CHAPTER 5: NUTRITIONAL SUPPLEMENTS AND BOTANICALS





INTRODUCTION

This section encompasses nutritional supplements, botanicals (herbs), and compounds that are naturally found in the body. Although some of these are also classed as pharmaceuticals, nearly everything in this section can be purchased without a prescription. (The exception is injectables.) We have not included each and every supplement that is available on the market, but have limited our selection to those for which there is relevant medical research, or which are in common use either by CFS/ME clinicians or by CFS/ME patients themselves.





Nutritional supplements are an essential component of any CFS/ME treatment protocol. Research has shown that people with CFS/ME are routinely deficient in many important nutrients (notably zinc, magnesium, and carnitine). These deficiencies, in and of themselves, can decrease the degree to which the body can absorb and make use of other nutrients. Even when there are no clinical nutritional deficiencies, the physiological demands of a chronic illness make it necessary to provide additional nutritional support – especially in light of the numerous GI problems prevalent in the CFS/ME population, which may lead to malabsorption. For these reasons, and because most CFS/ME doctors recommend supplements, this section attempts to be as inclusive as possible.





There is a method to taking nutritional supplements. As with pharmaceuticals, supplements should initially be taken in very small doses to test for sensitivity. Even if a supplement consists of something “natural” there is nothing natural about taking it in concentrated doses. Your body reacts to these as it would to any chemical. For that reason, it is wise to take supplements with food, unless instructed otherwise.





“Take with food” means eat a little first, then take the supplement, then eat some more. By sandwiching the supplement within a meal, you lower the risk of reactions, as the supplement is processed along with food. Sandwiching supplements also reduces the risk of heartburn. When a supplement is taken with water only it floats to the top of the stomach, where it can easily flow back into the esophagus, causing irritation.





New supplements should be taken one at a time. That is, don't start several supplements at once, even if they act synergistically. Take the new supplement for three or four days before introducing another. This allows you to evaluate the supplements for possible negative reactions or sensitivities.





Supplements can be quite expensive and are not usually covered by health insurance. But purchasing the cheapest brand is not always the wisest course to take. There is a wide range in quality when it comes to nutritional supplements. Some of the cheapest brands may not even contain the ingredients on the label. It is best to stick to well-known brands and to purchase from reputable suppliers. (See Appendix D: Mail Order Suppliers.) Purchasing online, rather than from retail outlets can cut the cost of expensive supplements in half. Whenever possible, we have included recommendations in each entry.





Most online suppliers include product label information on their websites, but for those who wish to compare the product labels of a supplement made by different manufacturers, or check into recalls or FDA notices for specific supplements, there are several helpful websites that will provide this information:

The Dietary Supplements Labels Database. This is a very useful website that allows searches for product labels by manufacturer and by product. From the website: “The Dietary Supplements Labels Database offers information about label ingredients in more than 6,000 selected brands of dietary supplements. It enables users to compare label ingredients in different brands. Information is also provided on the "structure/function" claims made by manufacturers.” http://dietarysupplements.nlm.nih.gov/dietary/index.jsp

Natural Products Foundation. The NPF keeps an excellent database of supplements, as well as the medical conditions they are used for. From the website: “The Dietary Supplement Information Bureau™ (DSIB™) was founded in 2001 to promote the responsible use of vitamins, minerals, herbs and specialty supplements. In June 2008 DSIB became part of the Natural Products Foundation, a not-for-profit organization whose mission is to promote and facilitate research and education related to natural products for the benefit of consumers and industry.” http://www.naturalproductsinfo.org/

Consumer Healthcare Products Association. The CHPA website provides a search for government warnings and decisions regarding most OTC medications and supplements. From the website: “The Consumer Healthcare Products Association (CHPA), founded in 1881, is a member-based association representing the leading manufacturers and distributors of nonprescription, over-the-counter (OTC) medicines and dietary supplements.” http://www.chpa-info.org/





FURTHER READING

Dowson, David, MD. “Nutrition Toxicity and ME/CFS.” http://www.annhilltrust.org/nutrition-toxicity-and-me.html





5-HTP





DESCRIPTION. 5-Hydroxytryphophan (5-HTP) is a naturally occurring amino acid which serves as a precursor to the neurotransmitter serotonin.





BACKGROUND. 5-HTP is a precursor as well as a metabolic intermediate in the synthesis of serotonin and melatonin from tryptophan. Through the action of vitamin B6, 5-HTP is converted in the liver and nervous system to 5-HP (serotonin). Most commercially marketed 5-HTP is derived from the seeds of the Griffonia simplicifolia. a woody climbing shrub native to West Africa.





Serotonin is the most abundant neurotransmitter in the human body. In the brain it plays a crucial role in sleep, mood, learning, memory and appetite. However, the vast majority of serotonin, 90%, is produced in the lining of the intestines, which has led Dr. Michael Gershon, chairman of the department of anatomy and cell biology at Columbia University, to refer to the gut as the “second brain.” This eponym is apt, for today gastroenterologists routinely prescribe serotonin enhancers for treating GI motility problems.





USES IN CFS/ME. Several studies have shown that 5-HTP is an effective overall treatment for fibromyalgia. For people with CFS/ME, 5-HTP is most often used as a sleep aid.





PROTOCOL. Dr. Rodger Murphree, a chiropractor and nutritionist who has been treating CFS/ME for over 15 years, recommends taking 5-HTP 30 minutes before bed, on an empty stomach, with four ounces of juice. Start with 100 mg, then go to 150 and then to 200. Don’t go above 300 mg. It may take several nights to take effect. If it doesn’t work in two weeks, Dr. Murphree suggests stopping and switching to melatonin. According to Dr. Murphree, patients who stay on 5-HTP for more than three months should take a broad-based amino acid supplement to balance out the other neurotransmitters.





PROS AND CONS. 5-HTP, like many antidepressants, can cause strange, vivid dreams. These dreams usually diminish over time. Excessively high serotonin levels can cause insomnia, hyperactivity, headache, and increased heart rate. CFS/ME patients who have a negative reaction to 5-HTP should either lower the dose or stop.





AVAILABILITY AND COST. 5 HTP is sold in most health food stores and by online distributors. A bottle of 60 tablets can cost as little as $8.00.





CAUTION: High doses of 5-HTP can cause serotonin syndrome, a condition in which serotonin is raised to dangerous levels. Taking 5-HTP with serotonin-enhancing pharmaceuticals such as triptans (for migraines), antidepressants, Demerol, Robitussin, and Ultram can also lead to serotonin syndrome.





FURTHER READING

Good summary of 5-HTP as a CFS/ME treatment: http://www.immunesupport.com/98wtr002.htm

Discussion of 5-HTP as a CFS/ME treatment: http://aboutmecfs.org.violet.arvixe.com/Trt/5-HTP.aspx

Dr. Teitelbaum on 5-HTP and other natural sleep aids: http://www.healthy.net/scr/Column.aspx?Id=647

General information on 5-HTP: http://www.herbwisdom.com/herb-5-htp.html





PATIENT REVIEWS

CFS/ME patient reviews of 5-HTP: http://www.revolutionhealth.com/drugs-treatments/rating/5-htp-5-hydroxytryptophan-for-chronic-fatigue-syndrome-cfs-cfids-me





RESEARCH

Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V. “Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome.” J Int Med Res. 1990 May-Jun;18(3):201-9. http://www.ncbi.nlm.nih.gov/pubmed/2193835 (Abstract)

Sarzi Puttini P, Caruso I, “Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: a 90-day open study.” J Int Med Res.1992 Apr;20(2):182-9. http://www.ncbi.nlm.nih.gov/pubmed/1521674 (Abstract)





ALPHA KETOGLUTARATE





DESCRIPTION. Alpha ketoglutarate (AKG) is an ionic form of alpha ketoglutarate acid, an intermediate in the tricarboxylic cycle (Krebs cycle, or citric acid cycle).





BACKGROUND. Alpha ketoglutarate (AKG) fulfills a vital role in the metabolism and utilization of carbohydrates, proteins, and long-chain fatty acids. Its best known function is as a component of a number of energy-producing cycles at the cellular level. The first of these, the Krebs cycle, breaks down and transforms citric acid through a series of enzyme-controlled reactions to produce adenosine triphosphate (ATP), a crucial energy source for many cell processes. AKG, as an early intermediate in the Krebs cycle, forms the basis for all further transformations. It is also required for catabolism of many amino acids, another process that generates energy.





Another important function of AKG involves the formation of nonessential amino acids (amino acids that are biosynthesized in the body), notably glutamate and, through its action, proline, alanine, aspartic acid, and asparagine. AKG is also one of the most important transporters of cellular nitrogen, combining with nitrogen in the cell to prevent an overload of ammonia in the body.





USES IN CFS/ME. AKG is used as a short-term energy enhancer and for Krebs cycle support in patients with CFS/ME. Because of its essential role in energy production and carbohydrate metabolism, it may be useful as a general CFS/ME treatment as well. AKG is also beneficial for the intestines. Many people with CFS/ME suffer from digestive problems, including food sensitivities, dysbiosis, slow transit time, small intestine bacterial overgrowth (SIBO) and a host of other disorders. AKG is converted in the intestines into glutamate, which regulates gastric emptying and provides an environment for healthy gut flora. AKG also prevents damage to the mucosal lining of the intestines by inhibiting oxidative stress.





PROTOCOL. The suggested dosage of AKG is one or two 300 mg capsules per day, which can be taken with meals. Because of its location in the Krebs cycle, alpha ketoglutarate is generally more effective if taken with other Krebs cycle supports such as vitamin C, B vitamins, essential fatty acids (evening primrose oil, borage oil, or fish oil), magnesium, nutritional supplements, and NAC (N-acetyl-L-cysteine).





PROS. Because alpha ketoglutarate is not a stimulant but works through natural metabolic pathways, it is a relatively risk-free source of energy. People who take alpha ketoglutarate usually do not "crash" afterward. It has no reported side effects at recommended doses. Patients with low levels of AKG (as confirmed by an Organic Acids Test) have noted significant improvement in energy levels with alpha ketoglutarate supplementation.





CONS. Results tend to be less dramatic than those obtained with CoQ10, which may make this product less attractive to those who want a greater boost. Among its many function, AKG leads to production of nitric oxide (NO), which Dr. Pall has implicated in many CFS/ME symptoms. He has recommended that NO should be down regulated in people with CFS/ME. Because AKG is normally combined with excitatory amino acids, it can cause insomnia.





AVAILABILITY AND COST. Pure AKG is difficult to find. Most suppliers combine AKG with an amino acid, such as arginine or glutamine. Douglas Labs sells a 90-tablet bottle of AKG (300 mg) combined with vitamin B6, calcium and phosphorus for $18.





FURTHER READING

Benefits of AKG and its functions in the Krebs cycle: http://www.ei-resource.org/articles/general-environmental-health-articles/influencing-your-krebs-cycle/

A detailed description of Krebs cycle intermediaries, including AKG. Very technical. http://www.nutritionreview.org/library/krebs.php





RESEARCH

Hou Y, Wang L, Ding B, Liu Y, Zhu H, Liu J, Li Y, Kang P, Yin Y, Wu G. “Alpha-Ketoglutarate and intestinal function.” Front Biosci. 2011 Jan 1;16:1186-96. http://www.ncbi.nlm.nih.gov/pubmed/21196226 (Abstract)





ALPHA LIPOIC ACID





DESCRIPTION. Alpha lipoic acid, or lipoic acid, is a an organic compound derived from caprylic acid. It is both fat and water soluble.





BACKGROUND. Alpha lipoic acid (ALA) has been referred to as the “mother” of all antioxidants. This well-deserved epithet is due to the fact that not only does it act as a potent free radical scavenger, it can transform an oxidant into an antioxidant. Notably, when glutathione is oxidized, ALA can transform it back into its reduced form, thus increasing the pool of glutathione.





ALA is produced throughout the body through the biosynthesis of fatty acids. Although it is found in many foods (especially organ meats, yeast extract and leafy green vegetables), alpha lipoic acid is not readily available through dietary sources. As a consequence, all alpha lipoic acid supplements must be synthesized.

Alpha lipoic acid has been studied for its effects on many disease states, including treatment for cardiovascular disease, prevention of migraines, preventing organ dysfunction, slowing the progression of Alzheimer's disease, reducing inflammation, and the treatment of chronic diseases involving oxidative stress. A study conducted in 1999 by Kishi et al found that the reduced glucose uptake in diabetes was completely reversed with alpha lipoic acid, which not only corrected the deficit, but improved the peripheral neuropathy found in diabetics.





A detailed proposal submitted to the National Cancer Institute by the Chemical Selection Working Group (see below) indicates that ALA may work best when combined with acetyl L-carnitine. Acetyl-L-carnitine facilitates the movement of fatty acids into the mitochondria for energy and is also used to generate acetyl coenzyme A, while ALA is involved in mitochondrial ATP production and can recycle other antioxidants. The authors propose that the combination of acetyl L-carnitine and ALA may have significant synergistic effects – increasing energy and reducing oxidative stress.





USES IN CFS/ME. A number of CFS/ME clinicians and researchers, notably Martin Pall and Dr. Myhill, have pointed out that oxidative stress is a primary component in the cascade of CFS/ME symptoms. Oxidative stress can affect every system in the body, and has particularly deleterious effects on oxygen transport systems (blood). ALA has been shown to improve the integrity of red blood cells (which are often abnormal in CFS/ME patients) leading to elevated glutathione levels. Glutathione, one of the body's most potent antioxidants, is often diminished in CFS/ME patients.





PROTOCOL. The “R” form is the most bioavailable and stable form of alpha lipoic acid. (The “S” form deteriorates rapidly.) There is no set protocol for ALA. CFS/ME patients who have tried ALA recommend beginning at the lowest dose (100 mg) to avoid detox symptoms (headache, “hungover” feeling).





PROS. ALA has no documented side effects at low doses. Many people have noted an increase in energy, muscle strength, and mental alertness, particularly when taken with acetyl-L carnitine.





CONS. Too high a dose can cause insomnia and stomach upset. ALA lowers blood sugar, which may pose a problem for people with hypoglycemia. There is one study that suggests that ALA competes with biotin (vitamin B7) in rats, but the results have not been confirmed in humans. Those who take large quantities of lipoic acid may wish to independently supplement with biotin.





AVAILABILITY AND COST. ALA is widely available in health food stores and through online distributors. It is not expensive. A 60-capsule bottle of R-ALA (100 mg) can cost less than $10.





FURTHER READING

This article questions the necessity of supplementing lipoic acid with biotin. http://www.geronova.com/content/lipoic-acid-biotin





RESEARCH

Kishi, Yutaka, James D. Schmelzer, Jeffrey K. Yao, Paula J. Zollman, Kim K. Nickander, Hans J. Tritschler, and Phillip A. Low. “ a-Lipoic Acid: Effect on Glucose Uptake, Sorbitol P a t h w a y, and Energy Metabolism in Experimental Diabetic Neuropathy.” Diabetes, VOL. 48, October 1999 http://diabetes.diabetesjournals.org/content/48/10/2045.full.pdf





Mirjana M, Jelena A, Aleksandra U, Svetlana D, Nevena G, Jelena M, Goran P, Melita V. “Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats.” Eur J Nutr. 2011 Nov 18. http://www.ncbi.nlm.nih.gov/pubmed/22094580 (Abstract)





“Acetyl-L-Carnitine/a-Lipoic Acid Supplements.” This is a proposal prepared for the National Cancer Institute by the Chemical Selection Working Group (CSWG) on behalf of Technical Resources International, Inc. It contains a thorough and exhaustive account of the mechanisms of alpha lipoic acid. http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/carnliposupp.pdf





AMINO ACIDS





Carnitine, Glutamine, Lysine, Taurine





DESCRIPTION. Amino acids are nitrogen-containing chemical units (amines) that, bound together, make up protein.





BACKGROUND. The amino acids, in various combinations, form the hundreds of types of proteins present in every living organism. These proteins are essential for nearly all processes that induce cell growth and repair, as well as for continued maintenance of every body tissue, organ, and structure within the body. Amino acids link together to form tens of thousands of proteins and enzymes, each of which has a specific function. They can also perform as individual units. Single amino acids can act as neurotransmitters or as precursors to neurotransmitters in the central nervous system. Therefore, not only are they responsible for providing and maintaining the very substances of which we are made, but also for the communications system that enables us to plan, dream, think, feel, and direct our every action.





There are 20 primary amino acids. About 80% are produced in the liver and the remaining 20% must be obtained from food. Whether an amino acid can be produced within the body is what distinguishes the essential from nonessential amino acids. The essential amino acids (those which must be obtained from food sources) are arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Nonessential amino acids (those which can be produced within the body) include alanine, glutamine, asparagine, glycine, proline, and serine. Given the countless functions that amino acids perform, a protein shortage or congenital defect in amino acid synthesis can lead to problems that involve every system in the body.





Amino acids occur in two isomers: L and D. The L isomer is the form most commonly found in nutritional supplements.





USES IN CFS/ME. Specific amino acids, both essential and nonessential, have been recommended as treatments by a number of CFS/ME clinicians. Their applications include mediation of hyperactive nervous system responses, repair of leaky gut and other intestinal disturbances, and regulation of the fundamental CFS/ME metabolic dysfunction that results in loss of cellular energy.





A number of researchers have documented imbalances in amino acid ratios among people with CFS/ME. In an article published in 1994, Dr. Alexander Bralley and Dr. Richard Lord noted that people with CFS/ME commonly have deficiencies in tryptophan, phenylalanine, taurine, isoleucine, and leucine. They also found lower than normal amounts of arginine, methionine, lysine, threonine, and valine in a smaller number of CFS/ME patients. It is significant that the most common deficiencies found by Drs. Bralley and Lord are of phenylalanine and tryptophan because these two amino acids are precursors to the catecholamines and serotonin, neurotransmitters that are closely involved with sleep function, stress responses, and regulation of pain and mood.





Dr. Scott Rigden has also noted that many of his patients with metabolic abnormalities have an imbalance in amino acid ratios. The implication is that, for these patients, amino acids may be either synthesized or utilized at a slower rate or appear in such disequilibrium that they no longer function together with full efficiency – perhaps giving a clue to the origins of the collagen formation problems and enzyme disturbances common in many patients with CFS/ME.

An extensive study published in 2005 by Jones et al compared organic acids in people with CFS/ME, major depression, and rheumatoid arthritis. The researchers found lower levels of taurine, GABA, histidine and tyrosine in the group with CFS/ME. The researchers also found low levels of histidine in plasma from rheumatoid arthritis patients, leading the team to speculate that a similar etiology might be involved for the two illnesses (i.e. inflammation).





A more recent study by Niblett et al confirms specific deficiencies in CFS/ME patients of asparagine, phenylalanine, leucine, isoleucine, valine, and the organic acid, succinic acid, as well as increases in 3-methylhistidine (an amino acid associated with protein loss) and tyrosine. The authors concluded that “urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.”





In 2012 a team of Australian researchers identified low levels of glutamine and ornithine, along with other metabolites that participate in the urea cycle, in a group of CFS/ME patients. (CFS/ME patients are consistently low in uric acid.) The researchers suggested that a specific disturbance of amino acid and nitrogen metabolism was implicated in CFS/ME which might potentially serve as a biomarker.





Amino acid supplementation has received particular attention as a treatment for CFS/ME from nutritionists. Using an amino acid analyzer to measure specific imbalances, Drs. Bralley and Lord tailored a supplement to correct amino acid deficiencies. In a study of 25 CFS/ME patients, they found that correcting specific amino acid imbalances resulted in 50% to 100% improvement in symptoms (Journal of Applied Nutrition, 1994). The greatest effect was noted in energy levels. Two patients who had had CFS/ME symptoms for 15 years experienced dramatic improvement. Patients also reported improvement in cognitive function and elimination of "brain fog."





It should be noted that single amino acids taken as dietary supplements may not be well tolerated by patients with serious metabolic disturbances. Also note that tyrosine, an amino acid often found to be deficient in CFS/ME patients, is seldom recommended. Tyrosine is a dopamine precursor which triggers symptoms in patients with inflammatory disorders such as migraine, interstitial cystitis, and rosacea. Dr. Bell has observed that in CFS/ME patients, dopamine precursors make the majority of CFS/ME patients feel much worse.





FURTHER READING

Bralley J., Alexander and Richard S. Lord. “Treatment of Chronic Fatigue Syndrome with Specific Amino Acid Supplementation.” Journal of Applied Nutrition, Vol 46, No 3, 1994. http://www.metametrix.com/files/learning-center/articles/Chronic-Fatigue-Amino-Acids.pdf





Dr. Michael Rosenberg's amino acid protocols for treating CFS/ME. http://www.prohealth.com/library/showarticle.cfm?id=4337&t=CFS/ME_FM





RESEARCH

Armstrong, Christopher W., Neil R. McGregor, John R. Sheedy, Ian Buttfield, Henry L. Butt, Paul R. Gooley. “NMR metabolic profiling of serum identifies amino acid disturbances in Chronic Fatigue Syndrome.” Clinica Chimica Acta. Available online 21 June 2012.

http://www.sciencedirect.com/science/article/pii/S0009898112003270





Jones, Mark G., Elizabeth Cooper, Saira Amjad, Stewart C. Goodwin, Jeffrey L. Barron, Ronald A. Chalmers. “Urinary and plasma organic acids and amino acids in chronic fatigue syndrome.” Clin Chim Acta. 2005 Nov;361(1-2):150-8. http://www.cfids-cab.org/cfs-inform/Hypotheses/jones.etal.05.pdf





Niblett SH, King KE, Dunstan RH, Clifton-Bligh P, Hoskin LA, Roberts TK, Fulcher GR, McGregor NR, Dunsmore JC, Butt HL, Klineberg I, Rothkirch TB. “Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome.” Exp Biol Med (Maywood). 2007 Sep;232(8):1041-9. http://www.ncbi.nlm.nih.gov/pubmed/17720950 (Abstract)





CARNITINE





DESCRIPTION. Carnitine (L-carnitine) is one of the methyl group donors. It is crucial for the transport of long-chain fatty acids into the mitochondria of cells, providing energy to skeletal and heart muscle. Carnitine also aids in reducing toxic buildup of organic acids which are a natural byproduct of cell metabolism. Carnitine deficiency produces fatigue, muscle weakness, malaise, exercise intolerance, heartbeat abnormalities, and tissue acidosis. Carnitine deficiency can result from congenital metabolic defects as well as the administration of antibiotics containing pivalic acid (e.g., Pondocillin).





USES IN CFS/ME. Japanese researchers have shown that CFS/ME patients have a deficiency in intracellular levels of acylcarnitine. They found no deficiency in serum levels of free carnitine, however, indicating the deficiency is not the result of lack of carnitine in the system but of its derivative, acylcarnitine. Acylcarnitine deficiency can be expected to produce not only the fatigue and weakness characteristic of interruption in mitochondrial processes but also the malaise typical of autointoxication. Dr. Hiroko Kuratsune and colleagues discovered that in their sample group of 38 CFS/ME patients, low levels of acylcarnitine covaried with the severity of the illness (Clinical Infectious Diseases, 1994). As symptoms improved, so did acylcarnitine levels. In a study comparing amantadine and carnitine, Dr. Audrius Plioplys and Dr. Sigita Plioplys found "statistically significant clinical improvement" after eight weeks of treatment with L-carnitine (Neuropsychobiology, 1997).





A subsequent study in 2004 by Okada et al, found secondary proof for acetyl-carnitine deficiency in CFS/ME patients. Using MRI imaging, they found that there was a reduction in gray matter in the prefrontal cortex of CFS/ME patients as compared to controls. The researchers concluded that their results were “consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.”





In a recent study conducted in 2011, researchers from the University of South Australia compared L-carnitine levels of 44 CFS/ME patients to 49 controls. They found that levels of acylcarnitine was 30-40% lower in CFS/ME patients. The authors hypothesized that the administration of omega-3 fatty acids in combination with L-carnitine would improve chronic fatigue syndrome symptomology.





PROTOCOL. Carnitine can be taken in liquid or pill form as an over-the-counter nutritional supplement. As a food supplement, the general recommended dosage is 1000 mg/day taken with a meal. The liquid is often better tolerated than the pill form although patients with chemical sensitivities should note that the liquid may also contain artificial flavors, colors, preservatives (methylparaben), and sucrose.





Dr. Teitelbaum has observed that in his experience acetyl-L-carnitine is much more effective that L-carnitine. This is due to the fact that acetyl-L-carnitine crosses the blood-brain barrier, as opposed to L-carnitine, which is too rapidly excreted by the kidneys to be adequately utilized by the brain. Dr. Teitelbaum recommends taking 500 mg of pure acetyl-L-carnitine 2-3 times a day. In low doses, acetyl-L-carnitine can mimic the effects of pyridostigmine and galantamine, increasing the availability of acetylcholine in both the peripheral and central nervous systems.





Because carnitine interferes with thyroid hormone production, thyroid levels (free T3 and T4, as well as TSH) should be taken before beginning supplementation. Even if thyroid hormone levels fall within the normal range, carnitine should not be taken for more than a month. Signs of thyroid suppression are dry skin, low energy level, weight gain, excessive sleep, and hormonal disturbances.





PROS. L-Carnitine as a food supplement is widely available. Patients have reported increased muscle function, decreased weakness, and overall improved stamina and well-being after a few weeks of carnitine supplementation. In some cases, the benefits remain even after finishing the course of treatment.





CONS. Carnitine is not recommended for patients with low thyroid function, as it interferes with thyroid hormones. Excess amounts of carnitine can cause diarrhea and stomach upset, so start with low doses.





AVAILABILITY AND COST. A 12 oz bottle of the liquid nutritional supplement Mega L -Carnitine (Twin Labs) can be purchased online at Vitacost for $10. At the recommended dosage of 1 tablespoon a day, the bottle will last for 1 month. A 30-capsule bottle of acetyl-L-carnitine costs around $18. (There are many brands. Check Vitacost for a cost comparison.)





FURTHER READING

Dr. Teitelbaum's carnitine protocol: http://www.endfatigue.com/health_articles_c/CFS_FM-acetyl-l-carnitine_for_cfs.html





RESEARCH

Benvenga S, Amato A, Calvani M, Trimarchi F. “Effects of carnitine on thyroid hormone action.” Ann NY Acad Sci. 2004 Nov;1033:158-67. http://www.ncbi.nlm.nih.gov/pubmed/15591013 (Abstract)

Colucci S, Mori G, Vaira S, Brunetti G, Greco G, Mancini L, Simone GM, Sardelli F, Koverech A, Zallone A, Grano M. “L-carnitine and isovaleryl L-carnitine fumarate positively affect human osteoblast proliferation and differentiation in vitro.” Calcif Tissue Int. 2005 Jun;76(6):458-65. http://www.ncbi.nlm.nih.gov/pubmed/15906015 (Abstract)

Eder K, Felgner J, Becker K, Kluge H. “Free and total carnitine concentrations in pig plasma after oral ingestion of various L-carnitine compounds.” Int J Vitam Nutr Res. 2005 Jan;75(1):3-9. http://www.ncbi.nlm.nih.gov/pubmed/15830915 (Abstract)

Ho JY, Kraemer WJ, Volek JS, Fragala MS, Thomas GA, Dunn-Lewis C, Coday M. Häkkinen K, Maresh CM. “L-Carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women.” Metabolism. 2010 Aug;59(8):1190-9. http://www.ncbi.nlm.nih.gov/pubmed/20045157 (Abstract)

Holme, Elisabeth, Carl-Eric Jacobson, Ingalill Nordin, Joachim Greter, Sven Lindstedt, Bengt Kristiansson, Ulf Jodal. “Carnitine Deficiency Induced by Pivampicilin and Pivmecillinam Therapy.” The Lancet. Volume 334, Issue 8661, Pages 469 - 473, 26 August 1989. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)92086-2/abstract (Abstract)

Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T. “Acylcarnitine deficiency in chronic fatigue syndrome.” Clin Infect Dis. 1994 Jan;18 Suppl 1:S62-7. http://www.ncbi.nlm.nih.gov/pubmed/8148455 (Abstract)

Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. “Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome.” BMC Neurol. 2004 Oct 4;4(1):14. http://www.ncbi.nlm.nih.gov/pubmed/15461817 (Abstract)

Patano N, Mancini L, Settanni MP, Strippoli M, Brunetti G, Greco G, Tamma R, Vergari R, Sardelli F, Koverech A, Colucci S, Zallone A, Grano M. “L-carnitine fumarate and isovaleryl-L: -carnitine fumarate accelerate the recovery of bone volume/total volume ratio after experimentally induced osteoporosis in pregnant mice.” Calcif Tissue Int. 2008 Mar;82(3):221-8. http://www.ncbi.nlm.nih.gov/pubmed/18265928 (Abstract)

Plioplys AV, Plioplys S. “Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome.” Neuropsychobiology. 1997;35(1):16-23. http://www.ncbi.nlm.nih.gov/pubmed/9018019 (Abstract)

Reuter SE, Evans AM. “Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitinepalmitoyltransferase-I activity.” J Intern Med. 2011 Jul;270(1):76-84. http://www.ncbi.nlm.nih.gov/pubmed/21205027 (Abstract)

Spiering BA, Kraemer WJ, Vingren JL, Hatfield DL, Fragala MS, Ho JY, Maresh CM, Anderson JM, Volek JS. “Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate.” Journal of Strength and Conditioning Research. 2007 Feb;21(1):259-64. http://www.ncbi.nlm.nih.gov/pubmed/17313301 (Abstract)

Vermeulen RC, Scholte HR. “Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome.” Psychosom Med. 2004 Mar-Apr;66(2):276-82. http://www.ncbi.nlm.nih.gov/pubmed/15039515 (Abstract)





GLUTAMINE





DESCRIPTION. Glutamine is the most abundant nonessential amino acid in the body. It is a precursor to glutathione.





BACKGROUND. Glutamine plays an important role in many biological functions, including protein synthesis, providing cellular energy, and as a non-toxic transporter of ammonia in the bloodstream. When converted to glutamic acid, it acts as an excitatory neurotransmitter in the brain.





In the intestinal tract, glutamine strengthens the gut's function as an immune barrier by supporting the production of secretory immunoglobulin A (sIgA), which helps maintain the structure, metabolism, and function of the mucosal lining of the intestines. Glutamine can help heal injured gut mucosa after surgery and, in a high percentage (92%) of patients, completely heals ulcer damage. Glutamine is an important detoxifying agent for ammonia, a neurotoxin and one of the toxic by-products of protein metabolism. It is used to treat sugar craving, fatigue, ADHD, peptic ulcers, and personality disorders. Dietary sources of glutamine include beef, chicken, fish, eggs, milk, dairy products, wheat, cabbage, beets, beans, and spinach.





USES IN CFS/ME. Because it is so important in gastrointestinal growth and function, glutamine is primarily used to treat leaky gut. Clinicians recommend taking 1000 mg of glutamine daily on an empty stomach, divided into equal doses (Patients with many sensitivities may want to test a very small amount of this amino acid before taking the full dose.)





PROS. A number of CFS/ME patients have noted improvement in gut function and increased food tolerance with this treatment as well as a decrease in “brain fog.” Side effects from this amino acid are relatively rare (but see below).





CONS. L-glutamine can cause gastrointestinal symptoms such as nausea and diarrhea. In patients with small intestinal bacterial overgrowth (SIBO) glutamine may actually worsen symptoms. Because glutamine is an excitatory neurotransmitter it may cause insomnia in individuals who do not tolerate stimulants. People who are sensitive to MSG should not take glutamine.





AVAILABILITY AND COST. Glutamine is available at health food stores and online in both powder and pill form. It is inexpensive. A 100-tablet bottle can cost as little as $6. Glutamine is also available from some compounding pharmacies as enteric coated tablets which are formulated to bypass the stomach and increase bioavailability.





RESEARCH

Blachier, François, Claire Boutry, Cécile Bos, Daniel Tomé. “Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines.” Am J Clin Nutr September 2009 vol. 90 no. 3 814S-821S. http://www.ajcn.org/content/90/3/814S.abstract





LYSINE





DESCRIPTION. Lysine is an essential amino acid. (It cannot be synthesized in the body.)





BACKGROUND. Lysine is needed for bone growth in children and to maintain nitrogen balance in adults. It also aids in the production of antibodies, hormones, and enzymes as well as helping in collagen formation, muscle building, and tissue repair. Lysine deficiency can result in hair loss, anemia, bloodshot eyes, loss of energy, and irritability. Food sources of lysine include meat, eggs, legumes and milk.





USES IN CFS/ME. Lysine is recommended chiefly because of its ability to inhibit reproduction of herpesviruses (herpes simplex virus, varicella zoster virus, human herpesvirus 6, and Epstein-Barr virus), which require arginine in order to reproduce. Lysine's structure is similar enough to arginine, however, that herpesviruses can be fooled into using lysine instead. Since the virus cannot use lysine for replication, the virus loses its ability to reproduce, effectively halting the spread of the infection. Some CFS/ME doctors recommend lysine to treat frequent outbreaks of cold sores (herpes simplex) or shingles (herpes zoster).





PROTOCOL. Dr. Charles Lapp recommends 1000 to 2000 mg of lysine, taken daily with meals. Foods high in arginine, such as chocolate, nuts, raisins, whole wheat, cereal, and brown rice, should be avoided.

PROS. Lysine appears to be a safe, effective treatment for cold sores.





CONS. Side effects of lysine can include dizziness, sweating, nausea, appetite loss, and difficulty swallowing. Lysine should be discontinued if these symptoms develop.





AVAILABILITY AND COST. Lysine is available in most health food stores and can be purchased inexpensively. Most brands retail for less than $10 for a 100-capsule bottle (500 mg).





RESEARCH

Griffith RS, Walsh DE, Myrmel KH, Thompson RW, Behforooz A. “Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis.” Dermatologica 1987;175(4):183-90. http://www.ncbi.nlm.nih.gov/pubmed/3115841 (Abstract)





TAURINE





DESCRIPTION. Although taurine is usually classified as an amino acid, it is actually an organic acid, which is an organic compound with acidic properties but without a carboxyl group.





BACKGROUND. Taurine acts as a building block for all other amino acids and consequently is present in every cell in the body. It is a prime component of bile (thus aiding in fat digestion and vitamin absorption) and is found in high concentrations in heart muscle, skeletal muscle, white blood cells, and the central nervous system (CNS). Anxiety, hyperactivity, and poor brain function are related to taurine deficiency. Taurine can be synthesized in the body from cysteine, with the aid of vitamin B6.





Taurine is unusual in that it not only functions as a neurotransmitter, but as a potent antioxidant. When taurine interacts with the oxidant hypochlorous acid it forms taurine monochloramine, which inhibits the transcription iNOS gene as well as the expression of COX-2 protein, both of which are primary sources of inflammation.



Taurine lowers NF-kappaB activity, which helps inhibit another important inflammatory pathway. It also acts to reduce intracellular calcium levels, thus lowering the production of nitric oxide. In its role as a neuromodulator, taurine stimulates the synthesis of GABA, the primary inhibitory neurotransmitter. It also stimulates glycine receptors, leading to a down regulation of excitatory NMDA receptors. (Glycine is also used in the biosynthesis of hemoglobin, which is very important in the maintenance of red blood cell integrity and oxygen transport.)





USES IN CFS/ME. Dr. Majid Ali, author of The Canary and Chronic Fatigue, makes extensive use of taurine as an antioxidant and has reported excellent results in treating fatigue and chronic constipation. Dr. Cheney has observed that taurine may also be of benefit in treating hyperactive nervous system responses. CFS/ME patients have been shown to have high amounts of glutamate in the brain, which increases neuroexcitatory responses. Because taurine slows CNS impulses, it may help relieve symptoms such as insomnia, anxiety, and restlessness, especially when taken in conjunction with magnesium. Taurine is transported easily across the blood-brain barrier, allowing taurine supplements to work in the brain.





PROTOCOL. Dr. Ali recommends a dosage of 250 mg/day, along with magnesium and potassium. Dr. Cheney recommends ½ cc of injectable magnesium (250 mg) accompanied by ½ cc injectable taurine.





PROS AND CONS. Taurine has very few side effects, however, excess doses can cause GI upset (yellow diarrhea, gas, pale stools).





AVAILABILITY AND COST. Taurine can be purchased in most health food and vitamin stores and costs less than $10 a bottle. Powdered forms can be purchased, for those who prefer to titrate dosage.





FURTHER READING

Very thorough discussion of the role of taurine: http://me-cfsmethylation.com/viewtopic.php?f=3&t=149





RESEARCH

El Idrissi A , Trenkner E. “Taurine as a modulator of excitatory and inhibitory neurotransmission.” Neurochem Res. 2004 Jan;29(1):189-97. http://www.ncbi.nlm.nih.gov/pubmed/14992278 (Abstract)

Liu, Y, Tonna-DeMasi, M, Park, E, Schuller-Levis, G, Quinn, MR. "Taurine chloramine inhibits production of nitric oxide and prostaglandin E2 in activated C6 glioma cells by suppressing inducible nitric oxide synthase and cyclooxygenase-2 expression. "Brain Res. Mol. Brain Res. 59,189-195. http://www.sciencedirect.com/science/article/pii/S0169328X98001454

Nakagawa K, Kuriyama K. “Effect of taurine on alteration in adrenal functions induced by stress.” Jap. J. Pharmacol. 1975 Dec;25(6):737-46. http://www.ncbi.nlm.nih.gov/pubmed/6814 (Abstract)

Park E, Jia J, Quinn MR, Schuller- Levis G. “Taurine chloramine inhibits lymphocyte proliferation and decreases cytokine production in activated human leukocytes.” Clin Immunol. 2002 Feb;102(2):179-84. http://www.ncbi.nlm.nih.gov/pubmed/11846460 (Abstract)





ANTIOXIDANTS





DESCRIPTION. Antioxidants are a group of vitamins, minerals, and enzymes that help protect cells from free radical damage.





BACKGROUND. Antioxidants have long been used as preservatives because of their ability to retard the oxidation that causes oils to become rancid. However, they have garnered increased attention over the past few years for their medical value. The same process that allows them to prevent oils from becoming rancid also protects the body from damage caused by free radicals. Free radicals are atoms or groups of atoms that have lost an electron. These molecules containing unpaired electrons are highly unstable and can easily pick up other elements, causing volatile reactions. When large numbers of free radicals are formed, whether from exposure to radiation, toxic chemicals or rancid oils, or because of prolonged illness and immune activation, significant damage can result. When dangerously high levels of free radicals are present, they can cause changes in protein structure. The body may identify the altered proteins as foreign elements and launch an immune system attack.





The body has its own defenses against excess free radical formation. The three most potent antioxidants produced in the body are superoxide dismutase (SOD), CoQ10, and glutathione peroxidase. However, the group of biochemicals known as antioxidants are also found abundantly in nature in the form of vitamins, minerals, and enzymes. Among the most widely used antioxidants are vitamins A, C, and E, alpha lipoic acid (ALA), gamma-linoleic acid (GLA), the amino acid cysteine, glutathione, taurine, the mineral selenium, CoQ10, and the bioflavonoids in pycnogenol, milk thistle, and gingko.





Antioxidants operate in concert to prevent free radical damage. A single antioxidant, once it has neutralized the free radical, can itself cause cell damage. The action of other antioxidants is necessary to return antioxidants to their reduced state, in which they can continue to scavenge free radicals. Therefore, antioxidants should be taken in combination rather than single forms. An article in the New England Journal of Medicine reports that heavy smokers in Finland who took very high doses of the antioxidant beta carotene had a higher rate of lung cancer than those taking a placebo (CFIDS Chronicle, Spring 1995). However, when beta carotene was combined with vitamin E, this was not the case.





Due to the potential of antioxidants to mitigate the more damaging effects of chronic illnesses (including cancer and diabetes) research on antioxidants is rapidly evolving. In 2004 Rezk et al proposed a new class of antioxidants based on the mechanism of vitamin E. In a study comparing the activities of different forms of vitamin E, the researchers discovered that vitamin E phosphate prevented the transfer of free radicals by forming a detergent barrier.





USES IN CFS/ME. Several studies have confirmed oxidative damage in CFS/ME patients. In 2000 a team of Italian researchers investigating the source of muscle pain found oxidative damage to DNA and lipids (fats) in the muscle tissue of CFS/ME patients. They also found significant differences in the composition of muscle membranes as compared to controls and patients with FM. The researchers concluded that their data “support an organic origin of CFS, in which muscle suffers oxidative damage.”





Patients with CFS/ME who experience depression also show evidence of free radical formation. In a 2001 study conducted by Maes et al, glutathione peroxidase levels were found to correlate with depressed mood and autonomic symptoms. The lower the glutathione levels, the greater the depression. The researchers recommended supplementation with glutathione, NAC and selenium.





Two studies conducted independently in 2000 and 2005 found that oxidative stress in CFS/ME patients could be measured through blood samples. In Australia, Richards et al measured methemoglobin in CFS/ME patients and controls. Methemoglobin (pronounced “met-hemoglobin”) is an altered form of hemoglobin that does not bind well to oxygen, limiting the blood's ability to carry oxygen to tissues and organs. The formation of methemoglobin can be caused by various health problems and is a sign of oxidative stress. The study found that in CFS/ME patients, symptoms such as sleep disturbance, pain, and fatigue correlated with methemoglobin levels. They concluded that their data suggested that “oxidative stress due to excess free radical formation is a contributor to the pathology of CFS and was associated with symptom presentation.”





A second study by Kennedy et al. investigated free radical damage in CFS/ME symptoms using the “gold standard” of oxidative stress: isoprostanes. Isoprostanes are prostaglandin-like compounds which are formed after free radicals catalyze essential fatty acids. They have long been recognized as an accurate predictor of oxidative stress. Kennedy et al found that in CFS/ME patients, raised levels of isoprostanes correlated with post-exertional malaise. They postulated that in CFS/ME the excessive free radical formation could be due to persistent viral infection, to inflammation, or to metabolic abnormalities in mitochondria and lipids.





Antioxidants fall into many classes. The most commonly recommended antioxidants for CFS/ME patients are:

Vitamins: A, C, E

Vitamin co-factors: CoQ10

Minerals: Manganese, selenium, zinc

Hormones: Melatonin

Flavonoids: Quercetin, pycnogenol, grape seed extract, Ecklonia cava

Phenols: Silymarin

Plant sources: Capsaicin, bilberry

Enzymes: SOD

Various Others: N-acetyl cysteine, alpha lipoic acid, essential fatty acids, glutathione, taurine

PROTOCOL. Most, if not all, CFS/ME doctors have included some form of antioxidant therapy into their protocols. Usually they recommend a broad-spectrum approach, as opposed to single-supplement therapy, accompanied in many cases by bioflavonoids such as pycnogenol (which is a potent antioxidant), grape seed extract, or “super foods” such as blue-green algae. Vitamin E, because it is the only fat-soluble antioxidant, is particularly good in combination with other antioxidants.

Martin Pall, one of the leading researchers of oxidative stress in CFS/ME, recommends vitamin C, flavonoids, Ecklonia cava extract, B12, CoQ10, vitamin E, lipoic acid, as well as a host of other antioxidants to combat free radical damage.

Dr. Cheney recommends daily doses of 2000-4000 mg vitamin C, 400-800 IU of Vitamin E, 200 mg of CoQ10, 100-300 mg of lipoic acid, omega-6 and omega-3 essential fatty acids and flavonoids. He stresses that because high doses of antioxidants can increase oxidative stress, flavonoids should be taken to mitigate potential free radical damage stemming from excessive antioxidant activity.

Dr. Myhill recommends 300 mg of CoQ10 daily for three months, then reduced to 100 mg daily, 250 mg of glutathione daily together with 20 mcg of selenium as well as minerals to help produce the powerful free radical scavenger, superoxide dismutase. (Please see below for her discussion of antioxidants.)





FURTHER READING

Dr. Myhill's excellent discussion of antioxidants: http://drmyhill.co.uk/wiki/Antioxidants

Logan, Alan C. and Cathy Wong. “Chronic Fatigue Syndrome: Oxidative Stress and Dietary Modifications.” Altern Med Rev 2001;6 (5): 450-459. http://www.altmedrev.com/publications/6/5/450.pdf

This article contains an excellent summary of research concerning oxidative stress in CFS/ME as well as a proposed list of antioxidant treatments.

Martin Pall's supplement list: http://esme-eu.com/supplements/supplements-in-me-cfs-by-prof-martin-pall-article276-139.html

Dr. Cheney's talk on CFS/ME treatments, including antioxidants: http://www.me-cfs.info/cheneyII3.pdf





RESEARCH

Fulle S, Mecocci P, Fan G, Vecchiet I, Vecchini A, Racciotti D, Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. “Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome.” Free Radic Biol Med. 2000 Dec 15;29(12):1252-9. http://www.ncbi.nlm.nih.gov/pubmed/11118815 (Abstract)

Kennedy, Gwen, Vance A. Spence, Margaret McLaren, Alexander Hill, Christine Underwood, Jill J.F. Belch. “Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome.” Free Radical Biology & Medicine 39 (2005) 584 – 58. http://www.cfids-cab.org/rc/Kennedy.pdf

Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. “Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis /chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression.” Neuro Endocrinology letters. 2011;32(2):133-40. http://www.ncbi.nlm.nih.gov/pubmed/21552194 (Abstract)

Miwa K, Fujita M. “Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome.” Heart Vessels. 2010 Jul;25(4):319-23. http://www.ncbi.nlm.nih.gov/pubmed/20676841 (Abstract)

Rezk BM, Haenen GR, Van Der Vijgh WJ, Bast A. “The extraordinary antioxidant activity of vitamin E phosphate.” Biochim Biophys Acta. 2004 Jul 5;1683(1-3):16-21. http://www.ncbi.nlm.nih.gov/pubmed/15238215 (Abstract)

Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. “Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome.” Redox Rep. 2000;5(1):35-41. http://www.ncbi.nlm.nih.gov/pubmed/10905542 (Abstract)

Saransaari, P, Oja S. “Nitric oxide is involved in taurine release in the mouse brainstem under normal and ischemic conditions.” Amino Acids. 2008 Apr;34(3):429-36 http://www.ncbi.nlm.nih.gov/pubmed/17665274 (Abstract)





BETAINE HCl





DESCRIPTION. Betaine HCl is a synthesized chemical compound consisting of betaine, a methyl group donor, and hydrochloride, a salt.





BACKGROUND. Betaine is a vitamin-like substance that was originally derived from beets. For many years Betaine HCl was added to over-the-counter digestive aids, until in 1993 the FDA determined that it has not been proven “generally safe and effective.” At that point Betaine HCl began to be sold as a separate supplement.





Betaine HCl is still marketed as a digestive aid, particularly for the treatment of hypochloridia, a condition in which the stomach does not produce enough acid. Hypochloridia can occur after taking stomach acid suppressors (antacids, proton pump inhibitors), through H. Pylori infections (which interfere with stomach acid production), as well as any disease process that causes inflammation in the stomach lining. Stomach acid is often low in the elderly.





Lack of stomach acid can lead to the phenomenon known as “dumping,” in which the stomach's contents (chyme) are released into the small intestines before having been adequately broken down. The ability of the small intestines to further break down the chyme can result in poor absorption of nutrients, leading to deficiency states, particularly of minerals, which require acid to be absorbed. One of the most common symptoms of hypochloridia is reflux, which is frequently misdiagnosed as excess acid.





The most reliable test to determine hypochloridia is the Heidelberg Capsule test. The capsule contains a high frequency transmitter attached to a string. When the capsule is swallowed and drawn back up the esophagus, it gives an instant pH reading.





USES IN CFS/ME. A number of clinicians have proposed that low levels of stomach acid are responsible for many of the GI symptoms found in CFS/ME patients. Dr. Cheney routinely recommends Betaine HCl as a supplement to correct hypochloridia and prevent dumping. Dr. Myhill also maintains that people with CFS/ME chronically suffer from low levels of stomach acid.





PROTOCOL. Dr. Cheney recommends starting with a capsule (or ½ capsule) with meals. Paradoxically, too low a dose may actually increase reflux, as there still isn't enough stomach acid to trigger the opening of the sphincter that releases chyme into the intestines. The food that then returns through the esophagus contains not only normally occurring stomach acid, but the additional Betaine HCl as well. According to Dr. Cheney, increasing the dose will actually reduce reflux.





PROS AND CONS. Although Betaine HCl does not contain hydrochloric acid (the HCl, in this case, is a salt), some people report improved digestion. The supplement does have mild acidifying properties, which is perhaps why people report having to take so many capsules with their meals (up to seven). It is quite possible that many of its benefits may actually come from the betaine, which acts as a liver support.





AVAILABILITY AND COST. Betaine HCl is easily available from health food stores and from online suppliers. It is inexpensive. Vitacost markets a 100-capsule bottle of Twinlab's Betaine HCl for about $7.





FURTHER READING

Dr. Sara Myhill's excellent discussion of hypochloridia: http://www.drmyhill.co.uk/wiki/Hypochlorhydria_-_lack_of_stomach_acid_-_can_cause_lots_of_problems

Basic information about Betaine HCl: http://www.encyclopedia.com/doc/1G2-3435100086.html

A good explanation of the Heidelberg capsule test and hypochloridia. http://www.antiagingwellnesscenter.com/phcapsule.shtml

Dr. Paul Cheney on dumping, hypochloridia, and Betaine HCl supplementation. http://www.prohealth.com/library/showarticle.cfm?libid=8037





BIOFLAVONOIDS





Grape seed extract, Pycnogenol, Quercetin





DESCRIPTION. Bioflavonoids are glycosides (sugars) derived from citrus, paprika, and other plants, which serve to protect capillaries. Although formerly known as "vitamin P," bioflavonoids are not vitamins.





BACKGROUND. Bioflavonoids were first extracted from paprika in 1936 by a scientist who claimed that the substance had a greater effect than vitamin C in reducing capillary bleeding. It was later shown that the substance, or rather substances, helped maintain capillary strength by inhibiting permeability of the walls (rather than maintaining the actual structure, as does vitamin C). This may be because bioflavonoids inhibit oxidation of epinephrine (adrenaline), the hormone directly responsible for capillary wall integrity. Bioflavonoids enhance absorption of vitamin C and, when taken together, can help protect and preserve capillaries, increase circulation, prevent cataracts, and produce a mild antibacterial effect. Flavonoids have anti-allergic, anti-inflammatory and anti-microbial effects.





Dietary sources include buckwheat, black currants, peppers, and the white part of citrus peel. There are many bioflavonoids available for purchase through health food stores and online vitamin suppliers.

Bioflavonoids are rapidly absorbed in the system, and almost as rapidly excreted through the kidneys. Peak blood levels occur roughly two hours after ingestion, which means that to be effective, they should be taken throughout the day.





USES IN CFS/ME. Bioflavonoids are poorly absorbed, so for better utilization its best to take several. The most active intracellular free radical scavengers are lycopene, a carotenoid found in red fruits (except strawberries) and lutein, found in green leafy vegetables. Dr. Pall recommends FlaviNOx, which is a combination of standardized bioflavonoids derived from herbs (gingko, bilberry, milk thistle, grape seed extract, decaffeinated green tea extract, cranberry and hawthorn). The combination of antioxidants in FlaviNOx is designed to scavenge peroxynitrite and superoxide, two highly damaging free radicals.





AVAILABILITY AND COST. A 90-capsule bottle of FlaviNOx (Allergy Research Group) costs roughly $35.





GRAPE SEED EXTRACT





DESCRIPTION. Grape seed extract is a polyphenolic compound derived from grape seeds.





BACKGROUND. Grape seeds contain polyphenols, procyanidins, and proanthocyanidins, which are antioxidants many times more powerful than vitamin C or E. Grape seed extract is reported to be a potent peroxynitrite scavenger, and therefore can protect the cells from intracellular damage. The effects of polyphenols are far-reaching, including the inhibition of skin cancer, reduction of inflammation, neuroprotective action, improvement of cerebral circulation, acceleration of wound healing, modulation of intestinal flora, repairing leaky gut, and immune system regulation.





USES IN CFS/ME. Grape seed extract is often used as a less expensive alternative to pycnogenol. Patients report that it helps with pain.





PROTOCOL. One 100 mg tablet taken with food.





AVAILABILITY AND COST. Grape seed extract is widely available in health food stores and through online distributors. A bottle of 120 capsules can cost as little as $13. Grape seed extract is frequently combined with other bioflavonoids, such as green tea and resveratrol (found in grape skin) to increase its antioxidant effects.





FURTHER READING

Sloan Kettering's review of the mechanisms of grape seed extract. Includes a list of studies. http://www.mskcc.org/cancer-care/herb/grape-seed





RESEARCH

Afaq F, Katiyar SK. “Polyphenols: Skin Photoprotection and Inhibition of Photocarcinogenesis.” Mini Rev Med Chem. 2011 Oct 28. http://www.ncbi.nlm.nih.gov/pubmed/22070679 (Abstract)

Lin, B. “Polyphenols and Neuroprotection against Ischemia and Neurodegeneration.” Mini Rev Med Chem. 2011 Oct 28 http://www.ncbi.nlm.nih.gov/pubmed/22070681 (Abstract)

Vendrame S, Guglielmetti S, Riso P, Arioli S, Klimis-Zacas D, Porrini M. “Six-week consumption of a wild blueberry powder drink increases bifidobacteria in the human gut.” J Agric Food Chem. 2011 Nov 7. http://www.ncbi.nlm.nih.gov/pubmed/22060186 (Abstract)





PYCNOGENOL





DESCRIPTION. Pycnogenol (proanthocyanadin) is a bioflavonoid antioxidant derived from the bark of the French maritime pine tree.





BACKGROUND. Pycnogenol is a potent free radical scavenger. Studies have shown that, as an antioxidant, pycnogenol is up to 50 times more effective than other antioxidants to clear free radicals created from chemical sources (air pollution and food additives). It is 20 times more effective than vitamin C in scavenging superoxide, hydroxyl, and peroxide radicals. Pycnogenol is reported to enhance immune system function, increase energy, promote healing, and reduce allergic reactions. It is particularly effective in the brain.





USES IN CFS/ME. Pycnogenol has not been widely investigated for use in CFS/ME patients although it has been researched for other virally induced diseases. Some patients who have used pycnogenol report small increases in mental and physical energy and better resistance to bacterial and viral infections as well as stress.

PROTOCOL. The recommended dosage is 50 mg a day, taken with food. Some CFS/ME patients report that pycnogenol is more effective on an empty stomach.





AVAILABILITY AND COST. Pycnogenol can be purchased from health food stores and vitamin catalogs. Twinlab markets a 60-capsule bottle of pycnogenol (50 mg) for $25 through Vitacost.





FURTHER READING

Sloan Kettering's excellent summary of the mechanisms of pycnogenol. Contains a list of research studies: http://www.mskcc.org/cancer-care/herb/pine-bark-extract

Iravani S., and B. Zolfaghari. “Pharmaceutical and nutraceutical effects of Pinus pinaster bark extract.” PhD. Res Pharm Sci. 2011 Jan-Jun;6(1): 1–11. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203267/

A thorough review of all research articles investigating pycnogenol.





RESEARCH

Feng WY, Tanaka R, Inagaki Y, Saitoh Y, Chang MO, Amet T, Yamamoto N, Yamaoka S, Yoshinaka Y. “Pycnogenol, a procyanidin-rich extract from French maritime pine, inhibits intracellular replication of HIV-1 as well as its binding to host cells.” Jpn J Infect Dis. 2008 Jul;61(4):279-85. http://www.ncbi.nlm.nih.gov/pubmed/18653969 (Abstract)





QUERCETIN





BACKGROUND. Quercetin, a flavonol, is chiefly used to treat asthma and allergies. Quercetin has properties similar to that of the antihistamine disodium cromoglycate (found in Gastrocrom and Nasalcrom). It can inhibit mast cell production and block histamine release, two functions that together can curb many allergic responses. In its antioxidant function, quercetin decreases the synthesis of pro-inflammatory leukotrienes, and inhibits free radical production and lipid peroxidation.





Quercetin is reported to help relieve muscle pain, particularly along the upper back and shoulders. It is commonly found in many food sources: green tea, apples, red onions, red grapes, citrus fruits, tomato, broccoli, leafy green vegetables, cranberries and raspberries, among others.





USES IN CFS/ME: An interesting study conducted in 2009 by Davis et al found that quercetin increased the genesis of mitochondria in mice, significantly improving exercise tolerance. The reason this study is important is that it was done in vivo. (Most studies on antioxidants are performed in test tubes.) As exercise intolerance is the hallmark symptom of CFS/ME, quercetin may play an important role in improving physical stamina among people with CFS/ME.





PROTOCOL. Because it is so poorly absorbed, quercetin needs to be taken with bromelain, an enzyme found in pineapple. Dr. James Balch, author of Prescription for Nutritional Healing, recommends 1000 to 2000 mg one to three times a day to prevent or lessen the severity of asthma attacks and allergies. CFS/ME patients are advised to start with much smaller doses, 200-1200 mg a day.





PROS AND CONS. Quercetin is the most widely used bioflavonoid among patients with CFS/ME. A number of allergy-prone patients with CFS/ME have noted that allergy symptoms subside with quercetin. For patients with many allergies, this may provide overall improvement because allergy symptoms can cause systemic problems. Some patients with interstitial cystitis have noted an improvement in symptoms after taking quercetin. The primary side effect is that high doses may cause diarrhea.





AVAILABILITY AND COST. Quercetin (with bromelain) is available from health food stores and online vitamin catalogs. A three-month supply may cost as little as $8. ProHealth markets a 100-tablet bottle of a quercetin-bromelain combination (also containing vitamin C and magnesium) for about $15.





FURTHER READING

Davis JM, Murphy EA, Carmichael MD, Davis B. “Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance.” Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1071-7. http://www.ncbi.nlm.nih.gov/pubmed/19211721 (Abstract)

Park HH, Lee S, Son HY, Park SB, Kim MS, Choi EJ, Singh TS, Ha JH, Lee MG, Kim JE, Hyun MC, Kwon TK, Kim YH, Kim SH. “Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells.” Arch Pharm Res. 2008 Oct;31(10):1303-11. http://www.ncbi.nlm.nih.gov/pubmed/18958421 (Abstract)

Pearce FL, Befus AD, Bienenstock J. “Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells.” J Allergy Clin Immunol. 1984 Jun;73(6):819-23. http://www.ncbi.nlm.nih.gov/pubmed/6202731 (Abstract)

Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, Madhappan B, Vecchiet J, De Lutiis MA,Caraffa A, Cerulli G. “Role of quercetin (a natural herbal compound) in allergy and inflammation.” J Biol Regul Homeost Agents. 2006 Jul-Dec;20(3-4):47-52. http://www.ncbi.nlm.nih.gov/pubmed/18187018 (Abstract)





BUTYRIC ACID (BUTYRATE)





DESCRIPTION. Butyrates (butanoic, or butyric acid) are short-chain saturated fatty acids found naturally in the human intestine and in butter fat.





BACKGROUND. Short-chain fatty acids (volatile fatty acids) are produced in the colon as natural by-products of the bacterial fermentation of fiber. These fatty acids provide an energy source for the mucosal cells of the lining of the colon, enabling them to check the proliferation and establishment of pathogens (such as salmonella and Candida) and allowing greater absorption of magnesium and vitamin K. Deficiency of these fatty acids results in malabsorption, diarrhea, and, over the long term, colitis.





Of the three fatty acids found in all mammals – butyrate, acetate, and propionate – butyrate is the preferred energy substrate. It stimulates the normal proliferation of mucous cells, enabling greater efficiency of all colonic functions. Butyrates have been used successfully to treat Candida overgrowth (yeast infection), cancer, ulcerative colitis, and nonspecific inflammatory conditions of the colon. It is one of the treatments recommended for leaky gut and for alleviating food sensitivities.





USES IN CFS/ME. A significant number of people with CFS/ME suffer from gastrointestinal problems. According to Dr. Cheney, 90% of his CFS/ME patients have small intestinal bacterial overgrowth (SIBO), a condition in which bacteria from the large intestine migrate into the small intestines, interfering with fat and carbohydrate metabolism and causing a spate of GI symptoms. Rao et al found that 50% of CFS/ME patients meet the criteria for irritable bowel syndrome (IBS), a gut motility disorder. Butyrates, because they provide a substrate for beneficial intestinal flora, can be used in conjunction with probiotics to help restore gut mucosa damaged by SIBO as well as maintaining gut motility.





Although butyrates are primarily recommended for treating digestive disorders, it may also have a positive effect on some neurological problems associated with CFS/ME. Dr. Cheney proposes that an imbalance in the actions of the neuroexcitatory chemical NMDA (N-methyl-D-aspartate) and the neuroinhibitor GABA (gamma amino butyric acid) may lead to many of the troubling neurological symptoms experienced by patients with CFS/ME (insomnia, intolerance of sensory stimuli, seizure-like activity, pain) (CFIDS Chronicle, Spring 1995).





For many patients, down regulation of the NMDA receptors, accomplished with small doses of Klonopin (clonazepam), magnesium, Nimotop (nimodipine), melatonin, or calcium channel blockers, leads to general improvement of all symptoms. Butyrate, because it forms a component of GABA, may also rectify some of this neurochemical imbalance by increasing the amount of neuroinhibitory action in the brain.





PROTOCOL. Butyrate is usually taken orally. The suggested dose is one or two capsules with each meal. It smells awful, so you may want to store it in the refrigerator.





PROS AND CONS. Butyrate is inexpensive, safe, and does not require a prescription.





AVAILABILITY AND COST. ButyrEn tablets, marketed by Allergy Research Group, are hypoallergenic, containing no yeast, wheat, corn, soy, dairy products, or artificial colors or resins. The tablets are buffered with calcium and magnesium. ButyrEn is available from online distributors and some specialized vitamin stores. One bottle of 100 capsules costs as little $9 on amazon. PureFormulas markets a 90-capsule bottle of Cal-Mag Butyrate made by Ecological Formulas for $10.50. Shipping is free.





FURTHER READING

Life Extension is a bit pricier than other suppliers, but their website contains a very thorough description of the mechanisms of butyric acid. http://www.lifeextensionvitamins.com/bualregr.html





RESEARCH

Rao, A Venket, Alison C Bested, Tracey M Beaulne, Martin A Katzman, Christina Iorio, John M Berardi and Alan C Logan. “A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome.” Gut Pathogens 2009, 1:6. http://www.gutpathogens.com/content/1/1/6





CHOLINE





DEFINITION. Choline is an amine (a nitrogen-containing compound) similar in function to B vitamins.





BACKGROUND. Choline is an essential nutrient, which means it cannot be synthesized by the body and must be obtained through food sources. Foods high in choline include egg yolk, liver, fatty meats, nuts and brown rice.





Choline performs three vital biological functions: 1) It is an important component of phosphatidylcholine, which forms cell walls and supports cellular function; 2) Choline serves as a precursor to acetylcholine, the neurotransmitter responsible for memory formation and muscle movement; 3) Choline is an important methyl donor, supporting the methylation cycle through its metabolite, trimethylglycine (betaine).





A deficiency in choline can lead to liver damage (“fatty liver”) and a reduction in kidney function. Lack of choline in the diet can also cause infertility, growth impairment, bone abnormalities, and hypertension. Because choline plays such an important role in nervous system development, a deficiency in early life can lead to neurological deficits. Vegans and athletes are particularly prone to choline deficiency.





USES IN CFS/ME. Because choline serves as a marker for certain types of brain damage, it is one of the compounds that is measured in magnetic resonance (MR) spectroscopy. For example, high amounts of choline accompanied by low amounts of creatine and N-acetyl aspartate (NAA) are indicative of stroke (cerebral ischemia and hypoxia). MR spectroscopy can also be used to monitor changes in tumors, stroke, epilepsy, metabolic disorders, infections, and neurodegenerative diseases.





In 2004 Chaudhuri and Behan used MR spectroscopy to assess brain chemistry in CFS/ME patients. They found that in CFS/ME patients, choline levels in the occipital cortex and basal ganglia were raised, but NAA and creatine were normal. The researchers concluded that in the absence of NAA and with no structural abnormalities, the increase in choline was probably due to increased phospholipase activity (the enzyme that breaks down the phospholipids that make up cell walls) rather than to inflammation. They theorized that viral activity could possibly contribute to the increased choline, as many viruses increase the activity of phospholipase.





While Chaudhuri and Behan concluded that inflammation in the brain was not indicated by their test results, further research indicates otherwise. Martin Pall has suggested that activation of NMDA receptors (due to oxidative stress) provides the missing inflammatory pathway that Chaudhuri and Behan were unable to identify. In fact, an increase in choline can be an early signal of an inflammatory process, even in the absence of NAA. The mechanism which induces release of choline was identified by Gasull et al as an inhibition of phosphatidylcholine synthesis rather than phospholipase degradation. The researchers found that the increase in extracellular choline was induced by NMDA receptor activation, which ties in with Martin Pall's theory. In addition, Gasull's group found that early choline release was directly related to excitotoxic cell death caused by glutamine.





PROTOCOL. Given the important role of choline in neuronal protection from oxidative stress, as well as the fact that it is a component of acetylcholine, choline comprises a valuable addition to any CFS/ME treatment plan. Dr. Cheney recommends taking 50 mg of choline bitartrate a day. Dr. Teitelbaum recommends the same dose, accompanied by vitamin C.





High doses (10 to 16 grams/day) of choline are not recommended. Side effects from excessive intake of choline have been associated with a fishy body odor, vomiting, salivation, and increased sweating. (The fishy body odor results from excretion of trimethylamine, a metabolite of choline.) Taking large doses of choline in the form of phosphatidylcholine (lecithin) does not generally result in fishy body odor. However, lecithin is not usually well-tolerated by CFS/ME patients.





AVAILABILITY AND COST. Choline bitartrate supplements are not widely available, so most people decide to purchase lecithin powder, which is inexpensive and easy to find. PureFormulas.com markets a bottle of 100 choline bitartrate capsules (235 mg) for roughly $10. Purebulk.com sells a 100-gram container of choline bitartrate powder for $4.25. The powder may be a more viable option for most people as it allows for titration. Many B vitamin formulations contain choline, so check labels. It may be worthwhile to purchase a good-quality B-complex supplement that includes choline, as this will give you the proper balance of B vitamins as well.





FURTHER READING

This Oregon University site provides excellent information about choline. http://lpi.oregonstate.edu/infocenter/othernuts/choline/

“What are Choline and Inositol?” (Good overview): http://www.livestrong.com/article/326852-what-are-choline-inositol/

“Choline on the Brain? A Guide to Choline in Chronic Fatigue Syndrome.” Cort Johnson. Aug, 2005. http://aboutmecfs.org.violet.arvixe.com/Rsrch/CholineBrain.aspx

Ray Sahelian's sensible advise on choline: http://www.raysahelian.com/cdp.html

“Fundamentals of MR Spectroscopy.” John R. Hesselink. (A nice summary of MR spectroscopy.) http://spinwarp.ucsd.edu/neuroweb/Text/mrs-TXT.htm





RESEARCH

Chaudhuri, A., P.O. Behan. “In vivo magnetic resonance spectroscopy in chronic fatigue syndrome.” Prostaglandins, Leukotrienes and Essential Fatty Acids 71 (2004) 181–183. http://www.cfids-cab.org/cfs-inform/MitochondrialATP/chaudhuri.behan04.pdf

Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM. “Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome.” Neuroreport. 2003 Feb 10;14(2):225-8. http://www.cfids-cab.org/cfs-inform/Brainscans/chaudhuri.etal03.pdf

Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. “Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.” JAMA. 1995 Sep 20;274(11):902-7. http://www.nutrasal.com/library/pdfs/21.pdf

Doležal, Vladimír, Stanislav Tuček. “Activation of muscarinic receptors stimulates the release of choline from brain slices.” Biochem Biophys Res Commun. 1984 May 16;120(3):1002-7. http://www.ncbi.nlm.nih.gov/pubmed/6732780 (Abstract)

Gasull, Teresa, Nuria DeGregorio-Rocasolano, Agustin Zapata and Ramon Trullas. “Choline Release and Inhibition of Phosphatidylcholine Synthesis Precede Excitotoxic Neuronal Death but Not Neurotoxicity Induced by Serum Deprivation.” First Published on March 28, 2000. The Journal of Biological Chemistry, 275,18350-18357. http://www.jbc.org/content/275/24/18350.full





COQ10 (UBIQUINONE, UBIQUINOL)





DESCRIPTION. CoQ10 (ubiquinone) is a fat-soluble coenzyme found in the mitochondria of most mammal cells.





BACKGROUND. CoQ10 was first discovered by R.A. Morton, a biochemist who gave it the name ubiquinone after its ubiquitous presence in nearly all living things. "Co" stands for coenzyme (a vitamin-like substance), "Q" for quinone (the group of organic chemicals to which CoQ belongs), and "10" for the number of isoprene units that characterize the particular coenzyme found in animal cells.





CoQ10 is vital for electron transport, the intracellular function that ultimately provides the energy necessary to sustain life. CoQ10 is also a powerful antioxidant and is important in immune system function. The Japanese have successfully used CoQ10 to treat gum disease, heart disease, and high blood pressure, and to enhance the effectiveness of the immune system. Research performed in Japan and elsewhere indicates that CoQ10 can be of benefit in treating allergies (owing to its ability to block the effects of histamine), asthma, candidiasis, obesity, diabetes, mental function diseases such as Alzheimer's disease, and can slow the aging process (CoQ10 levels decline with age).





High amounts of CoQ10 occur naturally in fatty saltwater fish, especially mackerel, salmon, and sardines.

USES IN CFS/ME. CoQ10 is one of the most frequently used supplements for the treatment of CFS/ME-related fatigue because of its importance in the production of adenosine triphosphate (ATP), the cellular source of energy. In addition to reducing fatigue, CoQ10 may alleviate muscle weakness and pain. It is also one of the few supplements that seems to reduce cognitive dysfunction. Its role as a free radical scavenger may lead to improvement in immune responses in patients with CFS/ME. Although its effects as a natural antihistamine have not yet been specifically explored in CFS/ME, patients with allergies may benefit from CoQ10.





There is also evidence that CoQ10 is deficient in CFS/ME patients. In 2009 Maes et al measured plasma CoQ10 in 58 CFS/ME patients. Compared to normal controls, the CFS/ME group had values significantly below the lowest recorded levels of the control group. Patients with very low levels of CoQ10 suffered significantly more from concentration and memory disturbances. The researchers concluded that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that “symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion.” Their results suggested that patients with CFS/ME would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome.





PROTOCOL. Nearly all CFS/ME physicians recommend supplementation with CoQ10. CoQ10 can be taken in a single dose or divided into two doses taken at different times during the day. There is evidence that dividing the dose is more effective than taking it all at once. The normal recommended dose is between 30 and 200 mg/day. Dr. Lapp and Dr. Klimas recommend 120 mg a day. Sublingual CoQ10, reputedly more effective against cognitive dysfunction, may be taken at higher doses. Oral CoQ10, although primarily absorbed by the digestive tract and liver, is also effective for some patients. The oral dosage varies, but is usually 25 to 50 mg/day. It may take up to eight weeks to see effects from oral CoQ10. Because CoQ10 is fat-soluble, it should be taken with a meal that contains some kind of fat or oil.





PROS. Taken at lower doses, CoQ10 is a supplement with very few side effects. Patients report improvements in energy, stamina, light-headedness, and syncope (fainting). Dr. Lapp reports that half of his patients see improvement after taking CoQ10. A significant number of patients, particularly those with fibromyalgia, find that CoQ10 increases their energy over the course of the day.





CONS. Some patients report that CoQ10, while giving them an initial energy boost, also increases insomnia and causes jitters. Some people report, paradoxically, that CoQ10 produces exhaustion, although this effect may be more common in the acutely ill than in those with stable symptoms. CoQ10 lowers blood sugar levels, which may be problematic for patients with hypoglycemia. High doses can cause flu-like symptoms.





AVAILABILITY AND COST. CoQ10 can be purchased at most health food stores and from online distributors. There is a mind-boggling array of CoQ10 products. High-grade brands are preferred. (CoQ10 deteriorates rapidly when exposed to heat and light.) Because CoQ10 is fat-soluble, it should be purchased as a softgel (not capsule), preferably with a natural preservative (such as vitamin E).





Sublingual CoQ10 can be purchased from online sources without a prescription. Intensive Nutrition, Inc. markets a sustained-release sublingual CoQ10 for $25 (80 mg, 30 count). Source Naturals sells sublingual CoQ10 for $14 (30 mg, 120 count).





CoQ10 is also available by prescription as a gel. Unlike other forms of CoQ10, the gel is water soluble, and bypasses the GI tract completely. The gel is more easily absorbed that oral forms, so less CoQ10 needs to be taken. CoQ10 gel has been given orphan status by the FDA for treating mitochondrial dysfunction. (Orphan status means that a drug has been approved for the treatment of rare disorders.)





A more easily absorbed form of CoQ10, ubiquinol, is currently being marketed in the U.S. CoQ10 is converted in the body to ubiquinol, which is the active form of the enzyme, and therefore, more potent. Not only is ubiquinol more easily absorbed, it is longer acting than ubiquinone. Ubiquinol can be purchased from health food stores and online distributors. Vitacost sells a wide variety of ubiquinol products, ranging in cost from $8 to $74. (Read the labels carefully to confirm that the product contains pure ubiquinol.) Olympian Labs sells a bottle of 60 ubiquinol softgels (50 mg) with relatively few additives for $27.62.

Oral CoQ10 is not usually covered by insurance, as it is classed as a supplement.





FURTHER READING

Excellent summary of CoQ10 in CFS/ME: http://phoenixrising.me/?page_id=4759

An interesting and useful site containing a discussion of ubiquinol, a comparison of ubiquinol to CoQ10, links and research: http://ubiquinol.org/what-is-ubiquinol

Website of the International CoQ10 Association: http://www.icqa.org/ICQA/home.html

Ray Sahelian's informative site. Effects of CoQ10, studies and FAQs. http://www.raysahelian.com/coq10.html

Compounding pharmacies that make CoQ10 troches: http://www.mitoaction.org/blog/coq-10-update

Information on CoQ10 gel: http://www.epic4health.com/noname.html





PATIENT REVIEWS

Patient reviews of CoQ10: http://www.revolutionhealth.com/drugs-treatments/rating/coenzyme-q10-coq10-for-chronic-fatigue-syndrome-cfs-cfids-me?sort=recent





RESEARCH

Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. “Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.” Neuro Endocrinol Lett. 2009;30(4):470-6. http://www.ncbi.nlm.nih.gov/pubmed/20010505 (Abstract)





D-RIBOSE





DESCRIPTION. D-Ribose is a water-soluble simple sugar that is an important component of nucleic acids, vitamin B2, and various coenzymes.





BACKGROUND. Ribose was first identified in 1891 by Emil Fischer, a German chemist and recipient of the Nobel Prize in Chemistry. Fischer's primary work concerned sugars and the identification of their various functions. Ribose is an extremely important sugar in that it comprises the backbone of RNA, one of the three major macromolecules essential to all forms of life. Ribose is also a component of ATP, NADH and several other compounds that control the metabolism of carbohydrates, proteins, and fat.





USES IN CFS/ME. Mitochondrial defects that lead to low production of ATP, the principal source of cellular energy, have been thoroughly documented in people with CFS/ME. Low levels of ATP are responsible for the hallmark symptoms of CFS/ME, exercise intolerance and fatigue. However, direct supplementation with ATP seems to have no effect on either fatigue or stamina. This is due to the fact that ATP has a molecular weight of more than 500, which means that it is nearly impossible to absorb. Therefore, the mitochondrial defects leading to low ATP production must be addressed at a lower level in the metabolic chain.





The body makes ATP through the Krebs cycle, in which various enzymes convert citric acid into ATP. These enzymes are often deficient in people with CFS/ME, resulting in a lower production of ATP. The body can also make ATP from glucose, but the process involves first converting glucose into lactic acid, which then accumulates in the muscles, causing the familiar “burn” of over-exertion. This is also a longer and less efficient process than the Krebs cycle. D-Ribose cuts the time required to produce ATP because the body can quickly convert D-Ribose into ATP without converting it first into lactic acid.





In a 2006 pilot study, Teitelbaum et al found that in 36 CFS/FM patients, 66% experienced improvement in energy, pain, sleep, mental clarity and overall well-being after treatment with D-Ribose. The average improvement in energy was 45%, while the global improvement was 30%. The researchers concluded that D-Ribose “significantly reduced symptoms in patients suffering from fibromyalgia and chronic fatigue syndrome.”





Apart from its uses in CFS/ME, D-Ribose is among the most popular nutritional supplements to have been recently patented. In 2010, Bioenergy Inc, the company which markets Corvalen (the brand recommended by Dr. Teitelbaum), achieved its highest revenue earnings in the history of the company.





PROTOCOL. The serving size recommended by Jarrow is 2 grams (½ tsp/one scoop) up to three times a day. Dr. Teitelbaum recommends 5000 mg (5 grams) of D-Ribose three times a day for two to three weeks, then twice a day. Dr. Myhill also recommends 15 grams a day. Interestingly, she notes that the effects of D-Ribose can be enhanced by caffeine. She notes that D-Ribose has a short half-life, which is why it must be taken in small doses throughout the day. D-Ribose should be taken with food.





While initial doses of 15 grams are recommended by Drs. Teitelbaum and Myhill, it should be remembered that many CFS/ME patients are sensitive to supplements. Dr. Cheney has observed that fully one-third of his patients cannot tolerate D-Ribose. To test for sensitivities, an initial small dose (1 to 2 grams a day) is recommended.

PROS. D-Ribose appears to be generally well tolerated by people with CFS/ME. Patients usually notice improvement in energy levels within two or three days, although one patient commented that “within an hour, it was like a super thick fog bank had dissipated.” D-Ribose works particularly well with brain fog, daytime sleepiness and hypersomnia.





CONS. Some patients report that D-Ribose makes them sleepy, and that it saps them of energy. Those who take high doses (15 grams a day) have reported diarrhea, nausea, and headache. Because D-Ribose is derived from corn, those with corn allergies may not be able to tolerate this supplement. Although D-Ribose does not have the same properties as table sugar, it can be converted back to glucose, which may have an adverse effect on patients with Candida, as well as those with blood sugar problems. D-Ribose supplementation is not advised for diabetics. Nor is it recommended for those with gout, as it causes an increase in uric acid levels (which are usually low in people with CFS/ME).





AVAILABILITY AND COST. D-Ribose is widely available in health food stores and from online suppliers. Costs range from $10 to $75, depending on the brand. Corvalen, the brand Dr. Teitelbaum prefers, sells for roughly $30 for a 280-gram container (56 servings, or roughly an 18-day supply at three scoops a day). Vitacost markets a 100-gram bottle made by Jarrow for about $10 (45 scoops).





FURTHER READING

Dr. Teitelbaum addresses questions about D-Ribose: http://www.endfatigue.com/web-newsletters/Newsletter_3_questions_d-ribose.html

Dr. Teitelbaum explains the functions and benefits of D-Ribose. http://www.endfatigue.com/health_articles_d-e/D-ribose-powerful_body_energizer.html

Teitelbaum JE, JA St. Cyr, C Johnson. “The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot Study” J Alternative and Complementary Medicine2006;12(9):857-862. http://www.fibroandfatigue.com/files/d-ribose.pdf

Dr. Lapp's list of supplements, including D-Ribose: http://www.prohealth.com/library/showarticle.cfm?libid=16109

Myhill, Sarah, Norman E. Booth, and John McLaren-Howard. “Chronic fatigue syndrome and mitochondrial dysfunction.” Int J Clin Exp Med.2009;2(1): 1–16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

(This is a very long paper. You may want to jump to the following site.)

A summary of the information in the previous paper: http://www.drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure

Creatine and D-Ribose studies: http://www.vrp.com/energizers/mitochondrial-restoration-part-iii-d-ribose-and-creatine-increase-mitochondrial-energy-production

A patient's encouraging report of her experiences with D-Ribose. http://www.healingwell.com/community/default.aspx?f=15&m=1253136





DIGESTIVE ENZYMES





DESCRIPTION. Gastrointestinal enzymes are secreted in the GI tract for the purpose of breaking down large food molecules into smaller molecules that are more easily absorbed.





BACKGROUND. Digestive enzymes are secreted in the mouth by salivary glands, in the stomach, in the pancreas and throughout the small intestine. Enzymes are classed into groups according to their function: proteases split proteins into amino acids, lipases split fat into fatty acids and glycerol, carbohydrases split sugars and carbohydrates into glucose, and nucleases split nucleic acids into nucleotides, which form RNA and DNA. Nucleotides also potentiate the production of ATP.





The mouth is where the digestive process is initiated. Enzymes which are released by salivary glands include lingual lipase, to start the digestion of fats; and amylase, which starts the conversion of carbohydrates into glucose; as well as immune system chemicals such as IgA to battle bacterial toxins, and R-factor which helps with the absorption of B12.





The main enzyme produced in the stomach is pepsin, which breaks down proteins. There are a number of other gastric secretions in the stomach which aid the process of breaking down food, the most important of which are hydrochloric acid (HCl ), which activates pepsin and destroys bacteria; intrinsic factor, which aids in the absorption of B12 by protecting it from HCl ; and gastrin, the hormone which stimulates the stomach lining to produce HCl and intrinsic factor.





The pancreas produces trypsin, which further breaks down proteins into amino acids; pancreatic lipase, which breaks down fats; pancreatic amylase, which further breaks down carbohydrates into glucose; protease, for breaking down proteins; and several nucleases.





The small intestines, among many other chemicals, produce sucrase, to break down sugars; lactase, to break down lactose in milk; and maltase, which breaks maltose down into glucose.





USES IN CFS/ME. Given the broad range of GI disturbances in CFS/ME patients, as well as the importance of the GI tract in maintaining both nutritional health and immune system functioning, digestive enzymes can play a critical role in treatment. Dr. Cheney believes enzyme supplementation is essential for all CFS/ME patients.





PROTOCOL. Dr. Cheney recommends one or two tablets of Ultrazyme (made by Douglas Labs). Ultrazyme provides a broad spectrum of enzymes, including lipase, amylase, protease, ox bile extract, cellulase, pepsin and L-lysine. Dr. Myhill recommends Polyzyme Forte, a broad-spectrum enzyme supplement made by BioCare (available the U.K.). Enzymes are sensitive to temperature extremes. They should be taken with warm water or food. Enzymes are activated by moisture, so make sure you keep the tablets dry.





PROS. Many patients swear by enzymes, claiming that they help eradicate digestion problems as well as many food sensitivities.





CONS. Enzymes can be hard on the stomach. For those who are prone to reflux, or heartburn, enzymes may exacerbate these problems. Stomach problems can be mitigated by taking enzymes with food (rather than on an empty stomach).





AVAILABILITY AND COST. Enzymatic supplements are readily available at any health food store and from online suppliers. A 60-tablet bottle of Ultrazyme (Douglas Labs) sells for around $15 on amazon.com. Enzymatic supplements can also be purchased in powder form. Plant-based enzymes, which are not degraded by stomach acid, should always be purchased.





FURTHER READING

Dr. Cheney discusses gut dysbiosis and CFS/ME symptoms: http://www.cheneyclinic.com/gut-dysbiosis-modulates-significant-cfs-symptoms/247

Dr. Cheney discusses Betaine HCl and the function of enzymes. (Written by Carol Sieverling) http://www.prohealth.com/library/showarticle.cfm?libid=8037

Lots of articles about enzymes: http://www.enzymestuff.com/





DHEA





NOTE: Not all CFS/ME patients have low levels of DHEA. Before embarking on a course of DHEA, make sure to have your DHEA level tested.





DEFINITION. DHEA (dehydroepiandrosterone) is a naturally occurring adrenal hormone.





BACKGROUND. DHEA, a hormone produced in the adrenal cortex, generates the sex hormones estrogen and testosterone. It is the most common hormone in the blood and is found in greatest concentrations in the brain. Perhaps because DHEA levels decrease with age, it has been called "the fountain of youth." A substantial body of research has provided evidence that DHEA may help the elderly by strengthening bones and muscles, decreasing joint pain, and improving sleep and mood. In addition to influencing hormone production, DHEA has several effects on immune system function, not the least of which is the regulation of lymphokine production.





A study conducted in 1993 by researchers at the University of Tennessee showed that DHEA decreases the amount of circulating interleukin-6 (a potent bone resorber and pro-inflammatory cytokine) and enhances the function of natural killer cells. Another study conducted in 1998 confirmed an inverse correlation between DHEA levels and IL-6 (as DHEA drops, IL-6 increases). DHEA has also been used to treat osteoporosis. A twelve-month study conducted in Canada confirmed that in post-menopausal women the application of DHEA in the form of 10% cream stimulated bone formation.





USES IN CFS/ME. Inspired by mounting evidence of adrenal cortical hypofunction in CFS/ME, clinicians have tested for blood levels of DHEA in CFS/ME patients. Some have discovered lower than normal levels. Based on these results, low doses of DHEA have been administered in hopes of raising immune function and normalizing the metabolic and endocrine disturbances that commonly accompany CFS/ME. It is believed that DHEA could also act as an antiviral agent because testosterone, a DHEA derivative, has demonstrable antiviral effects.





PROTOCOL. The usual dosage of DHEA is 25 to 100 mg/day, although a number of clinicians report good results with smaller doses. Dr. Majid Ali states that he frequently prescribes DHEA in doses of 50 mg taken on alternating days for up to several months. In contrast, Dr. James McCoy found that smaller doses (10 mg or less) are equally, if not more, effective than larger doses (CFIDS Chronicle, Fall 1993). He recommended starting at one tenth the normal dose to minimize the chance of negative reactions. Many patients with CFS/ME confirm that smaller doses (10 mg) work well for them.





PROS. Patients with CFS/ME have reported weight loss, increased energy, improved cognitive function, and better immune system responses with DHEA.





CONS. A number of patients have reported heart palpitations, jitters, and altered mental and emotional states. Female patients have experienced hair loss and acne. Dr. Paul Cheney points out that DHEA is often most beneficial in mild CFS/ME. He notes that even in cases where DHEA deficiency can be documented, administration of this hormone has caused severe relapse in some of his more profoundly ill patients (CFIDS Chronicle, Spring 1995).





Researchers have noted side effects in older women given standard doses of DHEA (25-200 mg a day), including acne and hirsutism (facial hair growth). DHEA also lowers cortisol, an anti-inflammatory adrenal hormone responsible for raising blood sugar levels. It is important to remember that even though DHEA is a natural substance, it is still a powerful hormone. Hormones, because they are released directly into the bloodstream, produce profound metabolic effects, not all of which are intended. Like other steroid or hormone treatments, DHEA is not without some risk and must be approached with caution.





AVAILABILITY AND COST. DHEA can be purchased online and at most health food stores. It is inexpensive. Vitacost sells many brands for less than $10. Mexican wild yam products containing diosgenin should be avoided, as the body cannot convert diosgenin to DHEA.





Although DHEA is sold as a supplement in the U.S., it cannot be purchased in the U.K. and Canada without a prescription. South Dakota and Missouri prohibit the sale of DHEA. Those under the age of 18 cannot purchase DHEA without a prescription. Most bottles of DHEA contain the warning: “Not for women under the age of 35.”





One of the natural precursors to DHEA, pregnenolone, may be less risky than DHEA. Patients report increased energy, enhanced mental clarity, and general improvement after taking pregnenolone. The dosage is 10 mg every other day in patients younger than 50 years, and 20 mg every other day in patients over 50 years old. Pregnenolone can be purchased from online suppliers at roughly the same cost as DHEA. Pregnenolone carries the same warnings as DHEA.





FURTHER READING

Very thorough overview of DHEA. Many studies are cited. http://www.tidesoflife.com/dhea__basic_information.htm

Dr. Cheney on DHEA and other supplements (1995). http://www.immunesupport.com/news/95sum003.htm

Good article on the effects of DHEA on aging: http://www.anti-agingmd.com/dhea.html





PATIENT REVIEWS

CFS/ME patient reviews of DHEA: http://www.revolutionhealth.com/drugs-treatments/rating/dehydroepiandrosterone-for-chronic-fatigue-syndrome-cfs-cfids-me





RESEARCH

Casson PR, Andersen RN, Herrod HG, Stentz FB, Straughn AB, Abraham GE, Buster JE. “Oral dehydroepiandrosterone in physiologic doses modulate immune function in postmenopausal women.” Am J Obstet Gynecol. 1993 Dec;169(6):1536-9. http://www.ncbi.nlm.nih.gov