The Endocannabinoid System and how it has a fundamental role in our body’s health and maintenance systems

By Dr Margo – Medical/Scientific Director Pure Organic CBD

Queen Victoria’s physician was quoted as saying that Cannabis is the “best medicine on earth”

Cannabis is a genus of flowering plants in the Cannabaceae family, which consists of three primary species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Hemp, a strain of Cannabis sativa, discussed in this report, has its growth controlled so that it does not contain more than 0.3% THC (USA and, 0.2%, UK) and, contains more than 100 known phytocannabinoids, including delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD)1. Marijuana is another strain of Cannabis sativa which contains more than 0.3% and, up to 80% THC (the compound which has psychoactive properties) and is illegal in most countries. The medicinal as well as psychoactive properties of Cannabis have been recognised as early as the third millennium BC in ancient Chinese and Indian texts, reporting it’s use to alleviate pain, cramps and anxiety2.

Unfortunately, worries about the abuse of using this medicinal wonder and, perhaps governmental/early pharma pressure to stop people from growing medication in their own gardens, led to it being banned in 1928 in the UK and in 1937 in the United States. Recognition with some peer-reviewed research and public pressure relating to the widespread medicinal properties of Cannabis eventually led to extracts of it being legalised in the UK in November 2018 as an unlicensed, Schedule II drug, under the Misuse of Drugs Act 2001, only to be prescribed by GMC registered, specialist doctors3 and, available for private purchase. The legal extracts include Cannabidiol (CBD) and tetrahydrocannabinol (THC). These can be sold combined in our Full Spectrum product up to a strength of 40% CBD, with 0.2% THC or, as Broad Spectrum CBD, up to 10% CBD, containing no THC, for those who may be subject to drug testing through sport or employment.

Other trace phytocannabinoids in our products include: CBC; CBG and CBN.

• Cannabichromene (CBC) is one of the lesser-known non-psychoactive phytocannabinoids. Unlike other popular cannabinoids, CBC does not appear to affect the psychoactive effects of THC. CBC is not active at the CB1 or CB2 receptors, but is thought to bind with the transient receptor potential TRPV1 and TRPA1 receptors in the endocannabinoid system, which are responsible for regulating pain sensitivity, temperature, and neurogenic inflammation4.

• Cannabigerol (CBG) serves as the precursor to several other cannabinoids. During the growth process, most of the CBG in cannabis is converted into THC and CBD, leaving about 1% CBG in the mature plant. CBG is non-psychotropic, but unlike CBD, CBG displays binding affinity to both the CB1 and CB2 receptors.

• Cannabinol (CBN) is a mildly-psychoactive cannabinoid found only in trace amounts in cannabis. CBN is the strongest cannabinoid identified for promoting sleep and is responsible for what people call the “couch-lock” effect from old Cannabis indica predominant strains. Cannabinol has also been shown to exhibit analgesic properties.

Phytocannabinoids are exogenous, plant-derived ligands which interact with endogenously produced proteins, receptors, enzymes and endogenous ligands in an ancient biologically preserved system which is thought to be six hundred million years old. This endocannabinoid system (ECS), evolved as a stress or harm regulation network and is a naturally occurring, extensive, endogenous signalling system, with multiple elements, ubiquitous amongst every animal species, except insects, modulated by various factors such as sleep, stress, diet and exercise4. The ECS is up- or down-regulated continually, according to biological requirements and communicates with all other body systems with a multi-regulatory role in both health and disease. Scientists are continuing to elucidate this role in human and animal health and disease. New techniques allowing the modulation of the endocannabinoid system in laboratory conditions are revealing the widespread therapeutic scope to control diseases ranging from mental health disorders, neurological and movement disorders, including epilepsy and multiple sclerosis, pain, autoimmune and inflammatory disease, spinal cord injury, cancer, cardiometabolic disease, stroke, osteoporosis, asthma, hypoxia-ischaemia and even those suffering from cannabis and tobacco addiction2,4.

The ECS was discovered during the search for the active ingredients of Cannabis. CBD was first isolated from a Cannabis extract in 1940 but not fully characterised until 1963. THC was first isolated and characterised in 19644. CBD and THC are hydrophobic organic compounds which can be transported in the bloodstream by albumin or lipoproteins1. They effectively bind to natural CB1 and CB2 cannabinoid receptors within the ECS, located throughout the body, including the central nervous system and some peripheral tissues – immune cells, adipose tissue, liver, kidney, lungs, muscle and reproductive cells (CB1) and peripheral immune system, gastrointestinal tract, heart, liver and, at low density in the central nervous system (CB2)2,4,5. Interestingly, CB1 receptors are absent in the cardiac and respiratory centres of the brainstem which is why cannabis does not depress respiration or stop the heart from beating, unlike opioids, which can be fatal, due to respiratory depression mediated by receptor activation in these vital brain centres.

Naturally occurring endocannabinoids and ECS receptors and the disease process

The endogenous cannabinoid anandamide-N-arachidonoylethanolamine (AEA), which exhibits similar effects as CBD was identified in 1992, with a second endocannabinoid, 2-Arachidonoylglycerol (2-AG), in 1995. Receptors within the ECS for THC and other endocannabinoids, CB1 and CB2 were discovered subsequently. Endocannabinoids are naturally occurring signalling molecules of the endocannabinoid system. They are lipid soluble neuro-transmitters, safeguarding all physiological body systems through inter- and intra-cellular communication. As a result, there exists the potential for a plethora of disease pathology, through dysregulation of this delicate, intrinsic interplay of endocannabinoid synthesis, degradation, receptor expression and enzymatic functioning. Scientists have hypothesised that many pathophysiological conditions, including migraine, fibromyalgia, irritable bowel syndrome, autoimmune disease, epilepsy, cardiovascular disease, anxiety, depression, failure to thrive, schizophrenia, multiple sclerosis, Parkinson’s disease and others, alleviated by Cannabis, may be, in fact, due to deficiencies or, alterations within the ECS, termed as Clinical Endocannabinoid Deficiency (CECD)6. As a result, exogenous phytocannabinoids, like CBD and THC have a major role in boosting this finely tuned, but vital, internal system.

Dosage indications, mode of delivery and metabolism of phytocannabinoids

The World Health Organisation (WHO), Cannabidiol critical review report in 20185 quotes well-tolerated oral dosages in scientific studies between 100-800mg of CBD per day in humans6a. Doses of 200-300mg per day in adult studies of epilepsy, reported markedly reduced seizures compared to the placebo group, with doses of 100mg per day not showing marked improvement in seizure frequency5,5a. Doses of up to 20mg/Kg/day were safely administered to children aged 4-10 years with Dravet Syndrome6b, a rare form of childhood epilepsy. Studies into reducing positive symptoms of schizophrenia have indicated that doses of 1000mg/day were effective7a.
In adults, low initial doses would be recommended at 5mg/Kg/day (for a 70Kg person, this would equate to 350mg/day or 1.75ml of our 20% CBD product per day). Medium dose would be 10mg/Kg/day (approximately 3.5ml of 20% CBD product per day) and high dose would be 20mg/Kg/day (7ml of 20% CBD product per day).

Comprehensive reviews of the safety and adverse effects of CBD, conducted in 2011 and 2017 showed that even chronic use at doses of up to 1.5g/day were safe and well-tolerated with no adverse effects, abuse potential or addictive traits7,8.

Both CBD and THC can be taken as an aerosol, combined in oil-based capsules, orally or, in certain cases, as a suppository or, dissolved in oil, as in our case, with Pure Organic CBD to be taken sublingually. Due to these compounds being hydrophobic, absorption from the gastro-intestinal tract can be reduced by stomach acid and, initial break down by the liver (first pass effect), once into the blood stream. To counter this effect, for optimal absorption, Pure Organic CBD is recommended to be taken sublingually and, for the user to retain the drops under the tongue, without swallowing, if possible, until it is naturally absorbed through the submucosa into the blood stream. If swallowed, it should be taken after a fat-based drink or food, like olive oil, avocado or oily fish.

Cannabinoids and disease moderation

Functions of the ECS include neuro-regulation by modulating the release of neurotransmitters, both excitatory and inhibitory, with a major role in neurophysiology within the body. The CB1 receptor, prolific in the central nervous system, when activated, always results in a reduction of neurotransmitter release by the negative feedback process of retrograde inhibition of pre-ganglionic neurones. Cannabinoids, including THC, bind to CB1 receptors in these neurones, resulting in depolarisation-induced suppression of nerve function. CBD does not directly stimulate either CB1 or CB2 receptors but is thought to act as an allosteric-modulator, binding near to these receptors to modulate their activity or, to non-endocannabinoid receptors to indirectly block anandamide re-uptake and the inhibition of its degradation8a.

Neuronal disease – CBD has been reported to reduce the neuronal diseases Parkinsons, Multiple Sclerosis and Alzheimers19b. Sativex is a pharmaceutical combination of CBD:THC, used to treat multiple sclerosis.

The function of cannabinoids which has been most widely researched is in epilepsy. Depolarisation-induced suppression of nerve stimuli is one of the ways that the ECS protects the nervous system from hyperactivity during seizures. Endocannabinoids are naturally produced during a seizure which act on cannabinoid receptors in the brain. Phytocannabinoids, similarly, tend to be anti-convulsant, reducing seizures and subsequent irreversible neuronal death9. In 2018, CBD was released as the proprietary drug “Epidiolex”, currently undergoing Phase III trials in America, to treat two severe forms of epilepsy – Lennox-Gastaut syndrome and Dravet syndrome as well as other forms of epilepsy and treatment-resistant epilepsy10.

Traumatic brain injury (TBI) has been discovered as being minimised via the homeostatic endocannabinoid regulators anandamide and 2-AG. There is also evidence that exogenous phytocannabinoids, given within four hours of TBI can limit glutamate toxicity and nerve damage11.

Ischaemic events (stroke) – studies have found that endocannabinoid levels are raised spontaneously during a stroke which can reduce the infarct size and outcome. The exogenous cannabinoid CBD has been found to be a powerful neuroprotector in animal studies of ischaemia produced by coronary artery occlusion, if given within four hours of the ischaemic event12.

Autocrine, Paracrine Signalling and Gastrointestinal (GI) Function – Normal homeostasis is controlled by both autocrine and paracrine cell signalling, via endocannabinoids. Autocrine stimulation occurs within the same cell, for example, during liver cell regeneration. Paracrine signalling occurs when cells produce factors which affect the activity of other cells, frequently observed in the immune system between T- and B-cells and natural killer cells (NK) and also during wound healing. Cannabinoids affect auto- and para-crine signalling in the gastrointestinal system in inflammatory conditions such as irritable bowel disease (IBS), where they are responsible for a decrease in the production of inflammatory markers. Both endogenous and exogenous cannabinoids have been found to be involved in normal GI function. Anandamide and THC delay gastric emptying, gastric secretions and reduce intestinal motility with CBD emitting anti-emetic effects which have been widely researched13. CBD has been shown to help diminish the inflammatory process in Chron’s disease and ulcerative colitis19b.

Metabolic Function – the ECS has control over metabolic homeostasis both centrally and peripherally in the cardiovascular, hepatic and musculoskeletal systems, GI tract and various cell types. Endocannabinoid receptors and ligand expression are altered in various metabolic diseases, including cardiovascular disease, hypertension, diabetes, sleep apnoea and obesity14.

Energy Balance and obesity – the ECS modulates food intake centrally through neurotransmission of appetite signalling as well as locally within the GI system. Endogenous cannabinoids like anandamide stimulate appetite and it is thought that genetic impairment of the ECS may be implicated in obesity disorders15.

Mood and anxiety disorders – The ECS has a role in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis controlling mood, anxiety and fear. Cannabinoids have been demonstrated in neuroendocrine functioning in this system but more research is required to verify the implications using phytocannabinoids16.

Pain and Inflammation – numerous studies have indicated the beneficial effects of cannabinoids, including CBD in both acute and chronic pain, as well as neuropathic pain17. The mechanisms underlying CBD-induced analgesia are not yet well understood although it is clear that cannabinoids are powerful inflammatory modulators and most probably function through a complex mechanistic interplay18. Inflammatory skin disease such as atopic dermatitis and psoriasis have also been reported to be diminished by treatment with CBD19b.

Reproductive System and Embryogenesis – Endocannabinoids are involved in local and central regulation of reproduction and, are found in most reproductive fluids and tissues. This system helps orchestrate gamete production, fertilisation, pregnancy, childbirth and lactation. CB1 blockage of ECS signalling leads to a failure of pregnancy, with the endogenous cannabinoid anandamide being of major importance in successful reproduction19.

Cancer – there are unpublished reports that high dose THC can reverse tumour effects by diminishing tumour size, proliferation rate and angiogenesis. Many studies report chronic inflammation, infection and irritation as a precursor to tumour formation and progression19a. CBD has been shown to diminish inflammation, tumour proliferation and induce apoptosis in tumour cells (programmed cell death) in various tumour types, including breast, lung, colon, brain19b.

Transplantation and graft versus host disease – recent studies have reported a therapeutic for CBD in transplant acceptance, diminishing the development of graft versus host disease after haematopoeitic stem cell transplants20a.

Drug Addiction – Preclinical studies suggest that CBD may have therapeutic properties on opioid, cocaine and psychostimulant addiction as well as tobacco and even cannabis addiction20b.

Mechanisms of action of phytocannabinoids

CBD is an allosteric modulator. It binds near the site of the CB1 receptor to influence signalling by either antagonising or supporting the binding of other ligands like THC and 2-AG. CBD’s widespread biological effects are attributable to its allosteric binding as well as binding to non-cannabinoid receptors such as opioid, serotonin, adenosine and nuclear receptors20. The cannabinoids, both exogenous and endogenous are thought to maximise their entourage effect by a complex interplay of pharmacokinetic and pharmacodynamic interactions between biologically active constituents, including terpenes and terpenoids. Studies have shown that THC and CBD within Cannabis compete with anandamide for binding with non-cannabinoid receptors, thereby inhibiting cellular uptake and catabolism of this endocannabinoid. In other words, phytocannabinoids work in harmony with endocannabinoids to optimise the function of the endocannabinoid system21.


The ancient and prolific endocannabinoid system, developed over millennia as a stress or danger response network is clearly fundamental for the health and propogation of most animal species, including humans. Extracts of the Cannabis sativa plant, our products CBD and delta9-THC, act as exogenous cannabinoids which interact with the endogenous cannabinoids, such as anandamide and 2-AG in a complex interplay of body processes designed to optimise health and alleviate the effects of disease.

Contact: for further information and discussion contact Dr Margo Livingston at:

[email protected] or email me via the website.
To purchase our products go to: Pure Organic CBD


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