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Ever wonder why the hundreds of phytocannabinoids like cannabidiol (CBD), cannabigerol (CBG), or even tetrahydrocannabinol (THC) work? Most people use Cannabis Sativa plants like hemp and marijuana to experience these cannabinoids as a wellness aid or to get “high.” But the thing is, we could not experience the therapeutic benefits of the effects of cannabis if our body did not have a biological system to interact with them.

The endocannabinoid system (ECS) allows us to use CBD for pain, anxiety, etc. and enjoy our favorite cannabis plant strains. The ECS serves super important functions for our overall health and well-being because it can help regulate our internal biological processes.

In this article, we will dive in-depth into common questions about what is the endocannabinoid system, as well as, how it works and what it influences.  Please refer to the articles “Table of Contents” below for specific topics within this article.

When Was The Endocannabinoid System Discovered?

In 1988, the government-funded United States study at St. Louis University School of Medicine officially documented and scientifically proved that mammals (humans, etc) have receptor sites that respond to the chemical compounds found in cannabis. These receptor sites are known as neurotransmitters.

In 1990, a team led by Lisa Matsuda at the National Institute of Mental Health in the United States mapped the DNA sequence that encodes cannabinoid receptors in the brain. This study was eye-opening and led to G-protein-coupled receptors, called endocannabinoids, like CB1 and CB2 to be directly identified.

CB1 is a dominant receptor in the brain, responsible for signaling to the rest of the ECS once influenced by cannabinoids. CB2 is a second receptor, mostly located in the immune and peripheral nervous systems.

In 1992, at the Hebrew University in Jerusalem, Dr. Lumir Hanus along with American researcher Dr. William Devane discovered other endocannabinoids like 2-AG, 2-AGE, DEA, and NADA. These scientific discoveries gave light into the complex metabolic pathways and interactions between phytocannabinoids and endocannabinoids. This molecular signaling system was called The Endocannabinoid System.

Sources:

  • Hanus. Lumir. O. (2007). Discovery and Isolation of Anandamide and Other Endocannabinoids. Chemistry and Biochemistry. Vol. 4. Pages 1828-1841.
  • Lee, Martin. A. (2012). Smoke Signals – A Social History of Marijuana Medical, Recreational, and Scientific. New York, New York: Scribner.
  • Pertwee. Roger. G. (2006). Cannabinoid Pharmacology: the first 66 years. British Journal of Pharmacology. Vol. 147. Pages 163-171.

What Is The Role Of The Endocannabinoid System?

The Endocannabinoid system is a large complex chain of receptors, endocannabinoids, and enzymes that comprise neural pathways throughout the body. This system helps regulate many functions in humans like:

  • appetite and digestion
  • metabolism
  • chronic pain
  • inflammation and other immune system responses
  • mood
  • learning and memory
  • motor control
  • sleep
  • cardiovascular system function
  • muscle formation
  • bone remodeling and growth
  • liver function
  • reproductive system function
  • stress
  • skin and nerve function

The goal is to help the body maintain a stable internal balance, despite external influence from stress, pain, inflammation, etc. In essence, the ECS helps regulate the scientific term – homeostasis.

Perfectly balanced stack of CBD products demonstrate zen like harmony of homeostasis

HOMEOSTASIS

The best definition we found on Homeostasis that shares both its importance, as well as a clearcut, comprehensive description, was found on Britannica.  Thus, we will quote them word-for-word.

Homeostasis defined by Britannica.com:

Homeostasis is any self-regulating process by which biological systems tend to maintain stability while adjusting to conditions that are optimal for survival. If homeostasis is successful, life continues; if unsuccessful, disaster or death ensues. The stability attained is actually a dynamic equilibrium, in which continuous change occurs yet relatively uniform conditions prevail.

When our body experiences pressure from outside it can synthesize CBD, CBG, CBN, THC, etc to help the ECS work against these stressors.

Homeostasis in the human body is the desire of our internal systems – organs, bones, muscles, neural pathways, etc. to communicate with each other perfectly and promote a completely balanced management system.

For example, our body works hard to maintain the correct internal temperature (98.6 degrees) and the correct blood sugar and blood pressure levels (80-120). This is because our cells have to be in the right environment to execute correctly. Cells make up every part of the body so this is extremely important.

By stimulating and supporting your endocannabinoid system one can find relief from many illnesses and conditions.

What Does The Endocannabinoid System Do?

Let’s look closer at the parts of the Endocannabinoid system to better clarify and comprehensively explain with more accuracy what the ECS actually does.

The Three Main Parts of The Endocannabinoid System

The Human Endocannabinoid System is primarily composed of three parts:

  • Cannabinoid Receptors: these receptors are present on the surface of cells and when it comes to association with Phytocannabinoids (Phyto = plant-derived), these cannabinoid receptors are commonly broken down into two categories; CB1 & CB2 receptors
  • Endocannabinoids – also called endogenous cannabinoids (cannabinoids naturally found within the human body) are chemical compounds/molecules that communicate or activate the above receptors
  • Metabolic Enzymes – proteins that break down and reuptake the phytocannabinoids and endocannabinoids once they have activated the receptors

Why do we have cannabinoid receptors and what are they?

In the endocannabinoid system, cannabinoid or phytocannabinoid receptors are located on the surface of the cells. These receptors play an important role in monitoring the body’s internal environment for changes. They send any info about changing conditions to the inside of the cell which will relay this information to promote the necessary cellular response to counteract the change.

In the ECS and CNS, the two most known and studied cannabinoid receptors are CB1 and CB2 (CB literally stands for cannabinoid). Another interesting fact is that CB1 receptors are some of the most numerous receptors in the human brain and the ones that get you high! CB2 receptors come more into play in the immune and nervous systems. Endocannabinoids stimulate presynaptic and postsynaptic nerve endings in both systems and relay information from the brain through the spinal cord to the rest of the body.?

What Are Endocannabinoids?

Endocannabinoids are molecules produced naturally in the human body that activate the above receptors. Our body naturally produces many endocannabinoids when they are needed and exposed to phytocannabinoids, but the two main ones are anandamide or N-arachidonoylethanolamine (AEA) and 2-ArachidonoylGlycerol (2-AG).

These endocannabinoids are produced in our cell membranes. Anandamide is a fatty-acid neurotransmitter often referred to as the “bliss molecule.”. 2-ArachidonoylGlycerol (2-AG) is present mostly in the central nervous system (CNS) and has been seen to be naturally occurring in maternal cow and human milk.

What Are Metabolic Enzymes?

The third main component of the endocannabinoid system is the metabolic enzymes that destroy endocannabinoids once they are used, called reuptake. The metabolic enzyme that breaks down AEA is called Fatty acid amide hydrolase (FAAH). The enzyme protein responsible for getting rid of 2-AG is called Monoacylglycerol lipase (MAGL). Just like other aspects of cell function, these enzymes are very essential because they make sure all endocannabinoids are fully used when needed.

Endocannabinoids are quite unique from other molecular signals like hormones and neurotransmitters because:

They don’t transmit signals that last longer than needed
They don’t get repackaged for later use by the cell; they are created on an as-needed basis

Almost all of our body’s organs and systems contain these three components of the ECS. They all also generally help in some way to regulate homeostasis, even if not directly stimulated by phytocannabinoids. Now that we know the integral parts of the endocannabinoid system, let’s look at how they work together to regulate homeostasis in the nervous system and the immune system’s inflammatory response.

Sources:

  • Gunduz-Cinar O, Hill MN, Mcewen BS, Holmes A. Amygdala FAAH, and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013;34(11):637-44. [PDF]
  • Ligresti A, De Petrocelli’s L, Di Marzo V. From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology. Physiol Rev. 2016;96(4):1593-659. [PDF]

Endocannabinoid Regulation

As briefly touched on in section 2 of this article (What Is The Role Of The Endocannabinoid System), we believe it is pertinent to dive in just a little deeper on two of the specific roles; the Nervous System and inflammation.

We are targeting these two specifically because they have a very strong impact on keeping our bodies in homeostasis.  Further, when either of these regulatory management systems is out of whack, health issues and concerns are sure to follow.

Endocannabinoid regulation of the nervous system

Our brains work by sending electrical signals or impulses through neurons. Each neuron interacts with another like a chain and relays information to the body. Ever been over stimulated? Well, neurons in the brain can experience similar situations and this is where endocannabinoids can come to the rescue. Endocannabinoids stop neural aging and toxicity by lessening overwhelming and overloading signals.

When a neuron becomes overwhelmed endocannabinoids will interact with the neural pathway through its CB1 receptors. CB1 will instruct the neuron to lessen its transmitting signal or quiet down. This function allows receiver neurons to regulate the amount of information they are receiving. An important and interesting thing to note here is that endocannabinoids actually work in reverse (the signal they send is called “retrograde”).

Endocannabinoid regulation of inflammation

Inflammation is actually a necessary and preventative response by our body’s immune system. When we have an infection or get physically injured, fluid builds up to remove germs and damaged cells from the site of trauma. The body’s use of inflammation is sometimes though less than ideal. Inflammation can spread to other areas beyond where it is needed, and it can also last longer than it is needed. This is often due to nerve damage or some underlying health condition like autoimmune diseases activating the response inappropriately.

Endocannabinoids have been shown to apparently stop or limit the immune system’s inflammatory signals. They release just like other immune cells in response to damage, and they function similarly to how they do in the brain – by limiting the inflammatory response and immune response so that it isn’t overwhelming.

Sources:

  • Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296(5568):678-82. [PDF]
  • Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333-49. [PDF]

How Does CBD Affect The Endocannabinoid System?

Cannabidiol (CBD) is less understood than THC in its interactions with the endocannabinoid system. Experts do know that it does not bind to CB1 and CB2 receptors in the same way that THC does. Most believe instead that its functions work to keep endocannabinoids from being broken down, letting them be more effective. It is also possible that since the science is still relatively new that CBD interacts with other neurotransmitters not yet discovered.

WHAT WE DO KNOW:

  • Hemp extracted CBD has been shown to interact with numerous presynaptic receptors in the brain
  • It affects overall cannabinoids in the brain (endocannabinoid tone)
  • CBD inhibits the enzyme Fatty acid amide hydrolase (FAAH) and delays the time it takes to break down anandamide (AEA)

It is very interesting to note that in anxiety disorder studies, inhibiting the FAAH enzyme, in general, has been beneficial in stopping anxiety disorders. CBD for anxiety is one of the most purported benefits of CBD.

Also, we all know hemp-extracted CBD, but CBD is also the second-highest produced cannabinoid in marijuana plants as well. Unlike THC, CBD itself doesn’t cause the euphoric effect or “high” that some people dislike about marijuana use, even if it helps them.

Other benefits of CBD shown in research laboratory settings are dampening pain and nausea symptoms, making them less strong.

How Does THC Affect The Endocannabinoid System?

The effects of 9-Tetrahydrocannabinol (THC) are much more understood because their interactions have been studied for quite some time now. THC is:

  • The most produced cannabinoid in marijuana plants
  • The direct phytocannabinoid that interacts with the endocannabinoid system and CB1 – CB2 receptors
  • The cannabinoid that produces a “high” or mind-altered state when ingested, inhaled, or applied

THC has been shown to help reduce pain and inflammation, stimulate appetite, even aid in conditions like glaucoma. The problem though for some is that it can also increase anxiety issues, sometimes even causing paranoia – this, of course, adds fuel to skeptics as negative effects of weed. Scientists are looking to produce synthesized THC and other synthetic cannabinoids that aren’t psychoactive, but this innovation is still currently in its infancy.

Why does marijuana get you high?

You might ask yourself if our endocannabinoid system has all these structures in place internally, why doesn’t our body experience a high during uptake. First THC isn’t the exact same molecule as our own natural endocannabinoids, different molecules mean a different reaction. Also, remember the enzymes that break down our body’s endocannabinoids that the cells naturally produce? Well, those are also less effective on THC. In a more concise way:

  • THC causes a stronger and more intense reaction on our cannabinoid receptors versus our naturally produced endocannabinoid
  • THC doesn’t break down in the enzymatic process instantly like our natural endocannabinoids

Sources:

  • Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol, and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215. [PDF]

Endocannabinoid Deficiency

Just like how our bodies can become naturally deficient in vitamins and minerals, some clinical studies have even identified endocannabinoid deficiency or CECD, where endocannabinoid levels may vary wildly. While still a theory, it is believed and backed by some research that if our body does not produce high enough levels of endocannabinoids naturally, it may lead to certain conditions. Endocannabinoid dysfunction may contribute to:

  • Migraines
  • Fibromyalgia
  • Irritable bowel syndrome

More research is needed but this is especially interesting because these conditions currently have no clear underlying cause, they are not really treatable, and they may develop together. Anyone that suffers from these conditions knows they are real and debilitating.

Imagine the possibilities if supplementing phytocannabinoids actually helped stop CECD!

SUMMARY FROM THE AUTHOR

Christopher Visser Why CBD Works! The Fascinating Answer to “What Is The Endocannabinoid System?”

Christopher Visser
Founder, Owner, & CEO of Cannabidiol Life

When we look at the Endocannabinoid system, it is clear to see that this complex system of cannabinoid receptors, endocannabinoid molecules, and metabolic enzymes does have serious functions, especially when it comes to homeostasis. We should, however, remember that our body is tightly regulated, and overstimulation of the ECS could be detrimental long term or have side effects we just don’t know.

 

Behind the science, there is a strong argument for trying CBD and THC from Cannabis Sativa, but it should be discussed with medical and healthcare professionals first. It is easy to find CBD for sale online in products like CBD oil and CBD gummies, but just like vitamin use, it’s best to have a clear reason for taking the product beyond just the trend. Using CBD for anxiety or pain is perfectly understandable, and now that you understand how it works in the body, you appreciate hemp-extracted products even more.

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