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The Endocannabinoid System: Everything You Should Know

Published by Dr. Venn-Watson
Dr. Eric Venn-Watson’s Highlights
  • The endocannabinoid system (ECS) is a complex system of synapses that control how our bodies function. 

    The three main parts of the endocannabinoid system are endocannabinoids, receptors, and enzymes. 

    Endocannabinoids support bodily homeostasis. When your body is in a state of homeostasis, your blood sugar is regulated, you are fully hydrated, and you have enough electrolytes floating around to ensure all systems are in proper, functioning order. 

    Modulation of the ECS could help rebalance and re-regulate health conditions to help us preserve our health longer. 

With the discovery of the potential health benefits of cannabis, several countries and numerous states have legalized the use of it, at least medicinally. However, studying these benefits isn’t complete unless you understand how it interacts with the body. 

The body is home to a system that lay undiscovered until the late nineties. The endocannabinoid system (also known as the endocannabinoid signaling system) is a complex system of synapses that control how our bodies function. 

Together, we’ll discuss what the system is and how it works. We’ll also cover how the phytocompounds in cannabis interact with the system and learn how further research into the endocannabinoid system could result in helping us lead healthier longer lives. 

Let’s first begin by understanding what a cannabinoid is and why there’s an entire bodily system designed to interact with them. 

What Is a Cannabinoid?

The term “cannabinoid” refers to any chemical compound, whether synthetic or natural, that interacts with cannabinoid receptors in the body. Cannabinoids, also known as phytocannabinoids found in nature, come from the Cannabis sativa plant.

Humans can use different cannabinoids for recreational, medicinal, or holistic wellness purposes. 

Recreational use involves marijuana, while medicinal and wellness uses focus on the properties of the cannabinoids in the plant and how they can help interact with the endocannabinoid system to help support health and wellness. 

How Many Phytocannabinoids Are There?

The cannabis plant produces about 130 cannabinoids and 300 other plant-based chemicals, like terpenes, that researchers suggest may also have therapeutic effects on the body. 

Of all the cannabinoids found in cannabis, delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most potent.


THC is the ingredient in some cannabis strains that creates a psychoactive response in the brain. By connecting with CB1 receptors in the brain, this compound creates the “high” a user feels when using recreational cannabis.

THC also has other therapeutic properties on the body, including the ability to stimulate appetite and produce soothing, calming effects on the mind. Because we can now separate THC from the cannabis plant, regulating the amount of THC in a plant starting as early as the growth stage is possible. 

This is why you can now find full-spectrum CBD products containing less than 0.3 percent of THC in some states. 


The other important cannabinoid found in the cannabis Sativa plant is CBD. Unlike THC, CBD doesn’t bind well with CB1 or CB2 receptors (which we will cover in a moment), but when used along with THC, it helps regulate the side effects of the cannabinoid and offers other therapeutic benefits. 

CBD is the most highly studied cannabinoid and is available in different isolations and spectrums, including formulas that do not contain any detectable THC.

What Is the Endocannabinoid System?

The system that interacts with the cannabinoids we just discussed is called the endocannabinoid system. This system is a new discovery, having gained recognition in the 1990s. Arguably, the hipsters of the 1970s knew how to engage it; they just didn’t know the biochemical mechanics of it.

Who Discovered the Endocannabinoid System?

In a very which-came-first scenario, the discovery of the endocannabinoid system came after the discovery of plant-based cannabinoids. Discovered and cataloged in the 1960s by a scientist named Raphael Mechoulam, cannabinoids were known to interact with the body and mind, but we didn’t know how they interacted.

The discovery of the endocannabinoid system came later. By the 1990s, CB1 and CB2 receptors had been discovered in laboratory rats. This discovery led Mechoulam to conclude that the receptors don’t exist because of the presence of plants but because of compounds within our bodies

In 1992, Mechoulam’s lab successfully isolated the first endocannabinoid, and research into the endocannabinoid system hit full steam ahead. 

We now know three main parts of the endocannabinoid system (ECS): endocannabinoids, receptors, and enzymes. 


Your body’s endocannabinoid system produces compounds very similar to cannabinoids found in the cannabis plant. These are endogenous cannabinoids, endocannabinoids, or eCBs, “endo” meaning they are produced inside of the body. 

So far, two of these molecules have been identified and studied. 

  1. Anandamide. Also known as AEA, this neurotransmitter comes from a fatty acid called arachidonic acid. Known as the “bliss molecule,” this endocannabinoid engages with receptors that support memory, appetite, sleep, and discomfort. 

  2. 2-Arachidonoylglycerol (2-AG). This compound, abundant in the central nervous system, helps regulate neurotransmitter release. By interacting with the CB1 receptor, this molecule helps support emotion, cognitive function, energy homeostasis, and soothe discomfort.

      The body produces these molecules on an as-needed basis, which can vary from person to person. As such, it’s hard to approximate what a normal level of each of them would be for every person.

      Endocannabinoid Receptors

      The receptors that interact with the endocannabinoids your body produces, and the cannabinoids from synthetic or plant sources make up the other side of the ECS coin. Receptors sit on top of cells, waiting for neurotransmitters to bond with them. 

      There are two main receptors: CB1 and CB2. 

      Because these receptors only respond to endocannabinoids or cannabinoids, they are sometimes called cannabinoid G-protein coupled receptors. These receptors interact with the endocannabinoids your body produces. 

      1. CB1. These receptors are found mainly in the central nervous system (CNS) parts, including the brain and spinal cord. 

      2. CB2. These receptors are found in the peripheral nervous system (PNS), which includes all the nerves in your body. They are also found in immune cells and therefore play a role in the function and support of the immune system. 

          The PNS can further be broken down into the autonomic and somatic nervous systems. The autonomic nervous system regulates involuntary movements and helps your glands to function properly. The somatic nervous system regulates muscle movement and plays a role in hearing, vision, and sensation. 

          Endocannabinoids produced by your body can bind with either of these two receptors. The outcome depends on where the receptors are and whether AEA or 2-AG binds to them.


          The third part of the endocannabinoid system is the enzymes. Enzymes have two jobs: synthesizing the two endocannabinoids your body needs and getting rid of them when they are no longer needed. 

          1. Enzymes must make these lipid-based molecules out of fat to create endocannabinoids. 

          2. Once an endocannabinoid is no longer needed, transport proteins help remove it to a special storage site where the same enzymes work to break them down in a process known as degradation.

            Because both endocannabinoids are different, they require different synthesis and degradation. Don’t worry; there’s an enzyme for that!

            • Fatty acid amide hydrolase. Also known as FAAH, this enzyme hydrolyzes AEA. 
            • Monoacylglycerol lipase (MAGL), which breaks down 2-AG.

            Once the endocannabinoid signaling finishes, the party is over, and the enzymes play clean up. Now, let’s look at what processes in your body are affected by the ECS.

            What Are the Functions of the Endocannabinoid System?

            The discovery of the ECS in the 1990s was profound because it revealed an entire web of biochemical pathways and gave us much more data about how our body stays healthy and functions properly in its pure, homeostatic state.

            First, let’s talk about what we mean by homeostasis. Homeostasis is the perfectly balanced state of the human body. In other words, when your body is in a state of homeostasis, your blood sugar is regulated, you are fully hydrated, and you have enough electrolytes floating around to ensure all systems are in proper, functioning order. 

            When your body is not in homeostasis, you may experience imbalances resulting in illnesses and disease. Cardiovascular problems, insulin resistance, lowered immune responses, and even cognitive dysfunction can occur when there is an imbalance in your body. 

            The endocannabinoid system helps maintain that balance. Research suggests that the ECS plays a major supporting role in the following bodily functions and systems:

            • Appetite, including regulation of appetite, suppression of appetite, and digestion 
            • Physical discomfort such as tension in the head and neck, aching joints, and sore muscles
            • Immune responses 
            • Mood, including mood regulation and transmission of neurons that produce feelings of well-being and soothe worried feelings
            • Cognitive function and sharpness
            • Sleep, including your ability to ease into rest
            • Skin and nerve functionality
            • Reproductive health
            • Liver function, including metabolism
            • Bone growth and stimulation
            • Cardiovascular health and function, including the function and health of blood vessels

            All of these functions make up a total, balanced being. The ECS, through the modulation of certain signaling pathways, helps keep these systems in a state of homeostasis. 

            Can You Be Deficient in Endocannabinoids?

            Because it’s hard to measure how many endocannabinoids a particular person produces on any given day, it can be hard to determine whether the level produced in your body is too low or too high. 

            Even so, researchers have a threshold they believe each person should meet. If you fall below that threshold, you may have a clinical endocannabinoid deficiency (CECD). This possibility is still being researched, especially as they relate to certain illnesses and autoimmune disorders that often seem to have no other cause. 

            It may also explain why some bodily functions become unbalanced. Cell systems age as we age and become less able to communicate with one another. Losing these connections can result in conditions as simple as mild fatigue and an inability to sleep or maintain healthy blood sugar levels. 

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            The Effects of Cannabis

            We discussed how cannabis contains phytocompounds, called cannabinoids, that interact with the body’s endocannabinoid system. Once we knew that our bodies respond to cannabinoids as they respond to endocannabinoids, it became clear that learning to harness the power of cannabinoids in safe concentrations was important for using cannabis in different therapies. 


            THC interacts with both CB1 and CB2 receptors. It triggers the release of dopamine in the brain and also plays a role in helping soothe discomfort and support a healthy appetite. However, THC also lowers inhibitions and disrupts cerebellum function, leading to dizziness, loss of balance, and delayed reaction time. 

            In some, THC can also trigger feelings of paranoia or anxiety. Because CBD is a THC antagonist, it can reduce these negative effects when taken alongside it. For this reason, CBD that contains a trace amount of THC, also known as full-spectrum CBD, is considered a better alternative to balance the psychoactive effects.


            Cannabidiol, unlike THC, doesn't bind to the CB1 or CB2 receptors — it interacts with the ECS to support natural bodily functions. 

            CBD has shown promise in helping soothe feelings of stress and physical discomfort and helping settle your digestive system. One thing we know is that CBD can help soothe the symptoms of epilepsy. The evidence was so overwhelming that the FDA recently approved a prescription CBD medication for epilepsy patients. 

            What Now?

            As we learn more about the endocannabinoid system, we learn more about how the body regulates its necessary functions. 

            Suppose we understand how the ECS supports these functions and how the body’s endocannabinoids play a role. In that case, it may be possible to shift how our bodies function, helping restore homeostasis. Here are just a few examples. 


            We know that the ECS can help support a healthy appetite, but we don’t know how this system modulates glucose and lipid metabolization. New research shows that individuals who are obese (considered anyone with a BMI over 30) have a higher concentration of the two main endocannabinoids we mentioned earlier, AEA and 2-AG

            Because the body makes these two endocannabinoids from fatty acid synthesizes, it has been suggested that supplementing with a different fatty acid could potentially decrease the amount of AEA and 2-AG the body produces. With less AEA and 2-AG, it may help maintain a healthy weight. 


            Research into the regulation of sleep by the endocannabinoid system is also ongoing. We know that, especially in the aging population, the body’s sleep/wake cycle regulation begins to decline

            Although there is much evidence in the field of pharmacology as to the heavy hand the endocannabinoid system has in supporting the sleep cycle, researchers suspect that modulation of the cycle, especially in aging populations, may help them achieve better rest. 

            Even more surprising is that this would likely not involve using products like CBD oils or tinctures but rather a modulation of how the body synthesizes fatty acids. In other words, giving the body a different fatty acid could shift the amount of AEA and 2-AG the body needs to produce, which could support good sleep. 

            Age-Related Illness

            It’s no secret that the older we get, the more we are prone to developing conditions like: 

            • Unhealthy blood sugar levels 
            • High blood pressure
            • High LDL cholesterol and low HDL cholesterol
            • Excess weight, especially around the midsection 

            These negative health markers make up a condition known as metabolic syndrome. Metabolic syndrome can increase a person’s risk of developing cardiovascular disease, heart attack, and stroke. 

            Because the ECS helps regulate functions that underlie these illnesses, it’s hypothesized that modulation of the ECS could help rebalance and re-regulate these conditions to help us preserve our health longer. 

            Endocannabinoid Discovery

            The second-ever discovered full-acting endocannabinoid is pentadecanoylcanitine (PDC). A full-acting endocannabinoid activates both CB1 and CB2 receptors.

            The study showed that C15:0 (a recently discovered essential fatty acid) can support the body's production of PDC. C15:0 on its own provides many health benefits including:

            • Mitochondria function. Cells are able to generate energy more efficiently.

            • Stronger cell membranes. C15:0 protects cell membranes better than leading omega supplements.

            • Improved cellular signaling. C15:0 activates PPARs, which regulate homeostatic functions like sleep, appetite, mood, and metabolism.

            • Improved cardiometabolic health. C15:0 binding to PPARs promotes healthy cholesterol, triglyceride homeostasis, and heart health.

            C15:0 goes into our cells and binds with carnitine to make PDC. Once made, PDC is used by our mitochondria to generate energy. 

            The study showed that taking C15:0 can provide not only the long-term health benefits of C15:0, but it may provide the added benefit of supporting your endocannabinoid system, including supporting better sleep, a balanced mood, and joint comfort. 

            Where can you get a pure, science-backed, award-winning C15:0 supplement? Fatty15.

            Discovering the Endocannabinoid System

            This newly discovered endocannabinoid system holds much promise for helping us lead healthier, longer lives. Understanding how the body’s endocannabinoids work with the specialized receptors of the ECS can help us learn whether other fatty acids may be able to support the ECS and change the way it works. 

            For more information on the endocannabinoid system and to learn more about healthy aging, check out our blog



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            The discovery of the endocannabinoid system: Centuries in the making|Newswise.com

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            The Endocannabinoid System May Modulate Sleep Disorders in Aging - PMC

            Profile photo for Eric Venn-Watson

            Eric Venn-Watson M.D.

            Eric is a physician, U.S. Navy veteran, and Co-founder and COO of Seraphina Therapeutics. Eric served over 25 years as a Navy and Marine Corps physician, working with the special forces community to improve their health and fitness. Seraphina Therapeutics is a health and wellness company dedicated to advancing global health through the discovery of essential fatty acids and micronutrient therapeutics.

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