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From the Townsend Letter
July 2018

Insights from the International Center for Cannabis Therapy Part 3:
Reviewing the Many Applications of Cannabinoid-Rich Hemp Oil and the Role of the Gut-Brain Axis
by Chris D. Meletis, ND, and Kimberly Wilkes
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Gut-Brain Axis and Endocannabinoids
The gut-brain axis refers to the bidirectional interplay between the gut microbiota and the nervous system whereby the gut microbiota can impact behavior and cognition and the central nervous system can influence enteric microbiota composition. The gut-brain axis is thought to explain the association between chronic inflammatory bowel disease and depression.33
Accumulating evidence points to the endocannabinoid system's important role in both normal gastrointestinal function and gastrointestinal pathology.34 The endocannabinoid system is involved in the regulation of motility, gut-brain-mediated fat intake and hunger signaling, and inflammation and gut permeability.34 The endocannabinoid system also works together with the gut microbiota to maintain gut health.34 Additionally, cannabinoids help recruit immune cells to the site of intestinal inflammation.35 In models of colitis, cannabidiol also has been shown to suppress the synthesis of pro-inflammatory cytokines, such as TNF-α and IFN-γ.35-38 This anti-inflammatory role in gut health was also reflected in a study where intestinal tissues of individuals with ulcerative colitis had concentrations of the endocannabinoid PEA that were 1.8 fold higher compared with healthy patients, likely in an attempt to help heal the inflammation.39 The anti-inflammatory effect of cannabinoids in the gastrointestinal system may be mediated by the gut microbiota. In mice, dysbiosis of the microbiota caused by antibiotics resulted in a general inflammatory state and altered endocannabinoids in the gut.33 (The concept of an endocannabinoidome will be addressed in much further detail in the ICCT certification program). Mitochondrial transport in enteric nerves may also be controlled by CB1 receptors, further lending support to the role of cannabinoids in gut health.40
The interplay between the gut, the brain, and the endocannabinoid system is involved in the development and progression of inflammatory bowel disease and irritable bowel syndrome. CB1 receptors in sensory ganglia modulate visceral sensation. During ongoing psychological stress, epigenetic pathways change the transcription of CB1 receptors, a mechanism which may explain the link between stress and abdominal pain.41 Furthermore, in rodent models, the endocannabinoid system is altered by early-life stress, leading to the development of irritable bowel syndrome (IBS).42,43
In tissue from humans with inflammatory bowel disease, there is elevated epithelial CB2-receptor expression.44 This indicates that CB2 receptors modulate immunity in this disorder.45 The CB2 receptors impact mucosal immunity and act together with CB1 receptors in the colonic epithelium to encourage epithelial wound healing.44
Research suggests that type 1 vanilloid receptors (TRPV1) may regulate some cannabinoid effects. One study observed a 3.5-fold increase in TRPV1-immunoreactive nerve fibers in biopsies from IBS sufferers compared with controls.45 This elevation may promote visceral hypersensitivity and pain in IBS.45 One scientist concluded, "Thus, a rationale exists for therapeutic interventions that would boost AEA levels or desensitize TRPV1, such as cannabidiol (CBD), to treat the condition [IBS]."25

Conference on Chronic PathologiesCannabinoids, Autoimmunity, Strokes, Epilepsy, and Other Disorders
Cannabidiol may have a role to play in autoimmune health. Animal models indicate it exerts beneficial actions in a number of autoimmune disorders including multiple sclerosis (MS), type 1 diabetes, and autoimmune myocarditis.46,47 Autoimmune disease develops due to transformed subsets of T cells into autoreactive memory T cells. These cells are falsely directed to target the body's own cells resulting in tissue degeneration and autoimmune disease development such as type 1 diabetes, rheumatoid arthritis, and MS.46 CBD is able to modulate autoreactive T cell function.46 In one study it weakened the function of encephalitogenic Th17 cells.46 CBD also increased anti-inflammatory actions in activated memory T cells including enhanced synthesis of the anti-inflammatory IL-10 cytokine.48 Furthermore, CBD produced anti-inflammatory effects in animal models of T cell-mediated collagen-induced arthritis,49 autoimmune diabetes,50 and autoimmune hepatitis.51 It also has reversed the development of type 1 diabetes mellitus in mice.52 Most of the human studies showing cannabinoids are beneficial in multiple sclerosis have used a pharmaceutical combination of THC and CBD.53,54
Cannabinoids are important to other aspects of immunity. Specifically, they possess strong antibacterial activity. All five major cannabinoids (cannabidiol, cannabichromene, cannabigerol, Delta (9)-tetrahydrocannabinol, and cannabinol) significantly inhibited a number of methicillin-resistant Staphylococcus aureus (MRSA) strains.55 THC use by itself, however, was associated with increased susceptibility of mice to infection with the pathogen Legionella pneumophila.56
Another application of CBD may include protection against stroke.57 In vivo and in vitro stroke models indicate cannabidiol reduces infarct size.57 A study of human brain microvascular endothelial cells and human astrocyte co-cultures suggests that CBD can prevent permeability changes in the blood brain barrier.57
Another promising role for cannabidiol is in the improvement of schizophrenia. Modulating the endocannabinoid system using THC, the main psychoactive component in cannabis, can cause acute psychotic effects and cognitive impairment in schizophrenia patients.58 Conversely, CBD may possess antipsychotic actions and may have a role to play in supporting schizophrenia patients. Evidence to this effect is emerging thanks to small-scale clinical studies with CBD for the treatment of patients with psychotic symptoms.59 The results demonstrated that CBD is effective, safe, and well-tolerated in patients with schizophrenia, although large randomized clinical trials are needed.59
Cannabidiol has also been used successfully in clinical practice and in human studies in patients with epilepsy. It has been found to improve brain tumor-related seizures.60 Additionally, patients with Sturge-Weber syndrome, a disorder characterized by medically refractory epilepsy, stroke, and cognitive impairments, experienced up to a 50% reduction in seizures after supplementation with cannabidiol.61 It's important to note that CBD supplementation can alter the serum levels of certain anti-epilepsy medications. This is not always a bad thing as CBD may reduce the side effects of some epilepsy medications by lowering their dosage.62 However, the blood levels of these pharmaceuticals should be monitored when taking CBD.
Dr. Meletis will discuss these and other clinical applications of CBD in the ICCT medical certification course and will also talk about the proper dosing to ensure that doctors who suggest CBD aren't doing more harm than good. This is especially important in regard to seizures as too much CBD may actually cause seizures.

Dosing, Side Effects, and Drug Interactions
Cannabidiol is a safe substance, with a half-life of 18-32 hours,63 but it can have minor adverse effects in some people. Potential side effects are dry mouth, low blood pressure, light-headedness, drowsiness, tiredness, diarrhea, and changes of appetite or weight.62,64 There is also cross-reactivity between medical marijuana and certain foods as well as molds, dust mites, plants, and cat dander.65 It's unclear whether these same reactions occur with cannabidiol. In fact, one mouse study indicated CBD in a dose-dependent manner markedly reduced inflammatory reactions associated with delayed-type hypersensitivity reactions.66 These are allergic reactions that develop days after exposure to the offending substance.
It is also important to keep in mind that cannabidiol can affect levels of medications. This is indicated by the fact it is an inhibitor of multiple cytochrome P450 enzymes, which are involved in the metabolism of drugs.67
The issues of potential side effects, proper dosing, and how to balance the endocannabinoid system without overwhelming its receptors are complex topics that Dr. Meletis and other scientists and doctors at the ICCT discuss in the certification program.

This three-part series began with an article discussing the ICCT's certification for cannabinoid-rich hemp oil manufacturing facilities and products and how American Nutritional Products was the first company in the US to become ICCT-certified. It also discussed a new medical certification program for healthcare practitioners. This certification program is essential for any doctor recommending cannabinoid-rich hemp oil who wants to be aware of the legal ramifications and develop a greater level of trust among patients. The second part of the series discussed the endocannabinoid system's interaction with the adrenals, sex hormones, and gut with an emphasis on the management of pain and inflammation. Finally, we wrapped up our discussion in this article with many of the clinical applications for cannabidiol.
Cannabinoid-rich hemp oil is being used successfully for a number of conditions. But we want to leave you with the caution that, as noted in the first part of this series, many manufacturers are producing inferior-quality products contaminated with pesticides. Healthcare practitioners who enroll in the certification program at will know how to differentiate between these poor quality products and ones that are more likely to benefit patients in a safe and effective manner.

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Part 1 is also online
Part 2 is also online

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Dr. Chris D. Meletis is an educator, international author, and lecturer. His personal mission is "Changing America's Health One Person at a Time." He believes that when people become educated about their bodies, that is the moment when true change and wellness begins. Dr. Meletis served as dean of naturopathic medicine and chief medical officer for 7 years at National College of Natural Medicine (NCNM) and was awarded the 2003 Physician of the Year award by the American Association of Naturopathic Physicians.

Kimberly Wilkes is a freelance writer specializing in health, science, nutrition, and complementary medicine. She has written more than 300 articles covering a variety of topics from the dangers of homocysteine to sugar's damaging effects on the heart. She is the editor of ProThera ® Inc.'s practitioner newsletter and enjoys scouring the medical literature to find the latest health-related science.

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