. Activation of the CB1 receptor is also what gives patients relief from nausea, pain, and depression.

CB2 Receptor

CB2 Receptors in the body

The main bulk of cannabis’ physical remedial effects is thanks to the CB2 receptor.

It is distributed mainly around immune tissues, especially in the spleen and gastrointestinal system. Stimulation or lack thereof of the CB2 receptor mediates immune response, especially inflammation.

While THC sometimes binds to the CB2 receptor, it is not affected by CBD by direct binding. Rather, CBD affects how the CB2 receptor can bind to other cannabinoids, and this is what causes CBD to have a remedial effect via the CB2 receptor.

How Cannabinoid Receptors Work

Cannabinoids and cannabinoid receptors can be thought of like a lock and key. When the key (cannabinoid) enters the lock (receptor), the door opens for chemical signals to be transferred around the body.

This is basically what happens when a person consumes cannabis — it is as though they have supplemented the volume of cannabinoids circulating in the body.

What makes the ECS unique compared to other chemical signaling mechanisms of the body is that it works in reverse. When something has become “too much” in the body, endogenous cannabinoids are created on demand, and they act like a dimmer switch on whatever is overloading.

In the case of inflammation, for example, triggering the ECS reduces the inflammatory response. In the case of stressed muscles, the ECS relaxes them. In a sense, it is not excitatory.

The ECS essentially checks and balances the body. When there is too much of something, it makes an endocannabinoid that can slow it down. When that endocannabinoid finds the receptor, the body begins to recover from stressful stimuli.

How The CB2 Receptor Balances The CB1 Receptor

The balance between CB receptors is unique to every individual.

This balance is called “expression”, and while there may be a high expression of CB1 receptors in one person, there may be a lower expression in another. The overall expression of both CB1 and CB2 receptors is the balance between the two.

This also explains why different people respond to cannabinoids differently.

In a person with a high concentration of CB1 receptors in the brain, THC may be extremely powerful and lead to an anxious or paranoid response. But in a person with a high concentration of CB2 receptors in the intestines, CBD may help to ease any inflammation in that area.

Dr. Ethan Russo has coined a medical condition called Clinical Endocannabinoid Deficiency, which he believes is at the root of many different conditions such as migraine, Crohn’s Disease, and fibromyalgia.

This would also explain why cannabinoids are so effective for these people.

Essentially, an over or underexpression of CB1 or CB2 receptors and endogenous cannabinoids can lead to a complete imbalance in the body. The final result is a disease.

Cannabinoid Receptors And The Entourage Effect

One of the biggest questions that biomedical scientists are asking is, “how can we target the CB2 receptor?”. Even though THC has a mild affinity for the CB2 receptor, CBD does not.

And overall, we know the many therapeutic tools that the CB2 receptor can activate, but we don’t know how to activate the CB2 receptor. The answer might lie in a phenomenon called the entourage effect.

The entourage effect is essentially the combined effort of all of the compounds in cannabis. Rather than being competitive with each other, they hold each other up, potentiate each other and are responsible for the overall healing effect of cannabis.

Dr. Ethan Russo says that the reason cannabis can cause relief from so many different symptoms is the synergy between all the different elements in the plant.

So we may not be able to target the CB2 receptor with a single cannabinoid yet. This is probably because we are looking in the wrong place.

Instead of looking at exactly which chemical will stimulate CB2, we are better of looking at which combination of chemicals stimulates the CB2.

Cannabinoid Receptors At Work

The treatment of different conditions with cannabis is characterized by different cannabinoids and how they bind to receptors. This is why THC is better for some conditions while CBD is better for others again.

IBS And Crohn’s

Crohn's Disease icon

As mentioned earlier, there is a high concentration of CB2 receptors in the gastrointestinal system. This also forms the basis of why Ethan Russo believes Crohn’s Disease is one of the conditions caused by a clinical endocannabinoid deficiency.

Increased inflammation in the intestines and stomach is not dealt with by the ECS but can be managed with the combined effort of THC and CBD.

PTSD

Those with PTSD find success when using THC thanks to the concentration of CB1 receptors in the hippocampus and limbic system, the parts of the brain associated with PTSD.

In fact, a 2014 study, researchers concluded that in PTSD brains, there is an incorrection or abnormality in CB1 receptor-mediated anandamide signaling. Consumption of THC may restore the chemical signaling, therefore providing relief.

Epilepsy

The CB1 receptor is implicated in the regulation of spontaneous seizures in patients with epilepsy. This forms the entire basis of GW Pharmaceutical’s two products; Sativex and Epidiolex.

In fact, it is found that endogenous cannabinoids mediate seizure response (by communicating with the CB1 receptor), and it is perhaps a deficiency in this endogenous cannabinoid that allows many seizures to take place.

The same research concluded that the ECS can help to modulate neuroexcitation, as it has the ability to diminish or reduce responses to neuroexcitation such as seizure.

The Importance Of The CB2 Receptor

It is almost alarming that we would not know of the existence of the CB2 receptor if it weren’t for studying marijuana.

Essentially, the study of this magical plant is what led us to the understanding that we even have an endocannabinoid system, and that this system is implicated in so many different health conditions.

Farma Health Desk Editor