The Microbiota and Mitochondria: How They Work Together To Protect or Damage Your Health

The human body is interconnected in many ways. Conventional medicine often works in a fragmented manner, where doctors specialize in different parts of the body. Integrative and functional medicine doctors, on the other hand, take a more global view where they look at how a dysfunction in one part of your body may affect another. It’s this broader approach to treating disease that is often the most successful in the long- term. That’s why today I’d like to discuss the interplay between two aspects of health: the microbiome and the mitochondria. Dysfunctions in both the microbiome and mitochondria can make a patient more susceptible to many health concerns such as cancer and autism or worsen the symptoms of a given disease.

Microbial communities reside in many places within your body. This population of microbial communities is known as the microbiota or microbiome. In fact, there are an estimated 100 trillion of these microbes—10 times more than there are cells in the human body. The microbiome also is estimated to include at least 100-fold more genes than the human genome. Among many other benefits, supplementing the microbiota in your body by taking various forms of probiotics may decrease total and low-density lipoprotein (LDL) cholesterol levels,1 reduce the amount of time that flu symptoms last,2 reduce eczema symptoms,3 and maintain the body’s ability to use insulin effectively even after overeating a high-fat meal.4

The gut microbiome is highly enriched for genes that play an important role in energy production and metabolism. Mitochondria are involved in cellular function and metabolism by producing ATP, the energy molecule that serves as fuel to your body.

cell phone with low battery warningI like to compare the mitochondria to batteries in a flashlight or cell phone. If those batteries are underpowered, the device won’t work properly. It’s the same with the cells in the human body. They need energy to function and ATP provides that energy.

Mitochondrial dysfunction—when the mitochondria aren’t producing enough ATP to properly fuel cells—is associated with many diseases including chronic fatigue syndrome,5 diabetes,6,7 Alzheimer’s5 and Parkinson’s disease,8 cancer,5 heart disease,9 fibromyalgia,10 and autoimmune disorders.5

When the mitochondria produce too many reactive oxygen species—otherwise known as free radicals—this affects the microbiota’s ability to regulate the gut epithelial barrier.11 The gut epithelial barrier is the lining of the intestinal wall that prevents undigested food particles, toxins, and other substances from entering into the systemic circulation and causing allergies and disease. Researchers also have found that microbiota release metabolites that can directly interfere with ATP production in the mitochondria.11

Microbiota can influence the activity of mitochondria by regulating the production of free radicals through interactions with toxins, proteins, or other metabolites released by gut microbiota.12 This interaction can be harmful or beneficial, depending on the microbiota strain quality and diversity. Researchers now believe that the microbiota by way of their ability to regulate the mitochondria can influence the health of cells.12

According to one group of scientists, “All these data suggest that microbiota target mitochondria to regulate its interaction with the host. Imbalance of this targeting may result in pathogenic state as observed in numerous studies.”11

There’s more evidence that the mitochondria and microbiota work together.  Short-chain fatty acids are produced by the microbiota during fermentation of dietary carbohydrates and some proteins and present to some extent in the diet.  These short-chain fatty acids may have both beneficial and harmful effects on mitochondrial activity.13

If the interplay between the microbiome and the mitochondria isn’t working properly it can also lead to the development of cancer and other signs of cellular dysfunction. When an individual consumes a poor diet filled with excess sugar and refined carbohydrates and fruits and vegetables covered in pesticides it can change the gut microbiome, which in turn changes cellular metabolism and affects the mitochondria in such a way as to increase susceptibility of cells to becoming susceptible to a diseased state.14

The Autism Connection

More evidence linking the mitochondria and the gut microbiota comes from studies on autism. A large number of people who have autism spectrum disorder (ASD)

have both mitochondrial dysfunction and gastrointestinal (GI) problems.15 It’s estimated that the prevalence of mitochondrial dysfunction in people who have ASD is 5%, much higher than in people who don’t have ASD.16 In addition, one study found that 80% of children with ASD demonstrated below normal function of the electron transport chain in blood cells known as lymphocytes.17 The electron transport chain is an important part of the mitochondrial process that generates ATP.

Gastrointestinal problems are common in people who have mitochondrial disorders and are also common in people who have mitochondrial disorders coinciding with autism, which offers further support that the gut microbiota may undergo changes in mitochondrial disorders.15

Because mitochondria are known for their role in producing cellular energy, the most affected body organs and systems in people who have mitochondrial dysfunction are those that have the highest energy demand, including the GI tract and the microbiota that reside there. These are some of the same organs and systems commonly affected in children with ASD.15

Additionally, rodents given high intravenous doses of propionic acid, a short-chain fatty acid produced by the gut microbiota Clostridia, Bacteriodetes, and Desulfovibrio, develop symptoms similar to ASD.18 The brain tissue of rats treated intravenously with propionic acid exhibits many neurochemical changes similar to those seen in ASD, including neuroinflammation, increased oxidative stress (free radical damage), and depletion of the antioxidant glutathione.18 These changes directly or indirectly are involved in mitochondrial dysfunction by way of interfering with processes that are dependent on the amino acid carnitine- dependent pathways. Antibiotics also are known to damage these carnitine-dependent pathways in part by changing the gut flora so that it favors bacteria that produce propionic acid.18

The fact that these excessive levels of propionic acid are associated with mitochondrial dysfunction, lends further support to the idea that the microbiota works together with the mitochondria.19

Supporting Your Microbiota and Mitochondria

Taking a good probiotic is the best way to ensure that your body is populated with enough healthy microbes to counteract the pathogenic varieties. To support the mitochondria, I recommend my patients supplement with a few foundational supplements including coenzyme Q10, creatine monohydrate, and alpha-lipoic acid. Resveratrol can also be added to this regimen. In cells from early-onset Parkinson’s disease, resveratrol enhanced mitochondrial function and ATP production.20 It also halted the development of diabetic cardiomyopathy in diabetic rats, in part by its favorable effects on the mitochondria.20

References:
1. Cho YA, Kim J. Medicine (Baltimore). 2015;94:e1714.
2. Jespersen L, et al. Am J Clin Nutr. 2015;101:1188-96.
3. Inoue Y, et al. Int Arch Allergy Immunol. 2014;165:247-54.
4. Hulston CJ, et al. Br J Nutr. 2015;113:596-602.
5. Pagano G, et al. Oxid Med Cell Longev. May 4, 2014;2014:541230.
6. Amer MA, et al. 2011;10:3722-30.
7. Khan S, et al. Translational Research. 2011;158:344-59.
8. Di Monte DA, et al. Ann Neurol. 1992;32 Suppl:S111-5. 9. Yu E. Heart. 2014;100 Suppl 3:A128-9.
10. Cordero MD, et al. Arthritis Res Ther. January 28, 2010;12:R17.
11. Saint Georges Chaumet Y, Edeas M. Pathog Dis. 2015 Oct 23. pii: ftv096. [Epub ahead of print.]
12. Saint Georges Chaumet Y, et al. Cell Mol Biol (Noisy le grand). 2015;61:121-4.
13. MacFabe DF. Microb Ecol Health Dis. 2015;26:28177.
14. Hagland HR, Søreide K. Cancer Lett. 2015;356:273-80.
15. Frye RE, et al. Microb Ecol Health Dis. 2015;26:27458.
16. Rossignol DA, Frye RE. Mol Psychiatry. 2012;17:290-314. 17. Giulivi C, et al. JAMA. 2010;304:2389-96.
18. MacFabe DF. Microb Ecol Health Dis. 2012;23:10.3402/ mehd.v23i0.19260.
19. Frye RE, et al. Microb Ecol Health Dis. 2015;26:26878.
20. Ferretta A, et al. Biochim Biophys Acta. 2014;1842:902-15.

This newsletter contains the opinions and ideas of the author. It is intended to provide helpful and informative material on the subjects addressed in the publication.
The content is shared with the understanding that the author and publisher are not engaged in rendering medical, health, psychological, or any other kind of personal professional services. If the reader requires personal medical, health, or other assistance or advice, a competent professional should be consulted.
The author and publisher specifically disclaim all responsibility for any liability, loss, or risk, personal or otherwise, that is incurred as a consequence, directly, or indirectly, of the use and application of any of the contents of this newsletter.

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The Endocannabinoid System’s Intriguing Role in Gut Health

The Endocannabinoid System’s Intriguing Role in Gut Health

by Chris D. Meletis, ND, and Kimberly Wilkes

Cannabis has been used medicinally for centuries in people suffering from disorders associated with the gastrointestinal tract (GI), including abdominal pain, cramps, diarrhea, nausea, and vomiting.1,2 An extensive amount of recent research offers justification for the traditional use of not only cannabis but also other phytocannabinoids such as cannabidiol (CBD) for GI health. This research points to a strong connection between the endocannabinoid system and various aspects of gut health. The gut-brain axis, which refers to the ability of intestinal function to alter various aspects of mental and cognitive health, has drawn considerable attention in the medical literature. New research indicates that actions of the gut-brain axis may be in part mediated by the endocannabinoid system.3

The endocannabinoid system refers to cannabinoids produced within the body (endocannabinoids), neurotransmitters that bind to cannabinoid receptors 1 and 2 (CB1 and CB2), thus regulating many aspects of health. Enzymes that play an important role in the synthesis and breakdown of endocannabinoids and molecules required for endocannabinoid uptake and transport are also involved in the endocannabinoid system. Phytocannabinoids like CBD may exert their health benefits in part through their actions on this system. It has long been known that the endocannabinoid system regulates many functions in the body including mental health and pain control. Its role in other areas of health has only recently begun to be appreciated. One of those areas is the role it plays in the intestines.

The Endocannabinoid System’s Role in Gut Health

An extensive amount of evidence indicates the endocannabinoid system plays a significant role in intestinal health. High concentrations of the endocannabinoids 2-arachidonoyl-glycerol (2-AG) and anandamide are observed in the colon along with significant fatty acid amide hydrolase (FAAH) activity,4 which is involved in the breakdown of anandamide.

The enteric nervous system (ENS) of the GI tract contains approximately 500 million nerve endings.5 The highest levels of immune cells in the body are also found in the gastrointestinal tract.5 Roughly 20% of the nerves in the GI tract are intrinsic primary afferent neurons, which alert the brain when subtle changes within the GI tract occur.5 This communication occurs through the vagus nerve. Endocannabinoids may regulate neurotransmission in the gut, as indicated by the presence of the CB2 receptor on enteric neurons and its expression by immune and epithelial cells in the GI tract.6,7 Furthermore, altering the activity of CB1 receptors can regulate sensory processing from the gut, brain integration of the brain-gut axis, extrinsic control of the gut, and intrinsic control by the enteric nervous system.4

The effect of both endocannabinoids and phytocannabinoids on colon carcinogenesis in rodents further supports the role of the endocannabinoid system in gut health. Studies using CBD or a Cannabis sativa extract with high cannabidiol content inhibited the initiation of aberrant crypt foci, polyps, and tumors in the colon of mice.8,9 Cannabidiol also suppressed cell proliferation in colorectal carcinoma cell lines.8

The Endocannabinoid System and Gut Motility

Endocannabinoids are known to regulate gut motility, the time it takes for food to move through the intestines. Slow gut motility is more commonly called constipation and fast gut motility is known as diarrhea. Evidence indicates that the endocannabinoid system plays an important role in gut motility. In obese mice fed high-fat diets, the endocannabinoid system in the gut underwent alterations, leading to an increase in gut motility.10 Many studies also indicate that CB1 receptor activation suppresses peristalsis and gastrointestinal contraction. The CB1 receptor is activated by THC, the psychoactive component in marijuana.11,12 Because CBD does not directly affect the CB1 receptor, it may be less likely to produce constipation. This was indicated in a mouse model of sepsis, which demonstrated that CBD slowed gastrointestinal motility in the animals with sepsis but did not affect motility in normal mice.13 Furthermore, CBD regulates the activity of FAAH, an enzyme involved in gastrointestinal motility through its actions on anandamide.13 Additional evidence that the endocannabinoid system is involved in gut motility was provided by a mouse model of constipation in which inhibiting diacylglycerol lipase (DGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, improves gut motility.14

Endocannabinoids, the Gut, and Obesity

Through pathways associated with the gut-brain axis, alterations in the endocannabinoid system can result in obesity and accompanying inflammation.15 Endocannabinoid signaling in the gut may modulate food intake and energy balance by indirectly interacting with the vagus nerve,16 which permits neurotransmission between the gut and brain.17

A rodent model found fasting leads to the synthesis of 2-AG and activates the CB1 receptor through efferent vagal activation of receptors in the small intestine, which may signal hunger.18

The endocannabinoid system’s role in food intake was shown in a study demonstrating increased endocannabinoid signaling occurs after hedonic eating (consuming food for pleasure).18 In both normal-weight and obese humans, thinking about eating or eating a highly palatable food such as chocolate or pudding, leads to circulating levels of endocannabinoids that are higher compared with a nonpalatable control diet.19-21

The Endocannabinoid System and Inflammatory Bowel Disease

Endocannabinoids and phyto¬cannabinoids are involved in inflammatory regulation in the gut. Endocannabinoids help signal immune cell movement to intestinal inflammation sites.22,23 Cannabidiol has been shown to suppress the synthesis of proinflammatory cytokines, such as TNF-α and IFN-γ, and reduce intestinal inflammation.24,25 Due to its role in regulating gut inflammation, it’s not surprising that the endocannabinoid system has also been shown to modulate inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Tissue from humans with IBD is characterized by increased epithelial CB2-receptor expression, suggesting CB2 receptors act in an immunomodulatory capacity in this disorder.26 This in turn affects mucosal immunity in the inflamed colon and interacts with the actions of CB1 receptors in the colonic lining to promote wound healing.26 In fact, CB1 receptors play an important role in gut health as evidenced by the increased incidence of diarrhea in people administered CB1 receptor antagonists.27

Other evidence supporting the endocannabinoid system’s role in modulating colonic inflammation was provided by rodent models showing that suppressing FAAH, leading to a rise in anandamide levels, stops the development of colitis.28,29 Likewise, inhibiting FAAH and the inflammatory enzyme cyclooxygenase (COX) in mice with colitis reduces the severity of the disease by elevating anandamide levels and acting on the CB1 receptor.30 Blocking FAAH and COX correlated with higher concentrations of the endocannabinoids palmitoylethanolamide (PEA) and oleoylethanolamide. In intestinal tissue from ulcerative colitis patients, PEA levels are 1.8-fold higher compared with healthy patients, likely a result of the PEA attempting to help heal the inflammation.31 PEA has pronounced anti-inflammatory properties that inhibit features of colitis in mice as well as the synthesis of inflammatory cytokines.32

The phytocannabinoids CBD, THC, and cannabigerol have significantly reduced intestinal inflammation in animal models. In one of those models, both CBD and THC proved beneficial.33 However, THC was the most effective in rats with experimental colitis, although CBD enhanced the effects of an ineffective THC dose to the point where the combination of CBD and lower-dose THC was the equivalent of a higher THC-only dose.33 The phytocannabinoid cannabigerol (CBG) has also proved beneficial in rodent models of colitis. In one study, CBG inhibited colitis in mice and lowered the synthesis of reactive oxygen species in intestinal epithelial cells.34

Polymorphisms in the gene encoding CB1 receptors are associated with irritable bowel syndrome, further establishing the link between the endocannabinoid system and this disease.35 Variants of the CB1 receptor gene (CNR1) and FAAH genes have been noted in individuals with diarrhea-predominant and alternating forms of IBS.36,37 In intestinal tissues of patients with constipation-predominant IBS, lower levels of FAAH mRNA were observed.38 In a study of patients with constipation predominant IBS (C-IBS), diarrhea-predominant IBS (D-IBS), and mixed IBS (M-IBS) who suffered from chronic abdominal pain and functional dyspepsia, there was a relationship between the non-wild type FAAH genotype and functional bowel disease phenotypes and with increased colonic transit in IBS-D patients.39 Likewise, in another study, there was a pronounced association between a polymorphism in the cannabinoid receptor 1 (CNR1) gene and IBS symptoms, colonic transit in IBS-D, and intestinal gas.40 However, pain was not associated with this polymorphism. Furthermore, researchers found that the CNR1 mutations correlated with the emergence of IBS symptoms, as observed in two studies of a Korean and Chinese population with IBS.41,37

Human research using a CBD supplement further corroborates the potential benefits of modulating the endocannabinoid system in IBD/IBS. In a 10-week study of patients with ulcerative colitis given a CBD-rich botanical extract, the primary endpoint of percentage of patients in remission after treatment was similar between the placebo and CBD group.42 However, subjective physician’s global assessment of illness severity, subject global impression of change, and patient-reported quality-of-life outcomes were improved in the CBD group. Additionally, the placebo group experienced more gastrointestinal-associated adverse effects. Furthermore, in human colonic cultures derived from ulcerative colitis patients, CBD suppressed enteric reactive gliosis and reduced inflammation, thus inhibiting intestinal damage.25 The researchers concluded, “Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.” Clearly, as another group of researchers stated, the endocannabinoid system “in the gut is a potential therapeutic target for IBS and other functional bowel disorders.”

Psychological Stress and the Endocannabinoid System

The endocannabinoid system regulates abdominal pain (visceral hyperalgesia) caused by chronic stress and may explain, at least in part, the relationship between chronic stress and IBD/IBS.27,43 Rodent models indicate that early-life stress alters the endocannabinoid system, which increases the susceptibility to IBS.44 The endocannabinoid system is a key player in the regulation of visceral pain and the means by which psychological stress impairs GI function may involve this system.44 Chronic stress reduces levels of the endocannabinoid anandamide while elevating 2-AG in the brain and downregulating CB1 receptors in sensory ganglia, which regulate visceral pain.45 During chronic psychological stress, CB1 receptor activity is altered through epigenetic pathways, which may explain the association between stress and abdominal pain.46 Epigenetics refers to the alteration of gene expression through pathways other than the genetic code. It refers to the changes that occur in our genes due to lifestyle or environmental factors. Through these epigenetic actions, chronic stress affects the CB1 gene promoter, leading to lower levels of CB1 in sensory neurons that innervate the colon and other pelvic organs.47

The Microbiota and the Endocannabinoid System

Perhaps one of the most interesting aspects of the endocannabinoid system’s role in gut health is its interaction with the gut microbiota. The gut microbiota can modulate intestinal endocannabinoid tone.48 A microbiota profile associated with obesity also correlates with an increased intestinal concentration of anandamide, which leads to increased gut permeability (leaky gut).48 In fact, the link between the gut microbiota and obesity may be mediated by the endocannabinoid system.48 The results of a study where the bacterium, Akkermansia muciniphila, was administered to obese and type 2 diabetic mice daily support this concept.49 In that study, the bacterium reversed diet‐caused obesity. It accomplished this by increasing intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion.
On the other end of the spectrum, endocannabinoids from adipose tissue can also modulate the composition of the gut microbiota.35 This indicates there is bidirectional communication between the microbiota and the endocannabinoid system.35 Evidence of this cross-talk between the endocannabinoid system and the microbiota is reinforced by studies showing that the beneficial effects of probiotic supplementation on gut health may in part involve this system. The probiotic Lactobacillus given orally to rodents reduced visceral pain while simultaneously upregulating CB2 receptors in the intestinal epithelium.50 Inhibiting CB2 eliminated the beneficial effects of the probiotic. In a model of chronic colonic hypersensitivity, Lactobacillus acidophilus NCFM resulted in analgesia.50 This study also indicated that CB2 receptors may be involved in the association between gut microbiota and visceral hypersensitivity. Furthermore, dysbiosis of the gut microbiota caused by antibiotics correlates with a general inflammatory state and alteration of certain endocannabinoids in the gut of mice as well as accompanying depression.51 However, in a human study of individuals consuming Lactobacillus acidophilus NCFM over a period of 21 days, CB2 receptors were not upregulated in colonic mucosal biopsies.52

Conclusion

An abundance of evidence is pointing to the conclusion that the endocannabinoid system is involved in gut health and that it may even be an important mediator of the actions of the gut-brain axis. The damaging effects of chronic psychological stress on the intestinal tract may also be driven by the endocannabinoid system. Targeting this system by the use of CBD oil or other phytocannabinoids may be one way to reduce colonic inflammation and reduce the effects of stress on the gut. In my clinical practice I also use a specific high potency PEA that has helped many patients.

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47. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010 Jul;6:392.
48. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 28;110(22):9066-71.
49. Rastelli M, Knauf C, Cani PD. Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders. Obesity (Silver Spring). 2018 May;26(5):792-800.
50. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007 Jan;13(1):35-7.
51. Guida F, Turco F, Iannotta M, et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav Immun. 2017 Sep 7. [Epub ahead of print.]
52. Ringel-Kulka T, Goldsmith JR, Carroll IM, et al. Lactobacillus acidophilus NCFM affects colonic mucosal opioid receptor expression in patients with functional abdominal pain – a randomised clinical study. Aliment Pharmacol Ther. 2014 Jul;40(2):200-7.

Posted by DrMeletis in Hemp and Endocannabinoid, Townsend

Overfed and Undernourished

Do You Need a Multivitamin? Read This and Find Out.

I often get asked the question of whether a multivitamin is necessary and, if so, what is the best type of multivitamin to take. This is a particularly important question because as a Westernized nation, we're overfed and undernourished. We're eating heavily processed foods that have been put into "suspended animation," and are consequently devoid of enzymes, making them harder to digest. These foods are often enriched to "try to make up" for the travesty of destroying our foods for longer shelf life and convenience. There's a saying I routinely use with my patients: "Dead food for dying people, live food for living people."

According to a 2009 report by the Centers for Disease Control and Prevention, only 33% of adults are eating the recommended two or more servings of fruit per day and 27 percent eat the recommended three or more servings of vegetables per day.1 That means 73% are falling short of eating enough vegetables and 67% are falling short of eating enough fruit per day.

And if Americans weren't meeting the old five-a-day guidelines, they're certainly not meeting the latest dietary guidelines that recommend five to thirteen servings of fruits and vegetables per day based upon how many calories a person eats.2 For example, someone who needs 2,000 calories per day for a healthy weight would need to eat nine servings of fruits and vegetables per day. That's a lot of fruits and vegetables to eat in three meals a day. Even if you eat a healthy snack, getting in nine servings would be a challenge. These statistics make it clear that we're not getting enough nutrients from our diet. And we're paying the price. One study in England published in 2014 found that eating seven or more servings of fruit and vegetables per day lowered the risk of death from all causes by 42%.3 Fruit and vegetable consumption also was linked to reduced death from cancer and cardiovascular causes.3 Vegetables were more protective than fruit. Conversely, eating frozen or canned fruit was linked to increased mortality.3

table of nutrient deficiencies due to low stomach acid

Not only are we starving ourselves of nutrients due to the overly processed food we often consume and the low level of fruit and vegetable consumption—the nutrients we are consuming are often depleted by medications or other factors. One of the biggest offenders in this area is the stomach acid-blocking medications known as proton pump inhibitors. By lowering stomach acid, proton pump inhibitors have been reported to causes deficiencies in vitamin B12 and some researchers have expressed concern that these drugs may lower iron, calcium, and magnesium as well.4

Stomach acid levels also decline at a greater rate as we get older, with as many as 30% of all elderly people suffering from atrophic gastritis, which is characterized by low stomach acid.5 Studies in Japan have shown that more than 60% of 50 year olds have low stomach acid.6 In North America, a small study of 79 healthy, elderly men and women indicated the prevalence of low stomach acid in the elderly is 11%.7

graphic showing symptoms of helicobacter pylori

An infection with Helicobacter pylori, a common bacterium linked to stomach cancer, is another factor that's known to lower stomach acid. H. pylori infections are quite common, due to its presence in many grocery store foods and the fact it's transmitted among people. One study of 1,200 U.S. veterans found that 28.9% of the subjects were infected with H. pylori.8  Globally, half of the world's population is thought to be infected with H. pylori.9 Oral contraceptives are also guilty of lowering certain nutrients. Studies show that oral contraceptives cause deficiencies in folic acid, vitamins B2, B6, and B12, vitamins C and E, and magnesium, selenium, and zinc.10

Multivitamins: The Grout Between the Tiles

image of fruit and veggies with capsules spilling out of bottle in foregroundYou can think of a good multivitamin as the "grout between kitchen tiles." In other words, a good multi fills in the gaps, yet is NOT a substitute. It is a SUPPLEMENT to a good diet filled with live, non-processed foods.

What makes a good multivitamin? The answer to that question is a multivitamin that contains the forms of vitamins and minerals that your body can use most effectively. A good multivitamin should use the 5-MTHF form of folate rather than folic acid. The reason why 5-MTHF is superior to folic acid is because some people have a genetic defect in the MTHFR gene that prevents them from transforming folic acid into the biologically active form of folate.11 Unmetabolized folic acid is then released into the bloodstream. In adults, this release of unmetabolized folic acid can occur with amounts as low as 200 mcg per day of folic acid.12

Why is unmetabolized folic acid bad? The concern is that it may explain why in some studies, folic acid supplementation and food fortified with folic acid has been linked to the development of some forms of cancer, including colon cancer.13,14 This folic acid-cancer link has not been found in other studies,15,16 however, so researchers need to conduct more research in this area.

Supplementing with 5-MTHF eliminates some of the other disadvantages of folic acid supplementation. 5-MTHF can skip the step that converts folic acid to 5-MTHF, making it more desirable for people who have a MTHFR gene defect.17  Folic acid also can make it difficult to diagnose megaloblastic anemia because it obscures the symptoms of this condition whereas 5-MTHF does not have this same effect.18 Another advantage: 5-MTHF is less likely to reduce the effect of antifolate drugs, a problem that also occurs with folic acid.18 

Before your body can use vitamins, they must be converted into the active, coenzyme forms. That's why I also recommend that my patients use multivitamins that contain either the methylcobalamin or adensylcobalamin form of vitamin B12. These are the coenzymated, activated forms of vitamin B12. Other forms of vitamin B12 are inactive and therefore can't be used by the body as effectively.

It's thought that methylcobalamin is used more effectively by subcellular organelles of neurons. Consequently, this form of vitamin B12 may be more likely to nourish the nervous system by way of enhanced systemic or local delivery.19 Studies have shown that methylcobalamin can enhance nerve conduction in patients with diabetic neuropathy and has also been beneficial in rheumatoid arthritis, Bell's palsy, and sleep-wake rhythm disorder.19 It also has pain-relieving effects.19

When looking at the type of vitamin E in multivitamins, I always warn patients to avoid the synthetic version of vitamin E which appears on the label as d,l alpha-tocopherol. Instead, I recommend they look for multivitamins that contain the natural form of vitamin E, which is labeled as d-alpha tocopherol, d-alpha tocopheryl acetate, or d-alpha tocopheryl succinate, along with mixed tocopherols.

Natural vitamin E is better absorbed compared with synthetic vitamin E. In one study in Japan, scientists alternated between giving natural and synthetic vitamin E to seven healthy female subjects. The subjects had to take 300 mg synthetic vitamin E to achieve the blood levels attained with a 100-mg dose of natural vitamin E.20 What's more, synthetic vitamin E is removed from the body three times faster than natural vitamin E.21

Vitamin E is actually composed of a family of eight isomers: four tocopherols (alpha, beta, delta and gamma) and four tocotrienols (alpha, beta, delta and gamma). The gamma-tocopherol form of vitamin E is more effective than alpha-tocopherol in suppressing cancer, including colon and prostate cancer.22  

In addition, gamma-tocopherol is more effective than alpha-tocopherol in increasing the expression of PPAR-gamma, which is involved in not only colon cancer prevention,23 but also prevention of diabetes, inflammation, and cardiovascular disease.23  In addition, in one study, gamma-tocopherol was more effective than alpha-tocopherol in lowering oxidative stress in the brain.24 When you take supplements that contain only alpha-tocopherol without also taking other forms of vitamin E, it can block your body's ability to use gamma-tocopherol. This means alpha-tocopherol may increase the risk of cancer. That's why you want to look for a multivitamin that contains ideally all eight forms of vitamin E.

One Other Critical Addition to Your Supplement Regimen 

In addition to taking a multivitamin with the most biologically available nutrients, supplementing with pyridoxal-5-phosphate (P5P) is a beneficial addition to your supplement regimen. P5P, the biologically active form of vitamin B6, is a cofactor in more than 160 enzyme activities that play an important role in many metabolic pathways, including the production of neurotransmitters and their degradation.

For vitamin B6 to work effectively, the liver must convert it into pyridoxal 5-phosphate. However, some people are not able to convert vitamin B6 to P5P.25 In these people, supplementing with P5P ensures that they are able to use of the active form of vitamin B6 without having to undergo the conversion.

Dietary Supplements Fill in the Nutritional Gaps

The modern, Westernized diet is severely lacking in nutrients. In addition, many people are taking drugs that interfere with the absorption of critical nutrients. Other people have low stomach acid, which prevents the absorption of many vitamins and minerals. The only way to fill in the gaps and prevent nutritional deficiencies is to take a multivitamin containing active coenzyme forms of key nutrients and to consume other dietary supplements such as pyridoxal 5-phosphate.

References:

  1. Centers for Disease Control and Prevention. http://www.cdc.gov/media/pressrel/2009/r090929.htm
  2. Dietary Guidelines for Americans, 2005. http://www.health.gov/DietaryGuidelines/dga2005/document/default.htm
  3. Oyebode O, et al. J Epidemiol Community Health. March 31, 2014;1-7. doi:10.1136/jech-2013-203500
  4. Fashner J, Gitu AC. FP Essent. 2013 Oct;413:29-39.
  5. Russell RM. JAMA. 1997;278(20):1659.
  6. Morihara M, et al. Biological and Pharmaceutical Bulletin. 2001;24(3):313-15.
  7. Russell TL, et al. Pharm Res. 1993 Feb;10(2):187-96.
  8. Nguyen T, et al. Helicobacter. 2015 Feb 17. [Epub ahead of print.]
  9. http://emedicine.medscape.com/article/176938-overview
  10. Palmery M, et al. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1804-13.
  11. Czeizel AE, et al. Ann Nutr Metab. 2011;58:263-71.
  12. Sweeney MR, et al. Br J Nutr. 2006;95:145-51.
  13. Hirsch S, et al. Eur J Gastroenterol Hepatol. 2009;21:436-9.
  14. Mason JB, et al. Cancer Epidemiol Biomarkers Prev. 2007;16:1325-9.
  15. Vollset SE, et al. Lancet. 2013;381:1029-36.
  16. Qin X, et al. Int J Cancer. 2013;133:1033-41.
  17. Czeizel AE, et al. Ann Nutr Metab. 2011;58:263-71.
  18. Pietrzik K, et al. Clin Pharmacokinet. 2010 Aug;49:535-48.
  19. Ming Zhang, et al. Neural Plast. 2013; 2013: 424651.
  20. Kiyose C, et al. Am J Clin Nutr. 1997 Mar;65(3):785-9.
  21. Traber MG, et al. FEBS Lett. 1998 Oct 16;437(1-2):145-8.
  22. Campbell S, et al. Crit Rev Oncol Hematol. 2003 Sep;47(3):249-59.
  23. Campbell SE, et al. BMC Cancer. 2003 Oct 1;3:25.
  24. Williamson KS, et al. Nitric Oxide. 2002 Mar;6(2):221-7.
  25. Carter TC, et al. J Nutr. 2015 May 13. [Epub ahead of print.]

This newsletter contains the opinions and ideas of the author. It is intended to provide helpful and informative material on the subjects addressed in the publication.

The content is shared with the understanding that the author and publisher are not engaged in rendering medical, health, psychological, or any other kind of personal professional services. If the reader requires personal medical, health, or other assistance or advice, a competent professional should be consulted.

The author and publisher specifically disclaim all responsibility for any liability, loss, or risk, personal or otherwise, that is incurred as a consequence, directly, or indirectly, of the use and application of any of the contents of this newsletter.

Posted by DrMeletis in Newsletter, 0 comments

Strategies for Finding Peace in Our Stressful Modern World

In this hectic world we live in, it’s impossible to escape chronic stress. Most of us are overcome by the sense that we have too much to do and not enough time to do it, from answering emails, to meeting work deadlines, to helping the kids with homework, to caring for an elderly relative or doing chores around the house. I like to tell my patients that the state of stress is NOT a state of “Ease.” Rather, it is a state of “Dis-EASE” leading to disease!

This disease-causing process starts in childhood. Children who are exposed to stress early in life are less likely to be healthy throughout their lives. Infants who experienced stressful events and had high levels of the stress hormone cortisol suffered more often from 12 of the 14 most common childhood diseases up until age 10 compared to infants with lower cortisol levels.1

Stress in childhood has effects that can last the rest of a child’s life. Stress reduces the length of telomeres, caps on the ends of your chromosomes. Telomeres stop the chromosomal DNA from unraveling and are often compared to the tips on the ends of shoelaces. Each time a cell divides, telomeres become shorter until eventually the cell is no longer able to divide and dies. One study showed that children who had a stressful childhood had significantly shorter telomeres as adults compared to children who had happier childhoods.2

The Price We Pay for Being Stressed Out

When you’re exposed to chronic stress, your adrenal glands pay the price. The adrenal glands are part of a larger system known as the hypothalamic-pituitary-adrenal axis. This system is made up of three endocrine glands—the hypothalamus, the pituitary gland, and the adrenal glands—which interact to influence the way your body reacts to stress. The hypothalamus and pituitary and adrenal glands are often referred to as the hypothalamic-pituitary-adrenal axis—the HPA axis for short. The hypothalamus secretes vasopressin and corticotrophin-releasing hormone (CRH), which in turn triggers the pituitary to produce adrenocorticotropic hormone (ACTH), which then sends a message to the adrenal glands to produce the stress hormone cortisol.

Balanced cortisol levels are healthy. But chronic stress, like the kind we’re constantly exposed to in modern times, disrupts normal cortisol production, so that quite often cortisol levels are too low or too high. At the beginning stages of stress, the adrenal glands tend to produce an excessive amount of cortisol, so that levels often test very high. On the other hand, over time, the adrenals become “burned out” and produce less and less cortisol. Each of these states can contribute to feeling fatigued and can lead to many different diseases.

When the adrenals are overproducing cortisol this can eventually lead to a number of problems such as an increase in “belly fat.” This excess weight leads to more wear and tear and strain on the body, which in turn causes the adrenals to produce more cortisol to cope with the extra stress, which in turn leads to more inflammation, more weight gain, and more excess stress.

The over-activity of the HPA axis that occurs with aging and the increased production of cortisol are linked to many different diseases, including type 2 diabetes, atherosclerosis (hardening of the arteries), hypertension, dementia, and depression.3 In addition, cortisol levels that stay high for a long time can weaken immunity and contribute to gastric ulcers, headaches, and osteoporosis.4

In response to internal and external stress the body attempts to stabilize itself, a process researchers call allostasis. However, the body pays a price for allostasis, because it has no choice but to try to adapt to potentially harmful situations.5 Prolonged allostasis creates a burden on the body known as the allostatic load. This is one of the ways in which stress damages your body.

Buffers Against Stress

Our adrenal glands serve as a buffer against stress. They accomplish this by producing not just cortisol, but other hormones such as pregnenolone and DHEA. Your adrenal glands are also affected by your hormonal health. Cortisol is made from progesterone, another hormone that’s important for helping the body cope with stress. In both men and women, progesterone drops with age. There is also a drain on progesterone when you are under stress, because the more cortisol your body needs to cope with stress, the more progesterone it needs to produce the cortisol. If progesterone levels are low, then your body may be under fueled, not producing the cortisol you need to handle stress.

This is a problem I often see in my female patients. The modern woman is trying to juggle so many items on her to do list that she’s under a great deal of stress. Consequently, producing all the cortisol she needs to handle stress is depleting her progesterone levels. This drop in progesterone can result in blood sugar issues, anxiety, insomnia—even weakened bones.6 As a woman’s progesterone levels are depleted she won’t have the building block needed to make cortisol and will make less and less of it. And she won’t be able to handle stress.

A drop in progesterone due to the need for cortisol and an imbalance between progesterone and estrogen can affect men, too. The weight gain, low libido, and prostate enlargement that can occur in men during aging are partly due to an imbalance in progesterone and estrogen.

The NeSID Theory

I have proposed a theory called the NeSID (Neuroendocrine Stress Induced Dysfunction), which I am going to discuss in an upcoming issue of the Townsend Letter. This theory describes exactly how stress wreaks havoc on your body and the different mechanisms behind which stress can cause disease. Most importantly, it describes how your body tries to prevent an overly high rise in cortisol levels.

For example, stress increases levels of 5-alpha reductase, the enzyme that transforms the male hormone (androgen) testosterone to dihydrotestosterone (DHT). 5-alpha reductase also helps degrade cortisol to its metabolites. Receptors for androgens are more likely to bind with DHT compared with testosterone. In addition, testosterone detaches from the receptors more readily than does DHT. This can be harmful to health because DHT is associated with male pattern baldness, benign prostatic hyperplasia (BPH), and prostate cancer.7

In obese men and women, insulin resistance causes 5-alpha reductase levels to go up. These elevated 5-alpha reductase levels inactivate cortisol levels in the liver. That’s why researchers have proposed that the rise in 5-alpha reductase is the body’s way of trying to protect against excessively high cortisol levels. However, this approach by the body to defend against high cortisol backfires. It leaves the body at the mercy of the DHT produced.7,8

Not everyone reacts to stress in the same way. For some people, a given situation may elicit anxious feelings while for others the situation is “no big deal.” Some people also can cope with stress better than others. My NeSID theory explains why this is so. Having a greater resiliency to stress has to do with the activity of an enzyme called catechol-O-methyltransferase, encoded by the COMT gene. Catechol-O-methyltransferase helps inactivate the brain neurotransmitters dopamine, epinephrine, and norepinephrine. People can have different variations of the COMT gene and the type of variation a person possesses determines how easily they can cope with and recover from stress.9

How To Protect Yourself from Stress

When I talk to my patients about stress, I usually take a dual approach of recommending stress-reduction strategies while at the same time suggesting nutritional supplements that will help them cope better with stress.

On top of the list of stress-reduction strategies is getting enough sleep. When you are well rested you’re better able to handle stressful situations and sleep loss can cause cortisol imbalances.10 If you snore, have high blood pressure and/or heart disease, or wake up a lot in the middle of the night, having your doctor test you for sleep apnea is a good idea. Sleeping in a dark room also is essential. Additionally, I recommend lessening our connectivity to information overload by turning off email, computers, and cell phones at least an hour or two before bedtime.

There’s also some good evidence in the medical literature that mindfulness mediation and mindfulness-based stress reduction can help relieve insomnia.11,12 Mindfulness meditation is a type of meditation where the person focuses on their breathing and notices in an accepting, non-judgmental way when the mind becomes distracted. Mindfulness-based stress reduction, which combines mindfulness meditation and yoga, was developed at the University of Massachusetts Medical Center.

One of my favorite nutritional supplements to balance cortisol levels and help patients cope with stress is a standardized/patented combination of Magnolia bark extract and Phellodendron bark extract known as Relora®. Studies have shown this combination can lower cortisol and help people feel more relaxed, while encouraging weight loss in people who eat when stressed.13

In one study, researchers measured the effects of Relora® on competitive athletes who were under pressure due to their intense exercise routines combined with their daily living activities. After four weeks of taking Relora®, cortisol levels were significantly lower compared to subjects taking the placebo. Subjects taking Relora® were in a better mood and experienced less stress, tension, depression, anger, fatigue, and confusion. They also had more vigor. To see how impressive Relora® was at reducing stress, take a look at the table below, which gives more specifics about the study results.13

Other supplements that I like to use to help lower excessively high cortisol levels include ashwagandha (Withania somnifera) and Rhodiola rosea. In several human studies, ashwagandha has reduced anxiety and stress. For example, in one randomized, double-blind, placebo-controlled study of 64 subjects with a history of chronic stress, ashwagandha root extract significantly reduced stress and serum cortisol levels.14 In a study of Rhodiola, a dose of 200 mg twice daily reduced stress after only three days and even greater improvements occurred after one and four weeks of taking this botanical.15

Another supplement I find to be useful for lowering stress levels is L-theanine, an amino acid found in green tea that can trigger your brain to produce a more relaxed pattern of brain waves. L-theanine can reduce many of the symptoms of stress including a high heart rate.16 I often take L-theanine prior to traveling and other stressful situations and find it has a calming effect.

Take Charge of Your Life

Finally, if we are going to brush off the effects of stress, we should all make every effort to take charge of our lives. We need to actively live our lives, not have our lives live us. We need to refocus on our original goals and dreams, but not allow the pursuit of them to blind us to the fact that each day that we have our health is a day to enjoy and not squander by giving in to the pressures of modern life.

References:

1. Karlén J, et al. Pediatrics. 2015;135:e1450-7.

2. Tyrka AR,et al. Biol Psychiatry. 2009 Oct 13. Published Online Ahead of Print.

3. Martocchia A, et al. Aging Clin Exp Res. 2015 Mar 27. [Epub ahead of print.]

4. Dean W. Neuroendocrine Theory of Aging: Chapter 2. Adaptive Homeostat Dysfunction. www.warddeanmd.com/articles.

5. Picard M, et al. Nature Reviews Endocrinology. 2014;10:303-10.

6. Samaras N, et al. Clin Interv Aging. 2014 Jul 23;9:1175-86.

7. Tomlinson JW, et al. Diabetes. 2008;57:2652-60.

8. Baudrand R, et al. Metabolism. 2011;60:1775-80.

9. Kang JI, et al. Neuropsychobiology. 2013;68:174-80.

10. Leproult R, et al. Sleep. 1997;20:865-70.

11. Black DS, et al. JAMA Intern Med. 2015;175:494-501.

12. Ong JC, et al. Sleep. 2014;37:1553-63.

13. Talbott SM, et al. J Int Soc Sports Nutr. 2013;10:37.

14. Chandrasekhar K, et al. Indian J Psychol Med. 2012;34:255-62.

15. Edwards D, et al. Phytother Res. 2012;26:1220-5.

16. Kimura K, et al. Biol Psychol. 2007;74:39-45.

This newsletter contains the opinions and ideas of the author. It is intended to provide helpful and informative material on the subjects addressed in the publication.

The content is shared with the understanding that the author and publisher are not engaged in rendering medical, health, psychological, or any other kind of personal professional services. If the reader requires personal medical, health, or other assistance or advice, a competent professional should be consulted.

The author and publisher specifically disclaim all responsibility for any liability, loss, or risk, personal or otherwise, that is incurred as a consequence, directly, or indirectly, of the use and application of any of the contents of this newsletter.

Posted by DrMeletis in Newsletter, 0 comments
Reviewing the Many Applications of Cannabinoid-Rich Hemp Oil and the Role of the Gut-Brain Axis

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

This is the third and final installment of a series of articles discussing cannabinoid-rich hemp oil and a new certification program for dietary supplement manufacturers and healthcare practitioners offered by the International Center for Cannabis Therapy (ICCT). As 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. Last month, we discussed the endocannabinoid system, its role in health, and how the endocannabinoid system interacts with the adrenals, sex hormones, and gut. We also shared 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. In this article, we’ll address the use of cannabinoid-rich hemp oil in applications such as Alzheimer’s disease, depression, anxiety, irritable bowel syndrome, stroke, schizophrenia, autoimmunity, and epilepsy, among other uses. We’ll also discuss the role of cannabinoids in the gut-brain axis.

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.

A Brief Review of the Endocannabinoid System

Endogenous endocannabinoids that are produced within the body including anandamide (arachi-donylethanolamide) and 2-arachidonylglycerol (2-AG) are able to activate receptors in the endocannabinoid system. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa, and cannabidiol (CBD), a non-psychoactive component, are also able to activate endocannabinoid receptors. 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. CB2 is primarily expressed in the immune system. Endocannabinoids and phytocannabinoids also act upon other receptors to achieve some of their beneficial effects. When the endocannabinoid system is stressed, there is a loss of homeostasis; and a number of diseases can result. For more detail about endocannabinoids and their receptors as well as supporting references, we recommend you read part two of this article.

The Endocannabinoid System and Neurological Diseases

An impaired endocannabinoid system may play a role in neurodegenera­tive disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Endogenous cannabinoid signaling performs many functions in the central nervous system (CNS), such as modulating neuroinflammation and neurogenesis, as well as regulating synaptic plasticity, and the response to stress.1,2 Furthermore, upregulation of type-2 cannabinoid (CB2) receptors is associated with many neurodegenerative disorders. Consequently, influencing CB2 receptor signaling may be neuroprotective.2

Endocannabinoids possess a broad-spectrum of activity, which is advantageous in neurodegenerative diseases where neural dysfunction is caused by a combination of different factors including protein misfolding, neuroinflammation, excitotoxicity, oxidative stress, and mitochondrial dysfunction.2 The endocannabinoid signaling system is thought to regulate each of these factors.2 The endocannabinoid system also modulates brain tissue homeostasis during aging and/or neuroinflammation.2

CB2 receptors exert neuroprotective properties through their ability to suppress inflammation.3 Activation of CB2 receptors regulates the production of cytokines, proteins that play a significant role in immune function and inflammatory responses.4 Conversely, rather than inhibiting neurodegenerative diseases via an immunological pathway, the CB1 receptor suppresses cell death through protecting against excitotoxicity, overstimulation of excitatory receptors and simultaneous calcium release.2

In the neurons of healthy brains, there is a lower expression of CB2 receptors. However, a significant increase in expression of these receptors is noted in reactive microglia and activated astrocytes during neuroinflammation.5,6 Microglia are cells in the brain and spinal cord. When they become reactive, it is associated with neurodegenerative diseases. Activated microglia modulate inflammatory responses to pathogens and injury by signaling the synthesis of pro-inflammatory cytokines. Similarly, diseases that impact the central nervous system activate astrocytes. The fact that CB2 receptors are highly expressed when both these types of cells are activated may indicate they are needed to combat inflammation. This led researchers to conclude, “Therefore, the CB2 receptors have the potential to restrain the inflammatory processes that contribute to the declines in neural function occurring in a number of neurodegenerative disorders.”2

The involvement of CB2 receptors in Alzheimer’s disease was demonstrated in a number of human studies. Inspections of postmortem brains from individuals with Alzheimer’s disease showed that CB2 receptors are upregulated in cells that are linked to amyloid beta (Aβ)-enriched neuritic plaques.7-10 The deposition of amyloid beta plaques in the brain are involved in Alzheimer’s disease pathology. Other researchers found markedly higher CB2 receptor levels in individuals with severe Alzheimer’s disease compared with age-matched controls or people with moderate Alzheimer’s.11 Activation of the CB2 receptor has resulted in beneficial effects in Alzheimer’s disease, including the inhibition of microglial activation in mice.12

Further support for the role of the endocannabinoid system in Alzheimer’s is provided by preclinical studies showing that cannabidiol, the non-psychoactive component of Cannabis sativa, may be beneficial in Alzheimer’s. In one of these studies, mice inoculated with Aβ then injected with CBD (2.5 or 10 mg/kg) for seven days had anti-inflammatory and neuroprotective effects as evidenced by its ability to suppress a marker of activated astrocytes.13 A rat model of Alzheimer’s-related neuroinflammation further elucidated the role CBD may play in Alzheimer’s. In this study, adult male rats were inoculated with human Aβ42 in the hippocampus.14 Then, for 15 days, they were given 10 mg/kg CBD either with or without a PPAR-γ or PPAR-α receptor antagonist. CBD counteracted many of the pathogenic mechanisms of Aβ, and its effects involved the regulation of PPAR-γ. This makes sense since PPAR-γ receptors are increased in people with Alzheimer’s disease.

Parkinson’s Disease

The progressive loss of dopaminergic neurons primarily in the substantia nigra (SN) is the distinguishing characteristic of Parkinson’s disease. This dopaminergic neuron loss impairs the basal ganglia leading to bradykinesia (slowness of movement), rigidity, and tremors. Inflammation is a prominent player in Parkinson’s disease pathogenesis. Post-mortem evaluations of Parkinson’s disease patients observed microglia activation in the SN.15  Structural brain imaging studies have also shown that activated microglia and an increase of proinflammatory cytokines occur in the nigrostriatal system of Parkinson’s disease patients.16,17 A post-mortem study indicated that individuals with Parkinson’s disease have increased expression of CB2 receptors in microglial cells of the SN.18 This and other evidence suggests that targeting the CB2 receptor may serve as an anti-inflammatory approach in Parkinson’s.2

In support of the idea that modulating the endocannabinoid system is beneficial in Parkinson’s disease are a number of small studies investigating the use of cannabidiol in this group of patients. In a double-blind, placebo-controlled study of 21 Parkinson’s patients without dementia or comorbid psychiatric conditions, 300 mg/day cannabidiol enhanced well-being and quality of life.19 In an open-label pilot study, six Parkinson’s disease outpatients (four men and two women) who suffered from psychosis for at least three months received CBD starting with an oral dose of 150 mg/day for four weeks combined with their usual therapy.20 CBD intervention resulted in a marked decline in psychotic symptoms as measured by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire. CBD also lowered the total scores of the Unified Parkinson’s Disease Rating Scale. Furthermore, cannabidiol significantly reduced the frequency of sleep behavior disorder (RBD) in four patients with Parkinson’s disease.21

Anxiety and Post-Traumatic Stress Disorder

The endocannabinoid system regulates stress and anxiety, and modulation of the endocannabinoid system has been found to reduce anxiety. Repeated injections of cannabidiol to mice exposed to chronic unpredictable stress reduced anxiety in the animals.22 This effect was mediated by CB1, CB2, and serotonin (5HT1A) receptors. In a double-blind randomized trial investigating subjects with generalized social anxiety disorder not receiving medication, 600 mg of cannabidiol reduced anxiety and cognitive impairment caused by simulated public speaking and improved the participants’ comfort level in their speech performance.23 Another study of 10 individuals with generalized social anxiety disorder observed that 400 mg of cannabidiol was associated with markedly reduced subjective anxiety.24 Furthermore, advanced imaging studies indicate that the endocannabinoid system is underactive in post-traumatic stress disorder.25 Preliminary studies in humans have observed that cannabinoids may improve PTSD symptoms such as sleep quality and hyperarousal.26 Nabilone, a synthetic cannabinoid, reduced PTSD-related nightmares in a small group of Canadian military personnel.27 In an animal model, cannabinoids given shortly after experiencing a traumatic event blocked the development of a PTSD-like phenotype.26

For more information about the interaction between the endocannabinoid system and anxiety, we recommend you enroll in the ICCT medical certification program at www.icctcertification.com. This is a vast topic that cannot be addressed in one article alone.

Depression

Dysregulation of the endocannabinoid system may be involved in the development of depression. Suppressing the CB1 receptor results in a phenotypic state that is comparable to melancholic depression, with identical symptoms such as decreased appetite, increased anxiety, arousal, and wakefulness, an inability to release aversive memories, and increased sensitivity to stress.28 Furthermore, some antidepressant medications enhance endocannabinoid activity.28

One mechanism by which CBD reduces depression may be via its ability to protect against the effects of stress. Stress can lead to anxiety and depression. In animal models, CBD lowers autonomic indices of stress and behavioral effects of depression and anxiety and improves the delayed emotional consequences of stress via mechanisms that involve serotonin receptors.29,30 CBD is also thought to reduce depressive symptoms by enhancing hippocampal neurogenesis. Ongoing administration of CBD in mice undergoing chronic unpredictable stress improved depressive- and anxiety-like behaviors and triggered hippocampal progenitor proliferation and neurogenesis.31

CBD is thought to stimulate neurogenesis by elevating hippocampal levels of the endocannabinoid anandamide (AEA). A clinical study found that higher serum concentrations of AEA were associated with reduced anxiety in patients with major depression, although in this group of patients AEA levels were not associated with major depressive symptoms.32 Conversely, in people with minor depression, AEA concentrations were elevated compared to controls, suggesting that these levels might be raised as the body’s way to compensate for the depression and that they may have a neuroprotective role in patients with less severe depressive symptoms.

The role of cannabinoids in depression is a vast topic, and we recommend that you enroll in the ICCT medical certification program to understand how phytocannabinoids can be safely used in depression.

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

Cannabinoids, 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.

Conclusion

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 https://www.icctcertification.com/international-cannabinoid-therapy-clinical-mastery/ 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.

References

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  46. Kozela E, et al. Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells. J Neuroinflammation. 2016 Jun 3;13(1):136.
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Posted by DrMeletis in Hemp and Endocannabinoid, Townsend
Evidence for the Clinical Use of Cannabinoid-Rich Hemp Oil in the Management of Pain, Inflammation, and Stress

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

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.

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.

The 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 Δ9-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 endocannabinoid 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, endocannabinoids 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

Beyond 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

Endocannabinoid System Burdens

A number of factors can interfere with the proper functioning of the endocannabinoid system, throwing the body out of homeostasis. For example, obesity is associated with an over activated endocannabinoid system in adult subjects.28 Moreover, offspring of female rodents that consumed a high-fat diet during pregnancy were obese with fat cell hypertrophy and buildup of lipids in brown adipose tissue.29 These effects correlated with alterations in the endocannabinoid system of the rat pups. In male offspring of mothers fed a high-fat diet, CB1 and CB2 receptor levels declined in subcutaneous adipose tissue. In female offspring of mothers fed a high-fat diet, visceral CB1 levels increased while subcutaneous concentrations decreased. CB1 concentrations increased in brown adipose tissue from both male and female offspring of mothers that consumed the high-fat diet.

Toxins can serve as another disrupter of the endocannabinoid system. For example, the mechanism by which BPA causes fatty liver is thought to involve up-regulation of the endocannabinoid system.30

An imbalance of the gut microbiota known as dysbiosis is another threat to the optimal functioning of the endocannabinoid system. A rodent study found that dysbiosis of the gut microbiota led to changes in the endocannabinoid system.31 In this study, researchers administered antimicrobials to mice for two weeks in order to cause dysbiosis. Afterward, the animals were given 109 CFU/day of Lactobacillus casei DG or a placebo for up to a week. Antimicrobial administration resulted in dysbiosis of the microbiota. At the same time, there was a general inflammatory state and changes in some aspects of the endocannabinoid system in the gut. These changes were accompanied by behavioral alterations, including increased immobility in the tail suspension test (an indicator of depression), as well as biochemical and functional changes in the brain such as neuronal firing in the hippocampus and rearrangements of non-neuronal cells in brain regions controlling emotional behavior. Probiotic intake eliminated most of these changes.

Sex Hormones and Cannabinoids

The association between the endocannabinoid system and estrogen indicates that declining estrogen levels with menopause may disrupt this system. The endocannabinoid system has an under-recognized role in male and female health. Cannabinoids and sex hormones influence common molecular pathways involved in cell proliferation.32 Furthermore, estrogen plays an important role in the endocannabinoid system expression in the female reproductive tract.12 Administering the estrogen estradiol to ovariectomized rats caused a marked increase in CB1, CB2, the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and COX-2 expression.12 These effects were estrogen-receptor dependent. Anandamide levels also increased in the plasma after estradiol treatment. According to the study authors, “Thus, estradiol may have a direct regulatory role in the modulation of ECS [the endocannabinoid system] in female reproductive tissues.”

These findings may explain anecdotal reports of CBD oil reducing hot flashes and other symptoms of surgically induced menopause in women.

Endocannabinoid Imbalance and Psychological Stress

One characteristic of an imbalanced endocannabinoid system is the inability to cope with stress.33-35 That’s why this system is often dysfunctional in people with post-traumatic stress disorder. Stimulation of the endocannabinoid system inhibits the activation of the hypothalamus-pituitary-adrenal axis that occurs after stress.33-35 In this way, this system helps us recover from anxious experiences and brings us back to homeostasis. In male rodents, when the CB1 receptor is blocked, it takes longer for the HPA axis to recover from stress.36

Significant concentrations of nitric oxide (NO) are found in the brain and adrenal glands and NO may be involved in the stress response. During stress, anandamide suppresses the activity of the nitric oxide synthase enzyme, indicating that endocannabinoids may reduce stress by inhibiting the generation of NO in the hypothalamus and adrenals.37
An impaired endocannabinoid system may also be one of the reasons why stress impacts gastrointestinal function.38 The endocannabinoid system in the gastrointestinal tract regulates motility, secretion, sensation, emesis, satiety, and inflammation. It also influences visceral sensation.

Beyond stress, there are many other consequences of a dysfunctional endocannabinoid system including pain, cognitive dysfunction, depression, epilepsy, and more. We will discuss some of these in further detail in this article while we will address others in next month’s issue of Townsend Letter.

Improving Endocannabinoid System Function with Cannabinoid-Rich Hemp Oil

Cannabinoid-rich hemp oil is an ideal choice to optimize the endocannabinoid system. Throughout the remainder of this article and the next part of this article we will discuss the justification for using hemp oil in a variety of clinical applications. The primary cannabinoid in hemp oil is CBD. However, it also contains other phytocannabinoids as well as terpenes, which work with CBD to support endocannabinoid system function and therefore make hemp oil uniquely suited to enhance areas of health regulated by the endocannabinoid system. The entourage effect – sometimes called the “hemptourage effect” – refers to the ability of other more minor components of hemp oil such as the terpenes to support the activity of its main player, CBD. For example, the terpenes limonene, pinene, and linalool can provide a complementary action to CBD’s cognitive-enhancing abilities by improving mood.39 Pinene is also known to enhance mental clarity, thus acting synergistically to CBD.39 The entourage effect is a fascinating aspect of cannabinoid therapy, and Dr. Chris Meletis explores this effect in more detail in the ICCT medical certification program.

Like so many herbals that are popularly used around the world, hemp has been employed for centuries with many health benefits. The moment we start eliminating certain constituents we may lose certain therapeutic benefits often attributed to the entourage or hemptourage effect. Yet, even with that said, we still don’t fully know all the effects of the cannabinoids and terpenes either as standalone substances or in concert.

Cannabinoid-Rich Hemp Oil and Pain Control

As noted earlier, various receptors in the endocannabinoid system are involved in the regulation of pain including CB1, CB2, and TRPV1. Pain is a common complaint among patients as evidenced by the fact sales of opioid drugs almost quadrupled from 1999 to 2014.40 CB2 indirectly activates opioid receptors, thus blocking painful stimuli.41 In part through this mechanism, cannabinoids reduce inflammatory and neuropathic pain, which are notoriously difficult to successfully treat.42 Animal models, human studies, and experience from clinical practice indicate that cannabinoid-rich hemp oil or CBD are useful in various types of pain. In a rodent model of osteoarthritis, CBD administered locally to the area surrounding the joint reduced the initial inflammatory response and thus subsequent pain and inflammation.43 Furthermore, cannabinoid-rich hemp oil reduced body pain and improved other symptoms in girls who had an adverse reaction to the human papillomavirus (HPV) vaccine.44 Other evidence indicates the oil of cannabis seeds reduces pain in patients with chronic musculoskeletal inflammation, an effect attributed to the ideal omega-3/omega-6 ratio content.45

Treating pain properly involves addressing more than just physical discomfort. Pain is a multidimensional problem that also encompasses impairments in mood, cognition, and function. This is one way where management of pain with opioids goes wrong as opioids can actually worsen all of these components of pain. Phytocannabinoids found in hemp oil, on the other hand, can improve all of these accompanying mental health factors as we will discuss in the next part of this article.

Proper Dosing Is Crucial

Before concluding this article, we want to caution that it is important to keep in mind proper dosing protocols when employing cannabinoid-rich hemp oil. CBD is less potent than THC and much higher doses may be needed for its beneficial effects on pain and inflammation. At the same time, it’s crucial not to over activate the endocannabinoid system as scientists at the ICCT have found that overdosing on CBD can worsen certain conditions such as epilepsy. It’s best to begin dosing at modest levels and then increase the dose slowly over two weeks.

Diligent education and a conservative approach to dose for each individual patient and the patient pool in general needs to be in the forefront of the prescriber. As Dr. Meletis has shared in the classroom setting as an associate professor of natural pharmacology, if a natural substance is strong enough to nudge a biochemical pathway towards optimized homeostasis, it also holds the potential to disturb homeostasis when not employed judiciously. Keeping up with the rapidly growing and burgeoning research field on hemp is critical. This is one reason why Dr. Meletis applauded the ICCT when they decided to create their certification programs. The medical certification program is a more precise way to establish the proper dose by using established ICCT protocols.

We also recommend that healthcare practitioners seek out hemp-oil manufacturers who are recommending the use of products that have been certified by the ICCT so as to avoid hemp oil products that may have contaminants or overly high concentrations of THC.

Conclusion

From long before birth, our bodies are dependent upon the homeostasis provided by the endocannabinoid system, which casts a wide net over various aspects of health including pain management and control of psychological stress, among many others. The endocannabinoid system functions through the activation of a number of receptors. Endocannabinoids as well as phytocannabinoids such as those found in hemp oil interact with these receptors. Consequently, supporting the function of the endocannabinoid system is an under-recognized way to enhance virtually every aspect of health.

References
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11. Gebeh AK, Willets JM, Marczylo EL. Ectopic pregnancy is associated with high anandamide levels and aberrant expression of FAAH and CB1 in fallopian tubes. J Clin Endocrinol Metab. 2012 Aug;97(8):2827-35.
12. Maia J, Almada M, Silva A. The endocannabinoid system expression in the female reproductive tract is modulated by estrogen. J Steroid Biochem Mol Biol. 2017 Nov;174:40-7.
13. Jokisch V, et al. Endocannabinoid Levels in Newborns in Relation to the Mode of Delivery. Am J Perinatol. 2015 Oct;32(12):1145-50.
14. Ramírez-López MT, et al. Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring. Front Behav Neurosci. 2016 Nov 1;10:208.
15. Fride E. The endocannabinoid-CB(1) receptor system in pre- and postnatal life. Eur J Pharmacol. 2004 Oct 1;500(1-3):289-97.
16. Shouman B, et al. Endocannabinoids potently protect the newborn brain against AMPA-kainate receptor-mediated excitotoxic damage. Br J Pharmacol. 2006 Jun;148(4):442-51.
17. McLaughlin RJ, et al. Inhibition of anandamide hydrolysis dampens the neuroendocrine response to stress in neonatalrats subjected to suboptimal rearing conditions. Stress. 2016;19(1):114-24.
18. O’Hearn S, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017 Dec;6(Suppl 2):S209-14.
19. Breivogel CS, et al. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol. 2001 Jul;60(1):155-63.
20. Hájos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106(1):1-4.
21. del Río C, et al. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways. Sci Rep. 2016 Feb 18;6:21703.
22. O’Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. 2007 Nov;152(5):576-82.
23. Campos AC, et al. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016 Oct;112:119-27.
24. del Río C, Navarrete C, Collado JA. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways. Sci Rep. 2016; 6:21703.
25. Mishima K, et al. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke. 2005 May;36(5):1077-82.
26. Pazos MR, et al. Mechanisms of cannabidiol neuro-protection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharmacology. 2013 Aug;71:282-91.
27. Ibrahim MM, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3093-8.
28. Engeli S, et al. Peripheral endocannabinoid system activity in patients treated with sibutramine. Obesity (Silver Spring). 2008 May;16(5):1135-7.
29. Almeida MM, et al. Perinatal maternal high-fat diet induces early obesity and sex-specific alterations of the endocannabinoid system in white and brown adipose tissue of weanling rat offspring. Br J Nutr. 2017 Nov;118(10):788-803.
30. Martella A, et al. Bisphenol A Induces Fatty Liver by an Endocannabinoid-Mediated Positive Feedback Loop. Endocrinology. 2016 May;157(5):1751-63.
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33. Ganon-Elazar E, Akirav I. Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. J Neurosci. 2009 Sep 9;29(36):11078-88.
34. Hill MN, et al. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology. 2009 Dec;34(13):2733-45.
35. Patel S, et al. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology. 2004 Dec;145(12):5431-8.
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37. Surkin PN, et al. Pharmacological augmentation of endocannabinoid signaling reduces the neuroendocrine response to stress. Psychoneuroendocrinology. 2018 Jan;87:131-40.
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Posted by DrMeletis in Hemp and Endocannabinoid, Townsend
New Certification Program for Hemp Oil Benefits Manufacturers, Healthcare Practitioners, and Consumers, Part 1

New Certification Program for Hemp Oil Benefits Manufacturers, Healthcare Practitioners, and Consumers, Part 1

Cannabinoid-rich hemp oil has emerged as a promising botanical therapeutic with both clinical experience and published studies to support its use. The Stanley brothers are largely credited for first awakening the public to its benefits. The six Colorado siblings developed a hemp extract low in Δ9-Tetrahydrocannabinol (THC), the psychoactive component in marijuana, and high in cannabidiol (CBD), a phytocannabinoid that is not associated with the intoxicating effects of the plant. That hemp extract came to be known as Charlotte’s Web after the parents of a little girl named Charlotte Figi convinced the brothers to provide their daughter with CBD-rich hemp oil.1  Charlotte suffered from a severe type of medication-resistant epilepsy known as Dravet syndrome. She was having 300 seizures per week and her heart frequently stopped. After consuming three to four milligrams of the hemp oil per pound of body weight, Charlotte’s seizures disappeared. The case received a lot of publicity in major media outlets such as CNN.1

Since then the demand for hemp as a medicinal has skyrocketed and so too has the number of companies producing it and doctors prescribing it. Its benefits have been demonstrated both clinically and in the scientific literature. Based on that scientific research and clinical observations, I employ hemp oil in clinical practice to support the health of patients with epilepsy, anxiety, depression, post-traumatic stress disorder, schizophrenia, inflammation, and pain among other applications. Upcoming articles in Townsend Letter will discuss its clinical applications and the evidence in the medical literature. In this article, I will discuss a new cannabinoid certification program for both manufacturers and healthcare practitioners.

Why Manufacturers and Practitioners Need a Certification Program

When new segments of most fields of commercial enterprise enter the marketplace, there are the initial well-intentioned pioneers. This is also true in the hemp oil marketplace. However, like the dietary supplement industry in its early years, the hemp oil marketplace is a Wild Wild West. Up until now, no entity was ensuring the consumer that optimal quantities of the beneficial cannabinoids found in hemp oil were actually contained in the purchased product. As a manufacturer, in order to maintain a respectable reputation and avoid legal complications, it’s important to ensure that the hemp oil you’re producing lives up to its label specifications.  A 2017 article in JAMA tested 84 CBD/hemp oil extracts purchased online and found that although CBD oil labeling had the highest degree of accuracy compared to other products tested, 55% of the CBD oil products tested were either underlabeled (more CBD was detected in the product than claimed on the label) or overlabeled (CBD content that was negligible or less than 1% of the amount on the label).2 In this study, the overlabeled CBD products contained insufficient levels similar to concentrations that resulted in Food and Drug Administration (FDA) warning letters sent to 14 businesses in 2015-2016. Some of the products also contained more THC than noted on the label. In the United States, only cannabinoid-rich hemp oil brands that contain less than 0.3% of the psychoactive cannabinoid THC are legal. Therefore, certainty surrounding the THC content of a particular brand is essential.

The International Center for Cannabis Therapy (ICCT) found similar inaccuracies when its scientists tested hemp oil products sold mainly in online shops in Europe. Not one of the products tested was legally compliant as European legislation requires zero THC in hemp oil. Furthermore, the vast majority of products contained very little CBD and/or high concentrations of heavy metals and pesticides.

Another challenge that has arisen with the availability of hemp oil is that up until now, healthcare practitioners could not tap into a centralized knowledge base where they could have their cannabis questions answered. Because of hemp oil’s relative newness in the dietary supplement arena, there are many healthcare practitioners who are unclear of the proper dosage. Some of them have employed hemp products in their practice with little success not realizing that the product may have contained insufficient CBD. I have also encountered uncertainty among practitioners about the best way to incorporate hemp oil into already-prescribed supplement regimens, whether there are any contraindications to its use, and how its effects differ from marijuana. In interacting with attendees of lectures I have conducted on the endocannabinoid system, it became clear to me that a number of healthcare practitioners have many questions and concerns about the prescribing of hemp oil as well as the endocannabinoid system on which it acts.

“It is essential that health professionals know what the cannabinoid content of a product is because depending on the illness being treated, too much or too little CBD can affect the outcome,” said Petr Kastanek, PhD the director of the ICCT. “A Dravet syndrome patient for example will get strong relief from seizures using CBD, but too much CBD can actually trigger a seizure.”

This echoes my clinical experience that as functional medicine providers we must always remember that all receptors throughout the body have an optimal tolerance – not only receptors for CBD – and there is such a thing as too much. This is particularly the case when there is an endogenous pathway which is being augmented, such as the endocannabinoid system. After all, achieving and sustaining homeostasis is the goal.

The ICCT’s certification program will instruct practitioners (based on proven protocols) on the ideal amount of hemp oil. “Due to its non-toxic nature, a healthy patient won’t suffer side effects, but flooding the CB1 and CB2 receptors with cannabinoids is not necessary or advised,” said Petr Kastanek. “Micro dosing cannabinoids to activate the receptors creates a potent medical benefit in ICCT’s experience.”

Clearly, standards are needed both for all cannabis products and for practitioners prescribing them.

The International Center for Cannabis Therapy (ICCT)

The ICCT recognized the need for standards in the cannabis industry and consequently introduced three new certification programs: product certification, manufacturing facility certification, and medical certification for practitioners prescribing CBD and other active constituents of hemp. The ICCT is a Czech-based partnership of qualified doctors and scientists who specialize in the medical application of all forms of cannabis. ICCT scientists have spent decades conducting extensive research on the health benefits of medical cannabis as well as product development and medical treatment with an emphasis on enhancing the patients’ quality of life.

The organization’s certification programs are based on a decade of research conducted by more than 70 ICCT scientists from the Czech Republic and Israel. I recently became aware of the impressive ICCT’s mission, clinical work, and the high-caliber of people associated with it. In addition to maintaining my naturopathic practice in Oregon, I accepted the role of Chief Medical Officer–USA of the ICCT.

ICCT Certification for Hemp Oil Manufacturers

The ICCT certification will standardize CBD-rich products and raw materials for human consumption. It uses metabolomic fingerprinting technology to construct a metabolic profile of the cannabinoid product through the pairing of data-rich analytic techniques with multivariate data analysis. The product will be analyzed for cannabinoid profile, pesticides, and contaminants. Manufacturers also have the option to obtain certification for their manufacturing facility similar to cGMP or NSF certification. The ICCT certification ensures that the manufacturer is compliant with local and state regulations. It also tests the quality and consistency of raw materials and provides staff training, product formulation, and compliant labeling. Annual randomized facility inspection is also a component of the manufacturing facility certification.

American Nutritional Products was the first hemp oil manufacturer to become certified by ICCT. “It is because of my 28 years in the supplement industry that I first realized what challenges were going to lie ahead for cannabis and hemp,” said Maria Watson, president and CEO of American Nutritional Products, Inc. and former co-owner of Vitamin Research Products (VRP). “The supplement world started out with no known certification body and little control on quality. When we owned VRP, as an industry leader, we drove the movement to clean up our industry – that now needs to happen in the cannabis space.”

The ICCT Medical Certification

Medical certification from ICCT for healthcare practitioners involves eight online webinar modules, plus one bonus lecture on marketing your certification to the community and to prospective patients. Conducted by myself and other experts, the webinar modules are based on ICCT research by a team of 70 scientists, the evidence-based peer-review literature, my experience in clinical practice, and proven protocols based on clinical studies. Practitioners enrolled in the certification course will also learn vital information that ensures patients do not overdose on CBD. Additionally, the modules will address other topics crucial to the proper prescribing of hemp oil as described below.

The Entourage Effect of Hemp Oil.

The entourage effect is a concept originally proposed by Doctors Mechoulam and Ben- Shabat two decades ago. It originally referred to the ability of certain endocannabinoid system components to enhance the beneficial effects of the two most important actors in this system: anandamide and 2-arachidonylglycerol.3,4 Since then, the definition of the entourage effect evolved. It now can refer to the fact that components of cannabis or hemp oil other than THC and CBD – such as phytocannabinoids and terpenes – can actually act synergistically to THC, CBD, or each other. The ICCT certification online course will explain why the entourage effect is important in clinical practice.

CBD Receptors and Pain Perception.

Hemp oil may be the answer to today’s opioid and pain crisis. Opioid overdose is associated with more than 115 deaths per day in the United States.5 Finding an alternative to their use is therefore critical.

The endocannabinoid system is closely associated with pain management. The receptors in this system including CB1 and CB2 are activated by endogenous endocannabinoids. However, CBD as a phytocannabinoid and other phytocannabinoids in hemp oil also affect receptors in this system as does THC, the psychoactive component of cannabis.6,7

The certification course will include an in-depth discussion of endocannabinoid receptors and their role in pain management.

Hemp Oil and Neurodegenerative Conditions and Mood Disorders.

An abundance of evidence indicates hemp oil impacts the pathophysiology, progression, cause, and ecology of neurodegenerative conditions, mood disorders, and epilepsy. The certification program will help the busy healthcare provider digest this research and discover how it can be applied in clinical practice.

The Gut-Brain Axis and Cannabinoids.

An increasing amount of evidence points to an interplay between intestinal and neurological systems and that this connection is modulated by the gut microbiota, the population of microorganisms found in the intestinal tract. This link between neurological and intestinal systems has become known as the gut-brain axis. Intriguing evidence has emerged that the endocannabinoid system is involved in this interaction.8,9 The certification program will delve deeply into the role of the endocannabinoid system in the gut-brain axis and how this knowledge can be used to reduce inflammation and support the health of patients with anxiety and depression.

Legal Considerations of Prescribing Hemp Oil.

Based on the expertise of a leading attorney in this field of practice, practitioners who receive their cannabinoid certification will move forward with confidence and reassurance on the clinical application of hemp thanks to information presented in a comfortable and simple manner. A number of questions about the legality of hemp oil often arise. These include:

1) What is the difference between federal and state law and the issues of intrastate commerce?

2) Is it true that hemp oil is legal in all 50 states?

3) Is it likely for a person who tests positive to THC, that it could be from hemp oil use alone?

4) Do I need to have special charting or record keeping if I sell hemp oil to patients?

5) If a product that I sell as hemp contains THC beyond the “Legal Limit” to be considered hemp, what is my risk?

Hoban Law Group, the leading cannabis business law firm which has presented on behalf of the industry in front of the 9th circuit court, will answer these questions and discuss legal considerations of implementation of hemp oil therapy in practice.

“If you are carrying a hemp product or selling a product with more than 0.3 percent THC then you are dispensing marijuana,” said Jason Searns counsel to Hoban Law Group. “It is legally essential to know without question what you are dispensing. With the legal system and U.S. government delineating the role of hemp oil, it is important for clinicians to adhere to a high standard of education as offered by organizations such as the international research and educational organization ICCT.”

The Endocannabinoid System and Immunity, Cancer, Senescence, and Healthy Aging.

The endocannabinoid system has been found to play an important role in diverse aspects of health. Hemp oil, through its modulation of this system, is a likely option for many health challenges faced by our patients. For example, endocannabinoids are synthesized by most immune cells and upregulate or downregulate a number of immune functions.10 The CB2 receptor is also involved in reducing oxidative stress associated with cellular senescence, indicating the endocannabinoid system is involved in healthy aging.11 The certification program will help practitioners understand the myriad ways in which the endocannabinoid system is involved in health and how modulating that system through hemp oil can achieve beneficial results.

Essential Facts Practitioners Must Know About Employing Hemp Oil in Clinical Practice.

The different delivery mechanisms of cannabis can influence how it affects the body. The certification program will allow healthcare providers to become proficient in understanding these delivery systems. For example, there is a next generation of CBD products moving into the American market. These products have efficient, transdermal properties so they bring the active substances deep into the tissue. It is also important when using hemp oil not to unduly disturb the endocannabinoid system and overwhelm natural production of the endocannabinoids or alter receptor activity. The certification program will help practitioners understand how to achieve the benefits of hemp oil without causing this undesirable effect. Processing and extraction processes commonly used and pharmacokinetics, pharmacodynamics will also be discussed.

Anti-Inflammatory Properties.

CBD and other phytocannabinoids and constituents of hemp oil modulate inflammatory pathways. CBD reduces the inflammatory mediators interleukin-6 (IL-6) and TNF-α in rodent models.12-14 The certification program will discuss in detail hemp oil’s role in influencing inflammatory pathways in various disease states.

Other Benefits of Certification.

ICCT’s certification includes a marketing module conducted by Marketing Unlimited, a firm with 28 years’ experience in the natural products industry. This lecture will provide recommendations for marketing the ICCT certification to patients and prospective patients in order to help build clinicians’ practice.

Raising the Bar on Hemp Oil Manufacturing and Prescribing

ICCT’s ultimate mission in offering its certification programs is to bring European regulatory standards into the US cannabis market. The only type of products carrying ICCT certification will be those that incorporate the efficient use of cannabinoids in well-constructed products to maximize the medical benefit for patients. The ICCT anticipates that consumers will actually seek out doctors who have obtained its certification in cannabinoid therapy and products that have obtained ICCT’s blessing as an assurance of quality and safety.

For more information about the ICCT certification programs, visit www.icctcertification.com and join the ICCT mission of education and empowerment.

Download Article:   New Certification Program for Hemp Oil Benefits Manufacturers, Healthcare Practitioners, and Consumers, Part 1

References
1. Young S. Marijuana Stops Child’s Severe Seizures. CNN. August 7, 2013. https://www.cnn.com/2013/08/07/ health/charlotte-child-medical-marijuana/index.html Accessed February 3, 2018.
2. Bonn-Miller MO, et al. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017 Nov 7;318(17):1708-9.
3. Piomelli D, Russo EB. The Cannabis sativa Versus Cannabis indica Debate: An Interview with Ethan Russo, MD. Cannabis Cannabinoid Res. 2016;1(1):44-6.
4. Ben-Shabat S, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998 Jul 17;353(1):23-31.
5. National Institute on Drug Abuse. Opioid Overdose Crisis. February 2018. https://www.drugabuse.gov/ drugs-abuse/opioids/opioid-overdose-crisis Accessed February 3, 2018.
6. Miller RJ, Miller RE. Is cannabis an effective treatment for joint pain? Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):59-67.
7. Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-31.
8. DiPatrizio N. Endocannabinoids in the Gut. Cannabis Cannabinoid Res. 2016 Feb;1(1):67-77.
9. Storr MA, Sharkey KA. The endocannabinoid system and gut-brain signalling. Curr Opin Pharmacol. 2007 Dec;7(6):575-82.
10. Chiurchiù V. Endocannabinoids and Immunity. Cannabis Cannabinoid Res. 2016 Feb 1;1(1):59-66.
11. Hu Y, et al. N-stearoyl-l-Tyrosine inhibits the cell senescence and apoptosis induced by H2O2 in HEK293/Tau cells via the CB2 receptor. Chem Biol Interact. 2017 Jun 25;272:135-44.
12. Durst R, et al. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3602-7.
13. Barichello T, et al. Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. Eur J Pharmacol. 2012 Dec 15;697(1-3):158-64.
14. Li K, et al. Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas. 2013 Jan;42(1):123-9.

Posted by DrMeletis in Articles, Hemp and Endocannabinoid, Townsend
Common Ocular Conditions in Clinical Practice

Common Ocular Conditions in Clinical Practice

by Chris D. Meletis, ND, and Kimberly Wilkes

The eyes are often called the “window into one’s soul,” and with good reason. The eyes are the only part of the body where a doctor – using an ophthalmoscope and looking through the pupil – can non-invasively observe blood vessels and nerves. This is an amazing way to glean health status or trends, because the eyes are also windows into overall health. Damage that occurs in the eyes can indicate damage happening in the brain. Likewise, age-related macular degeneration can signal concurrent imbalances in thyroid hormones in some people.

This article will review many of the most common eye disorders, their risk factors, and the connection between ocular health and the health of other areas of the body. We will also discuss the research behind both well-known and lesser utilized but highly effective dietary supplements as well as lifestyle and dietary support for vision.

Age-Related Macular Degeneration

In individuals older than 50 years, age-related macular degeneration (AMD) is the most common reason for the occurrence of irreversible vision loss, particularly in developed countries.1 As the average age of the population rises, the number of individuals with AMD is expected to triple in the next three to four decades from 20 to 25 million to 60 to 75 million people globally.2

Macular degeneration occurs when the macula, the part of the eye involved in central vision and seeing fine details, is damaged. Most macular degeneration is age related. There are two types of age-related macular degeneration: nonexudative (dry) AMD and neovascular (wet) AMD. Dry AMD is the early stage of AMD. Eighty-five to 90% of all cases are the dry form.3

The presence of fatty deposits called drusen in the macula are a hallmark of dry AMD, which is associated with little to no vision loss, but increases the risk of developing advanced AMD. Wet AMD is the advanced form of the disease and accounts for only 10 to 15% of cases but is responsible for 90% of AMD-related blindness.

AMD progresses to the wet form when blood vessels begin to grow in an abnormal manner at the back of the eye (what’s known as angiogenesis). Blood or fluid from these vessels escapes into the macula. Scars develop that harm central vision and may lead to permanent blind spots.

Beyond aging itself, a number of risk factors exist for AMD, including cigarette smoking, genetics,1 and exposure to light, especially short wavelength light, including ultraviolet and blue light.4-6 Exposure to blue light is associated with abnormal synthesis of factors that trigger angiogenesis and cause the development or progression of AMD. The blue light spectrum in natural sunlight is believed to be the most important cause of ocular damage.

Due to the possibility that blue light exposure may play a role in the development of AMD, blue light-filtering intraocular lenses (IOLs) are being used as an alternative to traditional IOLs that only filter UV sunlight.7

Beyond sun exposure, modern humans encounter many other sources of blue light including fluorescent and LED lighting, flat-screen televisions, display screens of computers, electronic notebooks, smartphones, and other digital devices. Although these devices emit considerably less blue light than the sun, people spend a lot of time in front of these gadgets, often with their eyes close to the screens.

Another risk factor for AMD is high levels of homocysteine, an amino acid associated with an increased risk of cardiovascular disease.8,9 Studies have demonstrated a direct correlation between high homocysteine blood levels and an increased risk of AMD.8,9 In one study, homocysteine concentrations were 27.9% higher in individuals with wet AMD compared with the dry AMD group, and 21.9% higher compared with controls.10 Supplementation with folate, vitamins B6 and B12, and betaine are known to lower homocysteine concentrations, indicating homocysteine may be a modifiable risk factor for AMD.11,12 Furthermore, a randomized trial of women at increased risk of cardiovascular disease found that daily supplementation with folic acid, pyridoxine (vitamin B6), and vitamin B12 lowered the risk of AMD.13

Epigenetics are also involved in AMD. Epigenetics refer to modification of gene expression rather than changes in the genetic code itself. Epigenetics serve as a switch that turn genes on and off. Many environmental factors such as diet or exposure to toxins trigger these epigenetic changes in gene expression. One way in which gene expression is altered is through micro-RNAs (miRNAs). miRNAs are thought to be involved in the development of the retina and abnormal miRNA expression correlates with the development of AMD.14 Resveratrol inhibits neovascularization in the retina during rodent experiments and its beneficial ocular effects in animals and humans may be due to its ability to impact the expression of miRNAs.15 A study in rats indicated that resveratrol may be able to protect the retina against ischemia in part through a mechanism that involves its effects on miRNAs.16

Another factor related to an increased risk of AMD is eating a high-glycemic diet. Mice that consumed a high-glycemic diet developed many features of AMD, including retinal pigmented epithelial cell hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration.17 These abnormalities were not observed in mice that consumed a lower-glycemic diet. Interestingly, switching from the high-glycemic to the low-glycemic diet late in life halted or reversed these AMD features. Low-glycemic diets limited the accumulation of advanced glycation end products (AGEs), proteins or lipids that become glycated due to their exposure to sugars. Low-glycemic diets also were associated with reduced accumulation of long-chain polyunsaturated lipids and their peroxidation end-products and an increased amount of carnitine in the retina. The mechanism by which the diet affected the retina was thought to involve the microbiota. In mice consuming a low-glycemic diet, the microbiota produced a number of metabolites, especially serotonin, which inhibited the development of AMD features.17 Microbiota in the Clostridiales order were associated with AMD and the high-glycemic diet, whereas the low-glycemic diet correlated with a prevalence of Bacteroidales organisms, which were protective against AMD features. In a human study of 1,952 participants 49 years or older followed for 10 years, consumption of food with a higher mean dietary glycemic index correlated with an increased risk of early AMD.18 Conversely, individuals who ate low-glycemic breads and cereals such as oatmeal had a lower risk of incident early AMD.

Another connection exists between AMD and thyroid hormones. Human retinal pigment epithelial cells express thyroid hormone receptors, an effect which may lead to thyroid hormones triggering damaging effects including depletion of hyaluronic acid.19 In a study of 5,573 people 55 years old or older, even among subjects whose free thyroxine (FT4) levels were normal, individuals who had the highest FT4 levels had a 1.34-fold greater risk of developing AMD, compared to those whose FT4 concentrations hovered in the middle range.20 Furthermore, higher FT4 concentrations were associated with an increased risk of retinal pigment alterations. This led the researchers to conclude that thyroid hormone is involved in more than just promoting the progression of AMD and may actually be involved in its development.

In addition to addressing all of the aforementioned risk factors for AMD, supplementation with the carotenoids lutein and zeaxanthin provide effective support. In some studies, lutein has improved macular pigment optical density and visual sensitivities in patients with early AMD.21 A combination of nutrients used in the Age-Related Eye Disease Study 2 (vitamin C, vitamin E, zinc, copper, and lutein) along with 10 mg meso-zeaxanthin given to patients with non-advanced AMD led to significant increases in macular pigment and improvements in measures of visual function.22 Lutein and zeaxanthin have been shown to reduce the progression from early AMD to the late form of the disease.21 Dietary intake of lutein and zeaxanthin may result in a 26% reduced risk for late AMD.23

Cataracts

A cataract causes the normally clear lens of the eye to become cloudy or opaque. In the United States, over half of those aged 65 and over have cataracts.24 There are three types of age-related cataracts: nuclear cataracts that affect the center of the eye lens, cortical cataracts that impact the edges of the lens, and posterior subcapsular cataracts, which affect the rear of the lens.

Risk factors vary depending on the type of cataract. Aging, higher hemoglobin A(1c) – a marker of blood sugar control over time – and history of diabetes mellitus are independent risk factors for cortical-only lens opacities.24 Aging, smoking cigarettes, and myopia (nearsightedness) independently increase the risk of nuclear-only cataracts.24 Higher systolic blood pressure and history of diabetes are both independent risk factors for posterior subcapsular cataracts.24 Aging, myopia, diabetes, higher systolic blood pressure, female gender, and large drusen independently raise the risk for mixed cataracts.24

Diabetes is an important risk factor for all types of age-related cataracts. High blood sugar is thought to increase the risk of cataracts through direct glycation of lens proteins.24 Furthermore, sugar alcohols synthesized through the aldose reductase pathway are directly toxic to the lens of the eye.24 Individuals with diabetes mellitus may also have high levels of calcium, impacting the lens crystallins and leading to opacification of the lens.25 Better diabetes control may therefore inhibit the formation of cataracts.

Myopia is another common risk factor. The role that myopia may play in nuclear cataracts may involve a longer vitreous cavity in this group of subjects resulting in reduced delivery of nutrients to the posterior lens and consequently impaired oxidative defense mechanisms leading to free radical damage.25,26

N-acetylcarnosine lubricant eye drops may play a role in improving visual function in people with cataracts. In older subjects with cataracts treated with 1% N-acetylcarnosine lubricant eye drops, visual acuity and glare sensitivity markedly improved compared with controls, who did not experience any improvement in visual function.27 There is indication that the mechanism of action of N-acetylcarnosine may involve reducing the rate of telomere shortening in lens cells exposed to oxidative stress in the absence of sufficient antioxidant protection.27 Telomeres are protective caps at the end of chromosomes. As telomeres are worn down with aging and other factors, this leaves the chromosomes vulnerable to damage.
As with macular degeneration, dietary intake of lutein and zeaxanthin correlated with a lower risk of nuclear or posterior subcapsular cataracts in a dose-response manner.28

Glaucoma

Glaucoma is a neurodegenerative disorder that damages the optic nerve and leads to impaired vision and blindness. Globally, 64.3 million people suffer from the disease and that number is expected to rise to 111.8 million in 2040.29 Open-angle glaucoma is characterized by increased intraocular pressure. Glaucoma-related degeneration occurs due to direct damage to the retinal ganglion cells caused by high intraocular pressure, ischemia, and aging. Recent evidence also suggests that glaucoma may be a disease that originates in the central nervous system (CNS) and moves downstream to the optic nerve and retinal ganglion cells.30 It is known that injury to the visual cortex and/or optic nerve, which then leads to damage to the retina, may be involved in the development of glaucoma.30,31 All of these factors inhibit oxygen supply and impair retinal function.30,31

High blood pressure is a risk factor for glaucoma, as are genetics, aging, and ethnicity (African Americans and Mexican Americans are at greater risk).32 Recently, researchers have proposed that glaucoma may be diabetes type 4 (the brain diabetes theory).33,34

According to this theory, glaucoma is a result of brain insulin resistance or central insulin signaling impairment, triggering the development of transsynaptic neurodegeneration. This theory indicates that therapeutic options for primary open angle glaucoma/normal pressure glaucoma should potentially target the brain as well as the eye.35

Oral and topical forskolin in the form of eye drops, alone or with other dietary supplements, has been shown to improve glaucoma symptoms.36 Coleus forskohlii is an aromatic herb found in India from the Himalayas to the southern part of the country. Forskolin is derived from the roots of this plant. In one study, patients with primary open angle glaucoma who were taking intraocular pressure-lowering drugs also consumed an oral supplement containing forskolin, homotaurine, carnosine, folic acid, vitamins B1, B2, and B6, and magnesium for a year.37 Patients in the forskolin supplement group experienced a further decrease in intraocular pressure and an improvement in Pattern Electroretinogram (PERG) amplitude – an electrical retinal response caused by stimuli in the visual field. Light sensitivity in the fovea, a small depression in the retina of the eye where visual acuity is the greatest, also improved. The improvements in PERG and foveal sensitivity suggested that the supplement produced a short-term neuroactive benefit.

In another study, an oral combination of forskolin and rutin reduced the rise in intraocular pressure that occurs after laser iridotomy, a procedure used in the treatment and prevention of closed angle glaucoma.38 Italian researchers also investigated the oral combination of forskolin and rutin in 52 patients with primary open angle glaucoma who were taking anti-glaucoma drugs and 45 controls.39 All patients in the forskolin-rutin intervention group, independent of the combination of medications they were treated with, experienced an additional 10% decline in intraocular pressure, beginning one week after supplementation began and continued for the 30-day study. The improvement was more pronounced in patients with higher intraocular pressure (≥21 mmHg) compared with subjects with low (<21) intraocular pressure. Intraocular pressure in the control group remained stable throughout the study.

The Connection Between Eye Diseases and Cognitive Function

Alzheimer’s disease and mild cognitive impairment are associated with a number of ocular problems.40 The manifestations of Alzheimer’s impact not only the brain, but also the retina, which is an extension of the brain. The retinas of Alzheimer’s patients exhibit a number of abnormalities such as retinal ganglion cell degeneration, reduction of blood flow, and vascular alterations.41

There are many commonalities between the brain and the retina. Like the brain, the retina contains neurons, astroglia, microglia, and a blood barrier.41 Axons of the optic nerve directly join the retina and the brain.42 Amyloid β-protein (Aβ) deposits are known to accumulate in the brains of patients with Alzheimer’s and are a hallmark of the disease. Evidence indicates that retinal ganglion cells (RGCs) synthesize amyloid precursor protein42 and in Alzheimer’s patients, Aβ deposits accumulate in the retina.40

The connection between cognitive and ocular health is further supported by the fact that higher levels of carotenoids such as lutein – known to reduce the risk of AMD and cataracts – also lower the risk of dementia and Alzheimer’s.43,44 Furthermore, lutein supplementation in older women enhanced cognitive function.44

Other Non-Ocular Diseases Connected to Eye Health

In addition to Alzheimer’s, other conditions are related to poor eye health. Because the retina and optic nerve are components of the central nervous system, their impairment may be indicative of not only eye diseases like glaucoma but also neurodegenerative disorders such as Parkinson’s.30 Furthermore, open-
angle glaucoma is associated with an increased risk of stroke in people who also have hypertension and/or diabetes.45 Additionally, depression and anxiety are common in older individuals with poor vision. One study found that the incidence of depression and anxiety in older people with ocular conditions is double that of older individuals in general.46 Even dry eye disease is associated with a high prevalence of depression.47 Therefore, in elderly patients with vision impairment, it is prudent to monitor for depression and anxiety in addition to directly treating ocular health.

Mitochondrial Involvement

Proper functioning of the mitochondria – the powerhouses of the cell responsible for manufacturing the energy molecule ATP – is crucial for eye health. This is not surprising given that within the brain, the visual system has some of the highest need for energy.48

Mitochondrial dysfunction plays a key role in many eye diseases. For example, mitochondria are thought to have a causal role in the development of glaucoma.49 Mitochondrial function is associated with oxidative metabolism and reactive oxygen species (ROS) production.49 Excessive ROS synthesis leads to the death of retinal ganglion cells and ultimately the loss of vision.49

In AMD, mitochondria in human retinal pigment epithelium cells are damaged, fragmented, and disrupted.50 As the age of the subjects from whom the retinal cells were derived increased, there was a significant decline in the number and area of mitochondria, as well as other mitochondrial abnormalities.50 Although these alterations were found in the mitochondria of retinal cells from both AMD and control subjects, these abnormalities were more pronounced in AMD compared with normal aging.50 Other researchers have observed that AMD severity correlates with a greater amount of mitochondrial DNA lesions and fragmentations in retinal pigment epithelium cells.51

Excessive reactive oxygen species (free radical) generation caused by mitochondrial dysfunction is also known to be involved in cataracts. Lipid peroxidation in the eye, the means by which lipids in the body undergo oxidation after exposure to reactive oxygen species, is one of the mechanisms involved in the development of cataracts.52 As one of the primary sources of reactive oxygen species, mitochondria therefore likely play a role in the lipid peroxidation of the eye lens.

Mitochondrial dysfunction occurs in diabetic retinopathy as well. In rats, dysfunction in mitochondrial energy production in the retina occurs as early as two months before development of diabetic hyperglycemia and retinopathy.53 Additionally, metabolic abnormalities caused by high glucose lead to retinal cell loss associated with diabetic retinopathy.54

Due to the important role of the mitochondria in eye health and the ocular damage that occurs after excessive reactive oxygen species production, supporting mitochondria with effective antioxidant nutrients is advised. A number of studies have demonstrated that antioxidants such as vitamins C and E, coenzyme Q10 (CoQ10), omega-3 fatty acids and other substances such as green tea and gingko biloba may support normal intraocular pressure and protect retinal neurons against oxidative stress in primary open-angle glaucoma.55

Coenzyme Q10 also has been found to protect the mitochondria in AMD.56 It is a particularly important nutrient for eye health in the elderly since CoQ10 concentrations in the retina decline by approximately 40% during aging.57

Melatonin, by virtue of its ability to act as an antioxidant and mitochondrial protector as well as other mechanisms, can support the health of individuals with a number of eye diseases including cataracts, glaucoma, AMD, and diabetic retinopathy.58.59

Modern Threats to Vision Health

The large amount of time individuals spend in front of their computer results in a new type of eye strain unique to modern man. Computer use results in eye fatigue, which can impair visual function. After the benefits of bilberry were publicized in a 2015 study, Dr. Meletis began recommending this botanical to his patients who spend a lot of time staring at a computer screen. In the study, a prospective, randomized, double-blind, placebo-controlled trial, 88 office workers aged 20 to 40 years who were frequent computer users were randomized to receive either 480 mg/day of bilberry or a placebo for eight weeks.60 Eye dryness and various symptoms of eye fatigue were determined using a questionnaire. The researchers observed improved measures of eye fatigue in the group receiving bilberry extract compared with controls. Compared with controls, Bilberry extract reduced subjective symptoms of eye fatigue, including ocular fatigue sensation caused by computer viewing, ocular pain, eye heaviness, uncomfortable sensation, and the sense that there was a foreign body in the eye.

Dry Eyes and Floaters

Dry eyes and floaters are two other common ocular problems. Dry eyes occur more often in people over 67 years, although the prevalence of this condition becomes less common after the age of 80.61 Dry eye leads to oxidative stress since tears soothe the eyes with molecules that protect against oxidative damage to the cornea.62 Consequently, supplementation with antioxidants may protect the ocular surface against oxidative damage. In one study, a combination of essential polyunsaturated omega-3 fatty acids combined with vitamins A, C, and E, tyrosine, cysteine, glutathione, zinc, copper, and manganese given to patients with dry eyes, lowered markers of inflammation and dry eye symptoms.63

In his clinical practice, Dr. Meletis has used oral hyaluronic acid (HA) in patients with dry eye and observed good results. HA protects the ocular surface epithelium due to its moisturizing effect.65 A number of studies in humans and animals have shown that eye drops containing HA reduce symptoms and signs of dry eye.64,65-67 In one study, eye drops containing crosslinked HA and CoQ10 given to 40 patients with mild to moderate dry eye disorder improved symptoms of dry eye more effectively than HA alone.68

HA can be effective for floaters as well. Floaters – those wiggly lines or dots that appear to float in front of your eyes – occur due to alterations in the vitreous body, the gel that fills much of the hollow sphere of the eye. Most of the vitreous gel is water, but 1% is comprised of solid elements including HA and collagen. HA plays an important role in regulating the gel consistency of vitreous through HA’s affinity for water molecules. However, with aging, HA levels decline.69

This age-related breakdown in HA molecules causes them to release their water supply and form liquefied gaps in the vitreous gel. At the same time, collagen filaments clump together to form larger fibrils, which leads to further destruction of the vitreous gel. The collagen fibrils are suspended in the liquid vitreous pockets, appearing to float. The breakdown of the vitreous gel can lead to posterior vitreous detachment, where the vitreous completely separates from the retina. Most cases of posterior vitreous detachment occur in people over the age of 70. While there are no studies that we are aware of demonstrating a beneficial effect of HA supplementation on floaters, Dr. Meletis has used HA in patients experiencing this condition and believes the important role that HA plays in maintaining the integrity of the vitreous gel warrants its use in people with floaters.

Another Beneficial Nutrient for Ocular Health

Curcumin is emerging as a nutrient with potential benefits for eye health. A number of rodent studies have indicated it has a variety of beneficial effects on ocular health including inhibiting the development and progression of retinitis pigmentosa,70 a group of inherited neurodegenerative diseases characterized by the reduction of photoreceptor cells, ultimately leading to blindness. Rodent studies also demonstrate a beneficial effect of curcumin in the management of diabetic retinopathy.71,72 In humans, a lecithinized curcumin delivery system assisted with the management of diabetic microangiopathy and retinopathy.73

Conclusion

Many threats to eye health exist, especially as we grow older. However, a number of dietary supplements including lutein, forskolin, melatonin, hyaluronic acid, bilberry, CoQ10, and N-acetylcarnosine eye drops can protect vision. Furthermore, lifestyle changes such as eating a low-glycemic diet can also strengthen the eyes.

Download Article:  Common Ocular Conditions in Clinical Practice

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5. Mainster MA. Light and macular degeneration: a biophysical and clinical perspective. Eye (Lond). 1987;1(Pt 2):304-10.
6. Vila N, et al. Blue-light filtering alters angiogenic signaling in human retinal pigmented epithelial cells culture model. BMC Ophthalmol. 2017 Nov 2;17(1):198.
7. Sparrow JR, Miller AS, Zhou J. Blue light-absorbing intraocular lens and retinal pigment epithelium protection in vitro. J Cataract Refract Surg. 2004 Apr;30(4):873-8.
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9. Nowak M, et al. Homocysteine, vitamin B12, and folic acid in age-related macular degeneration. Eur J Ophthalmol. 2005 Nov-Dec;15(6):764-7.
10. Axer-Siegel R, et al. Association of neovascular age-related macular degeneration and hyperhomocysteinemia. Am J Ophthalmol. 2004 Jan;137(1):84-9.
11. Homocysteine Lowering Trialists’ Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005 Oct;82(4):806-12.
12. Mazza A, et al. Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial. J Biol Regul Homeost Agents. 2016 Jul- Sep;30(3):921-7.
13. Christen WG, et al. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women’s Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med. 2009 Feb 23;169(4):335-41.
14. Ren C, et al. Circulating miRNAs as Potential Biomarkers of Age-Related Macular Degeneration. Cell Physiol Biochem. 2017;41(4):1413-23.
15. Richer S, et al. Observation of human retinal remodeling in octogenarians with a resveratrol based nutritional supplement. Nutrients. 2013 Jun 4;5(6):1989-2005.
16. Liu XQ, et al. Resveratrol mitigates rat retinal ischemic injury: the roles of matrix metalloproteinase-9, inducible nitric oxide, and heme oxygenase-1. J Ocul Pharmacol Ther. 2013 Feb;29(1):33-40.
17. Rowan S, et al. Involvement of a gut-retina axis in protection against dietary glycemia-induced age-related macular degeneration. Proc Natl Acad Sci U S A. 2017 May 30;114(22):E4472-81.
18. Kaushik S, et al. Dietary glycemic index and the risk of age-related macular degeneration. Am J Clin Nutr. 2008 Oct;88(4):1104-10.
19. Duncan KG, et al. The human fetal retinal pigment epithelium: A target tissue for thyroid hormones. Ophthalmic Res. 1999;31(6):399-406.
20. Chaker L, et al. Thyroid function and age-related macular degeneration: a prospective population-based cohort study – the Rotterdam Study. BMC Med. 2015 Apr 23;13:94.
21. Huang YM, et al. Effect of supplemental lutein and zeaxanthin on serum, macular pigmentation, and visual performance in patients with early age-related macular degeneration. Biomed Res Int. 2015;2015:564738.
22. Akuffo KO, et al. The Impact of Supplemental Antioxidants on Visual Function in Nonadvanced Age-Related Macular Degeneration: A Head-to-Head Randomized Clinical Trial. Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5347-60.
23. Ma L, et al. Lutein and zeaxanthin intake and the risk of age-related macular degeneration: a systematic review and meta-analysis. Br J Nutr. 2012 Feb;107(3):350-9.
24. Richter GM, et al. Risk factors for cortical, nuclear, posterior subcapsular, and mixed lens opacities: the Los Angeles Latino Eye Study. Ophthalmology. 2012 Mar;119(3):547-54.
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27. Babizhayev MA, Yegorov YE. Telomere Attrition in Human Lens Epithelial Cells Associated with Oxidative Stress Provide a New Therapeutic Target for the Treatment, Dissolving and Prevention of Cataract with N-Acetylcarnosine Lubricant Eye Drops. Kinetic, Pharmacological and Activity-Dependent Separation of Therapeutic Targeting: Transcorneal Penetration and Delivery of L-Carnosine in the Aqueous Humor and Hormone-Like Hypothalamic Antiaging Effects of the Instilled Ophthalmic Drug Through a Safe Eye Medication Technique. Recent Pat Drug Deliv Formul. 2016;10(2):82-129.
28. Ma L, et al. A dose-response meta-analysis of dietary lutein and zeaxanthin intake in relation to risk of age-related cataract. Graefes Arch Clin Exp Ophthalmol. 2014 Jan;252(1):63-70.
29. Tham YC, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a
systematic review and meta-analysis. Ophthalmology. 2014 Nov;121(11):2081-90.
30. Calkins DJ, Horner PJ. The Cell and Molecular Biology of Glaucoma: Axonopathy and the Brain. Invest Ophthalmol Vis Sci. 2012 May 4;53(5):2482-4.
31. Crish SD, Calkins DJ. Central visual pathways in glaucoma: evidence for distal mechanisms of neuronal self-repair. J Neuroophthalmol. 2015 Sep;35 Suppl 1:S29-37.
32. National Eye Institute. Facts About Glaucoma. https:// nei.nih.gov/health/glaucoma/glaucoma_facts Accessed January 2, 2018.
33. Faiq MA, et al. Glaucoma–diabetes of the brain: a radical hypothesis about its nature and pathogenesis. Med Hypotheses. 2014 May;82(5):535-46.
34. Faiq MA, Dada T. Diabetes Type 4: A Paradigm Shift in the Understanding of Glaucoma, the Brain Specific Diabetes and the Candidature of Insulin as a Therapeutic Agent. Curr Mol Med. 2017;17(1):46-59.
35. Dada T. Is Glaucoma a Neurodegeneration caused by Central Insulin Resistance: Diabetes Type 4? J Curr Glaucoma Pract. 2017 Sep-Dec;11(3):77-9.
36. Majeed M, et al. Efficacy and safety of 1% forskolin eye drops in open angle glaucoma – An open label study. Saudi J Ophthalmol. 2015 Jul-Sep;29(3):197-200.
37. Mutolo MG, et al. Oral Administration of Forskolin, Homotaurine, Carnosine, and Folic Acid in Patients with Primary Open Angle Glaucoma: Changes in Intraocular Pressure, Pattern Electroretinogram Amplitude, and Foveal Sensitivity. J Ocul Pharmacol Ther. 2016 Apr;32(3):178-83.
38. Nebbioso M, et al. Forskolin and rutin prevent intraocular pressure spikes after Nd:YAG laser iridotomy. Panminerva Med. 2012 Dec;54(1 Suppl 4):77-82.
39. Vetrugno M, et al. Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. J Ocul Pharmacol Ther. 2012 Oct;28(5):536-41.
40. Hart NJ, et al. Ocular indicators of Alzheimer’s: exploring disease in the retina. Acta Neuropathol. 2016 Dec;132(6):767-87.
41. Koronyo Y, et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight. 2017 Aug 17; 2(16): e93621.
42. Morin PJ, et al. Amyloid precursor protein is synthesized by retinal ganglion cells, rapidly transported to the optic nerve plasma membrane and nerve terminals, and metabolized. J Neurochem. 1993 Aug;61(2):464-73.
43. Feart C, et al. Plasma Carotenoids Are Inversely Associated With Dementia Risk in an Elderly French Cohort. J Gerontol A Biol Sci Med Sci. 2016 May;71(5):683-8.
44. Xu X, Lin X. [Advances in the researches of lutein and alzheimer’s disease]. [Article in Chinese, Abstract in English.] Zhonghua Yu Fang Yi Xue Za Zhi. 2015 May;49(5):456-60.
45. Lee WJ, et al. Relationship Between Open-angle Glaucoma and Stroke: A 2010 to 2012 Korea National Health and Nutrition Examination Survey. J Glaucoma. 2018 Jan;27(1):22-7.
46. Heesterbeek TJ, et al. The incidence and predictors of depressive and anxiety symptoms in older adults with vision impairment: a longitudinal prospective cohort study. Ophthalmic Physiol Opt. 2017 Jul;37(4):385-98.
47. Zheng Y, et al. The Prevalence of Depression and Depressive Symptoms among Eye Disease Patients: A Systematic Review and Meta-analysis. Sci Rep. 2017 Apr 12;7:46453.
48. Wong-Riley M. Energy metabolism of the visual system. Eye Brain. 2010;2: 99-116.
49. Cheung LTY, et al. Targeted Delivery of Mitochondrial Calcium Channel Regulators: The Future of Glaucoma Treatment? Front Neurosci. 2017;11:648.
50. Feher J, et al. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging. 2006 Jul;27(7):983-93.
51. Karunadharma PP, et al. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5470-9.
52. Babizhayev MA. Mitochondria induce oxidative stress, generation of reactive oxygen species and redox state unbalance of the eye lens leading to human cataract formation: disruption of redox lens organization by phospholipid hydroperoxides as a common basis for cataract disease. Cell Biochem Funct. 2011 Apr;29(3):183-206.
53. Han WH, et al. Modifications in Retinal Mitochondrial Respiration Precede Type 2 Diabetes and Protracted Microvascular Retinopathy. Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):3826-39.
54. Tien T, et al. High Glucose Induces Mitochondrial Dysfunction in Retinal Müller Cells: Implications for Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):2915-21.
55. Pinazo-Durán MD, et al. Strategies to reduce oxidative stress in glaucoma patients. Curr Neuropharmacol. 2017 Jul 5. [Epub ahead of print.]
56. Zhang X, et al. Therapeutic potential of co-enzyme Q10 in retinal diseases. Curr Med Chem. 2017 Aug 1. [Epub ahead of print.]
57. Qu J, Kaufman Y, Washington I. Coenzyme Q10 in the human retina. Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1814-8.
58. Crooke A, et al. The role and therapeutic potential of melatonin in age-related ocular diseases. J Pineal Res. 2017 Sep;63(2).
59. Dehdashtian E, et al. Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress. Life Sci. 2017 Dec 1. [Epub ahead of print.]
60. Ozawa Y, et al. Bilberry extract supplementation for preventing eye fatigue in video display terminal workers. J Nutr Health Aging. 2015 May;19(5):548-54.
61. Ottobelli L, et al. Age-related changes of the ocular surface: a hospital setting-based retrospective study. J Ophthalmol. 2014;2014:532378.
62. Higuchi A, et al. Selenoprotein P controls oxidative stress in cornea. PLoS One. 2010 Mar 29;5(3):e9911.
63. Pinazo-Durán MD, et al. Effects of a nutraceutical formulation based on the combination of antioxidants and ω-3 essential fatty acids in the expression of inflammation and immune response mediators in tears from patients with dry eye disorders. Clin Interv Aging. 2013;8:139-48.
64. Choi JH, et al. Efficacy of the mineral oil and hyaluronic acid mixture eye drops in murine dry eye. Korean J Ophthalmol. 2015 Apr;29(2):131-7.
65. Groß D, Childs M, Piaton JM. Comparison of 0.2% and 0.18% hyaluronate eye drops in patients with moderate to severe dry eye with keratitis or keratoconjunctivitis. Clin Ophthalmol. 2017 Apr 6;11:631-8.
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67. Simmons PA, et al. Efficacy and safety of two new formulations of artificial tears in subjects with dry eye disease: a 3-month, multicenter, active-controlled, randomized trial. Clin Ophthalmol. 2015 Apr 15;9:665- 75.
68. Postorino EI, et al. Efficacy of eyedrops containing cross-linked hyaluronic acid and coenzyme Q10 in treating patients with mild to moderate dry eye. Eur J Ophthalmol. 2017 Aug 2. [Epub ahead of print.]
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70. Emoto Y, et al. Curcumin suppresses N-methyl- N-nitrosourea-induced photoreceptor apoptosis in Sprague-Dawley rats. In Vivo. 2013 Sep- Oct;27(5):583-90.
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72. Li J, et al. Curcumin Inhibits Neuronal Loss in the Retina and Elevates Ca²⁺/Calmodulin-Dependent Protein Kinase II Activity in Diabetic Rats. J Ocul Pharmacol Ther. 2015 Nov;31(9):555-62.
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Posted by DrMeletis in Articles, Townsend
Supporting Healthy Estrogen Metabolism During Bioidentical Hormone Replacement Therapy

Supporting Healthy Estrogen Metabolism During Bioidentical Hormone Replacement Therapy

by Chris D. Meletis, ND, and Kimberly Wilkes

As we grow older, an important component of any health-related regimen is the balancing of hormones to compensate for declining levels of estrogen and testosterone. Bioidentical hormone replacement therapy (BHRT) is a common and effective way to achieve this goal. However, one common mistake is to use BHRT without taking the correct dietary supplements to offset the poor metabolism of hormones. Gut health and any imbalances in the gut microbiota – the population of bacteria, fungi, and other microorganisms that inhabit the intestines – also need to be addressed to ensure the body is able to properly use estrogen and testosterone.

In this article, we will discuss the reasons why an imbalanced gut microbiota leads to dysfunctional hormone metabolism during menopause, as well as which dietary supplements are helpful in ensuring the body processes estrogen in a safe and efficient way. Finally, we will discuss why mitochondrial support is an often-neglected but critical component of bioidentical hormone replacement therapy.

The Gut as A Source Of Steroid Hormones

When considering the origin of estrogen production, the ovaries and adrenals normally come to mind. Surprisingly, however, it is now known the intestine can generate and metabolize sex hormones.1 Bioactive steroids have been identified in both the rodent and human gut.1 The cells lining the intestines (known as epithelial cells) are a cellular source of steroid production.1 In addition, intestinal epithelial cells are able to metabolize estrogen.1

17β-estradiol, a powerful estrogen made primarily by the ovaries of females and the testes of males, influences the development and function of the reproductive system. 17β-estradiol also is produced in tissues not related to reproduction where it governs a number of actions, including inflammatory responses. Lymph nodes located in a membrane that attaches the intestine to the abdominal wall and lymphatic tissue in the small intestine produce 17β-estradiol.2 In mice, these intestinal lymphatic areas contained 17β-estradiol levels significantly greater than those in blood, and there was more 17β-estradiol in lymph-related organs compared with the ovaries and testes.2

The estrogen estradiol also protects the lining of the intestines known as the epithelial barrier from damage.3 It keeps the gut walls strong and stops “leaky gut,” what scientists call intestinal permeability, where bacteria and food allergens slip through a weak intestinal lining and out into the blood stream, where they can wreak havoc in the body.3

Further evidence of a link between estrogen and the gut comes in the form of studies that show there is a relationship between estrogen and inflammatory bowel syndrome (IBS).4 Estrogen helps regulate the development of IBS in part through its ability to interact with the hormone serotonin,4 a large amount of which is produced in the gut and helps regulate intestinal function. Estrogen also reduces the effect of psychological stress on the brain and the gut.4 Some studies have found that, while in postmenopausal women, there is a significant decrease in incidence of IBS,5 symptom severity may increase following menopause.6

Estrogen and Your Gut Bacteria

The beneficial microbes in a woman’s gut are affected by age and her declining estrogen levels.7 But the relationship between the gut microbiota and estrogens is a two-way street because the gut microbiota also help regulate levels of estrogens.7

The parent estrogens estrone and estradiol are metabolized in several ways including the 2-, 4-, and 16-hydroxylation pathways. Each of these estrogen metabolites differs in how easily they are used by the body and the strength of the metabolite. And each of these estrogen metabolites has different effects on the body. In many cell culture and animal studies, a higher level of 2-hydroxylated estrogen metabolites is associated with a lower risk of postmenopausal breast cancer. The gut microbiota may play an important role in assuring that estrogen is metabolized through the safer 2-hydroxylated pathway. One group of researchers found that in 60 postmenopausal women, greater diversity of the microbiota was associated with higher ratios of 2- and 4-hydroxylated metabolites to parent estrogens such as estrone and estradiol, suggesting that gut microbes are associated with estrogen metabolism and optimal counts of beneficial bacteria may reduce postmenopausal breast cancer risk.7

Researchers also have shown that the use of conventional estrogen replacement therapy is able to boost levels of beneficial vaginal bacteria.8 In one study of 40 postmenopausal women receiving hormone replacement therapy (HRT) and 20 who were not on HRT, the probiotic species lactobacilli were present in the vagina of 95% or more of the participants in both groups.8 However, in the HRT group, Lactobacillus was more often the dominant and only beneficial species present. In addition, in the HRT group, there were significantly fewer harmful bacteria. Plus, an infection known as bacterial vaginosis occurred less often in the HRT group compared with the women not receiving HRT.

Adding to the evidence that there is a connection between steroid hormones and the gut is the fact that the probiotic organism Lactobacillus reuteri when given to mice in their drinking water, improved markers of gonadal aging.9 The study authors believe this was due to the anti-inflammatory actions of the probiotic. Even though this study was done in male mice, it provides an interesting perspective that could be applied in clinical practice to females.

The Microbiota’s Far-Reaching Role in Postmenopausal Health

Declining estrogen levels during menopause makes women more vulnerable to increased bone loss and fracture risk.10,11 The microbiota are involved in protecting against age-related bone loss. In mouse models of menopause, supplementation with the probiotic L. reuteri stopped bone loss and reduced bone breakdown related to estrogen deficiency.12

The way the gut microbiota accomplishes its bone-protecting effects is in part through raising levels of insulin-like growth factor 1 (IGF-1), which plays a role in bone health.13 Clinically, IGF-1 also serves as a marker of biological aging and growth hormone levels.14,15 The lower your IGF-1, the lower your growth hormone levels and the faster you age and suffer from effects like cognitive decline.15

Phytoestrogen Supplements and Gut Bacteria

Menopausal women commonly use phytoestrogen supplements to ease symptoms such as hot flashes. Phytoestrogens such as soy have a similar chemical structure to human estrogens, produce estrogenic activities, and cause effects similar to estrogen. Intestinal bacteria metabolize phytoestrogens into compounds that are more bioavailable and have more estrogenic/anti-estrogenic and antioxidant activity than the parent phytoestrogens themselves.16,17 These compounds also have anti-inflammatory effects, stop the multiplication of cells, which is linked to cancer, and trigger the death of unhealthy cells.17,18

Some individuals have the ability, through the actions of the intestinal microbiota, to convert phytoestrogens into these more bioavailable metabolites, which may make them less vulnerable to hormone-dependent diseases.19-21 The intestinal microbiota’s transformation of phytoestrogens into their bioavailable metabolites is critical to the reduction of menopausal symptoms and certain chronic diseases, such as cancer, cardiovascular disease, and osteoporosis.19-21

One group of researchers suggested, “the clinical effectiveness of soy protein in cardiovascular, bone, and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol” and that this transformation was dependent on intestinal bacteria.22 The researchers pointed out that past studies did not distinguish between participants who were “equol-producers” and “nonequol producers,” which could explain why studies on the health benefits of soy have yielded conflicting results.

The Importance of Blocking a Harmful Enzyme

The body processes hormones as well as drugs and environmental toxins using a sugar called glucuronic acid. In the liver, this sugar attaches itself to drugs, hormones, and toxins meant to be excreted from the body through the bile duct to the GI tract. In doing so, glucuronic acid neutralizes the potentially harmful substance. However, an enzyme called beta-glucuronidase searches for this sugar because it needs to use it as a source of carbon. Once beta-glucuronidase separates the glucuronic acid from the hormone, toxin, or drug, metabolites of these substances are  not always completely eliminated from the body.23 They can be reactivated and highly toxic to GI tissues.23 That’s why it is essential that beta-glucuronidase levels be balanced in people on BHRT, so that estrogen does not become reabsorbed.

A small number of the thousands of intestinal microbiota organisms – about 50 species, including E. coli – can release beta-glucuronidase.24 On the other hand, a number of probiotic organisms can inhibit the production of beta-glucuronidase. A study of the fecal water of 15 people who were a variety of ages (children, adults, and elderly) found that when the water was incubated with a carcinogen, the toxicity and the beta-glucuronidase activity of the water was increased.25 However, the probiotic organism Lactobacillus paracasei reduced beta-glucuronidase by 76% in the fecal water of the children and by 82% in the elderly.

Another study investigated the effects of a multispecies probiotic supplement consisting of Lactobacillus rhamnosus GG, Lactobacillus rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermanii JS, and Bifidobacterium breve on intestinal microbiota and beta-glucuronidase in patients with irritable bowel syndrome (IBS).26 In this placebo-controlled, double-blind trial, 55 IBS patients received either the multispecies probiotic or a placebo daily for six months. At the study’s conclusion, researchers observed a decline in beta-glucuronidase activity in 67% of the subjects given the probiotic compared with only 38% of participants given the placebo.

In an animal study, rodents that were exposed to one of three conditions – a chemical that causes colon cancer, atherosclerosis triggered by a high-fat diet, or an imbalance of the gut microbiota caused by antibiotic administration – were supplemented daily with Lactobacillus plantarum alone or combined with antibiotics.27 In the rats exposed to the cancer-causing chemical, the probiotic lowered beta-glucuronidase activity. In the atherosclerosis group and the imbalanced gut microbiota rodents, combining the probiotic with an antibiotic also reduced beta-glucuronidase activity.

Calcium D-Glucarate

Calcium-D-glucarate is the calcium salt of D-glucaric acid, which humans synthesize naturally in small amounts. Many fruits and vegetables, especially oranges, apples, grapefruit, and cruciferous vegetables, are also a source of glucaric acid. Oral supplementation of calcium D-glucarate blocks the beta-glucuronidase enzyme for five hours.28

Calcium-D-glucarate’s ability to suppress beta-glucuronidase helps hormones such as estrogen to be excreted before they are reabsorbed. Large oral doses of calcium-D-glucarate fed to rats resulted in a 23% drop in serum estrogen levels.28 In rats exposed to a chemical carcinogen that causes breast cancer in the animals, calcium D-glucarate blocked tumor development by over 70%.29

Scientists have also studied calcium-D-glucarate in breast, lung, colon, and liver cancers in rodent models, and the beneficial results occurred due to a variety of mechanisms including inhibiting beta-glucuronidase activity.28,30,31

Because calcium D-glucarate blocks beta-glucuronidase and therefore improves the excretion of estrogen from the body, Dr. Meletis uses it in his clinical practice in patients on estrogen replacement therapy as a precaution against estrogen re-absorption and the resulting harmful effects.

Funneling Estrogen Through the Safest Pathway

As we mentioned earlier, there are several ways in which estrogens are metabolized in the body, including the 2-, 4-, and 16-hydroxylation pathways. A type of estrogen produced in the body known as 17beta-estradiol can be converted into 16alpha-hydroxyestrone (16alphaOHE1) or 2-hydroxyestrone (2OHE1). Compared with 2OHE1, which can act as an anti-estrogen, 16alphaOHE1 is extremely estrogenic; and in cell culture studies, it caused estrogen-sensitive breast cancer cells to multiply.32 Consequently, researchers have hypothesized that changing the way 17beta-estradiol is metabolized from the 16alphaOHE1 pathway toward the 2OHE1 pathway could lower the risk of estrogen-sensitive cancers, including breast cancer.33,34

However, the scientific community is debating the extent to which the urinary 2OHE1:16OHE1 ratios can protect against breast cancer risk, based on conflicting results among studies. A trial of 272 women with breast cancer and 291 controls concluded that the ratio of 2-OHE1 to 16alpha-OHE1 did not predict breast cancer risk.35 In another study of 66 breast cancer patients and 76 control patients, the mean level of urinary 2-OHE1, which is thought to be protective against breast cancer, was actually higher in the women with breast cancer compared with controls.36

Evidence to the contrary includes one study of 65 women with breast cancer, in which the ratio of 2OHE1 to 16OHE1 significantly predicted whether the women would develop breast cancer or not.37 In another study of 42 postmenopausal breast cancer patients and 64 women who visited the hospital for a routine mammogram, 16OHE1 was a strong risk factor for breast cancer as was a higher level of 16OHE1  compared with 2OHE1.38 Another group of researchers studied 10 normal women and 33 breast cancer  patients. The scientists found that there was greater 16 alpha-hydroxylation in the women with breast cancer.39

A recent trial offered one explanation as to why not all studies show that higher levels of 2-hydroxylation are associated with breast cancer risk. In this trial, researchers measured levels of the estrogens estradiol, estrone, and 13 metabolites in 1,298 postmenopausal women with breast cancer and 1,524 matched controls.40 There was a strong link between total estrogen levels and an increased risk of breast cancer. When the researchers normalized estrogen levels in the women, they observed that both a relative increase in levels of 2-hydroxylation and an increase in the ratio of 2-hydroxylation to 16-hydroxylation resulted in a lower risk of breast cancer. The greatest risk of breast cancer occurred in women who had the highest estrogen levels accompanied by lower levels of 2-hydroxylation or a lower ratio of 2-hydroxylation to 16-hydroxylation. Past studies finding that the 2OHE1:16OHE1 ratio is not associated with breast cancer risk did not determine how total estrogen levels impacted the risk associated with the 2OHE1:16OHE1 ratio.

It is also interesting to note that mutations in the catechol-O-methyltransferase (COMT) gene can lead to the body processing estrogen metabolites differently compared to women who don’t have this mutation. If a person has a defect in the COMT gene, it can lead to altered levels of 2OHE1 and 16OHE1.41 Tests are available to detect COMT genetic mutations.

Nutrients That Encourage the Safe Metabolism of Estrogen

Cruciferous vegetables such as broccoli, cauliflower, kale, and Brussels sprouts contain the phytochemical indole-3-carbinol (I3C). In the body, I3C is broken down to 3,3-diindolylmethane – DIM, for short. Studies in animals and humans have shown that supplementation with I3C or DIM or eating a lot of cruciferous vegetables can change the way the body metabolizes estrogen from the possibly harmful 16-hydroxylation pathway to the safer 2-hydroxylation pathway.34

Increased urinary 2OHE1 levels or urinary 2OHE1:16αOHE1 ratios have occurred in a number of controlled clinical trials using oral supplementation with 300-400 mg/day of I3C in women. In one of those studies, 400 mg/day of I3C daily for three months resulted in a significant mean increase in the 2OHE1:16alphaOHE1 ratio in all but three of 20 women.42 In another study of both men and women, I3C significantly increased 2-hydroxylation and lowered levels of nearly all other estrogen metabolites, including estradiol, estrone, estriol, and 16alpha-hydroxyestrone.43 In a trial of 60 women who had an increased risk of breast cancer, 300 mg/day of I3C improved the urinary estrogen metabolite ratio of 2OHE1 to 16alphaOHE1.44

DIM works similarly to I3C. Supplementation with 108 mg/day of DIM in postmenopausal women with a history of early stage breast cancer increased urinary 2OHE1 levels.45 In women with thyroid proliferative disease, 300 mg of DIM per day led to an increase in the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone.46 In a randomized, controlled clinical trial, 2 mg/kg/day of DIM was shown to cause a high rate of improvement in cervical dysplasia,47 a precancerous condition where cells grow abnormally on the outside of the cervix or in the opening between the uterus and the vagina.

Supporting Mitochondria During Hormone Therapy

All hormones originate in the mitochondria, where the conversion of cholesterol to pregnenolone – the precursor to all steroid hormones – occurs.48,49 Additionally, the electron transport chain of mitochondria plays a role in testosterone production and altering this pathway increases production of testosterone.50

More evidence that hormones are involved in mitochondrial function is that receptors for estrogens, androgens, and thyroid hormones are located in the mitochondria of many cell types.51,52  Scientists have found estrogen receptors in mitochondria of rat uterine and ovarian cells, breast cancer cells, cultured human lens epithelial cells, and rat hippocampus and neuronal cells. Moreover, estrogen receptors were found in mitochondria of heart cells, liver cancer cells, osteosarcoma cells, human sperm cells, and in human ligament cells of the gums.51 Estrogens and male hormones play a role in shielding the mitochondria from damage.53 Plus, estrogen controls many aspects of mitochondrial function as well as the generation of new mitochondria.54,55

Because of the relationship between estrogen and mitochondrial health, Dr. Meletis often includes a mitochondrial-supporting supplement in the regimen of patients on hormone replacement therapy. Coenzyme Q10 (CoQ10), alpha-lipoic acid, acetyl-L-carnitine, and quercetin can all be used to support mitochondrial function.

CoQ10 is one of the best-known mitochondria-supporting nutrients. Human studies have shown that giving CoQ10 to patients before cardiac surgery raises levels of this nutrient in the mitochondria of the heart and makes the mitochondria more efficient.56 It also protects the mitochondria from the stress that occurs when blood vessels are deprived of oxygen during surgery and then reoxygenated.56 In people with mitochondrial diseases known as mitochondrial cytopathies, taking 150 mg of CoQ10/day for six months improved brain health and enhanced mitochondrial function in the skeletal muscle of the CoQ10 group compared with controls.57

In animal models of aging, alpha-lipoic acid and/or acetyl-L-carnitine block the generation of harmful oxidants and improve mitochondrial function.58 In humans with coronary artery disease, alpha-lipoic acid and acetyl-L-carnitine lowered blood pressure and improved vascular function, probably in part through enhancing mitochondrial function.59

Quercetin has also emerged as a mitochondrial rejuvenating nutrient. In untrained men, 1,000 mg/day of quercetin led to a small but significant improvement in 12-minute treadmill time trial performance and a modest improvement in mitochondrial function and genes related to the creation of new mitochondria.60 Quercetin improved mitochondrial function and/or stimulated the production of new mitochondria in models of traumatic brain injury,61 the muscle atrophy that occurs after disuse,62 and aluminum-caused free radical damage.63

Conclusion

When implementing a bioidentical hormone replacement therapy regimen, it is essential to support the safe metabolism of estrogen. The gut is an important source of steroid hormones such as estrogen, and probiotic organisms play a role in how the gut metabolizes estrogens. A balanced gut microbiota also increases the effectiveness of phytoestrogen supplements such as soy. I3C and DIM are important supplements that ensure that estrogen is escorted out of the body through the safest possible pathway. Calcium-D-glucarate also assists with estrogen metabolism as it blocks an enzyme known as beta-glucuronidase, which interferes with the body’s ability to safely process estrogen and potentially harmful substances such as drugs and toxins. Additionally, mitochondrial support also is recommended during hormone replacement therapy, as all hormones originate in the mitochondria, which possess steroid hormone receptors.

Download Article:   Supporting Healthy Estrogen Metabolism During Bioidentical Hormone Replacement Therapy

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  20. Yohwan Y, et al. Isoflavones from phytoestrogens and colorectal cancer risk: A nested case-control study within the Korean Multicenter Cancer Cohort. [abstract 4823]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res. 2013;73(8 Suppl).
  21. Poluzzi E, et al. Phytoestrogens in postmenopause: the state of the art from a chemical, pharmacological and regulatory perspective. Curr Med Chem. 2014;21(4):417-36.
  22. Setchell KD, et al. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002 Dec;132(12):3577-84.
  23. Wallace BD, et al. Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity. Chem Biol. 2015 Sep 17;22(9):1238-49.
  24. Pellock SJ, Redinbo MR. Glucuronides in the Gut: Sugar-Driven Symbioses Between Microbe and Host. J Biol Chem. 2017 Apr 7. pii: jbc.R116.767434.
  25. Nowak A, Śliżewska K. β-Glucuronidase and β-glucosidase activity and human fecal water genotoxicity in the presence of probiotic lactobacilli and the heterocyclic aromatic amine IQ in vitro. Environ Toxicol Pharmacol. 2014 Jan;37(1):66-73.
  26. Kajander K, et al. Effects of multispecies probiotic supplementation on intestinal microbiota in irritable bowel syndrome. Aliment Pharmacol Ther. 2007 Aug 1;26(3):463-73.
  27. Hijová E, et al. Ability of Lactobacillus plantarum LS/07 to modify intestinal enzymes activity in chronic diseases prevention. Acta Biochim Pol. 2017;64(1):113-116.
  28. No authors listed. Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9.
  29. Walaszek Z, et al. Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis. Carcinogenesis. 1986 Sep;7(9):1463-6.
  30. Hanausek M, et al. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44.
  31. Zoltaszek R, et al. Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice. Oncol Lett. 2011 Jan;2(1):145-54.
  32. Telang NT, et al. Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992 Apr 15;84(8):634-8.
  33. Bradlow HL, et al. 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol. 1996 Sep;150 Suppl:S259-65.
  34. Higdon JV, et al. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007 Mar;55(3):224-36.
  35. Cauley JA, et al. Estrogen metabolites and the risk of breast cancer in older women. Epidemiology. 2003 Nov;14(6):740-4.
  36. Ursin G, et al. Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1999 Jun 16;91(12):1067-72.
  37. Ho GH, et al. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore. 1998 Mar;27(2):294-9.
  38. Kabat GC, et al. Urinary estrogen metabolites and breast cancer: a case-control study. Cancer Epidemiol Biomarkers Prev. 1997 Jul;6(7):505-9.
  39. Schneider J, et al. Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci U S A. 1982 May;79(9):3047-51.
  40. Sampson JN, et al. Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women. Cancer Res. 2017 Feb 15;77(4):918-25.
  41. Tworoger SS, et al. Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2004 Jan;13(1):94-101.
  42. Bradlow HL, et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev. 1994 Oct-Nov;3(7):591-5.
  43. Michnovicz JJ, et al. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21;89(10):718-23.
  44. Wong GY, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl. 1997;28-29:111-6.
  45. Dalessandri KM, et al. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7.
  46. Rajoria S, et al. 3,3’-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: a pilot study. Thyroid. 2011 Mar;21(3):299-304.
  47. Del Priore G, et al. Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol. 2010 Mar;116(3):464-7.
  48. Ramalho-Santos J, Amaral S. Mitochondria and mammalian reproduction. Mol Cell Endocrinol. 2013 Oct 15;379(1-2):74-84.
  49. Strushkevich N, et al. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10139-43.
  50. Le B, et al. New targets for increasing endogenous testosterone production: clinical implications and review of the literature. Andrology. 2014 Jul;2(4):484-90.
  51. Psarra AM, Sekeris CE. Steroid and thyroid hormone receptors in mitochondria. IUBMB Life. 2008 Apr;60(4):210-23.
  52. Wickramasekera NT, Das GM. Tumor suppressor p53 and estrogen receptors in nuclear-mitochondrial communication. Mitochondrion. 2014 May;16:26-37.
  53. Vasconsuelo A, et al. Role of 17β-estradiol and testosterone in apoptosis. Steroids. 2011 Nov;76(12):1223-31.
  54. Gigli I, Bussmann LE. Exercise and ovarian steroid hormones: their effects on mitochondrial respiration. Life Sci. 2001 Feb 16;68(13):1505-14.
  55. Klinge CM. Estrogenic control of mitochondrial function and biogenesis. J Cell Biochem. 2008 Dec 15;105(6):1342-51.
  56. Rosenfeldt F, et al. Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue. J Thorac Cardiovasc Surg. 2005 Jan;129(1):25-32.
  57. Barbiroli B, et al. Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cell Mol Biol (Noisy-le-grand). 1997 Jul;43(5):741-9.
  58. Hagen TM, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5.
  59. McMackin CJ, et al. Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. J Clin Hypertens (Greenwich). 2007 Apr;9(4):249-55.
  60. Nieman DC, et al. Quercetin’s influence on exercise performance and muscle mitochondrial biogenesis. Med Sci Sports Exerc. 2010 Feb;42(2):338-45.
  61. Li X, et al. Protective Effects of Quercetin on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2 Signaling Pathway. PLoS One. 2016 Oct 25;11(10):e0164237.
  62. Mukai R, et al. Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice. J Nutr Biochem. 2016 May;31:67-76.
  63. Sharma DR, et al. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway. Neurotoxicology. 2015 Dec;51:116-37.
Posted by DrMeletis in Articles, Townsend
Beyond Cholesterol

Beyond Cholesterol

by Chris D. Meletis, ND and Kimberly Wilkes

In pursuit of disease management, the status quo of the westernized medical model all too often becomes myopic in regards to risk management. One of the best examples of this is cardiovascular disease, which encompasses so much more than cholesterol management. Yet billions of dollars per year of statin drugs are prescribed along with generalized diet and lifestyle recommendations without adequate testing for other risk factors for cardiac health.

The hyper-focus on cholesterol means that not only are people over-treated for lipid problems but also, if their cholesterol levels are normal, they are given a clean bill of health when in reality other cardiovascular concerns may be brewing under the surface. Far too many of Dr. Meletis’ patients in his clinical practice in Portland, Oregon, have participated in corporate wellness programs and have been given glowing results. The patients will arrive at the clinic, proudly stating that their cholesterol levels are great. They will present with numbers such as total cholesterol 187, low-density lipoprotein (LDL) 120, high-density lipoprotein (HDL) 57, and fasting glucose 87.

These numbers are definitely a good start, yet further testing reveals a completely different picture in regards to their risk of cardiovascular disease. These same patients who thought they had a clean bill of health actually have raised levels of other cardiovascular risk factors such as small particle pattern LDL as well as less than favorable Lp-PLA2 levels and an imbalance in apolipoprotein B (ApoB) and lipoprotein(a), to name a few.

This article will review these and other often neglected cardiovascular disease risk markers and interventions that proactive functional medicine providers use to enhance their patients’ circulatory health.

An Inflammatory Disease

There is a lot of evidence to show inflammation is a major culprit for all the major cardiovascular concerns. In fact, scientists now believe inflammation is actually a cause of cardiovascular disease and not just a consequence.1 One way scientists know that there is a strong link between inflammation and cardiovascular disease is because levels of two inflammatory markers – C-reactive protein (CRP) and fibrinogen – are elevated in people who suffer from heart disease and stroke. In one study, elevated fibrinogen and high CRP levels independently predicted subclinical atherosclerosis in postmenopausal women with hypertension, whereas established traditional cardiovascular risk factors such as obesity, diabetes, smoking habits, family history of coronary artery disease, and high cholesterol did not have as strong an association with the disease.1

Higher levels of CRP are associated with an increased risk of developing ischemic heart disease (IHD).2 CRP causes inflammation in cells lining the coronary arteries known as endothelial cells.3 This means CRP may be directly involved in the inflammatory component of atherosclerosis.3 In another study, patients with the highest levels of C-reactive protein (more than 10 mg per liter) were significantly more likely to die from cardiac causes compared with people whose CRP levels were 2 to 10 mg per liter or less than 2 mg per liter.4

High CRP levels also are associated with stroke. Researchers compared the CRP levels in people who had a more severe type of stroke (progressive cerebral infarction) with a less severe type (non-progressive cerebral infarction).5 In the subjects with the more severe type of stroke, there was a significant rise in CRP three days after the stroke, followed by a decline on day 7 and day 14, and the CRP level was much higher compared with people who had a less severe stroke. In patients on statin drugs, scientists have found that high CRP levels increase the risk of having a stroke in the future.6

Statin drugs are known to significantly reduce CRP levels by up to 60% and therefore may have anti-inflammatory actions, but statin drugs may also dramatically reduce levels of coenzyme Q10,7 a nutrient critical for heart health. In addition, statins damage the mitochondria,8 the powerhouses of the cells that also are critical to heart health. Consequently, there may be an advantage to relying on natural agents to reduce CRP levels. For example, people who regularly take more than 78 mg vitamin E/day along with vitamin C, carotenoids, selenium, and zinc, have 22% lower high-sensitivity CRP levels compared to people who don’t supplement with vitamin E.9 A review of 12 studies involving a total of 246 participants given vitamin E and 249 people given a placebo found that two forms of vitamin E, alpha-tocopherol or gamma-tocopherol, were effective at lowering CRP levels.10

Like CRP, elevated fibrinogen levels are another indication of inflammation. Fibrinogen plays a critical role in blood clots through its conversion to fibrin, the main component of a clot’s structure. Fibrinogen rises every decade of a person’s life by an average of 25 points. This elevation in fibrinogen increases the viscosity of the blood, making it “thicker.” Clinical studies have demonstrated higher levels of fibrinogen in people with cardiovascular disease and who have an increased risk of blood clots.11 Evidence from human studies indicates the likelihood of dying from cardiac causes is greater in people with the highest fibrinogen levels (at least 4.0 gram per liter) compared with people who have the lowest levels (less than 3.4 g per liter).4

Two of the most effective natural agents used to lower fibrinogen levels, reduce the risk of stroke, and improve the health of the circulatory system are nattokinase and lumbrokinase. Nattokinase is a fermented soy extract derived from the traditional Japanese food natto. Human studies have shown nattokinase can reduce certain cardiovascular risk factors and that an important mechanism of action is the reduction of fibrinogen. In one study, healthy volunteers, people with cardiovascular risk factors, and dialysis patients were given two capsules of nattokinase (2,000 fibrinolytic units per capsule) daily for two months.12 Plasma levels of fibrinogen as well as two other coagulation factors (factor VII and factor VIII) continuously declined during nattokinase supplementation. Nattokinase did not affect blood levels of lipids.

Nattokinase can also reduce blood pressure, another risk factor for stroke, according to a double-blind, randomized, placebo-controlled study where supplementation with nattokinase was associated with a drop in both systolic and diastolic blood pressure.13 Although the decline in systolic blood pressure occurred in both genders, it was greater in males taking the nattokinase supplement, whereas in the females ingesting nattokinase, researchers also observed a decline in von Willebrand factor (vWF), which is involved in coagulation.

Like nattokinase, lumbrokinase benefits the heart in part through its ability to reduce fibrinogen levels.14,15 Due to its clot-destroying activity, lumbrokinase has been used in ischemic encephalopathy, coronary heart disease, diabetes, and deep vein thrombosis.14 In patients with cerebral infarction (stroke), lumbrokinase inhibits coagulation and reduces fibrinogen by increasing the activity of tissue plasminogen activator (t-PA), a protein that plays a role in the breakdown of blood clots.16

Niacin is another natural substance that can lower fibrinogen levels, and studies have also shown it can reduce CRP levels.17 Niacin should be used with caution in diabetics as it can worsen blood sugar levels.17

The Powerhouses of the Cells Protect the Circulatory System

Mitochondria are the cell’s batteries, and these powerhouses are responsible for producing ATP, the fuel the body needs for metabolic processes. Needless to say, these tiny organelles are responsible for the proper functioning of many organs in the body and the heart is no exception. Mitochondrial dysfunction may play an important role in the development of atherosclerosis.18 Mitochondrial DNA (mtDNA) damage can increase inflammation,18 and inflammation, as noted earlier in this article, is directly linked to cardiovascular disease.

Human and animal studies have found that an increase in the generation of reactive oxygen species (ROS), also known as free radicals, the build up of mtDNA damage, and dysfunction in the mitochondria’s respiratory chain are all related to atherosclerosis or cardiomyopathy.19-21 When researchers gathered aortic samples from people with severe atherosclerosis and compared them to samples from people without this condition, they found that people with atherosclerosis had more mtDNA damage compared to the people without.22

In mice, the extent of mtDNA damage matches the severity of atherosclerotic lesions and precedes the development of atherosclerosis.22 Mitochondrial dysfunction also increased mtDNA damage and advanced the development of atherosclerosis in mice, supporting the belief that ROS generation and mtDNA damage occurs early in the development of atherosclerosis.22

Additionally, conditions involved in the development of atherosclerosis such as high cholesterol, high blood sugar, high triglyceride levels, and aging itself all cause mitochondrial dysfunction.19,23 Researchers have shown that high levels of serum LDL cholesterol and triglycerides in mice cause mitochondrial damage and dysfunction, which leads to the development of atherosclerosis lesions and affects their composition and progression.23

Over time, excessive generation of mitochondrial reactive oxygen species destroys the insulin-producing beta-cells of the pancreas, increases oxidation of LDL cholesterol, and harms the endothelial cells lining the blood vessels.19 Each of these factors encourage the development of atherosclerosis.19

Properly functioning mitochondria are also required for the normal growth and function of vascular cells. Dysfunctional mitochondria trigger a process called apoptosis that results in the removal of unhealthy cells.24 However, apoptosis encourages the rupture of plaques, which in turn enhances the progression of atherosclerotic lesions.24 Plaque rupture can lead to heart attacks and strokes.19 Oxidized LDL, a more harmful form of LDL cholesterol that has been attacked by free radicals, triggers apoptosis of cells involved in plaque rupture and atherosclerosis,25,26 and mitochondria dysfunction is involved in this process.27  This may explain why the oxidation of LDL is an important step in the development of atherosclerosis.27

Mitochondrial dysfunction is associated with hypertension, another cardiovascular disease risk factor.19 Declines in mitochondrial energy and calcium overload are involved in the development of hypertension.19,28 In mice where the mitochondrial antioxidant system is dysfunctional, arterial blood pressure rises with age or when eating a high-salt diet.29 In humans, mitochondrial mutations lead to hypertension, high cholesterol, and low magnesium levels.30

People who have diabetes are at a greater risk of developing coronary artery disease,31 and people with type 2 diabetes are more likely to experience ischemic events and death after a first heart attack.32,33 One of the ways in which diabetes may increase the risk of cardiovascular disease is through mitochondrial dysfunction.34 Research indicates that mitochondrial dysfunction is involved in the vascular damage caused by glucose.34 Lowering levels of mitochondrial ROS prevents blood-sugar-related damage and the formation of advanced glycation end products (AGE), harmful compounds involved in vascular damage and atherosclerosis.34

Given the role that mitochondrial dysfunction plays in diabetes, it is disturbing that conventional treatment for type 2 diabetes includes statin drugs. As noted earlier in this article, statin drugs cause mitochondrial dysfunction.

Due to the mitochondria importance in cardiovascular health, supplements that support mitochondrial function may be beneficial. One of the most well-known mitochondrial-supporting supplements is coenzyme Q10 (CoQ10). People who received 300 mg/day of CoQ10 supplements for 2 weeks before cardiac surgery experienced improved mitochondrial CoQ10 levels in their hearts and enhanced mitochondrial efficiency.35 During cardiac surgery, arteries are deprived of oxygen as the blood supply is stopped; and when the blood and oxygen supply is reintroduced, it leads to hypoxia-reoxygenation stress, which is damaging to the heart. CoQ10 improves the heart tissue’s tolerance to this hypoxia-reoxygenation stress.35

Alpha-lipoic acid and acetyl-L-carnitine, two other agents known to enhance mitochondrial function, improved arterial health in a study of people with hypertension.36 Over eight weeks, the combination of alpha-lipoic acid and acetyl-L-carnitine lowered systolic blood pressure in all 36 subjects. The blood-pressure-lowering effect was the most significant in participants with higher blood pressure and in subjects with the cluster of heart disease risk factors known as the metabolic syndrome.

Antioxidant supplements can help support the mitochondria by controlling levels of ROS and reduce the oxidation of LDL. Green tea, CoQ10, red wine, and red grape seed extract are just some of the supplements and dietary components that can lower oxidized LDL.37-40

An Often-Neglected Aspect of Cardiovascular Health

When physicians evaluate cardiac risk factors in their patients, one aspect of cardiovascular health that is often neglected is testing nitric oxide levels. Maintaining optimal levels of nitric oxide is crucial for the health of the cardiovascular system. Lower levels of nitric oxide are associated with many cardiovascular diseases including hypertension, atherosclerosis, stroke, and heart failure.41 Scientists believe that increased levels of ROS are to blame for decreased nitric oxide absorption.41

L-Citrulline and beetroot juice both have a lot of research backing up their ability to raise nitric oxide levels. Heart failure is characterized by increased activity of angiotensin–converting enzyme and reduced peripheral blood flow, both of which reduce the generation of nitric oxide.42 L-Citrulline has improved dilation of the blood vessels of stable systolic heart failure patients.42 Studies also have shown that L-citrulline can reduce arterial stiffness in middle-aged men and postmenopausal women43,44 and that it can reduce postoperative pulmonary hypertension.45 L-Citrulline is especially effective when combined with the antioxidant glutathione, since glutathione prevents the oxidative damage to nitric oxide caused by exposure to ROS.46

Beetroot juice works in a manner similar to L-citrulline in that is raises levels of nitric oxide.47 In peripheral arterial disease, not enough blood reaches tissues resulting in intermittent claudication pain during walking. In peripheral arterial disease patients, beetroot juice increased nitric oxide levels and improved peripheral tissue oxygenation in areas of hypoxia (low oxygen).48 It also increased exercise tolerance, and patients given beetroot juice walked for 17% longer compared to people taking a placebo.48 In addition, studies have shown beetroot juice enhances vascular function in people with high cholesterol49 and improves muscle power in individuals with systolic heart failure.50

A Good Night’s Sleep Equals a Healthy Heart

During obstructive sleep apnea, a person stops breathing intermittently throughout the night. Sleep apnea can mirror peripheral ischemia as sleep apnea literally is low oxygen  levels due to nighttime desaturation. When asking a patient about how they are sleeping, a doctor recognizes it is just as much about how much oxygen the person is receiving as it is about insomnia.

There is a strong link between sleep apnea and daytime hypertension and it may also be associated with pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias.51 One study of Hispanics found that sleep apnea increases the risk of peripheral artery disease.52 People with sleep apnea also have increased carotid and aortic wall thickness and high-risk carotid atherosclerosis plaques.53

Proper sleep in a dark room also allows the body to secrete healthy amounts of melatonin, a hormone that acts like an antioxidant. Melatonin is important in maintaining the endothelium, the lining of the blood vessels.54 An analogy can be made between a healthy blood vessel (the circulatory system) and a non-stick pan. It is not until there is damage to the non-stick coating that there is an issue with the frying pan and food begins to stick. Yet, it’s not the item that is sticking to the pan that caused the problem in the first place. It was the problem with the non-stick coating. The endothelium lining of the blood vessel walls is like that non-stick coating. Therefore, we must address issues that are occurring in the endothelium, otherwise it will do no good to lower cholesterol.

Melatonin is an important ally in keeping the endothelium strong and healthy.54 To study the effect of melatonin on the endothelial cells lining the blood vessels, researchers evaluated this hormone’s effects on intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), CRP, and nitric oxide in patients with three-vessel coronary disease.54 The study participants were given either 10 mg oral melatonin one hour before sleeping for one month or a placebo. After one month, people taking the melatonin experienced a significant drop in levels of ICAM, VCAM, and CRP while people taking the placebo experienced an increase in VCAM. Nitric oxide levels also increased in the melatonin group, whereas they decreased in the placebo group.

According to the researchers, “The results of this study suggested that melatonin may have beneficial effects on endothelial oxidative stress even in patients with severe and advanced atherosclerosis.”

Genetic Risk Factors

Folate is critical for cardiovascular health. Yet, due to a genetic mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), many people lack the ability to convert the folic acid found in supplements and fortified foods into the biologically active form of folate known as L-5-Methyltetrahydrofolate (L-5-MTHF). Functional medicine providers often look for this genetic risk factor, specifically the MTHFR 1298 mutation and C677T mutation. When these mutations are not adequately compensated for, it’s common for homocysteine levels to also be elevated.55 Homocysteine is an amino acid linked to cardiovascular disease.

Often one of the first clues that a person has a MTHF mutation is that their mean corpuscular volume (MCV) is starting to creep above 90. The average red blood cell lives 90 to 120 days and can serve as the proverbial coal miner’s canary in regards to vitamin B12 and folate deficiency. It is important that anyone with these MTHF mutations supplement with L-5-MTHF rather than folic acid.

Cholesterol Isn’t the Only Lipid To Be Worried About

Besides LDL cholesterol, there are several other lipid risk factors for coronary heart disease and stroke, yet these risk factors are usually ignored in conventional medicine settings. One of these lipid risk factors is lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that serves as a marker for vascular inflammation and rupture-prone plaque.56 Most heart attacks and strokes are caused by ruptured plaque rather than blocked blood vessels. Higher Lp-PLA2 activity is associated with a greater risk for fatal and nonfatal coronary heart disease events.57 Because Lp-PLA2 is vascular specific, testing for it can be more beneficial than testing for CRP,58 which is a marker for systemic inflammation and can be elevated for other reasons besides heart disease.

Another lipid-related cardiovascular risk factor is small dense low-density lipoprotein particles, which are especially prone to triggering atherosclerosis and are much more harmful than larger particle LDL. This is why only testing total and LDL cholesterol levels does not present a complete picture of a person’s coronary health. One study found that eating a Mediterranean diet supplemented with nuts increased the LDL particle size.59

Finally, it’s also important to monitor levels of lipoprotein(a) and apolipoprotein B (ApoB), components of lipids involved in atherosclerosis and cardiovascular disease. Niacin is one supplement known to lower lipoprotein(a) levels60 while omega-3 fatty acids have lowered ApoB.61

Other Cardiovascular-Supporting Supplements

In addition to the dietary supplements already discussed in this article, other nutrients show promise in enhancing circulatory health. Berberine is a botanical that has anti-inflammatory, antioxidant, and heart-protective properties.62 In patients with congestive heart failure, 1.2 to 2 grams/ day of berberine decreased ventricular premature complexes and reduced mortality.63 Berberine also improves insulin resistance, which is another way in which it improves cardiovascular health.64

Another important addition to a cardiovascular health regimen is vitamin D. Low levels of vitamin D are linked to peripheral artery disease65 and an increased risk of heart attacks.66 Vitamin D combined with gamma-tocopherol, vitamin C, and tetrahydrobiopterin (BH4) was effective in blocking atherogenesis and formation of plaques.67 Vitamin E reduces the risk of venous thromboembolism68 while B vitamin deficiency may increase the risk of venous thrombosis.69

Conclusion

Cholesterol is only one piece of the cardiovascular disease puzzle. Other, possibly even more important, risk factors for heart disease and stroke include fibrinogen, CRP, mitochondrial dysfunction, nitric oxide levels, sleep apnea, the MTHFR genetic mutation, Lp-PLA2, small dense low-density lipoprotein particles, lipoprotein(a), and ApoB. The most effective regimens for supporting cardiovascular health address all of these risk factors.

Download Article: Beyond Cholesterol

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