1. health and fitness
2. disease
3. cholesterol

Dietary supplements and functional foods: 2 sides of a coin?1–3
Charles H Halsted
KEY WORDS
Dietary supplements, herbal products, functional
foods, challenges to medical practitioners
INTRODUCTION
In 1994 the US Congress enacted the Dietary Supplement
Health and Education Act (DSHEA) (1). This act defines a
dietary supplement as “a product (other than tobacco) that is
intended to supplement the diet and that bears or contains one or
more of the following dietary ingredients: a vitamin, a mineral,
an herb or other botanical, an amino acid, a dietary substance for
use by man to supplement the diet by increasing the total daily
intake, or a concentrate, metabolite, constituent, extract or combinations of these ingredients.” Furthermore, a dietary supplement is intended for ingestion in pill, capsule, tablet, or liquid
form; is not represented for use as a conventional food or as the
sole item of a meal or diet; and is labeled as a dietary supplement
(1). In a recent Science forum, Zeisel (2) provided 2 additional,
useful working definitions. A neutraceutical can be defined as “a
diet supplement that delivers a concentrated form of a biologically active component of food in a non-food matrix to enhance
health.” The US Food and Drug Administration (FDA) does not
recognize the term neutraceutical. Functional foods, according
to Zeisel, are not dietary supplements but rather “are consumed
as part of a normal diet and deliver one or more active ingredients (that have physiologic effects and may enhance health)
within the food matrix” (2).
Dietary supplements
Among his “bedside teachings,” Sir William Osler stated,
“The desire to take medicines is one feature which distinguishes
man, the animal, from his fellow creatures” (3), a viewpoint
recently corroborated by the finding of medicinal herbs in the
intestine of the 5300-y-old frozen “iceman” who was recently
discovered in the Swiss Alps (4). Botanicals with medicinal
properties have been used from time immemorial in all cultures
and, with the introduction of ingredient assays and standards in
the early 20th century, form the foundation for modern Western
pharmacology (5). On the other hand, the consumption and market value of herbs and other nutritional supplements has reached
astonishing proportions in the United States. According to recent
FDA testimony, dietary supplements, including vitamins, were consumed by 158 million Americans in the year 2000—that is, more
than half the US population (6). This compares with a 1997 survey
that showed that alternative medical therapies, principally herbals,
were used by 83 million people (7). In 2000, the total dietary supplement market included 32% as herbals and 38% as vitamins. The
sales of dietary supplements in the United States doubled after passage of the DSHEA in 1994, to $17.1 billion in 2000, and are anticipated to continue increasing by 10% per year (5).
Although the FDA was charged with implementing stringent
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
Education Act of 1990, which permitted health claims for
nutritional supplements that were restricted to several categories, including osteoporosis, hypertension, heart disease, and
cancer. Spurred by intensive industry lobbying, Congress passed
the DHSEA in 1994 to broaden the availability of all dietary
supplements by authorizing their claims for functional specific
health benefits, but not specific disease prevention or cure. The
FDA established a Center for Food Safety and Applied Nutrition
1
From the Department of Internal Medicine and Nutrition, University of
California, Davis.
2
Presented at the Third Heelsum International Workshop, held in Heelsum, the Netherlands, December 10–12, 2001.
3
Reprints not available. Address correspondence to CH Halsted, Department of Internal Medicine and Nutrition, University of California, Davis, TB
156, One Shields Avenue, Davis, CA 95616, United States. E-mail: chhalsted@
ucdavis.edu.
Am J Clin Nutr 2003;77(suppl):1001S–7S. Printed in USA. © 2003 American Society for Clinical Nutrition
1001S
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ABSTRACT
Dietary supplements are used by more than
one-half of the adult US population. In contrast to pharmaceuticals, dietary supplements may be sold in the United States with
little regulation other than listing of ingredients and the potential
health benefits. By contrast, herbal products in Germany are
carefully regulated by the same standards as drugs, and efforts
are under way to standardize their regulation in the entire European Union. Most herbal users do not inform their physicians
that they are taking these supplements, and most physicians do
not inquire. Although some herbal products have clinically
proven benefits, it is increasingly apparent that many contain
potentially toxic substances, particularly in relation to interactions with drugs. Hence, it is essential that practicing physicians
develop a working knowledge of herbals—specifically, about
claims for their usage and potential or proven efficacies and
toxicities—and that they incorporate such knowledge into the
evaluation and management of their patients. By contrast, functional foods—integral components of the diet that are understood to contribute added health benefits—are the subject of
intense and widespread research in food and nutritional science.
Examples include many polyphenolic substances, carotenoids,
soy isoflavones, fish oils, and components of nuts that possess
antioxidant and other properties that decrease the risk of vascular diseases and cancer. Practicing physicians are advised to stay
abreast of these emerging findings in order to best advise their
patients on the value of health-promoting diets in disease prevention.
Am J Clin Nutr 2003;77(suppl):1001S–7S.
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alternative therapies were fraudulent, potentially harmful
because they supplanted conventional therapy, and/or a waste of
time and money. Most patients derived their information from
advertising or Internet sources (15).
In summary, dietary supplement usage is widespread because
of successful marketing strategies and popularization by word of
mouth, advertising, and Internet information sources. Although
certain patient groups, such as pregnant women, tend to have
lower herbal usage than the average person, others with
intractable chronic and/or fatal diseases, such as Parkinson’s,
arthritis, and cancer, are more likely to turn to alternative therapies, particularly herbal supplements. Most striking, physicians
are unlikely to ask and unlikely to be told of their patients’ herbal
habits. In view of the uncertain composition of most herbs, their
potential interaction with prescription drugs, and their propensity to cause side effects, widespread herbal usage poses a potentially significant risk to the health of patients.
What should practicing physicians be concerned about
regarding herbals and other dietary supplements? A lot, as summarized in a recent editorial that emphasizes the differences
between conventional and nonconventional medicine (16).
Before the application of science to medicine in the early 20th
century, botanicals were the major source of nonsurgical therapy. Practitioners of herbal medicine had no way of knowing
the concentrations or purity of their remedies, and toxicities
from such medicines as foxglove, opium, and cinchona bark
were common. Proving the safety and efficacy of botanicals
was not feasible until the advent of chemical approaches to
identifying and ensuring the purity of active ingredients and of
the scientific approach of well-controlled randomized clinical
trials. Nevertheless, the burgeoning dietary supplement industry, with its lack of rigorous scientific testing, threatens to
inundate the public with ineffective and potentially harmful
remedies. In the absence of patent opportunities for dietary
supplements, manufacturers have little incentive to prove the
efficacy and safety of their products.
The literature on dietary supplements is vast and rife with
reports of unsuspected toxicities from unregulated dietary supplements. The issue is complicated by the variety of regulations
in different countries, where a botanical product may be classified as an approved medicine, a dietary supplement, or a recreational herb (17). Most nation members of the European Union
regulate vitamins and minerals as foods if provided within the
accepted recommended dietary allowances, but they have no specific regulations on dietary supplements as long as no medicinal
claims are made (18). Several countries have established commissions to assess the safety and efficacy of herbals. For example, Commission E of the German Federal Health Agency has
published more than 300 monographs that evaluate the efficacy
and safety of different herbal products according to acceptable
clinical trials (19). Ongoing reports of herbal toxicities may not
appear in recent book form and must be sought in the current literature. For example, it has only recently been appreciated that
fulminant hepatic failure may occur during the chronic use of
kava (20, 21). Understanding potential efficacies and hazards of
dietary supplements is a daunting task for practitioners. For
example, the Physicians’ Desk Reference for Herbal Medicines
lists 80 under letter A alone in its common name index and lists more
than 350 side effects for all herbals (22). The recently published
Physicians’ Desk Reference for Nuritional Supplements describes
more than 200 nonherbal supplements (vitamins, minerals, amino
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(CFSAN) with responsibility for oversight of new supplemental
products, including the marketing of clearly identified products
declared to be of known composition and strength. New dietary
supplements are reviewed by the FDA under the rubric of the
same good manufacturing practice regulations that apply to conventional foods. The manufacturer is responsible for ensuring
that the “supplement facts” label and ingredient lists are accurate, that the dietary ingredients are safe, and that the content
matches the amount declared on the label. However, the FDA
does not require accurate chemical analyses as a basis for the
identification and quantification of ingredients. The label must
also contain the disclaimer, “This product is not intended to
diagnose, treat, cure, or prevent any disease.” This policy
bypasses the usual FDA procedures of requiring proof of safety
from the manufacturer before approval of a drug for public consumption, and puts the postmarketing burden of proving significant risk on the FDA. Supplements that were produced before
1994 are assumed safe, whereas the safety of those marketed
after 1994 is the responsibility of the manufacturers. The
specifics of the role of the FDA in regulating dietary supplements can be found in a recently posted website: http://www.
cfsan.fda.gov/dms/ds-oview.html (8).
How frequently do people use dietary supplements? A 2001
survey of 376 randomly selected adults living in Minneapolis
found that 61.2% used supplements, most commonly ginseng.
Few were advised by their physicians, and most obtained information on herbs from family, friends, or the Internet. Although
the promotion of well-being was given as the main reason for
herbal usage, fewer than 60% found satisfaction (9). A survey of
118 patients attending 16 different family practices in Calgary,
Canada, found vitamin, mineral, or herbal supplement usage
among 79% of women and 44% of men, and that 25% of those
over age 50 and 70% of those under age 50 chose not to inform
their physicians. Based on Internet information, the younger
patients believed that supplements were safer and more effective than prescription drugs (10). Among 242 pregnant women,
25% had used herbals on a regular basis—typically garlic, echinacea, and ginseng—before pregnancy, and 9% continued
herbal use during pregnancy (11). A study of women with earlystage breast cancer found that the usage of alternative medicine
had increased from 10.6% before diagnosis to 28.1% after diagnosis and initiation of therapy, and that that increase was associated with depression and fear of cancer recurrence. Of interest, one-third of this group hid their alternative approaches from
their physicians (12). An accompanying editorial suggested that
widespread marketing and a lack of physician interest in dealing
with or time to address illness-related anxieties are the main
reasons that cancer patients turn to alternative remedies (13).
Among 201 patients with established Parkinson’s disease, 40%
used various forms of alternative medicine, most commonly
herbals (14). An informal non-peer-reviewed survey of arthritis
patients and their physicians found that 79% used or were interested in using alternative therapies, including herbs, chondroitin, glucosamine, massage, or chiropractic, but only 40% of
users informed their physicians, and only 40% of physicians
asked their patients about their alternative treatments. Reasons
given for patients’ having not informed their physicians
included fear of disapproval and the perception that the physician would be unable to provide advice on alternative
approaches. One-third of the physicians felt they did not know
enough to provide meaningful advice and 20% considered that
DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS
warfarin, leading to their ineffectuality in therapeutic situations (30). Valerian, used for its sedative properties, potentiates the effects of benzodiazepines and may result in withdrawal delirium (42).
The health claims and potential side effects of some of the most
commonly used herbals are shown in Table 1 (19, 22, 43, 44).
Functional Foods
In contrast to most dietary supplements, functional foods are
components of the usual diet that may have special disease prevention attributes and are the topic of current traditional scientific investigation. According to the Food and Nutrition Board of
the Institute of Medicine, a functional food is “any food or food
ingredient that may provide a health benefit beyond the traditional nutrients it contains” (45). Unlike dietary supplements that
can claim only general health benefits, functional foods may
claim specific health benefits because they are considered part of
the diet (46). The literature on functional foods is vast and growing exponentially, and this review can touch on only a few points
that are essential for the practitioner. A recently published handbook provides excellent summaries (45).
Polyphenols and flavonoids
The term polyphenol encompasses simple phenols and flavonoids, which are found in fruits, vegetables, and nuts and their
products, and possess important antioxidant properties. Flavonoids include proanthocyanidins, quercetin, and epicatechin, found
mainly in chocolate, tea, and wine. Red wine also contains resveratrol, a nonpolyphenol antioxidant product of grape skins. The
“French paradox” refers to the epidemiologic finding that the
incidence of coronary heart disease was significantly lower in
wine-drinking regions of France than in areas where wine was not
the main alcoholic beverage (47). Subsequently, it was shown that
wine phenols inhibited the oxidation of low-density lipoprotein
(LDL) (48), an accepted reason for the preventive effect of
polyphenols on the development of atherosclerosis. More recent
studies demonstrate that the attenuation of coronary heart disease risk in wine drinkers is probably due as much to their
lifestyle consumption of high amounts of polyphenol-containing
fruits and vegetables as to wine (49). A 5-y prospective Dutch
study of 800 elderly men found that the ingestion of flavonoids,
mainly in tea, onions, and apples, was associated with significant
reduction in mortality from coronary heart disease (50). In addition to antioxidant effects on LDL, other potentially cardioprotective effects of polyphenols include inhibition of platelet aggregation and vascular relaxation through the production of nitric
oxide (51). Although polyphenols have the capacity to decrease
LDL oxidation, inhibit platelet aggregation, and induce vascular
relaxation, their clinical efficacy is modulated by many factors
that include differences in wine and tea preparation, volatility,
and absorbability. For example, green tea has a higher concentration of polphenols than black tea, which may be affected by the
method of brewing (52). Wine should be consumed in moderation
only, to avoid the chronic effects of alcohol. The year 2000
Dietary Guidelines for Americans identifies moderation as no
more than 1 drink per day for women and 2 drinks per day for
men, where a drink constitutes 5 oz of wine (53). Although these
studies support the principle that fruits and vegetables should provide the main staple of a healthy diet, varied amounts of polyphenols in different foods and effects of food preparation and absorption hinder the establishment of clear-cut dietary and clinical
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acids, and other products) cross-referenced to more than 300
potential side effects (23). Given that herbals and nutritional supplements are taken by mouth, it is not surprising that the most
common side effects relate to the gastrointestinal tract, including
diarrhea, nausea, and vomiting. Because many plants have natural toxins that were developed for survival, hepatocellular damage is not uncommon after ingesting herbs, including comfrey,
senna, and mixtures of ill-defined Chinese herbs (24). Additional
problems arise from the presence of unregulated or unknown
amounts of toxic substances within herbal preparations. For
example, in a 1998 analysis of 251 Asian patent medicines performed by the California Department of Health Services, 10%
were found to contain lead, 14% arsenic, and 14% mercury at
potentially toxic levels (25). Others found toxic amounts of mercury in Chinese imported “herbal balls” and arsenic at levels that
could result in daily accumulation of 73 mg arsenic and more
than 1200 mg mercury (26). Aristolochia fangchi, or “birthwort,”
used for gastrointestinal symptoms, was strongly associated with
nephropathy and development of urothelial carcinoma in women
attending a Belgian weight reduction clinic (27, 28). Underscoring the problem of lack of quality control, 2 case reports
described the symptoms and laboratory evidence of digitalis toxicity after ingestion of plantain, an herbal ingredient of a mixture
claimed to “cleanse the body,” that was contaminated with Digitalis lanata (29).
A recent survey indicated that 30% of patients undergoing
surgery use herbal medications, about twice the usage in the general US population (30), and that 70% of herbal users failed to
mention their use of dietary supplements in the routine preoperative evaluation (31). Preoperative herbal use is particularly hazardous, because different herbs may influence operative survival
and/or alter the metabolism and pharmacologic effects of conventional anesthesia and postoperative drugs. For example, prolonged preoperative use of the immunostimulant echinacea may
result in immunosuppression with prolonged wound healing and
postoperative infections (32). Ephedra, a stimulant and the source
of ephedrine and methamphetamine, increases blood pressure,
heart rate, and risks of arrhythmias and vasospasm, which
together increase the risks of myocardial infarction and stroke
(33). In 1997 the FDA issued a warning on the use of ephedra as
an herbal weight loss drug because of its potential adverse stimulant effects on both the circulatory and nervous systems (34).
Although garlic lowers serum cholesterol to a modest amount
(35), ajoene, a constituent of garlic, may potentiate platelet
inhibitors and thereby increase the risk of bleeding complications of surgery (30). Ginkgo, used to enhance memory and
improve peripheral vascular circulation, also has platelet-inhibiting properties that may result in intracellular hemorrhage and
subdural hematomas (36, 37). Ginseng may lower postprandial
blood glucose in type II diabetic patients but can induce hypoglycemia and inhibit platelet aggregation (38, 39). Kava, used
for its sedative and antianxiety properties, can interact with barbiturates and benzodiazepines, prolonging sleep and even inducing coma (40), and has recently been associated with fulminant
hepatic failure requiring liver transplantation (20, 21). A 2002
FDA consumer advisory cited 25 reports of liver-related injury in
kava users and advises caution on its use, particularly in individuals with known liver disease (41). St John’s wort, used to prevent depression, inhibits serotonin reuptake, which results in serotonin excess and increases the metabolic rate of many cytochrome
P450 drugs, including cyclosporin, midazolam, lidocaine, and
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TABLE 1
Herbal supplements
Common name
Claim, current use
Possible mechanisms
Efficacy, clinical evidence
Black cohosh (black Cimicifuga
snakeroot, rattleracemosa
weed, rattleroot,
bugbane, bugwort,
squaw root) (19, 44)
Comfrey (19, 44)
Symphytum
officinale
Formal name
Improves menopausal
symptoms, premenstrual syndrome, and
dysmenorrhea
Suppresses lutenizing
hormone secretion in
menopausal women;
weak binding to
estrogen receptors
Allantoin promotes cell
growth; Tannins are
vaso-constrictive
Many clinical studies
Gastric discomfort
showed favorable results
Echinacea (cone
flower) (19, 44)
Echinacea
angustifolia
Stimulates leukocyte
Positive clinical trials
mobility, phagocytosis, showing shortened
and T-cell functions
duration of common cold
but not prevention
Ephedra (ma huang)
(19, 34, 44)
Ephedra sinica
Stimulates immune
response; promotes
wound healing; treats
common cold and yeast
infections
Relieves nasal
congestion and asthma,
promotes weight loss,
and enhances athletic
performance
Active constituent is
ephedrine, a
sympathomimetic
Traditional use for
2000 years in Chinese
medicine to treat
bronchospasm
Garlic (19, 44)
Allium sativum
Reduces cardiovascular
risk and serves as
anti-inflammatory
Lowers LDL cholesterol Can potentiate other platelet
and triacylglycerols in
inhibitors or cause
clinical trials; antibacterial bleeding
in vitro (19)
Ginkgo (43, 44)
Ginkgo biloba
Improves memory,
cognition, intermittent
claudication, vertigo,
tinnitus, and sexual
performance
Inhibits platelet
aggregation, reduces
cholesterol (35),
and has antioxidant
properties
Promotes vasodilation,
modulates neurotransmitter activity,
and inhibits platelet
aggregation
Ginseng (43, 44)
Panax ginseng
Kava-kava
(19, 41, 44)
Piper
methysticum
Improves physical
Unknown; possible
performance, energy
pharmacologic effects
level; cancer prevention; attributed to steroidal
blood sugar reduction
saponins
Elevates mood and
May interact with brain
relieves anxiety and
-aminobutyric acid
menopausal symptoms
receptors (19)
Saw palmetto
(22, 44)
Serenoa repens
(sabal fructus)
Reduces prostatic hypertrophy, builds sexual
vigor, and increases
sperm production
St John’s wort
(19, 43, 44)
Hypericum
performatum
Yohimbe
(19, 44)
Pausinystalia
yohimbe
Serves as mild to
Inhibits serotonin,
Positive clinical trials for Causes photosensitivity;
moderate antidepressive, norepinephrine, and
mild to moderate
may interact with
and as antiviral
dopamine reuptake;
depression
benzodiazepines and
(22)
inhibits monoamine
warfarin (30)
(MAO)
Works as aphrodisiac
Dilates blood vessels of Several studies show
Active MAO inhibitor; may
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)
Heals skin wounds
Liver failure, death. Pyrrolizidine
alkaloids are hepatoxoic
when taken by mouth;
may be absorbed through skin
Immune suppression during
surgery (30)
Increases blood pressure and
heart rate and can cause
headache, insomnia, dizziness, seizures, arrhythmias,
addiction, and death (34)
Clinical trials show that it Diarrhea, nausea, vomiting;
may improve cognitive
intracranial bleeding
performance and memory reported (30, 37)
in the morning; mixed
results in Alzheimer’s
disease
Mixed data on regulation Insomnia, diarrhea and
of blood glucose and
hyperactivity
cancer prevention
Positive clinical studies
Weakness, allergies, interaction with benzodiazepines
(40, 41)
Similar to finasteride in
Feminization
reducing symptoms of
prostatitis, but with fewer
side effects
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Has antiandrogenic
action
Uncertain
Adverse effects
DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS
recommendations of polyphenol-rich fruits and vegetables in the
nutritional prevention of heart disease.
Soy isoflavones
Carotenoids
There are several plant-derived carotenoids in the human diet,
of which -carotene, -carotene, lutein, zeaxanthin, and lycopene appear to have the most significance for health. Being lipid
soluble, carotenoids are absorbed with fats and circulate bound
to different lipoproteins. -carotene is a limited precursor of
vitamin A, and excessive amounts of -carotene lead to
reversible carotenemia but not to vitamin A toxicity. The principal biological effects of carotenoids relate to their antioxidant
properties, which form the basis of potential protection against
lipid peroxidation, atherogenesis, DNA oxidation, and cancer
(61). Clinical studies suggest but have not yet proven that either
-carotene or lycopene is cardioprotective (62, 63). Aortic atherosclerosis incidence was significantly inversely correlated with
the intake of dietary lycopene in the Rotterdam study of
108 patients and control subjects (64). A review of more than
30 studies concluded that there is an inverse relationship
between lycopene in tomato products and the risk of cancers of
the prostate, lung, and stomach (65), and one study demonstrated
a 21% reduction in prostate cancer with consumption of diets
high in tomato-derived lycopene (66). A study of more than
25 000 middle-aged male Finnish smokers found that the incidence of lung cancer was increased in those receiving -carotene
supplements (67). In large cohorts followed over time, cataract
formation was reduced significantly by dietary intake of fruits
and vegetables rich in lutein and zeaxanthin (68, 69). Recent
data suggest a potential preventive relationship between intake
of these carotenoids and risk of macular degeneration (70).
Fish oils
Dietary fish oils appear as n3 polyunsaturated fatty acids
mainly in cold water fish, compared with n6 polyunsaturates
mainly from plants and saturated fatty acids from animal sources.
Diets in which cold water fish such as mackerel, salmon, halibut,
and trout are the main staple are associated with reduced incidence of coronary heart disease but increased risk of hemorrhage. Studies of susceptible men from Holland, Japan, and the
United States showed that sudden death from coronary artery
disease is reduced by half when 1–2 fish meals are consumed
weekly (71–73). The biological effects of fish oils include inhibition of hepatic synthesis and secretion of triacylglycerol and
very low density lipoprotein with reduced postprandial lipemia,
increased circulating high-density lipoprotein, inhibition of
platelet aggregation, and prevention of cardiac arrhythmias (73).
Eicosapentaenoic acid (EPA) and its elongated product docosahexaenoic acid are the predominant fatty acids in fish, whereas
-linolenic acid, the precursor of EPA, is found in canola,
flaxseed, and walnut oils. A Mediterranean diet rich in these oils
was found to reduce cardiac deaths by 70% in France (74). By
virtue of anti-inflammatory properties and effects on cell membranes, fish oils are also thought to have a beneficial effect in the
treatment of rheumatoid arthritis, although conclusive clinical
studies are lacking (75).
Nuts
Although nuts are relatively high in fat, most of this fat is in the
mono- or polyunsaturated form. Beneficial nuts include almonds,
Brazil nuts, peanuts, walnuts, pistachios, and pecans. Three large
prospective studies demonstrated that the consumption of 1–4
servings of nuts per week was associated with about a 40% reduction in risk of coronary heart disease, even after adjusting for conventional risk factors such as hypertension, smoking, diabetes, and
hyperlipidemia (76–78). The purported beneficial effects of nuts
include improvement of serum lipid profiles with a predicted 16%
reduction in LDL cholesterol and presence of relatively high
amounts of the nitric oxide precursor arginine, dietary fiber, and
antioxidant vitamin E (78). Walnuts are particularly noteworthy
for having a high content of n3 linolenic acid (78).
Probiotics and prebiotics
Probiotics can be defined as “live microbial food supplements
which benefit the host by improving the intestinal microbial
form” (79). As such, probiotics can be consumed as either a
functional food, such as a fermented milk product, or a supplement if provided separately in capsule or pill form. The rationale
for probiotics is to improve intestinal immune tolerance to beneficial proteins and to maintain a normal immune intestinal
barrier and permeability to exogenous foreign antigens (80).
Intestinal organisms constitute the greatest cell population of the
body, existing in 500 different species. Provision of normal
human organisms that resist acid and bile destruction and adhere
to the gut mucosa triggers a healthy immune response. The most
beneficial organisms include those of the Lactobacillus and Bifidobacterium genera. Whereas controlled clinical trials are ongoing,
beneficial effects have been reported in the treatment of food
allergies, acute infant diarrheas, traveler’s diarrhea, antibioticassociated colitis, and, potentially, inflammatory bowel disease
(81). Prebiotics are “non-digestible food ingredients that selectively stimulate the growth of a limited number of bacteria in the
colon” (82). More specifically, prebiotics are short-length carbohydrates, such as fructooligosaccharides, that resist digestion or
are fermented in the colon to produce short-chain fatty acids,
such as acetate, butyrate, and propionate, which have positive
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Soy isoflavones are phytoestrogens that are derived from the
protein fraction of the soybean and its food products (eg, soy milk,
soy flour, tofu, miso), include genistein and daidzein, and possess
estrogenic properties because of the similarities of their chemical
structures to estrogenic compounds. Clinical trials identified the
potential efficacy of soy isoflavones in the prevention of coronary
heart disease, osteoporosis, and breast and prostate cancer. A
meta-analysis of 37 clinical studies suggested that soy protein up
to 45 g per day can lower serum cholesterol levels by 10% (54),
but the long-term effects of soy on cardiac risk are unknown.
Because phytoestrogens compete with estrogen for binding to
estrogen receptors, their use could have beneficial effects in preventing osteoporosis and sex hormone–mediated malignancy, such
as breast and prostate cancer. The clinical data are mixed and
inconclusive on the effect of soy isoflavones on bone turnover and
bone density (55). Data are mixed on whether soy isoflavones promote or protect against breast cancer (56–58), and one retrospective study of 1300 non-Asian women with breast cancer history
found no association of phytoestrogen use and breast cancer risk
(59). Although prostate cancer rates are lower in Eastern cultures
where soy products play a major role in the diet, and although
genistein inhibits the growth of prostate cancer cells, clinical studies to date have failed to demonstrate positive effects of dietary
soy products on reducing the risk of prostate cancer (60).
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effects on colonic cell growth and stability, generate many of the
same bacteria as provided in probiotics, and may promote
improved bowel habit but also increased flatus (83).
11.
12.
The author has no financial or personal potential or actual conflicts of
interest with any manufacturer of herbal products or supplemental foods.
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14.
15.
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17.
18.
19.
20.
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25.
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27.
28.
29.
REFERENCES
1. Dietary Supplement Health and Education Act (DSHEA). 42 USC
287C–11. 1994.
2. Zeisel SH. Regulation of “nutraceuticals.” Science 1999;285:1853–5.
3. Bean WB. Sir William Osler: aphorisms from his bedside teaching and
writing. Springfield, IL: Charles C Thomas, 1968;1–164.
4. Capasso L. 5300 years ago, the Ice Man used natural laxatives and
antibiotics. Lancet 1998;352:1864 (letter).
5. Goldman P. Herbal medicines today and the roots of modern pharmacology. Ann Intern Med 2001;135:594–600.
6. US Food and Drug Administration. Statement by Joseph A. Levitt
before the U.S. House of Representatives Committee on Government Reform. Internet: http://www.cfsan.fda.gov/lrd/st010320.html
(accessed 20 March 2001).
7. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up
national survey. JAMA 1998;280:1569–75.
8. US Food and Drug Administration. Overview of dietary supplements.
Internet: http://www.cfsan.fda.gov/dms/ds-oview.html (accessed 3 January 2001).
9. Harnack LJ, Rydell SA, Stang J. Prevalence of use of herbal products
by adults in the Minneapolis/St Paul, Minn, metropolitan area. Mayo
Clin Proc 2001;76:688–94.
10. Durante KM, Whitmore B, Jones CA, Campbell NR. Use of vitamins,
30.
31.
32.
33.
34.
35.
36.
37.
38.
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SUMMARY AND CONCLUSIONS
There are striking differences between dietary supplements
and functional foods. Whereas dietary supplements, herbs in particular, are considered time-tested but are in most cases scientifically unproven, functional foods are components of the normal
human diet that are increasingly shown by rigorous science to be
inherently valuable for maintaining human health. Whereas
herbal sales skyrocket and feed false public perception of the
irrelevance of science to health, the era of functional foods
promises to propel nutritional science to the forefront of preventive medicine for the most common diseases of humans.
Together, this new era of nutrition presents imposing challenges
to practitioners of medicine. It is incumbent on them to become
fluent in the knowledge of commonly used herbals, including
recognition of their potential benefits, side effects, and lifethreatening effects when combined with certain drugs. Although
advice-seeking patients typically have rudimentary knowledge
of the ingredients and rationales for the herbs they ingest, physicians must be in a position of knowledge to maintain their
patients’ confidence as a prerequisite to providing credible counsel. Furthermore, because most patients are curious and somewhat knowledgeable about their diets, physicians must establish
a basic knowledge of conventional functional foods, which is
viewed increasingly as an adjunct to sound medical advice.
These are heady days for nutritional scientists as newer understandings of food and health promise to bring clinical nutrition
to the forefront of clinical medicine. Practitioners must become
nutritionally educated and oriented if they are to maintain their
patients’ confidence and stay abreast of this aspect of continuously evolving modern medicine.
minerals and herbs: a survey of patients attending family practice clinics. Clin Invest Med 2001;24:242–9.
Gibson PS, Powrie R, Star J. Herbal and alternative medicine use during
pregnancy: a cross-sectional survey. Obstet Gynecol 2001;97:S44–5.
Burstein HJ, Gelber S, Guadagnoli E, Weeks JC. Use of alternative
medicine by women with early-stage breast cancer. N Engl J Med
1999;340:1733–9.
Holland JC. Use of alternative medicine—a marker for distress?
N Engl J Med 1999;340:1758–9.
Rajendran PR, Thompson RE, Reich SG. The use of alternative therapies by patients with Parkinson’s disease. Neurology 2001;57:790–4.
Horstman J. The dangerous divide: why doctors aren’t asking and you
aren’t telling. Arthritis Today 2002 June 28:34–44.
Angell M, Kassirer JP. Alternative medicine—the risks of untested and
unregulated remedies. N Engl J Med 1998;339:839–41.
De Smet PA. Health risks of herbal remedies. Drug Safety 1995;13: 81–93.
Mason P. Dietary supplements. 2nd ed. London: Pharmaceutical Press,
2001.
Blumenthal M, Goldberg A, Brinckmann J. Herbal medicine: expanded
Commission E monographs. Newton, MA: Integrative Medicine Communications, 2000.
Stevinson C, Huntley A, Ernst E. A systematic review of the safety of
kava extract in the treatment of anxiety. Drug Safety 2002;25:251–61.
Kraft M, Spahn TW, Menzel J, et al. Fulminant liver failure after
administration of the herbal antidepressant Kava-Kava. Dtsch Med
Wochenschr 2001;126:970–2.
Physicians’ Desk Reference. PDR for herbal medicines. 1st ed. Montvale, NJ: Medical Economics, 1998.
Physicians’ Desk Reference. PDR for nutritional supplements. 1st ed.
Montvale, NJ: Medical Economics, 2001.
Kaplowitz N. Hepatotoxicities of herbal remedies: insights into the
intricacies of plant-animal warfare and cell death. Gastroenterology
1997;113:1408–12.
Ko RJ. Adulterants in Asian patent medicines. N Engl J Med 1998;
339:847 (letter).
Espinoza EO, Mann MJ, Bleasdell B. Arsenic and mercury in traditional Chinese herbal balls. N Engl J Med 1995;333:803–4.
Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma
associated with the use of a Chinese herb (Aristolochia fangchi).
N Engl J Med 2000;342:1686–92.
Kessler DA. Cancer and herbs. N Engl J Med 2000;342:1742–3.
Slifman NR, Obermeyer WR, Aloi BK, et al. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med 1998;
339:806–11.
Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative
care. JAMA 2001;286:208–16.
Kaye AD, Clarke RC, Sabar R, et al. Herbal medicines: current trends
in anesthesiology practice—a hospital survey. J Clin Anesth 2000;12:
468–71.
Boullata JI, Nace AM. Safety issues with herbal medicine. Pharmacotherapy 2000;20:257–69.
Haller CA, Benowitz NL. Adverse cardiovascular and central nervous
system events associated with dietary supplements containing ephedra
alkaloids. N Engl J Med 2000;343:1833–8.
US Food and Drug Administration. Dietary supplements containing
ephedrine alkaloids: proposed rule. Fed Regist 1997;62:30678–717.
Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia: a meta-analysis of randomized clinical trials. Ann Intern
Med 2000;133:420–9.
Matthews MK Jr. Association of Ginkgo biloba with intracerebral
hemorrhage. Neurology 1998;50:1933–4.
Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996;46:1775–6.
Vuksan V, Sievenpiper JL, Koo VY, et al. American ginseng (Panax
quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Intern Med
2000;160:1009–13.
DIETARY SUPPLEMENTS AND FUNCTIONAL FOODS
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
Wildman REC, ed. Handbook of nutraceuticals and functional foods.
Boca Raton, FL: CRC Press, 2001:143–56.
Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin
status and carotid atherosclerosis in the elderly. Am J Clin Nutr
2001;74:402–8.
Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr
2000;71(suppl):1691S–5S; discussion 1696S–7S.
Klipstein-Grobusch K, Launer LJ, Geleijnse JM, Boeing H, Hofman A,
Witteman JC. Serum carotenoids and atherosclerosis: the Rotterdam
Study. Atherosclerosis 2000;148:49–56.
Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer:
review of the epidemiologic literature. J Natl Cancer Inst 1999;91:317–31.
Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA,
Willett WC. Intake of carotenoids and retinol in relation to risk of
prostate cancer. J Natl Cancer Inst 1995;87:1767–76.
Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and
beta-carotene supplements and lung cancer incidence in the alphatocopherol, beta-carotene cancer prevention study: effects of base-line
characteristics and study compliance. J Natl Cancer Inst 1996;88:1560–70.
Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of
carotenoid and vitamin A intakes and risk of cataract extraction in US
women. Am J Clin Nutr 1999;70:509–16.
Brown L, Rimm EB, Seddon JM, et al. A prospective study of
carotenoid intake and risk of cataract extraction in US men. Am J Clin
Nutr 1999;70:517–24.
Johnson EJ, Hammond BR, Yeum KJ, et al. Relation among serum and
tissue concentrations of lutein and zeaxanthin and macular pigment
density. Am J Clin Nutr 2000;71:1555–62.
Albert CM, Hennekens CH, O’Donnell CJ, et al. Fish consumption
and risk of sudden cardiac death. JAMA 1998;279:23–8.
Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse
relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205–9.
Connor WE. n3 Fatty acids from fish and fish oil: panacea or nostrum? Am J Clin Nutr 2001;74:415–6.
de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart
disease. Lancet 1994;343:1454–9.
Volker DH, Garg ML. n3 polyunsaturated fatty acids and rheumatoid arthritis. In: Wildman REC, ed. Handbook of nutraceuticals and
functional foods. Boca Raton, FL: CRC Press, 2001:353–76.
Fraser GE, Lindsted KD, Beeson WL. Effect of risk factor values on
lifetime risk of and age at first coronary event: the Adventist Health
Study. Am J Epidemiol 1995;142:746–58.
Hu FB, Stampfer MJ. Nut consumption and risk of coronary heart disease: a review of epidemiologic evidence. Curr Atheroscler Rep
1999;1:204–9.
Sabate J, Radak T, Brown J. The role of nuts in cardiovascular disease
prevention. In: Wildman REC, ed. Handbook of nutraceuticals and
functional foods. Boca Raton, FL: CRC Press, 2001:477–95.
Dunne C, O’Mahony L, Murphy L, et al. In vitro selection criteria for
probiotic bacteria of human origin: correlation with in vivo findings.
Am J Clin Nutr 2001;73(suppl):386S–92S.
Isolauri E. Probiotics in human disease. Am J Clin Nutr 2001;
73(suppl):1142S–6S.
Saavedra JM. Clinical applications of probiotic agents. Am J Clin Nutr
2001;73(suppl):1147S–51S.
Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics—
approaching a definition. Am J Clin Nutr 2001;73(suppl):361S–4S.
Cummings JH, Macfarlane GT, Englyst HN. Prebiotic digestion and
fermentation. Am J Clin Nutr 2001;73(suppl):415S–20S.
Downloaded from ajcn.nutrition.org by guest on June 15, 2014
39. Kimura Y, Okuda H, Arichi S. Effects of various ginseng saponins on
5-hydroxytryptamine release and aggregation in human platelets.
J Pharm Pharmacol 1988;40:838–43.
40. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med 1996;125:940–1.
41. US Food and Drug Administration. Kava and severe liver injury. FDA
Consum 2002;36:4 (letter).
42. Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delirium associated with valerian root withdrawal. JAMA 1998;280:1566–7.
43. Tyler VE, Foster S. Tyler’s honest herbal: a sensible guide to the use
of herbs and related remedies. 4th ed. New York: Haworth Herbal
Press, 1999.
44. Tyler VE, Robbers JE. Tyler’s herbs of choice: the therapeutic use of
phytomedicinals. New York: Haworth Herbal Press, 1999.
45. Wildman REC. Handbook of nutraceuticals and functional foods.
Boca Raton, FL: CRC Press, 2001.
46. Ross S. Functional foods: the Food and Drug Administration perspective. Am J Clin Nutr 2000;71(suppl):1735S–8S; discussion 1739S–42S.
47. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French
paradox for coronary heart disease. Lancet 1992;339:1523–6.
48. Frankel EN, Kanner J, German JB, Parks E, Kinsella JE. Inhibition of
oxidation of human low-density lipoprotein by phenolic substances in
red wine. Lancet 1993;341:454–7.
49. Tjonneland A, Gronbaek M, Stripp C, Overvad K. Wine intake and
diet in a random sample of 48 763 Danish men and women. Am J Clin
Nutr 1999;69:49–54.
50. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D.
Dietary antioxidant flavonoids and risk of coronary heart disease: the
Zutphen Elderly Study. Lancet 1993;342:1007–11.
51. Dubick M, Omaye ST. Modification of atherogenesis and heart disease
by grape wine and tea polyphenols. In: Wildman REC, ed. Handbook
of nutraceuticals and functional foods. Boca Raton, FL: CRC Press,
2001:235–60.
52. Prior RL, Cao G. Antioxidant capacity and polyphenolic components
of teas: implications for altering in vivo antioxidant status. Proc Soc
Exp Biol Med 1999;220:255–61.
53. Dietary Guidelines Advisory Committee. Report of the Dietary Guidelines Advisory Committee on Dietary Guidelines for Americans. 5th
ed. Washington, DC: US Department of Agriculture, 2000.
54. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the
effects of soy protein intake on serum lipids. N Engl J Med
1995;333:276–82.
55. Messina M, Gugger ET, Alekel DL. Soy protein, soybean
isoflavones, and bone health: a review of the animal and human data.
In: Wildman REC, ed. Handbook of nutraceuticals and functional
foods. Boca Raton, FL: CRC Press, 2001:77–98.
56. Sirtori CR. Risks and benefits of soy phytoestrogens in cardiovascular
diseases, cancer, climacteric symptoms and osteoporosis. Drug Safety
2001;24:665–82.
57. de Lemos ML. Effects of soy phytoestrogens genistein and daidzein on
breast cancer growth. Ann Pharmacother 2001;35:1118–21.
58. Kurzer MS. Hormonal effects of soy in premenopausal women and
men. J Nutr 2002;132:570S–3S.
59. Horn-Ross PL, John EM, Lee M, et al. Phytoestrogen consumption
and breast cancer risk in a multiethnic population: the Bay Area Breast
Cancer Study. Am J Epidemiol 2001;154:434–41.
60. Mitchell J. Phytoestrogens: involvement in breast and prostate cancer.
In: Wildman REC, ed. Handbook of nutraceuticals and functional
foods. Boca Raton, FL: CRC Press, 2001:99–111.
61. Faulks RM, Southon S. Carotenoids, metabolism and disease. In:
1007S