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The Endocannabinoid System

The body’s endocannabinoid system is composed of three parts: receptors, ligands, and metabolic enzymes. The two most common endocannabinoid receptors are CB1 and CB2. They are both located throughout the body, but CB1 receptors are more common in the central and peripheral nervous systems and the gastrointestinal system, while CB2 receptors cluster in the immune system, including the spleen and lymph nodes. Two main endocannabinoids have been identified to date: anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These endogenous cannabinoids are agonists, or ligands, acting on endocannabinoid receptors. Metabolic enzymes synthesize and degrade the endocannabinoids, regulating their levels. CB1 receptors are primarily located on presynaptic neurons. When a CB1 receptor is activated (by THC, endocannabinoids, or nabilone), it activates a signalling cascade that prevents the release of neurotransmitters into the synaptic cleft (for both excitatory and inhibitory neurons). Endocannabinoids are produced by postsynaptic neurons and work on the presynaptic terminal in a retrograde signalling process. CB2 receptors, on the other hand, are primarily found on immune cells and affect the release of cytokines and other molecules.

How cannabinoids work
Via the CB1 and CB2 receptors, cannabinoids act on a number of pathways in the body, which allow them to affect systems as diverse as feeding behaviours, insulin sensitivity, stress responses, gut permeability, inflammation, and emotional states. THC exerts its effects primarily through the activation of CB1, while CBD doesn’t bind to either CB1 or CB2, but inhibits or activates other receptors, enzymes, and molecules. The pathways underlying cannabis analgesia are only beginning to be understood, partly because there is no single site activated in the brain when pain is felt, and partly because cannabis may act on more than 20 pain pathways, including those not mediated by endocannabinoids. However, CB1 receptors are distributed more densely in the frontolimbic part of the brain, and this suggests that cannabis may preferentially target the affective qualities of pain. Studies using functional neuroimaging support this, showing that cannabis affects the activity of the anterior midcingulate cortex and the amygdala, both of which play a role in the emotional interpretation of pain.

Using Cannabinoids in Practice

Cannabis is available as dried flowers, as cannabis oil, and as softgels or capsules containing the oil. It can be administered by ingestion of the oil or by smoking or vaporizing the dried flowers. Ingestion of oil, capsules, or softgels provides the most accurate dosing. Vaporizing (heating the cannabis to a temperature that volatilizes the cannabinoids and other compounds without combusting them) is preferred over smoking because it is associated with fewer toxic by-products and adverse health effects. In addition, many cases of small patient populations, lack of randomization, lack of blinding, and a short duration of interventions have limited the conclusions that can be drawn. Rather than demanding larger and more rigorous RCTs (using which products? at what doses?) in order to learn more about medical cannabis use, it has been suggested that researchers look for surrogates, such as open-label, longitudinal, or case control studies. With enough data, statistical significance would be reached. Another approach is the use of registries. Unlike RCTs, which tend to exclude patients with comorbid conditions, registries can include a wide range of patients and thus get data on the effects of cannabis use on concurrent conditions such as depression, anxiety, and insomnia.

Experts have also suggested that clinicians personalize their cannabis patient management through the use of n-of-1 trials: individual patient case studies in which experimental and control interventions are tried sequentially with their order randomized (to achieve patient and sometimes physician blinding). This approach is the epitome of individualized medicine and can be used in cannabis patients to determine the most effective combination of plant varieties and dosage forms.

Cannabis in Chronic Pain
Every chronic pain patient is different, and many chronic pain conditions are resistant to currently available treatment options. This is a ripe area for cannabis-based medicines, especially if they can reduce opioid use and the possibility of overmedication among pain patients. Few human trials have been performed using cannabis-based medicines, especially in inflammatory pain conditions. For example, the only trial done in rheumatoid arthritis pain was a randomized, double-blind, parallel-group trial comparing Sativex® with placebo in 58 patients. 4 Sativex produced statistically significant improvements in pain on movement, pain at rest, sleep quality, 28-joint Disease Activity Score (DAS28), and the short-form McGill Pain Questionnaire “pain at present” component. There were no adverse event–related withdrawals or serious adverse events in the Sativex-treated group. No clinical trials have been done in osteoarthritis pain, but two have examined intractable cancer pain. In their 2017 report, the National Academies of Sciences, Engineering, and Medicine in the United States concluded that there is moderate-grade evidence supporting the effectiveness of cannabinoids for the treatment of fibromyalgia.

Other Indications

Public support has grown for the availability of medical cannabis for palliative care patients, and reported benefits include improvements in pain, nausea, weight loss, appetite loss, insomnia, spasticity, stress management, and mood. However, evidence has been relatively disappointing to date.
A 2017 systematic review and meta-analysis of the efficacy, safety, and tolerability of cannabinoids (dronabinol, nabiximols, and herbal cannabis) in palliative medicine found only nine randomized controlled and/or crossover studies with a total of 1,561 participants, with quality of evidence rated low to very low.14 In cancer patients, the analysis found no differences between cannabinoids and placebo in caloric intake, appetite, nausea/vomiting, pain reduction, or sleep. In HIV patients, cannabinoids were superior to placebo for weight gain and appetite but not for nausea/vomiting. Safety and tolerability were similar to placebo in both groups.
However, a recent trial, not included in that meta-analysis, produced somewhat more promising results.15 Nearly 400 advanced cancer patients with chronic pain (≥ 4 and ≤ 8 on a 0–10 rating scale) unalleviated by optimized opioid therapy were randomized to Sativex (n = 199) or placebo (n = 198) and allowed to self-titrate for two weeks before remaining on the same dose for three weeks. Results showed improvement in the primary end point (median percent improvements in average pain score from baseline to five weeks) in the per-protocol population but not the intent-to treat population. Quality of life scores, however, showed significant improvements in the Sativex group, especially at Week 5 and especially in American patients, possibly due to patients in other parts of the world having more advanced disease.

Although there is a great deal of public interest in the cancer-fighting abilities of cannabis products, clinical trial evidence is lagging behind. However, there is a great deal of suggestive preclinical evidence. Since 1975, when Munson reported that THC reduced the growth of implanted Lewis lung carcinomas in mice,16 there have been dozens of investigations of THC and CBD in vitro and in mice and rats, many of which have produced positive results. In one encouraging human safety study, THC was injected directly into glioblastoma multiforme tumours in nine patients who had failed standard therapy (surgery, radiation, and chemotherapy) and had evidence of tumour progression. The primary end point was the safety of intracranial THC administration, which was successfully demonstrated.
In addition, tumour growth was curbed for about nine weeks in one patient, along with clear improvement in clinical symptoms, and another patient’s clinical symptoms were largely improved. Cannabis may have a greater role to play in the management of cancer symptoms and chemotherapy side effects.
For example, dronabinol is effective in the management of breakthrough chemotherapy-induced nausea and vomiting (CINV) and is included among recommended CINV treatments by major oncology guidelines. One survey found that cancer patients themselves perceived improvements in pain, general well-being, appetite, and nausea with the use of cannabis.

An open-label trial gave patients with severe, intractable, childhood-onset, treatment-resistant epilepsy (who were receiving stable doses of antiepileptic drugs) oral CBD at 2–5 mg/kg/day, uptitrated until intolerance or to a maximum dose of 25 or 50 mg/kg/day.38 Of the 162 patients in the safety and tolerability analysis, 128 (79%) reported adverse events, particularly somnolence, decreased appetite, diarrhea, fatigue, and convulsions. In the 137 patients in the efficacy analysis, monthly motor seizures were reduced by a median of 36.5% and completely resolved in some patients.

The social and occupational safety concerns associated with cannabis use in the home or the workplace tend to echo those associated with the use of opioids: driving, working with heavy machinery, tending small children, and so on. Unfortunately, most studies focusing on these issues have involved recreational, rather than medical, cannabis users. As with opioids, common sense is vital: patients need to be reminded to be particularly cautious during the first days of cannabis use or after increasing the dosage. The College of Family Physicians of Canada recommends that medical users of dried cannabis be advised not to drive for at least four hours after inhalation, at least six hours after oral ingestion, and at least eight hours after either of those if the patient experiences euphoria.

The metabolism of cannabinoids involves cytochrome P450 (CYP450) enzymes, which brings up the possibility of drug interactions with other agents. However, very few clinical studies have shown relevant drug interactions with cannabinoids:
• Rifampin (a CYP inducer) decreases the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of both THC and CBD.
• Ketoconazole (a CYP inhibitor) increases the Cmax and AUC of THC and CBD.
• Theophylline clearance is higher in frequent marijuanasmokers.
• Clobazam metabolism is inhibited by CBD (thus increasing clobazam concentrations).
• Abnormalities of liver transaminases and platelets were seen with concomitant THC/CBD therapy and valproic acid. The April 2018 Canadian Pharmacists Association (CPhA) monograph for cannabis lists a number of additional potential drug interactions (anticholinergics, CNS depressants, CYP1A2 substrates, other CYP inducers and inhibitors, disulfiram, transdermal nicotine, and stimulants) but notes that many of these are theoretical or based on anecdotal reports from recreational cannabis consumers using high doses. One study investigated the interactions between cannabinoids and opioids. Although it was a small trial of short duration, the results showed that cannabinoids had no significant effect on opiate metabolism and did not change opioid serum levels—and that cannabis appeared to augment the analgesic effects of opioids. In general, additive adverse events are a greater consideration than drug interactions when prescribing cannabis in patients taking other medications. Adverse events associated with cannabis-based medicines are primarily mediated by THC and tend to be dose-dependent.

Some currently known uses and applications
Hundreds of peer-reviewed studies indicate that CBD possesses almost unbelievable clinical potential.
Anti-emetic (reduces nausea and vomiting)
Anti-convulsant (supresses seizure activity)
Anti-psychotic (combats psychosis disorders)
Anti-inflammatory (combats inflammatory disorders)
Anti-oxidant (combats neurodegenerative disorders)
Anti-tumoral/anti-cancer (combats tumour and cancer cells)
Anxiolytic/anti-depressant (combats anxiety and depression disorders)
Vasorelaxant to help with glaucoma
Stress reduction and mood regulation
Improved sleep quality
Improves hair and skin health
Inflammatory pain relief
Neuroprotective qualities
Assists in some symptoms of Multiple Sclerosis and Parkinson’s Disease

What is CBD?

CBD (cannabidiol) is a cannabinoid – a biologically active cannabis compound that has been proven to have significant health benefits. The cannabis plant is composed of a complex chemical mixture that includes phyto-cannabinoids, terpenoids, flavanoids, steroids and enzymes. Cannabinoids help by modulating many physiological systems in the human brain and body. There are many active cannabinoids that have been identified in cannabis and of these tetrahydrocannabinol (THC) and cannabidiol (CBD) are usually present in the highest concentrations and have been studied the most extensively. THC is the psycho-active component, which is used recreationally to give the “high”. CBD is non-psychoactive, meaning it does not make people feel “high or stoned” so that means daily tasks, like driving, taking care of children and working, will not be affected or put at risk by using CBD. There are no dulled senses to inhibit consumers. While this makes CBD is a poor choice for recreational users, it gives a significant advantage as a tonic, since it has minimal side effects. This makes CBD an appealing option for people looking for relief from various conditions such as inflammation, pain, anxiety, psychosis, seizures, spasms, etc — without feelings of lethargy. CBD rich hemp oil, the essential oil of the hemp plant, has over 480 natural compounds including 100 or so cannabinoids (CBD and THC are two) and over 120 terpenes (part of a plants essential oils which contribute to a plant’s scent, flavour and colour) along with amino acids, proteins, enzymes, ketones, fatty acids, steroids, flavonoids, vitamins and more. The term CBD has come to mean this whole plant extract high in cannabidiol (CBD) with much smaller amounts of the other compounds. Although there are synthetic cannabinoid substances produced by pharmaceutical companies, it is believed that the naturally occurring plant substances (phyto-cannabinoids) act synergistically, known as the “Entourage Effect”, for optimal benefits. By using selective breeding techniques, cannabis growers have managed to create varieties with high levels of CBD and next to zero levels of THC. CBD was first isolated in the 1930s (and further in the 1940s), but its structure and configuration were first fully described decades later—in the 1960s—by Professor Raphael Mechoulam and his team of researchers in Israel. As of early 2014, PubMed.gov, a service of the National Institutes of Health, has indexed over 1,650 peer-reviewed papers on CBD. What is the difference between Hemp (aka Industrial Hemp) and Cannabis? When trying to wrap your head around the differences between hemp and cannabis, it is important to begin with this simple concept: both hemp and cannabis come from the same plant. Whether you call something hemp or cannabis will depend on a variety of factors. However, despite the fact that the terms hemp and cannabis are often used interchangeably, they do have separate connotations.

Unfortunately, prohibition has spurred a lack of education surrounding the cannabis plant. This has led to countless rumours about what makes hemp different from cannabis. Everything from “hemp plants are male and cannabis plants are female” to “cannabis is a drug and the other is not” are incorrectly being preached as common knowledge to unknowing bystanders. So, how are these terms supposed to be used? Let’s find out. “Health Canada defines hemp as products of cannabis sativa which contain less than 0.3 percent THC, whereas US law defines hemp as all parts of any cannabis sativa plant containing no psychoactive properties, except for defined exceptions.” According to a 1976 study published by the International Association of Plant Taxonomy concluded “both hemp varieties and marijuana varieties are of the same genus, cannabis, and the same species, cannabis sativa. Further, there are countless varieties that fall into further classifications within the species cannabis sativa.” However, depending on how the plant is grown and utilized will determine which term is correct. For instance, the term cannabis (or marijuana) is used when describing a cannabis sativa plant that is bred for its potent, resinous glands (known as trichomes). These trichomes contain high amounts of tetrahydrocannabinol (THC), the cannabinoid most known for its psychoactive properties. Hemp, on the other hand, is used to describe a cannabis sativa plant that contains only trace amounts of THC. Hemp is an extremely versatile and high-growing plant, typically bred for manufacturing where it is used in thousands of commercial and industrial products from clothing and construction to oils and topical ointments, and much, much more. Only products made from industrial hemp (less than 0.3% THC) are legal to sell, buy, consume, and ship. This single factor (0.3%) is how most people distinguish between what is classified as “hemp” and what is classified as “cannabis.” So to summarize, the term cannabis refers to the entire hemp family of plants, marijuana the ‘pot’ sub species of Sativa and Indica generally refers to the psychoactive varieties containing over 0.3% THC, and hemp refers to the non-psychoactive CBD rich plants containing below 0.3% THC.

Some History of CBD

Usage CBD has a long history of being used to alleviate the symptoms of health problems. Queen Victoria used cannabis for menstrual cramps in the 19th century. Animal studies had long suggested that CBD lessens anxiety and reduces the severity and frequency of seizures and today this is a proven outcome on humans. The cannabis plant has been used for thousands of years in medicine for its sedative/hypnotic, antidepressant, analgesic, anticonvulsant, antiemetic, anti-inflammatory, anti-spasmodic and appetite-stimulating effects. The roots of CBD extend back thousands of years; to the end of the first ice age. Archaeological finds suggest that the source plant for the CBD compound, cannabis sativa, was likely one of the first agricultural crops planted by early man. In fact, growing cannabis sativa, something we tend to think of as modern, is often associated with the birth of agriculture 12,000 to 10,000 years ago. The astronomer Carl Sagan an icon of scientific credibility, put forth the possibility that Cannabis may have been world’s first agricultural crop, leading to the development of civilization itself. Looking at time lines, it is clear that cannabis plants have been integral to mankind since earliest times. Cannabis plants are exceptionally versatile. Both the seeds and cannabis oil were used for food in China as early as 6,000 BCE. Two thousand years later, in 4,000 BCE, there is evidence of textiles made from hemp (cannabis) used in both China and Turkestan. The influence of the plant seems to have been global. In 850, the Vikings transported hemp rope and seeds to Iceland, and by the year 900, Arabs were learning techniques for making paper from hemp. By 1000, Italians were using ropes made of hemp on their sailing ships.

Today, consumers are primarily interested in the healthful properties of cannabis compounds, and there is a long thread of cannabis applications for health running through all eras of history. Stories about the healing properties of hemp (cannabis) mention Greek philosophers, Herodotus, Napoleon and other legendary figures. The physician for Nero’s army, for example, included cannabis in his inventory. In 1563, the health benefits of cannabis were discussed in a report by Portuguese physician Garcia da Orta. A few years later, China’s Li Shih-Chen documented the antibiotic and anti-nausea effects of cannabis. In contrast to today’s modern restrictions of growing cannabis sativa, England’s King Henry VIII actually fined farmers if they did not raise hemp for industrial use. This was in 1533. Less than one hundred years later, settlers in Jamestown, Virginia began growing hemp plants for hemp’s unusually strong fibre. Once the plant demonstrated its usefulness, it became illegal to NOT grow hemp in Virginia USA. By 1850, Cannabis was added to list of The US Pharmacopeia, a respected compendium of Medicines and Dietary Supplements. That same year, marijuana was used throughout United States as a legal drug and could easily be purchased in pharmacies and general stores. This lasted until about 1915. Cannabis as medicine is not a new concept. Prior to prohibition, major pharmaceutical companies produced a wide variety of cannabis-based medicines and 1840 to 1937 were considered the “golden age” for cannabis medicine. Although cannabis has a long history, what is new is the recent discovery (1992) of the body’s endocannabinoid system (ESC) (see section below). Also discovered was that the cannabis plant is loaded with phytocannabinoids that can stimulate the ECS receptor sites of this system. It is this combined discovery that is leading cannabis, in all forms, back into the limelight again as a viable tonic for good health. The Endocannabinoid System In addition to cannabinoids produced by the plant (phyto-cannabinoids), there are endogenous (which means having an internal cause or origin) cannabinoids (such as anandamide and 2AG) that occur naturally in the mammalian brain and body. There are also synthetic cannabinoids which are synthetically engineered in labs. Regardless of the type, cannabinoids act as neuromodulators and help regulate every physiological system such as our nervous system, digestive system, reproductive system, immune system, endocrine system and muscular system. Research on cannabis’ effects led directly to the discovery of a hitherto unknown biochemical communication system in the human body, the Endocannabinoid System (ECS), which plays a crucial role in regulating our physiology, mood, and everyday experience. The ECS is also known as “the body’s own cannabinoid system”. It is made up of groups of cannabinoid receptors which are mainly located in the human brain and central and peripheral nervous systems. The discovery of receptors in the brain that respond pharmacologically to cannabis—and the subsequent identification of endogenous cannabinoid compounds in our own bodies that bind to these receptors—has significantly advanced our understanding of human biology, health, and disease.

The ECS is estimated to be over 600 million years old and is found in all vertebrate species. We are just beginning to understand how widespread and important it is to our functioning. The primary purpose of the ECS revolves around maintaining balance in the body; this is known as homeostasis. Various studies show that these receptors allow two-way communication between body systems and are the reason CBD is so easily utilised by the human body. It is an in-built mechanism for effectively utilising cannabinoids (both from cannabis and from our own biological production) to help with numerous human processes and sensations. These studies have revealed that cannabinoids act as neuromodulators for a variety of processes, including motor learning, appetite, and pain sensation, among other cognitive and physical processes. The two primary endocannabinoid receptors are CB1 (found mainly in the brain and central and peripheral nervous system, and also in the liver, kidneys and lungs) and CB2 (found mainly in the immune system and spleen). These receptors are specifically designed to work with both the endocannabinoids that our bodies naturally produce (such as after exercise), and also with plant based cannabinoids such as THC and CBD. Sensations such “runners high” were once thought to be produced by endorphins. However recently it has been proven that this feeling is actually due to the body producing its own cannabinoids. The fundamental function of the CB1 and CB2 receptors is either to “excite” or to “inhibit”. This excite or inhibit process will determine how other hormones and body systems are regulated in the body. The ECS is fundamentally a hormone regulation system throughout the body and it helps to keep the body in balance. CB1 is mainly responsive to THC so when THC is present it is effective for the therapeutic moderation of pain intensity. Remember that THC is the psycho-active component of cannabis and produces the intoxicated effect that it is mostly known for. Importantly, CB1 receptors are not present in the part of the brain that regulates heart rate and respiration, so unlike narcotics, there is no lethal dosage threshold for THC. CBD does not directly act on the CB1 and CB2 receptors but instead interacts and enhances other signalling systems. It acts indirectly by stimulating endogenous cannabinoid signalling and activating the release of other endocannabinoids, that work on both CB1 and CB2 receptors. CBD also works indirectly on other receptors besides CB1 and CB2 mainly affecting receptors such as serotonin, adenosine and vanilloid. Recent studies have shown how CBD is involved in the stimulation of 5-HT1a serotonin receptor which is known to produce the antidepressant effect. This receptor is common to a huge range of other processes such as appetite, pain perception, nausea, anxiety and addiction mechanisms. CBD is non-psychoactive because it does not act on the same pathways as THC. One of the effects of CBD is that it moderates the effects of THC. It actually knocks THC off the CB1 receptor, so if someone is experiencing THC intoxication, a strong dose of CBD can counteract those effects. Researchers are finding out that by modulating the endocannabinoid system, the symptoms of a number of diseases and pathological conditions may be alleviated. Conditions such as multiple sclerosis, cancer, stroke, obesity/metabolic syndrome, anxiety disorders, neuropathic pain, Huntington’s disease, glaucoma, seizure disorders, Parkinson’s and osteoporosis are just a sampling of the disease symptoms helped.

Human breast milk and the cannabis plants have something in common – some of the same cannabinoids. Breast milk is abundant in cannabinoids. These similar cannabinoids protect the infant against disease, stimulate the suckling response and help to regulate the appetite. Endocannabinoid production, therefore cannabinoid levels in the body, are nutrition dependent, so the levels drop with poor nutrition, including being deficient in omega-3 oils. Omega-3 fatty acids are the precursor for the body to be able to produce its own endocannabinoids. Omega-3 fatty acids help repair and grow CB1 receptors and the CB1 receptors cannot work properly if starved of Omega-3. It would be very helpful for anyone using a cannabis preparation (or not) to incorporate Omega-3 fatty acids into their diet, priming the CB1 receptors to be at their best for endocannabinoids or phyto-cannabinoids. Omega-3’s are found naturally in a variety of foods including walnuts, flaxseeds, chia seeds, sardines, salmon, tuna, fresh basil, spinach, beans, brussels sprouts, cauliflower, broccoli and avocado’s to get you started. Good diet, exercise and staying well hydrated are also important for good health. The fact that there is a system in our body that produces cannabinoids, and is specifically designed to accept just them, should be overwhelming proof of cannabis’ efficacy as a health tonic. We have just scratched the surface of a world of possibilities. People are waking up to the benefits of these tonics as more researchers are exploring the infinite possibilities inherent in this seemingly simple plant.

“In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs … modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few…” Currently there are no documented studies that show undesirable effects from CBD, which is why this particular cannabinoid is legal in most parts of the world. However, there are many studies showing CBD to cause only desirable effects or no effects at all. In virtually every test on CBD’s effectiveness, only desirable effects were obtained; the only negative side effect that has been proven is slight fatigue (and only when a lot of CBD was used). CBD is now used to treat health conditions like neurological degeneration, for which no other successful medication has yet been found. CBD is suggested as potentially useful as a therapy for schizophrenia due to the opposing effects it has. Not only that, but it may be able to relax those suffering from anxiety disorders and offer comfort.