Much ado about the Endocannabinoid System

The Endocannabinoid System (ECS) is all about homeostasis. Yin and yang are all about balance. Whole-system treatment may be common in Chinese Medicine, but the idea was completely foreign to European-based medicine. It took an American, Walter Cannon, to introduce homeostasis in the medical lexicon in 1930.[i]

A handful of biological systems work together to achieve the many complex tasks we need to make it through a day. These systems are “made up of many networks that are integrated at and communicating on multiple scales.”[ii] An example is the skeletal system, which consists of all of the bones, joints, cartilage, tendons and ligaments in the body.[iii] It is mainly used for “locomotion, support of the body, and the protection of internal organs.”[iv]

Homeostasis means “same” and “steady”. “Homeostasis is the ability of an organism to maintain a stable, constant internal environment, even when the external environment changes”[v]. A common example of this is when the human body sweats to cool down. The water on the skin absorbs body heat as it evaporates off of the body.[vi]

Homeostasis works the same at the cellular level. The cells seek to maintain an equilibrium inside the cell walls as they live in their respective dynamic environments. Through homeostasis, these cells can do a variety of things. The Endocannabinoid System (ECS) is on organs throughout the body and is used to maintain the health of these cells.

The brain, nervous system, liver, kidneys, and immune cells are among the organs that contain the ECS. The system is made of primarily of two receptors, CB1 and CB2. The existence of the ECS in Western (Eastern to me) medicine was discovered in rat brains in 1988 by Allyn Howlett, PhD.[vii]

Then, in 1990 the National Institute of Mental Health published a letter to Nature Magazine that documented the discovery of CB1 receptors in the cerebral cortex of rats. A few years later, in 1993, cannabis receptors were found in the spleen. Now that the CB2 receptor was found, Eastern (Western to most) science took off on researching the ECS.

There are exogenous cannabinoids and there are endogenous cannabinoids that interact with these receptors. Exogenous cannabinoids are cannabinoids that are found in the cannabis plant. CBDs, THCs, and other cannabinoids are examples of exogenous cannabinoids. Endogenous cannabinoids occur naturally in the human body. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are examples of endogenous cannabinoids. There is a third cannabinoid category too. It is the scary stuff; lab-made cannabinoids, or synthetic cannabinoids. Spice (HU-210) and Marinol (dronabinol) are two types of synthetic cannabinoids.

Endogenous cannabinoids, or endocannabinoids(ECs), “act as hydrophobic lipid messengers”[viii]. In the CNS, they act as “receptive messengers or synaptic modulators”[ix] and are “produced on demand”[x]. This is unique in the ECS. Other neurotransmitters, such as acetylcholine and dopamine, are already synthesized and stored for later use. [xi]

Lipid messengers are important because they bind to receptors in the cell and use that location for cell signaling. Cell signaling is important because it is how the cell stays healthy. Cells need to “perceive and correctly respond to their microenvoronment”.[xii] Things like tissue repair, homestasis, and immunity must happen in the cell. Otherwise, diseases like cancer and diabetes can set in.[xiii] The ECS a part of the G-coupled protein receptor family, the largest of the cell surface receptors.[xiv]

According to lipidhome, a resource for understanding the chemistry of lipids, “Endocannabinoids exist in dynamic equilibria with many other lipid-derived mediators, including eicosanoids and other oxylipins (oxygenated natural products which are formed from fatty acids by pathways involving at least one step of dioxygen dependent oxidation; many of them have physiological importance)[xv], as part of a versatile system involved in fine-tuning different physiological and metabolic processes, including inflammation, in a tissue- or cell-specific manner.”[xvi]

 

Endocannabinoids

The endocannabinoid AEA is “produced by immune cells and neurons, and is more selective for CB1R than CB2R. It is found in the brain, spleen, skin, kidney, and uterus”.[xvii] It was dubbed “the bliss molecule” because it “mimics the behavioral actions of exogenous compound”[xviii] THC. According to Dr. Mechoulam, who discovered AEA with Drs. William Devane and Lumir Hanus, in 1992, “THC is an aromatic compound, while AEA is a fatty acid derivative”[xix].

AEA is produced on demand and has many anti-inflammatory and anti-cancer properties.[xx] It has benefits to the cardiovascular system. It can help lower blood pressure. AEA also affects metabolism by increasing the amount of food consumed. Macrophage-defined AEA has “anti-inflammatory effects both in the peripheral and central nervous system”.[xxi] AEA is also a key player in apoptosis (programed cell death) of many different cell types in the body.

It took three short years for the next endocannabinoid to be discovered. Dr. Mechoulam et al discovered 2-AG in 1995. These endocannabinoids were first found in the brain, but they have been found in other places since. These are also made-on-demand. These seem to be the more important ligands for the CBRs in the body. They are full-agonist ligands, as opposed to the partial-agonist nature of AEA.[xxii]

Full-agonist ligands will fully activate the cell, while partial-agonist ligands will partially activate the cell.[xxiii]

These endocannabinoids interact with cells through receptors throughout the body. CB1and CB2 receptors are part of the G-coupled protein receptor (GCPR) superfamily[xxiv], and the passive member of the Transient Receptor Potential (TRP) family, the Vanniloid Receptor (TRPV1) are a few of the cannabinoid receptors that have been discovered.

 

CB Receptors

CB1 receptors express themselves primarily in the brain and central nervous system (CNS). They are not limited to the CNS, however, and are found in organs like the liver and the prostate. These receptors are associated with energy balance and may also “play a role in synaptic plasticity”[xxv]. Synaptic plasticity means that synapses are “able to change their strength as a result of either their own activity or through activity in another pathway”[xxvi].

CB2 receptors are primarily expressed in the immune system. There are small amounts in “human B cells, NK cells, monocytes, polymorphonuclear neutrophils and T cells”[xxvii] CB2Rs are also expressed in the thymus and spleen. The exciting thing about CB2R’s, however, is that they show up in dendritic cells. Dendritic cells are antigen-presenting cells (APC) that are key regulators of the immune system.[xxviii]

CB2Rs have also been found in “astrocytes, microglia, neural subpopulations and oligodendroglial progenitors in healthy brains”.[xxix] Microglia are “resident immune cells of the central nervous system” and “are critical players in the development of pain hypersensitivities that characterize chronic pain”[xxx].

TRPV1 Receptors were discovered in 1997 by Dr. David Julius et al. They are located in many organs of the gut, including kidneys, spleen, bladder, and lungs. TRPV1 receptors can also be found in the Central Nervous System[xxxi]. A wide variety of spices can activate these receptors. The most prominent spice is capsaicin, the component that makes chilies hot. Capsaicin has also been found in black pepper, garlic, ginger, horseradish, and cinnamon.

 

The Gut

The gut is a constantly under attack from antigens. Therefore, we have a wide variety of defenses in our guts to fight these invading antigens. Phagocytes (cells that eat bacteria and other small cells) and dendritic cells (“professional antigen presenting cell, capable of activating naïve T cells and stimulating the growth and differentiation of B cells”)[xxxii], “which are present abundantly in the small intestine lamina propia (siLP), play an instrumental role in maintaining this exquisite balance between inflammation and tolerance.”[xxxiii]

A recent study published in the National Academy of Sciences found that AEA and ECBS in the gut is largely responsible for “maintaining tolerance in the gut”[xxxiv]. Tolerance is important because it suppresses the production of cytokines and the proliferation of t-cells in the gut.[xxxv] The study broke the maintenance down to two steps:

1: “through maintenance/differentiation of the well-known immune regulatory CX3CR1”[xxxvi] macrophage population.

2: “mediating the expansion of regulatory T cells called Tr1 cells.”[xxxvii]

The study also found that these immune-regulatory macrophages expressed themselves the most on the CB2 and TRPV1 receptors. Also, for both CB1R and CB2R, different conformations correspond to different agonists stimuli, consequently activating different signaling pathways (functional selectivity).

 

The Brain and Central Nervous system

 

The brain and central nervous system are full of CB1 receptors. These receptors have been found in the mitochondria of some astrocytes (large star-shaped cells of the glia[xxxviii] (supporting tissue intermingled with the essential elements of nervous tissue especially in the brain, spinal cord, and ganglia)[xxxix]), leading some to believe that CB1 receptors can be involved in synaptic plasticity (important for memory use) and energy balance.[xl]

The list comes from “Distribution of the Endocannabinoid System in the Central Nervous System”

[xli]

  • Retinas- amacrine cells, horizontal cells, densely expressed in the inner plexiform layer, rod and cone photoreceptor terminals.
  • Cerebral Cortex- “CB1 receptors are densely expressed in all regions of the cortex”.[xlii] These regions include the cingulate gyrus, frontal cortex, secondary somatosensory, and motor cortex.
  • Olfactory-in descending orderàhighest in the inner granular cell layer, then the inner piniform layer, less in the external plexiform layer, glomerular layer, and the accessory olfactory bulb
  • Hippocampus- “high levels of CB1 receptors on large CCK-positive basket and Schaffer collateral- associated interneurons in the hippocampal pyramid cell layer.”[xliii] CB1 is also highly expressed in the molecular layer and the granule cell layer in the dentate gyrus.
  • Cortical subplate- mainly expressed in the CCK-positive GABAergic basket cells in high levels.
  • Subcortical Nuclei- basal ganglia has the highest amount of CB1 expression.
  • Striatum-low-to- moderate level expression in the nucleus accumbens. “However, CB1 receptors seem to be absent in the dopaminergic terminals projecting from the ventral tegmental area(VTA) to the accumbens”[xliv]
  • Striatum Medial- basal forebrain, medial and lateral septum and the nucleus of the diagonal band has moderate levels of CB1 receptors
  • Cerebellum-The authors called the CB1 expression patterns “striking”. “CB1 receptors are mainly expressed in the terminals of the climbing fibers, parallel fibers, and (some)basket cells, suggesting a prominent presynaptic localization of CB1 receptors, mediating modulatory effects of (endo)cannabinoids at glutamatergiv and GABAergic inputs onto Purkinje neurons.”[xlv]
  • Deep Cerebellar Nuclei-Medial, lateral, and interposed nuclei have weak Cb1 immunoreactivity throughout the neuropil.
  • Brainstem- Thalamus has low Cb1 expression in most parts. CB1 is strong in the lateral habenular nucleus, the anterior dorsal thalamic nucleus, and the reticular thalamic nucleus.
  • Hypothalamus- much CB1 expression in the arcuate, paraventricular, ventromedial, dorsomedial nuclei, the external zone of the median eminence, infundibular stem, and lateral hypothalamic area.
  • Mesencephalon- extremely high levels of CB1 in the substantia nigra (SN) pars reticulate and low levels in the exact same place. This suggests that “the high levels of CB1 protein are restricted to incoming axonal projections from other brain regions[xlvi].”
    • Ventral Tegmental Area- dense CB1 neuropil labeling.
    • Periaqueductal Gray- There are low to moderate expressions of CB1 receptors found in the Periaqueductal Gray. This is “where the ECS is involved in the control of pain sensation, including stress-induced analgesia”.[xlvii]
  • Hindbrain-low CB1 expression in the medullary respiratory control centers. This is in contrast to the opioid receptors, which “likely explains the low mortality caused by cannabinoid intoxication.”[xlviii]
  • Spinal Cord-spinal dorsal horn. Scientists believe that this is where the “application of cannabinoids has been found to suppress pain…)”.[xlix]

The endocannabinoid system has led to many discoveries within the scientific community. A handful of pharmaceutical companies have already set out to create cannabis-derived medicines to remedy rare diseases, like Dravet Syndrome. Some companies have since returned positive results while others made fatal mistakes in the drug development process.

The most notable company to successfully bring a CBD-derived drug to market is GW Pharmaceutical, in Britain. Their oral spray, Sativex, is used to help people with multiple sclerosis. They are working on another drug called Epidiolex. This orally-administered, CBD-derived medicine has shown amazing results in its clinical trials with the Food and Drug Administration (FDA).

Positive FDA results in this final set of trial runs could be a game-changer for the official Federal stance on the cannabis plant moving forward. The giant ideological wall that is the current Trump administration, however, is a different story. The sitting Attorney General will never accept FDA findings that prove that cannabis must be descheduled. It will instantly be disregarded as “fake!”. A smear campaign will follow, and the men and women of the FDA will be in its crosshairs. And we will continue to move on in two diverging roads, with many Americans continuing down a different road than our government is paving.

 

References:

https://Mechoulam.tcmworld.org/what-is-tcm/yin-yang-theory/

http://norml.org/library/item/introduction-to-the-endocannabinoid-system

https://agelessherbs.com/yin-yang-theory/

http://Mechoulam.orientalmedicine.com/yin-yang

https://Mechoulam.ncbi.nlm.nih.gov/pmc/articles/PMC2993256/pdf/zpg588.pdf

https://Mechoulam.ncbi.nlm.nih.gov/pmc/articles/PMC3775668/pdf/nihms510207.pdf

https://Mechoulam.ncbi.nlm.nih.gov/pubmed/21079038

https://Mechoulam.scientificamerican.com/article/what-is-homeostasis/

https://Mechoulam.reference.com/science/concept-homeostasis-112a53029f85f5c4

https://Mechoulam.ncbi.nlm.nih.gov/pubmed/2848184

https://Mechoulam.ncbi.nlm.nih.gov/pmc/articles/PMC2768535/pdf/nihms99606.pdf

http://www.yourdictionary.com/oxylipin

http://lipidhome.co.uk/lipids/simple/endocan/index.htm

https://Mechoulam.researchgate.net/publication/41427483_Cannabinoids_and_the_immune_system_An_overview

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/pdf/nihms155268.pdf

http://druglibrary.net/olsen/HEMP/IHA/iha01113.html

“Distribution of the Endocannabinoid system in the Central Nervous System.” Sherry Shu-Jung Hu and Ken Mackie. Sept 2015 Handbook of Experimental Pharmacology

http://neuroscience.uth.tmc.edu/s1/chapter07.html

https://Mechoulam.researchgate.net/publication/41427483_Cannabinoids_and_the_immune_system_An_overview

http://Mechoulam.medicinenet.com/script/main/art.asp?articlekey=19035

https://Mechoulam.researchgate.net/publication/307511132_Topography_of_microglial_activation_in_sensory-_and_affect-related_brain_regions_in_chronic_pain

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802457/pdf/nihms131900.pdf

http://www.pnas.org/content/early/2017/04/18/1612177114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292724/

“Endocannabinoid system acts as a regulator of immune homeostasis in the gut”. Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030; and Division of Diabetes and Endocrinology, Connecticut Children’s Medical Center, Farmington, CT 06032. Nandini Acharya, Sasi Penukonda, Tatiana Shcheglova, Adam T. Hagymasi, Sreyashi Basua,

and Pramod K. Srivastava. March 20, 2017

http://www.medicinenet.com/script/main/art.asp?articlekey=19035

https://www.merriam-webster.com/dictionary/glia

https://www.merriam-webster.com/dictionary/astrocyte

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

 

 

[i] https://Mechoulam.scientificamerican.com/article/what-is-homeostasis/

[ii] https://www.systemsbiology.org/about/what-is-systems-biology/

[iii] https://www.systemsbiology.org/about/what-is-systems-biology/

[iv] https://www.systemsbiology.org/about/what-is-systems-biology/

[v] https://Mechoulam.reference.com/science/concept-homeostasis-112a53029f85f5c4

[vi] https://Mechoulam.reference.com/science/concept-homeostasis-112a53029f85f5c4

[vii] https://Mechoulam.ncbi.nlm.nih.gov/pubmed/2848184

[viii] https://Mechoulam.ncbi.nlm.nih.gov/pmc/articles/PMC2768535/pdf/nihms99606.pdf

[ix] https://Mechoulam.ncbi.nlm.nih.gov/pmc/articles/PMC2768535/pdf/nihms99606.pdf

[x] https://Mechoulam.ncbi.nlm.nih.gov/pmc/articles/PMC2768535/pdf/nihms99606.pdf

[xi] http://dictionary.sensagent.com/Cell%20signaling/en-en/

[xii] http://dictionary.sensagent.com/Cell%20signaling/en-en/

[xiii] http://dictionary.sensagent.com/Cell%20signaling/en-en/

[xiv] http://dictionary.sensagent.com/G-protein%20coupled%20receptors/en-en/

[xv] http://www.yourdictionary.com/oxylipin

[xvi] http://lipidhome.co.uk/lipids/simple/endocan/index.htm

[xvii]https://Mechoulam.researchgate.net/publication/41427483_Cannabinoids_and_the_immune_system_An_overview

[xviii] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/pdf/nihms155268.pdf

[xix] http://druglibrary.net/olsen/HEMP/IHA/iha01113.html

[xx] http://lipidhome.co.uk/lipids/simple/endocan/index.htm

[xxi] http://lipidhome.co.uk/lipids/simple/endocan/index.htm

[xxii] http://lipidhome.co.uk/lipids/simple/endocan/index.htm

[xxiii] http://membranereceptors.com/membrane-receptors/agonists-and-antagonists/

[xxiv]  https://Mechoulam.ncbi.nlm.nih.gov/pubmed/21079038

[xxv] Distribution of the Endocannabinoid system in the Central Nervous System. Sherry Shu-Jung Hu and Ken Mackie. Sept 2015 Handbook of Experimental Pharmacology

[xxvi] http://neuroscience.uth.tmc.edu/s1/chapter07.html

[xxvii]https://Mechoulam.researchgate.net/publication/41427483_Cannabinoids_and_the_immune_system_An_overview

[xxviii] http://Mechoulam.medicinenet.com/script/main/art.asp?articlekey=19035

[xxix]https://Mechoulam.researchgate.net/publication/41427483_Cannabinoids_and_the_immune_system_An_overview

[xxx]https://Mechoulam.researchgate.net/publication/307511132_Topography_of_microglial_activation_in_sensory-_and_affect-related_brain_regions_in_chronic_pain

[xxxi] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802457/pdf/nihms131900.pdf

[xxxii] http://www.medicinenet.com/script/main/art.asp?articlekey=19035

[xxxiii] “Endocannabinoid system acts as a regulator of immune homeostasis in the gut”. Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030; and Division of Diabetes and Endocrinology, Connecticut Children’s Medical Center, Farmington, CT 06032. Nandini Acharya, Sasi Penukonda, Tatiana Shcheglova, Adam T. Hagymasi, Sreyashi Basua,

and Pramod K. Srivastava. March 20, 2017

[xxxiv] http://www.pnas.org/content/early/2017/04/18/1612177114

[xxxv] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292724/

[xxxvi] http://www.pnas.org/content/early/2017/04/18/1612177114

[xxxvii] http://www.pnas.org/content/early/2017/04/18/1612177114

[xxxviii] https://www.merriam-webster.com/dictionary/astrocyte

[xxxix] https://www.merriam-webster.com/dictionary/glia

[xl] https://www.merriam-webster.com/dictionary/astrocyte

[xli]https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xlii]https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xliii] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xliv] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xlv] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xlvi] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xlvii] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xlviii] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

[xlix] https://www.researchgate.net/publication/282244852_Distribution_of_the_Endocannabinoid_System_in_the_Central_Nervous_System

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