The Endocannabinoid System: A Complete Scientific Introduction

The endocannabinoid system consists of cellular receptors that are found in very large amounts all throughout the body, and endocannabinoids—internally synthesized chemical compounds that entice these endocannabinoid receptors.

Both endocannabinoids from our body, and cannabinoids from the cannabis plant activate cell receptors that produce a certain behaviour in the cell. This reaction is dependent on the type of cell that was activated through these receptors, but also on the condition the body is struggling with at the moment.

Role of the endocannabinoid system

The endocannabinoid system (also known as the ECS) is a vast “network” that’s comprised of:

  • Cellular cannabinoid receptors — these receptors are located on the membranes of many different cells, spread throughot the body.
  • Endocannabinoids — signaling molecules produced by our body. They are structurally very similar to the active compounds found in cannabis. These internal cannabinoids activate cannabinoid receptors (just like the ones from cannabis), and by doing this trigger a specific response from a cell.
  • Different enzymes that are responsible for the creation and degradation of these molecules.

What’s truly amazing about the endocannabinoid system is that the cells which express these specialized cannabinoid receptors are located in all of the most important parts of our body, including:

  • The central nervous system (brain, spinal cord);
  • All vital organs;
  • The reproductive organs;
  • Various glands;
  • The immune system;
  • Gastrointestinal tract;
  • Connective tissues.

Human body

So, we have this extremely widespread network of cell-receptors that react to endocannabinoids and cannabinoids, but what is the actual function of this system?

The sole purpose of ECS is to maintain balance within an organism.

This is achieved by performing different tasks within an individual cell, because depending on what type of cell it is (nerve cell, immune cell, skin cell, muscle cell, secretory cell and so forth), the precise mechanism of action on that specific cell will be different.

The way a specific cell reacts when a cannabinoid activates its receptor is also dependent on the type of condition that an organism is afflicted with.

This entails that the ECS is very adaptive and can trigger an extremely wide range of biological responses inside of a single cell, depending on what exactly is wrong at that given time.

In an ideal situation, all systems of the body function optimally and this is called the homeostasis, which can be also understood as a dynamic state of equilibrium.

The endocannabinoid system is a primary “instrument” in charge of maintaining homeostasis, and this is why the cells of all these different systems and tissues have cannabinoid receptors.

In a nutshell, the endocannabinoid system helps to maintain health on a cellular level in every of system of the body, vigilantly reacting and adapting to the continuous changes our body encounters.

Human system

Unfortunately, the ECS does not function properly in everyone and this malfunction is associated with the body’s inability to heal itself optimally.

Even though the precise causes of ECS malfunction remain elusive, it is hypothesized that numerous different factors including genetics, diet, lack of exercise, various pollutants and stress are all responsible for an insufficiently effective endocannabinoid system.

An inactive ECS can also be responsible for “helping” some conditions and diseases to occur, but we’ll get to all of that later.

Endocannabinoid system discovery

Uncovering how cannabinoids stimulate cellular receptors in our body was not a simple task.

Over the course of history, numerous cultures have been using cannabis for medicinal reasons.

During the 19th century cannabis-derived products were also used for health-related purposes across Europe and the US because of the pioneer work of a doctor from Ireland named William O’Shaughnessy and a French scientist Jacques-Joseph Moreau.

As the science of chemistry wasn’t fully developed, they only understood that cannabis brings relief for numerous conditions, without comprehending how the healing actually occurs.

Let’s briefly check out the precise timeline of scientific discoveries in the field of cannabis:

  • 1895—the first cannabis-based compound named cannabinol (CBN) was isolated;
  • 1930—the precise chemical structure of cannabinol (CBN) was mapped;
  • 1940—the second cannabis-based compound cannabidiol (CBD) was isolated;
  • 1963—the precise chemical structure of cannabidiol (CBD) was mapped;
  • 1964—the psychoactive tetrahydrocannabinol (THC) was isolated;
  • 1988—cannabinoid receptors were first located;
  • 1990—a cannabinoid receptor was first cloned;
  • 1993—internal endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were first identified.

As you can see, discoveries that happened in the last three decades include the identification of both cannabinoid receptors and endocannabinoids, and these discoveries are absolutely crucial for understanding how the endocannabinoid system functions, but also how cannabinoids from cannabis affect and influence this system.

Through all these years numerous scientists gave their contributions to help uncover the secrets of cannabis, but one person helped take cannabis research into a whole new level.

That person is Dr. Raphael Mechoulam, a famed Israeli organic chemist and a professor of medicinal chemistry in Jerusalem.

He was involved in mapping the structure of CBD in 1963, and one year later he and his team identified and isolated THC. During the 90’s he also participated in the discovery of the body’s own endocannabinoids anandamide and 2-AG.

Funny thing about it is that the ECS was discovered by accident.

In the 1980’s researchers were trying to uncover how cannabis (more precisely THC) makes people “high”, and found that certain cells in our body have specific cellular receptors to which THC fits perfectly.

scientist

Researchers theorized that these receptors must have some purpose and that our body must produce its own endogenous compounds that are structurally similar to THC.

After several years of research (more precisely in 1993), anandamide and 2-AG were first identified.

These compounds fit perfectly into the discovered receptors, and since cannabis prompted the research, Dr. Mechoulam and his team named these compounds endocannabinoids (endo meaning produced by the body) and cannabinoids meaning they fit into the newly discovered cannabinoid receptors.

By discovering the cannabinoid receptors and endocannabinoids, scientists have hypothesized the existence of a previously unknown physiological system.

Fast forward several decades and we now know that this system has an incredibly beneficial influence on practically every other system in the body. It also functions as a tool for healing and helps maintain optimal health.

Here are a few interesting facts about the ECS:

  • Besides humans, every other vertebrate species (animals with a spine) possess an endocannabinoid system.
  • The most primitive animal that has an ECS is the sea-squirt (also called tunicate), which has evolved around 600 million years ago.
  • In humans, the endocannabinoid system is fully operational before we leave our mother’s uterus. (1)

Receptors of the endocannabinoid system

These cellular receptors are responsible for our body’s reaction to endocannabinoids, but also to active compounds found in marijuana.

There are main two distinct types of cannabinoid receptors, and they can be considered as “locks” that are present on the membranes of different types of cells in our body.

All cannabinoids act as “keys” which trigger a specific response from these cell, upon entering the “lock” of the receptors.

Cell

CB1 receptors are mostly located in the central nervous system

CB1 receptors are the most abundant cannabinoid receptors in the body, and they are mostly located in the central nervous system (CNS), more precisely the brain and the spinal cord.

In the brain, the largest quantity of CB1 receptors is present in the:

  • Frontal cortex (where thinking happens)
  • Hippocampus (in charge of memory)
  • Cerebellum (in charge of movement)
  • Basal ganglia (associated with voluntary movement, learning, cognition and emotion)

Other than the central nervous system, CB1 receptors are found in the vital and reproductive organs, various glands, gastrointestinal and urinary tract, white blood cells and connective tissues.

CB2 receptors

CB2 receptors are the second most prominent cannabinoid receptors and are mostly found in the gastrointestinal (GI) tract, where the most of the body’s immune system is located.

Large concentrations of CB2 receptors are also found in the tonsils and the thymus gland, and both sections of the body are also valuable assets of the immune response.

CB2 receptors are (just like CB1) also expressed in some neuron cells (like the microglia) in the brain and other parts of the central nervous system, but in much smaller quantities than CB1.

Another captivating attribute of the ECS is that both cannabinoid receptors and endocannabinoids get synthesized in the body on demand.

This basically means that when our body “senses” that an additional receptor will return our organism into a state of balance, it produces that receptor along with a compound that activates it.

Studies have shown that this trait of ECS occurs in situations like nerve injury, inflammation and tissue damage. (2)

Here are a few more facts about the endocannabinoid receptors:

  • It is speculated that CB1 and CB2 receptors are more numerous than any other receptor system in the human body (including the receptors of neurotransmitters dopamine and serotonin).
  • Numerous parts of our body contain both CB1 and CB2 receptors, and they are found in many intersections of our body (the borders of two or more different physiological systems), contributing to the communication and cooperation of differing types of cells.
  • Besides CB1 and CB2, certain endocannabinoids activate other receptors in the body, including the TRP (transient receptor potential), and PPAR’s (peroxisome proliferator activated receptors).

Endocannabinoids

Very similar to our current understanding of cannabis-derived cannabinoids, contemporary science has currently figured out the precise mechanisms of action of two internal endocannabinoids, anandamide and 2-AG.

Even though we don’t understand everything, the ongoing research has provided us with great insight about the functioning of the ECS, and the extremely diverse roles of these endogenous compounds.

Anandamide (N-arachidonoylethanolamine, or AEA)

Anandamide is the most thoroughly studied endocannabinoid, and was discovered in 1993 by Raphael Mechoulam. Its name is derived from the sanskrit word “ananda”, meaning bliss or delight, which is one of the main cerebral effects of anandamide.

The role of this compound is profoundly diverse, helping to regulate numerous processes that include the immune system function, central nervous system function, appetite, pain, memory and much more.

Anandamide is an activator (agonist) of both CB1 and CB2 receptors, meaning it is created (synthesized) throughout the tissues of our body, which also explains its divergent effect on our organism.

I already mentioned that both endocannabinoids and endocannabinoid receptors get synthesized on demand, meaning our body makes them once it “senses” the need for these compounds.

Exercise boosts anandamide levels

The best example of this phenomena is the “runner’s high”, where long-distance runners experience an intensely visceral euphoric feeling, and this sensation is actually anandamide’s doing.

Scientists have observed that prolonged aerobic exercise (over 30 minutes) increases anandamide levels (3), complimenting to that joyous feeling we experience after hard physical labour.

Marathon and triathlon competitors experience increased levels of anandamide in the greatest possible extent as their aerobic exercise is really intense and very durable at the same time.

Anandamide affects memory and forgetting

What’s also fascinating is the effect anandamide has on memory.

Naturally you’d assume that it increases or enhances our memory, but the truth is this compound has a very important role in helping us forget.

This might seem somewhat unusual at first, but consider how much input we receive from our senses on a daily basis. For instance, the amount of faces we see every time we ride the subway.

For our brain to store things worth remembering and not go haywire, it needs to “delete” unwanted information.

Anandamide’s “forgetting” function is also very important for traumatic and extremely stressful events, and people suffering from PTSD have a very hard time disconnecting from the trauma they’ve experienced.

This is why CBD works wonders for anxiety (4) and also PTSD patients.

I previously mentioned that endocannabinoids are created and degraded by certain enzymes in our body.

Cannabidiol (CBD) lessens the production of a specific enzyme that is responsible for degrading (or “recycling”) anandamide.

By diminishing the amounts of the FAAH (fatty acid amide hydrolase) enzyme, anandamide is left to engage the receptors of the endocannabinoid system for extended periods of time, leading to a diminishment of general anxiety, but also the stress caused by PTSD.

Genetic mutations increase anandamide levels

The exact same mechanism of degrading anandamide with the FAAH enzyme is also what separates entire happy from unhappy nations, which was noticed by examining their “levels of happiness”. (5)

This research gave us an insight that specific genetic mutations are responsible for different levels of FAAH enzyme in the body, and lesser quantities of this enzyme directly correlates with a constantly better mood, and a general sense of well-being.

The science team behind this study also noted that a sense of happiness of course isn’t only dependent on this connection, but also depends on a complex mixture of economic and political factors.

Foods that increase anandamide production

Some foods can boost anandamide levels, and some can slow down the metabolization of the FAAH enzyme which degrades it.

Dark chocolate

Pure chocolate affects anandamide levels in two ways: It increases the number of available endocannabinoid receptors that can be triggered by anandamide, and it diminishes the FAAH levels.

Black truffles

Unlike chocolate which influences the ECS in more subtle ways, black truffles have anandamide in them, and when eaten they directly increase the levels of this endocannabinoid in our body.

What’s also fascinating about these mushrooms is that they don’t have any endocannabinoid receptors whatsoever, and it is theorized that the presence of anandamide acts as a tactic for spreading the spores (their asexual reproductive units), by attracting predators to eat them and subsequently spreading their spores to nearby surfaces.

Kaempferol

This compound is found in many fruits and vegetables like apples, grapes, onions, potatoes, tomatoes and broccoli. Besides being a powerful antioxidant and reducing oxidative stress, kaempferol also inhibits the synthetization of the FAAH enzyme, thus prolonging the duration and effects of anandamide.

Omega 3 fatty acid

Consuming these polyunsaturated fatty acids found in fish oil, krill oil, hemp and flax seeds has shown to increase the vigilance of the endocannabinoid system (6).

2-AG (2-Arachidonoylglycerol)

This is the second most prominent endocannabinoid, but currently it isn’t nearly as researched as anandamide.

What we do know so far is that 2-AG is present in much larger quantities in the central nervous system (brain and spinal cord) than anandamide.

2-AG is also an agonist (triggers a biological response) of both CB1 and CB2 endocannabinoid receptors.

What’s also interesting is that 2-AG is a high efficacy agonist of endocannabinoid receptors, while anandamide is described as a low efficacy agonist for CB1, and a very low efficacy agonist of CB2 receptors (7).

What additionally separates anandamide and 2-AG is that the enzymes which synthesize and degrade these endocannabinoids are completely different: Anandamide is degraded by FAAH, and 2-AG is degraded by an enzyme called MAGL (monoacylglycerol lipase).

This entails that they have completely different roles within the ECS, but both are tools for maintaining balance within an organism, which is the primary function of the endocannabinoid system.

Researchers will undoubtedly provide us with additional knowledge about this enigmatic compound soon.

Endocannabinoid system deficiency

Clinical Endocannabinoid Deficiency (8) (or CECD), is a health condition where the body doesn’t produce adequate quantities of endocannabinoids, or it doesn’t produce the needed amount of endocannabinoid receptors.

Another possible cause for CECD can also be that the body produces too many enzymes (FAAH, MAGL), that break down the endocannabinoids before they get the chance to affect the receptors.

As a result of this deficiency, a weakened ECS cannot properly maintain homeostasis (a balance of interconnected systems within an organism).

Clinical Endocannabinoid Deficiency was first described by Dr. Ethan Russo, who’s been on the forefront of modern cannabis research during the last two decades.

According to his research, clinical ECS deficiency can have a negative influence on many conditions and diseases, including:

All of this may seem a bit far-fetched to someone who isn’t acquainted with the incredibly diverse role the ECS plays in our body.

But if official scientific research concluded that a malfunctioning endocannabinoid system is connected to so many physiological issues, this directly coincides with why cannabis is a valid and successful treatment method for so many conditions, disorders and diseases, such as:

Summary

Even though the number of scientific studies that deal with medical cannabis, endocannabinoid system and cannabinoids counts over 24.000 different articles, many are still very skeptical about the healing properties of cannabis.

This survey from 2013 was conducted by the Medical Cannabis Evaluation and had the goal of finding out if medical schools in the US teach endocannabinoid system as a part of their curriculum.

The survey found that ECS is taught in only 13% of medical schools.

What’s also very important to understand is that by consuming cannabinoids from cannabis we also increase the quantity of both cannabinoid receptors, and our internal endocannabinoids.

Small and carefully thought-out doses “force” our body to produce more of its endogenous cannabinoids like anandamide and 2-AG, and at the same time increase the concentration of cannabinoid receptors CB1 and CB2 (9).

References

  1. Fride E, Gobshtis N, Dahan H, Weller A, Giuffrida A, Ben-Shabat S; The endocannabinoid system during development: emphasis on perinatal events and delayed effects; 2009; 139-58
  2. Balapal S Basavarajappa; Neuropharmacology of the Endocannabinoid Signaling System-Molecular Mechanisms, Biological Actions and Synaptic Plasticity; 2007; 81–97
  3. Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P; A runner’s high depends on cannabinoid receptors in mice; 2015; 112(42)
  4. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA; Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients; 2011; 36(6)
  5. Michael Minkov, Michael Harris Bond; A Genetic Component to National Differences in Happiness; April 2017; pp 321–340
  6. Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ; Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions; 2011; 345-50
  7. Hui-Chen Lu, Ken Mackie; An introduction to the endogenous cannabinoid system; 2016; 516-525
  8. Ethan B. Russo; Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes; 2016; 154–165
  9. Shenglong Zou and Ujendra Kumar; Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System; 2018
Categories Health

12 thoughts on “The Endocannabinoid System: A Complete Scientific Introduction”

    • Thanks Mary, I’m really glad you liked it 🙂

      This subject matter is undeniably complex, but it is truly essential for understanding how cannabis creates its medicinal effects.

  1. This is a lot of very good information. I am an herbalist and I’m very interested in working with cannabis and herbs and have on some levels. I have cannabis and cancer and very recently added two years to my husband’s life with cannabis. I cannot afford licenses and all that’s involved in it and I’m 70 years old I just want to know. I want to know where and if I can get a printed copy of this it is so well-written.

    • I appreciate your kind words Juanita. I’ll be sending you a pdf version of this article to your email, so you can easily print it out.

  2. I need a PDF also, so I can read and study it. Due to eye troubles I’m not suppose to stay on line viewing stuff. thank you. I’m interested in the BBC video that shows natural manufacturing of this substance by singing 40% versus dancing at 20%. are you familiar with that?

    • I’ll send it to you right away, and I’m not sure I follow this dancing and singing stuff, if you could please elaborate on that 🙂

  3. Please send a PDF my way as well. This information is useful and I join the others in congratulating you on your well-written article, and in expressing gratitude for your efforts. Much appreciated!

    • Thank you so much Monica, I’ve spent a great number of hours working on this particular piece, and it’s really rewarding to see our readers positively responding to it 🙂

  4. Such a well written article! I would love to have a PDF of it so that I could share it with patients if that’s okay with you.

  5. First of all, thanks to you, and all the Greencampstaff for the excellent writing in your articles about all the aspects of cannabis.

    In 1970 I was a graduate student in pharmacology and was doing behavioral research with cannabis which was quite rare then. Unfortunately, I had some issues of my own (a divorce, death of mother) and did not complete my PhD. I made photocopies of articles from that period on chemistry, pharmacology, and psychology of cannnabis, all of which I still have.

    I would very much like to give them to someone who would find value in them.

    I hope you, and perhaps your senior staff, could be, or find, that place.

    Thank you

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