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From the Townsend Letter
June 2018

Insights from the International Center for Cannabis Therapy, Part 2: Evidence for the Clinical Use of Cannabinoid-Rich Hemp Oil in the Management of Pain, Inflammation, and Stress
by Chris D. Meletis, ND, and Kimberly Wilkes
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Part One is also online

In last month's Townsend Letter, Dr. Chris Meletis discussed the International Center for Cannabis Therapy (ICCT) cannabinoid certification programs for dietary supplement manufacturers and healthcare practitioners. As the Chief Medical Officer–USA of the ICCT, a Czech Republic-based partnership of qualified doctors and scientists who specialize in the medical application of cannabis, Dr. Meletis is an expert on the clinical applications and research supporting the use of cannabinoid-rich hemp oil and its effects on the endocannabinoid system. In this article, we will talk about the endocannabinoid system, its role in health, and how the endocannabinoid system interacts with the adrenals, sex hormones, and gut. We'll also share pre-clinical and clinical research and Dr. Meletis' observations about the use of cannabinoid-rich hemp oil in clinical practice, with an emphasis on the management of pain and inflammation and how to balance the endocannabinoid system without overwhelming its receptors. The next part of this article in a future issue of Townsend Letter will address the use of cannabinoid-rich hemp oil in applications such as epilepsy, stroke, irritable bowel syndrome, depression, anxiety, and psychosis, among other uses.

SUPPORTTownsend Letter provides a platform for those examining and reporting on functional and integrative medicine. Please support these independent voices.

These articles can only touch the surface of everything there is to know about the endocannabinoid system and hemp oil. Healthcare practitioners who want to delve deeper into the benefits of cannabinoid-rich hemp oil, understand the legal ramifications of prescribing it, and become certified as a respected hemp oil expert who understands proper dosing and other nuances of hemp oil use, can sign up for the ICCT online medical certification program at www.icctcertification.com.
     
Methylation SummitThe endocannabinoid system is a fascinating regulator of many aspects of our health. Endogenous endocannabinoids that are produced within the body, including anandamide (arachi-donylethanolamide) and 2-arachidonylglycerol (2-AG), are able to activate receptors in this system. Phytocannabinoids such as Δ
9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa, and cannabidiol (CBD), a non-psychoactive component, are also able to activate endocannabinoid receptors. Additionally, synthetic cannabinoids have been synthesized and have an effect on endocannabinoid system pathways.
     
Two of the main receptors in the endocannabinoid system are CB1 and CB2. CB1 is the primary receptor in the nervous system. It is also found in the adrenal gland, adipose tissue, heart, liver, lungs, prostate, uterus, ovary, testis, bone marrow, thymus, and tonsils.1 Its expression is weak in the areas of the brain stem that regulate respiration, which is why respiratory depression, a potentially fatal adverse effect of opioid drugs, does not occur when using phytocannabinoids as painkillers.1
     
The CB2 receptor is typically not expressed in neurons, which is why it was originally called the peripheral cannabinoid receptor. The immune system is the primary site of its expression. However, its presence has been detected in dorsal root ganglia, a cluster of cells in spinal nerves.2 CB2 receptors can also be expressed in bone, the gastrointestinal tract, and in activated microglia in the central nervous system.2 Microglia are cells found in the brain and spinal column that defend the central nervous system against immune assaults. Because antibodies are too large to penetrate the blood brain barrier, microglia serve as the last defense against pathogens that enter the brain. Activated microglia, sometimes referred to as reactive microglia, create an inflammatory response linked to diseases of the brain.3 The presence of CB2 receptors in activated microglia indicate they may be involved in blocking the effect of painful stimuli in inflammatory processes of the nervous system.4
     
Different phytocannabinoids have different effects on endocannabinoid receptors. THC directly acts on CB1 receptors of the endocannabinoid system,5 which are primarily expressed in the brain. CBD indirectly acts on the CB1 receptors by suppressing the enzymatic breakdown of the endogenous cannabinoid anandamide, increasing the duration of time it stays in the system.6  CBD's effects on the CB1 receptor counteract the psychoactive effects of THC.7 CBD thus inhibits adverse effects of THC including intoxication, sedation, and tachycardia.7  CBD also acts on the CB2 receptor, which is expressed in the periphery and is involved in immunity.8

From Fetus to Newborn: The Endocannabinoid System's Important Role
The endocannabinoid system plays an important role in our health long before we are born. The endocannabinoid system has been observed in cell types that play a role in male reproduction.9 Endocannabinoids and cannabinoid receptors have been detected in testicular tissue, including Sertoli and Leydig cells and spermatozoa.10 The endocannabinoid system also is involved in the hypothalamus-pituitary-gonadal (HPG) axis.10 The anandamide-degrading enzyme FAAH regulates key steps in sperm biology pathways, and this action involves the CB1 receptor.10
     
Furthermore, the endo-cannabinoid system is important and highly expressed during fetal development. Too much cannabinoid resulting in the over expression of anandamide could lead to negative outcomes such as ectopic pregnancy.11 Therefore, anandamide concentrations in the uterus must be tightly regulated for conception to occur.12 During vaginal birth, the newborn's exposure to high endocannabinoid levels assists with the transition from fetus to becoming an infant. During birth, the levels of anandamide and an anti-inflammatory fatty acid amide known as palmitoylethanolamide (PEA) are markedly higher in vaginally delivered babies compared with infants delivered by cesarean section,13 indicating that vaginally born infants would have a naturally higher degree of protection against pain and inflammation.
     
Another rodent study serving as a good example of the importance of the endocannabinoid system in prenatal and postnatal health involved female rats who were subjected to dietary restriction involving 20% fewer calories than a normal diet during pre-gestation and gestation. At birth, a significant decline in the levels of anandamide, 2-AG, and PEA were detected in the hypothalamus of the offspring of the calorie-restricted rodents. As adults, these offspring were more likely to gain excessive weight and body weight and be overweight as well as have increased anxiety-related responses.14
     
Furthermore, endo-canna-binoids have been detected in breast milk, and activation of CB1 receptors was found to be critically important for milk sucking by newborn mice, helping them to develop oral-motor musculature.15 This means that if a baby is delivered by C-section and then is bottle fed, he or she may be seriously depleted in endocannabinoids and may be at a disadvantage both as infants and later in life both mentally and physically. CB1 receptors are temporarily present in white matter regions of the pre- and postnatal nervous system.15 This implies that CB1 receptors have a part to play in brain development and endocannabinoid deprivation in newborns can therefore be especially concerning.
     
The importance of the endocannabinoid system to infants is supported by a study showing that anandamide was neuroprotective against lesions induced in perinatal rodents.16 Another study demonstrated that in rats that receive poor rearing during the neonatal timeframe, the neuroendocrine response to early life stress is reduced. Increasing anandamide levels ameliorates these stress-induced changes in glucocorticoid synthesis in these rats.17 

Chronic Pathologies ConferenceBeyond CB1 and CB2 Receptors
Research is beginning to look beyond the classical CB1 and CB2 receptors as potential mediators of some of the beneficial effects of phytocannabinoids. Other receptors targeted by phytocannabinoids include G-protein coupled receptors (GP- CRs: GPR18, GPR55 and GPR119). Both GPR18 and GPR55 may recognize the phytocannabinoid CBD. Evidence indicates this phytocannabinoid serves as a GPR55 antagonist, as well as a weak partial agonist.1 GPR18 is expressed primarily in immune cells while GPR55 is expressed in several brain regions as well as in the dorsal root ganglia in neurons with larger diameters, the hippocampus, frontal cortex, cerebellum, striatum, and hypothalamus. GPR55 may also be expressed in the immune system as well as in the microglia and bone.1
     
Research suggests that type 1 vanilloid receptors (TRPV1) may regulate some cannabinoid effects. The TRPV1 receptor has been identified in neurons that play a role in pain signaling.18 Other undiscovered cannabinoid receptors may exist, and these receptors may partly mediate some of the analgesic effects associated with cannabinoids.19,20

Interaction of CBD Receptors and Other Physiological Pathways
The role of endocannabinoids and phytocannabinoids in mood enhancement and reduction of pain and inflammation cannot be completely explained by their effects on CB1 and CB2 receptors alone as well as the other receptors mentioned above. Cannabinoids influence other pathways and their effects on these pathways may play a role in their myriad health benefits. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is one of those pathways. PPAR-gamma is a nuclear receptor whose actions include regulation of glucose homeostasis and inflammatory processes and connective tissue health.21 Mice experiencing a loss of PPAR-gamma function in fibroblasts were more likely to suffer from skin fibrosis.21 Some endocannabinoids and associated signaling lipids as well as certain natural and synthetic cannabinoids can activate PPAR-gamma including THC and CBD.22 The anti-inflammatory effects of anandamide and 2-arachidonoylglycerol are mediated by PPAR-gamma.22
     
Moreover, CBD blocks microglial activation in vitro through a mechanism that involves the activation of PPAR-gamma.23 This effect was mediated by the inhibition of the inflammatory nuclear kappa factor beta (NF-KΒ
) pathway.23  The ability of cannabinoids to target both CB receptors and PPAR-gamma may explain their regulation of a number of processes including neuroprotection, inflammation, immunomodulation, and vascular responses.24
     
Cannabinoids also interact with 5HT1A serotonin receptors. It has been shown that the anxiety-reducing effects of CBD are dependent upon neurotransmission that is mediated by 5HT1A.23 It is thought that CBD indirectly influences the 5HT1A receptors through interactions with the receptor binding site and/or modulating intracellular pathways.23 CBD's effects on stress-reduction and anxiety as well as its mood-enhancing abilities are also mediated through the 5HT1A receptor.23 Furthermore, CBD's ability to reduce brain tissue damage in mice caused by cerebral artery occlusion is blocked when 5HT1A receptors are inactivated.25 The fact that CBD interacts with multiple receptors was shown in an animal study where CBD's ability to prevent hypoxic-induced brain damage was dependent upon both 5HT1A and CB2 receptors.26
     
CB2 receptors themselves are able to indirectly stimulate opioid receptors located in primary afferent pathways, and this may be a means by which CBD inhibits pain.27

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