Understanding the Endocannabinoid System and the use of Cannabidoil (CBD) in Healthcare

According to the World Health Organization, 2.5% of the world’s population consumes cannabis. While the recreational use of cannabis is still a controversial topic, the wide variety of therapeutic applications has now, uniquevically, convinced the scientific world of its medical importance. Despite that, only 6% of existing studies on cannabis analyze its medicinal properties. Meanwhile, an increasing number of stories depicting how this amazing plant has helped people and their medical conditions are appearing on web platforms, contributing to a deeper social awareness about the multiple benefits of this incredible plant.

Healthcare practitioners have found staying ahead of public awareness difficult. To close the wide gaps between what research, clinicians and the lay public are learning from the internet on their own, this report will aim to equip the healthcare practitioner with the fundamentals and important clinical applications of cannabis medicine that are based in validated scientific research. In particular, the roles of the endocannabinoid system and phytocannabinoids will be discussed in detail, with an emphasis on the medical use of CBD.

Since the Food and Drug Administration (FDA) has not yet taken a clean stance on the health benefits of cannabinoid-based products, patients are looking to their healthcare providers for information and validation. It is time that clinicians are supported in helping patients to find answers and comprehensive solutions to their medical cannabis questions and medical concerns.

Read: CBD Oil Statistics 2021 – The Who, How, and Why of Using CBD Oil for Health

The Endocannabinoid System (ECS) and Cannabidoil (CBD)

“Relax, eat, sleep, forget and protect” – Di Marzo

The major components of the ECS:

– Receptors: CB1 and CB2
– Endocannabinoids: Anandamide (N-arachidonoylethanolamine or AEA) and 2-arachidonoylglycerol (2-AG )
– Synthesizing enzymes: Diacylglycerol lipase (DGL)
– Degrading enzymes: Fatty acid amide hydrolase (FAAH), Monoacylglycerol lipase (MGL)

The ECS was discovered in 1989 as a lipid-based signaling system now known to be common to all mammals – all vertebrate organisms have one. The ECS is comprised of cannabinoid (CB) receptors, endogenous ligands, and the synthesizing and degrading enzymes that build and break down the endogenous ligands on demand. The primary CB receptors are named CB1 (c. 1988) and CB2 (c. 1990).

CB1 receptors are neuromodulating, G-protein-coupled receptors located throughout the central and peripheral nervous systems, while sparing the brain stem. They can also be found on end organs, such as the lungs, liver and kidneys, as well as on endocrine and reproductive organs. CB2 receptors are immunomodulating and are found in immune tissues, hematopoietic cells, the digestive tract, and throughout the circulatory system. CB receptors are also found in adipocytes and in musculoskeletal tissues.(1, 4–7, 9, 10, 14–17, 19–34)

The brain not only contains the densest concentration of CB receptors in the body, but therein exists more CB receptors than any other receptor type. The ECS manages excitatory and inhibitory processes in the brain, modulating the neurogenesis of hippocampal granule cells, which regulate the timing of endocannabinoid release in accordance with the brain’s needs, management of memory, pain perception, mood, synaptic plasticity, motor learning, appetite and taste regulation, and metabolic function (which regulates the storage of energy and transport of cellular nutrition). CB receptor binding sites located in the brain are associated with higher cognitive function, movement control and sensory functions attributed to the autonomic nervous system, and more. (1, 4, 20, 21)

Cannabinoids (whether endogenous or plant-derived) bind to the receptors in the brain and elsewhere they exist. The endogenous cannabinoids, anandamide and 2-AG are physiological ligands for the CB receptors and are produced locally on demand, acting as retrograde transmitters that modulate and balance cellular neurotransmission and signaling. Remember that the ECS modulates homeostasis and therefore chiefly operates in response to over- or under-stimulation at synapse or cell surfaces.

Amongst many mechanisms of action, known and suspected, are the modulation of neurotransmitter release from central and peripheral neurons, and cytokine secretion from macrophages in the marginal zone of the spleen. Phytocannabinoids, in their ability to bind to CB receptors, mimic homeostatic mechanisms. Phytocannabinoids confer unique physiological effects on the human body as well, but yet and still are considered to all have a generally positive effect on modulating homeostasis. (4, 5)

CBD, a non-intoxicating cannabinoid, can be extracted from agricultural hemp. CBD does not bind directly to CB receptors (binding allosterically), but does interact with various other receptors in the body. For example, CBD affects stress genes, such as Soat2 and Cyp27a1, which control sterol (i.e., cholesterol) metabolism. CBD is also an agonist at 5-HT1A (serotonin) receptors and TRPV1 receptors, affecting mood and pain perception respectively.

CBD has also been shown to increase and sustain the concentration of anandamide and other vital lipids by blocking degrading enzyme production. This increases the availability of circulating serum endocannabinoids that might otherwise be subject to premature degradation, and increases the binding rates of endocannabinoids at CB receptors. (6)

CBD can also reduce the ‘high’ that might be experienced with THC intake. THC, upon binding to a cannabinoid receptor can cause a ‘high,’ while CBD, working allosterically to the THC-CB binding site, reduces that ‘high.’

Clinical Endocannabinoid Dysfunction: Deficiency and Excess

A 2004 study proposed that ‘clinical endocannabinoid deficiency’ (CECD) is causative in pathological conditions like migraine, fibromyalgia and IBS. The hypothesis was that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, their production, metabolism, and the relative abundance and state of cannabinoid receptors. In certain conditions, whether congenital or acquired, this overall endocannabinoid tone becomes deficient and productive of pathophysiological syndromes.

Continued review of studies over the decade that followed this initial hypothesis has more firmly established the case. Given CBD’s effectiveness in raising serum concentrations of endocannabinoids, the research study suggests that the use of CBD could have therapeutic benefits in the treatment of the conditions of endocannabinoid deficiency. (7)

Research reviews have further illustrated that ECS dysfunction goes beyond CECD and can also be characterized by overactivity. Whether overactive or underactive, as in CECD, ECS dysfunction has three primary categories: genetic, acquired and idiopathic autoimmune.

Genetic dysfunction relates to a hereditary acquisition of the disorder; acquired refers to an infectious or traumatic origination, and idiopathic autoimmune refers to etiologies for endocannabinoid deficiencies which do not have apparent genetic or infectious causations, but confer dysfunctional immunomodulatory effects.

Diseases and disorders can be assigned to one or more of these categories, as secondary disorders often arise with the physiological changes associated with primary diagnoses. For example, IBS is considered an acquired CECD condition, as it commonly originates from dietary source or prescription drug exposure. The development thereafter of multiple sclerosis, which affects the neurological system, would be considered an idiopathic autoimmune manifestation of CECD. Because the ECS facilitates communication and coordination between various cell types, deficiencies in any area directly and indirectly affect physiological homeostasis locally and remotely. The direct effect of both CECD and ECS hyperactivity correlates much more broadly to multisystemic clinical outcomes, contributing to conditions such as dementia, cardiovascular disease, multiple sclerosis, hyperinsulinemia, diabetes, and obesity to name a few. (7, 35)

In fact, one of the most common metabolic diseases affecting an upwards of 1.9 billion people worldwide is obesity. According to the World Health Organization, 39% of adults are considered overweight and more than 650 million are obese, and these numbers are increasing. It has reached global epidemic levels, leading to the escalating prevalence of many common medical conditions such as diabetes, cardiovascular disease, cancer, and an increased risk of death. Visceral fat, which is an indicator of GI inflammation, accumulates in the human gastrointestinal system as a consequence of a diet with a high content of fat and refined sugar (i.e. the ‘Western Diet’). Moreover the increased amount of visceral fat can lead to a chronic inflammatory and immunologic response, which is often the cause of many common diseases.

The immune system, which is activated by the inflammation process, is modulated to a considerable degree by the endocannabinoid system. 70-80% of the body’s immune tissue is in the digestive or GI tract and is lined with CB receptors. As such, the inflammatory properties of the Western Diet directly interfere with endocannabinoid production and the system’s overall tone (i.e. health), causing either an acquired CECD or hypertonicity.

When the immune system activates excessive metabolic cascades in response to digestive inflammation and injury, it results in more inflammation, microvascular deterioration and endocannabinoid dysfunction. In the wake of ECS dysregulation, the resultant chronic inflammation and destruction in the GI tract can be a challenge to restore to balance whilst exposed to the Western Diet. This phenomenon, repeated on a daily basis, leads to metabolic syndromes and obesity, which are directly associated with insulin resistance, diabetes mellitus and the consequences thereof. (6, 7, 12-14, 22, 23, 32)

The acquired ECS dysfunctions of metabolic syndrome, obesity, insulin resistance and diabetes are further associated with disorders affecting neurological function. Inflammatory processes in the brain associated with this aspect of endocannabinoid dysfunction include Alzheimer’s and vascular dementia. The decline in vascular system flexibility and increased inflammation prevents synaptic communication and neurological decline. Restoration of proper endocannabinoid function and adequate intake of phytocannabinoids, like CBD, is associated with neurological health and improvement in function. And, indeed, research (and US patent number 6-630-507) supports that plant-derived CBD has neuroprotective benefits.

Read: How is CBD metabolized?

CBD in Lifestyle Medicine

In light of the above-mentioned considerations that classify the ECS as one of the mainstays of human and mammalian homeostasis, preventative education becomes imperative. Metabolic dysfunction is a root cause of morbidity and mortality worldwide, and a healthy ECS is critical in its prevention.

Exercise, sleep and nutrition have always been and will continue to be key lifestyle factors to consider in maintaining good health and balancing physiologic functioning in the human body, and this is especially true in the context of metabolic syndrome and its associated diseases. But they do not tell the whole story. For example, even in the presence of reduced caloric intake, exercise does not always correlate with weight loss or, more importantly, the loss of the visceral fat implicated in metabolic derangement as a consequence of ECS dysfunction, as ECS dysfunction can and does lead to dysregulation in other pertinent physiological processes.

For example, recent studies have shown that the ECS plays a significant role in the modulation of the production and release of nitric oxide (NO), a principal molecule involved in the control and pathogenesis of inflammation. NO gives an anti-inflammatory effect under normal physiological conditions, but is considered a pro-inflammatory mediator that induces inflammation from overproduction in abnormal situations, and is implicated in the development of metabolic syndrome. This makes sense when considering that cardiovascular, immunological and neurological functions are associated with finely tuned NO body levels. Given the ECS’ primary role in maintaining NO metabolism, it might come as no surprise that studies have established the positive correlation between body levels of NO and the consumption of cannabinoids. (15-17, 167)

Lifestyle Medicine involves a non-drug, evidence-based approach to treating, reversing and preventing symptoms and disease through natural diets, exercise, sleep, stress management, and the avoidance of risky substance use. To this list can be added dietary phytocannabinoids to enhance the restoration of healthy ECS tone, thereby correcting downstream metabolic pathways, as well as promoting symptom and disease reversal naturally.

CBD Recapped

To recap, CBD is a psychoactive/psychotropic (denoting any chemical known to change mental states or mood) but non-intoxicating and non-euphoric phytocannabinoid, which has been demonstrated to positively affect the human endocannabinoid system. CBD, derived from C. sativa, demonstrates anti-inflammatory and immune-modulating properties. CBD has a low affinity for CB1 and CB2 receptors in the human body, but acts as 1) an indirect antagonist of their agonists by modulating cytokines and neurotransmitter release and 2) an agonist at other receptor types.

In addition to metabolic disorders, CBD has further shown to be a valuable phytocannabinoid with promising results in preliminary tests conducted in vivo for the treatment of epilepsy, heart failure, emesis, inflammation, cancer, and many other conditions. (8–11)

CBD has been demonstrated to cross the blood-brain barrier and exert antioxidant, antimicrobial and neuroprotective properties, rendering it valuable in the prevention andtreatment of oxidative neurological disorders and diseases, as well as infectious diseases. (4, 6–11, 20, 22–34, 36–97)

CBD is of significant therapeutic relevance. CBD oil from legal agricultural hemp contains less than 0.3% THC, rendering it non-inebriating, and as such, the potential breadth of impact without the unwanted side effects of THC (nor the toxic side effects like those of prescription drugs) cannot be ignored.

Summary

Modulating endocannabinoid activity has therapeutic potential. The ECS is the principal regulator of homeostasis, and when a body is in homeostasis, it can heal itself. A number of molecules, beyond both endocannabinoids and phytocannabinoids, interact with the ECS and can be used in a variety of therapeutic ways, but CBD remains of significant therapeutic relevance.

A number of physiological systems and related conditions can be affected by phyto- cannabinoids: the immune system and immunomodulation; inflammation, pain, stress, and anxiety; appetite and feeding; sleep cycles, mood, memory and the extinction of traumatic memory; blood pressure and blood sugar control; digestion, emesis and nausea; neuroprotection, reproduction and cancer immunosurveillance. The following chapters detail the systems and related conditions, and the ways in which CBD shows major promise.

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