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Dietary supplements and functional foods: 2 sides of a coin?

1–3
Charles H Halsted

ABSTRACT Dietary supplements are used by more than recognize the term neutraceutical. Functional foods, according
one-half of the adult US population. In contrast to pharmaceuti- to Zeisel, are not dietary supplements but rather “are consumed
cals, dietary supplements may be sold in the United States with as part of a normal diet and deliver one or more active ingredi-
little regulation other than listing of ingredients and the potential ents (that have physiologic effects and may enhance health)
health benefits. By contrast, herbal products in Germany are within the food matrix” (2).
carefully regulated by the same standards as drugs, and efforts
are under way to standardize their regulation in the entire Euro- Dietary supplements
pean Union. Most herbal users do not inform their physicians Among his “bedside teachings,” Sir William Osler stated,
that they are taking these supplements, and most physicians do “The desire to take medicines is one feature which distinguishes
not inquire. Although some herbal products have clinically man, the animal, from his fellow creatures” (3), a viewpoint
proven benefits, it is increasingly apparent that many contain recently corroborated by the finding of medicinal herbs in the
potentially toxic substances, particularly in relation to interac- intestine of the 5300-y-old frozen “iceman” who was recently
tions with drugs. Hence, it is essential that practicing physicians discovered in the Swiss Alps (4). Botanicals with medicinal
develop a working knowledge of herbals—specifically, about properties have been used from time immemorial in all cultures
claims for their usage and potential or proven efficacies and and, with the introduction of ingredient assays and standards in
toxicities—and that they incorporate such knowledge into the the early 20th century, form the foundation for modern Western
evaluation and management of their patients. By contrast, func- pharmacology (5). On the other hand, the consumption and mar-
tional foods—integral components of the diet that are under- ket value of herbs and other nutritional supplements has reached
stood to contribute added health benefits—are the subject of astonishing proportions in the United States. According to recent
intense and widespread research in food and nutritional science. FDA testimony, dietary supplements, including vitamins, were con-
Examples include many polyphenolic substances, carotenoids, sumed by 158 million Americans in the year 2000—that is, more
soy isoflavones, fish oils, and components of nuts that possess than half the US population (6). This compares with a 1997 survey
antioxidant and other properties that decrease the risk of vascu- that showed that alternative medical therapies, principally herbals,
lar diseases and cancer. Practicing physicians are advised to stay were used by 83 million people (7). In 2000, the total dietary sup-
abreast of these emerging findings in order to best advise their plement market included 32% as herbals and 38% as vitamins. The
patients on the value of health-promoting diets in disease pre- sales of dietary supplements in the United States doubled after pas-
vention. Am J Clin Nutr 2003;77(suppl):1001S–7S. sage of the DSHEA in 1994, to $17.1 billion in 2000, and are antic-
ipated to continue increasing by 10% per year (5).
KEY WORDS Dietary supplements, herbal products, functional Although the FDA was charged with implementing stringent
foods, challenges to medical practitioners governmental regulations for ensuring the accurate labeling,
safety, and efficacy of drugs, the food supplement industry was
under no specific regulations until the Nutrition Labeling and
INTRODUCTION Education Act of 1990, which permitted health claims for
In 1994 the US Congress enacted the Dietary Supplement nutritional supplements that were restricted to several cate-
Health and Education Act (DSHEA) (1). This act defines a gories, including osteoporosis, hypertension, heart disease, and
dietary supplement as “a product (other than tobacco) that is cancer. Spurred by intensive industry lobbying, Congress passed
intended to supplement the diet and that bears or contains one or the DHSEA in 1994 to broaden the availability of all dietary
more of the following dietary ingredients: a vitamin, a mineral, supplements by authorizing their claims for functional specific
an herb or other botanical, an amino acid, a dietary substance for health benefits, but not specific disease prevention or cure. The
use by man to supplement the diet by increasing the total daily FDA established a Center for Food Safety and Applied Nutrition
intake, or a concentrate, metabolite, constituent, extract or com-
binations of these ingredients.” Furthermore, a dietary supple-
ment is intended for ingestion in pill, capsule, tablet, or liquid 1
From the Department of Internal Medicine and Nutrition, University of
form; is not represented for use as a conventional food or as the
California, Davis.
sole item of a meal or diet; and is labeled as a dietary supplement 2
Presented at the Third Heelsum International Workshop, held in Heel-
(1). In a recent Science forum, Zeisel (2) provided 2 additional, sum, the Netherlands, December 10–12, 2001.
useful working definitions. A neutraceutical can be defined as “a 3
Reprints not available. Address correspondence to CH Halsted, Depart-
diet supplement that delivers a concentrated form of a biologi- ment of Internal Medicine and Nutrition, University of California, Davis, TB
cally active component of food in a non-food matrix to enhance 156, One Shields Avenue, Davis, CA 95616, United States. E-mail: chhalsted@
health.” The US Food and Drug Administration (FDA) does not ucdavis.edu.

Am J Clin Nutr 2003;77(suppl):1001S–7S. Printed in USA. © 2003 American Society for Clinical Nutrition 1001S
1002S HALSTED

(CFSAN) with responsibility for oversight of new supplemental alternative therapies were fraudulent, potentially harmful
products, including the marketing of clearly identified products because they supplanted conventional therapy, and/or a waste of
declared to be of known composition and strength. New dietary time and money. Most patients derived their information from
supplements are reviewed by the FDA under the rubric of the advertising or Internet sources (15).
same good manufacturing practice regulations that apply to con- In summary, dietary supplement usage is widespread because
ventional foods. The manufacturer is responsible for ensuring of successful marketing strategies and popularization by word of
that the “supplement facts” label and ingredient lists are accu- mouth, advertising, and Internet information sources. Although
rate, that the dietary ingredients are safe, and that the content certain patient groups, such as pregnant women, tend to have
matches the amount declared on the label. However, the FDA lower herbal usage than the average person, others with
does not require accurate chemical analyses as a basis for the intractable chronic and/or fatal diseases, such as Parkinson’s,
identification and quantification of ingredients. The label must arthritis, and cancer, are more likely to turn to alternative thera-
also contain the disclaimer, “This product is not intended to pies, particularly herbal supplements. Most striking, physicians
diagnose, treat, cure, or prevent any disease.” This policy are unlikely to ask and unlikely to be told of their patients’ herbal
bypasses the usual FDA procedures of requiring proof of safety habits. In view of the uncertain composition of most herbs, their
from the manufacturer before approval of a drug for public con- potential interaction with prescription drugs, and their propen-
sumption, and puts the postmarketing burden of proving signifi- sity to cause side effects, widespread herbal usage poses a poten-
cant risk on the FDA. Supplements that were produced before tially significant risk to the health of patients.
1994 are assumed safe, whereas the safety of those marketed What should practicing physicians be concerned about
after 1994 is the responsibility of the manufacturers. The regarding herbals and other dietary supplements? A lot, as sum-
specifics of the role of the FDA in regulating dietary supple- marized in a recent editorial that emphasizes the differences
ments can be found in a recently posted website: http://www. between conventional and nonconventional medicine (16).
cfsan.fda.gov/dms/ds-oview.html (8). Before the application of science to medicine in the early 20th
How frequently do people use dietary supplements? A 2001 century, botanicals were the major source of nonsurgical ther-
survey of 376 randomly selected adults living in Minneapolis apy. Practitioners of herbal medicine had no way of knowing
found that 61.2% used supplements, most commonly ginseng. the concentrations or purity of their remedies, and toxicities
Few were advised by their physicians, and most obtained infor- from such medicines as foxglove, opium, and cinchona bark
mation on herbs from family, friends, or the Internet. Although were common. Proving the safety and efficacy of botanicals
the promotion of well-being was given as the main reason for was not feasible until the advent of chemical approaches to
herbal usage, fewer than 60% found satisfaction (9). A survey of identifying and ensuring the purity of active ingredients and of
118 patients attending 16 different family practices in Calgary, the scientific approach of well-controlled randomized clinical
Canada, found vitamin, mineral, or herbal supplement usage trials. Nevertheless, the burgeoning dietary supplement indus-
among 79% of women and 44% of men, and that 25% of those try, with its lack of rigorous scientific testing, threatens to
over age 50 and 70% of those under age 50 chose not to inform inundate the public with ineffective and potentially harmful
their physicians. Based on Internet information, the younger remedies. In the absence of patent opportunities for dietary
patients believed that supplements were safer and more effec- supplements, manufacturers have little incentive to prove the
tive than prescription drugs (10). Among 242 pregnant women, efficacy and safety of their products.
25% had used herbals on a regular basis—typically garlic, echi- The literature on dietary supplements is vast and rife with
nacea, and ginseng—before pregnancy, and 9% continued reports of unsuspected toxicities from unregulated dietary sup-
herbal use during pregnancy (11). A study of women with early- plements. The issue is complicated by the variety of regulations
stage breast cancer found that the usage of alternative medicine in different countries, where a botanical product may be classi-
had increased from 10.6% before diagnosis to 28.1% after diag- fied as an approved medicine, a dietary supplement, or a recre-
nosis and initiation of therapy, and that that increase was asso- ational herb (17). Most nation members of the European Union
ciated with depression and fear of cancer recurrence. Of inter- regulate vitamins and minerals as foods if provided within the
est, one-third of this group hid their alternative approaches from accepted recommended dietary allowances, but they have no spe-
their physicians (12). An accompanying editorial suggested that cific regulations on dietary supplements as long as no medicinal
widespread marketing and a lack of physician interest in dealing claims are made (18). Several countries have established com-
with or time to address illness-related anxieties are the main missions to assess the safety and efficacy of herbals. For exam-
reasons that cancer patients turn to alternative remedies (13). ple, Commission E of the German Federal Health Agency has
Among 201 patients with established Parkinson’s disease, 40% published more than 300 monographs that evaluate the efficacy
used various forms of alternative medicine, most commonly and safety of different herbal products according to acceptable
herbals (14). An informal non-peer-reviewed survey of arthritis clinical trials (19). Ongoing reports of herbal toxicities may not
patients and their physicians found that 79% used or were inter- appear in recent book form and must be sought in the current lit-
ested in using alternative therapies, including herbs, chon- erature. For example, it has only recently been appreciated that
droitin, glucosamine, massage, or chiropractic, but only 40% of fulminant hepatic failure may occur during the chronic use of
users informed their physicians, and only 40% of physicians kava (20, 21). Understanding potential efficacies and hazards of
asked their patients about their alternative treatments. Reasons dietary supplements is a daunting task for practitioners. For
given for patients’ having not informed their physicians example, the Physicians’ Desk Reference for Herbal Medicines
included fear of disapproval and the perception that the physi- lists 80 under letter A alone in its common name index and lists more
cian would be unable to provide advice on alternative than 350 side effects for all herbals (22). The recently published
approaches. One-third of the physicians felt they did not know Physicians’ Desk Reference for Nuritional Supplements describes
enough to provide meaningful advice and 20% considered that more than 200 nonherbal supplements (vitamins, minerals, amino
DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS 1003S

acids, and other products) cross-referenced to more than 300 warfarin, leading to their ineffectuality in therapeutic situa-
potential side effects (23). Given that herbals and nutritional sup- tions (30). Valerian, used for its sedative properties, potenti-
plements are taken by mouth, it is not surprising that the most ates the effects of benzodiazepines and may result in with-
common side effects relate to the gastrointestinal tract, including drawal delirium (42).
diarrhea, nausea, and vomiting. Because many plants have nat- The health claims and potential side effects of some of the most
ural toxins that were developed for survival, hepatocellular dam- commonly used herbals are shown in Table 1 (19, 22, 43, 44).
age is not uncommon after ingesting herbs, including comfrey,
senna, and mixtures of ill-defined Chinese herbs (24). Additional Functional Foods
problems arise from the presence of unregulated or unknown In contrast to most dietary supplements, functional foods are
amounts of toxic substances within herbal preparations. For components of the usual diet that may have special disease pre-
example, in a 1998 analysis of 251 Asian patent medicines per- vention attributes and are the topic of current traditional scien-
formed by the California Department of Health Services, 10% tific investigation. According to the Food and Nutrition Board of
were found to contain lead, 14% arsenic, and 14% mercury at the Institute of Medicine, a functional food is “any food or food
potentially toxic levels (25). Others found toxic amounts of mer- ingredient that may provide a health benefit beyond the tradi-
cury in Chinese imported “herbal balls” and arsenic at levels that tional nutrients it contains” (45). Unlike dietary supplements that
could result in daily accumulation of 73 mg arsenic and more can claim only general health benefits, functional foods may
than 1200 mg mercury (26). Aristolochia fangchi, or “birthwort,” claim specific health benefits because they are considered part of
used for gastrointestinal symptoms, was strongly associated with the diet (46). The literature on functional foods is vast and grow-
nephropathy and development of urothelial carcinoma in women ing exponentially, and this review can touch on only a few points
attending a Belgian weight reduction clinic (27, 28). Underscor- that are essential for the practitioner. A recently published hand-
ing the problem of lack of quality control, 2 case reports book provides excellent summaries (45).
described the symptoms and laboratory evidence of digitalis tox-
Polyphenols and flavonoids
icity after ingestion of plantain, an herbal ingredient of a mixture
claimed to “cleanse the body,” that was contaminated with Digi- The term polyphenol encompasses simple phenols and flavon-
talis lanata (29). oids, which are found in fruits, vegetables, and nuts and their
A recent survey indicated that 30% of patients undergoing products, and possess important antioxidant properties. Flavon-
surgery use herbal medications, about twice the usage in the gen- oids include proanthocyanidins, quercetin, and epicatechin, found
eral US population (30), and that 70% of herbal users failed to mainly in chocolate, tea, and wine. Red wine also contains resver-
mention their use of dietary supplements in the routine preoper- atrol, a nonpolyphenol antioxidant product of grape skins. The
ative evaluation (31). Preoperative herbal use is particularly haz- “French paradox” refers to the epidemiologic finding that the
ardous, because different herbs may influence operative survival incidence of coronary heart disease was significantly lower in
and/or alter the metabolism and pharmacologic effects of con- wine-drinking regions of France than in areas where wine was not
ventional anesthesia and postoperative drugs. For example, pro- the main alcoholic beverage (47). Subsequently, it was shown that
longed preoperative use of the immunostimulant echinacea may wine phenols inhibited the oxidation of low-density lipoprotein
result in immunosuppression with prolonged wound healing and (LDL) (48), an accepted reason for the preventive effect of
postoperative infections (32). Ephedra, a stimulant and the source polyphenols on the development of atherosclerosis. More recent
of ephedrine and methamphetamine, increases blood pressure, studies demonstrate that the attenuation of coronary heart dis-
heart rate, and risks of arrhythmias and vasospasm, which ease risk in wine drinkers is probably due as much to their
together increase the risks of myocardial infarction and stroke lifestyle consumption of high amounts of polyphenol-containing
(33). In 1997 the FDA issued a warning on the use of ephedra as fruits and vegetables as to wine (49). A 5-y prospective Dutch
an herbal weight loss drug because of its potential adverse stim- study of 800 elderly men found that the ingestion of flavonoids,
ulant effects on both the circulatory and nervous systems (34). mainly in tea, onions, and apples, was associated with significant
Although garlic lowers serum cholesterol to a modest amount reduction in mortality from coronary heart disease (50). In addi-
(35), ajoene, a constituent of garlic, may potentiate platelet tion to antioxidant effects on LDL, other potentially cardiopro-
inhibitors and thereby increase the risk of bleeding complica- tective effects of polyphenols include inhibition of platelet aggre-
tions of surgery (30). Ginkgo, used to enhance memory and gation and vascular relaxation through the production of nitric
improve peripheral vascular circulation, also has platelet-inhibit- oxide (51). Although polyphenols have the capacity to decrease
ing properties that may result in intracellular hemorrhage and LDL oxidation, inhibit platelet aggregation, and induce vascular
subdural hematomas (36, 37). Ginseng may lower postprandial relaxation, their clinical efficacy is modulated by many factors
blood glucose in type II diabetic patients but can induce hypo- that include differences in wine and tea preparation, volatility,
glycemia and inhibit platelet aggregation (38, 39). Kava, used and absorbability. For example, green tea has a higher concentra-
for its sedative and antianxiety properties, can interact with bar- tion of polphenols than black tea, which may be affected by the
biturates and benzodiazepines, prolonging sleep and even induc- method of brewing (52). Wine should be consumed in moderation
ing coma (40), and has recently been associated with fulminant only, to avoid the chronic effects of alcohol. The year 2000
hepatic failure requiring liver transplantation (20, 21). A 2002 Dietary Guidelines for Americans identifies moderation as no
FDA consumer advisory cited 25 reports of liver-related injury in more than 1 drink per day for women and 2 drinks per day for
kava users and advises caution on its use, particularly in individ- men, where a drink constitutes 5 oz of wine (53). Although these
uals with known liver disease (41). St John’s wort, used to pre- studies support the principle that fruits and vegetables should pro-
vent depression, inhibits serotonin reuptake, which results in sero- vide the main staple of a healthy diet, varied amounts of polyphe-
tonin excess and increases the metabolic rate of many cytochrome nols in different foods and effects of food preparation and absorp-
P450 drugs, including cyclosporin, midazolam, lidocaine, and tion hinder the establishment of clear-cut dietary and clinical
1004S HALSTED

TABLE 1
Herbal supplements
Common name Formal name Claim, current use Possible mechanisms Efficacy, clinical evidence Adverse effects
Black cohosh (black Cimicifuga Improves menopausal Suppresses lutenizing Many clinical studies Gastric discomfort
snakeroot, rattle- racemosa symptoms, premen- hormone secretion in showed favorable results
weed, rattleroot, strual syndrome, and menopausal women;
bugbane, bugwort, dysmenorrhea weak binding to
squaw root) (19, 44) estrogen receptors
Comfrey (19, 44) Symphytum Heals skin wounds Allantoin promotes cell Uncertain Liver failure, death. Pyrrolizidine
officinale growth; Tannins are alkaloids are hepatoxoic
vaso-constrictive when taken by mouth;
may be absorbed through skin
Echinacea (cone Echinacea Stimulates immune Stimulates leukocyte Positive clinical trials Immune suppression during
flower) (19, 44) angustifolia response; promotes mobility, phagocytosis, showing shortened surgery (30)
wound healing; treats and T-cell functions duration of common cold
common cold and yeast but not prevention
infections
Ephedra (ma huang) Ephedra sinica Relieves nasal Active constituent is Traditional use for Increases blood pressure and
(19, 34, 44) congestion and asthma, ephedrine, a 2000 years in Chinese heart rate and can cause
promotes weight loss, sympathomimetic medicine to treat headache, insomnia, dizzi-
and enhances athletic bronchospasm ness, seizures, arrhythmias,
performance addiction, and death (34)

Garlic (19, 44) Allium sativum Reduces cardiovascular Inhibits platelet Lowers LDL cholesterol Can potentiate other platelet
risk and serves as aggregation, reduces and triacylglycerols in inhibitors or cause
anti-inflammatory cholesterol (35), clinical trials; antibacterial bleeding
and has antioxidant in vitro (19)
properties
Ginkgo (43, 44) Ginkgo biloba Improves memory, Promotes vasodilation, Clinical trials show that it Diarrhea, nausea, vomiting;
cognition, intermittent modulates neuro- may improve cognitive intracranial bleeding
claudication, vertigo, transmitter activity, performance and memory reported (30, 37)
tinnitus, and sexual and inhibits platelet in the morning; mixed
performance aggregation results in Alzheimer’s
disease
Ginseng (43, 44) Panax ginseng Improves physical Unknown; possible Mixed data on regulation Insomnia, diarrhea and
performance, energy pharmacologic effects of blood glucose and hyperactivity
level; cancer prevention; attributed to steroidal cancer prevention
blood sugar reduction saponins
Kava-kava Piper Elevates mood and May interact with brain Positive clinical studies Weakness, allergies, inter-
(19, 41, 44) methysticum relieves anxiety and -aminobutyric acid action with benzodiazepines
menopausal symptoms receptors (19) (40, 41)

Saw palmetto Serenoa repens Reduces prostatic hyper- Has antiandrogenic Similar to finasteride in Feminization
(22, 44) (sabal fructus) trophy, builds sexual action reducing symptoms of
vigor, and increases prostatitis, but with fewer
sperm production side effects

St John’s wort Hypericum Serves as mild to Inhibits serotonin, Positive clinical trials for Causes photosensitivity;
(19, 43, 44) performatum moderate antidepressive, norepinephrine, and mild to moderate may interact with
and as antiviral dopamine reuptake; depression benzodiazepines and
(22) inhibits monoamine warfarin (30)
(MAO)
Yohimbe Pausinystalia Works as aphrodisiac Dilates blood vessels of Several studies show Active MAO inhibitor; may
(19, 44) yohimbe and improves athletic skin and mucous positive value for erectile activate psychosis;
performance membranes dysfunction increases anxiety, blood
pressure, sleeplessness,
tachycardia, tremor, and
vomiting; ruled unsafe by
US Food and Drug
Administration (8)
DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS 1005S

recommendations of polyphenol-rich fruits and vegetables in the mainly from plants and saturated fatty acids from animal sources.
nutritional prevention of heart disease. Diets in which cold water fish such as mackerel, salmon, halibut,
and trout are the main staple are associated with reduced inci-
Soy isoflavones dence of coronary heart disease but increased risk of hemor-
Soy isoflavones are phytoestrogens that are derived from the rhage. Studies of susceptible men from Holland, Japan, and the
protein fraction of the soybean and its food products (eg, soy milk, United States showed that sudden death from coronary artery
soy flour, tofu, miso), include genistein and daidzein, and possess disease is reduced by half when 1–2 fish meals are consumed
estrogenic properties because of the similarities of their chemical weekly (71–73). The biological effects of fish oils include inhi-
structures to estrogenic compounds. Clinical trials identified the bition of hepatic synthesis and secretion of triacylglycerol and
potential efficacy of soy isoflavones in the prevention of coronary very low density lipoprotein with reduced postprandial lipemia,
heart disease, osteoporosis, and breast and prostate cancer. A increased circulating high-density lipoprotein, inhibition of
meta-analysis of 37 clinical studies suggested that soy protein up platelet aggregation, and prevention of cardiac arrhythmias (73).
to 45 g per day can lower serum cholesterol levels by 10% (54), Eicosapentaenoic acid (EPA) and its elongated product docosa-
but the long-term effects of soy on cardiac risk are unknown. hexaenoic acid are the predominant fatty acids in fish, whereas
Because phytoestrogens compete with estrogen for binding to -linolenic acid, the precursor of EPA, is found in canola,
estrogen receptors, their use could have beneficial effects in pre- flaxseed, and walnut oils. A Mediterranean diet rich in these oils
venting osteoporosis and sex hormone–mediated malignancy, such was found to reduce cardiac deaths by 70% in France (74). By
as breast and prostate cancer. The clinical data are mixed and virtue of anti-inflammatory properties and effects on cell mem-
inconclusive on the effect of soy isoflavones on bone turnover and branes, fish oils are also thought to have a beneficial effect in the
bone density (55). Data are mixed on whether soy isoflavones pro- treatment of rheumatoid arthritis, although conclusive clinical
mote or protect against breast cancer (56–58), and one retrospec- studies are lacking (75).
tive study of 1300 non-Asian women with breast cancer history
Nuts
found no association of phytoestrogen use and breast cancer risk
(59). Although prostate cancer rates are lower in Eastern cultures Although nuts are relatively high in fat, most of this fat is in the
where soy products play a major role in the diet, and although mono- or polyunsaturated form. Beneficial nuts include almonds,
genistein inhibits the growth of prostate cancer cells, clinical stud- Brazil nuts, peanuts, walnuts, pistachios, and pecans. Three large
ies to date have failed to demonstrate positive effects of dietary prospective studies demonstrated that the consumption of 1–4
soy products on reducing the risk of prostate cancer (60). servings of nuts per week was associated with about a 40% reduc-
tion in risk of coronary heart disease, even after adjusting for con-
Carotenoids ventional risk factors such as hypertension, smoking, diabetes, and
There are several plant-derived carotenoids in the human diet, hyperlipidemia (76–78). The purported beneficial effects of nuts
of which -carotene, -carotene, lutein, zeaxanthin, and lyco- include improvement of serum lipid profiles with a predicted 16%
pene appear to have the most significance for health. Being lipid reduction in LDL cholesterol and presence of relatively high
soluble, carotenoids are absorbed with fats and circulate bound amounts of the nitric oxide precursor arginine, dietary fiber, and
to different lipoproteins. -carotene is a limited precursor of antioxidant vitamin E (78). Walnuts are particularly noteworthy
vitamin A, and excessive amounts of -carotene lead to for having a high content of n3 linolenic acid (78).
reversible carotenemia but not to vitamin A toxicity. The princi-
Probiotics and prebiotics
pal biological effects of carotenoids relate to their antioxidant
properties, which form the basis of potential protection against Probiotics can be defined as “live microbial food supplements
lipid peroxidation, atherogenesis, DNA oxidation, and cancer which benefit the host by improving the intestinal microbial
(61). Clinical studies suggest but have not yet proven that either form” (79). As such, probiotics can be consumed as either a
-carotene or lycopene is cardioprotective (62, 63). Aortic ather- functional food, such as a fermented milk product, or a supple-
osclerosis incidence was significantly inversely correlated with ment if provided separately in capsule or pill form. The rationale
the intake of dietary lycopene in the Rotterdam study of for probiotics is to improve intestinal immune tolerance to ben-
108 patients and control subjects (64). A review of more than eficial proteins and to maintain a normal immune intestinal
30 studies concluded that there is an inverse relationship barrier and permeability to exogenous foreign antigens (80).
between lycopene in tomato products and the risk of cancers of Intestinal organisms constitute the greatest cell population of the
the prostate, lung, and stomach (65), and one study demonstrated body, existing in 500 different species. Provision of normal
a 21% reduction in prostate cancer with consumption of diets human organisms that resist acid and bile destruction and adhere
high in tomato-derived lycopene (66). A study of more than to the gut mucosa triggers a healthy immune response. The most
25 000 middle-aged male Finnish smokers found that the inci- beneficial organisms include those of the Lactobacillus and Bifido-
dence of lung cancer was increased in those receiving -carotene bacterium genera. Whereas controlled clinical trials are ongoing,
supplements (67). In large cohorts followed over time, cataract beneficial effects have been reported in the treatment of food
formation was reduced significantly by dietary intake of fruits allergies, acute infant diarrheas, traveler’s diarrhea, antibiotic-
and vegetables rich in lutein and zeaxanthin (68, 69). Recent associated colitis, and, potentially, inflammatory bowel disease
data suggest a potential preventive relationship between intake (81). Prebiotics are “non-digestible food ingredients that selec-
of these carotenoids and risk of macular degeneration (70). tively stimulate the growth of a limited number of bacteria in the
colon” (82). More specifically, prebiotics are short-length carbo-
Fish oils hydrates, such as fructooligosaccharides, that resist digestion or
Dietary fish oils appear as n3 polyunsaturated fatty acids are fermented in the colon to produce short-chain fatty acids,
mainly in cold water fish, compared with n6 polyunsaturates such as acetate, butyrate, and propionate, which have positive
1006S HALSTED

effects on colonic cell growth and stability, generate many of the minerals and herbs: a survey of patients attending family practice clin-
same bacteria as provided in probiotics, and may promote ics. Clin Invest Med 2001;24:242–9.
improved bowel habit but also increased flatus (83). 11. Gibson PS, Powrie R, Star J. Herbal and alternative medicine use during
pregnancy: a cross-sectional survey. Obstet Gynecol 2001;97:S44–5.
12. Burstein HJ, Gelber S, Guadagnoli E, Weeks JC. Use of alternative
SUMMARY AND CONCLUSIONS medicine by women with early-stage breast cancer. N Engl J Med
1999;340:1733–9.
There are striking differences between dietary supplements 13. Holland JC. Use of alternative medicine—a marker for distress?
and functional foods. Whereas dietary supplements, herbs in par- N Engl J Med 1999;340:1758–9.
ticular, are considered time-tested but are in most cases scientif- 14. Rajendran PR, Thompson RE, Reich SG. The use of alternative thera-
ically unproven, functional foods are components of the normal pies by patients with Parkinson’s disease. Neurology 2001;57:790–4.
human diet that are increasingly shown by rigorous science to be 15. Horstman J. The dangerous divide: why doctors aren’t asking and you
inherently valuable for maintaining human health. Whereas aren’t telling. Arthritis Today 2002 June 28:34–44.
herbal sales skyrocket and feed false public perception of the 16. Angell M, Kassirer JP. Alternative medicine—the risks of untested and
irrelevance of science to health, the era of functional foods unregulated remedies. N Engl J Med 1998;339:839–41.
17. De Smet PA. Health risks of herbal remedies. Drug Safety 1995;13: 81–93.
promises to propel nutritional science to the forefront of preven-
18. Mason P. Dietary supplements. 2nd ed. London: Pharmaceutical Press,
tive medicine for the most common diseases of humans. 2001.
Together, this new era of nutrition presents imposing challenges 19. Blumenthal M, Goldberg A, Brinckmann J. Herbal medicine: expanded
to practitioners of medicine. It is incumbent on them to become Commission E monographs. Newton, MA: Integrative Medicine Com-
fluent in the knowledge of commonly used herbals, including munications, 2000.
recognition of their potential benefits, side effects, and life- 20. Stevinson C, Huntley A, Ernst E. A systematic review of the safety of
threatening effects when combined with certain drugs. Although kava extract in the treatment of anxiety. Drug Safety 2002;25:251–61.
advice-seeking patients typically have rudimentary knowledge 21. Kraft M, Spahn TW, Menzel J, et al. Fulminant liver failure after
of the ingredients and rationales for the herbs they ingest, physi- administration of the herbal antidepressant Kava-Kava. Dtsch Med
cians must be in a position of knowledge to maintain their Wochenschr 2001;126:970–2.
22. Physicians’ Desk Reference. PDR for herbal medicines. 1st ed. Mont-
patients’ confidence as a prerequisite to providing credible coun-
vale, NJ: Medical Economics, 1998.
sel. Furthermore, because most patients are curious and some- 23. Physicians’ Desk Reference. PDR for nutritional supplements. 1st ed.
what knowledgeable about their diets, physicians must establish Montvale, NJ: Medical Economics, 2001.
a basic knowledge of conventional functional foods, which is 24. Kaplowitz N. Hepatotoxicities of herbal remedies: insights into the
viewed increasingly as an adjunct to sound medical advice. intricacies of plant-animal warfare and cell death. Gastroenterology
These are heady days for nutritional scientists as newer under- 1997;113:1408–12.
standings of food and health promise to bring clinical nutrition 25. Ko RJ. Adulterants in Asian patent medicines. N Engl J Med 1998;
to the forefront of clinical medicine. Practitioners must become 339:847 (letter).
nutritionally educated and oriented if they are to maintain their 26. Espinoza EO, Mann MJ, Bleasdell B. Arsenic and mercury in tradi-
patients’ confidence and stay abreast of this aspect of continu- tional Chinese herbal balls. N Engl J Med 1995;333:803–4.
27. Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma
ously evolving modern medicine.
associated with the use of a Chinese herb (Aristolochia fangchi).
N Engl J Med 2000;342:1686–92.
The author has no financial or personal potential or actual conflicts of
28. Kessler DA. Cancer and herbs. N Engl J Med 2000;342:1742–3.
interest with any manufacturer of herbal products or supplemental foods.
29. Slifman NR, Obermeyer WR, Aloi BK, et al. Contamination of botan-
ical dietary supplements by Digitalis lanata. N Engl J Med 1998;
REFERENCES 339:806–11.
1. Dietary Supplement Health and Education Act (DSHEA). 42 USC 30. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative
287C–11. 1994. care. JAMA 2001;286:208–16.
2. Zeisel SH. Regulation of “nutraceuticals.” Science 1999;285:1853–5. 31. Kaye AD, Clarke RC, Sabar R, et al. Herbal medicines: current trends
3. Bean WB. Sir William Osler: aphorisms from his bedside teaching and in anesthesiology practice—a hospital survey. J Clin Anesth 2000;12:
writing. Springfield, IL: Charles C Thomas, 1968;1–164. 468–71.
4. Capasso L. 5300 years ago, the Ice Man used natural laxatives and 32. Boullata JI, Nace AM. Safety issues with herbal medicine. Pharma-
antibiotics. Lancet 1998;352:1864 (letter). cotherapy 2000;20:257–69.
5. Goldman P. Herbal medicines today and the roots of modern pharma- 33. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous
cology. Ann Intern Med 2001;135:594–600. system events associated with dietary supplements containing ephedra
6. US Food and Drug Administration. Statement by Joseph A. Levitt alkaloids. N Engl J Med 2000;343:1833–8.
before the U.S. House of Representatives Committee on Govern- 34. US Food and Drug Administration. Dietary supplements containing
ment Reform. Internet: http://www.cfsan.fda.gov/lrd/st010320.html ephedrine alkaloids: proposed rule. Fed Regist 1997;62:30678–717.
(accessed 20 March 2001). 35. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholes-
7. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative med- terolemia: a meta-analysis of randomized clinical trials. Ann Intern
icine use in the United States, 1990–1997: results of a follow-up Med 2000;133:420–9.
national survey. JAMA 1998;280:1569–75. 36. Matthews MK Jr. Association of Ginkgo biloba with intracerebral
8. US Food and Drug Administration. Overview of dietary supplements. hemorrhage. Neurology 1998;50:1933–4.
Internet: http://www.cfsan.fda.gov/dms/ds-oview.html (accessed 3 Jan- 37. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associ-
uary 2001). ated with chronic Ginkgo biloba ingestion. Neurology 1996;46:1775–6.
9. Harnack LJ, Rydell SA, Stang J. Prevalence of use of herbal products 38. Vuksan V, Sievenpiper JL, Koo VY, et al. American ginseng (Panax
by adults in the Minneapolis/St Paul, Minn, metropolitan area. Mayo quinquefolius L) reduces postprandial glycemia in nondiabetic sub-
Clin Proc 2001;76:688–94. jects and subjects with type 2 diabetes mellitus. Arch Intern Med
10. Durante KM, Whitmore B, Jones CA, Campbell NR. Use of vitamins, 2000;160:1009–13.
DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS 1007S

39. Kimura Y, Okuda H, Arichi S. Effects of various ginseng saponins on Wildman REC, ed. Handbook of nutraceuticals and functional foods.
5-hydroxytryptamine release and aggregation in human platelets. Boca Raton, FL: CRC Press, 2001:143–56.
J Pharm Pharmacol 1988;40:838–43. 62. Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin
40. Almeida JC, Grimsley EW. Coma from the health food store: interac- status and carotid atherosclerosis in the elderly. Am J Clin Nutr
tion between kava and alprazolam. Ann Intern Med 1996;125:940–1. 2001;74:402–8.
41. US Food and Drug Administration. Kava and severe liver injury. FDA 63. Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr
Consum 2002;36:4 (letter). 2000;71(suppl):1691S–5S; discussion 1696S–7S.
42. Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delir- 64. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, Boeing H, Hofman A,
ium associated with valerian root withdrawal. JAMA 1998;280:1566–7. Witteman JC. Serum carotenoids and atherosclerosis: the Rotterdam
43. Tyler VE, Foster S. Tyler’s honest herbal: a sensible guide to the use Study. Atherosclerosis 2000;148:49–56.
of herbs and related remedies. 4th ed. New York: Haworth Herbal 65. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer:
Press, 1999. review of the epidemiologic literature. J Natl Cancer Inst 1999;91:317–31.
44. Tyler VE, Robbers JE. Tyler’s herbs of choice: the therapeutic use of 66. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA,
phytomedicinals. New York: Haworth Herbal Press, 1999. Willett WC. Intake of carotenoids and retinol in relation to risk of
45. Wildman REC. Handbook of nutraceuticals and functional foods. prostate cancer. J Natl Cancer Inst 1995;87:1767–76.
Boca Raton, FL: CRC Press, 2001. 67. Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and
46. Ross S. Functional foods: the Food and Drug Administration perspec- beta-carotene supplements and lung cancer incidence in the alpha-
tive. Am J Clin Nutr 2000;71(suppl):1735S–8S; discussion 1739S–42S. tocopherol, beta-carotene cancer prevention study: effects of base-line
47. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French characteristics and study compliance. J Natl Cancer Inst 1996;88:1560–70.
paradox for coronary heart disease. Lancet 1992;339:1523–6. 68. Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of
48. Frankel EN, Kanner J, German JB, Parks E, Kinsella JE. Inhibition of carotenoid and vitamin A intakes and risk of cataract extraction in US
women. Am J Clin Nutr 1999;70:509–16.
oxidation of human low-density lipoprotein by phenolic substances in
69. Brown L, Rimm EB, Seddon JM, et al. A prospective study of
red wine. Lancet 1993;341:454–7.
carotenoid intake and risk of cataract extraction in US men. Am J Clin
49. Tjonneland A, Gronbaek M, Stripp C, Overvad K. Wine intake and
Nutr 1999;70:517–24.
diet in a random sample of 48 763 Danish men and women. Am J Clin
70. Johnson EJ, Hammond BR, Yeum KJ, et al. Relation among serum and
Nutr 1999;69:49–54.
tissue concentrations of lutein and zeaxanthin and macular pigment
50. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D.
density. Am J Clin Nutr 2000;71:1555–62.
Dietary antioxidant flavonoids and risk of coronary heart disease: the
71. Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption
Zutphen Elderly Study. Lancet 1993;342:1007–11.
and risk of sudden cardiac death. JAMA 1998;279:23–8.
51. Dubick M, Omaye ST. Modification of atherogenesis and heart disease
72. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse
by grape wine and tea polyphenols. In: Wildman REC, ed. Handbook
relation between fish consumption and 20-year mortality from coro-
of nutraceuticals and functional foods. Boca Raton, FL: CRC Press,
nary heart disease. N Engl J Med 1985;312:1205–9.
2001:235–60. 73. Connor WE. n3 Fatty acids from fish and fish oil: panacea or nos-
52. Prior RL, Cao G. Antioxidant capacity and polyphenolic components trum? Am J Clin Nutr 2001;74:415–6.
of teas: implications for altering in vivo antioxidant status. Proc Soc 74. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-
Exp Biol Med 1999;220:255–61. linolenic acid-rich diet in secondary prevention of coronary heart
53. Dietary Guidelines Advisory Committee. Report of the Dietary Guide- disease. Lancet 1994;343:1454–9.
lines Advisory Committee on Dietary Guidelines for Americans. 5th 75. Volker DH, Garg ML. n3 polyunsaturated fatty acids and rheuma-
ed. Washington, DC: US Department of Agriculture, 2000. toid arthritis. In: Wildman REC, ed. Handbook of nutraceuticals and
54. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the functional foods. Boca Raton, FL: CRC Press, 2001:353–76.
effects of soy protein intake on serum lipids. N Engl J Med 76. Fraser GE, Lindsted KD, Beeson WL. Effect of risk factor values on
1995;333:276–82. lifetime risk of and age at first coronary event: the Adventist Health
55. Messina M, Gugger ET, Alekel DL. Soy protein, soybean Study. Am J Epidemiol 1995;142:746–58.
isoflavones, and bone health: a review of the animal and human data. 77. Hu FB, Stampfer MJ. Nut consumption and risk of coronary heart dis-
In: Wildman REC, ed. Handbook of nutraceuticals and functional ease: a review of epidemiologic evidence. Curr Atheroscler Rep
foods. Boca Raton, FL: CRC Press, 2001:77–98. 1999;1:204–9.
56. Sirtori CR. Risks and benefits of soy phytoestrogens in cardiovascular 78. Sabate J, Radak T, Brown J. The role of nuts in cardiovascular disease
diseases, cancer, climacteric symptoms and osteoporosis. Drug Safety prevention. In: Wildman REC, ed. Handbook of nutraceuticals and
2001;24:665–82. functional foods. Boca Raton, FL: CRC Press, 2001:477–95.
57. de Lemos ML. Effects of soy phytoestrogens genistein and daidzein on 79. Dunne C, O’Mahony L, Murphy L, et al. In vitro selection criteria for
breast cancer growth. Ann Pharmacother 2001;35:1118–21. probiotic bacteria of human origin: correlation with in vivo findings.
58. Kurzer MS. Hormonal effects of soy in premenopausal women and Am J Clin Nutr 2001;73(suppl):386S–92S.
men. J Nutr 2002;132:570S–3S. 80. Isolauri E. Probiotics in human disease. Am J Clin Nutr 2001;
59. Horn-Ross PL, John EM, Lee M, et al. Phytoestrogen consumption 73(suppl):1142S–6S.
and breast cancer risk in a multiethnic population: the Bay Area Breast 81. Saavedra JM. Clinical applications of probiotic agents. Am J Clin Nutr
Cancer Study. Am J Epidemiol 2001;154:434–41. 2001;73(suppl):1147S–51S.
60. Mitchell J. Phytoestrogens: involvement in breast and prostate cancer. 82. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics—
In: Wildman REC, ed. Handbook of nutraceuticals and functional approaching a definition. Am J Clin Nutr 2001;73(suppl):361S–4S.
foods. Boca Raton, FL: CRC Press, 2001:99–111. 83. Cummings JH, Macfarlane GT, Englyst HN. Prebiotic digestion and
61. Faulks RM, Southon S. Carotenoids, metabolism and disease. In: fermentation. Am J Clin Nutr 2001;73(suppl):415S–20S.