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Endocannabinoid Receptors and How They Work In Your Body to Heal You

Christine Kielhorn PHD
Endocannabinoid Receptor in the brain animation

The endocannabinoid system was hard to understand, until now. Here’s how it works.

The endocannabinoid system refers to a signaling system of receptors on the surface of certain body cells. It includes ligands, or endocannabinoids, that fit into the receptors and activate them. Also included in this system are enzymes responsible for making or degrading the endocannabinoids.

Young woman researcher in the lab

Image Credit: Anyai Vanova

In the 1980s, research was conducted on the brain and the effect of cannabinoids found in the cannabis plant. This is when we learned that there are specific binding sites for cannabinoids.  Then in the early 1990s, the two major cannabinoid receptors were identified and cloned. These are called CB1 and CB2 and both are G protein-coupled receptors.

Since their discovery, researchers have learned more about the endocannabinoid system and mechanisms for its involvement in various diseases. As a result, cannabis, or cannabinoids, have become the focus of developing new therapies, and the medical use of cannabis has become a target of public policy.

Indoor Cannabis Grow

Image Credit: Xela Person

CB1 Receptors in Nervous System

The first type of cannabinoid receptor, CB1, is found primarily in the brain and on tissues associated with the central nervous system, like neurons in the spinal cord. However, it has also been found in peripheral organs like the pancreas, digestive tract, and liver.

In the brain, CB1 receptors are present in high densities in certain structures, like the substantia nigra, basal ganglia, cerebellum, and hippocampus. Other areas of the brain have much lower densities, like the brainstem, which is why cannabis can’t be lethal; it doesn’t affect respiratory centers in the brain.

Medically Accurate Brain Animation

Image Credit: Sebastian Kaulitzki

CB1 receptors are thought to be responsible for the psychoactive effects of cannabis. These receptors also play an important role in brain development and in several signaling pathways in the brain. These pathways are responsible for: cognition, neuronal growth, and the regulation of reward and mood systems. Activation of the CB1 receptor is therefore not only responsible for the euphoric high associated with the recreational use of Cannabis but also for a variety of therapeutic effects like treating anxiety, pain, and post-traumatic stress disorder (PTSD).

Black American GI with PTSD

Image Credit: John Gomez

The CB1 receptor is activated by ligands made by the body, but also by the most famous of all the cannabinoids, delta-9-tetrahydrocannabinol (THC). THC binds strongly to the CB1 receptor, which is likely the reason for its psychoactive effects.

Cannabidiol (CBD) can bind to the CB1 receptor, but not very strongly; its affinity for the receptor is low. Another cannabinoid found in the cannabis plant, delta-9-tetrahydrocannabivarin (THCV) is also known to bind strongly to the CB1 receptor, although THCV blocks the binding site on the CB1 receptor, inhibiting its activation. So, it’s medicinal actions are different than THC.

Chemical Structure of THC and CBD

Image Credit: Stockish

In the brain, the CB1 receptor is often found in neural synapses. But, unlike the receptors associated with most neurotransmitters, the CB1 receptor is often found in the presynapse neuron. Endocannabinoids are made and released from the postsynaptic neuron. When the CB1 receptor is activated, it often prevents further release of neurotransmitters, so it seems that the endocannabinoid system functions as a negative feedback loop. For example, it can prevent the release of glutamate, which is thought to be how cannabis has a the neuroprotective effect.

CB2 Receptor is Part of Immune System

The CB2 receptor is primarily expressed by immune cells.  Some scientists hypothesize that the CB2 receptor evolved as a defense mechanism for the body since it is involved in suppressing inflammatory responses and in neuroprotective responses to brain injury.

The CB2 receptor is also thought to be involved in the pain relieving use of cannabis. THC and CBD both bind to the CB2 receptor, although again, CBD has a low affinity for it. THCV also inhibits the CB2 receptor, just as it does for the CB1 receptor. Many researchers have developed synthetic cannabinoid molecules that can bind specifically to the CB2 receptor and not to the CB1 receptor in order to obtain therapeutic effects of CB2 activation without causing psychoactive side effects.

Immune System concept

Image Credit: Blue Bay

The low affinity of CBD for both the cannabinoid receptors has caused some researchers to hypothesize that there may be other unidentified receptors in the endocannabinoid system. Other G protein-coupled receptors have also been identified as cannabinoid-like. I

n addition, there are other receptors, like the transient receptor potential vanilloid type 1 receptor (TRPV1) ion channel, that can be activated by cannabinoids like CBD, so there may be some crossover between the endocannabinoid and other signaling systems.

CBD is also thought to inhibit the activity of fatty acid amide hydrolase (FAAH), the enzyme responsible for breaking down endocannabinoid anandamide. As a result, CBD can contribute to elevated levels of anandamide, which targets the cannabinoid receptors with higher affinity than CBD but without psychoactive effects of THC.

Endocannabinoid Receptor in the brain animation

Image Credit: Juan Gaertner

There is no doubt that we are at the beginning of a very exciting learning curve for medicine. As we learn more about how cannabis interacts with the endocannabinoid receptors in our body, we will be able to develop strains that are targeted toward specific conditions.

Christine Kielhorn
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