​Behind the Scenes of the Endocannabinoid System

​Behind the Scenes of the Endocannabinoid System

Posted by Lily Kiepke on Oct 1st 2020

Have you ever wondered what happens to CBD after it enters your body?

You’re not alone. More than 6,500 people search monthly for more information about the endocannabinoid system.

But finding simple answers to your questions can seem impossible without a degree in physiology. With all the medical mumbo-jumbo and abbreviations, getting a clear and detailed picture of the endocannabinoid system can be challenging.

It doesn’t have to be. We’ll walk you through the basics of the endocannabinoid system with understandable language and clearly defined terms so that anyone can become an expert.

Let’s break down the system that breaks down cannabis.

A Brief History of the Endocannabinoid System

The endocannabinoid system, or ECS, was discovered and expanded upon during the late 80’s and early 90’s, spurred by investigations into the effects of cannabis.

Lab Roots describes a quick timeline of important figures and events in cannabis research in the article How the Endocannabinoid System Was Discovered :

1973: The brain’s opiate receptor is discovered by scientists

1988: A government-funded study at St. Louis University of Medicine led by Allyn Howlett and William Devane reveals all mammals have receptors in the brain that respond to cannabis

1990: Lisa Matsuda and her team at the National Institute of Mental Health map the DNA sequence of a cannabinoid receptor in the brain, and are able to clone it

1990: THC is given to knockout mice with no effect, confirming THC functions by activating cannabinoid receptors in the brain

1990: Another receptor, CB2, is identified in the immune and nervous systems; endocannabinoids (eCB), naturally occurring neurotransmitters, are discovered

1992: Dr. Raphael Mechoulam, Dr. Lumír Hanuš, and American Dr. William Devane discover the endocannabinoid anandamide (ANA) at the Hebrew University of Jerusalem

1995: Dr. Raphael Mechoulam and student Shimon Ben-Shabat isolate the endocannabinoid 2-arachidonoylglycerol (2-AG) in the canine gut

Sara Gottfried, MD, and Elnaz Karimian-Azari, PhD, of Metagenics Institute summarize the discovery of the ECS:

“By isolating and mapping the chemical structure of bioactive compounds in the Cannabis sativa plant, researchers discovered a new biological system within our bodies known as the endocannabinoid system.”

The Endocannabinoid System and Homeostasis

The endocannabinoid system (ECS) is a molecular signaling system that regulates a variety of the body’s functions. It consists of cannabinoid receptors, endocannabinoids, and enzymes.

The goal of the endocannabinoid system is homeostasis, or a stable internal environment in the body despite changing external conditions.

Metagenics Institute credits the ECS with the regulation of many functions, including:


●Immune function

●Pain sensation

●Metabolism and energy balance

●Stress response



●Fertility and pregnancy

●Pre- and postnatal development


●Neurogenesis (growth and development of nervous tissue)

Components of the Endocannabinoid System

The endocannabinoid system is largely composed of three main components: CB1 and CB2 cannabinoid receptors, naturally occurring endocannabinoids, and metabolic enzymes designed to break down cannabinoids.

1. Cannabinoid Receptors

Cannabinoid receptors are proteins found within the cell membrane on the surface of the cell. The body has a widespread network of cannabinoid receptors that send signals to the endocannabinoid system when cannabinoids bind to them.

Loren DeVito, PHD, describes how “these receptors, called cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), determine the behavioral effects of cannabis when consumed, as well as the effects of your body’s own cannabis chemicals, 2-AG and anandamide.”

There are two main types of cannabinoid receptors throughout the body:

●CB1 receptors in the brain and central nervous system

●CB2 receptors in peripheral organs and immune system cells

2. Endocannabinoids

Endocannabinoids, or eCBs, are molecules that are produced naturally by your body. Endocannabinoids can also be referred to as endogenous cannabinoids, meaning cannabinoids originating from within the body.

Gottfried and Karimian-Azari reveal “eCBS are produced and released on demand [...] in response to a stimulus and/or need, making the endocannabinoid system capable of adapting quickly to changing conditions.”

The two most extensively researched endocannabinoids are:

●anandamide (ANA), also known as N-arachidonoylethanolamine (AEA)

●2-arachidonoylglycerol (2-AG)

These small molecules bind to cannabinoid receptors, activating them to maintain homeostasis.

As neurotransmitters, endocannabinoids are the body’s chemical messengers; they carry, boost, and balance signals between nerve cells (neurons) and target cells (codocytes) throughout the body.

Endocannabinoids are unique because they travel “backwards” between nerve cells to find CB1 receptors on nearby nerve cells, classifying them as “ retrograde neurotransmitters .”

3. Metabolic Enzymes

Enzymes are proteins that break down substances; they are biological catalysts, meaning they speed up reactions.

Once endocannabinoids have been used up by the endocannabinoid system, they are destroyed by metabolic enzymes, or enzymes relating to the metabolism.

Different enzymes are designed to break down different substances. The two main enzymes active in the ECS are:

●Fatty acid amide hydrolase (FAAH), which breaks down anandamide (ANA)

●Monoacylglycerol acid lipase (MAGL), which absorbs 2-arachidonoylglycerol (2-AG)

CBD and the ECS: Phytocannabinoids

Phytocannabinoids are naturally occurring cannabinoids present in plants, including Cannabis sativa . CBD and THC are examples of phytocannabinoids with beneficial properties.

“Phytocannabinoids within the cannabis plant have specific and complementary effects on the endocannabinoid system either by interacting with cannabinoid receptors or inhibiting enzymes that are involved in breaking down endocannabinoids,” explains Gottfried and Karimian-Azari.

Additionally, Gottfried and Karimian-Azari connect CBD’s anti-inflammatory effects to suppression of the enzyme fatty acid amide hydrolase (FAAH), leading to higher concentrations of the endocannabinoid anandamide (ANA), another useful anti-inflammatory.

Both medical experts are hopeful for the future of CBD for treating endocannabinoid system deficiencies; noting “given the promising biochemical, physiologic, and preclinical data on CBD, several clinical studies have evaluated its effects in the treatment of conditions like movement disorders, psychosis, PTSD, anxiety, and sleep disorders.”

Clinical Endocannabinoid Deficiency

A deficiency in signaling in the endocannabinoid system is referred to as clinical endocannabinoid deficiency (CECD). CECD can be caused by a variety of factors, and typically affects the immune system the most.

According to the scientific networking site Lab Roots, the following circumstances can contribute to CECD:

●The body not synthesizing enough endocannabinoids

●The body not producing enough cannabinoid receptors

●An abundance of enzymes that break down cannabinoids

●Outside sources (foods, medications) decreasing signaling

An underactive ECS may present itself through migraines, irritable bowel syndrome (IBS), and fibromyalgia, which affects muscles, memory, mood, and more.

On the other hand, an overactive ECS is associated with obesity, metabolic syndrome (also known as syndrome X), and hepatic fibrosis, or overactive healing in the liver resulting in tissue build-up.

Supporting Your Endocannabinoid System

There are several simple lifestyle modifications that you can make to improve the function of your endocannabinoid system, such as:

●Maintaining a healthy weight

●Exercising regularly

●Eating anti-inflammatory foods, such as olive oil, fish, seeds, and nuts

●Avoiding foods treated with harmful pesticides, instead eating organically

●Limiting alcohol, tobacco, and caffeine use

●Managing stress

●Massage therapy and acupuncture

●Plant-derived phytocannabinoids, such as CBD

Wrapping It Up

Discovered during the 90’s, the endocannabinoid system (ECS) is a powerful network that influences many of the body’s functions.

It consists of CB1 and CB2 cannabinoid receptors, the endocannabinoids ANA and 2-AG, and FAAH and MAGL enzymes to break them down.

CBD and other phytocannabinoids can be used to treat clinical endocannabinoid deficiency (CECD), the root of many health issues.

Making small changes to your lifestyle, such as exercising and stress management, can improve the function of your ECS.

Still curious about all things CBD? Check out our ultimate guide for beginners:

What is CBD? 12 Answers That Will Make You an Expert

Follow PHD Organics on Instagram @phdorganics


Alger, B. (2013, November 1). Getting high on the endocannabinoid system. Retrieved September 30, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997295/

Cherry, K., & Morin, A. (2019, December 07). The Role of Neurotransmitters. Retrieved September 30, 2020, from https://www.verywellmind.com/what-is-a-neurotransmitter-2795394

DeVito, L. (2017, November 28). CB1 and CB2: Different Cannabinoid Receptors in the Brain: Health and Medicine. Retrieved September 30, 2020, from https://www.labroots.com/trending/health-and-medicine/7420/cb1-cb2-cannabinoid-receptors-brain

Gottfried, S., & Karimian-Azari, E. (n.d.). The Endocannabinoid System: Components, Actions, and Optimization. Retrieved September 30, 2020, from https://www.metagenicsinstitute.com/blogs/endocannabinoid-system-components/

Moore, M. (2018, April 05). How the Endocannabinoid System was discovered. Retrieved September 29, 2020, from https://www.labroots.com/trending/cannabis-sciences/8456/endocannabinoid-system-discovered

About the Author

Lily Kiepke is a freelance writer and blogger based in the Denver metropolitan area. She enjoys using CBD to relieve anxiety and improve sleep. When she is not writing about cannabis, she can be found hiking in the Rocky Mountains or curled up with a good true crime book.