Diet and Nutrition in the Prevention and Treatment of Chronic Disease

Gar Hildenbrand--Chair

Jonathan Collin, M.D.

Alan Gaby, M.D.

Marie Galbraith

Daniel Kanofsky, M.D., M.P.H.

Janet Smith

Jack Taylor, D.C.

CONTRIBUTING AUTHORS

Roberta Baer, Ph.D.

Claire Cassidy, Ph.D.

Lilian Cheung, Sc.D.

Harriett Harvey

Gar Hildenbrand

L. John Hoffer, M.D., C.M., Ph.D.

J. Daniel Kanofsky, M.D., M.P.H.

Lawrence H. Kushi, Sc.D.

Mildred Seelig, M.D., M.P.H.

James P. Swyers, M.A.

Walter Willett, M.D., Dr.P.H.

Introduction

Status of Diet and Nutrition Research in the United States

Diet and nutrition research goes on in almost every medical school, university, and pharmaceutical laboratory throughout the world. Thus, the knowledge of how to prevent illness and maintain health through nutrition grows every year. However, for such areas as reversing the effects of chronic disease through dietary or nutritional intervention or determining levels of nutrients required to achieve optimal metabolic or immune system functioning, there often is no critical mass of researchers or funds to follow up promising initial experimental results.

In fact, the history of nutrition research is marked by examples where, for one reason or another, preliminary reports of a positive therapeutic effect of a certain vitamin, mineral, or nutritional manipulation appear but are often not followed up by the overwhelming majority of the medical community. In cases where such therapies eventually are proven to be safe and effective, it is sometimes not until years or even decades after the initial reports. The result is that many individuals may die or suffer needlessly, while effective interventions are available but not yet validated.

For example, in the 1930s, Australian psychiatrist John Cade began a series of crude experiments on guinea pigs in which he injected them with the urine of psychiatric patients to test his hypothesis that mania--a mood disorder characterized by, among other things, periods of euphoria--might represent a state of intoxication resulting from an excess of some commonly occurring metabolite. Depression, on the other hand, might represent the effects of abnormally low levels of the same metabolite (Johnson, 1984). Although all the urine samples proved toxic to the guinea pigs--Cade traced the toxicity to the urea component of the urine--the urine from the manic patients was far more toxic than urine from the schizophrenic or depressive patients.

In his attempts to find out what was increasing the toxicity of the urea in the manic patients' urine, Cade happened upon the compound lithium citrate, which he eventually began injecting by itself into the guinea pigs to judge its effect. To his amazement, the guinea pigs became lethargic and unresponsive for several hours after receiving lithium, before fully recovering. In 1949, Cade published the results of a crude clinical trial, stating that lithium salts given to 10 manic patients resulted in a dramatic improvement in each one's condition (Cade, 1949). Unfortunately for Cade, just as his results were reaching the United States, a number of table salt substitutes containing lithium chloride had just been recalled by the Food and Drug Administration (FDA) due to toxic side effects and, in some cases, death with heavy use. So much publicity was given to the toxicity associated with these salt substitutes--which were marketed for use by people on salt-restricted diets--that for 5 years after Cade's original report, relatively little work with lithium was undertaken (Georgotas and Gershon, 1981).

According to medical historian Frederick Johnson (1984), "Cade's report of lithium treatment of mania might well have succumbed to the same fate as that suffered by many proposed therapeutic techniques before and after that time ... had lithium salts been at all expensive or hard to come by...." Instead, because canisters of lithium salts were to be found in most hospitals and pharmacies at the time, many psychiatrists in the mid-1950s, for lack of adequate treatments for manic disorders, simply started experimenting with lithium on their own. By the mid-1960s, a spate of reports appeared in the medical literature reporting on the effectiveness of lithium in the treatment of manic and other psychiatric disorders (Gershon and Yuwiler, 1960; Schlagenhauf et al., 1966). Today lithium, in some patients with bipolar disorders (i.e., mood swings), is the most successful therapeutic drug of the five major types of drugs currently used in psychiatry (Horrobin, 1990), often producing normalization in acute mania patients in 1 to 3 weeks.

A situation analogous to the lithium story occurred in the late 1980s in the United States. Just as reports were emerging that suggested the effectiveness of the amino acid L-tryptophan in treating mild depression (Boman, 1988), chronic insomnia (Demisch et al., 1987), and mood disorders (Maurizi, 1988), there was a severe outbreak of a sometimes deadly inflammatory disorder called eosinophilia myalgia syndrome (EMS). The cause of the EMS outbreak was linked by epidemiologists to the over-the-counter use of tryptophan (Varga et al., 1993). Although all cases of this disorder were eventually found to be caused by contaminants in batches of tryptophan produced by a single manufacturer in Japan (Barnhart et al., 1990) and not by the effects of tryptophan itself, this nutritional supplement was taken off the market by the FDA and is no longer available over the counter. Just as with lithium, the publicity about toxicities associated with tryptophan may have hindered rational scientific discourse about the effectiveness of this nutritional therapy for some time to come. In fact, FDA uses the tryptophan example to justify its efforts to regulate as drugs most dietary and nutritional supplements whose manufacturers make any health claims (U.S. Food and Drug Administration, 1992).

There have been numerous other instances in recent decades when individuals or groups of individuals have advocated nutritional interventions or alternative dietary lifestyles as a means of preventing or even treating disease and have met not only indifference but often hostility. This was especially true for those advocating vegetarianism or an extremely low-fat diet as a means of preventing or treating illnesses such as heart disease (see below). As was the case with John Cade and lithium, it took many decades for the facts to win out over misconceptions and biases.

The rest of this chapter discusses a number of areas of diet and nutrition research in which there is at least preliminary scientific evidence indicating the need for more in-depth studies, but for which there often is no critical mass of researchers or funds to follow up promising initial experimental results. However, it should be noted that only an overview of the field is presented, and it is by no means comprehensive. This field of research is so complex and diverse that no more than a few examples can be offered for each subsection.

First, however, it is instructive to discuss briefly the evolution of the modern affluent diet and evidence relating chronic disease with its excesses and micronutrient deficiencies. Also presented is a discussion of the evolution of present dietary guidelines and why some consider them inadequate.

Evolution of the Modern "Affluent" Diet

Over the course of evolution, human beings (and their primate predecessors) adapted gradually to a wide range of naturally occurring foods, but the types of food and mix of nutrients (in terms of carbohydrates, fats, and proteins) remained relatively constant. Food supplies were often precarious, and the threat of death from starvation was a constant preoccupation for most of the Earth's inhabitants.

About 12,000 years ago, an agricultural revolution brought profound dietary changes to many human populations. The ability to produce and store foods became widespread, and some foods, such as grains, were preferentially cultivated. These new techniques and the overabundance of some foods they produced presented novel challenges to the human digestive system.

The Industrial Revolution, which began about 200 years ago in Europe and soon spread to North America, introduced more radical changes in the human diet due to advances in food production, processing, storage, and distribution. Recent technological innovations, along with increased material well-being, or affluence, and lifestyles that have allowed people more freedom in deciding what and when they wish to eat (amplified by modern marketing techniques), have led to even further major dietary changes in developed countries. Indeed, such innovations as sugared breakfast cereals and a variety of snack items were unheard of before World War II; Hampe and Wittenberg (1964) estimated that 60 percent of the items on supermarket shelves in 1960 came into existence in the 15 years following World War II.

Health Consequences of the Modern Affluent Diet

Because changes in the dietary patterns of the more technologically developed countries, such as the United States, have been so dramatic and rapid, the people consuming these affluent diets have had little time to adapt biologically to the types and quantities of food available to them today. The longer term adverse health effects of the affluent diets prevailing in these countries--characterized by an excess of energy-dense foods rich in animal fat, partially hydrogenated vegetable oils, and refined carbohydrates but lacking in whole grains, fruits, and vegetables--have become apparent only in recent decades.

Comparisons of population groups have demonstrated a close and consistent relationship between the adoption of this affluent diet and the emergence of a range of chronic, noninfectious diseases, such as coronary heart disease, cerebrovascular disease, various cancers, diabetes mellitus, gallstones, dental caries (cavities), gastrointestinal disorders, and various bone and joint diseases (World Health Organization, 1990). Some nutrition and health experts believe that the relationship between rapid changes in a population's diet and rapidly changing disease and mortality profiles is reflected in many recently acculturated (i.e., adapted to the dominant culture) groups in the United States who are now eating a diet more akin to that of the northern European and U.S. general populations (see the sidebar on page 214).

For example, increasing rates of diabetes mellitus have been reported in Native American and other populations that suddenly switch from a traditional to a more modern lifestyle (West, 1974). This disease has only recently become a major health problem for Native Americans, who now often have rates much higher than those found in either U.S. Caucasian or African-American populations. Indeed, although the overall rate of diabetes in the general U.S. population is between 1 and 3 percent, and 5 to 6 percent for those over age 35, it ranges from 10 to 50 percent among Pima Indians 35 years of age and older (Bennett et al., 1979; Neel, 1976). Furthermore, in Hawaii, the incidence of breast cancer for Caucasians is similar to U.S. mainland rates, but the incidence among Hawaii's Japanese population is more than twice the rate in Japan and approaches the rate for Caucasians (Muir et al., 1987).

The reasons for these abnormally high disease rates in American Indian and other non-Caucasian populations are complex; however, they include obesity related to changes in activity patterns and, probably, the increased consumption of refined carbohydrates and sugar. Also, intake of dietary fiber has decreased dramatically. Excessive caloric consumption in some of these populations also may be a major contributor; one study found that obese American Indians consumed 250 to 1,600 more calories than were recommended for persons of their height, gender, age, and level of activity (Joos, 1984).

In one of the few studies of its kind, a group of Native Hawaiians with multiple risk factors for cardiovascular disease believed to be related to consuming a nontraditional diet were placed on a "pre-Western contact," or traditional, Hawaiian diet to assess its effect on obesity and cardiovascular risk factors. Twenty individuals were placed on a diet low in fat (7 percent), high in complex carbohydrates (78 percent), and moderate in protein (15 percent) for 21 days. The subjects were encouraged to eat as much as they wanted. At the end of the diet modification period, the average weight loss was 7.8 kilograms (approximately 17 lbs.), and the average serum cholesterol dropped by about 14 percent. Blood pressure decreased an average of 11.5 mm Hg systolic and 8.9 mm Hg diastolic (Shintani et al., 1991).

Evolution of Federal Dietary Guidelines

Due to the rapid rise in chronic illness related to diet in recent decades, the focus of nutrition research has shifted from eliminating nutritional deficiency resulting from undernutrition to dealing with chronic diseases caused by nutritional excess, or "overnutrition." Since the 1950s, researchers have identified a number of types of dietary excess that appear to influence the incidence and course of specific chronic diseases.

Another growing concern among nutrition researchers is the accumulation of evidence indicating that inadequate intakes of some micronutrients over a long time may increase the risk of developing a variety of disease conditions, including coronary heart disease, many cancers, cataracts, and birth defects. Earlier, many of these conditions were not even considered diet-related. Furthermore, many other components of foods, in addition to those traditionally considered nutrients, may be important in achieving optimal health. Unfortunately, the "standard" American diet, while rich in calories, contains processed foods deficient in many important micronutrients and other components of the original unrefined foods.

The Federal Government has been involved in developing nutrition guidelines for the American public since the mid-1800s, when the U.S. Department of Agriculture (USDA) was established. However, such guidelines traditionally had dealt with how to prevent nutritional deficiencies, as well as how to promote the consumption of U.S. agricultural products. Only in the past several decades, as the focus of public health policy has shifted from preventing disease caused by nutritional deficiencies to preventing disease caused by overnutrition or nutritional imbalances, have Federal dietary guidelines attempted to address the latter. Today, such guidelines are becoming more difficult to develop and often meet fierce resistance from various lobbying groups when they are disseminated (Nestle, 1993).

Nevertheless, since the early 1970s, USDA and other Federal agencies and advisory groups have periodically released diet and nutrition guidelines dealing with preventing chronic illness related to nutrition. This material typically targets public health policymakers, medical doctors, or the general public. Two of the better known current Federal dietary and nutritional guidelines, from which public health policy is made, are the recommended daily allowances (RDAs) and the Food Guide Pyramid.

RDAs are defined as the average daily amounts of essential nutrients estimated, on the basis of available scientific knowledge, as adequate to meet the physiological needs of practically all healthy persons (Monsen, 1990). (See figure 1.) To establish the standards for RDAs, which are updated periodically (most recently with the 10th edition in 1989; see Monsen, 1990), the Food and Nutrition Board of the National Academy of Sciences critically evaluates the literature on human requirements for each nutrient, examines the individual variability of requirements, and tries to estimate the efficiency with which the nutrients are biologically available and used from foods consumed. The RDAs are levels that should be reached as averages in a period of several days, not necessarily daily.

RDAs are not meant to be guidelines for consumers; they were initially designed to serve as standards for planning food supplies for population groups (National Research Council, 1989). However, they are used as a partial basis for the development of other guidelines that are intended for consumers, such as the Food Guide Pyramid, which was released by USDA in 1992 to replace the old "basic four" food groups. The Food Guide Pyramid is designed to give consumers information on how to eat a "balanced" diet that will provide them with the RDAs for essential nutrients while lowering their risks of chronic illness due to nutritional excesses (Journal of the American Dietetic Association, 1992). Sweets, fats, and oily foods are at the top of the pyramid, indicating that they should be consumed in small amounts. Dairy products such as milk, yogurt, and cheese, and meats, poultry, fish, dried beans, eggs, and nuts are just below, indicating they should be consumed in moderation. Fruits and vegetables follow; bread, cereal, rice, and pasta are at the bottom of the pyramid, indicating that they should be consumed in rather large amounts in comparison with the foods at the top of the pyramid (see figure 2).

Guidelines such as the Food Guide Pyramid are intended to inform consumers, as well as public health policymakers, about what kinds and amounts of certain foods are best suited for maintaining health and lowering the risks of nutrition-related illnesses. Generally, this approach to affecting health through diet and nutrition interventions involves manipulating the "typical," or mainstream, diet so that foods with less nutritional value are eaten less and foods with more nutritional value are eaten more.

The Federal Government's approach to dietary intervention, which has been formulated over the years by boards composed of nutrition scientists, generally does not recommend supplementing this "typical" diet with vitamins or nutritional supplements (National Research Council, 1989). It also does not take a "good food" or "bad food" approach (Herron, 1991) or suggest that certain foods are "off limits" because of their propensity to cause chronic disease (Nestle, 1993).

However, this is only one approach to promoting health and preventing illness through dietary intervention. There are many "alternative" dietary approaches that contend that no matter how much one manipulates the typical American diet, it is not enough to promote optimal health or stave off eventual chronic illness. Alternative approaches represent a continuum of philosophies, from the idea that diet supplementation somewhat beyond RDAs is necessary to promote optimal health to the idea that supplementation well above RDAs is often required to treat some chronic disorders. Further along this continuum is the approach advocating drastic modification of patients' diets--either completely eliminating or adding certain types of foods--to treat specific types of conditions, such as cancer and cardiovascular disease. Finally, there is the approach that promotes eating a less refined, more "naturalistic" diet as the only way to promote optimal health and prevent illness. This last approach holds that staples of the typical American diet (e.g., meat and dairy products) are basically unhealthful and should be avoided altogether. The remainder of this chapter describes representative alternative therapies along this continuum.

Alternative Approaches to Diet and Nutrition That May Prevent or Control Chronic Illness as Well as Promote Health

The 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 (McIntosh et al., 1988; Blair et al., 1989; Okawa, 1992) and that magnesium treatments offer the potential for minimizing such brain damage (McIntosh et al., 1989; Vink, 1991-1992; Smith et al., 1983).

Clinicians in Japan have shown in a small pilot study that intravenous magnesium infusions improved the cerebral flow of stroke victims (who before treatment had low magnesium levels in their cerebrospinal fluid) (Iwasaki et al., 1989). Indeed, 10 patients who received magnesium therapy had a better return of normal cerebral functioning than did ten control patients who did not receive magnesium after a stroke. Whether prompt magnesium treatment after a stroke and/or after brain trauma will improve the prognosis of such patient deserves further investigation.

Selenium. In certain regions of the world, including Great Britain and parts of the United States and Canada, selenium levels in food are so low that the possibility of subclinical deficiency (and a possibly related adverse effect on mood) exists. Benton and Cook (1991) conducted a double-blind, crossover trial of 50 subjects in ostensibly good health. They were randomly assigned to receive a 100-microgram selenium tablet or placebo each day for 5 weeks. After a 6-month washout, they received the alternate treatment for 5 weeks. Benton and Cook concluded that the intake of selenium tablets was associated with an elevation of mood, particularly in subjects whose diets were relatively deficient in the trace element.

Amino acids. A double-blind, randomized study showed S-adenosylmethionine--the physiologically active form of the amino acid methionine--to be a more rapidly acting antidepressant than the pharmaceutical drug imipramine in treating major depression (Bell et al., 1988). At the end of this 2-week study, 66 percent of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms versus 22 percent of the imipramine patients. If S-adenosylmethionine does turn out to be a more rapidly acting drug--taking days rather than weeks to achieve results--this characteristic may offer a considerable advantage in light of the known risk of suicide during the early nonresponding phase of treatment with most, if not all, other antidepressants.

Clinical trials of the amino acid glycine given orally to schizophrenic patients have yielded conflicting results. However, in the most recent double-blind study, Javitt and colleagues (1994) showed a statistically significant improvement in negative symptoms of schizophrenia when glycine was added to conventional antipsychotic drug regimens. This suggests that glycine may serve as a distinctive and valuable adjunctive treatment for schizophrenia.

Essential fatty acids. Vaddadi and colleagues (1989) reported the results of a double-blind crossover trial of essential fatty acid supplementation in 48 predominantly schizophrenic psychiatric patients. Active treatment produced highly significant improvements in total psychopathology scores and a significant improvement in memory.

Food and Macronutrient Modification Diets as a Method for Controlling and Treating Chronic Illnesses

This section is an overview of the theoretical basis and available research on a variety of diets that are advocated for the treatment of chronic conditions such as cancer, cardiovascular disease, and food allergies. Virtually all of these dietary interventions emphasize the intake of much more produce (fresh and freshly prepared vegetables, fruits, whole grains, and legumes), providing high nutrient density while at the same time restricting such "empty" calories as those provided by sweets, fats, and overprocessed foods. In these diets, moreover, overall caloric intake tends to be lower than that of the general U.S. population.

Nutrient modification for the treatment of cancer. Cancer accounts for one of every five deaths in the United States (American Cancer Society, 1990). More than 1 million cases of new cancers are diagnosed every year, and about 75 million, or one in three Americans now living, will eventually have cancer (Public Health Service, 1990). Cancer is not one disease but a constellation of more than 100 different diseases, each characterized by the uncontrolled growth and spread of abnormal cells. Cancer may strike at any age, though it does so more frequently with advancing age. Although corroborative intervention data are not yet available, it is estimated that 35 percent of cancer deaths may be related to diet (Eddy, 1986).

The rationale behind most dietary regimens for the treatment of cancer--and for vegetarian, low-fat, high-fiber dietary regimens in particular--is that if dietary excesses can lead to the development of certain cancers, then such cancers may be susceptible to dietary manipulation as well. These diets, for the most part, share certain characteristics with the kinds of foods currently recommended by mainstream groups, such as the American Cancer Society (ACS), for lowering the risk of developing cancer and heart disease. Recent ACS guidelines for cancer prevention suggest reducing the intake of fat, alcohol, and salt-cured and smoked foods while increasing the intake of fruits, vegetables, and whole grains (Nixon, 1990). One way these alternative dietary regimens for cancer differ, however, from mainstream preventive recommendations is that they may emphasize a few particular foods and limit or totally eliminate others.

In September 1990 the U.S. Congress Office of Technology Assessment (OTA) completed a study of a number of unconventional cancer treatments. Among these was a variety of dietary regimens developed for the treatment of cancer and/or the support of patients undergoing conventional cancer therapy. This report, Unconventional Cancer Treatments, focused on three of the most well-known dietary interventions for cancer: the Gerson therapy, the Kelley regimen, and the macrobiotic diet. These three regimens and a few others are reviewed below. Findings from the OTA report as well as studies done since that report was released are covered.

Gerson therapy. The Gerson therapy was developed by physician Max Gerson in the early part of this century. Gerson was born in Germany in 1881 and immigrated to the United States in 1936. He received his New York medical license in 1938 and his U.S. citizenship in 1944. He opened a private medical practice in New York City and in 1946 also began treating patients at nearby Gotham Hospital.

He gained renown in Germany through his success in treating tuberculosis of the skin through low-salt dietary management (Gerson, 1929). He then began testing modifications of this regimen in other conditions, including pulmonary tuberculosis (Gerson, 1934). He first used his diet for cancer in 1928, reportedly after a woman with a bile duct cancer that had spread to her liver insisted that he put her on his diet despite his reluctance to do so (Lerner, 1994). Much to his surprise, Gerson wrote, the woman recovered (Gerson, 1958). Afterward, Gerson tried variations and combinations of foods and other agents on his patients, noted the ones who reacted favorably, and adjusted subsequent patients' regimens accordingly (Gerson, 1978). By the time he came to America, he was focusing on treating cancer patients.

In 1946 Gerson testified before a subcommittee of the Senate Committee on Foreign Relations, which was holding a hearing on a proposed bill to authorize increased Federal spending for cancer research. Gerson reported to the Senate committee that he had developed a dietary regimen that was effective for the treatment of advanced cancer. According to the historian Patricia Spain Ward, Gerson's testimony was supported by the director of the Gotham Hospital, with which Gerson was affiliated, as well as others in attendance (Ward, 1988). Gerson described five patients in clinical detail and submitted written case histories of those and five more patients who had been treated with his regimen, in whom he had observed improvements in "general body health" and, in some cases, tumor reduction. In a later publication, Gerson noted that in six additional patients his treatment appeared to reduce inflammation around the tumors, relieve pain, improve psychological condition, and provide at least temporary tumor regression (Gerson, 1949). In the mid-1950s, Gerson first published explanations of the components of his regimen and the rationale for their use, along with some of the clinical outcomes he observed.

Gerson believed that his treatment regimen reversed the conditions he thought necessary to sustain the growth of malignant cells. He attached great importance to the elimination of "toxins" from the body and the role of a healthy liver in recovery from cancer. Gerson noted that if the liver was damaged (e.g., by cancer or cirrhosis) the patient had little chance of recovery on his or her treatment regimen (Gerson, 1949, 1986). He observed that cancer patients who died during treatment showed a marked degeneration of the liver, which he presumed was due to the release of unspecified toxic factors into the bloodstream by the process of tumor regression. He believed that these toxic tumor-breakdown products poisoned the liver and other vital organs (Cope, 1978).

Another central point of Gerson's approach concerned the balance of potassium and sodium in the body. He believed that an imbalance in the concentration of these substances contributes to cancer-induced edema, a condition in which cellular damage leads to infiltration by excess sodium and water, failure of cellular transport mechanisms, subsequent failure of cellular energy production, and, finally, loss of resistance to cancer. Therefore, he sought to eliminate sodium in patients' diets, supplement it with potassium, and thereby alter the internal environment supporting the tumor (Gerson, 1954a, 1954b, 1954c).

At present, the Gerson therapy is an integrated set of treatments that include the restriction of salt in combination with potassium supplementation of the diet. Thyroid supplements also are given to stimulate metabolism and cell energy production. Hourly feedings of fresh, raw juices of vegetables and fruits are given in addition to a basically vegetarian diet. Fat intake is restricted (to lower intake of potential tumor promotors), and protein is temporarily restricted (to promote nonspecific, cell-mediated immunities). Coffee enemas are provided to manage pain and to stimulate bowel and liver enzymes that may increase the release of toxins (Gerson Institute, undated-a). Other treatments beyond the ones specified by Gerson have been added to the current protocol in recent years. Gerson gave patients raw liver juice several times daily, but the practice has been abandoned by current practitioners because of bacteria in the liver juice that caused major infections in some patients (Office of Technology Assessment, 1990).

Critics of the Gerson therapy point to the fact that it is based on the beliefs of a physician who practiced many years ago and whose knowledge of the cause of cancer was rudimentary (Green, 1992). Proponents of the therapy argue, rather, that Gerson was far ahead of his time; however, they also note that many of Gerson's original assumptions and therapies have been updated to take into account the latest scientific evidence (Hildenbrand, 1986).

Because of such misconceptions about Gerson and how his therapy is currently administered, proponents contend that it has never been given a fair evaluation by mainstream science. Furthermore, they argue that such myths and misconceptions about the Gerson therapy are perpetuated by major medical journals that routinely publish articles attacking the basic tenets of the therapy while refusing to publish rebuttals to such attacks (Lechner and Hildenbrand, 1994).

Research base. There have been several attempts by a number of groups and individuals to assess the clinical effects of the Gerson regimen. However, none have yet offered any definitive results (Office of Technology Assessment, 1990). The following is an overview of early and more recent cases.

In 1959, NCI reviewed 50 case histories presented in Gerson's book, A Cancer Therapy: Results of Fifty Cases. NCI concluded that in the majority of cases a number of basic criteria were not met. NCI also concluded overall that Gerson's data provided no demonstration of benefit (Avery, 1982; U.S. Department of Health and Human Services, 1987). The Gerson Institute, however, disputed NCI's findings and charged that NCI had dismissed legitimate evidence on the basis of technicalities. In addition, the Gerson Institute claimed that even though NCI had indicated six cases were acceptable for further review and another 20 needed further documentation, NCI's own records indicate that such reviews were never done (Gerson Institute, undated-b).

More recently, an exploratory study of the clinical effects of some components of the Gerson regimen was conducted by Peter Lechner, M.D., at the University Hospital of Graz, Austria. This study used a modified Gerson therapy (i.e., liver juice and thyroid supplements were omitted, the number of coffee enemas was limited, and a high-calorie beverage was added to double energy consumption) as an adjunctive treatment. Lechner reported that patients following the modified Gerson regimen showed no side effects attributable to the treatment and did not become malnourished. One of the patients with inoperable liver metastases who followed the Gerson treatment showed a temporary regression. In Lechner's opinion, there were subjective benefits from the modified Gerson regimen: patients needed less pain medication, were in better psychological condition, and experienced less severe side effects from chemotherapy than did control patients (Lechner and Kronberger, 1990).

Lechner's study also suggested that a modified Gerson regimen might be effective in lowering rates of postsurgical complications and secondary infections, increasing tolerance of conventional radiotherapy and chemotherapy, reducing reliance on analgesics, providing for an improved overall psychological profile, retarding progress of liver metastases, and improving the state of malignant effusions (Lechner and Kronberger, 1990).

A research team from the University of London that visited the Mexican clinic offering the Gerson therapy (see below) in 1989 on behalf of a British insurance company studied 27 cases in detail. Of those cases, 20 were considered not assessible. Of the 7 assessible cases, 3 showed progressive disease, 1 showed stable disease, and 3 (43 percent of the accessible cases) were in regression. Moreover, the therapy clearly provided a subjective benefit for the patients and their families. In light of the poor prognosis of most of the patients they observed at the clinic, the British team concluded that the example of the Gerson therapy demonstrated a "way forward" for the treatment of cancer (Sikora et al., 1990).

The Gerson Research Organization of San Diego is currently conducting large retrospective reviews of treatment outcomes of more than 5,400 patient charts, including 5-year survival rates by stage (Hildenbrand et al., 1993), for patients treated by the Mexican medical group Centro Hospitalario Internacional del Pacifico, S.A. This facility, a semi-intensive care hospital, has offered Gerson's treatment since 1976. The review will include patients who either had no previous treatment or failed previous treatment as well as patients who received complementary conventional treatments.

Kelley regimen for cancer. In the 1960s, William Donald Kelley, an orthodontist by training, developed and publicized a nutritional program for cancer after reportedly being told by his doctor that he had metastatic pancreatic cancer and had only 2 months to live (Office of Technology Assessment, 1990). By trial and error, he self-administered doses of enzymes, vitamins, and minerals to treat his cancer. After his recovery, he applied his dietary program to his family; he also believed that his wife and two of his three children had developed cancer (Kelley, 1969). The Kelley regimen clearly derives from Gerson's. Common elements include carrot juice, a basically vegetarian diet, coffee enemas, and pancreatic enzymes, although pancreatic enzymes play a more emphatic role in the Kelley treatment. The Kelley regimen for cancer became one of the most widely known unconventional cancer treatments. Although Kelley is no longer practicing his treatment, the regimen has been continued in a variety of forms by his followers.

One of the people who adopted the Kelley regimen for the treatment of cancer patients was New York physician Nicholas Gonzalez, M.D. Gonzalez has examined the Kelley regimen and provided his own analysis of Kelley's individual metabolic profiles. According to Gonzalez, Kelley believed that human beings are of three genetically based types: sympathetic dominants, parasympathetic dominants, and balanced types. Sympathetic dominants, who have highly efficient and developed sympathetic nervous systems but inefficient parasympathetic nervous systems, evolved in tropical and subtropical ecosystems, eating plant-based diets. Parasympathetic dominants, in which the opposite is the case, evolved in colder regions, eating meat-based diets. Balanced types, whose nervous systems are equally developed, evolved in intermediate regions, eating mixed diets (Office of Technology Assessment, 1990).

Kelley developed a diet for each type according to the type's hypothesized historical origins. He had also traced a characteristic path of "metabolic decline" for each group when it consumed the wrong diet. He associated "hard tumors" with severely compromised sympathetic dominants, and "soft tumors" (cancers of the white blood cells and lymph system) with severely compromised parasympathetic dominants (Office of Technology Assessment, 1990).

As offered by Gonzalez, the Kelley program stresses biodiversity, tailoring diets to individual needs and ranging from purely vegetarian to diets requiring fatty red meat several times daily. Patients consume many supplements--vitamins, minerals, and trace elements--in 130 to 160 capsules daily.

Research base. In his 1987 manuscript One Man Alone: An Investigation of Nutrition, Cancer, and William Donald Kelley, Gonzalez presented case histories of 50 patients he selected from his files (Gonzalez, 1987). This case series has been singled out by proponents as one of the most convincing in support of an unconventional cancer treatment (Office of Technology Assessment, 1990).

In 1990, OTA attempted to find out whether the information presented in these cases would be convincing to the medical community by asking six physicians on its advisory panel to review the cases; three of the physicians supported some unconventional treatments, though none was associated with Kelley or Gonzalez, and the other three were mainstream oncologists. Fifteen cases were judged by the reviewers generally supportive of some unconventional medicine as definitely showing a positive effect from the Kelley program; in contrast, the mainstream oncologists found that 13 of these 15 were unconvincing and that 2 were unusual (Office of Technology Assessment, 1990).

Another nine cases were judged unusual or suggestive by the supportive group, and unconvincing by the mainstream group. Another 14 cases were judged by the supportive physicians as having been helped by a combination of the Kelley regimen and mainstream cancer therapy; the mainstream group found 12 of these cases unconvincing and 2 unusual. Finally, 12 cases were considered unconvincing by both groups of physicians. The different interpretations of these cases by physicians who are open to unconventional medicine and those who are not illustrates the difficulty in evaluating therapies that fall outside the bounds of conventional medical wisdom.

Gonzalez recently submitted to NCI a meticulously documented best case series (Friedman, 1993). At least 6 of the 24 cases reportedly document complete remissions of cancers, 5 of them metastatic to various sites including liver, pleura, brain, and bone. Two additional cases reportedly document partial remissions.

Macrobiotic diet for cancer. The philosophy and general components of the "standard macrobiotic diet" are described below in the "Alternative Dietary Lifestyles and Cultural Diets" section of this chapter. In the area of cancer management and treatment, the macrobiotic philosophy holds that the development of cancer is determined by dietary, environmental, social, and personal factors; by extension, existing cancers may be influenced by the same factors. The development of cancer is described as a long-term, multistep process that begins well in advance of actual tumor formation (Kushi and Jack, 1983).

According to macrobiotic teachings, accumulated toxins result from overconsumption of milk, cheese, meat, eggs, and other fatty, oily, or greasy foods. Also included in this list are foods with a cooling or freezing effect, such as ice cream, soft drinks, and orange juice (Kushi and Jack, 1983). Macrobiotics uses the traditional oriental concepts of yin (expansive) and yang (contractive) to devise a framework for explaining and formulating a set of dietary recommendations to treat each type of cancer.

A macrobiotic approach to treating cancer would first classify each patient's illness as predominantly yin or yang, or sometimes a combination of both, partly on the basis of the location of the primary tumor in the body and the location of the tumor in the particular organ. In general, tumors in peripheral or upper parts of the body or in hollow, expanded organs are considered yin; examples include lymphoma, leukemia, Hodgkin's disease, and tumors of the mouth (except tongue), esophagus, upper stomach, breast, skin, and outer regions of the brain. Tumors in lower or deeper parts of the body or in more compact organs are considered yang; examples include cancers of the colon, rectum, prostate, ovaries, bone, pancreas, and inner regions of the brain. Cancers thought to result from a combination of yin and yang forces include melanoma (skin cancer) and cancers of the lung, bladder, kidney, lower stomach, uterus, spleen, liver, and tongue (Kushi and Jack, 1983).

For cancers classified as predominantly yang, the standard macrobiotic diet is recommended, with slight emphasis on yin foods. The same diet is recommended for yin-classified cancers, with a slight emphasis on yang foods. Patients with cancers resulting from both yin and yang imbalances are advised to follow "a central way of eating," as suggested in the standard macrobiotic diet. Different cooking styles also are recommended on the basis of this disease classification (Kushi and Jack, 1983).

Research base. The available information on the effectiveness of the macrobiotic diet for treating cancer comes from retrospective case reviews and anecdotal reports, some of which come from the popular literature, and two unpublished retrospective studies (Office of Technology Assessment, 1990). A number of individual accounts of patients who attributed their recovery from cancer to their adherence to a macrobiotic diet have been written in recent years.

In one unpublished retrospective study, Carter and colleagues (1990) compared survival times between 23 pancreatic cancer patients maintained on a macrobiotic diet and similar patients who received conventional cancer therapy. The authors reported that the mean survival (the average) and the median survival (the point in time after diagnosis by which half the group died) was significantly longer for the macrobiotically maintained patients. A followup study by Carter also showed improved survival time for 11 patients with prostate cancer on a macrobiotic diet. However, OTA pointed out that the studies had design flaws that may have overstated the effect (Office of Technology Assessment, 1990).

In another unpublished manuscript, Newbold (undated) presented six case histories of patients with advanced cancer who adopted a macrobiotic diet in addition to using mainstream treatment. These cases were well described medically, including references to appropriate diagnostic tests (all but one case was definitely biopsy proven) and followup scans and tests (Office of Technology Assessment, 1990).

As in the review of the Kelley regimen, when OTA asked its independent advisory panel of six physicians to review Newbold's cases the three mainstream reviewers did not find any of the cases compelling, while two physicians who were open to unconventional therapies were more positive about the outcomes. One concluded that five of the six cases (all except the one without the biopsy-proven diagnosis) showed positive effects from the macrobiotic diet. The remaining physician found two cases that seemed "legitimate," two "highly suggestive," one "suggestive," and one not convincing (Office of Technology Assessment, 1990).

The retrospective studies presented by Carter and Newbold's case histories were later combined and published in the Journal of the American College of Nutrition (Carter et al., 1993). Although the design flaws noted by OTA were still extant in the study, an accompanying editorial suggested that these findings may provide clues to a new approach to the dietary management of cancer (Weisburger, 1993). The editorial stated that the macrobiotic diet has "been construed by classical nutritionists as inadequate. . . . Yet, the application to control the growth of cancer may actually be based on the fact that it is an inadequate diet." The editorial continued by stating that "Perhaps the time has come to teach nutritionists that, in some instances, a nutritional regimen clearly deficient in growth promoting substances might actually be helpful in controlling otherwise untreatable diseases."

Additional cancer diets. Additional cancer diets reviewed by the Office of Technology Assessment included the Livingston/Wheeler regimen and the Wigmore treatment.

Livingston/Wheeler regimen. This regimen is mentioned here because its practitioners advocate diet as a means of potentiating antitumor immunity. Based on Dr. Virginia Livingston's observation of a putative cancer-causing microorganism, the treatment combines vaccines, bacterial reagents, a patented retinoic acid, intravenously administered vitamins, long-term use of antibiotics, and a modified Gerson diet with coffee enemas. Her San Diego-based clinic has continued, after her death, to offer her treatment.

Wigmore treatment. This treatment is an empirically developed dietary regimen (Wigmore, 1985) that uses seed sprouts, wheat grass juice, and uncooked vegetables and fruits. The available literature contains accounts of positive outcomes in cancer, but they are presented without conventional documentation, making it impossible to confirm or deny them. Although advocates have gone to considerable lengths to present supportive literature for their practices (Wigmore, 1993), formal clinical testing has been limited to studies of the reversible, short-term effects of the diet on serum lipids, lipoprotein, and apolipoprotein (W. Ling et al., 1992), which findings are consistent with, if less extensive than, those of similar fat-restricted, basically vegetarian diets (Walford et al., 1992).

Fat-modified diets for treatment of cardiovascular disease and diabetes. Coronary artery disease is the leading cause of death and disability in the United States. Seven million people, nearly 3 percent of the U.S. population, have clinical coronary heart disease. Every year, 1.5 million Americans have acute heart attacks, which kill approximately 520,000 persons, 247,000 of whom are women (American Heart Association, 1991). In fact, cardiovascular diseases--primarily coronary heart disease and stroke--kill nearly as many Americans each year as all other diseases combined (National Center for Health Statistics, 1990). Furthermore, more than 60 million Americans, or 30 percent of the adult population, currently have high blood pressure (National Heart, Lung, and Blood Institute, 1985), which makes them prime candidates for stroke and heart or kidney disease.

Balloon angioplasty (inserting a tiny balloon into the circulatory system and inflating it to open up a plaque-blocked artery) is performed approximately 300,000 times a year in the United States. Although angioplasty provides immediate and possibly lifesaving relief for many patients, it is not a long-term solution. There is no evidence that angioplasty does anything to prevent future angina (severe chest pain) or heart attacks, and about 30 to 40 percent of all angioplasty-treated vessels block up again within 6 months, meaning another angioplasty must be performed (Becker, 1991). Each angioplasty procedure costs about $20,000.

For the most severe cases of heart disease, surgeons remove veins (usually from the legs) and use them to "detour," or bypass, around the clogged arteries of the heart. Even though people who undergo bypass operations experience a reduction in chest pain, the benefits of this surgery, which costs approximately $30,000, often wear off (Myrmel, 1993).

Researchers have known for several decades that a proper diet may prevent the onset of cardiovascular disease. However, once an individual develops this chronic condition, surgery and drugs have been considered the only available methods in mainstream medicine for trying to reverse its effects (Califf et al., 1989). Only recently has diet been considered an alternative to drugs and surgery for treating cardiovascular disease. In the mid-1970s, Nathan Pritikin began using an extremely low-fat, high-fiber diet along with exercise to treat heart disease patients and showed that he could lessen their clinical symptoms. Then in the late 1980s, San Francisco physician Dean Ornish set out to do the same. However, Ornish was armed with a powerful new tool: the angiogram, which is an interior picture of patients' blood vessels. Using "before" and "after" angiograms, Ornish was able to see how changes in diet and lifestyle affected the status of the blockage, or plaque, in the artery. The Pritikin and Ornish diets are described below.

Pritikin diet. The diet is named after the man who developed it, Nathan Pritikin, who had been told by his cardiologist that he was at great risk of death from myocardial infarction. Therefore, he patterned for himself a diet modeled after a vegetarian diet followed by the people of Uganda, who were shown to be essentially free from death by heart attacks (Martin, 1991). In the late 1960s, after a few years on this diet, Pritikin decided that it had saved his life and founded his clinic in Santa Monica to treat cardiac patents.

The Pritikin diet is basically vegetarian, high in complex carbohydrates and fiber, low in cholesterol, and extremely low in fat (less than 10 percent of daily calories). The Pritikin diet also requires 45 minutes of walking daily. Although this diet and exercise program can be followed completely on an outpatient basis, the Pritikin Longevity Center in Santa Monica recommends that patients attend a 26-day program to learn how to prepare their new type of meals and practice new daily exercise and living habits.

Ornish diet. This diet was developed by Dean Ornish, M.D., an assistant clinical professor of medicine at the University of California, San Francisco. The Ornish diet is basically vegetarian, allowing no meat, poultry, or fish, and permitting only the white of eggs. Also, no nuts, caffeine, or dairy products, except a cup a day of nonfat milk or yogurt, are allowed, and no oil or fat is permitted--not even for cooking. Two ounces of alcohol a day are allowed. Providing an average of about 1,800 calories a day, the diet provides 75 percent of its calories from carbohydrates and less than 10 percent from fat (Ornish, 1990). The American Heart Association's recommended adult "prudent diet" calls for total fat of less than 30 percent, which Ornish feels is not really low enough, even for healthy adults, but especially not for people trying to reverse atherosclerosis (Ornish, 1990). Ornish provides his patients all their lunch and dinner meals, precooked, packed in Tupperware, and handed out a week's worth at a time.

In many ways, the Ornish diet is similar to the Pritikin diet. Both are basically vegetarian (although Pritikin does allow 85 grams of chicken or fish per week), high in complex carbohydrates, high in fiber, low in cholesterol, and extremely low in fat (less than 10 percent of daily calories). However, Ornish's program--run on an outpatient basis--calls for stress reduction practices in addition to the diet and emphasizes emotional social support systems, particularly between members of the group. It also requires daily stretching and an hour's walk three times a week.

Research base. The following is an overview of the available research on these two ultra-low-fat dietary regimens.

Pritikin diet. In a study of men taking the Pritikin 26-day course, all 21 participants reduced their cholesterol level, 19 reduced their triglyceride level, and 16 had a reduction in their estradiol level (Rosenthal et al., 1985).

In another study assessing the effectiveness of the Pritikin diet and exercise program on cardiovascular hemodynamics, 20 subjects were divided in two groups (active/treatment and control). These data were compared to a group of 10 healthy individuals not involved in the program. Hemodynamic parameters were collected at admission and at the end of the 26-day program. In obese and hypertensive subjects not on medication who followed the Pritikin program, the cardiac index increased by 10 percent, mean arterial pressure decreased by 5 percent, and the systemic vascular resistance index decreased by 18 percent. Little change was seen in controls. There also was an improvement in ventricular performance (Mattar et al., 1990).

The Pritikin diet has also been studied in connection with adult-onset diabetes mellitus and peripheral vascular disease. Studies suggest that it may show promise in controlling newly diagnosed cases of adult-onset diabetes without drugs. One study (Barnard et al., 1982) evaluated 60 patients who had completed the Pritikin 26-day program. Of the 23 who were taking oral hypoglycemic agents upon entry, all but 2 were off medication by the end of the program. Of the 17 patients who were taking insulin, all but 4 were off medication at discharge. Two of those 4 had their insulin reduced by 50 percent, while the remaining 2 had no major change in their insulin dosage. Fasting blood glucose levels were significantly reduced in all patients; serum cholesterol levels were similarly reduced, as were triglyceride levels. The group as a whole lost an average of 4.3 kg of body weight and achieved 40.5 percent of their desired weight loss. Maximum work capacity increased significantly, while daily walking increased from approximately 11.7 minutes a day to approximately 103 minutes.

In another study, University of California, Los Angeles (UCLA) investigator Dr. James R. Barnard put 650 diabetic patients on the Pritikin diet. After 3 weeks, some 76 percent of the newly diagnosed diabetics, along with 70 percent of those on oral agents, had normal glucose levels (Barnard et al., 1992). However, only 40 percent of those already receiving insulin responded to the diet. According to Barnard, muscles, which may become severely insulin resistant during drug treatment, respond to exercise and a low-fat diet. In contrast, drugs may eventually weaken the pancreas while failing to reduce physically and financially devastating vascular complications (e.g., deterioration of eyes and kidneys).

Ornish diet. In what is now known as the Lifestyle Heart Trial, in the late 1970s and early 1980s Ornish conducted a series of trials in which patients with confirmed heart disease were placed on a diet and lifestyle modification program. In the first study, after 30 days people reported a substantial reduction in frequency of angina (heart pain), and many were pain free. Cholesterol levels were down about 20 percent, and high blood pressure was reduced (Ornish et al., 1979). In a followup study in the early 1980s, Ornish reported that 30 days of his regimen were enough to improve blood flow to the heart in some patients and that patients could exercise almost 50 percent more, on average, than they could before beginning the treatment (Ornish et al., 1983).

Finally, in a prospective, randomized, controlled trial to determine the effectiveness of his program over a longer time, Ornish and his colleagues put 28 men and women whose arteries were partially blocked on his program for a full year. Twenty other patients were assigned to a "usual care" group. After 1 year, without the use of lipid-lowering drugs, patients in the experimental group (i.e., receiving the Ornish treatment) reported a 91-percent reduction in the frequency of angina, a 42-percent reduction in the duration of angina, and a 28-percent reduction in the severity of angina. In contrast, control group patients reported a 165-percent rise in frequency, a 95-percent rise in duration, and a 39-percent rise in severity of angina (Ornish et al., 1990).

Patients in the experimental group also showed a significant overall regression, or reduction, of coronary atherosclerosis (blocked arteries) as measured by angiograms. In contrast, patients in the usual care group had a significant overall progression, or worsening, of their coronary atherosclerosis. This finding led Ornish to conclude that the conventional recommendations for patients with heart disease, such as a 30-percent fat diet, are not sufficient to bring about an improvement in many patients.

Ornish has never tested separately each component of his multifaceted program, so it is impossible to be sure which component contributed most to the improvements. If it was the dietary regimen that led to the improvements, it is a regimen that most Americans would have a hard time following, admits Ornish (Schardt, 1993). However, some researchers believe that it does not take such a radically restricted diet to start reversing the effects of heart disease. In a study in Germany, 56 men suffering from angina caused by partially blocked arteries were placed on a reduced-fat diet (less than 20 percent of calories from fat, 7 percent of calories from saturated fat, and 200 mg of cholesterol a day). As in the Ornish program, they also participated in an exercise program. After a year, angiograms showed that the blockages in 32 percent of the men on the low-fat diet had improved, compared with just 17 percent in the control group (Schuler et al., 1992).

In addition, in the late 1980s, researchers in Britain placed 26 men with partially blocked arteries and elevated blood cholesterol on carefully monitored diets and reduced their fat intake to 27 percent of calories--about three-fourths of what the average American eats. The diet's saturated fat and cholesterol amounts also were substantially less than most Americans eat, while its fiber content was slightly higher. Over the next 3 years, the men on the fat-restricted diet suffered only one-third as many deaths, heart attacks, and strokes as men in the control group--who were not told what to eat, and whose diets were not monitored (Watts et al., 1992). Furthermore, angiograms showed that the openings in the arteries of 38 percent of the men who changed their diets became slightly larger.

Food elimination diets for treatment of food allergies. Allergies to food, or food intolerance, have become a major area of research in recent years. Many of the researchers involved in this research specialize in environmental medicine (see the "Alternative Systems of Medical Practice" chapter), which is the science of assessing the impact of such environmental factors as chemicals, foods, and inhalants on health. It provides an understanding of the interface between the external environment and the biological function of the individual.

Dietary management of food allergies is based on avoidance of food antigens and the 4-day rotary diversified diet. With the rotary diet and avoidance of repetitive food exposures, it is possible to reduce sensitivity to foods and hasten recovery from food allergies. Nutritional supplements are prescribed as indicated by objective nutritional testing and the symptoms of the patient.

Research base. Miller (1977) studied eight chronically ill food-sensitive patients who were tested with provocation-neutralization techniques. The patients were treated with injections of allergy extracts and compared to those treated with placebos. In a rigidly controlled study, King (1988) showed a correlation between oral food challenge and provocation-neutralization testing. Treatment using results from this testing showed significant symptom relief. Using neutralization therapy, Rea and colleagues (1984) found significant improvement in 20 patients with known food sensitivity in signs and symptoms of allergy reactions to certain foods.

Food intolerance is also being studied as a causal or contributing factor in rheumatoid arthritis. In a clinical trial in Norway, Kjeldsen-Kragh and colleagues (1991) found that fasting followed by dietary restriction could relieve the symptoms of rheumatoid arthritis on a long-term basis. They subjected 27 rheumatoid arthritis patients to a 7-to 10-day fast (except for herbal teas, garlic, vegetable broth, a decoction of potatoes and parsley, and extracts from carrots, beets, and celery) followed by 1 year of an individually adjusted vegetarian diet. The diet-restricted patients stayed on a Norwegian health farm the first 4 weeks of the study. A control group of 26 patients stayed in a convalescent home for 4 weeks but ate an ordinary diet throughout the trial.

After 4 weeks, the diet group showed a decrease in pain score; a significant decrease in pain, morning stiffness, and the number of tender and swollen joints; and improved grip strength and ability to articulate the joints. There was also a significant improvement in a number of biochemical markers associated with inflammation. These improvements were maintained throughout the year. In contrast, the control group showed a decrease in pain score after its stay in the convalescent home, but none of the other indices improved. At the end of the study the conditions of the control patients had deteriorated.

This study suggests that there is a food allergy component to rheumatoid arthritis and that food restriction appears to be a useful supplement to the conventional medical treatment of rheumatoid arthritis. Darlington and colleagues (1986) and Beri and colleagues (1988) obtained similar results, but their studies lasted only 3 months.

There is also evidence that food elimination diets may benefit many children with hyperactivity (Kanofsky, 1986). Several research teams have used double-blind designs to demonstrate this point. The Institute of Child Health and Hospital for Sick Children in London undertook a randomized, crossover, placebo-controlled trial to evaluate the effect of diet on the development of hyperactivity (Egger et al., 1985). The first phase of the study consisted of placing 76 hyperactive children on a food elimination diet. The presupposition was that individuals can be sensitive to a food or food additive in their diet and that improvement occurs when the offending foods or food additives are removed from the diet. At the end of the first phase of the study, 62 of the 76 children (82 percent) improved on the diet, and a normal range of behavior was achieved in 21 (29 percent) of them. In addition to overactivity, other symptoms such as headaches, abdominal pain, antisocial behavior, and fits were also often alleviated.

In all, 48 foods were implicated as contributing to hyperactivity in the young patients. However, 34 of the 50 children for whom full data are available reacted to fewer than 7 foods. Two reacted to 30 foods. Five patients were also noted with symptoms from such inhalants as pollen, perfume, and house dust. Foods that frequently caused problems included cow's milk (64 percent of subjects tested), chocolate (59 percent), wheat (49 percent), and oranges (45 percent).

The second phase of the study included 28 children from the original group, who entered into a double-blind, crossover, placebo-controlled trial that reintroduced one incriminated food. Sy