Nutritrion Guide

Vitamins

B Vitamins

These are especially critical for energy production, and the RDAs I feel are very suboptimal (and one reason why many people call RDAs “Ridiculous Dietary Allowances”). B Vitamins are also important for immunity, nerve, and brain function, and much more. Using high but safe doses can be very important (while easy and low cost).

B1 (75 mg) – Thiamine

Vitamin B1 is critical for proper brain functioning, making it especially important in those with “brain fog.” It is also critical for heart function, which needs help in CFS patients (the heart is healthy, but the heart muscle needs help with energy production). In fact, a major cause of death in the U.S. is congestive heart failure, which is one symptom of vitamin B1 deficiency. Despite 33% of CHF patients being low in thiamine,⁴³ this easy treatment aid is ignored. Thiamine is also used therapeutically in dementia, anxiety, neuropathy, fatigue, alcoholism, confusion, depression, pain, memory loss, and disequilibrium.

In a double blind study by Dr. David Benton, an expert on thiamine, supplementation with vitamin B1 improved mood—possibly by increasing synthesis of acetylcholine, a neurotransmitter that is associated with memory.⁴⁴ Deficiency of this neurotransmitter has also been suspected to occur in CFS and supplementation with choline (see below) can also be helpful. Dr. Benton also found that giving 50 mg/day of thiamine (vs. placebo) was associated with reports of being more clearheaded, composed and energetic. These influences took place in subjects whose thiamine status, according to traditional criteria, was adequate.⁴⁵ Dr Benton notes that:

“Traditionally, the RDA has aimed to avoid a deficiency disease and has added a safety margin. My findings suggest that if you wish to redefine the RDA as achieving optimal functioning then the levels recommended would have to be increased.” He notes that subclinical thiamine deficiency can even affect school performance in young children stating that “there are clinical reports of youths who have developed aggressive behavioral problems to the extent that they entered a mental hospital. The origin of the problem was a diet that consists of little more than fast-food snacks on the street. Having failed to respond to psychiatric drugs, their unacceptable behavior disappeared when treated with thiamine supplements. In general, as poorer mood is known to influence cognitive functioning in all children, a poor mood is likely to be associated with poorer school performance.”

Dr. Derrick Lonsdale, another nutrition expert, has even found that thiamine supplementation can markedly diminish Sudden Infant Death Syndrome (SIDS). He found that by giving nutritional support:

“Gradually, it became obvious that I was merely supplying the missing components of energy metabolism and that these children were simply repairing their own tissues with the extra energy that was available to their cells. What was even more important was the fact that the enormous number of children with so-called emotional problems (attention deficit, hyperactivity and learning disability) plaguing the school system responded to their withdrawal from their cultural "goodies" and the use of vitamin therapy. This was published in the Journal of Clinical Nutrition in 1980. My present concept of the extreme danger of "high calorie malnutrition" was born. It has long been known that an increase in sugar in the diet automatically increases the need for thiamin. This is because glucose, which is the derivative of all sugars, is processed into the citric acid cycle and thiamin is the rate-limiting step. The ingestion of sugar in all forms in America is reported to be 150 pounds per capitum of population per annum.”

Dr. Lonsdale feels that inadequate thiamine can occur even if one is taking much more than the RDA. Interestingly, symptoms of thiamine deficiency can mimic symptoms often seen in CFS/FMS. He notes “Symptoms can be compared with "alarm bells" ringing. What thiamin deficiency does is to make the limbic system (the computer) much more sensitive to any form of stimulus. Thus, a person may have increased auditory, tactile or visual perceptions which are acute enough to be unpleasant. This gives rise to consciously perceived phenomena such as tachycardia, unusual sweating, abdominal pain with or without diarrhea, or a sense of panic/anxiety, fear, etc. These symptoms are easily perceived as fragments of the fight-or-flight reflex. Because of collective ignorance about the effects of dietary indiscretion, such symptoms are perceived as "nerves," "neurosis" or "functional" and are traditionally treated with a "tranquilizer." This is why I have termed the reaction Functional Dysautonomia. It is widespread and is frequently associated with mitral valve prolapse, premenstrual syndrome, temporo-mandibular syndrome and irritable bowel syndrome. There is really no such thing as a dose that suits all. Our biochemical mechanisms are variable from person to person and even within the same individual at different times. All we can do is to provide an excess, because the cell will use what it needs. The excess is lost in urine, sweat, etc. There are absolutely no side effects from thiamin unless it is given in thousands of time its physiologic dose. It has been used in Alzheimer patients in doses of 3 gms a day, with some benefit.⁴⁶

Professor Michael Gold also found that people with Alzheimer’s have lower serum thiamine levels than those with other types of dementia ^47. He also noted that in a small study of Chinese patients with Hepatitis, high dose B1 appeared to have anti-viral effects-which could also be potentially beneficial in CFS/FMS patients.

B2 – Riboflavin (75 mg)

This B vitamin is especially critical for energy production. In higher doses (75-400 mg/day) it has been repeatedly shown to decrease migraine frequency (a common problem in CFS/FMS) by 67% after 6-12 weeks. Vitamin B2 even helps decrease the risk of postpartum depression.⁴⁸

B3 – Niacin (50 mg)

Niacin is also critical for energy production, being a key part of the energy molecule NADH (which also helps make the neurotransmitter dopamine). Niacin may also prevent Alzheimer's. A five-year study of over 3,700 people published in the Journal of Neurology, Neurosurgery, and Psychiatry showed an inverse relationship between niacin intake and both Alzheimer's disease and age-related mental decline. The group getting a median 14 mg of niacin daily from diet and supplements were at highest risk (current RDA for niacin is 16 mg per day for men and 14 mg per day for women). While some benefits were noted to begin at 17 mg per day, a daily niacin intake of 45 mg offered the most protection from Alzheimer's disease and other causes of cognitive decline.⁴⁹ High doses over decades also seem to decrease the progression of arthritis. I recommend the niacinamide form, as regular niacin can cause marked flushing.

Pantothenic Acid (50 mg)

Pantothenic Acid and its cousin pantethine play many key roles in the body. Most importantly in CFS and fibromyalgia, pantothenic acid is critical for proper adrenal gland function. In addition, pantethine is also critical for proper handling of fats. For example, patients who have fatty liver and high triglycerides (blood fats) can have this condition resolve by taking pantethine.⁵⁰

B6 (Pyridoxine 85 mg)

Vitamin B6 (Pyridoxine) serves many critical functions, including enhancing immune function⁵¹ and decreasing the risk of heart disease.⁵² In a study of 61,433 women with no history of cancer followed for an average of 14.8 years, long term intake of dietary vitamin B6 was also associated with a 34% decreased risk of colon cancer in those whose B6 levels were in the highest vs. the lowest 20%.⁵³ I have also found that those with fluid retention benefit from vitamin B6 at a dose of ~ 200-250 mg/day—especially if you also optimize thyroid hormone levels. This has implications way beyond your rings being too tight. For example, B6 250 mg/day is very helpful at alleviating carpal tunnel syndrome (CTS). Although I have seen no studies on thyroid therapy in CTS, all of my patients who have taken B6, thyroid hormone, and a night-time “cock-up” wrist splint and do not have continuing repetitive stress injury have had their CTS go away without surgery in less than 3 months. This would make a wonderful study for insurance companies who would like to cut costs while improving patient outcomes and satisfaction (and I invite insurance companies to contact me about this).

B12 (500-1,000 mcg/day)

Vitamin B12 is another key nutrient in CFIDS. Technically, the B12 level is normal if it is over 208 picograms per deciliter (pg/dL) of blood. However, studies have shown that people can suffer severe and sometimes long term nerve and brain damage from B12 deficiency even if their levels are as high as 300 pg/dL.⁵⁴ Why are the “normal” levels set so low? In part, the normal values were initially set according to what prevents anemia. But the brain’s and nervous system’s needs for vitamin B12 are often much higher than those of the bone marrow. Also, as much as I hate to admit it, the medical establishment has greatly enjoyed poking fun at the old-time doctors who gave vitamin B12 shots for fatigue. The use of B12 shots despite “normal” levels is considered almost a symbol of unscientific, archaic medicine. As noted in an editorial in The New England Journal of Medicine, however, current findings suggest that those old-time doctors may have been right.⁵⁵ I suspect, though, that the modern medical establishment will be a little slow to eat crow.

I have been told (although I have been unable to confirm it), that a B12 level under 400 pg/dL is often considered abnormal in Japan and treated. In addition, a recent study using the respected Framingham database showed that metabolic signs of B12 deficiency occur even with levels over 500 pg/dL.⁵⁶

Furthermore, people with Alzheimer’s disease have been found to have an average B12 level of only 472 picograms per deciliter, compared with people who have confusion from a non-Alzheimer’s condition (such as a stroke), whose average B12 levels run 887 picograms per deciliter.⁵⁷ These and other studies suggest that many people need significantly higher B12 levels than what is currently considered normal. More importantly, recent research shows that despite their having normal B12 levels in the blood, CFIDS patients often have very low (and sometimes absent) B12 levels in their brains!⁵⁸ This suggests that, because of the metabolic problems present in CFIDS/FMS, you may need quite high B12 levels in your blood to get adequate levels past the blood-brain barrier (the membrane that separates the brain from the blood to protect the brain from circulating toxins) and into the brain, where B12 is needed. In addition, vitamin B12 helps reduce excessive levels of nitric oxide, a neurotransmitter that can be too high in people with CFIDS/FMS and that can easily contribute to symptoms. More and more, research studies are supporting what doctors who effectively treat CFIDS/FMS using B12 shots have said for years!

It is no surprise then, when their other problems are also treated, many people respond dramatically to B12 injections. If a patient’s B12 level is under 540 pg/mL, I treat that person with a 1-cc (1,000- to 3,000-microgram) injection one to five times a week for fifteen injections. These shots are very safe and fairly inexpensive. Although most regular pharmacies carry only the 1,000-microgram-per-cc strength, holistic pharmacies can make up injectable vitamin B12 that contains 3,000 micrograms per cc. I recommend that they use the methylcobalmin form or, if cost is an issue, hydroxycobalmin when making high dose injections. Usually, if a patient is going to benefit from the shots, I see improvement by ten weeks. I usually stop after ten to fifteen shots. If a patient feels worse when the injections are stopped, I resume giving the shots, usually every one to five weeks (but as often as three to four times a week in some cases) for an extended period of time. Most people, however, can maintain their B12 level after fifteen injections by taking the high amount in the Energy Revitalization System.

Why is a low B12 level such a common problem in CFIDS patients? Several possibilities exist. Among them are the following:

• Vitamin B12 is important for the repair of nerve injuries. Evidence suggests that brain dysfunction occurs in CFIDS. In repairing this injury, the body may over utilize vitamin B12 and deplete its stores.
• If an autoimmune process impairs the thyroid or adrenal gland, it may also attack the area responsible for our ability to absorb vitamin B12.
• Overgrowth of yeast or parasites in the bowel causing problems with absorption may prevent the proper absorption of vitamin B12.
• Nitric oxide excess is suspected in CFS and B12 is a nitric oxide scavenger.
• Vitamin B12 has trouble getting across the blood-brain barrier.⁵⁸
• Vitamin B12 may be important for, and used up in, detoxification.

The role of elevated nitric oxide in CFS has been explored by Professor Martin Pall of the University of Washington. He feels this is a major contributor to CFS and that high dose B12 is a key nitric oxide scavenger, and that this is a key reason it helps. Though complex, his ideas are well thought out, and I have added more detailed information on his theories in the web site notes. I would note that the approach discussed in this book is also effective at treating this problem.

Whatever the cause, I have found that treating patients with vitamin B12, even if their levels are technically normal, often results in marked improvement. This is good, as Vitamin B12 is both very safe and cheap and using high doses can be critical in CFS/FMS.

In addition to helping the CFS/FMS, B12 helps in many other ways. For example, in a study of people being treated for depression, participants with higher levels of vitamin B12 tended to get a greater benefit from antidepressants. The researchers theorized that a deficiency in vitamin B12 might result in high homocysteine levels, which may enhance depression.

In addition, Professor Vladimar Lerner, a major researcher on the role of nutrition and the brain, has noted that “Cobalamin [B12] and folic acid deficiency may contribute to the pathogenesis of neuropsychiatric disorders such as mental confusion, memory changes, cognitive slowing, mood disorder, violent behavior, fatigue, delirium, and paranoid psychosis.”⁵⁹ and this can occur because of B12 and folate’s role in methylation processes—which as we noted above are key players in treating CFS/FMS.

B12 is often better absorbed when taken as a supplement than when found in food.⁶⁰ This is especially important in the elderly, where suboptimal B12 levels are common. Giving RDA levels in this setting is not adequate. A 2005 study noted "The lowest dose of oral cyanocobalamin [B12] required to normalize mild vitamin B12 deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 µg daily," the authors write. "Clinical trials are currently assessing the effects of high doses of oral cobalamin on markers of cognitive function and depression. If such trials can demonstrate that the reported associations of vitamin B12 deficiency with cognitive impairment or depression are causal and reversible by treatment, the relevance of correction of vitamin B12 deficiency in older people could be substantial."⁶¹ Instead of waiting 10 years for those studies, I recommend people get 500 mcg/day of B12 now.

In addition, low B12 levels (which can cause high homocysteine levels) can increase the risk of osteoporosis by 200-300%.^62.63 and also significantly increase the risk of stroke.⁶⁴ Low B12 is also associated with increased blood clotting—a problem that is common in CFS.⁶⁵ High intakes of folate and vitamin B12 are also associated with decreased breast cancer risk, particularly among postmenopausal women.⁶⁶

Folic Acid (800 mcg/day)

This is the most that can legally be added to a vitamin, as there is a concern that folate could mask vitamin B12 deficiency—which is not a problem if the supplement also has high levels of B12. Optimal levels of folic acid (folate) are critical in CFS/FMS because of its role in immune function. In addition, it is critical in “methylation reactions” such as those that make SAMe.

The benefits of folate begin early in life. Folic acid is known to protect against serious neural tube birth defects that develop in the earliest weeks of pregnancy, such as spina bifida, in which parts of the brain or spinal cord don't develop properly. For this reason, doctors recommend that women who are pregnant or trying to get pregnant take a vitamin supplement that includes folic acid.About 4,000 U.S. pregnancies per year involve a neural tube defect. Because the neural tube closes about four weeks after conception, before many women know they are pregnant, folic acid needs to be taken before a woman conceives to be beneficial. In fact, to their credit, Johnson & Johnson wants to develop an oral contraceptive that contains folic acid. The goal is to reduce the risks of birth defects in babies of women who become pregnant while taking birth control pills, as well as others who conceive shortly after stopping pill use.

Mothers-to-be with lower levels of the vitamin folate in their body during early pregnancy are also more likely to have low weight babies, research published in the British Journal of Nutrition suggests. Low birth weight is associated with an increased risk of serious health problems, including respiratory disorders and diabetes. Since Canada started adding folic acid to foods, the number of children who developed neuroblastoma dropped 60%. Neuroblastoma is the most common cancer in infants, and the most common cause of cancer-related death in children between the ages of one and four.⁶⁷

Another major benefit of folate is in lowering elevated homocysteine levels and 800 mcg is an effective dose for this.⁶⁸ This may be one reason why an increased intake of folate has been associated with a 43% drop in heart attack rates.⁶⁹ A review of many studies suggests that taking 800 mcg of folic acid per day was associated with a 15% lower risk of heart attack and a 24% reduction in stroke.

Researchers have also identified a significant new risk factor for fractures in people with osteoporosis—high homocysteine levels. Two major studies, one conducted in Boston and the other in Amsterdam, found that the homocysteine levels' link to fractures was stronger than other factors such as smoking or low bone mineral density. The lead authors of both studies suggest that increased homocysteine levels may weaken the collagen that forms the framework for bones. Both studies conclude that supplemental folic acid, vitamin B12, and vitamin B6 are clearly essential in preventing potentially life-threatening hip fractures. The studies were reported in the May 13, 2004 issue of the New England Journal of Medicine.

Interestingly, since food makers began adding extra folate to flour in 1998 to prevent birth defects, heart disease, stroke, blood pressure, colon cancer and osteoporosis have all fallen, suggesting the general public may have been folate-deficient. Researchers are now advocating that the current fortification level, 140 micrograms of folic acid per 100 grams of grain, should be doubled.⁷⁰

Supplementing with 800 mcg of folate a day can also help memory. In one study, 818 cognitively healthy people ages 50 to 75 took either folic acid or placebo for three years. On memory tests, the supplement users had scores comparable to people 5.5 years younger, and on tests of cognitive speed, the folic acid helped users perform as well as people 1.9 years younger. “That's significant brain protection, with a supplement that's already well-known to be safe,” said Johns Hopkins University neuroscientist Marilyn Albert, who chairs the Alzheimer's Association's science advisory council.⁷¹

In addition, low folate is associated with Alzheimers.⁷² The results of a long-term study published in the inaugural issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association, indicate that consuming adequate levels of the B vitamin folate is associated with the greatest protection against Alzheimer's disease of any nutrient examined. Assistant professor of neurology Maria Corrada of the University of California Irvine's Institute for Brain Aging and Dementia and colleagues utilized data from the Baltimore Longitudinal Study of Aging which was begun in 1958 and includes over 1,400 participants. Dr Corrada noted, "The participants who had intakes at or above the 400 microgram recommended dietary allowance of folate had a 55% reduction in the risk of developing Alzheimer's. But most people who reached that level did so by taking folic acid supplements, which suggests that many people do not get the recommended amounts of folate in their diets."⁷³

Folate may also decrease the risk of ovarian cancer. Researchers from the Karolinska Institute in Stockholm analyzed data from a population-based group of more than 60,000 cancer-free women. Overall, women with the highest level of folate in their diet (at least 204 micrograms/day) were 33% less likely to develop ovarian cancer than those with the lowest levels (less than 155 micrograms/day). The results are published in a 2004 issue of the Journal of the National Cancer Institute. Folate may also help protect against colon cancer as well.⁷⁴

Folate also decreases the risk of hypertension. The January 19, 2005 issue of the Journal of the American Medical Association (JAMA) published the findings of Harvard researchers led by John P. Forman that intake of folate supplements is inversely related to the risk of hypertension in women.

Biotin (200 mcg)

This is a cofactor for a number of enzyme reactions, but seems especially important for healthy hair, skin and nails. Although it may take a year for hair loss to recover on this protocol, I am amazed at how many people are thrilled that their nails and hair have become strong and healthy along with the rest of their body!

Vitamin D (600-4,000 IU)

The importance of vitamin D deficiency is finally gaining increasing attention. This nutrient deficiency is critical, causing tens of thousands of unnecessary deaths in the U.S. each year. Because of this, and the deadly recommendation to avoid sunshine that people are given, I am going to cover the importance of this nutrient in depth.

Vitamin D deficiency is common. In fact, a review in the Mayo Clinic Journal showed that approximately 36% of healthy young adults and 57% of general medicine inpatients in the United States have inadequate levels of vitamin D.⁷⁵ Vitamin D deficiency is even more common in people with chronic pain.

This problem has increased since the horrible advice that doctors have given in telling people to avoid sunshine—and 90% of our vitamin D comes from sunshine. This misguided advice was given to decrease the number of dangerous skin cancers called melanomas. What doctors forget is that most of these melanomas are not in sun exposed areas (they are under our clothes). It is likely that the increase in melanomas is mostly occurring because of changes in diet, environment, and sleep which are resulting in weakened immune systems. The skin cancers usually caused by sunshine (e.g., basal cell cancers) are usually quite benign and easy to treat. Many other cancers increase in the face of vitamin D deficiency and, as 90% of our vitamin D comes from sun exposure, it is currently estimated that the advice to avoid sunshine is resulting in as many as 85,550 unnecessary cancer deaths each year! Sunshine is healthy—avoid sunburn, not sunshine!

To give more background about how avoiding sunshine (not sunburn) is counterproductive, two studies in the Journal of the National Cancer Institute shows that those with the most sunburns, the most beach vacations, and/or the most sunbathing were least likely to get lymphomas and leukemia (malignant white blood cell cancers). In addition, U.S. researchers report the surprising finding that people who get the most deadly kind of skin cancer (i.e., melanoma) are less likely to die of the disease if, in the past, they'd spent a lot of time in the sun. Researchers suggest that vitamin D has a lot to do with sunlight's anticancer effect.^76-9

Optimal vitamin D is also important to minimize breast cancer risk. Research findings show that “higher intakes of vitamin D and calcium from food and supplements are related to lower levels of breast density among premenopausal women. They suggest that increasing intakes of vitamin D and calcium may represent a safe and inexpensive strategy for breast cancer prevention."⁸⁰

Vitamin D also appears to lower prostate cancer risk. In a Harvard study, men with the highest levels of vitamin D had significantly lower overall risk (45%) of prostate cancer, including aggressive prostate cancer. According to Dr. Li "This research underscores the importance of obtaining adequate vitamin D through skin exposure to sunlight or through diet, including food and supplements," Dr. Li presented the report at the 2005 Multidisciplinary Prostate Cancer Symposium.

This is very important, as prostate cancer is one of the most common types of cancer in men in the U.S., and according to the American Cancer Society it's the second leading cause of cancer death in men. Almost 232,000 new cases will be diagnosed this year, and about 30,000 men will die of prostate cancer.⁸¹

High dose vitamin D is also important for those having surgery for lung cancer. Researchers at Harvard Medical School and Harvard School of Public Health studied the survival data of 456 patients with early stage lung cancer treated between 1992 and 2000. Patients who had high levels of vitamin D and had surgery in sunny months were more than twice as likely to be alive five years after surgery when compared to patients with low levels of vitamin D who had surgery in the winter, the researchers said. Lead researcher, Dr. David Christiani notes "The survival advantage at five years is pretty dramatic. 72% versus 29% when you compare the highest level of intake (of vitamin D) versus the lowest level of intake."⁸²

So impressive is the role of vitamin D in preventing cancer that Dr. Edward Giovannucci, a Harvard University Professor of Medicine and Nutrition, laid out his case in a keynote lecture at a recent American Association for Cancer Research meeting in Anaheim, California. His research suggests that vitamin D might help prevent 30 deaths for each one caused by skin cancer. "I would challenge anyone to find an area or nutrient or any factor that has such consistent anti-cancer benefits as vitamin D," Giovannucci told the cancer scientists. "The data are really quite remarkable." The talk so impressed the American Cancer Society's chief epidemiologist, Dr. Michael Thun, that the society is reviewing its sun protection guidelines.

Of course, having scientific research behind you may not offer much protection in academia. One of the world’s leading experts on vitamin D is Dr. Michael Holick, chief of endocrinology, nutrition and diabetes (and in the past a professor of dermatology) at Boston University. He published a book, "The UV Advantage," urging people to get enough sunlight to make vitamin D. "I am advocating common sense, not prolonged sunbathing or tanning salons,” Holick said.

“Repeated sunburns especially in childhood and among redheads and very fair-skinned people have been linked to melanoma, but there is no credible scientific evidence that moderate sun exposure causes it,” Holick contends. "The problem has been that the American Academy of Dermatology has been unchallenged for 20 years," he says. "They have brainwashed the public at every level." Despite the strong evidence supporting the role of common sense (i.e., avoid sunburn, not sunshine), the head of Holick's department, Dr. Barbara Gilchrest, called his book an embarrassment and stripped him of his dermatology professorship.

About a dozen major studies are under way to test vitamin D's ability to ward off cancer, said Dr. Peter Greenwald, chief of cancer prevention for the National Cancer Institute, and two recent studies reported encouraging signs in prostate and lung cancer. Edward Giovannucci, MD, of Harvard School of Public Health, and colleagues estimated vitamin D levels for 47,800 men who participated in the Health Professionals Follow-Up Study. Men whose vitamin D levels were in the top 10% of participants experienced a 22% lower risk of mortality from any cancer than those in the lowest tenth. The research team found that an increment in vitamin D levels of 25 nanomoles per liter (nmol/L) was associated with a 17% reduction in cancer incidence, a 29% reduction in cancer mortality, and a 45% reduction in digestive tract (colorectal, pancreatic, esophageal and stomach) cancer mortality.

Another study analyzing multiple studies concluded that an intake of 2,000 units of vitamin D a day (through a mix of sunshine, food and supplements) could decrease both breast cancer and colorectal cancer by over 50%.⁸³

This benefit applies to getting sunshine and not just supplements. Two new studies found evidence of a 40% reduction in breast cancer risk in women who had at one time worked outside. Women who participated in six or more outdoor activities between the ages of 12 and 19 had a 45% reduction in risk compared with women who had four or fewer activities.⁸⁴

In addition, higher vitamin D levels may slow the progression of breast cancer.⁸⁵

"Although melanomas account for approximately 7,000 deaths annually in males in the United States, 295,000 men die annually of all cancers," the authors conclude. "We estimated a 29% lower cancer mortality rate (i.e., 85,550 fewer deaths) if the predicted 25(OH)D [Vitamin D] level is increased 25 nmol/L. Thus, because current recommendations are adequate only to prevent extremely low vitamin D levels, establishing definitively whether cancer incidence and mortality rates are increased by inadequate vitamin D status should be a high priority. Achieving a 25(OH)D increment of 25 nmol/L may require vitamin D supplementation of at least 1,500 IU/day, a safe but not generally encouraged level.”⁸⁶

In an editorial in the same issue of the JNCI, Gary G. Schwartz, PhD, of Wake Forest University and William J. Blot, PhD, of the International Epidemiology Institute in Rockville, write, "The promising results from both observational and laboratory studies should usher in a new era of intervention studies of vitamin D and cancer risk."⁸⁷

To summarize, it is estimated that about 50,000-88,500 annual cancer deaths in the U.S. (10+% of all cancer deaths) could be prevented if all Americans had sufficient vitamin D. These deaths greatly outnumber the annual number of deaths from melanoma (8,000) and skin cancer (2,000). As an article in the BBC noted “Large Daily Dosage Of Vitamin D Lowers Risk Of Breast and Ovarian Cancers” (Article Date: 08 Jan 2006).

“A daily dosage of 1,000 international units of vitamin D can lower the risk of developing breast and ovarian cancers by about one-third," according to a study in the Dec. 27, 2005, online edition of the American Journal of Public Health.⁸⁸

Cedric Garland of the University of California-San Diego Moores Cancer Center and colleagues looked at 63 previous studies that examined the association between vitamin D and cancer.⁸⁹ Out of the 63 studies, 13 involved research on breast cancer and seven looked at ovarian cancer.⁹⁰ Garland said the previous studies found that the link between vitamin D intake and a lower risk of cancer is as apparent as the link between smoking and higher risk of lung cancer, Reuters reports. He added that people should consider taking vitamin D supplements to increase their daily intake to 1,000 international units, which is within National Academy of Sciences' safety guidelines.⁹¹

As for sunshine, experts recommend moderation until more evidence is in hand.

"The skin can handle it, just like the liver can handle alcohol," said Dr. James Leyden, Professor emeritus of dermatology at the University of Pennsylvania, "I like to have wine with dinner, but I don't think I should drink four bottles a day." Sounds like common sense may soon prevail.

For more information on the health benefits of sunshine, see the Sunlight, Nutrition and Health Research Center (SUNARC) website.⁹²

Besides causing upwards of 80,000 unnecessary and tragic cancer deaths each year, vitamin D deficiency is contributing to many of the hip fractures seen in the elderly, a major cause of these people losing mobility and therefore being in nursing homes. Vitamin D deficiency causes this in 2 ways. Low serum levels of vitamin D in the body may make elderly persons more susceptible to falls, researchers reported at the American Society of Mineral and Bone Research (ASBMR) 27th annual meeting. "Low levels of vitamin D were associated with low physical performance," said Ilse Wicherts, "This study shows that neuromuscular performance in those with lower levels of vitamin D was significantly lower than those with adequate levels. These individuals already are fragile. The lack of mobility places them at high risk of falls and fractures."⁹³

Low vitamin D levels also causes osteoporosis (weak bones). That low vitamin D is a disaster for the elderly is further reflected in research showing that vitamin D is low in 98% of the elderly who break their hip!⁹⁴ Fortunately, women who take 500 mg of calcium and 700 units of vitamin D daily are much less likely to even have a fall.⁹⁵

Unfortunately, despite media attention, vitamin D deficiency is alarmingly high in women with osteoporosis⁹⁶ and vitamin D deficiency in a pregnant women actually increases the risk of her child developing osteoporosis!^97,98

Vitamin D deficiency is wreaking havoc in many other ways as well. It is critical in regulating immune function, and this is likely why Multiple Sclerosis is much more common in northern latitudes which are less sunny. In fact, a very large study has confirmed the long-held theory that multiple sclerosis (MS) may be caused, in part, by a lack of sunlight. Harvard researchers took data from 187,563 women participating in the ongoing Nurses' Health Study and found that women taking a daily multiple with at least 400 international units of vitamin D were 40% less likely to develop MS. While women who had high intake of vitamin D from both foods and supplements were 33% less likely to develop the disease, relying solely on food as the source of vitamin D didn't offer any protection.⁹⁹

Vitamin D supplementation may also protect against rheumatoid arthritis. Researchers from the University of Alabama at Birmingham analyzed data from nearly 30,000 women between 55 and 69 years of age who participated in the Iowa Women's Health Study. Vitamin D supplements were associated with a 33% lower rheumatoid arthritis risk. "While the immuno-modulatory effects of vitamin D are not yet fully elucidated, the results from this study suggest a possible role for vitamin D in reducing the risk of an immunologic disorder," Dr. Merlino and colleagues write.¹⁰⁰

Vitamin D deficiency also increases the risk of diabetes. In a 2004 study, subjects with low levels of vitamin D had almost 3 times the risk of metabolic syndrome. Thus, the researchers conclude that low vitamin D leads to insulin resistance and noted "Now, we have one more reason to keep up vitamin D."¹⁰¹

This is supported by other research, where investigators noted “Vitamin D deficiency may, therefore, be involved in the pathogenesis [cause] of both forms of diabetes."¹⁰²

Vitamin D levels also tend to be low in diabetic children and vitamin D may even help to prevent the diabetes if given early.¹⁰³

Treatment with vitamin D can also improve lung function. Studies show lung function tests are worse in those with low vitamin D,¹⁰⁴ and that giving vitamin D to people with severe, steroid resistant asthma improves function.¹⁰⁵

In addition, pregnant Moms' who get higher doses of vitamin D than are typically recommended have a significantly lower risk of having children with asthma. Harvard Medical School researchers found that expectant mothers with the highest level of vitamin D intake—about 724 IU per day—had about half the risk of having a child with a wheezing illness at age three years of age, and less than half the risk of having a child at high risk for asthma.¹⁰⁶

Vitamin D may also decrease the risk of:

• Heart disease.¹⁰⁷
• Stroke.¹⁰⁸
• Diabetes — 61% of patients with diabetes have vitamin D deficiency¹⁰⁹ and higher intakes of vitamin D and calcium can lower the risk of getting diabetes.¹¹⁰
• Gingivitis.¹¹¹
• Inflammatory bowel disease.¹¹²

This leaves the question of what level of supplementation is optimal. I concur with Dr. Heike A. Bischoff-Ferrari, from the Harvard School of Public Health who notes “Recent evidence suggests that vitamin D intakes above current recommendations may be associated with better health outcomes. An intake for all adults of [at least] 1,000 IU of vitamin D/day is needed. Given the low cost, the safety, and the demonstrated benefit of higher vitamin D concentrations, vitamin D supplementation should become a public health priority to combat these common and costly chronic diseases."¹¹³

Vitamin K (50-500 mcg/day)

Although vitamin K plays a role in bone health, deficiency does not seem to affect bone density in peri-menopausal women.¹¹⁴

Vitamin K is also needed (along with magnesium and vitamin D) to build strong bones. Vitamin K (as K2) has been shown to decrease the risk of heart disease, and in men helps enhance insulin sensitivity. For the "science-minded" reader, the information below adds some background.

Vitamin K and Heart Disease

Professors Cees Vermeer and Leon Schurgers, of VitaK, at Maastricht University, the Netherlands, a leading research institute specializing in the role of vitamin K in the field of bone and cardiovascular health, provided the statement "There are two vitamins known to be involved in calcium metabolism: vitamin D and vitamin K. Increased calcium intake, especially if combined with vitamin D, results in increased absorption of calcium."

"However, vitamin K is required for activation of the vascular protein MGP, which is an inhibitor of calcification. In fact it is the strongest inhibitor of tissue calcification presently known and it is the only calcification inhibitor found in the vasculature. Using highly specific assays, the VitaK research group at the Maastricht University has demonstrated that the vitamin K intake by non-supplemented adults (almost without exception) is insufficient to completely activate MGP (at best 70% is activated). This means that healthy adults are not optimally protected against vascular calcification, even in the absence of an extra calcium load. Subjects of 50 years and older even have a still lower vitamin K status, and hence a higher fraction of their MGP is synthesized in an inactive form."

"When knowing these facts, it is only to be expected that an increased calcium intake will lead to increased artery calcification. This is what may happen if incomplete supplements are provided. It has been demonstrated in large population-based studies, in experimental animal studies and in cell culture studies that the efficacy of vitamin K2 in vascular calcification protection is far better than that of vitamin K1."

"However, at high intakes even K1 was shown to maintain vascular elasticity in a three-year study. Although a large clinical intervention trial on the cardio-protective effect of K2 at high calcium intakes has not yet been published, all data presently available suggest that supplements containing calcium and vitamin D without K2 are incomplete, and may have unexpected adverse side effect in the cardiovascular area."

A 2004 study published in the Journal of Nutrition, called the "Rotterdam Study," followed over 4,800 people for a ten year period. The study found increased intake of specifically vitamin K2 from dietary sources significantly reduced the risk of CHD mortality by 50% as compared to low dietary vitamin K2 intake.

Minerals

Boron (2-3 mg/day)

Boron is very helpful at improving bone strength—especially when combined with adequate magnesium. It may also help cognitive function. One researcher/professor gave half his class boron and the other half placebo for the semester, and the boron group did much better!

Chromium (200-500 mcg/day)

Chromium (and glutathione) is critical for proper insulin function and preventing diabetes and it can also decrease many of the symptoms of hypoglycemia. It can even be useful in treating some cases of depression, particularly when carbohydrate craving is a prominent symptom. A study of 113 people found that chromium supplements reduced depression-related cravings for sweets and starches, and provided an overall general improvement in depressive symptoms.¹¹⁵

Some physicians feel that it also helps cause weight loss.

Copper (500 mcg)

Copper is a “double edged sword.” Although critical for antioxidant production (such as SOD—super oxide dismutase, one of the body’s natural free-radical scavengers that reduce pain and inflammation) it also is a potent free radical trigger and is quite toxic in excess. For example, one study showed that men in the highest 25% of serum copper values were 50% more likely to die during the study when compared to subjects in the lowest quartile.¹¹⁶ To strike an optimal balance, I recommend ½ mg/day of copper.

Iodine (150-250 mcg/day)

Optimal iodine levels are critical for both healthy thyroid and breast tissue function. Iodine deficiency with secondary goiters used to be endemic in the U.S. until wheat flour, and to a lesser degree salt, had iodine added to them. This eliminated much of the problem until flour makers started adding bromine instead of iodine. This not only resulted in iodine intakes dropping by as much as half in the last decade but the switch can worsen the effects of iodine deficiency, as bromine may block thyroid function.

One of the main problems caused by iodine deficiency is hypothyroidism—which can cause a host of problems. These include not only fatigue, weight gain and pain, but also infertility and miscarriages. Low maternal iodine may cause hyperactivity disorder with a loss of 18 points in IQ score in their children.¹¹⁷

Iodine deficiency is also a common trigger for breast tenderness and fibrocystic breast disease, and I routinely supplement women who have these with iodine. It has even been suggested that seaweed, which is high in iodine, may lower breast cancer risk.¹¹⁸

In fact, one of the upcoming studies planned by our foundation will be to check iodine, bromine and fluorine levels (all related chemical “halides” which compete with one another) in tissue samples of women with breast cancer, fibrocystic breast disease and healthy breasts. We suspect that low iodine, or excessive levels of bromides and fluorides which may inhibit iodine, are factors that unnecessarily increase breast cancer risk.

Lithium

The neurological effect of the lithium ion Li⁺ makes some lithium salts useful as a class of mood stabilizing drugs, mostly for bipolar disorder. Therapeutically useful amounts of lithium (about 0.6 to 1.2 mmol/l) are only slightly lower than toxic amounts (>1.5 mmol/l), so the blood levels of lithium must be carefully monitored during treatment to avoid toxicity.

An important point that is often ignored is that at much lower doses, lithium is actually an important and natural nutrient. It helps protect brain function against injury from neurotoxins, improves mood, decreases aggressiveness and even has anti-viral properties. It is usually left out of multi-vitamins because of confusion between its use as a nutrient at very low dose (5-10 mg a day) and its use as a medication with significant side effects at 30-90 mg (300-900 mg of lithium carbonate) daily.

Magnesium (200 mg)

Magnesium is involved in hundreds of different body functions, but is routinely low in the American diet as a result of food processing. The average American diet supplies less than 300 milligrams of magnesium per day, while the average Asian diet supplies over 600 milligrams per day.^119,120 I generally recommend taking 1,800 milligrams of malic acid and 200-450 milligrams of magnesium glycinate a day for eight months, and then cutting back to 200 mg. If diarrhea and cramps are not a problem, you can take up to twice this amount. If your magnesium level is low, your muscles will stay in spasm and your fibromyalgia will not resolve. This is one of the reasons that taking magnesium is so critical. In addition, magnesium is important for the muscles’ and body’s strength and energy.¹¹⁹ Most of your magnesium is inside your cells and the blood test only measures the magnesium in your blood—making blood tests an unreliable measure. I suspect that magnesium has trouble getting into the cells in people with CFS/FMS. When CFS/FMS is properly treated, the magnesium may then be better able to get inside the cells. The cells then soak it in like a thirsty sponge and your blood level may even drop—despite taking large amounts of oral and even intravenous magnesium. So keep in mind that magnesium blood tests do not drop below normal until severe magnesium depletion occurs¹²¹ and everyone with CFS/FMS, fatigue, or muscle achiness should take magnesium. An exception is if you have kidney failure with a blood creatinine level over 1.6 milligrams per deciliter (mg/dL)—very rare in CFS/FMS (I’ve never seen this in a CFS patient). If you get uncomfortable diarrhea from the magnesium, cut the dosage back and then slowly increase the dose as is comfortable.

Magnesium absorption is very difficult, which is why I like to use the glycinate forms.

Let’s discuss some of the key functions of magnesium.

For starters, magnesium is simply critical for life. For example, 1 study showed that subjects who were in the highest 25% of serum magnesium values had a 40% decreased risk of dying during the study (with a 40% decrease in cardiovascular mortality and a 50% decrease in cancer deaths), compared to subjects whose magnesium levels were in the lowest 25% of the population!¹²²

Magnesium helps build bones, regulate body temperature, produce proteins and release energy stored in muscles. Because of the latter, magnesium deficiency causes muscle spasm/shortening, contributing markedly to fibromyalgia, migraine headaches, and other pains. In addition to magnesium deficiencies role in pain, it also likely contributes to the brain fog. A study by Massachusetts Institute of Technology researchers found that magnesium helps regulate a key brain receptor that plays an important role in learning and memory. The finding indicates that magnesium deficiency may result in reduced ability to learn and memorize, while cognitive function may be improved by an abundance of magnesium.¹²³

Magnesium is critical for producing energy in muscles. This means that low magnesium causes muscles to spasm and shorten, and this muscle shortening is a major cause of FMS pain. We frequently see marked pain relief with IV nutrient infusions that include magnesium (as well as increases in energy). Magnesium is critical for heart muscle function as well, and has been shown to improve both exercise endurance and cardiac function124—a key player in CFS.

Magnesium deficiency also contributes to obesity by causing insulin resistance. As the average weight gain in CFS is 32.5 pounds (which then often triggers sleep apnea) preventing insulin resistance, an important cause of weight gain, is one more benefit of magnesium supplementation.^125-6

In fact, people with high magnesium intakes followed over 15 years had a 31% lower chance of developing “metabolic syndrome”—a major cause of heart disease¹²⁷ as well as a decreased risk of developing diabetes.¹²⁸

Magnesium also:

• Helps protect against osteoporosis.^129-130
• Is associated with decreased inflammation levels (CRP-C Reactive Protein). offering further heart protection.¹³¹
• Is associated with a 23% lower risk of colon cancer.¹³²
• Improves asthma.¹³³
• Decreases the frequency of migraine headaches. In fact, the quickest and most effective way to eliminate a migraine headache is by giving 2 grams of magnesium IV over 5-10 minutes.
• Helps children with hyperactivity and attention deficit disorder when combined with vitamin B6.¹³⁴

For patients with CFS/FMS, magnesium (along with B-Vitamins and D-Ribose) represents the most critical nutritional need.

A Special Note About Jigsaw Health Magnesium:

Magnesium has long been recognized as a critical nutrient needed to "solve the puzzle" of chronic fatigue syndrome and fibromyalgia. Unfortunately, magnesium does have, shall we say, a bit of a "laxative action." This can sometimes be problematic in CFS and fibromyalgia, where underlying bowel infections are very common. For many people, this has limited their ability to get enough magnesium — even though they have found that taking magnesium markedly decreases their pain and improves their energy.

The good news? There is now a solution to this problem!

Jigsaw Health, Inc. has developed a sustained release magnesium product that really works. We were pleasantly surprised (we are used to seeing a lot of marketing hype) to find that it really did not cause diarrhea — yet was very effective. A bonus is its low cost. It also contains malate (malic acid) — another energy booster.

Magnesium is critical in over 300 reactions in our body, yet around half of magnesium in our food is lost during processing — resulting in magnesium deficiency being largely universal in the Western world. Even having a little more magnesium in the water supply has been shown to significantly decrease the risk of heart attack deaths. Meanwhile, magnesium causes tight muscles to relax, improves heart function, improves sleep, and increases energy.

In the past, because higher doses caused diarrhea, we limited the recommendation for magnesium intake for most people to the 200 mg found in the Energy Revitalization System vitamin powder. Now, with "diarrhea free" magnesium being available, I recommend that you try adding 2-4 tablets of the Jigsaw Health sustained release magnesium at bedtime. You'll be glad you did!

Jigsaw's sustained release magnesium has 125 mg of magnesium and 387 mg of malic acid (malate) per tablet (4 tablets contain 500 mg magnesium and 1,548 mg of malic acid).

Manganese (2-4 mg)

Manganese is an essential trace nutrient in all forms of life.

Most organisms living in the presence of oxygen use it to deal with the toxic effects of superoxide. The human body contains about 10 mg of manganese, which is stored mainly in the liver and kidneys. The classes of enzymes that have manganese cofactors include oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, lectins, and integrins. The best known manganese-containing polypeptides may be arginase, the diphtheria toxin, and Mn-containing superoxide dismutase (Mn-SOD).

Mn-SOD is the type of SOD present in eukaryotic mitochondria, and also in most bacteria. Manganese is also important in photosynthetic oxygen evolution in chloroplasts in plants (photosynthesis). Most broad-spectrum plant fertilizers contain manganese.

Though adequate amounts are helpful, too much can be toxic to the brain and nerves.

Molybdenum (250 mcg)

This mineral can be helpful for those with allergies, especially sulfite sensitivities (e.g., found in wine). It may also help detoxify acetaldehydes, which are made by yeast.

Phosphorus

Phosphorus is a key element in all known forms of life. Phosphorus is a component of DNA and RNA, as well as ATP, and is an essential element for all living cells. Phosphoric acid made from elemental phosphorus is used in food applications such as some soda beverages (especially Colas). It is also used in the processing of meat and cheese, in toothpaste, to soften water and for to prevent pipe/boiler tube corrosion. Because of this, phosphorus deficiency is rare in the American diet.

Due to its reactivity with air and many other oxygen-containing substances, phosphorus is not found free in nature but it is widely distributed in many different minerals.

An average adult human contains a little less than 1 kg of phosphorus, about 85% of which is present in bones and teeth in the form of apatite, and the remainder inside cells in soft tissues. A well-fed adult in the industrialized world consumes and excretes about 1-3 g of phosphorus per day in the form of phosphate.

In medicine, low phosphate syndromes are caused by malnutrition, by failure to absorb phosphate, and by metabolic syndromes which draw phosphate from the blood (such as re-feeding after malnutrition) or pass too much of it into the urine. All are characterized by hypophosphatemia, which is a condition of low levels of soluble phosphate levels in the blood serum, and therefore inside cells. Symptoms of hypophosphatemia include muscle and neurological dysfunction, and disruption of muscle and blood cells due to lack of ATP. Too much phosphate can lead to diarrhea and calcification (hardening) of organs and soft tissue, and can interfere with the body's ability to use iron, calcium, magnesium, and zinc.

Potassium (2,000+ mg/day; multivitamins are limited to 55 mg by FDA)

Potassium ion is a nutrient necessary for human life and health. It is important for neurons in the brain and nerves, and for influencing osmotic balance between cells and the interstitial fluid. It is important for allowing muscle contractions and sending of all nerve impulses. Potassium⁺ ions are larger than sodium ions, and the ion channels and pumps in cell membranes can distinguish between the two types of ions, actively pumping or passively allowing one of the two ions to pass, while blocking the other.

A shortage of potassium in body fluids may cause a potentially fatal condition known as hypokalemia, typically resulting from diarrhea, increased diuresis and vomiting. Deficiency symptoms include muscle weakness, paralytic ileus, ECG abnormalities, decreased reflex response and in severe cases respiratory paralysis, alkalosis and cardiac arrhythmia.

A deficiency of potassium is rare in healthy individuals eating a balanced diet since it is common in most fruits, vegetables and meats. Diets high in potassium can reduce the risk of hypertension. The 2004 guidelines of the Institute of Medicine specify a dietary reference intake of 4,000 mg of potassium, though most Americans and Europeans consume only half that amount per day. Individuals suffering from kidney diseases may suffer adverse health effects from consuming large quantities of dietary potassium. End stage renal failure patients undergoing therapy by renal dialysis must observe strict dietary limits on potassium intake, since the kidneys control potassium excretion, and buildup of blood concentrations of potassium may trigger fatal cardiac arrhythmia.

The FDA limits the amount of potassium that can be added to multivitamins to very low levels (55 mg) for this reason. To get a healthy amount of potassium, eat a banana and drink a 12 oz glass of V-8 or tomato juice daily.

Selenium (200 mcg)

Selenium is critical for optimal immune function. This is important to both eliminate the many infections seen in CFS/FMS, and also to prevent cancer. For example, a meta-analysis of 3 studies suggested that selenium may decrease the risk of colon cancer by ~ 1/3.¹³⁵

Selenium was also shown to increase longetivity and decrease cancer frequency in several studies.^136-7

Selenium is an antioxidant, and deficiency is associated with a shorter life, thyroid deficiencies and immune dysfunction.¹³⁸

In fact, low selenium is one of the problems that causes an under active thyroid with normal blood tests, as it is critical for converting inactive thyroid to the active form.

Sodium

Although we may not think of salt as a nutrient, it is essential to life.

Sodium is present in sodium chloride (table salt), and is necessary for regulation of blood and body fluids, transmission of nerve impulses, heart activity, and certain metabolic functions. Interestingly, although sodium is needed by animals, it is not needed by plants, and is generally toxic to plants. A completely plant-based diet, therefore, will be very low in sodium.

Sodium ions play a diverse and important role in many physiological processes. It is important for central nervous system function, which depends on the sodium ion motion across the nerve cell membranes. Sodium is the primary cation in extracellular fluids in animals and humans. These fluids, such as blood plasma and extracellular fluids in other tissues, bathe cells and carry out transport functions for nutrients and wastes. Relative loss of body water will cause sodium concentration to rise higher than normal, a condition known as hypernatremia. This ordinarily results in thirst. Conversely, an excess of body water caused by drinking will result in too little sodium in the blood (hyponatremia). The hypothalamus usually works well to cause drinking or urination to restore the body's sodium concentrations to normal.

In humans, a high salt intake was demonstrated to attenuate nitric oxide production. Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. The human requirement for sodium in the diet is about 500 mg per day, which is typically less than a tenth as much as many diets "seasoned to taste." Most people consume far more sodium than is physiologically needed.

Despite this, we forget that salt is supposed to have many of the other minerals present in sea salt, such as iodine. Most salt has had all of the minerals besides sodium and chloride removed. Iodized salt (rarely used in food processing) has a bit of iodine added back in. For home use, we recommend that sea salt be used (for example Celtic Sea Salt).

As an aside, the concept that high salt intake is harmful has been proven to be wrong (except in conditions like heart failure where low salt is needed). Repeated studies have shown that the more salt people eat, the longer they live.

Zinc (15-25 mg/day)

Zinc has been shown to be deficient in FMS and is very important as it is critical for optimal immune and antioxidant function.¹³⁹

Recurrent infections cause high zinc losses and, as discussed above, this is seen in AIDS as well as in FMS. Zinc is also very helpful for the rest of the population, and critical in CFS/FMS where the low zinc levels probably contribute to the many infections.

The poor immune function caused by zinc deficiency may have other ramifications as well. According to research published in the Journal of the National Cancer Institute. People with the highest zinc levels were 79% less likely to develop esophageal cancer than those with the lowest zinc levels.¹⁴⁰

Zinc may also help with cognitive function, even if taken with stimulants that can help in CFS. One study gave 44 children with ADHD either 55 mg of zinc or placebo each day for six weeks along with their Ritalin (which I think is overused in ADD and under used in CFS). While the behavior of all of the children improved during the study, those who had taken zinc had a more marked improvement. The study's authors believe that zinc may play a role in regulating the production of dopamine in the brain, which is often low in CFS/FMS. Dopamine is associated with feelings of pleasure and reward and has been linked to ADHD by other scientists. In addition, a study of seventh graders showed that 20 mg a day of zinc improved school performance with improved memory and attention span.¹⁴¹

Antioxidants

This category is so important that I am beginning the discussion of nutrition with 2 key antioxidants. Although necessary for life, oxygen is incredibly toxic. In fact, the greatest mass extinction in the history of the planet occurred when algae (which create large amounts of oxygen) began to grow in the seas. Putting large amounts of oxygen into the air, it is estimated that they drove over 95% of animal species then living into extinction—as oxygen is that toxic. Oxygen results in the production of toxic “free radicals,” which set up ongoing, self-sustaining chain reactions of molecular damage. Antioxidants end these chain reactions and are critical to life. Species that developed anti-oxidant defense systems and actually learned to thrive on oxygen survived the coming of algae. Doing so, however, is quite literally like playing with fire!

People with CFS/FMS are under increased oxidative stress.¹⁹ The importance of this problem is reflected in the work of Dr. Paul Cheney. This noted CFS expert believes that a major component of chronic fatigue syndrome stems from the heart muscle working poorly because of inadequate energy production. He theorizes that this occurs because the body's mitochondrial energy furnaces are unable to adequately handle oxygen free radicals and therefore shut down energy production. Antioxidants are the key tools that your body uses to neutralize free radicals. One antioxidant, called "glutathione," is especially critical. For over a decade we have talked about how glutathione deficiency may be one of the single most critical common denominators causing CFS and fibromyalgia. This theory has also been supported by the brilliant work of Rich Van Konynenburg, Ph.D. He proposes a number of triggers for glutathione depletion, including a block in the methylation cycle.

In addition to being critical for the production of energy, antioxidants also seem to be very important for maintaining health and youth. In fact, doctors who specialize in "anti-aging medicine" use antioxidants (as well as bioidentical hormones) as key tools.

Although supplementation can be critical, there are ways that are even more fun to get your antioxidants. This is why when I recommend avoiding sugar, I also add the three magic words “except for chocolate!” Chocolate’s high levels of antioxidants (especially dark chocolate), as well as it’s containing a natural mood enhancer, are the reasons for this recommendation. For example, according to the results of a study conducted at Cornell University, the concentration of cancer-fighting antioxidants in hot cocoa was significantly higher than those in red wine, green tea, or black tea.

Chocolate has other fringe benefits. Children born to women who regularly ate chocolate during their pregnancies were more likely to be “sweet natured.” Researchers at the University of Helsinki in Finland asked 300 pregnant women to track their stress levels and chocolate consumption. When their children were six months old, their moms were surveyed on their babies' behaviors. The results showed that babies born to stressed women who ate chocolate daily smiled more frequently, laughed more often, and showed less fear of new situations than babies of stressed women who did not indulge in chocolate. Taking high levels of antioxidants during pregnancy also decreases the risk of the baby having asthma.²⁰ I guess that eating chocolate is simply a sacrifice that we need to make for our children!

In men, taking even low dose antioxidants (120 mg of ascorbic acid, 30 units of vitamin E, 6 mg of beta carotene, 100 µg of selenium, and 20 mg of zinc, vs. a placebo for an average of 7.5 years) can prolong life.²¹ Men in the antioxidant group were 1/3 less likely to have died by the end of the study.

As one of many other examples, antioxidants such as Vitamin C can decrease the hearing loss that accompanies aging.²² In addition, it is estimated that 300,000 cases of macular degeneration (35% of cases), a leading cause of blindness, could be prevented simply by supplementation with antioxidants and zinc!²³ Anti-oxidants also protect against stomach cancer,²⁴ help in the treatment of liver disease,²⁵ are associated with a decreased risk of hip fractures,²⁶ and may protect against strokes.²⁷

Vitamin C (500-1,000 mg/day)

Thanks to low carb diets, scurvy is starting to make a come back. In a study done at the University of Arizona and published in the American Journal of Public Health, it was found that men and women aged 25 to 44 often fail to take in adequate amounts of vitamin C and are at high risk of getting scurvy. Because the disease is seldom considered by 21st century healthcare practitioners, people presenting with scurvy symptoms such as fatigue, limping, bleeding gums, or swollen extremities are often misdiagnosed and medicated for other disorders.

Vitamin C is well known as a critical nutrient, being important for proper immune, adrenal and antioxidant function, so I will not spend much time on it. I recommend you get at least 500 mg/day. To help encourage you to take it, too little vitamin C in the blood stream has been found to correlate with increased body fat and waist measurements. Nutrition researchers from Arizona State University report that the amount of vitamin C in the blood stream is directly related to fat oxidation—the body's ability to use fat as a fuel source—during both exercise and at rest.²⁸

Vitamins C and E also help to prevent osteoporosis²⁹ and vitamin C may protect against developing angina or strokes³⁰ though this was not found in a larger study.

As an aside, vitamin C actually does make you less likely to catch a cold. In one study, people taking 500 mg of vitamin C a day had 18% fewer colds than those in the 50 mg/day group.³¹ Vitamin C also helps improve sperm count and motility, and can be helpful in treating infertility.³² With sperm counts dropping dramatically around the planet, it could be that natural selection will mean that only those taking their supplements will eventually be able to reproduce!

Vitamin E (100 units/day)

This critical antioxidant serves many functions, but more is not always better. Many nutrients (such as beta carotene) are part of a larger “family,” so taking very high doses of only one type can actually suppress the others and become problematic. This is the case with vitamin E as well, as there are many types of tocopherols. Research suggests that taking over 150 units a day can actually be problematic,³³ so I recommend taking 100 units a day as the optimal level in multi-vitamins. If you are taking higher levels to treat a specific problem, take it for only a few months and use natural vitamin E (mixed tocopherols) which contain all of the different types of vitamin E.

Although more is not better, deficiency is a significant problem. For example, research suggests that 91% of 2-5 year olds are vitamin E deficient.³⁴ Taking vitamin E (200 units twice a day) can also significantly reduce the severity and duration of menstrual period pain. Writing in the British Journal of Obstetrics and Gynaecology, the researchers say: "The use of vitamin E for dysmenorrhoea [painful periods] in adolescent women is attractive because of the marked effect we have demonstrated, coupled with the absence of significant side effects from vitamin E in therapeutic doses." Peter Bowen-Simpkins, of the Royal College of Obstetricians and Gynaecologists notes: "This is particularly exciting because such treatment is readily available over the counter, is free from side effects, avoids the use of hormones or pain relievers and appears to be very effective."³⁵

Vitamin E in optimal doses (~ 100 units a day) may also be cancer protective. Two studies presented at the 2004 annual meeting of the American Association of Cancer Research found that people who had a high intake of dietary vitamin E or who had high levels in their bloodstream were the least likely to have cancer. In one of the studies, vitamin E supplements in addition to a vitamin E-rich diet lowered the bladder cancer risk. In the other, men with the most vitamin E in their systems had the lowest risk of prostate cancer. This was also discussed in another study published in the Journal of the National Cancer Institute, where high blood levels of vitamin E cut the risk of prostate cancer by about 50%,³⁶ and a third study which showed that vitamin E caused prostate cancer cells to “self destruct.”³⁷ Adequate vitamin E may also decrease the risk of breast cancer.³⁸

Given the above, one could argue that you’d need to be demented not to get adequate antioxidant support. I guess it’s not surprising then, that in a study on 1,033 people aged 65 years and older, low plasma levels of vitamin E were found to be associated with a more than doubled risk of becoming demented and of suffering from cognitive impairment!³⁹

Vitamin A (3,500 IU)

Vitamin A is critical for mucosal immunity and zinc function, but be careful not to get too much. Birth defects can occur in women taking over 8,000 units/day, and higher dosing of vitamin A (not beta carotene) can also aggravate osteoporosis. At doses of over 50,000 units/day, vitamin A can even cause liver injury, so I would only use doses over 8,000 units daily under the supervision of a holistic practitioner. Two examples of when higher doses may be used by your practitioner include acne, which is associated with low vitamin A levels⁴⁰ and improves with high dose vitamin A plus zinc (which augments vitamin A activity) and heavy menstrual periods during peri-menopause. Called “Dysfunctional Uterine Bleeding (DUB),” the bleeding often resolves without the need for a hysterectomy by taking 50,000 units of vitamin A (with 25 mg zinc) daily for 3 months. It is, of course, important to also treat the low thyroid and low iron, which are 2 other (and more common) important causes of heavy periods.

Beta Carotene (3,500 IU)

One of a large family of carotenoids (found in carrots), beta carotene is the main one added to supplements. In proper dosing it can be helpful, and higher doses (to a point) are associated with increased longetivity.⁴¹

Because beta carotene is part of a larger “family,” however, taking very high doses of only one type can actually suppress the others and become problematic. For example, taking 25,000 units a day was associated with an increased risk of lung cancer. So more is not always better!

Bioflavonoids (500 mg)

There are many members of this family, which can be found in the white part of citrus fruits just below the peel. They are important for blood vessel integrity and immune function. A high intake of flavonoids has been shown to lower heart attack risk⁴² and 500 mg a day (of the quercitin form) decreases the symptoms of prostatitis.

Glutathione (GSH)

Glutathione (GSH) is a tripeptide and is an antioxidant, protecting cells from free radicals. Glutathione is not an essential nutrient since it can be synthesized from the amino acids L-cysteine, L-glutamic acid, and glycine. While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis has been shown to be essential.

Glutathione exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, it is able to donate a reducing equivalent (H⁺+ e^-) to other unstable molecules, such as reactive oxygen species. Glutathione (GSH) participates as a cofactor for the enzyme glutathione peroxidase. It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile. Glutathione is also needed for the detoxification of methylglyoxal, a toxin produced as a byproduct of metabolism.

An increased GSSG-to-GSH ratio is considered indicative of oxidative stress.

Glutathione taken orally is not well absorbed across the GI tract. However, tissue and serum glutathione concentrations can be raised by increased intake of the precursor cysteine, or in chronic conditions, by S-adenosylmethionine (SAMe). Glutathione precursors rich in cysteine include N-acetylcysteine (NAC), glutamine, glycine, vitamin C and undenatured whey protein and these supplements have been shown to increase glutathione content (all present in the Energy Revitalization System vitamin powder — for this reason).

Superoxide Dismutase

The enzyme superoxide dismutase, catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. It is an important antioxidant defense in nearly all cells exposed to oxygen.

SOD can be naturally found in the cytosols of all eukaryotic cells with copper and zinc. It is in chicken liver (and nearly all other) mitochondria. Many bacteria contain a form with manganese (Mn-SOD).

SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity. Superoxide is one of the main reactive oxygen species in cells. The physiological importance of SODs is illustrated by the severe pathologies evident in mice genetically engineered to lack these enzymes.

Mutations in the first SOD enzyme can cause familial amyotrophic lateral sclerosis (ALS). Overexpression of SOD1 has been linked to Down's syndrome.

SOD has proved to be highly effective in treatment of colonic inflammation in experimental colitis and may be an important new tool for the treatment of inflammatory bowel disease. It is used in cosmetic products to reduce free radical damage to skin. Having adequate zinc (about 15 mg a day) and copper (1/2 mg a day) are key nutrients responsible for optimal SOD function. Too much copper, however, can actually increase oxidative stress, so more is not better.

Lipoic Acid

Lipoic acid, from potatoes, is a helpful antioxidant which restores and supports function of other antioxidants (such as vitamin E) and also can help heal nerve pain (the latter at a dose of 300 mg 2 times a day).

Alpha lipoic acid is an antioxidant which has been shown to be especially beneficial for diabetic neuropathy. Another study showed that it was also helpful in relieving "burning mouth syndrome." This syndrome is characterized by chronic pain on the tongue and sometimes the anterior palate and lips without any visible lesions. It is most often seen in postmenopausal women and has characteristics of being neuropathic pain. In a study of 60 patients, half received 200 mg of lipoic acid 3 times a day or a placebo for 2 to 5 months. Ninety-seven percent of the patients improved as compared to 40 percent of those in the placebo group. Thirteen percent had complete resolution of their pain, and another 74 percent had "decided improvement," whereas none of the placebo patients had this level of improvement. Almost all the patients showed some improvement by 2 months, with 73 percent still showing benefit at the end of 12 months despite having stopped the treatment. The fact that lipoic acid helps in several kinds of neuropathies suggests it is worth trying in others as well, especially since it is quite benign and not very expensive.

Amino and Fatty Acids

Amino acid supplementation, especially with whey protein, has many benefits. Using partially denatured whey protein has been shown to increase glutathione production and has been helpful in CFS. In a study conducted at James Madison University in Virginia and published in the Journal of Medicine & Science in Sports & Exercise, whey protein also increased endurance and decreased the muscle wear and tear that comes with intense exercise.¹⁴² Whey protein also coats harmful bacteria, which prevents them from adhering to the gut wall so they are less infectious.

Although all of the amino acids are important, I will focus on the ones that are most critical in CFS/FMS. As is the case with most nutrients, optimal levels are good (and likely better than the RDA) but more is not always better!

Arginine (100-200 mg)

This key amino acid is a “double edged sword.” Although it may help raise growth hormone, which would be beneficial in most CFS/FMS patients, it also can raise nitric oxide (which is postulated by Professor Martin Pall to be too high in CFS—for more on his theories see the web site notes). Interestingly, B12 shots act as powerful nitric oxide scavengers, and this may be another reason they are so helpful—even in those with normal B12 blood levels. My main concern with arginine is that it promotes the growth of some viruses in the herpes family, and therefore may also stimulate HHV-6 and Epstein Barr Viral growth. Therefore I recommend that only low levels be used in supplements for CFS/FMS.

Fish Oil

The two key Omega-3 essential fatty acids in fish oil are eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA), the latter being a major component of brain tissue. Perhaps the old wives tales were right in calling fish "brain food."

Fish oil decreases anger, anxiety, and depression and increased vigor — while improving various types of cognitive and physiological functions, and mood. It fights dry eyes and may help promote heart health while decreasing stroke risk.

Pregnancy

Fish oil intake (containing Omega-3 fatty acid) during pregnancy may boost a baby's growth rate. Research suggests the benefits may extend throughout a child's life — helping prevent asthma, as well as decreasing the risks of bipolar disorder and cancer (in females). It also helps prevent postpartum depression. Many consider fish oil deficiency to be the most important nutritional deficiency in pregnancy, but do not want to recommend increasing fatty fish for fear of their having high mercury levels. Taking pure and mercury free fish oils avoids this problem.

If you would not eat a piece of fish that tastes like the oil, then the oil is rancid and don't use it.

Lysine (500-1,000 mg)

Lysine helps make L-Carnitine, which is low in CFS and used by the body to burn fat for energy. Carnitine deficiencies can also appear as mental confusion or cloudiness, angina, and weight gain. Lysine is used to fight herpes because it lowers arginine levels (see above), starving the viruses. Unfortunately, the dose needed to do this may also lower growth hormone levels, so in CFS/FMS I prefer to use the anti-viral medications instead for cold sore and vaginal herpes prevention.

Methionine (100-300 mg)

Although the amino acid methionine is a key part of the production of SAMe, high levels seem to paradoxically decrease SAMe production and may also be associated with an increased heart attack risk.¹⁴³ Therefore, I recommend that only low levels be added to supplements.

NAC (N-Acetyl-Cysteine) (250-650 mg)

NAC is critical for making a key antioxidant called glutathione and for keeping vitamins C and E in their active forms. It has been speculated that glutathione deficiency may be a major “root cause” in CFS. Although taking glutathione by mouth has no effect on blood levels (it simply gets digested), taking NAC, glutamine (1,000 mg/day—which also helps bowel healing), and glycine (500-1,000 mg/day)—the 3 amino acid “building blocks” of glutathione—plus vitamin C can markedly increase glutathione levels. Supplementing these three amino acids is especially important in CFS, as NAC, glutamine and glycine levels decrease by 30-50% in post-viral fatigue (e.g., CFS). For NAC, I recommend 650-1,000 mg daily for 3-4 months and then 250 mg a day for maintenance. Low Glutathione levels may contribute to your immune dysfunction. including low “natural killer cell” activity—as glutathione protects your immune system from harm.

NAC (perhaps by raising glutathione) has other benefits as well. In one study, taking high dose NAC increased time to muscle fatigue by 30% while preventing a drop in glutathione¹⁴⁴ and can even help to protect the heart muscle during a heart attack.¹⁴⁵

NAC at doses of 600-3,000 mg/day even significantly decreased symptoms of OCD (obsessive compulsive disorder).¹⁴⁶ Other antioxidants may also help OCD.¹⁴⁷ NAC also plays a role in detoxification.

Serine (500-1,000 mg)

In one study presented at the Myopain Research Conference in Italy, Serine 500 mg/day significantly decreased symptoms of FMS. It supports antioxidant, brain and immune function.

Taurine (500-1,000 mg)

Taurine has been shown to increase energy, and can actually be found in a few energy drinks. Unfortunately, most of these “energy drinks” largely contain caffeine and sugar. which are loan sharks for energy and should be avoided.

Tryptophan (100-500 mg)

Tryptophan is critical for production of serotonin, which is critical for sleep and also called the “happiness molecule” as serotonin decreases depression. Unfortunately, the law limits what can be added to supplements.

Tyrosine (500-1,000 mg)

Tyrosine is critical for the production of adrenaline and dopamine, 2 neurotransmitters that are often also low in CFS (for you “adrenaline junkie” CFS'ers out there — you know who you are!).

Cofactors

Choline (100+ mg)

This nutrient is critical for brain function and production of the neurotransmitter acetylcholine. It is also a “methyl donor,” which is helpful in CFS.

Results of animal studies published in the April 2004 issue of the Journal of Neurophysiology have demonstrated that choline exposure in the womb may increase the size of brain cells associated with memory and help them function more efficiently. A pilot study assessing choline supplementation in pregnant women hopes to replicate these impressive findings. Conducted by nutrition researchers at the University of North Carolina, women participants will take the equivalent of twice as much choline as is in a normal diet by eating three eggs a day or taking a supplement from their 15th week of pregnancy until one month post partum.

Malic Acid (900-1,600 mg)

Malic acid, from apples, is critical for energy production. This becomes especially important when added to magnesium or a powerful energy producing compound called ribose.

Inositol (500-1,000 mg)

Inositol is a key component of your nerve coverings (called the “myelin sheath”) and losses of inositol in the urine of diabetics likely contributes to their nerve pain. Inositol is also helpful in treating anxiety. For CFS, inositol is critical to the production of SAMe, which has been shown to be helpful. In fact, it has been estimated that combining the nutrients discussed in this chapter (i.e., those that are found in the Energy Revitalization System powder) results in your body making the equivalent of ~ 400+ mg of SAMe a day—a much more effective and less expensive way to get this nutrient!

Trimethylglycine (Betaine)

Betaine acts as a methyl donor, which can be very helpful in CFS and for overall health. Betaine also helps lower elevated homocysteine—a compound associated with increased risk of heart attacks and strokes.¹⁴

References

1. R.M. Marston and B.B. Peterkin, “Nutrient Content of the National Food Supply,” National Food Review, Winter 1980, pp. 21–25.

2. William G. Crook, The Yeast Connection and the Woman (Jackson, TN: Professional Books, 1995).

3. R.M. Marston and B.B. Peterkin, op. cit.

4. J.H. Nelson, “Wheat: Its Processing and Utilization,” American Journal of Clinical Nutrition 41, supplement (May 1985): 1070-1076.

5. H.A. Schroeder, “Losses of Vitamins and Trace Minerals Resulting from Processing and Preservation of Foods,” American Journal of Clinical Nutrition 24 (5) (May 1971): 562–573.

6. S.B. Eaton and N. Konner, “Paleolithic Nutrition. A Consideration of Its Nature and Current Implications,” The New England Journal of Medicine 312 (5) (31 January 1985): 283–289.

7. H.C. Trowell, ed., Western Diseases: Their Emergence and Prevention (Cambridge, MA: Harvard University Press, 1981).

8. W. Mertz, ed., “Beltsville 1 Year Dietary Intake Survey,” American Journal of Clinical Nutrition 40, supplement (December 1984): 1323–1403.

9 . J.G. Travell and D.G. Simons, Myofascial Pain and Dysfunction: The Trigger Point Manual, Vol. I (Baltimore, MD: Williams & Wilkins, 1983), pp. 103–164.

10. B. Kennes, I. Dumont, D. Brohee, et al., “Effect of Vitamin C Supplements on Cell-Mediated Immunity in Old People,” Gerontology 29 (1983): 305–310.

11. R.K. Chandra, “Effect of Macro and Micro Nutrient Deficiencies and Excess on Immune Response,” Food Technology, February 1985, pp. 91–93.

12. S. Chandra, et al., “Undernutrition Impairs Immunity,” Internal Medicine 5 (December 1984): 85–99.

13. R.K. Chandra, et al., “NIH Workshop on Trace Element Regulation of Immunity and Infection,” Nutrition Research 2 (1982): 721–733.

14. M.C. Talbott, L.T. Miller, and N.I. Kerkvliet, “Pyridoxine Supplementation: Effect on Lymphocyte Responses in Elderly Persons,” American Journal of Clinical Nutrition 46 (4) (October 1987): 659–664.

15. S.N. Meydani, M.P. Barklund, S. Liu, et al., “Vitamin E Supplementation Enhances Cell-Mediated Immunity in Healthy Elderly Subjects,” American Journal of Clinical Nutrition 52 (3) (September 1990): 557–563.

16. Bartali B et al. Low Micronutrient Levels as a Predictor of Incident Disability in Older Women, Arch Intern Med. 006;166:2335-2340.

17. Nachtigal MC, Patterson RE, et al, “Dietary supplements and weight control in a middle-age population,” J Altern Complement Med., 2005; 11(5): 909-15.

18. The relationship between dietary intake and the number of teeth in elderly Japanese subjects,” Gerodontology, 2005; 22(4): 211-8.

19. Ozgocmen S, Ozyurt H, Sogut S, Akyol O, Ardicoglu O, Yildizhan H. Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns. Rheumatol Int. 2005 Nov 10;:1-6 [Epub ahead of print])

20. Litonjua AA, Rifas-Shiman SL, et al, "Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age," Am J Clin Nutr, 2006; 84(4): 903-11.

21. Hercberg S. et al. Arch Intern Med. 2004;164:2335-2342

22. Takumida M, Anniko M, “Radical scavengers: A remedy for presbyacusis. A pilot study,” Acta Otolaryngol, 2005; 135(12): 1290-5.

23. van Leeuwen R, Boekhoorn S, et al, “Dietary intake of antioxidants and risk of age-related macular degeneration,” JAMA, 2005; 294(24): 3101-7.and http://www.medscape.com/viewarticle/520823 .

24. Kim HJ, Kim MK, et al, “Effect of nutrient intake and Helicobacter pylori infection on gastric cancer in Korea: a case-control study,” Nutr Cancer, 2005; 52(2): 138-46.

25. Medina J, Moreno-Otero R, “Pathophysiological basis for antioxidant therapy in chronic liver disease,” Drugs, 2005; 65(17): 2445-61

26. Zhang J, Munger RG, et al, “Antioxidant intake and risk of osteoporotic hip fracture in Utah: an effect modified by smoking status,” Am J Epidemiol., 2006; 163(1): 9-17.

27. Kwun IS, Park KH, et al, “Lower antioxidant vitamins (A, C and E) and trace minerals (Zn, Cu, Mn, Fe and Se) status in patients with cerebrovascular disease,” Nutr Neurosci, 2005; 8(4): 251-7.)

28. http://www.medicalnewstoday.com/medicalnews.php?newsid=40914

29. Pasco JA, Henry MJ, et al, “Antioxidant vitamin supplements and markers of bone turnover in a community sample of nonsmoking women,” J Womens Health (Larchmt), 2006; 15(3): 295-300.

30. Das S, Ray R, et al, “Effect of ascorbic acid on prevention of hypercholesterolemia induced atherosclerosis,” Mol Cell Biochem, 2006 Feb 14

31. Sasazuki S, Sasaki S, et al "Effects of vitamin C on common cold: randomized controlled trial," European Journal of Clinical Nutrition, August 24, 2005 (e-pub ahead of print)

32. Akmal M, Qadri JQ, et al "Improvement in human semen quality after oral supplementation of vitamin C," J Med Food, 2006; 9(3): 440-2

34. Drewel BT, Giraud DW, et al. Less than adequate vitamin E status observed in a group of preschool boys and girls living in the United States,” The J of Nutr Biochem., 2006; 17(2): 132-138.

35. http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/4433059.stm

36. http://abcnews.go.com/Health/wireStory?id=544848.

37. Malafa MP, Fokum FD, et al, “Vitamin E succinate suppresses prostate tumor growth by inducing apoptosis,” Int J Cancer, 2005; [Epub ahead of print].

38. Sylvester PW, Shah SJ, “Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells,” Front Biosci, 2005 Jan 1; 10: 699-709.

39. Cherubini A, Martin A, et al,“Vitamin E levels, cognitive impairment and dementia in older persons: the InCHIANTI study,” Neurobiol Aging, 2005; 26(7): 987-94.

40. El-Akawi Z, Abdel-Latif N, et al, “Does the plasma level of vitamins A and E affect acne condition?” Clin Exp Dermatol, 2006; 31(3): 430-3

41. Ray AL, Semba RD, et al, “Low Serum Selenium and Total Carotenoids Predict Mortality among Older Women Living in the Community: The Women’s Health and Aging Studies,” J Nutr, 2006; 136(1): 172-6

42. Marniemi J. Dietary and Serum Vitamins and Minerals as Predictors of Myocardial Infarction and Stroke in Elderly Subjects. Nutr Metab Cardiovasc Dis. 2005 Jun;15(3):188-97. 43761 (10/2005)

43. Hanninen SA, Darling PB, et al, “The Prevalence of Thiamin Deficiency in Hospitalized Patients With Congestive Heart Failure,” Journal of the American College of Cardiology, 2006; 47: 354-61.

44. Neuropsychology 1995;32:98-105.

45. Thiamine Supplementation, Mood and Cognitive Functioning," Psychopharmacology, 1997;129:66-71. #26997

46. "Red Cell Transketolase Studies in a Private Practice Specializing in Nutritional Correction," Journal of the American College of Nutrition,1988;7(1):61-67.:and Interview in Medical Pearls with Kirk Hamilton #29204.

47. Gold M, "Plasma and Red Blood Cell Thiamin Deficiency in Patients With Dementia of the Alzheimer's Type," Archives of Neurology, November,1995;52:1081-1085. #23739

48. Miyake Y, Sasaki S, et al, “Dietary folate and vitamins B(12), B(6), and B(2) intake and the risk of postpartum depression in Japan: The Osaka Maternal and Child Health Study,” J Affect Disord., 2006 June 29; [Epub ahead of print].

49. http://my.webmd.com/content/Article/90/100791.htm

50. Osono Y, Hirose NNakajima KHata Y. The effects of pantethine on fatty liver and fat distribution. J Atheroscler Thromb. 2000;7(1):55-8.

51. Cheng CH, Chang SJ, et al, "Vitamin B(6) supplementation increases immune responses in critically ill patients," Eur J Clin Nutr, 2006; 60(10): 1207-13.

52. Lin PT, Cheng CH, et al, "Low pyridoxal 5' phosphate is associated with increased risk of coronary artery disease," Nutrition., 2006 Oct 9; [Epub ahead of print].

53. http://www.medscape.com/viewarticle/506337; Gastroenterology. June 2005;128:1830-1837

54. J. Lindenbaum, E.B. Healton, D.G. Savage, et al., “Neuropsychiatric Disorders Caused by Cobalamin Deficiency in the Absence of Anemia or Macrocytoses,” The New England Journal of Medicine 318 (26) (30 June 1988): 1720–1728.

55. W.S. Beck, “Cobalamin and the Nervous System,” editorial, The New England Journal of Medicine 318 (1988): 1752–1754.

56. J. Lindenbaum, I.H. Rosenberg, P.W. Wilson, et al., “Prevalence of Cobalamin Deficiency in the Framingham Elderly Population,” American Journal of Clinical Nutrition 60 (1) (July 1994): 2–11.

57. Karnaze, D.S., and R. Carmel, “Low Serum Cobalamin Levels in Primary Degenerative Dementia: Do Some Patients Harbor Atypical Cobalamin Deficiency States?” Archives of Internal Medicine 147 (3) (March 1987): 429–431.

58. B. Regland, M. Andersson, L. Abrahamsson, et al., “Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome,” Scandinavian Journal of Rheumatology 26 (4) (1997): 301–307.

59. Lerner V. “Vitamin B12 and Folate Serum Levels in Newly Admitted Psychiatric Patients,” Clin Nutr, 2006 Feb;25(1):60-7. Epub 2005 Oct 10. 44868 (6/2006).

60. Andres E, Affenberger S, et al, “Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment,” Am J Med., 2005; 118(10): 1154-9.

61. Arch Intern Med. 2005;165:1167-1172: http://www.medscape.com/viewarticle/505585.

62. Dhonukshe-Rutten RA, et al. Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people. J Bone Miner Res, 2005 Jun; 20(6):921-9

63. “Morris MS, Jacques PF, Selhub J, Relation between homocysteine and B-vitamin status indicators and bone mineral density in older Americans,” Bone, 2005; 37(2)

64. Robertson J, Iemolo F, et al, "Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products," CMAJ, 2005; 172(12): 1569-73)

65. Diaz DE Tuesta AM, Ribo MD, et al,"Low levels of vitamin B12 and venous thromboembolic disease in elderly men," Journal of Internal Medicine, 2005; 258(3): 244-249

66. Lajous M,et al.,Folate, Vitamin B6, and Vitamin B12 Intake and the Risk of Breast Cancer Among Mexican Women. Cancer Epidemiology Biomarkers & Prevention Vol. 15, 443-448, March 2006

67. http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/4739733.stm Published: 2005/08/04 23:00:08 GMT

68. Homocysteine Lowering Trialists’ Collaboration “Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials,” American Journal of Clinical Nutrition, 2005; 82(4): 806-812.).

69. Drogan D, Klipstein-Grobusch K, et al, “Dietary intake of folate equivalents and risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition (EPIC). Potsdam study,” Public Health Nutr., 2006; 9(4): 465-71.

72. Ravaglia G, Forti P, et al "Homocysteine and folate as risk factors for dementia and Alzheimer’s disease," American Journal of Clinical Nutrition, 2005; 82(3): 636-43.

73. http://www.lef.org/protocols/prtcl-006.shtml

74. Kono S, Chen K, “Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma,” Cancer Science, 2005; 96(9): 535-542.

75. Holick MF, “High prevalence of vitamin D inadequacy and implications for health,” Mayo Clin Proc., 2006; 81(3): 353-73.

76. Berwick, M. Journal of the National Cancer Institute, Feb. 2, 2005; vol 97: pp 195-199.

77. Ekström Smedby, K. Journal of the National Cancer Institute, Feb. 2, 2005; vol 97: pp 199-209.

78. Egan, K.M. Journal of the National Cancer Institute, Feb. 2, 2005; vol 97: pp 161-163.

79. http://my.webmd.com/content/Article/101/106006.htm

80. Berube , et al. Cancer Epidemiology Biomarkers & Prevention. Vitamin D and calcium intakes from food or supplements and mammographic breast density. Cancer Epidemiol Biomarkers Prev, 2005;14(7):1653-1659

81. 2005 Multidisciplinary Prostate Cancer Symposium, cosponsored by the American Society of Clinical Oncology, the Prostate Cancer Foundation, the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology, Orlando, Fla., Feb. 17-19, 2005. News release, Brigham and Women's Hospital and Harvard University School of Public Health.

82. Reuters Sun, Vitamin D Help Lung Cancer Survival – Study; Mon Apr 18, 2005)

83. http://www.medicalnewstoday.com/medicalnews.php?newsid=62413

84. Garland CF, et al. 2006. Evidence of need for increased vitamin D fortification of food based on pooled analysis of studies of serum 25-hydroxyvitamin D and breast cancer. ASCO/ASTRO Gastrointestinal Meeting.Abstract 4008. and Knight JA, et al. 2006. Potential reduction in breast cancer risk associated with Vitamin D. ASCO/ASTRO Gastrointestinal Meeting. Abstract 4009.

85. Palmieri C, Macgregor T, et al, J Clin Pathol., 2006 Oct 17;"Serum 25 hydroxyvitamin D levels in early and advanced breast cancer," [Epub ahead of print].

86. http://www.medscape.com/viewarticle/529426 and Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451–9

87. Schwartz G. JNCI, Vol. 98, No. 7, 428-430, April 5, 2006

88. Garland CF, Garland FC, et al, “The Role of Vitamin D in Cancer Prevention,” Am J Public Health, 2005 Dec 27; [Epub ahead of print].

89. Rose,New York Daily News, 12/29/05.

90. Hope, Daily Telegraph, 12/29/05.

91. Reuters, 12/28/05.

92. http://www.sunarc.org

93. http://www.medscape.com/viewarticle/513634 ASBMR 27th Annual Meeting: Abstract 1134. Presented September 26, 2005.

94. http://abcnews.go.com/Health/wireStory?id=997923.

95. Bischoff-Ferrari HA, Orav EJ, et al, “Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial.” Arch Intern Med, 2006; 166(4): 424-30.

96. “Vitamin D inadequacy among post-menopausal women: a systematic review,” Gaugris S, Heaney RP, et al, QJM, 2005; 98(9): 667-76.

97. “Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study,” Javaid MK, Crozier SR, et al, Lancet, 2006; 367(9504):36-43. and Cooper, et al Lancet 2006;367:36-43.

99. January 13, 2004 issue of Neurology.

100. Merlino et al. Arthritis Rheum. 2004:50:72-77)

101. Chiu et al. Am J Clin Nutr 2004;79:820-825. and Liu. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older US Women. Diabetes Care, 2005;28(12): 2926-2932.

102. Mathieu et al. Vitamin D and diabetes. Diabetologia, 2005;48(7):1247-1257.

103. Pozzilli P, Manfrini S, et al, “Low levels of 25-hydroxyvitamin D-3 and 1,25-dihydroxyvitamin D-3 in patients with newly diagnosed type 1 diabetes,” Hormone and Metabolic Research, 2005; 37(11): 680-683.

104. “Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey,” Black PN, Scragg R, Chest, 2005; 128(6): 3792-3798.

105. Xystrakis E, Kusumakar S, et al. Reversing the defective induction of IL10 secreting Tregulatory cells in glucocorticoid-resistant asthma patients. Journal of Clinical Investigation 2005, 8 December.

106. http://www.medpagetoday.com/Pulmonary/Asthma/tb2/2796. Vitamin D deficiency during pregnancy also contributes to low birth weights http://news.bbc.co.uk/1/hi/health/4938932.stm.

107. John WG, Noonan K, et al. “Hypovitaminosis D is associated with reductions in serum apolipoprotein A — I but not with fasting lipids in British Bangladeshis, American Journal of Clinical Nutrition, 2005; 82(3): 517-522.)

108. Marniemi J. Dietary and Serum Vitamins and Minerals as Predictors of Myocardial Infarction and Stroke in Elderly Subjects. Nutr Metab Cardiovasc Dis. 2005 Jun;15(3):188-97. 43761 (10/2005).

111. Dietrich T, Nunn M, et al “Association between serum concentrations of 25-hydroxyvitamin D and gingival inflammation,” American Journal of Clinical Nutrition, 2005; 82(3): 575-80.

112. HM Pappa, et al.Pediatrics. 2006 Nov;118(5):1950-61.

123. Bischoff-Ferrari HA, et al. Am J Clin Nutr. 2006;84:18-28 and http://www.medscape.com/viewarticle/541149.

114. Rejnmark L, Vestergaard P, et al, “No effect of vitamin K(1) intake on bone mineral density and fracture risk in perimenopausal women,” Osteoporos Int, 2006 May 9 [Epub ahead of print].

116. Leone N, Courbon D, “Zinc, copper, and magnesium and risks for all-cause, cancer, and cardiovascular mortality,” Epidemiology, 2006; 17(3): 308-14.

118. Skibola, C. Journal of Nutrition, February 2005; vol 135: pp 296-300. News release, University of California, Berkeley.

119. M.S. Seelig, “The Requirement of Magnesium by the Normal Adult,” American Journal of Clinical Nutrition 14 (June 1964): 342–390.

120. F.L. Lakshmanad, et al., “Magnesium Intakes and Balances,” American Journal of Clinical Nutrition 60 (6 Supplement) (December 1984): 1380–1389.

120. M.S. Seelig, op. cit.

121. M.J. Hoes, “Plasma Concentrations of Magnesium and Vitamin B1 in Alcoholism and Delirium Tremens. Pathogenic and Prognostic Implications,” Acta Psychiatrica Belgica 81 (1) (January-February 1981): 72–84.

122. Leone N, Courbon D, “Zinc, copper, and magnesium and risks for all-cause, cancer, and cardiovascular mortality,” Epidemiology, 2006; 17(3): 308-14.

123. Massachusetts Institute of Technology news release, Dec. 2, 2004. Study published in the Dec. 2,2004 issue of Neuron.

124. Pokan R et al.Oral magnesium therapy, exercise heart rate, exercise tolerance, and myocardial function in coronary artery disease patients British Journal of Sports Medicine 6 July 2006;40:773-778; doi:10.1136/bjsm.2006.027250.

128. Van Dam RM, Diabetes Care. 2006;29:2238-2243.

129. Ryder KM, et al. Magnesium Intake from Food and Supplements Is Associated with Bone Mineral Density in Healthy Older White Subjects. J Am Geriatr Soc. 2005;53(11):1875-1880

130. Carpenter TO, Delucia MC, et al, "A randomized controlled study of effects of dietary magnesium oxide supplementation on bone mineral content in healthy girls," J Clin Endocrinol Metab., 2006; 91(12): 4866-72.

131. King D. “Magnesium Supplement Intake and C-reactive Protein Levels in Adults,” Nutrition Research, 2006; 26(5):193-196. 44508 (9/2006)

132. Folsom AR, Hong CP “Magnesium intake and reduced risk of colon cancer in a prospective study of women,” Am J Epidemiol, 2006; 163(3): 232-5.

133. Gontijo-Amaral C, Ribeiro MA, et al “Oral magnesium supplementation in asthmatic children: a double-blind randomized placebo-controlled trial,” Eur J Clin Nutr., 2006 Jun 21; [Epub ahead of print].

134. Mousain-Bosc M, Roche M, et al, “Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. II. Pervasive developmental disorder — autism,” Magnes Res., 2006; 19(1): 46-52.

135. Jacobs ET, Jiang R, Alberts DS, Greenberg ER, Gunter EW, Karagas MR, Lanza E, Ratnasinghe L, Reid ME, Schatzkin A, Smith-Warner SA, Wallace K, Martinez ME. Selenium and colorectal adenoma: results of a pooled analysis. J Natl Cancer Inst. 2004 Nov 17;96(22):1669-75.

136. Akbaraly NT, Arnaud J, et al, “Selenium and Mortality in the Elderly: Results from the EVA Study,” Clin Chem, 2005; 51(11): 2117-23

137. Ray AL, Semba RD, et al, “Low Serum Selenium and Total Carotenoids Predict Mortality among Older Women Living in the Community: The Women’s Health and Aging Studies,” J Nutr, 2006; 136(1): 172-6.)

138. Arnaud J, “Selenium and Mortality in the Elderly: Results from the EVA Study,” Clin Chem. 2005 Nov;51(11):2117-23. Epub 2005 Aug 25. 44052 (3/2006).

139. Maes M, Mihaylova I, De Ruyter M.Lower serum zinc in Chronic Fatigue Syndrome (CFS): Relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2005 Dec 7; [Epub ahead of print]

141. James G. Penland April 4 at the Experimental Biology 2005 meeting in San Diego.

143. Virtanen JK, Voutilainen S, et al, “High dietary methionine intake increases the risk of acute coronary events in middle-aged men,” Nutr Metab Cardiovasc Dis., 2006; 16(2): 113-20.

144. Matuszczak Y, Farid M, et al, “Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise,” Muscle Nerve, 2005; 32(5): 633-8.

145. Yesilbursa D, Serdar A, et al, “Effect of N-acetylcysteine on oxidative stress and ventricular function in patients with myocardial infarction,” Heart Vessels, 2006; 21(1): 33-7.

146. Lafleur DL, Pittenger C, et al, “N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder,” Psychopharmacology (Berl), 2006; 184(2): 254-6.)

147. Ersan S, Bakir S, et al “Examination of free radical metabolism and antioxidant defence system elements in patients with obsessive-compulsive disorder,” Prog Neuropsychopharmacol Biol Psychiatry, 2006 May 6 [Epub ahead of print].

148. Schwab U, Torronen A, et al, “Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans,” J Nutr, 2006 136(1): 34-8.)

149. E. Braunwald, ed., Harrisons Principles of Internal Medicine, 11th ed. (New York: McGrawHill, 1987),(1), p. 1496. And T.F. Kirn, “Do Low Levels of Iron Affect Body’s Ability to Regulate Temperature, Experience Cold?” Journal of the American Medical Association 260 (5 August 1988): 607.

150. D.C. Rushton, I.D. Ramsay, J.J. Gilkes, et al., “Ferritin and Fertility,” letter to the editor,” The Lancet 337 (8757) (22 June 1991): 1554.

151. Marniemi J. Dietary and Serum Vitamins and Minerals as Predictors of Myocardial Infarction and Stroke in Elderly Subjects. Nutr Metab Cardiovasc Dis. 2005 Jun;15(3):188-97. 43761 (10/2005)

152. http://www.webmd.com/content/Article/122/114601.htm

153. Trost, L. B. Journal of the American Academy of Dermatology, May 2006; vol 54: pp 824-844.

154. S. Chandra, et al., “Undernutrition Impairs Immunity,” op. cit.

155. R.K. Chandra, et al., “NIH Workshop on Trace Element Regulation of Immunity and Infection,” op.cit.

156. T. Walter, S. Arredondo, M. Arevalo, et al., “Effect of Iron Therapy on Phagocytosis and Bactericidal Activity in Neutrophils of Iron-Deficient Infants,” American Journal of Clinical Nutrition 44 (6) (December 1986): 877–882.

157. Maes M, Mihaylova I, Leunis JC.In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation. Journal: Neuro Endocrinol Lett. 2005 Dec 28;26(6) [Epub ahead of print]

158. Puri BK.The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):399-401.)

159. Fontani G, Corradeschi F, et al, “Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects,” Eur J Clin Invest, 2005; 35(11): 691-9.

160. Bouzan C, Cohen JT, et al, “A quantitative analysis of fish consumption and stroke risk,” Am J Prev Med, 2005; 29(4): 347-52.

161. “Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women,” Miljanovic B, Trivedi KA, Am J Clin Nutr., 2005; 82(4): 887-93.),

162. http://my.webmd.com/content/Article/90/100860.htm and Oken E, Wright RO, Kleinman KP, et al, “Maternal fish consumption, hair mercury, and infant cognition in a U.S. Cohort,” Environ Health Perspect., 2005; 113(10): 1376-80.

163. Salam MT, Yi YF, et al, “Maternal fish consumption during pregnancy and risk of early childhood asthma,” J Asthma, 2005; 42(6): 513-8.

165. Peet M, Stokes C "Omega-3 fatty acids in the treatment of psychiatric disorders, Drugs, 2005; 65(8): 1051-1059

166. Frangou S, Lewis M, McCrone P, “Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomized double-blind placebo-controlled study,” Br J Psychiatry, 2006; 188: 46-50.

251. Elvin A, Siosteen AK, Nilsson A, Kosek E. Decreased muscle blood flow in fibromyalgia patients during standardised muscle exercise: A contrast media enhanced colour doppler study. Eur J Pain. 2006 Feb;10(2):137-44.