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The Endocannabinoid System & Phytocannabinoids

Endocannabinoid System & Phytocannabinoids Endocannabinoid System & Phytocannabinoids
EuroMedica
 
Kaneka

The popularity of CBD, or cannabidiol, has exploded and CBD sales are rapidly growing year after year. In fact, a report from the Brightfield Group predicts that the CBD market will hit $22 billion by 2022. Whether or not this turns out to be an exaggeration, there is no question about the unprecedented growth of this product category. That being said, many people are unaware of the importance of the endocannabinoid system in the body, and how it functions to provide the potential benefits of CBD and other phytocannabinoids. This article will provide an overview of the endocannabinoid system (ECS), and its interaction with phytocannabinoids.

Introduction to the ECS

“The discovery of the endocannabinoid system is the single most important scientific medical discovery since the recognition of sterile surgical technique. As our knowledge expands, we are coming to realize that the ECS is a master control system of virtually all physiology.”1

Per the above quote from David B. Allen, MD, the ECS is, arguably, the most important system in the human body since it provides some degree of master control over other body systems. In short, the ECS helps to balance many of our physiological systems and supports the body. The fact is, the ECS impacts just about everything, including appetite, immune response, calorie burn, pain and inflammation and even cellular health. Its most important overall function is homeostasis, which basically means that it helps to keep the body in a healthy balance. One researcher summarized this amazing system in this way: “Metaphorically the endocannabinoid system represents a microcosm of psychoneuroimmunology or mind-body medicine.”2

This is an apt summary when considering that 1) cannabinoids and their receptors are found throughout the body. This includes the brain, organs, connective tissues, glands and immune cells, and 2) though performing different tasks, the goal of the ECS is consistently the maintenance of a stable internal environment despite fluctuations in the external environment, aka, homeostasis.

Emerging literature documents the ‘‘ECS deficiency syndrome’’ as a contributing factor in the development of migraine, fibromyalgia, irritable bowel syndrome, psychological disorders and other conditions.3 Furthermore, enhancing endocannabinoid activity has broad therapeutic potential, including the treatment of patients with somatic dysfunction, movement disorders such as Parkinson’s and Huntington’s disease, chronic pain and neurodegenerative diseases, mood and anxiety disorders as well as inflammatory conditions, bowel dysfunctions, psychological disorders, multiple sclerosis and spinal cord injury, cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome and osteoporosis, to name just a few.4,5

Despite the importance of the ECS, the research and education of medical students involving the ECS has been restricted. In a recent survey of 157 medical schools in the United States, only 13 percent of them included any discussion of endocannabinoid science within the medical curriculum.6 This unreasonable exclusion from medical school curriculums appears to a function politics. Specifically, during the early 20th century, growing concerns over its abuse potential drove many states to pass laws prohibiting cannabis, along with opium and alcohol. In 1936, Harry J. Anslinger, commissioner of the newly established Federal Bureau of Narcotics, characterized marijuana as a dangerous drug and advised federal action. The American Medical Association called for further research, however Anslinger’s efforts led to the 1937 Marijuana Tax Act, which greatly diminished its use. Further shaping public opinion were films such as “Reefer Madness” (1936) and a chain of anti-marijuana articles published in newspapers owned by William Randolph Hearst.7

Components of the ECS

So, what exactly is the ECS? Simply put, it is a series of receptors found throughout the nervous system, as well as in other systems of the body. In addition to the receptors, the ECS also includes the endocannabinoids which the body makes to bind to the receptors (aka, endogenous ligands), as well as ligand metabolic enzymes which play complementary roles.8

Endocannabinoid Receptors

The two major endocannabinoid receptors are cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 is the most abundant receptor expressed in the brain, including substantia nigra, striatum, hippocampus and cerebral cortex, and negatively regulates the release of the neurotransmitters. CB1 is therefore the principal receptor mediating the psychoactivities of cannabis. CB1 receptor is also present in periphery such as adrenal gland, reproductive tissues and immune cells at lower levels.

The CB2 is principally expressed in the immune system including the spleen, thymus and lymph nodes and is involved in the immunomodulatory effects of cannabinoids. The expression levels of CB2 receptor in human blood cells can be found in B cells, natural killer cells, monocytes, polymorphonuclear neutrophil cells, CD8+ T cells and CD4+ T cells.9

Endogenous Ligands

Arachidonoylethanolamide, an ethanolamide derivative of arachidonic acid, was isolated as the first endocannabinoid from pig brain and named anandamide (AEA) based on the Sanskrit word ananda meaning “bringer of inner bliss.”10 Shortly after that, another derivative of arachidonic acid, 2-arachidonoylglycerol (2-AG), was also reported to show the same agonistic activity. It was surprising since 2-AG has been known for a long time simply as a common intermediate in the metabolisms of glycerophospholipids and triglyceride. Currently, 2-AG and anandamide are considered to be a full agonist and a partial agonist of cannabinoid receptors, respectively. Arachidonic acid is a polyunsaturated fatty acid well known as the precursor of bioactive prostaglandins and other eicosanoids. Endocannabinoids are thus considered to be other members of arachidonic acid-related lipid mediators.

Unlike classic neurotransmitters, AEA and 2-AG are not stored in vesicles (a cellular “sac” of sorts). Instead, they are synthesized and released on demand within the cell membrane. After they activate CB1 or CB2, AEA and 2-AG are broken down.

AEA and 2-AG exert a variety of bioactivities as cannabinoid receptor ligands, including the cannabinoid tetrad: analgesia, catalepsy, hypolocomotion and hypothermia. They also cause bradycardia and reductions of blood pressure and intraocular pressures. As mentioned above, anandamide is a partial agonist (i.e., a substance that initiates a physiological response when combined with a receptor) of CB1 receptor, while 2-AG is a full agonist of both CB1 and CB2 receptors. Furthermore, the tissue levels of 2-AG are generally hundreds to thousands of times higher than those of anandamide. Thus, 2-AG is recognized to be the true endogenous ligands of CB1 and CB2 receptors and is considered to play more important roles in vivo than anandamide.11

The effects of AEA and 2-AG can be enhanced by entourage compounds that inhibit their breakdown. It has been suggested that these entourage compounds, which include phytocannabinoids such as CBD,12 make a good case the use of hemp oil which provides a full-spectrum of naturally occurring phytocannabinoids.

Ligand Metabolic Enzymes

The primary endocannabinoid enzymes are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). FAAH breaks down anandamide, while MGL breaks down 2-AG.13 That’s where phytocannabinoids can help. When significant amounts of phytocannabinoids, such as CBD, are consumed, the endocannabinoid enzymes will be used to break them down, instead of breaking down the endocannabinoids. This helps maintain healthy levels of endocannabinoids and prolong their action.14

Endocannabinoids and Phytocannabinoids

ECS receptors respond to both endocannabinoids and phytocannabinoids. The difference between these two sets of compounds are as follows. Endocannabinoids are the compounds our bodies produce naturally to stimulate ECS receptors. The two most well understood of these AEA and 2-AG, previously described. They are synthesized on-demand and have a local effect and short half-life before being degraded by enzymes.

Phytocannabinoids are plant-derived compounds that stimulate ECS receptors. In 1964, Raphael Mechoulam isolated THC and CBD. Now, more than 100 cannabinoids, have been identified, including cannabigerol (CBG), cannabichromene (CBC), and cannabidolic acid (CBDA) as well.15 Though THC is the most psychoactive and well known of these compounds, other cannabinoids also stimulate ECS receptors, and have been shown in research to provide various healing properties.

The ECS and Omega-3 Fatty Acids

It should be noted that additional information on the importance of the ECS is continuing to emerge. For example, the health benefits of omega-3 fatty acids (O3FA) are mediated, in part, through metabolic conversion to bioactive epoxides. Research has now shown that naturally occurring O3FA-derived endocannabinoid epoxides are formed via enzymatic oxidation of O3FA by cytochrome P450s. These dual functional O3FA endocannabinoid epoxides are anti-inflammatory and vasodilatory and reciprocally modulate platelet aggregation. By virtue of their physiological properties, they are expected to play important roles in neuroinflammation and in cerebrovascular diseases such as stroke.16 Consequently, the powerful health benefits of O3FA would not be possible without the ECS.

Conclusion

The ECS, as well as the endocannabinoids and phytocannabinoids that interact with the ECS and play important roles in homeostasis of human health and well-being. Other articles written by me, as well as other authors, provide more information about the benefits associated with specific phytocannabinoids such as CBD.

References:

1 Allen DB. Survey Shows Low Acceptance of the Science of the ECS (Endocannabinoid System) at American Medical Schools. Outword Magazine. Retrieved December 19, 2018 from www.outwordmagazine.com/inside-outword/glbt-news/1266-survey-shows-low-acceptance-of-the-science-of-the-ecs-endocannabinoid-system.

2 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.

3 Pacher P, Bátkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol Rev. 2006 September; 58(3): 389–462.

4 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.

5 Pacher P, Bátkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol Rev. 2006 September; 58(3): 389–462.

6 Allen DB. Survey Shows Low Acceptance of the Science of the ECS (Endocannabinoid System) at American Medical Schools. Outword Magazine. Retrieved December 19, 2018 from www.outwordmagazine.com/inside-outword/glbt-news/1266-survey-shows-low-acceptance-of-the-science-of-the-ecs-endocannabinoid-system.

7 Mendizábal VE, Adler-Graschinsky E. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. British Journal of Pharmacology (2007) 151, 427–40.

8 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.

9 Tsuboi K, Uyama T, Okamoto Y, Ueda N. Endocannabinoids and related N-acylethanolamines: biological activities and metabolism. Inflamm Regen. 2018 Oct 1;38:28.

10 Mendizábal VE, Adler-Graschinsky E. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. British Journal of Pharmacology (2007) 151, 427–40.

11 Tsuboi K, Uyama T, Okamoto Y, Ueda N. Endocannabinoids and related N-acylethanolamines: biological activities and metabolism. Inflamm Regen. 2018 Oct 1;38:28.

12 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.

13 Pazos MR, Núñez E, Benito C, Tolón RM, Romero J. Functional neuroanatomy of the endocannabinoid system. Pharmacol Biochem Behav. 2005 Jun;81(2):239-47.

14 Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2:e94.

15 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.

16 McDougle DR, Watson JE, Abdeen AA, Adili R, Caputo MP, Krapf JE, Johnson RW, Kilian KA, Holinstate M, Das A. Anti-inflammatory ω-3 endocannabinoid epoxides. PNAS. 2017;114(30):E6034-43.

Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at gbruno@hchs.edu.