CB1 and CB2 Receptors: How the Endocannabinoid System (ECS) Works?

A detailed look at the CB1 and CB2 receptors and their endocannabinoid system (ECS) interactions.

How Does the Endocannabinoid System Work?

The brain has 100 billion nerve cells, which are inconsistent communication via synapses. Nerves send signals to these synapses through axons, which are extensions of the nerves. At the synapse, neurotransmitters are released, which cross the synapse and send the signal to the cannabinoid receptors in the endocannabinoid system.

The endocannabinoid system has been in the human body as far back as research can go but was only discovered in 1992 by researcher Dr. William Devane and scientist Dr. Lumir Hanus. Since then, the scientific community has sought to understand the way that it works, discovering that every animal except insects has this system, and that exercise and activity can activate parts of it.

The endocannabinoid system is a signaling system in the body that handles the various processes in the body to achieve balance. More specifically, keeping this system balanced allows biological processes – like the metabolism, pain, immune function, etc. – to operate at their best possible capacity. Studies have revealed that the cannabinoid receptors have the ability to alleviate some conditions impacted by this system, like pain.

What are Cannabinoid Receptors?

The cannabinoid receptors in the body are crucial to utilizing the compounds in cannabis and are crucial to balance in the body. Every single function in the body operates with homeostasis to perform effectively. Everything in this system relies on two main types of receptors – Cannabinoid-1 Receptors (CB1) and Cannabinoid-2 Receptor (CB2).

CB1 Receptors

CB1 receptors are a protein that is targeted by delta-9-THC, which is the main compound in cannabis that is known for its intoxicating effects. THC is the main activator of CB1, which is presently federally illegal. However, many states have legalized the substance as either medical use only or for recreational use as well.

Most of these receptors are located in the central nervous system, allowing them to regulate brain functions and sometimes skin concerns. The most prominent endogenous cannabinoids are Anandamide and 2-Arachidonoylglycerol (2-AG), binding with CB1 receptors. Due to the connection to THC, these receptors help consumers affect the euphoric feelings associated with cannabis use.

When in the human body, the CNR1 gene produces the CB1 protein, and DNA shows exactly how to create it. Since every person carries a different version of the CNR1 gene, many people have a different experience with the use of compounds like THC and CBD, which explains why they may help some and hinder others.

Continued use of cannabis over time can create a tolerance within the user, as CB1 is expressed at a lower rate in the brain. However, even just taking a break from the consumption of cannabis for two days is enough to push these levels back up to what a non-user would experience.

The CB1 receptor is part of a group of cell membrane receptors in the body that is found in the nervous system, which accesses nearly every area of the brain and almost every neuron type. These receptors span the inside of every cell wall, and the cannabinoids that come into the body activate them. At this point, considering that CB1 receptors can be found inside and across the cell wall, scientists are unsure of whether the receptors are actually active, or if they are waiting to make their way back to the surface of the cell.

Along with offering a place for THC to be bound to the cell, the CB1 receptor can be activated with allosteric modulators, which would potentially allow the therapeutic effects of THC without the intoxicating effects.

CB2 Receptors

CB2 receptors are a protein that is specifically meant to be involved with the immune system in the body. Based on their definition by WeedMaps.com, the CB2 receptor helps with inflammation in the body, and it circulates through the brain and body’s immune cells using the bloodstream. These types of receptors can also be found in bones, the liver, and the spleen.

Even though the CB1 receptors work with the central nervous system, CB2 isn’t typically found on any neurons but those in the hippocampus and the brainstem. Microglia, or non-neuronal brain cells, tend to release CB2 receptors when the individual experiences inflammation or is injured.

Other Cannabinoid Receptors

Many scientists have theorized the existence of other cannabinoid receptors in the body. For instance, a study published in the Journal of Pharmacological Reviews stated,

“It is now generally accepted that some endocannabinoids, including anandamide, 2-arachidonoyl glycerol, and N-arachidonoyl dopamine, as well as Δ9-THC and a number of synthetic CB1/CB2 receptor agonists and antagonists, can activate or block established non-CB1, non-CB2 GPCRs, ligand-gated ion channels, ion channels and/or nuclear receptors (PPAR receptors).”

“Abnormal cannabidiol” is believed to create the same effects that regular cannabinoids do, but do not activate the CB1 or CB2 receptors. It is powerful enough to lower the blood pressure and reduce inflammation, much like CBD. Anandamide, which was the first endocannabinoid studied by Professor Raphael Mechoulam, is believed to interact with this receptor, found in the Central Nervous System.

The study further stated,

“Anandamide, such example, displays such potency at T-type voltage-gated calcium channels, voltage-gated KV3.1 and KV4.3 potassium channels, calcium-activated potassium (BK) channels, NMDA receptors, glycine receptors, and allosteric sites on 5-HT3 and nicotinic acetylcholine receptors.”

Even though these theories have little research to back them up, the presence of these receptors is still no more than an idea.

What Do the Cannabinoid Receptors Do?

Even though both of these receptors can be activated in the body, their purpose is much different. There have been multiple studies that examine what these receptors can actually do when activated, including a study by the researchers at the University of Bristol.

CB1 is targeted specifically by “retrograde messengers,” as they connect the gap between two neurons. These messengers include endocannabinoids, anandamides, and 2-AG. After the molecules bind with the receptor, the intracellular tail of CB2 releases G proteins, which set off other intracellular processes, including neurotransmitter release.

Ultimately, the role of the CB1 receptor is to regulate the release of serotonin, dopamine, and glutamate (among other neurotransmitters) as a multi-faceted therapeutic target.

Activating Cannabinoid Receptors

Whenever a molecule binds to either of the cannabinoid receptors, there are certain effects that occur in the body. Some of these effects feel therapeutic, while others can inhibit the way that the body functions. While CB1 is activating through the use of THC from an external source, the CB2 receptors are only found in the brain when the body is injured or experiences inflammation.

Pain Relief

Pain relief is one of the most common effects of CB1, though it can technically be helped with CB2 activation as well. With CB1, the midbrain is able to alleviate pain through the descending pathway. Typically, as THC activates this receptor, cannabis is a better source of pain relief than CBD would be. CBD is not capable of activating the CB1 receptors, so it can be used to reduce the inflammation that CB2 receptors take over, but the pain is only soothed through THC and the activation of CB1.

Reducing Inflammation

Though CB1 receptor activation helps the body to experience less pain by inhibiting the signal to the brain, the activation of CB2 receptors has an anti-inflammatory effect. Cannabinoids bind with these receptors to inhibit inflammation that can be caused by chronic opioids as well, according to research published by the American Pain Society.

Fighting Opioid Overdose

When CB2 receptors inhibit the response of chronic opioids in the body, diminished tolerance has been linked with preventing consumers from overdosing on opioids. Ultimately, researchers are still studying the effects on this tolerance, but there is enough evidence to suggest that the right activation of these receptors can help fight addiction to opioids.

Reduced Risk of Stroke

The effects on the risk of stroke come back to the way that CB2 activation can reduce inflammation, according to both the American Stroke Association and the American Heart Association. The neural damage caused by strokes is tied directly to the inflammation involved, but the reduction in this inflammation with CB2 activation could protect the heart and the brain from succumbing to the extreme damage that stroke victims sustain. However, as a medical benefit, this effect doesn’t have conclusive evidence yet.

Sedation and Motor Impairment

When it comes to actually impair the body, the most likely receptor to have this effect is CB1, brought on by the use of THC. The receptors in the basal ganglia, the part of the brain that coordinates movement, has CB1 receptors that respond to the use of THC.

As CB1 activation can cause this area of the brain to be inflamed, consumers may find relief from this impairment with CB2 activation. When using CB2, studies have shown that CBD can reduce inflammation throughout the body, which could help with the impairment that the user sustains.

Cognitive and Memory Impairment

While there are many studies that suggest that the use of cannabis can help improve memory, the activation of CB1 receptors with THC creates the opposite effect. The receptors in the hippocampus are activated, and inflammation in this area of the brain is stimulated.

Some research indicates that this effect may be minimized with the activation of CB2 receptors, which are known to reduce inflammation in the body. By reducing the inflammation that clouds the mind, consumers may continue to feel the euphoria caused by CB1 activation still.

Tachycardia

Cannabis is linked to a faster heart rate in some users, which is also referred to as tachycardia, which can tie in the CB1 receptors involved in cardiac cells. The autonomic nervous system has a significant number of CB1 receptors, including within the medulla.

The medulla controls the involuntary functions of the body, like breathing and pumping the heart, which the individual cannot make happen on their own. More specifically, the CB1 receptors can be found in a high concentration in the medulla oblongata, which is the connection between the tip of the spinal cord and the brain where involuntary functions are stimulated and controlled.

Increased Appetite

One of the common, and the most comedically popularized, effects on the body is the stimulation of the appetite and the metabolism, which many people refer to as “the munchies.” CB1 can create an energetic craving to consume food, desiring to satisfy the need to eat for pleasure, rather than just to nourish the body. There are some studies that recently found a possible connection between the ECS and the gut microbiome, suggesting that CB1 can also stimulate the metabolism.

Increased Risk of Autoimmune Disorders

The CB2 receptor is largely controlled by processes happening within the body. However, a mutation of this gene can cause detrimental effects and has been connected with some forms of osteoporosis and other autoimmune diseases.

In general, the activation of this gene has been connected with the health of bones, as it nourishes the immune system. However, since the receptors can be genetically different from one individual to the next, the opposite effect could take place, putting the individual at risk for an autoimmune disorder if activated.

Treating the Body with Cannabinoid Receptor Activation

Presently, the Food and Drug Administration has only approved cannabis, whether prominent in THC or CBD, for the treatment of two specific types of epilepsy. However, each state features a list of qualifying conditions that stand to benefit from the activation of CB1 and CB2 receptors. These two receptors are 44% identical in the amino acid sequences they contain, which is why is important to speak with a doctor or licensed professional to determine the best way to treat the body with cannabis.

A certain balance is required with the use of these substances, as they have opposite effects. A research group, involving Chinese researchers, Russian biologists, and US biologists, showed that the activation of the receptors with one substance can actually prevent the other receptor from accurately working.

Petr Popov, a co-author in this study, stated,

“Every G protein-coupled receptor structure that is discovered has prospects for the rational design of more efficient drugs. Now that the structures of both cannabinoid receptors are known, we can design selective compounds targeting only one of the receptors, as well as agents with a desired polypharmacological profile targeting both receptors at once.”

Final Thoughts

The human body is still a mystery in so many ways, and the fact that the scientific community didn’t even discover this system until less than 30 years ago shows that there is still much to learn. Ultimately, cannabis clearly has a role to play in the body, though further research should be pursued to mitigate some of the problems caused by the activation of the receptors.

Melissa Meyer
Melissa is a Georgetown Law grad with a background startups, advocacy, and health. Melissa spent much of 2010 – 2013 in the Lombardi Cancer center where she was being treated for a life-threatening blood disease. In that same period, she experienced the loss of her two closest girl friends to cancer. Her life goals include destroying cancer and helping patients improve their quality of life through alternative medicine. She does everything for HealthMJ that she can’t find someone else to do better.

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