Dr. Jokūbas Žiburkus, PhD aka Dr. Z
“Indian hemp is not a poison. This statement is made, just here, because the writer thinks a fear of its toxic power is one reason why this drug is not more largely used. This mistaken idea lessens its value, because it is not pushed to the point of securing a full therapeutic effect. This is a fact.” Dr. J. B. Mattison, MD, 1891 from ‘The St. Louis Medical and Surgical Journal’.
The cannabis markets continue to burgeon around the globe,with the cannabis laws rapidly changing at the same time. Some of the largest economies in the world, like Germany, California, and Canada (to name a few) have legalized medical cannabis. Canada and California are about to legalize adult-use of cannabis as well. Simultaneously, cannabis dispensaries are opening and different cannabis companies and brands are being created at near exponential rates, potentially surpassing the Dot-Com Boom. Some advanced companies are standardizing their plant genetics, product lines, and some are additionally investing in technological advancements, and scientific and clinical research. At the same time, the cannabis market is highly fragmented because of the disparity in national and international laws and standards.
The fragmented cannabis market continues to be a source of concern for consumers and prolongs the stigmatization of this plant. A void of proper multi-level educationand training resources, serves as an additional disruption in the growth of legal medical cannabis patients. Consumers, local dispensaries, and healthcare practitioners carry the burden of deciphering various products in the marketplace, while hoping they consistently meet regulatory and product standards. Local jurisdictions have caught up and are beginning to regulate and set certain standards for pesticides for cannabis grows and cannabinoid concentrations in consumer products. However, when these standards, for example, like concentration of cannabinoids or THC, allow for ±15-30% variability, this leaves a loop hole for tight quality control, putting the burden of decoding the safety and proper dosage of the cannabis products on the patients and their healthcare providers (www.cannabinoidcalculator.com).
Legal cannabis market fragmentation, coupled with a lack of readily available and relevant educational resources, make healthcare practitioners reluctant to recommend legal medical cannabis to their patients. Such bottleneck exists in Germany and is due in large part to a fast developing market and deficiency in knowledge of the endocannabinoid system, effects of cannabinoids and terpenes on the human body, contra-interactions of cannabis compounds with already existing medications and supplements, and the composition and methods of use
ofavailable medical cannabis preparations. The US and Canada also experience similar problems. For example, in the US, this bottleneck is further complicated becausehealthcare practitioners can only recommend medical cannabis and, not prescribe it, as that violates US federal laws. Therefore, medical cannabis for healthcare professionals is a paradigm shift from the pharmaceutical system in which they were trained. Much needed accredited professional educational, patient safety and usage tools will certainly facilitate this transformation and lead to the most therapeutically effective cannabis products.
While most of the industry is scrambling to establish itself and build exponential value ‘early on’, efficacy and safety of cannabis products at large remain significantly underdeveloped. The marketplace also often forgets that cannabis and its use must be placed within a larger health and wellness model. The focus should be to unlock the complete gamut of therapeutic uses of cannabis and to create the most effective, individualized cannabinoid health and wellness system.
Thus, a system called the “Cannabis-Centric Entourage System”, when developed, could be useful for a clearer understanding of medical cannabis and its most effective, individualized use. The time for this system is ‘now’, because the time of medical cannabis is ‘now’. To build this entourage system, all of the major players – growers, manufacturers, scientists, patients, and clinicians – must pool their intellectual expertise, observations, and test results. Below are a few key concepts that need to be considered when developing individualized cannabinoid and medical cannabis treatment system.
I – Endogenous cannabinoid system
The endocannabinoid system (ECS) consists of synthesizing enzymes that make endocannabinoid molecules, which bind to cannabinoid receptors 1 and 2 – CB1 and CB2. CB1 and CB2 receptors are widely distributed in human bodies1. Activation of CB1 receptors in the brain causes the psychotropic ‘high’ effect of cannabis. However, CB1 receptors are also highly expressed in other organs, like the heart and the digestive system. CB2 receptors are also present in the brain, but they are more densely expressed in the organs and cells linked to the immune system functions, like the gall bladder.
The ECS, consisting of the two endocannabinoids and two receptors (in simple terms) is highly complex, because it is widespread and its components are present throughout very different body cells, organs, and systems. As such, the ECS is thought of as the major homeostatic body system, balancing transmission between neurons in the brain, engaging the immune response, and regulating the inflammatory processes2-6. Furthermore, apart from the CB receptors, the endocannabinoids target a number of other receptors that are involved in pain modulation (vanilloid and glycine receptors), nausea, appetite, and mood (serotonin receptors), and cell differentiation and lipid metabolism (peroxisome proliferator-activated receptors – PPARs). Thus, further understanding of the endocannabinoid system state and its interactions with other key body systems is very important within the context of individualized therapies.
II – Diversity of cannabis chemovars and acidic cannabinoids
The cannabis plant is thought to have over 1000 molecules7, hundreds of them with known biological activities. The genetic code of cannabis is limited to producing a maximum of 35-40% of phytocannabinoids. Aromatic terpenes8,9, which give cannabis its distinct and specific smells, can constitute several percentages of the total plant flower mass. Cannabis terpenes are unique in several ways: 1) unlike most herbs, cannabis strains are genetically highly diverse and express distinct terpenes; 2) cannabis is mostly consumed by smoking and vaporization, whereby millions of consumers are inhaling different terpenes; 3) some of the cannabis terpenes and phytocannabinoids have complementary biological activities, allowing them to form functional synergies.
During the growth cycle, concentrations of different cannabinoids and terpenes fluctuate10. Terpene production increases in response to stress, like a drastic change in temperature or wind. Terpenes protect cannabis from unwanted pests and intruders. Thus, the cannabis plant has its own complex chemical entourage of molecular interactions, some facilitating, and synergistic, and others containing detracting biological effects.
The chemical output of the cannabis strains are a result of the genetics, growth cycle, grow medium (soil, water (hydroponic), and air (aeroponic)) conditions, or the overall micro or macro environment of the plant, and its maturity level. In its natural state, over 90% of cannabinoids in plants are expressed as acidic cannabinoids, such as THCA, CBDA, and CBGA. Acidic cannabinoids, such as THCA are non-intoxicating. By this virtue, the cannabis plant is not intoxicating and for THCA to decarboxylate into THC, heat is required. Cold or raw cannabis extractions contain acidic cannabinoids, like THCA and CBDA. Acidic cannabinoids are emerging as effective anti-tumorigenic, antiemetic and anxiolytic compounds11,12. When used in combination, acidic and neutral cannabinoids are often therapeutically more effective.
III – Diversity of medical cannabis products
Medical cannabis is a paradigm change for consumers and healthcare practitioners. Cannabis is highly prevalent around the world and humanity has a long history with low THC hemp and high THC cannabis and their diverse applications. Medicinally, cannabis is one of the safest psychoactive substances. It is not lethal and it does not serve as a gateway drug. At the same time, the intoxicating property of THC via CB1 receptor in the brain, also has many other effects in other parts of the body. Pharmaceutical synthetic THC has been on the market for decades. Pharmaceutical plant-derived cannabinoids (THC and CBD) have been or are currently being introduced into the market. Pharmaceutical preparations are limited and their prescription is narrow, like for example, the treatment of spasticity in multiple sclerosis and nausea in cancer and chemotherapy.
Thousands of different medical cannabis products with different ratios of THC, CBD, and terpenes are available to millions of patients. Medical cannabis preparations are made from the plant and plant-derived isolated cannabinoids only. Unfortunately, these products will not have as much clinical evidence to back their use. Yet, at the same time, millions of patients with the help of their doctors have access to many alternative solutions with cannabis products, unlike prescription pharmaceuticals. Luckily, cannabis is a safe drug and cannot lead to death.
IV – Cannabis and human entourage
Ultimately, it is the interaction between the human biological systems and the cannabis product composition that determines the most effective treatment. There are many uses of each part of the cannabis plant: from roots to trichomecovered flower tops. The overwhelming majority of legal medicinal and adult-use markets are focused on THC, and, only as of lately, on CBD, terpenes, and other phytocannabinoids and molecules. Medicinal cannabis markets should be prepared to commercialize other phytocannabinoids, apart from THC and CBD. In fact, seasoned distributors and forward looking companies are already showing significant interest and see additional value in rare cannabis strains that are high in CBG (cannabigerol), CBDV (cannabidivarin), CBC (cannabichromene), THCV (tetrahydrocannabidivarin), and other phytocannabinoids and certain terpenes. Likewise, these plant-based cannabinoid isolates also come at a high premium, where CBG can be three times the price of CBD. Consumers will catch on to these new cannabinoids and recognize their distinct benefits over the next couple of years.
When speaking of the cannabis entourage effect, the starting point is to understand the most predominant plant components. Almost everyone starts by appreciating that cannabis contains a number of major and minor cannabinoids. Major cannabinoid THC is intoxicating and when used irresponsibly or at very high concentrations, it can lead to anxiety and panic attacks, and increase the risk of heart arrhythmias and attacks. However, when THC consumption is balanced with CBD and other elements in the plant13, CBD, for example, has ability to reduce anxiety and panic14, taming negative effects of THC. This happens, because CBD affects CB1 receptors in the brain, thus controlling effects of THC on that receptor. In addition, CBD has higher binding affinity to serotonin receptors thanto CB receptors and serotonin signaling iscrucial for controlling anxiety. In this way, synergistic effects of cannabinoids can affect our bodies via the same receptor or pathway, or by engaging distinct, complementary body systems.
Synergistic entourage interactions also depend on the phytocannabinoid-terpene interactions, because some of the terpenes target CB receptors and other overlapping targets of the cannabinoids. Some entourage of molecules may also act in an antagonistic, or even a negative fashion. Many future observational and clinical studies will delineate how aromatic terpenes, such as limonene, pinene, or geraniol, to mention a few, interact with the cannabinoids to create the most effective, individualized medical cannabis treatments9,15,16. An individual approach to cannabis products is very important, because cannabinoids and terpenes get metabolized at
different rates and each individual’stone of the endocannabinoid system varies. In this respect, drug-to-drug interactions of the existing medications and known cannabis component activity must be carefully evaluated. Thus, healthcare practitioners are guided by this rule when recommending medical cannabis products: “Start low, go slow”. Start with low concentrations of active ingredients and observe the effect slowly, before increasing the doses.
Finally, all of us have a preferred aromatic entourage in our daily lives. These are the smells and flavors that we surround ourselves with: cosmetic products, fragrances, foods, and drinks – lavender or citrus, rose or peppermint. These are not just fragrances, but are smells and tastes that affect our brains, mood, and well-being. When choosing certain cannabis strains or products, the daily entourage may inform a consumer of the favorable cannabis flavors, represented by the chemical composition of these biologically active ingredients.Certainly, it will take time and a concerted effort to create a user friendly cannabis-centric entourage (health and wellness) system. Until then, education on distinct cannabis components, the cannabis entourage, cannabis product compositions, and their uses will enable safe, effective, and supervised use of the panacea of medical cannabis products and, simultaneously, lead to the cannabis industry’s success.
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© Canntelligence and Dr. J. Žiburkus, PhD