Understanding Your Endocannabinoid System

This homework assignment explored the nuanced relationship between endocannabinoids, phytocannabinoids, exercise, and health, with an overview of the theory of clinical endocannabinoid deficiency.

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"Your body is not a temple, it's an amusement park. Enjoy the ride." — Anthony Bourdain

It is estimated that major depressive disorder affects nearly 20 million Americans (includingThis article dives into the intersection of life where endurance exercise, herbal molecules called cannabinoids (such as cannabidiol [CBD] and tetrahydrocannabinol [THC]), and positive attitude/use with intent can result in markedly improved health and wellness.

Biohacking, an emerging trend that is sometimes defined as do-it-yourself biology and framed as self-experimentation in medicine is an effort to decrease negative conditions—with the goal of improving health and even enhancing performance. While biohacking may convey a tone of bleeding edge or perhaps even sound intimidating to the average consumer, it is simply a framework for describing inputs and outputs.

Some ways in which one can engage in biohacking include intermittent fasting, different manipulations of diet (such as going gluten-free or eliminating certain toxins or allergens), improvements to sleep, breathing exercises, neurofeedback, and mindfully practicing gratitude and forgiveness.

Any effort to strategically enhance performance, by definition, means trying to minimize shortcomings or faults while simultaneously striving to increase strengths and benefits. Sometimes we can accomplish both, such as when we swap the consumption of alcohol or sugar for healthier molecules like linalool and CBD.

Be warned, however: There is no free lunch. Effective biohacking and realizing true improvements to one’s health requires self-discipline and commitment. Reaching your goal may demand fewer visits to the local bakery or pub. Perhaps it requires that you give up that pack-a-day tobacco habit that’s been robbing your energy—and your wallet. And let’s be honest, nearly all of us could use more exercise in our lives.

The potential payoff of such positive lifestyle changes can be immense and even life-saving. Those who biohack and integrate exercise + clean diet + organic herbal medicine into their daily and weekly routines sometimes enjoy significant benefits—such as prevention of disease or a decrease in negative symptoms (like the aforementioned anxiety, depression, lethargy, and pain).

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Readers are encouraged to do more than merely consume cannabinoids and terpenes. Engaging in activities such as hiking, meditation, yoga, and other forms of what is becoming known as "self-care" are critical to health and wellness.

Anandamide (also denoted as N-arachidonoylethanolamine or AEA) is a relatively special and rare molecule. It was first isolated and identified in 1992 by two independent research teams: The same Israeli researcher who discovered THC in 1964, Raphael Mechoulam and NIMH researchers William Devane and Dr. Lumir Hanus. Anandamide has been given the moniker of "the bliss molecule" by the popular press because of the role it plays in modulating mood and emotional balance in humans (among other functions, as we'll learn shortly):

"Back in the late 1980s, scientists observed that THC fitted perfectly into special receptors in the brain and central nervous system. They theorized that if we have this complex network of receptors, we must produce some kind of endogenous chemicals that also act as keys to the receptors’ lock-like mechanism. It took a while, but eventually they discovered anandamide, which scientists named after the Sanskrit for divine joy because of the blissful sensations it produces." — Mary Biles

Despite their many similarities, anandamide is a more volatile and fragile molecule than THC and breaks down in the human body more easily. This makes the efficacy experienced from anandamide relatively short-lived. It also begs the question: Did the ECS evolve with the dual function of manufacturing molecules such as anandamide while also accommodating their plant-derived cousins like CBD and THC?

Anandamide molecule

Technically, medical researchers categorize anandamide as both a neurotransmitter and an endogenous (internally produced) cannabinoid. Interestingly, this molecule is found in sources outside the human body, including black truffles and dark chocolate!

Of note is the fact that quality dark chocolate contains not only anandamide, but also two compounds that slow its breakdown. This means that the anandamide found in chocolate remains in the body longer than that derived from sources lacking such support molecules.

You know the "runner’s high" phenomenon that’s been touted in the popular press for decades? The euphoria experienced by people engaging in endurance exercise was originally attributed to endorphins (pain-killing chemicals produced in the central nervous system [CNS] and pituitary gland). Endorphins, however, can't cross the blood-brain barrier to bind with receptors in the brain to create euphoria (for multiple reasons; one of which is that they are too large).

It turns out that anandamide is the mystery molecule responsible for runner's high, not endorphins. More in future articles as we explore the topic of the entourage effect.

>> To deep dive on this topic, learn more here.

To truly understand the medicinal efficacy of molecules such as anandamide and THC for human health, one must be familiar with the basic mechanism and topology of the endocannabinoid system (ECS).

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The ECS is a network of microscopic cellular receptors that reaches every corner of the body. It is believed to heavily influence critical metabolic functions and states of being, including mood, appetite, energy level, immune function (ability to fight off infection and disease), sleep patterns, and even libido.

The ECS is comprised primarily of two types of cellular receptors: CB1 (found mostly in the brain and CNS) and CB2 (in the organs and tissues of the immune system that appear from head to toe). For you physiology nerds, CB1 and CB2 are part of the family of G-protein coupled receptors.

CB2 receptors do appear in the brain and CNS, but are far outnumbered by the CB1 variety. Likewise, CB1 receptors appear in areas of the body other than the brain and CNS, but in significantly lower numbers than their CB2 siblings.

Collectively, the receptors of the ECS, regardless of specific type, are concentrated in the brain, cardiovascular system, GI tract, liver, reproductive system, and skeletal muscles. They play a governing role in modulation of the immune system. Bone remodeling, bronchodilation, cancer, intraocular pressure, and nausea are all believed to be treatable by feeding cannabinoids—whether molecules like anandamide produced by the human body or a chemical such as CBD from a hemp plant—to one’s ECS.

>> To deep dive on this topic, learn more here.

Most references in popular media and literature to the ECS include only the two CB receptors. However, other types are known to exist, although their exact characteristics and dynamics are largely unknown and require more research. Dr. Benjamin Caplan, Chief Medical Officer at Solo Sciences, Inc. and founder of the CED Clinic in Boston, says that the existing two CB receptors constitute only a small portion of the functionality of the ECS.

“What we know is that CB1 and CB2 are a very small part of the full picture. Many more receptors, throughout the human body, bind—either directly or indirectly—with cannabinoid molecules”

Caplan told me during an exclusive interview.

A 2018 research study entitled “Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System” that was published in the International Journal of Molecular Sciences is among the most recent research to provide additional information regarding ECS receptor types.

"Despite only CB1R and CB2R are widely-acknowledged as CBRs, several other receptors, ranging from other G protein-coupled receptors (GPCRs) to ion channel and nuclear receptors, have been reported to interact with cannabinoids," wrote the researchers.

The phytocannabinoids (phyto = plant sourced) produced by the cannabis herb sometimes deliver beneficial efficacy for humans and mammals because they mimic endocannabinoids such as anandamide and 2-AG, fitting into the same CB1 and CB2 cellular receptors.

A theory has been developed around this concept called Clinical Endocannabinoid Deficiency Syndrome (CED or CECD). The theory was first proposed in a 2004 research study conducted by pioneering cannabinoid researcher Dr. Ethan Russo called "Clinical Endocannabinoid Deficiency (CECD): Can This Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and Other Treatment-Resistant Conditions?"

In the study, Russo proposed idea that a significant portion of humans suffer a wide range of diseases and negative conditions due to a deficiency in their ECS.

"Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines. — Dr. Ethan Russo

In 2016, Russo released a second study focused on the dynamics and underlying biochemical mechanisms of a potential endocannabinoid deficiency. In the study, Russo concluded, "The current review has examined the concept of CED and presented more than a decade of supportive objective evidence. However, certain caveats are necessary. One is that contradictory findings are not only possible but also common. This is due, in part, to the often reciprocal relationships between the two major endocannabinoids, AEA [anandamide] and 2-AG, as expansively demonstrated in a current review."

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The logical question that emerges regards the source of CED. It is believed to be a highly subjective combination of individual genetics, environmental pollutants and toxins, stress, poor diet, and lack of exercise (regular exercise has been shown to boost anandamide levels; more about this later in the series).

It should be noted that relatively little formal research has been conducted regarding the ECS and CED. As a species, humans remain relatively ignorant of the nuanced dynamics and overall functionality of this critical system within our bodies and those of our family pets.

What we know: The ECS is connected to many critical bodily systems within mammals. Its supplementation by the special molecules produced by cannabis and hemp appears to help prevent and fight disease (including the common psychological conditions of anxiety and depression).