Chapter 1: The Endocannabinoid System (ECS) and Cannabidiol (CBD)


“Relax, eat, sleep, forget and protect”

Di Marzo

Towards the end of the 80’s scientist first discovered the endocannabinoid system, a lipid signaling network common amongst all mammals. This network is made up of cannabinoid receptors (CB), endogenous ligands and the enzymes that can make or break them on demand. There are two primary receptors, CB1 these are G-protein-coupled neuromodulating receptors (alters nerve activity through stimuli delivery) found throughout the nervous system and also on end organs like lungs, liver, kidneys, and also on reproductive organs. CB2 receptors are immunomodulating receptors  (it stimulates or suppresses the immune system) in the immune tissue, digestive tract, the circulatory system and on hematopoietic cells. Cannabinoid receptors are also in adipocytes and musculoskeletal tissues.1-5, 7, 8, 12-15, 16-31

The endocannabinoid system (ECS) consists of four main components:

  1. Receptors:
    • CB1
    • CB2
  2. Endocannabinoids:
    • Anandamide (N-arachidonoylethanolamine/AEA)
    • 2-arachidonoylglycerol (2-AG)
  3. Synthesizing enzymes:
    • Diacylglycerol lipase (DGL)
  4. Degrading enzymes:
    • Fatty acid amide hydrolase (FAAH)
    • Monoacylglycerol lipase (MGL)

The highest concentration of CB receptors in the body is in the brain, which has more CB receptors than any other receptors.  The endocannabinoid system manages process within the brain. These processes are both excitatory and inhibitory and modulate the growth and development of nervous tissue (the hippocampal granule cells) responsible for regulating the release times of endocannabinoids based on the necessities of the brain. Hence the system manages regulation of memory, pain perception, mood, synaptic plasticity, motor learning, appetite, taste, and metabolic functions. The location of cannabinoid receptors binding sites in the brain is related to higher functions, cognitive, movement control and sensory functions of the autonomic nervous system and others.1, 2, 17, 18

Both phytocannabinoids and endocannabinoids bind to any receptors they find in the brain are throughout the body. The anandamide and 2-AG (the endogenous cannabinoids produced by the body) are physiological ligands produced on demand for the CB receptors. They act as reverse transmitters in charge of modulating and balancing signaling and cellular neurotransmission. The endocannabinoid system operates in response to over and under stimulation at synapse or cell surfaces in attempts of modulating homeostasis. The methods that ECS operates include the modulation of the release of neurotransmitters from peripheral and central neurons and secretion of cytokines from macrophages in the spleens marginal zone. The binding ability of phytocannabiniods to CB receptors imitate the mechanisms of homeostasis. The plant-derived cannabinoids have a unique physiological effect on the human body, but generally, have a positive effect on homeostasis modulation.2, 3

CBD is extracted from agricultural hemp; it is non-intoxicating and does not bond with the CB receptors directly. CBD binds allosterically; it interacts with a variety of receptors in the body. These receptors include stress genes like Soat2 and Cyp27a1 that are in charge of sterol metabolism or cholesterol. It also affects mood and pain perception through the 5-HT1A (serotonin) and TRPV1 receptors. Also, CBD was found to increase and preserve anandamide and other lipid concentrations by stopping the production the degrading enzyme. Consequently enlarging the density of endocannabinoid serum circulation, a density which was at risk of being prematurely degraded. It also hastens the binding rate of endocannabinoids at CB receptors.4

The feeling of ‘high’ that people acquaint with experimenting with THC can be alleviated by CBD; when THC binds with CB receptors, a ‘high’ can be induced. CBD will work at this binding site allosterically to reduce the ‘high’.

Neurons, nerve cells

Clinical Endocannabinoid Dysfunction: Deficiency and Excess

Previous studies have suggested that clinical endocannabinoid deficiency (CECD) is one of the reasons leading to pathological conditions that include a migraine, fibromyalgia, irritable bowel and other symptoms. The study stated that all humans possess an underlying endocannabinoid tone that reflects the levels of endocannabinoids (AEA and 2-AG) their synthesis, metabolism and the density of cannabinoid receptors in the brain.  If the endocannabinoid system becomes deficient for any reason, whether acquired or genetic; pathological conditions would develop. Further and more recent review of the study firmly supports the hypothesis and explain the therapeutic benefits of using CBD to rebalance the endocannabinoid system.5 The effectiveness of CBD comes in its ability to increase the serum concentrations of endocannabinoids. However, CECD is one condition, where the overactivity of the endocannabinoid system can also lead to dysfunctions. Both conditions will either be genetic as in the order was inherited, or acquired like an infection or trauma based, or idiopathic autoimmune; the latter is when it is not apparent where the endocannabinoid deficiency stemmed from, genetics or infectious but does result in dysfunctional immunomodulatory effects.

Diseases and disorders fall under one of these categories since all secondary disorders are a result of physiological alterations affiliated with the diagnoses; Irritable bowel syndrome (IBS) is a case in point. IBS is an acquired CECD condition; the syndrome develops either from dietary sources or exposure to prescription drugs. The following progression of multiple sclerosis would then be an idiopathic autoimmune expression of CECD. The physiological homeostasis is locally and remotely affected by deficiencies directly and indirectly; because the endocannabinoid system already expedites coordination and communication between the different cells. Both conditions CECD and endocannabinoid system overactivity is more closely contributing to conditions that include but not limited to cardiovascular diseases, dementia, diabetes, multiple sclerosis, and obesity.5, 32

Obesity one of the most prevalent metabolic diseases, has almost tripled in the past four decades, the World Health Organisation documented in 2016,  that almost a third of the world population is overweight, and 13% of all adults were obese. Obesity has become a serious issue that is a significant contributor to the development of cardiovascular diseases (the leading cause of death in 2012), diabetes, musculoskeletal disorders, and cancer. Gastrointestinal inflammation is a subsequence of current modern diets that contain high contents of fat and refined sugar; visceral fat builds up, a fat that is stored deeper inside the body, it is wrapped around vital organs like the liver and kidneys. This accumulation of fat often results in many common diseases through chronic inflammatory and immunologic responses.

Inflammation triggers the response of the immune system, a system which is harmonized to some degree by the endocannabinoid system. Between 70 to 80% of the immune tissue lined with cannabinoid receptors is located either in the digestive or the gastrointestinal tract. This set-up allows the properties of diets to influence the endocannabinoid system directly. A typical modern diet, like the Western diet, has inflammatory properties that would, therefore, activate an acquired CECD or extreme tension of ECS. A response from the immune system to inflammation or injury with trigger a metabolic surge that would inversely lead to more inflammation, microvascular deterioration, and endocannabinoid impairment. Trying to control the resultant damage in the gastrointestinal tract and the chronic inflammation will be challenging especially if exposure to the same diet persists, and an impaired ECS. Metabolic syndromes and obesity consequently will emerge if the same process repeats daily; metabolic syndromes and obesity link directly to severe issues that include insulin resistance and diabetes.4,5, 10-12, 19, 20, 29

An impaired endocannabinoid system due to metabolic syndrome, obesity, insulin resistance or diabetes would also lead to other neurological disorders. The brain inflammatory activity that relates to ECS dysfunction is closely associated with Alzheimer’s and vascular dementia. When the flexibility of the vascular system declines in the presence of increased inflammation, synaptic communications are hindered, and a neurological decline commences. A balanced intake of phytocannabinoids like CBD will lead the restoration of the endocannabinoid purpose and will improve neurological health and function. The neuroprotective benefit of plant-based CBD is supported by research and by US patent 6-630-507.

Cannabis extract

CBD in Lifestyle Medicine

Internal stability and balance of humans and mammals are dependent on the endocannabinoid system as discussed above; this dependency makes preventative education all-important. Metabolic syndrome a leading causality of global morbidity and mortality is preventable but almost impossible to achieve without a healthy ECS.

Lifestyle changes that are considered essential for maintaining a healthy body and balanced physiologic functioning include nutrition, physical activity, and sound sleep. While all these apply to metabolic syndrome and associated diseases, they are incomplete without addressing the central role of ECS in reaching human homeostasis. Nutritional change on its own will not guarantee weight loss, even if combined with exercise and does reduce weight it will not eliminate visceral fat associated with a metabolic disorder. The endocannabinoid system is imbalanced, and this disproportion is resulting in dysregulations and other physiological processes.

Nitric Oxide (NO) is a primary molecule involved in the regulation and development of inflammation; where under normal circumstances gives an anti-inflammatory effect. However, if circumstances were unusual NO would induce inflammation through overproduction, consequently a cause for the development of metabolic syndrome. Current studies have shown that the endocannabinoid system is an essential player in the regulating the production and release of nitric oxide. This relation correlates with data suggesting the association between tuned NO levels in the body with neurological, cardiovascular and immunological functions. The positive relationship between a tuned level of NO in the body and cannabinoid consumption is a natural consequence, considering the role of ECS in NO regulation.13, 15, 95

The approach of lifestyle medicine unlike conventional, it promotes drug-free, scientific evidence-based treatment, prevention, and reversal of diseases. It includes natural, nourishing diets, physical activity, stress management, alcohol, and nicotine avoidance and healthy relationships. Including phytocannabinoids in the diet plans will promote the balance of the endocannabinoid system and trigger a natural disease reversal and prevention.

Hemp health benefits

CBD Reviewed

Cannabidiol or CBD is a non-intoxicating, non-euphoric but psychoactive/psychotropic (it denotes any chemical that affects a person’s mental state) phytocannabinoid, which has been proven to have beneficial effects on the endocannabinoid system. CBD extracted from Cannabis Sativa has properties that are anti-inflammatory and immune-modulating. The CB1 and CB2 receptors in the human body and CBD  have low affinity. However, CBD does have an indirect effect on them; it inhibits action from their agonists by regulating the release of cytokines and neurotransmitters. For all other receptors in the human body, CBD is an agonist.

The phytocannabinoid CBD is not only beneficial for metabolic diseases but in vivo research has shown promising results in the treatment of many conditions that included epilepsy, heart failure, emesis, inflammation, and cancer.7-9 CBD has also proved to be valuable in the prevention and treatment of oxidative neurological and infectious disorders and diseases; due to its antioxidant, antimicrobial and neuroprotective attributes.2, 6-9, 17, 19, 31, 33-94

CBD oil is extracted from legal agricultural hemp and contains less than 0.3% THC; CBD is legal and non-inebriating. CBD has the potential for limitless applications without the impact of unwanted side effects of THC or any of the prescription drugs.


Balancing the endocannabinoid system is essential for the therapeutic benefits and reaching homeostasis. Once the body has a functioning ECS and homeostasis is maintained the body will be able to self-heal. CBD is not the only molecule that is beneficial to the endocannabinoid system, but it is one of the most crucial.

Phytocannabinoids can affect several physiological systems and their related conditions such as:

  • the immune system and immunomodulation
  • inflammation
  • pain
  • stress
  • anxiety
  • appetite
  • digestion
  • emesis
  • nausea
  • sleep cycles
  • mood
  • memory
  • traumatic memory elimination
  • control of blood pressure and blood sugar
  • neuroprotection
  • reproduction
  • cancer immunosurveillance

In the following chapters, this book is going to present these systems and their related conditions. It will also illustrate the potential benefit of CBD in their treatment.


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