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to Menu PageThe Use of Vitamins and Other Nutritional Supplements in the Prevention of Chronic Disease
Vitamins are organic substances required by all living organisms for healthy life and growth. Among their many properties, vitamins function as coenzymes (helpers to the primary enzyme) in metabolic reactions. Higher animals, particularly humans, cannot synthesize vitamins and therefore must ingest them as part of their diet. Deficiency in a particular vitamin results in a specific vitamin deficiency disease, such as rickets (a bone deformity from lack of vitamin D) and scurvy (the infamous sailors' deficiency disease of old, caused by lack of vitamin C-containing fruits and vegetables on sailing ships). Each type of deficiency disease is typically characterized by a "classic" set of symptoms.
Vitamins of the B complex and vitamin C are water soluble (i.e, they dissolve readily in ~water). The B complex vitamins are found in food sources such as whole wheat bread, fruits, green and yellow leafy plants, and animal sources such as eggs, dairy products, and liver. They include B1 (thiamine), B2 (riboflavin), B3 (nicotinic acid, or niacin), pantothenic acid, B6 (pyridoxine), biotin, folic acid, and B12. Certain other substances, such as choline, also may be considered as belonging to the B complex. Vitamin C (ascorbic acid) is present in certain fruits and green vegetables.
All the remaining vitamins (A, D, E, and K) are fat, or lipid, soluble (i.e., they dissolve more readily in oil than in water). Vitamin A (in the form of carotenoids) occurs naturally in green leafy and yellow vegetables; spinach, collards, kale, chard, carrots, and sweet potatoes are particularly good sources. Vitamin E (tocopherol) is found in many plant oils, such as corn oil. In adults vitamin K is supplied by intestinal bacteria.
A number of other minerals and nutrients, such as iron, calcium, magnesium, selenium, and zinc, have been found essential for preventing deficiency diseases. For example, magnesium, which is required for the activation of more than 300 enzymes in the body and for the use of ~some vitamins and minerals, is required for normal function and structure of the arteries, heart, kidneys, and bone (Seelig, 1980), and for the neuromuscular system (Durlach, 1988; Galland, 1991). There also are a number of "essential" amino acids and fats (that is, humans cannot synthesize them). Some other amino acids are considered "semiessential" because humans cannot synthesize them fast enough to meet metabolic needs.
Research base. The relatively few studies that have explicitly investigated the role of vitamin and mineral supplements in promoting health and preventing disease have generally found benefits from the supplements. In fact, evidence is increasing rapidly for a beneficial role of supplementation with a number of nutrients, including vitamins B6, C, and E; beta-carotene and other carotenes; folic acid; calcium; magnesium; and other factors. Although there is little dispute about the importance and functions of many vitamins and nutrients, questions arise regarding the levels necessary to produce optimum health. Many contend that the optimal levels of these compounds can be obtained in a normal diet and that the effect of additional amounts is negligible (National Research Council, 1989). To answer such questions, it is first necessary to compare some nutrient levels in the typical American diet with current RDAs as ~well as with what some now consider to be optimal levels based on the most recent research. The following includes data from recent studies on the minerals calcium, iron, and magnesium as well as the vitamins C, D, E, beta-carotene, and folic acid.
Calcium. Some authorities have recommended that women (including young women) consume 1,000 to 1,500 milligrams (mg) of calcium per day to develop and maintain bone health and prevent osteoporosis (Office of Medical Applications of Research, 1984). Although it is technically feasible to achieve this level by diet alone, most people in the United States do not get that much calcium in their diet. In fact, the median intake among American women is only 600 mg per day, or around half the optimal level. Furthermore, 25 percent of women consume less than 400 mg per day (based on an average of 4 nonconsecutive days over 1 year) (U.S. Department of Agriculture, 1988).
Iron. Approximately 8 percent of low-income women and 10 to 20 percent of low-income children are believed to be iron deficient (Public Health Service, 1989). While the RDA for women is 15 mg per day, only slightly more than 10 percent of women achieve this goal ~from diet alone; less than 10 percent of low-income women achieve this level (Block and Abrams, 1993; U.S. Department of Agriculture, 1988). Iron deficiency is not an important public health problem among men; indeed, some evidence suggests that iron overload in men may be a source of illness, such as heart disease (Sullivan, 1992). Absorption of iron from supplements and plant sources is quite low if body stores of iron are adequate; however, iron from red meat continues to be absorbed even if body stores of iron are plentiful (Ascherio and Willett, 1994). Therefore, until this hypothesis can be more fully studied, it may be prudent for men to avoid daily consumption of red meat.
Magnesium. Extensive metabolic balance studies done by the USDA Research Service showed that the ratio of dietary calcium to magnesium that best maintained equilibrium (i.e., output equaling intake) was 2:1 (Hathaway, 1962). This ratio is achieved at the median magnesium intake of approximately 600 mg per day. However, dietary surveys taken in the last decade have found that most Americans' diets provide less than 300 mg/day (Lakshmanan et al., 1984; Morgan and Stampley, 1988; Spillman, 1987). Thus, like that of calcium, the median daily intake of magnesium in the United States appears to be ~inadequate.
Long-term magnesium deficiency causes damage to arteries and the heart in all species of animals tested--rodents, cats, dogs, cattle, and monkeys (Seelig, 1980; Seelig and Heggtveit, 1974). It also adversely affects fat metabolism, increasing the "bad" lipids--low-density lipoprotein (LDL) cholesterol and triglycerides, which are associated with atheromas (fat deposits in arteries)--and decreasing the levels of "good" lipids--high-density lipoprotein (HDL) cholesterol, which remove fat deposits from the arterial wall (Altura et al., 1990; Rayssiguier, 1981, 1984, 1986; Rayssiguier et al., 1993).
On the other hand, magnesium supplementation appears to be effective in reversing this process. For example in a double-blind, placebo-controlled study, 47 patients with coronary artery disease and heart attacks were treated with oral magnesium or placebo for 3 months. Those who received the magnesium experienced a 27-percent decrease in the "bad" lipids in contrast to a slight increase in the placebo group. There was also a tendency toward increased HDL in the magnesium group (Rasmussen et al., 1989a). The investigators ~observed that these findings support the assumption that magnesium deficiency might be involved in the causation of coronary artery disease. Oral magnesium preparations have also favorably influenced blood lipids in diabetes mellitus, lowering high levels of LDL and raising low levels of HDL (Corica et al., 1994).
In another study in which about half of 374 men at high risk for serious cardiovascular disease were put on a diet high in magnesium (a predominantly vegetarian diet containing 900 to more than 1,200 mg of magnesium daily) and half were put on a regular diet (containing about 300 to 500 mg of magnesium daily), sudden cardiac deaths were 1.5 times more common in the low-magnesium group. Total complications occurred in 60 percent of the low-magnesium group versus 28.6 percent of the high-magnesium group (Singh, 1990). Total mortality was 18 percent and 10.7 percent in the low-and high-magnesium groups, respectively. Furthermore, in a 6-week study of 206 non-insulin-dependent diabetic patients there was significant lowering of LDL levels and slight raising of HDL levels on a high-magnesium diet versus no change in 194 comparable patients on their usual diets (Singh et al., 1991).~Epidemiological evidence also supports the premise that magnesium protects against cardiovascular disease in humans. Areas of the world where the intake of magnesium is high from either drinking water or diet have low prevalence of cardiovascular disease (Anderson et al., 1980; Durlach et al., 1989; Eisenberg, 1992; Hopps, 1981; Leary, 1986; Marier, 1978). In the United States, the Southeast (where water is soft and is low in magnesium) is known as the heart attack-kidney stone belt, whereas the northern Midwest Plains states (where water is hard and is high in magnesium) have lower cardiovascular disease rates and longer life expectancies (Hopps, 1981; Hopps and Feder, 1986).
In Germany, large-scale retrospective studies of nearly 5,000 patients indicate that magnesium supplements added to drugs used to prevent preterm delivery resulted in improved weights of infants, reducing incidence of low birth weights (whether due to prematurity or intrauterine growth retardation), and decreased the incidence of toxemias of pregnancy, including pregnancy-induced hypertension, preeclampsia, and eclampsia (Conradt, 1984; Conradt and Weidinger, 1982; Conradt et al., 1984). Two randomized double-blind studies of a total of 1,500 pregnant women, half of whom received placebo ~and the other half a magnesium salt supplement, showed that significantly fewer of the magnesium group developed eclampsia; in addition, there were significantly fewer low birth weights among the infants of the magnesium group. The conclusion was that magnesium supplements during pregnancy improved the outcome (Kovacs et al., 1988; Spaetling and Spaetling, 1987). It has been suggested that magnesium deficiency is a contributory factor in these conditions (Conradt et al., 1984; Kontopoulos et al., 1980; Seelig, 1980; Weaver, 1988), a concept that has been proved in magnesium deficiency-induced hypertension of pregnancy and in low birth weight of lambs born to ewes fed low-magnesium diets (Weaver, 1986, 1988). That preeclamptic women retain more magnesium after a loading test (injection of magnesium salt solution) than normal women do is direct evidence of the magnesium deficit in toxemia of pregnancy (Kontopoulos et al., 1980; Valenzuela and Munson, 1987).
Vitamin C. Vitamin C is an important antioxidant nutrient that is synthesized by most animal species but not by humans. The current RDA is 60 mg, an amount easily obtainable in diet. Nevertheless, 25 percent of women consume less than 40 mg per day in their 4-day average ~(U.S. Department of Agriculture, 1988). The optimal level of vitamin C intake is unknown, but a diet rich in fruits and vegetables can provide 250 to 500 mg per day (Becker, 1993). Interestingly, estimates of nutrition during the Paleolithic Age (the Old Stone Age, roughly 1,000,000 to 9,000 B.C.) suggest that early humans may have consumed as much as 390 mg per day of vitamin C (Eaton and Konner, 1985). As with vitamin E (see below), there is evidence that intakes well above 60 mg per day may reduce the risks of cataracts. The potential therapeutic attributes of vitamin C are discussed in detail in the next section, Orthomolecular Medicine.
Vitamin D. The current RDA for adults is 200 international units (IUs). However, there are few studies in adults to verify that this is the optimal level (Gloth et al., 1991). Although this vitamin can be synthesized by humans by exposure to the sun, many elderly persons, for example, who are often inside much of the day get little or no sun. Since fortified milk is the principal dietary source of vitamin D, persons who obtain little calcium from milk or who have inadequate sun exposure may have inadequate vitamin D intake (Gloth et al., 1991).
~Vitamin E. Vitamin E, or alpha-tocopherol, is another important antioxidant nutrient. The current RDA for vitamin E is 8 IU for women and 10 for men. This is a reduction from an earlier RDA of 30 IU for both men and women. A well-selected diet containing numerous servings of fruits and vegetables, nuts, whole-grain breads, and vegetable oils can achieve a diet containing 30 IU (Becker, 1993). However, few Americans consume such a diet.
Current median intake in the U.S. population is approximately 5 IU, with 10 percent of the population consuming little more than 3 IU. Levels of 100 IU or higher have been associated with significantly reduced risk of coronary heart disease in both men and women (Rimm et al., 1993; Stampfer et al., 1993). However, this effect has been seen at levels obtainable only from supplements. Indeed, the use of vitamin E supplements for 2 or more years was associated with a 41-percent decrease in risk of coronary disease among women (Stampfer et al., 1992) and a 37-percent decrease in men (Rimm et al., 1993). In addition, consumption of supplements containing vitamin E has been associated with significant reduction in risk of oral cancer (Gridley et al., 1992). This effect was seen even after controlling for factors such as smoking and alcohol consumption. Moreover, although ~persons with a high intake of fruits and vegetables had a 40-percent reduction in risk of oral cancer, those who used a vitamin E supplement in addition to high fruit and vegetable intake had an 80-percent reduction in risk.
Cataracts are a major cause of blindness worldwide and represent a significant fraction of health care costs in the United States. A number of studies have found that ingesting antioxidants, such as vitamin E, significantly reduced the risk of cataracts (Taylor, 1992). In one study, daily supplementation with 400 IU of vitamin E was associated with a 60-percent reduction in risk of cataracts, whereas daily use of 300 mg or more of vitamin C resulted in a 75-percent reduction in cataract risk (Robertson et al., 1989). Others have also found a high intake of dietary carotenoids associated with reduced cataract risk (Hankinson et al., 1992; Jacques et al., 1988).
Beta-carotene. This antioxidant is found in orange fruits and vegetables such as carrots, sweet potatoes, and squash, and in dark green leafy vegetables. As much as 20 to 30 mg can be obtained from just a few fresh carrots. This also is the level currently being used as ~the test dose in a number of intervention studies to determine whether it can reduce cancer risk (see below). However, current median intake is less than 2 mg per day, and approximately 25 percent of Americans consume 1 mg per day or less (U.S. Department of Agriculture, 1988). There also is evidence that other naturally occurring carotenoids, in addition to beta-carotene, may be important as antioxidants in reducing the risk of disease.
A number of recent studies have suggested that beta-carotene, among other antioxidants, may have a protective effect against certain cancers. For example, low blood levels of beta-carotene are consistently associated with the subsequent development of lung cancer (Ziegler, 1991).
Furthermore, in a recent prospective trial in China funded by the National Cancer Institute (NCI) and the Cancer Institute of the Chinese Academy of Medical Sciences, 29,584 adults were given several combinations of vitamin and mineral supplements. Linxian, a rural county in Henan province, northern China, has one of the highest rates of esophageal cancer in the world. Death rates for this cancer in Linxian are 10 times higher than the Chinese average ~and 100 times greater than for American whites.
During the period of the study, there were 2,127 deaths among study participants, with 32 percent of all deaths resulting from esophageal or stomach cancer. Only the combination of beta-carotene, vitamin E, and selenium significantly reduced death rates in the study population, and most of the reduction was due to lower cancer rates. This included not only a reduction in esophageal cancer and stomach cancer but also a 45-percent reduction in fatal lung cancer that did not reach statistical significance (Blot et al., 1994). The doses in the study were typically two to three times the U.S. RDA, and the risk reduction appeared to begin 1 to 2 years after vitamin and mineral supplementation began.
However, two other recent trials to assess the ability of beta-carotene to prevent cancer have not shown such positive results. A Finnish study in which almost 30,000 male smokers aged 50 to 59 were given daily supplements of vitamin E (alpha-tocopherol), beta-carotene, or both found no reduction in the incidence of lung cancer (Heinonen and Albanes, 1994). In fact, the study observed a higher incidence of lung cancer among men who received the ~beta-carotene than among those who did not. Nor was there any reduction in the formation of colon polyps--a precursor of colon cancer--in a study in which 864 individuals received placebo or beta-carotene (25 mg daily), vitamin C (1 g daily), and vitamin E (400 mg daily) for 4 years (Greenberg et al., 1994).
There are several problems with trying to compare these studies. Most important is whether a period of 4 to 6 years is sufficient to detect a beneficial effect of an agent that acts early in the development of cancer--which could be decades before the cancer is diagnosed. Also, it is possible that only persons with low levels of beta-carotene may benefit from supplementation. The New England Journal of Medicine managing editors warned in a recent editorial that consumers should not overinterpret the latest negative findings, just as they should not overinterpret the earlier positive findings (Angell and Kassirer, 1994).
Folic acid (folate). The current RDA for folate is 180 micrograms (mg) per day for women, but recent studies have shown that intake of 400 mg by pregnant women can greatly reduce the risk of neural tube defects (i.e., defects of the spinal cord tube) (Willett, 1992). Intake ~must be at this level in the earliest weeks after conception to be effective. Unfortunately, most women are not yet aware that they are pregnant then.
Researchers examining the role of folate in preventing cancer and cardiovascular disease have found that less than optional levels of folate may be linked to these diseases. For example, a recent study of almost 1,500 male physicians revealed that the risk of suffering a heart attack was elevated more than threefold by a common metabolic abnormality called homocysteinemia, which is correctable by consuming more folate. None of the study participants who suffered heart attacks would be considered folate deficient by current nutritional standards. However, the results of this study indicate that their intake of folate was clearly less than optimal for preventing cardiovascular disease (Stampfer et al., 1992). In addition, folic acid supplementation was associated with reduced risk of colorectal cancer (Giovannucci et al., 1993). In contrast, folate from food alone was not significantly related to reduced risk of colon cancer.
In another double-blind, placebo-controlled trial of 96 healthy persons over age 65, the ~consumption of vitamin and mineral supplements was associated with a significant reduction in illness from infections and improved immune function (Chandra, 1992). The vitamin used was a therapeutic-level, multiple vitamin containing, among other nutrients, 400 mg of folate and 16 mg of beta-carotene. Participants receiving the vitamin formulation experienced half as many days of infection-related illness over the treatment year as did persons receiving the placebo (i.e., 23 days for the treatment group compared with 48 days for the untreated group).
Thus, it may be that approximately 400 mg per day of folic acid is necessary for men and women of all ages. Although this level can be obtained from a well-chosen diet containing, for example, six servings of fruit or vegetables and fortified cereal per day (Block and Abrams, 1993), few in the United States consume such a diet. In fact, a recent study found that 25 percent of pregnant women who were surveyed consumed only 128 mg or less of folate and 10 percent consumed only 90 mg per day in their 4-day average (Johnson et al., 1994).
~Risks associated with vitamin and mineral supplementation. All vitamins, as well as other substances, including water, can be toxic at some upper level. Under certain conditions or for particular subgroups, dangers may arise in taking large doses of some vitamins and minerals. For example, persons on anticoagulant (blood-thinning) therapy should avoid high doses of vitamin E, because prolonged bleeding can occur. Accidental poisonings of children have occurred with a number of vitamins, most notably with large doses of iron and vitamins A and D. Indeed, the accidental fatal poisoning of children by ingestion of their mothers' high-dose iron tablets is a health problem that deserves wider recognition. Childproof caps have been required on iron tablets for several years, but greater awareness among parents is needed to prevent children from removing such protective devices.
Nevertheless, evidence suggests that most vitamins are safe for long-term use at levels well above the RDAs for most adults. For example, Hathcock (1991) found a "possible adverse effect level" for vitamins C, E, B6, and folate only with long-term ingestion at 10 times the RDA or greater and at 5 times the RDA for vitamin A. Minerals such as iron, zinc, and selenium, however, may be associated with greater risk of toxicity at levels of less than 10 ~times the RDA for long-term use.
The use of pharmacological doses (i.e., levels of intake substantially above those traditionally assumed necessary to prevent deficiency) of some vitamins and magnesium salts is an accepted practice in mainstream medicine for treatment of a few established conditions. However, such cases are relatively isolated, and the use of pharmacological doses of vitamins for many diseases remains controversial. This subject is discussed next.
Orthomolecular Medicine: Therapeutic Use of High-Dose Nutrient Therapy in Treatment of Chronic Disease
Varying the concentrations of substances normally present in the body may control mental disease.
--Linus Pauling
~In theory, the concept behind orthomolecular medicine is quite simple. Orthomolecular medicine is the pursuit of good health and the treatment of disease with the optimal concentration of substances normally present in the body. Nobel laureate Linus Pauling first used the term orthomolecular in his 1968 article, "Orthomolecular Psychiatry," in the journal Science (Pauling, 1968). The prefix ortho implies correct or proper; in using the term orthomolecular, Pauling was calling for the "right molecules in the right amounts" (Huemer, 1986).
Pauling's Science article concentrated on the psychiatric implications of the concept. It referred to the work of two Canadian psychiatrists, Abram Hoffer and Humphrey Osmond, who had for several years been treating acute schizophrenia with large doses of nicotinic acid (vitamin B3) and vitamin C as enhancements to or replacements for the then state-of-the-art therapies, electroconvulsive therapy (ECT) and major tranquilizer therapy. Hoffer and Osmond first became interested in vitamin B3 as a therapeutic biochemical agent because of reports in the literature that patients with pellagra, a disease caused by a vitamin B3 deficiency, displayed many of the same psychiatric symptoms as did patients with ~schizophrenia.
In a series of double-blind, placebo-controlled clinical trials in the 1950s and early 1960s, Hoffer and Osmond began giving patients with schizophrenia up to 6 grams a day of vitamin B3, as well as large doses of vitamin C and other vitamins, in addition to the normal treatment regimen. They reportedly doubled the recovery rate, halved the rehospitalization rate, and practically eliminated the suicide rate among this patient group in comparison with the patients receiving only ECT or tranquilizers. These positive results were reported in 5-, 10-, and 15-year followups (Hoffer and Osmond, 1960, 1964; Osmond, 1969).
In his Science article, Pauling indicated some of the ways orthomolecular concepts could be usefully applied to many other areas of medicine. He then suggested that increasing the intake of such nutrients to levels well above those usually associated with prevention of overt deficiency disease could have previously unrecognized health benefits for some, but not all, people (Pauling, 1968).
~One outcome of the increased attention focused on the megavitamin issue by Pauling's Science article was the publication of a report by the American Psychiatric Association's Task Force on Megavitamin Therapy in Psychiatry (Lipton et al., 1973), which roundly criticized the work of Hoffer and Osmond and declared megavitamin therapy to be of no value. Proponents of this new form of medical intervention criticized these reports as having numerous misstatements and inaccuracies. In particular, orthomolecular psychiatry proponents argued that the two reports had based their conclusions on flawed studies that attempted to replicate the use of niacin for the treatment of schizophrenia in chronically hospitalized psychotic patients. The treatment, according to proponents, had been shown effective only in acute schizophrenia of relatively recent onset (i.e., within a few months to a year or two), which meant that trials in chronically ill patients were doomed to failure (Hoffer, 1974; Pauling, 1974).
Concurrent with the studies of niacin in psychiatry in the early 1970s, Pauling began collaborating with Scottish surgeon Evan Cameron on a series of retrospective studies to determine whether vitamin C was effective in the treatment of cancer. In the late 1970s, ~Pauling and Cameron reported a significant prolongation of lifespan of vitamin C-treated patients over that of cancer patients who did not receive vitamin C therapy (Cameron and Pauling, 1976). These studies were undertaken as followups to a clinical trial conducted by Cameron with Alan Campbell, which reported complete cessation of tumor progression in 3 patients and complete tumor regression in 5 patients of 50 advanced-cancer patients treated intravenously for long periods with high doses of vitamin C (Cameron and Campbell, 1974).
The results of Pauling and Cameron's retrospective studies were published in the Proceedings of the National Academy of Sciences (PNAS), which took the unusual step of running an accompanying editorial along with the second PNAS paper criticizing its methodology and calling for better designed double-blind prospective studies to confirm or refute vitamin C's anticancer activity. Following this, the NCI funded two highly publicized clinical trials of vitamin C at the Mayo Clinic in Rochester, MN, both of which reported negative results for the use of vitamin C in the treatment of cancer (Creagan et al., 1979; Moertel et al., 1985). However, Pauling argued that the first Mayo Clinic study was flawed because almost all the patients had previously received chemotherapy, which may have ~affected their response to vitamin C. He contended that the second study was flawed as well, in part, because it did not use Cameron's protocol and vitamin C therapy was not carried out for long enough (Richards, 1986).
Despite the negative results of the Mayo Clinic studies, Pauling and others continued to promote vitamin C and other immune-modulating substances as important adjuvants to the treatment of cancer. They believed that neither surgery, radiation, nor chemotherapy could ever be completely effective in eliminating all the cancer cells from a patient's body. Thus it is necessary, they argued, to enhance the patient's immune defenses against cancer with large doses of vitamin C (Cameron and Pauling, 1976). The rationale for this is based on earlier observations that cancer patients tended to be significantly depleted of vitamin C (Baird and Cameron, 1973; Bodansky et al., 1951) and that those animals that have the ability to produce their own vitamin C significantly increased their own production of vitamin C--to an equivalent of 16 grams per day for the average human--when challenged with a potent carcinogen or when experimentally burdened with cancer (Burns et al., 1960; Schmidt et al., 1963). However, Cameron and Pauling never suggested that vitamin C (or other nutrients) should be used instead of conventional cancer therapy but rather as an adjunct to therapy (Cameron and Pauling, 1976). Pauling and others also have advocated high doses of vitamin C as a means of treating or preventing other diseases, including the common cold and influenza (Pauling, 1976).
Although the negative results from the Mayo Clinic studies as well as results from the American Psychiatric Association study managed to put a damper on claims made by the proponents of orthomolecular medicine for more than a decade, interest in this subject has been renewed recently. One reason is that in isolated instances, orthomolecular treatments have indeed proved effective in treating certain chronic illnesses. For example, megadose niacin is now routinely prescribed to treat hypercholesterolemia (i.e., abnormally high levels of LDL cholesterol in the blood) and has been shown to reduce cardiac mortality in large-scale trials (Vega and Grundy, 1994; Zhao et al., 1993). Likewise, vitamin A in dosages substantially higher than the RDA is a highly effective treatment for an uncommon form of leukemia (Bunce et al., 1994; Skrede et al., 1994), and the effectiveness of high-dose vitamin E in surgical wound healing and burn therapy has been recognized for ~years (Haberal et al., 1987; Zhang et al., 1992).
Finally, as the data have mounted on the role such antioxidants as vitamin C may play in preventing disease and maintaining health, younger investigators are increasingly being attracted to this field. These investigators are now equipped with more accurate and sensitive methods for exploring the validity of theories that were previously rejected outright but were never adequately tested (Barinaga, 1991).
Research base. The following are examples of orthomolecular treatments for which there is at least preliminary evidence suggesting their effectiveness in treating various chronic, debilitating illnesses but for which larger, more detailed studies are needed. This is by no means a comprehensive list. For the reader's convenience, these therapies are presented by type of conditions for which they are applied. These conditions include AIDS, cancer, a variety of heart and vascular conditions, lymphedema, and mental and neurological disorders.
~Acquired immunodeficiency syndrome (AIDS). AIDS is a clinical disorder caused by a retrovirus infection (i.e, human immunodeficiency virus, or HIV), which is the end stage of a progressive sequence of immunosuppressive changes. The drawbacks of current pharmacological therapy for HIV infection, such as zidovudine (AZT), include deleterious toxic side effects, inability to improve the immune dysfunctions and undernutrition initiated by the retrovirus infection, and the occurrence of AZT-resistant HIV strains. These drawbacks necessitate new strategies for developing novel therapies to treat AIDS. Low toxicity nutritional agents with immuno-enhancing and antioxidant activities may help normalize retrovirus-induced immune dysfunctions, undernutrition, and other pathological symptoms, thereby retarding the progression of the disease to AIDS. Data on the immune-stimulating effects of vitamin A and beta-carotene in HIV-infected individuals are presented below.
Vitamin A. In the early 1980s, Seifter and colleagues showed through a series of experiments that vitamin A or beta-carotene (its precursor) decreases the immune deficiency that results when animals are exposed to a wide variety of immunocompromising conditions such as trauma, infection, irradiation, and treatment with cytotoxic agents (Seifter et al., ~1982, 1983a, 1983b, 1984). Seifter and others also studied the effects of vitamin A supplementation in animals infected with the Moloney murine sarcoma virus, a retrovirus having many features in common with human immunodeficiency virus (HIV), the virus that causes AIDS (Kanofsky et al., 1987, 1990; Seifter et al., 1982, 1985, 1991). The vitamin A supplementation Seifter and his colleagues used in those experiments was approximately 10 to 15 times the recommended dietary allowance.
There is evidence suggesting that vitamin A supplementation in immune-compromised individuals may be necessary to correct a vitamin A deficiency caused by HIV infection. For example, Lack and colleagues (1993) found that approximately 50 percent of 120 HIV-positive patients, who were both symptomatic and asymptomatic, had a low serum vitamin A level. In another study, Semba and colleagues (1993) measured serum vitamin A levels in HIV-positive drug abusers and concluded that vitamin A deficiency may be common during HIV infection. Low vitamin A status was independently associated with decreased CD4 cells and a much greater mortality rate.
~Beta-carotene. Alexander and colleagues (1985) reported that extremely large oral doses of beta-carotene (180 mg per day) can increase the number of CD4 cells in the blood of healthy humans, with no observable toxicity. The CD4 cell is the white blood cell that becomes markedly depressed in AIDS patients. According to these researchers, "Our data suggest that beta-carotene administration might be considered for patients with AIDS."
Coodley and colleagues (1993), in an 8-week, double-blind crossover study of 21 HIV-positive patients, compared 180 mg per day of beta-carotene with placebo. The results showed a statistically significant increase in total white blood cell count, percent change in CD4 count, and percent change in CD4:CD8 ratios. The CD4:CD8 ratio is often used as an indicator of whether a patient's status is getting worse, holding steady, or improving.
Watson and colleagues gave a much smaller dose of beta-carotene (60 mg per day) to 11 HIV-infected patients over 4 months. The authors saw no change in T-helper lymphocytes (CD4), T-suppressor lymphocytes (CD8), or total T-cell lymphocytes. However, they did ~see an increase in the number of cells with natural killer markers and markers of activation (IL-2R, transferrin receptors) (Garewal et al., 1992). This indicates that beta-carotene may be enhancing certain aspects of the immune response.
Furthermore, Fryburg and colleagues (1992) gave 120 mg per day of beta-carotene and 1 multivitamin tablet a day to seven AIDS patients for 4 weeks. The mean CD4 count at baseline (i.e., before treatment) was approximately 53 cells/mm3. After 4 weeks of beta-carotene therapy, it rose to 76 cells/mm3. However, it returned to approximately 53 cells/mm3 6 weeks after treatment was stopped. A recommendation was made for beta-carotene to be tried in larger groups of patients.
Bianchi-Santamaria and colleagues (1993) gave 60 mg per day of beta-carotene 20 days of each month for 21 months to 64 patients with AIDS-related complex, which is the stage of HIV infection that occurs just before full-blown AIDS. This is the study with by far the longest duration and also is the largest and most recent. Mean CD4 count at baseline was approximately 451 cells/mm3. After 21 months of beta-carotene treatment, the mean CD4 ~count rose to approximately 519 cells/mm3, an increase of 15 percent. Normally, the mean CD4 count in these patients would be expected to drop. Furthermore, the authors suggested that the beta-carotene accounted for the apparent recovery of patients from asthenia, fever, nocturnal sweating, diarrhea, and weight loss. Unfortunately, this study did not have a control group.
Bronchial asthma.
Asthma, better termed hyperactive airway disease, is an autoimmune disease characterized by increased responsiveness of the tracheobronchial tree to exogenous and endogenous stimuli. The hallmark of this illness is widespread inflammation and narrowing of the tracheobronchial tree. This is manifested clinically by dyspnea (shortness of breath), wheezing, and cough, which generally occur simultaneously.
Asthma is typically managed with bronchodilator therapy and/or anti-inflammatory drugs. However, currently used pharmaceutical formulations for bronchodilation, such as ~theophylline, have a narrow therapeutic margin because adverse effects often occur at concentrations high enough to be effective (Taburet and Schmit, 1994). In addition, prednisone, the most common anti-inflammatory drug used to treat asthma, is also associated with a variety of adverse side effects. Such limited effectiveness of presently available treatments has recently sparked research into less toxic, immune-enhancing nutritional approaches to treating asthma. Data on the efficacy of vitamin C and magnesium in the treatment of this condition are presented below.
Vitamin C. Bielory and Gandhi (1994) conducted a comprehensive literature search of relevant English-language papers pertaining to the use of vitamin C in in the treatment of asthma and allergy and analyzed the studies according to their design, inclusion and exclusion criteria, population studied, variables or factors tested, method of intervention or treatment with vitamin C, and results and conclusions. They found a number of studies that support the use of vitamin C in asthma and allergy. Significant results included positive effects of vitamin C on pulmonary function tests; bronchoprovocation challenges with methacholine, histamine, or allergens; improvement in white blood cell function and motility; and a decrease in ~respiratory infections. On the other hand, their review also revealed several studies that did not support a beneficial role for vitamin C in asthma and allergy. These studies did not report improvements in pulmonary function tests or bronchoprovocation challenges or on other reactivity or specific immunologic factors and levels.
From their review, the researchers concluded that the majority of the studies were too short-term and assessed immediate effects of vitamin C supplementation. Rather, long-term supplementation with vitamin C or delayed effects need to be examined for the studies to be valid. The researchers went on to note that although the current literature does not support a definite indication for the use of vitamin C in asthma and allergy, the promising and positive studies were worth following up. Furthermore, the researchers suggested, with a large portion of health care dollars being spent on alternative medicine and vitamin C in particular, further studies are needed to define its role, if any, in the treatment of this condition.
Magnesium. First reported almost 50 years ago (Haury, 1938), the efficacy of magnesium in the treatment of bronchial asthma has received considerably more attention in the past few ~years. Its bronchodilating effect was reported in patients with mild asthmatic attacks, and when that was found effective, applied to those with severe attacks (Okayama et al., 1988). Intravenous magnesium sulfate was found to relieve respiratory failure in asthmatic patients not responsive to standard drug therapy (Hauser and Braun, 1991; McNamara et al., 1989; Neves et al., 1991; Noppen et al., 1990; Okayama et al., 1991; Skobeloff et al., 1989) and has been considered lifesaving (Dellinger, 1991; Kuitert and Kletchko, 1991).
Not all published trials of magnesium treatment of bronchial asthma, however, have been successful (Green and Rothrock, 1992; Kufs, 1990). However, the protocols of those studies reporting no therapeutic benefit of magnesium in asthma patients have been criticized on the grounds that insufficient dosages were used, with the result that the serum levels found effective in the treatment of preeclampsia and eclampsia (see below) were not achieved (Fesmire, 1993). Another criticism leveled at the negative efficacy reports was that the study group was too small for significance; this was countered by pointing out that analysis of results from the first 40 patients indicated withholding magnesium from comparably compromised patients would be unethical, so the study was ended and the results were ~reported (Skobeloff and McNamara, 1993).
Cancer. The rationale for the use of high dosages of vitamins, particularly vitamin C, to treat cancer was discussed in the beginning of this section. The following is a review of more recent data that have emerged since the negative results of the Mayo Clinic studies for vitamin C, as well as quite intriguing data on the use of high dosages of coenzyme Q10 in the treatment of certain cancers.
Vitamin C. The possible value of vitamin C as an adjuvant in cancer therapy is supported in animal and human studies. Indeed, vitamin C, used in conjunction with other treatment modalities, has been shown to improve the effectiveness of those treatments (Meadows et al., 1991; Poydock, 1991; Tsao, 1991). Of equal interest, vitamin C supplementation has been shown to reduce the toxicity of conventional chemotherapeutic agents, such as adriamycin (Fujita et al., 1982), and to reduce the toxicity and improve therapeutic gain of radiation therapy (Okunieff, 1991). There also is evidence that some of the severe toxicity associated with interleukin-2/LAK cell therapy may result from the drastic reduction in ~plasma vitamin C levels that this therapy causes (Marcus et al., 1987). Thus, these examples suggest that the use of vitamin C or other nutrients as adjuncts to therapy may reduce toxicity and thereby permit the use of more effective doses of the therapeutic agent.
Coenzyme Q10. Recently, Lockwood and colleagues (1994) treated 32 breast cancer patients with antioxidants, fatty acids, and 90 mg of coenzyme Q10 (CoQ10) per day and reported partial tumor regression in six patients. In one of the cases, the dosage was increased to 390 mg per day and, reportedly, within 2 months the tumor was no longer detectable by mammography. Encouraged by this, Lockwood and colleagues treated another patient with a verified breast tumor with 300 mg per day, and after 3 months they could find no sign of remaining tumor. Folkers reported that administration of this enzyme increases levels of immunoglobulin G, an antibody that is known to participate in antibody-dependent cellular toxicity against virally infected cells and, possibly, against cancer cells (Folkers et al., 1982, 1993). The same studies also showed increases in T4 lymphocytes--the immune cells targeted and destroyed by HIV infection--when CoQ10 was given with pyridoxine to AIDS patients.~Arteriosclerosis, heart attacks, arrhythmias, sudden cardiac death, strokes, and toxemias of pregnancy. Vitamin E. Postoperative thromboembolism, a major complication of surgery, involves the formation of blood clots in the deep veins of an extremity. The clots can break off and travel to blood vessels in the lungs, causing a pulmonary embolism that can be fatal. This is often a major postoperative complication despite the use of various treatments that are partially effective in preventing it. As far back as the late 1940s, Alton Ochsner repeatedly advocated the administration of vitamin E to prevent postoperative thromboembolism. His vitamin E regimen consisted of 200 to 600 IU of alpha-tocopherol per day, administered intramuscularly or by mouth, beginning no later than the day of surgery and continuing through the postoperative period (Kay et al., 1950; Ochsner, 1964, 1968; Ochsner et al., 1950a, 1950b, 1951). As late as 1968 he wrote, "For 15 years I have used alpha-tocopherol (vitamin E) routinely in the treatment of patients who have been subjected to trauma of any magnitude. None of these patients have had pulmonary embolism" (Ochsner, 1968).
In 1981, Kanofsky and Kanofsky completed a search of the American and British literature, ~which disclosed six studies comparing a vitamin E-treated group with a control group (Coon and Whitrock, 1951; Coon et al., 1952; Crump and Heiskell, 1952; Ochsner et al., 1951; Kawahara, 1959; Moorman et al., 1953; Wilson and Parry, 1954). All these controlled studies were published between 1951 and 1959. That none of the studies used a double-blind design is unfortunate, since the diagnosis of deep-vein thrombosis or pulmonary embolism was primarily based on the observations of clinicians, which can be easily influenced by bias. However, Kanofsky and Kanofsky analyzed the data from the six studies and found a highly statistically significant effect from the vitamin E treatment. There was a twofold greater risk of deep vein thrombosis, a sixfold greater risk of all pulmonary embolism, and a ninefold greater risk of fatal pulmonary embolism in the control group than in the vitamin E-treated group (Kanofsky and Kanofsky, 1981). The authors postulated that the physiological mechanism that might explain these results involved the ability of vitamin E to inhibit platelet aggregation.
Magnesium. Magnesium also has anticoagulant activity, acting directly on the steps involved in blood coagulation, counteracting the procoagulant effect of calcium (Greville and ~Lehmann, 1944; Herrmann et al., 1970; Seelig, 1993), and decreasing platelet clumping. In the 1950s there were reports of use of magnesium to prevent and treat clinical thrombotic conditions (Hackethal, 1951; Heinrich, 1957, Schnitzler, 1957). Animal studies demonstrated that magnesium supplements prevented formation of coronary artery thromboses when the animals were fed a thrombogenic diet (Savoie et al., 1973; Szelenyi et al., 1967). Case reports have been published of patients with magnesium deficiency characterized by neuromuscular disorders and whose thromboemboli were prevented from recurring by magnesium supplements; when the supplements were discontinued, the thromboemboli recurred (Dupont et al., 1969; Durlach, 1967). Recent findings have demonstrated that magnesium inhibits blood coagulation and arterial constriction by increasing the production of factors with antithrombotic and vasodilating activities by the inner lining (endothelium) of blood vessels. These findings have shed light on magnesium's usefulness in both eclampsia and heart attacks.
The anticoagulant activity of magnesium has found practical application in microsurgery, in which local application during the surgical procedure prevented thrombotic and subsequent ~scarring lesions (Acland, 1972). When used intravenously in dogs and rabbits with partially constricted coronary arteries, magnesium prevented formation of microthrombi distal to the partial occlusion, a finding considered pertinent to human angina with and without blockage of coronary arteries (Gretz et al., 1987).
Since the 1920s, large doses of magnesium (producing blood levels as high as two to three times normal) had been shown to be effective in the treatment of preeclampsia (hypertension with proteinuria or edema, or both, due to the influence of pregnancy or recent pregnancy) (Lazard, 1925). Diuretics and anticonvulsants eventually replaced magnesium as the preferred treatment for this condition, until studies showed that magnesium treatment resulted in better outcomes, including more live births (Zuspan and Ward, 1965) and was the more appropriate treatment (Sibai, 1990).
It appears that adequate magnesium is necessary to maintain the integrity of the inner lining of the blood vessel and to increase its production of the vasodilating, anti-platelet-aggregating (antithrombosis) substance (Briel et al., 1987; Watson et al., 1986). This activity of ~magnesium in inhibiting thrombosis has provided the rationale for its use in patients who have had a heart attack. In a large, double-blind study of 2,300 patients, called the second Leicester Intravenous Magnesium Intervention Trial, half of the patients received an intravenous injection of magnesium within three hours of a heart attack. This was followed by a 24-hour magnesium infusion in a dose sufficient to raise the blood level of magnesium to twice that of normal levels. This treatment, which was given in conjunction with the standard treatment for a heart attack, reduced heart failure and mortality by 25 percent in comparison with patients who received only the standard treatment (Woods et al., 1992; Woods and Fletcher, 1994).
However, a much larger "megatrial" of magnesium therapy in heart attack victims failed to find such an effect (Casscells, 1994; Unsigned Commentary, 1994). It has been proposed that the failure of the megatrial (called ISIS-4) to find the lifesaving effect of magnesium in heart attack patients may have been due to the institution of magnesium treatment only after use of a clot-dissolving treatment. This resulted in a delay of almost 8 hours before the magnesium was given. In contrast, in the earlier study, the magnesium was given immediately ~upon hospitalization. Thus, in ISIS-4, the magnesium may have been given after the damage to the heart muscle was done (Casscells, 1994; Woods and Fletcher, 1994).
Lymphedema. Lymphedema, a swelling of the arms or legs resulting from pathology in the lymphatic system, often can be disabling or even crippling. It has been estimated that 32 to 75 percent of women who undergo surgery for breast cancer will have some chronic lymphedema of the arm on the affected side (Casley-Smith and Casley-Smith, 1986). Unfortunately, the treatment of this side effect of breast cancer surgery is often neglected (Farncombe et al., 1994). Recently, however, there has emerged an orthomolecular treatment for this condition using benzopyrones. An overview of the studies utilizing this compound for the treatment of lymphedema is presented below.
Benzopyrones. Since the mid-1980s, J.R. Casley-Smith has recommended the use of large doses of benzopyrones for the treatment of lymphedema. The benzopyrones, though now frequently synthesized, were originally derived from plants. The coumarins and flavonoids, such as rutin, are benzopyrones. Szent-Gyorgi, the Nobel prize winner who isolated vitamin ~C, discovered that a lack of benzopyrones caused greatly increased capillary fragility and permeability (Casley-Smith and Casley-Smith, 1986). Since then, benzopyrones have sometimes been called "vitamin P" or "P factors."
Casley-Smith and colleagues believe that large doses of benzopyrones alleviate lymphedema by stimulating macrophage cells to break down unwanted proteins in the edema fluid (Piller et al., 1988). Once excess protein is eliminated, the edema fluid that it causes is no longer retained. Thus, they believe that the benzopyrones safely change a slowly worsening condition into a slowly improving one. There now are at least six double-blind studies demonstrating that the benzopyrones are a safe and effective treatment for lymphedema (Casley-Smith et al., 1986, 1993; Cluzan and Pecking, 1989; Desprez-Curely et al., 1985; Piller et al., 1985, 1988).
Unfortunately, no benzopyrones are available as pharmaceuticals in the United States. Approval for drugs containing rutin and other bioflavonoids was withdrawn in 1970 by FDA on the grounds that there was no substantial evidence of the effect they were purported to ~have. However, Casley-Smith has argued that FDA used old, greatly outmoded data, which allegedly showed that these drugs could not be absorbed (Casley-Smith and Casley-Smith, 1986). He and others are emphatic that more recent data show that the benzopyrones are absorbed and are effective. Moreover, Casley-Smith and others believe that because benzopyrones possess specific immune-stimulating properties and can reduce every type of high-protein edema, they eventually will become extremely valuable therapeutic agents in a wide variety of clinical conditions (Casley-Smith and Casley-Smith, 1986).
Mental and neurological disorders. Despite continued widespread skepticism among mainstream psychiatric professionals about the effectiveness of vitamin therapy in the treatment of neurological disorders, a small but growing number of researchers persist in studying the use of vitamins for such conditions. In fact, reports continue to surface on the effectiveness of vitamins such as folic acid as well as a variety of antioxidant vitamins in treating various mental and neurological disorders.
Folic acid. Low serum folate has been reported in 10 to 33 percent of psychiatric patients. ~In one retrospective survey, psychiatric patients treated with folic acid spent less time in the hospital and made significantly better social recoveries than those in whom low serum folates were not treated (Carney and Sheffield, 1970). Godfrey and colleagues recently demonstrated that 41 (33 percent) of 123 patients with depression or schizophrenia had borderline or definite folate deficiency. These patients took part in a double-blind, placebo-controlled trial of methylfolate (the actively transported form of folate), taking 15 mg daily for 6 months in addition to standard psychotropic medication. Among both depressed and schizophrenic patients, methylfolate significantly improved clinical and social recovery (Godfrey et al., 1990). These researchers speculate that folate or methylfolate may have a direct pharmacological action irrespective of whether the subjects were folate deficient.
Antioxidant therapy. Antioxidant therapy with nutrients such as vitamin C, vitamin E, and beta-carotene has been hypothesized as a treatment for schizophrenia (Lohr, 1991). The hypothesis is based on evidence that the serum of schizophrenics has high levels of lipid peroxides and the enzyme superoxide dismutase. Both these substances are indicators of ~unwanted oxidative products (mainly free radicals).
Just focusing on vitamin C, there is a substantial body of animal and clinical data that ascorbic acid may have an antipsychotic effect (Beauclair et al., 1987; Giannini et al., 1987; Heikkila et al., 1983; Kanofsky et al., 1988, 1989a; Milner, 1963; Rebec et al., 1984; Thomas and Zemp, 1977; Tolbert et al., 1979a, 1979b), which seems to be most apparent when ascorbic acid is given in combination with antipsychotic medication. A double-blind study showed that vitamin C increases the antipsychotic effects of haloperidol in treating PCP psychoses (Giannini et al., 1987). Observational studies and one double-blind study have indicated a similar adjunctive role for vitamin C in treating schizophrenia (Beauclair et al., 1987; Kanofsky et al., 1989a, 1989b; Milner, 1963). No one has studied the simultaneous use of several antioxidants in the treatment of schizophrenia, which seems a worthwhile avenue of research (Kanofsky and Sandyk, 1992; Lohr, 1991).
Double-blind studies have shown that tardive dyskinesia (a late-occurring, movement-disorder side effect of antipsychotic medication) can be treated with vitamin E ~supplementation. The therapeutic effect of vitamin E seems most likely when it is introduced within several years after the onset of the disorder (Adler et al., 1993; Egan et al., 1992; Elkashef et al., 1990). Several studies of patients with Alzheimer's disease have been performed in which brain tissue at autopsy showed evidence of increased brain lipid peroxidation (Farooqui et al., 1988; Hajimohammadreza and Brammer, 1990; Subbarao et al., 1990). Conceivably, antioxidants such as vitamin C and vitamin E might prevent this increase; however, much more research needs to be done before this treatment could be seriously considered (Lohr, 1991). In view of current evidence that vitamin E, either alone or in combination with deprenyl (an inhibitor of monoamine oxidase in the brain), fails to delay continued neurological deterioration in Parkinson's disease (Parkinson Study Group, 1993), it is also possible that to be most effective, antioxidant therapy must be introduced very early in the development of neurological and psychiatric disorders--prior to the point at which irreversible cell damage has occurred. A similar argument can be made with regard to the effectiveness of orthomolecular therapy in schizophrenia itself.
Magnesium. A condition known as "latent tetany" syndrome, which is seen in some patients ~with slight magnesium deficiency, is characterized by depressive anxiety, weakness, irritability, fatigue, and many ill-defined complaints (Durlach, 1988; Fehlinger et al., 1987; Galland, 1991-1992). This syndrome has characteristics that resemble premenstrual syndrome as well as chronic fatigue syndrome, both of which have responded favorably to supplementation with magnesium compounds alone or with other nutritional supplements (Abraham and Lubran, 1981; Stewart and Howard, 1986; London et al., 1991; Facchinetti et al., 1981).
There is evidence suggesting that magnesium deficiency participates in the abnormalities of migraine headaches and that migraines will respond to treatment with magnesium (Swanson, 1988; Weaver, 1990). Transient ischemic attacks, another disorder which like migraine is associated with cerebral arterial spasms, has also been found to respond to magnesium (Fauk et al. 1991). These clinical findings of magnesium's protective effects against ischemia (loss of blood flow) and hypoxia (oxygen deprivation) make it worthwhile to examine the considerable animal evidence that magnesium deficiency increases susceptibility to brain damage caused by cerebral arterial spasm, arterial blockage (i.e., stroke), or trauma