THE ENDOCANNABINOID SYSTEM:

What is it and what does it do?

To fully understand how CBD works, it is helpful to first understand a little about the endocannabinoid system. The endocannabinoid system (ECS) is the inter-connected system of receptors in the body that is "turned on" by endocannabinoids like cannabidiol. These receptors, found throughout the brain and central nervous system, can help the body heal and regulate itself when "triggered" by endocannabinoids. The body can make its own endocannabinoids, but only in small amounts. These chemicals engage with the receptors in the body, like keys in special locks, and cause the body to release more or less of other chemical signalers and hormones that trigger a whole host of health effects. These same cannabinoid receptors can also be unlocked with phytocannabinoids, which are plant-based natural cannabinoids like THC or CBD. THC, as you probably guessed, acts mainly upon the receptors in the brain, triggering mood and psychological effects that responsible for the "high" of marijuana. CBD affects some of these same receptors, but without the "high", and is more likely to trigger feelings of calm then high levels of euphoria. While THC is a well-known pain reliever, CBD activates many of the same receptors, and eases pain and discomfort in a similar way, with longer-term effects. While the effects of THC seem to spike and dissipate quickly, CBD has a more sustained effect, gently coaxing the endocannabinoid system to help the body heal and modulate itself. While these two prevalent cannabinoids have similar methods of interacting with the body's endocannabinoid system, many of the effects are different, and different people respond differently to the use of cannabinoids for their health.

The History of the Endocannabinoid System

The ECS was first discovered in the 1990's by Dr. L.A. Matsuda and his team when they discovered the CB-1 receptor and hypothesized that cannabinoid receptors existed for endocannabinoids that are naturally produced in the human body, instead of for phytocannabinoids (cannabinoids derived from plants).

Since then the scientific community has made leaps and bounds in understanding the function of the ECS. As the interactions between the ECS, endocannabinoids and phytocannabinoids are better understood in maintaining general health and the treatment of disease(1), medical caregivers, clinicians and researchers are becoming more serious about cannabis as a viable treatment option for many of their patients. The recent passage of the new 2018 Farm Bill finally removed CBD completely from the purview of the DEA, opening up the possibility of new clinical and university studies with federal funding. FDA approval has recently been granted to a CBD-based medication for the treatment of certain diseases as well.

So, what is the ECS? How does it work? And how do plant-derived cannabinoids help humans and other mammals stay healthy and vibrant in addition to helping relieve such a wide range of symptoms?

The Biology of the Endocannabinoid System

Fundamentally, the ECS is comprised of three different components:

  1. The CB-1 and CB-2 cannabinoid receptors that endocannabinoids and phytocannabinoids like CBD bind to.
  2. The endocannabinoids which are retrograde neurotransmitters that work like a kind of "dimmer switch" that modulates neuronal signaling.
  3. The metabolic enzymes, that break down the endocannabinoids once they have done their work.

Cannabinoid Receptors

The ECS consist of a remarkably complex network of cannabinoid receptors. Thus far, two types have been identified, namely type 1 (CB-1), and type 2 (CB-2). Each of these are associated with a specific set of receptors and their associated cannabinoids that help to modulate and maintain a wide variety of biological and physiological functions.

CB-1(2) receptors are primarily located within the brain and central nervous system but are also present in the lungs, gastrointestinal tract, liver, and kidneys. These type 1 CB's are thought to primarily be responsible for modulating the release of neurotransmitters, thus maintaining homeostasis (a state in which the body is in perfect equilibrium) within the body by preventing excessive or inadequate amounts of neuronal activity. Scientists believe that it is this modulation of other peripheral neuronal activity that allow CB-1 receptors to successfully aid in the reduction of pain and inflammation(3), in addition to helping relieve symptoms such as anxiety, aggression(4) and short-term depression(5). CB-1 receptors have also been implicated in regulating appetite(6) and digestion(7), motor control(8) and even in reducing drug-seeking(9) behaviors.

In turn, CB-2(10) receptors are predominant in the immune system but can also be found in the spleen, tonsils, thymus gland(11), and even retinal cells. Thought to be involved with immune function and response, cell death, and cell migration during tissue development(12), CB-2 receptor sites are of particular interest in the study for the treatment of gastrointestinal illnesses such as Chron's disease, inflammatory bowel diseases, as well as ulcerative colitis as these have been shown to modulate intestinal inflammatory responses(13). CBD can act on both of these types of receptors in the body.

Endocannabinoids

As mentioned, endocannabinoids are a special type of retrograde neurotransmitter(14) that work like a kind of dimmer switch, modulating how, where and how much of other neurotransmitters are released, distributed and deployed within the body. Where "normal" anterograde neurotransmitters travel one-way down the signaling pathway of a neural network, retrograde neurotransmitters can also travel back up that same pathway. When this happens, it modulates communication between the cells that were activated by the anterograde neurotransmitter, in effect "dimming" the signal.

A real life example of this is when, say for instance an epileptic is experiencing a seizure(15) (an over-excitement of electrical activity caused by an imbalance of neurotransmitters), endocannabinoids will travel back up those signaling pathways, stopping further neural signaling and eventually helping in the cessation of the convulsive response. This is why CBD and other cannabinoids have been approved as a treatment for seizure disorders, and received FDA approval in drug form to be prescribed to people suffering from seizure diagnoses.

To date, there are five known endocannabinoids produced by the body: anandamide(16) (AEA); 2-arachidonoylglycerop(17) (2-AG); O-arachidonoyl ethanolamine(18) (O-AEA); 2-arachidonyl glyceryl(19) (Noladin); and the most recently discovered (20)N-Arachidonoyl dopamine (NADA). There are over 80 known phytocannabinoids found in the hemp plant, and many of these have yet to be fully studied for their potential health benefits.

Metabolic Enzymes

Enzymes ensure that endocannabinoids are only produced and used when needed, helping to break them down once their job is done. Unlike other hormones, endocannabinoids do not persist, nor are they stored for later use, meaning a deficiency can occur. The two major enzymes are Fatty acid amide hydrolase(21) (FAAH), and Monoacylglycerol lipase(22) (MAGL). Both of these break down endocannabinoids after use by the body, and can cause a deficiency if the cannabinoids are not replenished.

Clinical Endocannabinoid Deficiency Syndrome

When the ECS is working properly, the body remains in a state of homeostasis - a kind of dynamic equilibrium, or "Goldilocks zone" - where everything is just right. However, when the ECS becomes dysfunctional or damaged, the body gets kicked out of homeostasis and certain conditions can develop. Left too long, the system has a more difficult time returning the body to a state of homeostasis, and more health issues can develop. Treatment or supplementation with phytocannabinoids like CBD can reverse this deficiency.

According to the Clinical Endocannabinoid Deficiency(23) (CED) hypothesis, everything from neurodegenerative disorders(24), rheumatoid arthritis(25), and cancer(26), to pain, migraines(27), and IBS(28) can result from changes in endocannabinoid levels(29) and the ECS. This potentially makes the ECS an ideal target for the treatment of a wide variety of health issues as well as restoring health and balance within the body, without the downside risk of prescription medications that may bring about unwanted side effects. Much remains to be studied about how the ECS can benefit those suffering from health issues related to a potential endocannabinoid deficiency, and how much benefit supplementing with exogenous cannabinoids like CBD and THC can provide.

Phytocannabinoids & the ECS

Both anecdotally as well as in clinical trials, researchers note that when phytocannabinoids such as cannabidiol are (re)introduced into the body, people start feeling better. Users report less pain symptoms, better mood, less stress, and better sleep. Researchers(30) hypothesize that this is due to the way in which cannabinoids interact both directly, and indirectly on the ECS.

In the context of the CED hypothesis as discussed earlier, when the ECS is dysfunctional, the (re)introduction of cannabinoids into the body can help the ECS to function optimally once more, aiding in the restoration of homeostasis, which in turn not only help to relieve the symptoms of disease directly, but also help in the long term by giving the body the ability to heal itself.

Although researchers aren't clear on which comes first - changes in the ECS causing disease, or disease causing changes in the ECS - what is clear is that many chronic health issues can be traced back to a disfunction within the ECS. Likewise, supplementing the body's own systems with endocannabinoids can help reverse health problems stemming from other causes and stresses. As such, more and more medical practitioners and clinicians are opening up to the idea that phytocannabinoids, and CBD in particular, have powerful therapeutic potential in a variety of different ailments, and a very low risk of side effects. While supplementing with CBD, or any natural supplement, is never a magic bullet, the science is getting clearer each and every day. CBD has already helped people from all walks of life with their health, and it is worth talking with your health care professional to determine if CBD can help you too.

Footnotes

1 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241751/

2 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241751/

3 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/

4 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206034/

5 - http://www.nature.com/articles/nn.2974

6 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705914/

7 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575196/

8 - https://www.sciencedirect.com/science/article/pii/S0091305700002811?via=ihub

9 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481525/

10 - https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

11 - https://www.researchgate.net/profile/Ken_Mackie/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System/links/561fceef08aed8dd19403f4e/Distribution-of-the-Endocannabinoid-System-in-the-Central-Nervous-System.pdf

12 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226756/

13 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219529/

14 - https://en.wikipedia.org/wiki/Retrograde_signaling

15 - https://link.springer.com/article/10.1007/s11064-017-2287-8

16 - https://en.wikipedia.org/wiki/Anandamide

17 - https://en.wikipedia.org/wiki/2-Arachidonoylglycerol

18 - https://en.wikipedia.org/wiki/Virodhamine

19 - https://en.wikipedia.org/wiki/2-arachidonyl_glyceryl_ether

20 - https://en.wikipedia.org/wiki/N-Arachidonoyl_dopamine

21 - https://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase

22 - https://en.wikipedia.org/wiki/Monoacylglycerol_lipase

23 - https://www.ncbi.nlm.nih.gov/pubmed/18404144

24 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288380/

25 - https://www.ncbi.nlm.nih.gov/pubmed/24440992

26 - https://www.ncbi.nlm.nih.gov/pubmed/25855725

27 - http://kdarr.com/docs/pubs/cannabisPubs/ECmigraine.pdf

28 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219529/

29 - https://europepmc.org/abstract/med/18404144

30 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

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