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Can phytocannabinoids be used to modulate the endocannabinoid system to positively affect other organ systems?
Dr. John Lewis Ph. D.
30 September 2017
Have you heard about the rising interest in the use of marijuana for medical purposes?  I am sure you have, as the issue is increasing in notoriety and concern among citizens all over the world.  People have smoked marijuana for recreational purposes due to its content of tetrahydrocannabinol or THC for its psychoactive effects.  However, marijuana and other plants, such as hemp, have many additional compounds known as phytocannabinoids.  You may have heard of at least one phytocannabinoid, cannabidiol or CBD, as it is most prevalent in these plants, but over 100 phytocannabinoids have been discovered.  In addition, animals, including humans, have been shown to have what is called the endocannabinoid system, which functions in unison with our other organ systems to help us maintain health and keep us physically and emotionally stable.  Scientists have discovered two receptors, CB1 and CB2, which are located in the central and peripheral nervous systems and take part in multiple pathways of cellular signaling.  The science of understanding what phytocannabinoids are and how the endocannabinoid system works has advanced considerably in the last 30 years.  The scientific evaluation of phytocannabinoids has been largely empirical and only tested in a few specific conditions related to appetite, motor learning, pain, wasting disorders, and chemotherapy-induced nausea and vomiting, as a result of their socially undesirable psychoactive properties and the legal status of marijuana in most areas.

Nonetheless, the recognized significance of the endocannabinoid system is increasing rapidly, even though most scientists and clinicians are unfortunately unaware of it because of the almost worldwide prohibition of marijuana.  The endocannabinoid receptors, the endocannabinoids, and their biosynthetic and biodegrading enzymes comprise the endocannabinoid system, the discovery of which started a quest to determine its physiological and pathophysiological roles in human health.  This system helps to regulate homeostasis, and its receptors are ubiquitous throughout every major organ, particularly the brain.  It is hypothesized that disease states at least partially arise due to the dysregulation of this system.  Thus, this is one reason why phytocannabinoids may ultimately prove to be effective as a therapeutic option for multiple health challenges.  Additionally, the discovery of the endocannabinoid system also led to increased investigation of the interactions of the phytocannabinoids with this system.

The discovery of the two cannabinoid system receptors, CB1 (predominantly centrally located) and CB2 (predominantly peripheral expressed principally by cells of the immune system), which mimic some of the effects of cannabinoids in vivo, their G-protein coupled receptors, and their synthetic and metabolizing enzymes, has prompted preclinical studies aiming to explore the role of the endocannabinoid system in health and disease.  CB1 receptors are the most abundant G-protein coupled receptor in the mammalian brain, and they are now known to be in almost all peripheral tissues and cell types, albeit at much lower densities than in the brain, and are recognized for their important regulatory functions.  CB1 is also present under pathological conditions, e.g., a high-fat, atherogenic diet and obesity.  CB2 receptors are largely restricted to immune and hematopoietic cells, although functionally relevant expression has been found in specific regions of the brain and in the myocardium, gut, endothelial, vascular smooth muscle, and Kupffer cells, exocrine and endocrine pancreas, bone, and reproductive organs/cells, and in various tumors.

According to the United States National Institutes of Health, the endocannabinoid system is involved in many pathophysiological processes in the peripheral and central nervous systems and in various peripheral organs suggesting that modulating system activity may have therapeutic potential in almost all diseases affecting humans!  Their statement is supported with in vitro studies or from in vivo experiments in animals, including, but not limited to:  (a) obesity and metabolic syndrome, (b) diabetes and diabetic complications, (c) neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, and skin diseases, (d) pain, and (e) cancer.  These studies have shown that the endocannabinoid system is inherently linked to untold pathophysiological processes, both in the peripheral and central nervous systems and in various peripheral organs and thus modulating the endocannabinoid system may infer therapeutic potential in almost all diseases affecting humans.  Moderate evidence that suggests that phytocannabinoids are effective for improving short-term sleep outcomes in adults with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.  Fair evidence suggests that phytocannabinoids may improve symptoms of anxiety, stress, and post-traumatic stress disorder.  Nonetheless, these preliminary findings set the stage for additional studies to shed light on how phytocannabinoids can correct pathophysiological functioning of the endocannabinoid system, such as within sleep disturbances and in the reaction to chronic stress, in humans.

To date, few studies have used phytocannabinoids as the treatment or intervention in humans.  Thus, many questions remain to be answered about how phytocannabinoids may be utilized for therapeutic efficacy in a host of diseases and disorders.  Although the results of clinical trials are still limited, some key points can be made.  CBD and other phytocannabinoids demonstrate utility and efficacy and provide a group of molecules that demand expanded research evaluation, particularly in areas like neurodegenerative disorders that currently have little conventional treatment options.  Despite the relatively high concentrations required at some targets, CBD is known to cross the blood-brain barrier well, with no major toxicity, genotoxicity, or mutagenicity.  CBD doses as high as 1,200 mg have been safely tolerated in human trials.  CBD, as a compound with a multi-modal mechanism of action, with clear therapeutic potential in a number of areas, befits its status as the second most prevalent phytocannabinoid to THC in cannabis.  Thus, the future of phytocannabinoids as safe and efficacious agents to combat multiple disorders and diseases holds great pharmacological and therapeutic promise.

Nonetheless, many questions need to be addressed with research in humans.  For example, the intracellular and extracellular actions of endocannabinoids versus those of exogenously introduced cannabinoids may vary and have dissimilar physiological consequences.  Many cannabinoid receptors also interact with a wide range of non-cannabinoid receptor targets and regardless of whether they are endogenous, synthetic, or plant cannabinoids the pharmacological profiles of these compounds are often unique.  An effective therapeutic strategy for disease management, e.g., MS, Parkinson’s, schizophrenia, hypertension, inflammatory bowel disorder, Alzheimer’s, depression, obsessive compulsive disorder, and cancer, may occur by increasing extracellular levels of a released endocannabinoid by inhibiting metabolizing enzymes or by inhibiting the cellular uptake of anandamide.  Thus, further research is required to assess whether other, as yet uninvestigated, phytocannabinoids modulate the endocannabinoid system and how that affects symptoms across various disorders, particularly since very little human data are available.  Clinical trials investigating the effect of phytocannabinoids on both disease progression and symptom control for a range of disorders are required to determine if and how they can benefit these patients, all of whom have significant unmet clinical needs.  Encouragingly, most phytocannabinoid-based treatments investigated to date, independent of the target disorder, appear to be well-tolerated, a promising sign for further clinical studies.  Clinical data for effects of individual (or mixed) phytocannabinoids may be usefully extended to trials for feeding-related disorders, neurodegenerative diseases, affective disorders, and epilepsy, among others.  While the current data look promising, much more work needs to be done to understand the ultimate utility of phytocannabinoids within the endocannabinoid system through basic and clinical science crossing multiple disciplines.  For now, you can consider a high-quality phytocannabinoid supplement as part of your daily routine to maximize your health.

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