Dietar y Supplements

Commonly Us e d for
Prevention
Wadie Najm, MD, MEda,*, Desiree Lie, MD, MEdb
KEYWORDS
 Complementary & alternative medicine  Herbals
 Evidence  Prevention  Benefit  Harm

Surveys in the United States and other countries show that 30% to 90% of the population are using or have used some form of complementary and alternative medicine
(CAM) for managing health problems and in particular chronic medical conditions.
Recent studies show that approximately 20% of people in the United States report
using herbal supplements to treat a medical condition and/or for health promotion.1
In fact, herbal supplements have become so popular that it is estimated that expenditures exceeds $4.2 billion per year in the United States.2
A dietary supplement, as defined by the Dietary Supplement Health and Education
Act,3 is a product taken orally and meant to supplement a diet. These dietary ingredients may include: vitamins, minerals, amino acids, herbs or other botanicals, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary
supplements may be offered as tablets, capsules, extracts, concentrates, soft gels,
gelcaps, liquids, or powders. Dietary supplements do not need approval from the
US Food and Drug Administration (FDA) before they are marketed, except in the
case of a new dietary ingredient (not sold in the United States as a dietary supplement
before October 15, 1994), where premarket review for safety data and other information is required by law.
REGULATION AND USAGE IN THE UNITED STATES

Unlike medications, the manufacturer, and not the FDA, is responsible for ensuring
that its dietary supplement products are safe before they are marketed. Once marketed, the FDA only can take action or remove it from the market after showing that
a dietary supplement is unsafe. The popular use of herbal supplements, together

Predoctoral Education, Department of Family Medicine, University of California, Irvine School

of Medicine, 101 The City Drive South, Building 200, Suite 512, Irvine, CA 92868, USA
b
Faculty Development, University of California, Irvine School of Medicine, 101 The City Drive
South, Building 200, Suite 512, Irvine, CA 92868, USA
* Corresponding author.
E-mail address: winajm@uci.edu (W. Najm).
Prim Care Clin Office Pract 35 (2008) 749767
doi:10.1016/j.pop.2008.07.010
primarycare.theclinics.com
0095-4543/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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with the limited regulation by the FDA, creates a dilemma for users and health care
providers alike. In addition, people taking these products are often unaware of the
safety, efficacy, and possible adverse reactions they can cause.
In addition to managing chronic medical conditions, recent reports have identified
disease prevention and improving general wellness as additional reasons for which
people use herbal supplements.4 A useful framework for health care providers to consider when reviewing or discussing supplements or other CAM therapies with their patients was put forth by Eisenberg.5 He proposed to carefully review the safety and
efficacy data for each of those herbal supplements. An herbal supplement can be recommended if evidence exists for its safety and efficacy. Herbal supplements lacking
evidence of efficacy and safety or showing evidence of harm should be avoided. Clinicians, however, should be very careful and use good judgment for those supplements that fall in between ie, where there is paucity of evidence for safety, harm, or
efficacy.
The most used herbal supplements vary by year depending on their popularity and
marketing. The top 20 commonly sold herbal supplements in 2005 included garlic,
echinacea, saw palmetto, ginkgo, cranberry, soy, ginseng, black cohosh, St. Johns
wort, milk thistle, green tea, evening primrose, valerian, horny goat weed, grape
seed extract, bilberry, red clover, yohimbe, horse chestnut seed, and ginger.6 This article reviews some of the commonly used herbal supplements and others focusing
mainly on disease prevention. A summary table of medical conditions is provided,
and when possible, a summary of efficacy and safety is provided to facilitate decision
making.
REVIEW OF BESTSELLING SUPPLEMENTS

Dietary supplements may be indicated or used for various conditions related to wellness and prevention. The following section provides an outline of the most commonly
purchased supplements in the US.7 For each supplement, a discussion of evidence to
support efficacy, potential harms, and safety considerations are provided with references. Table 1 offers an outline of some available reparations and commonly used
dosages and evidence for efficacy and safety allowing relative benefits and risks to
be assessed for individual supplements.
Black Cohosh (Cimicifuga Racemosa)

Black cohosh (Cimicifuga racemosa) is obtained from the root of the plant and should
not be confused with blue cohosh (Caulophyllum thalictroides), which may cause hypertension and cardiac problems. It also is known as actaea macrotys, actaea racemosa L, amerikanisches Wanzekraut, black snakeroot, bugwort, cimifuga, rattle
root, and squaw root among other names. The herb has been used in Native American
cultures in traditional medicine practices, and in the United States has been used for
over 100 years, mainly for gynecologic complaints.8,9 Most studies use the brand
name product Remifemin, which is standardized to contain 1 mg of 27-deoxyacteine
at a dose of 20 mg per tablet.10
Evidence for the efficacy of black cohosh comes from clinical trials on Remifemin1113 compared with placebo or conjugated estrogens; an aqueous/ethanolic extract compared with placebo; and from studies comparing black cohosh alone or in
combination with isoflavones, with placebo, and with conjugated estrogens.1417
Duration of trials tends to be short, limited to 12 to 14 weeks, with follow-up of up
to 1 year. Outcomes examined include measures of vasomotor symptoms, vaginal
dryness, depression, quality of life, and adverse effects. Several randomized trials

Dietary Supplements Commonly Used for Prevention

suggest a benefit of black cohosh over placebo. Some, however, suggest a lack of
benefit, while in others, benefit is not demonstrated clearly in comparison with conjugated estrogens. Limitations of the studies include the tendency of vasomotor
symptoms to decline over time, a strong placebo effect, and uncertainty about the
effect of individual components when combination herbs were studied. The most
convincing evidence for efficacy in hot flashes comes from a 2005 well-designed multicenter randomized trial using Remifemin 20 mg twice daily versus placebo. Results
showed Remifemins superiority over placebo and its equivalence to low-dose transdermal estradiol or conjugated estrogens.11 Black cohosh has been reported to be
tolerated well for up to 6 months, with infrequent occurrence of adverse effects
such as rash and gastrointestinal (GI) symptoms, headache, nausea, dizziness, seizures, sweating, or constipation. Hypotension has also been reported, and its safety
during pregnancy and breastfeeding has not been established.10
Cranberry (Vacinicum Macrocarpon)

Cranberry is used widely to prevent urinary tract infection (UTI), with the primary mechanism of action believed to be antiadhesive properties of proanthocyanadin, preventing bacteria from adhering to uroepithelial cells.18 A recent Cochrane review affirmed
its efficacy for prophylaxis of UTI.19 Most studies have focused on preventing Escherichia coli UTI in well patients20 and those with chronic illnesses2124 with variable dosing. Although it has been used for treating UTIs,25 evidence for this indication is
lacking.26 It is available in juice (pure and mixed), capsule, concentrate, and tincture
forms, but optimal dosing and dosing frequency are not established. There is no
evidence to support efficacy as an antifungal or antiviral agent and limited data on
antioxidant properties of cranberry. Other uses, including prevention of Helicobacter
pylori infection and dental plaque, are under investigation.10 There is no standardization of cranberry products. Doses of up to 300 mL/d of cranberry juice for 3 months in
children and 4 L per day in adults have not been shown to be toxic.10 Adverse effects
reported include oxalate urinary stones27 and theoretic potential for interaction with
warfarin and proton pump inhibitors.
Echinacea

Echinacea species are perennial plants originating in Eastern North America, and both
the roots and herbs are used for their immune stimulant properties, for a range of infections and malignancies.10 In the United States, echinacea sales represent up to
10% of the supplement market. Echinacea extract has been standardized to 4% to
5% echinoside or cichoric acid, but the active ingredient has not been definitively
identified. The quality and availability of echinacea in commercial preparations are variable.28 Echinacea preparations are available as capsules, expressed juice, tincture,
tea and a semisolid reparation for oral intake and a topical preparation for external
use for skin infection. The most recent studies consisting of randomized, placebocontrolled trials2931 refute earlier reports of efficacy in reducing the duration and
severity of upper respiratory infection or the common cold in adults32,33 and update
conclusions from a Cochrane review.34 More studies are expected to be reported in
the future to address the conflicting evidence. Efficacy for other uses including hastening recovery from skin infections and atopic dermatitis, acne, bee stings, boils, burn
wounds, lower respiratory infections, and malignancies are unproven by randomized
clinical trials. Safety has been established for up to 8 weeks of use, with reported
allergic reactions in atopic patients a concern. In children, the risk of rash suggests
that risks outweigh benefits.30 Safety during pregnancy has not been established.

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Table 1
Dietary supplements (United States) and evidence for disease prevention
Level of Evidence

Conditions and Product

Products Used
(Examples)

Form Used

Common Dosages (Adults)

Efficacy

Safety

Common cold

Echinacea

Capsule

5001000 mg three times daily 57 days

Tincture

0.751.5 mL gargled and swallowed 25

times daily

Tea

4 g echinacea in water for 5 days

Juice

90480 mL cocktail or 1530 mL

unsweetened 100% juice daily

Capsule

16 300400 mg capsules hard gelatin

extract twice daily

Concentrate

45 mL frozen concentrate twice daily

230 g/d

No established dose

Urinary tract infection

prophylaxis

Cranberry

Cancer prevention breast and prostate

Grapes

Cancer (general)

Fish oil
Remifemin

2040 mg twice daily

Tablets
Menopausewellness

Black cohosh

Rhizome

40200 g/d

Tea

12 g/d

Tincture

46 mL/d

Flaxseed

Same dose as lipoprotein profile

GastrointestinalConstipation

Flaxseed

Same dose as lipoprotein profile

Inflammatory bowel disease

Fish oil

No established dose

Cardiovascular diseasegeneral

red grape
polyphenol extract

600 mg

Cardiovascularsecondary prevention

Fish oil

EPA and DHA 850 to 1800 mg/d

Liver health

Capsule

Lipoprotein profile

Grape
Flaxseed

Powder

36 g

Juice

100 mL/d

Tablet

1 three times daily with water

Powder

1060 g powder/d
0

1
1

Flaxseed oil

15 mL/d
Capsule

Musculoskeletal osteoarthritis (knee)

Cognitive function dementia, Alzheimers
disease

1000 mg/d

Glucosamine

Capsule

500 mg three times daily liquid

Chondroitin

Capsule

400 mg three times daily liquid

No established dose

Fish oil
Ginger

Tablet

1g

Gingko

Tablet

120 mg twice daily

Memory enhancement (mild impairment)

Gingko

Tablet

120 mg twice daily

Mountain sickness

Gingko

Tablet

80 mg three times daily

Cancer (general)

Green tea

Tea

110 cups/d

Cardiovascular disease

Green tea

Tea

110 cups/d

Cancer (prostate)

Lycopene

Tomato/vegetables

5 servings

Benign prostatic hypertrophy (BPH)

Lycopene

Tablets

15 mg/d

Age-related macular degeneration

(ARMD)

Lutein

Tablets

10 mg

Cataracts

Lutein

Tablets

10 mg

Liver inflammation

Milk thistle

Tablets

200400 mg

Travelers diarrhea

Probiotics

Tablets

10100 billion live organismsa

Pouchitis

Probiotics

Packets/capsules (VSL#3)

3 g twice daily

Crohns disease

Probiotics

Tablets

10100 billion live organisms

Level of evidence. Efficacy (1 good evidence for efficacy, - evidence suggests no efficacy, 0 evidence is equivocal). Safety (1 no harm, - harm, 0 insufficient
information).
a
For preventing diarrhea in children, 5 to 10 billion live Lactobacillus GGs have been used twice daily.

Dietary Supplements Commonly Used for Prevention

Nausea/vomiting
Memory enhancement (healthy adults)

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Other less-commonly reported adverse effects include transient nausea or vomiting,

urticaria, and possible leucopenia and renal toxicity from case reports.10
Fish Oil

The beneficial components in fish oil and fish oil supplements are the omega-3 acids
docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), while nuts and vegetable oils (such as canola, soybean, olive, and flaxseed) contain alpha-linoleic acid
(ALA).10 There is good evidence from randomized clinical trials and prospective cohort
studies to support the cardioprotective role of fish oil and fish oil supplements for secondary prevention35 by means of multiple mechanisms including an antioxidant action, lowering triglycerides, reducing risk of arrhythmias and platelet aggregation,
and lowering blood pressure. The evidence for primary prevention of cardiovascular
disease is more controversial,36,37 and more evidence is needed. The evidence available does not support the role of fish oils in cancer prevention,38 prevention of dementia or Alzheimers disease39,40 or relapse of inflammatory conditions such as
inflammatory bowel disease,41,42 or improvement of intermittent claudication.43 Dosing for fish oil is based on DHA and EPA content, and 5 g of fish oil contains approximately 170 to 560 mg of EPA and 72 to 310 mg of DHA. The World Health
Organization (WHO) recommends an daily intake of 300 to 500 mg of EPA and
DHA, while 850 to 1800 mg of EPA and DHA are recommended for secondary cardiovascular prevention.10
Flaxseed

Flaxseed and its derivatives flaxseed and linseed oil are a rich source of ALA, a precursor of omega-3 fatty acids used for cardiovascular protection. Flaxseed is a source of
fiber and a rich source of lignans, a class of phytoestrogens, and it is available as
a food product in the form of flour, bruised flaxseed, and meal, ground, and whole flaxseed. Flaxseed oil, however, available as capsule or liquid, contains only the ALA and
not the lignan component in flaxseed.10 Although uses of flaxseed have been cited
based on some studies, for promoting wellness related to lipid control4446 constipation,4749 menstrual conditions such as mastalgia,50 and menopausal symptoms,51 the
quality of evidence for these indications is poor. A recent review52 concluded that the
quality of evidence for 13 conditions for which flaxseed has been studied was insufficient to recommend flaxseed and its derivatives for any of these indications. Flaxseed
should be taken with caution in patients at risk of intestinal obstruction because of its
potential to exacerbate or trigger this problem, and in men who have prostate cancer
and women who have estrogen-dependent cancers because of its theoretical hormonal effects.10
Ginger (Zingiber Officinale)

Ginger is a valuable spice and condiment used in traditional medical practices for
digestive problems, arthritis, and for treating and preventing nausea and vomiting.
Ginger contains phenolic compounds that may enhance GI motility, bile excretion, inhibit platelet aggregation, and act as an antioxidant.53 Recent studies provide new evidence that ginger may act on serotonin receptors, primarily on 5-HT3 receptors in the
ileum, which are the same receptors used by ondansetron (Zofran), a well-known
antiemetic.54
A meta-analysis of five randomized trials (total of 363 patients) demonstrated that
a fixed dose (at least 1 g of ginger) is more effective than placebo for preventing postoperative nausea and vomiting relative risk [RR] 0.69 (95% CI 0.54 to 0.89) and postoperative vomiting (RR 0.61 (95% CI 0.45 to 0.84)).55 Ginger, in some studies, is found

Dietary Supplements Commonly Used for Prevention

to reduce the severity of nausea and vomiting in some pregnant patients with morning
sickness.56
Ginger generally is tolerated well. Common adverse effects include abdominal discomfort, heartburn, and diarrhea. A theoretic risk of bleeding exists because of the
antiplatelet activity; however, increased risk of bleeding has not been demonstrated
with doses up to 4 g/d.57
Glucosamine and Chondroitin

Chondroitin sulfate is manufactured from shark or bovine cartilage and is used to treat
osteoarthritis (OA). It is available alone or in combination with other products such as
manganese ascorbate, glucosamine sulfate, or glucosamine hydrochloride and is also
available in combination with iron for treating iron deficiency anemia. Glucosamine is
available as a hydrochloride and a sulfate preparation, and both have been examined
in clinical trials on OA. Glucosamine is derived from marine exoskeletons or manufactured synthetically, and based on in vitro animal studies, it is theorized to act by stimulating the metabolism of chondrocytes in articular cartilage and synovial cells in
synovial tissue.10
For OA, a dose of 500 mg of glucosamine hydrochloride three times daily alone or
with chondroitin sulfate 400 mg three times daily has been recommended10 based on
doses used in available clinical trials. A preparation containing 1500 mg/d of glucosamine hydrochloride and 1200 mg/d of chondroitin sulfate with 228 mg/d of manganese ascorbate is available. The tolerable upper limit for manganese is 11 mg/d,
however, and caution is suggested when using combinations containing manganese
because of the potential for central nervous system (CNS) toxicity.10,58
A meta-analysis59 examining 20 studies found superiority of a preparation of glucosamine compared with placebo for pain and function in patients who had OA, but did
not commit to specific doses linked to specific beneficial outcomes. Glucosamine sulfate alone has been examined for up to 3 years,60,61 demonstrating radiologic slowing
of OA progression and a 20% decrease in knee pain, respectively. In a large randomized clinical trial, when glucosamine alone, chondroitin alone, and the two combined
were examined for their impact on painful knee OA in older adults62 compared with
placebo or celecoxib, clinical response was slightly greater for the combination than
for either agent alone compared with placebo. Only the combination, however, was
significantly better than placebo, with the magnitude of response still lower than
that seen with celecoxib (6.5 % points versus 10.0 % points). Overall, response was
better in patients who had moderate-to-severe baseline pain than mild pain. A topical
preparation containing both glucosamine and chondroitin used in the short term
(8 weeks) has been found to be useful for pain control in a small pilot study of 63
patients in knee OA compared with placebo.63
Adverse effects of chondroitin are rare, and reported effects include occasional
epigastric pain and nausea, eyelid edema, alopecia, and extrasystoles.10 Potential
adverse effects of glucosamine, although uncommon, center around theoretic concerns about metabolic effects on glucose metabolism, although long-term studies
of up to 3 years did not indicate adverse effects on HbA1c, glucose, or lipid
levels.6467 Asthma exacerbation and GI effects also have been described.10
Green Tea (Camellia Sinensis)

Green tea and black tea both come from the same plant. A main difference between
them is in the preparation process. Green tea is made by lightly steaming the fresh tealeaf, whereas black tea is made by fermentation of the tea leaf. Steaming maintains the
polyphenols and preserves flavanols including epigallocatechin gallate (EGCG)

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responsible for many the benefits (antioxidant and anti-inflammatory). Green tea is
also a source of caffeine, a methylxanthine, known to stimulate the CNS, relax the
smooth muscle, and act as a diuretic. Green tea is used commonly for managing various chronic medical conditions and disease prevention including cancer prevention.
Studies demonstrate that EGCG inhibits mitogen-activated protein kinases (MAPK),
growth factor-related cell signaling activator protein 1 (AP-1) and nuclear factor-B
(NF-kappaB), topoisomerase 1, matrix metalloproteinases and other cancer cell targets, hence inhibiting carcinogenesis in various tissues.68,69 The clinical evidence
looking at green tea for cancer prevention, however, is not strong. Studies looking
at ovarian cancer are encouraging but not sufficient to draw conclusions. Studies
for gastric and colorectal cancer prevention are mainly epidemiologic and remain inconclusive; however, evidence is slightly better for bladder, esophageal,70,71 and pancreatic cancer prevention.7274
Green tea also is proposed to be helpful for preventing cardiovascular diseases in
which oxidative stress and inflammation are principal causes. EGCG lowers the inflammatory reaction and reduces the lipid peroxidation and nitric oxide (NO)- generated radicals.75 Epidemiologic observations indicate that an inverse correlation
exists between habitual consumption of green tea beverages and the incidence of cardiovascular events.76 Although all the evidence from research on green tea is very
promising, future well-designed prospective studies are necessary to asses whether
the observational data on cardiovascular benefit holds up in the clinical setting.
To date, no specific dose of green tea has been identified. Doses used in the different studies vary significantly, but usually range between 1 and 10 cups daily based on
common use in Asian countries. Green tea is generally safe if used in moderation.
Adverse effects are mainly theoretic and based on its caffeine content.
Lutein

Lutein is a carotenoid found in dark green leafy vegetables such as spinach, plus various fruits, corn, and egg yolks. Lutein and zeaxanthin are the two major carotenoid
pigments found in human macula and retina.77 Lutein and zeaxanthin are antioxidants
thought to filter the high-energy, blue wavelengths of light from the visible light spectrum. Epidemiologic studies repeatedly have documented that those who have high
intake of vegetables and fruits have a lower risk of age-related macular degeneration
(ARMD).7880 In a 12-month randomized double-blind study of 90 subjects with ARMD
receiving lutein (10 mg), lutein with antioxidants, or placebo, visual function was improved with lutein alone or lutein together with other nutrients.81 In a follow-up study,
Richer and colleagues82 reported that individuals who had the lowest macular pigment
optical density (MPOD) were the most likely to benefit from either the lutein (10 mg) or
lutein plus antioxidant supplementation. They also noted that in those individuals who
responded to supplementation, their macular pigment optical density continued to improve after 12 months of supplementation.
The Physicians Health Study and Nurses Health Study both reported 20% protection against cataract in subjects who had the highest levels of serum lutein.83,84 In a
2-year prospective study, Olmedilla and colleagues85 confirmed those findings, suggesting that a higher intake of lutein, through lutein-rich fruit and vegetables or supplements, enabled patients with age-related cataracts to have a better visual function.
Subjects taking a 10 mg supplement of lutein in the Lutein Antioxidant Supplementation Trail (LAST) experienced better visual function, acuity, glare sensitivity, and
improved macular pigmentation.
There are no known adverse effects reported. Lutein supplements of 10 mg/d have
been shown to be safe after 1 year.

Dietary Supplements Commonly Used for Prevention

Lycopene

Lycopene is a red pigment, found most abundantly in tomatoes, tomato-based products, strawberries, and watermelon. Lycopene is an antioxidant in the carotenoid
family.86 Interest and use of lycopene remain high for its potential protective effect
against prostate and other cancers. Several casecontrol and large prospective studies focusing on dietary assessment show that the intake of tomatoes and tomato products may be associated with a lower risk of prostate cancer.87 Lycopene in one clinical
study was found to decrease by 53% insulin-like growth factor 1 (IGF-1, a mediator of
prostate cancer) at a dose of 15 mg twice daily over 3 to 4 weeks. In a clinical study,
supplementation with lycopene 4 mg twice daily showed improvement in men who
had high-grade prostate intraepithelial cancer.88 Evidence of the usefulness of lycopene remains controversial, with studies on both sides of the issue. This is well-illustrated in one study that does not support the hypothesis that greater consumption of
lycopene/tomato products protects from prostate cancer.89 Another study following
subjects for 4.2 years indicates that vegetable and fruit consumption was not related
to prostate cancer risk overall. Risk of extraprostatic prostate cancer (stage 3 or 4 tumors), however, decreased with increasing vegetable intake (RR 5 0.41, 95% CI 5
0.22 to 0.74, for high versus low intake; P 5 .01).90 A recent small study explored
the effect of 15 mg/d of lycopene on benign prostatic hyperplasia (BPH). After 6
months, the authors concluded that lycopene at a dose of 15 mg/d decreased
prostate-specific antigen (PSA) levels in men (P < .05), whereas there was no change
in the placebo group. The progression of BPH occurred in the placebo group as assessed by transrectal ultrasound (P < .05) and digital rectal examination (P < .01); however, the prostate did not enlarge in the lycopene group. Symptoms of the disease, as
assessed by means of the International Prostate Symptom Score questionnaire, were
improved in both groups, with a significantly greater effect in men taking lycopene
supplements.91
No adverse effects have been identified . No specific amount of has been established in cancer prevention studies. Lycopene supplements of 30 mg/d have been
used safely.

Milk Thistle (Silybum Marianum)

Milk thistle is part of the daisy family. The seeds contain sylmarin, a mixture of flavonolignans, of which silybinin is the most common. Milk thistle is used commonly to
protect the liver from hepatotoxins or to treat liver disease. Its exact mechanism of action is not clear; however, silybinin is known to be an antioxidant, a free radical scavenger, and an inhibitor of lipid peroxidation.92,93 In vitro silybinin has shown an affinity
for binding to p-glycoprotein94 and inhibits 5-lipoxygenase, hence reducing the formation of inflammatory leukotrienes.95 Silybinin also has been shown in vitro to have a
regenerating effect on the livers96 by stimulating DNA polymerase, increasing the synthesis of ribosomal RNA, and stimulating liver cell regeneration.97
Most clinical trials studying milk thistle focused on treatment of established alcoholic and nonalcoholic (drug- or toxin-induced) liver disease. Existing evidence suggest benefits of milk thistle; however most effect sizes are small or not statistically
significant. Systematic reviews concluded that the clinical efficacy of milk thistle for
liver disease could not be established.98,99 Few studies focused on prevention:
Twenty-nine subjects who had normal liver function tests were randomized to receive
antituberculosis therapy alone or with milk thistle. A 28% decrease in the risk of developing liver injury was seen in the milk thistle compared with the control group.100

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Interest also exists in the use of milk thistle for cancer treatment and prevention
based on animal and laboratory studies. Because of absence of human clinical trials,
there is insufficient evidence to recommend milk thistle for cancer prevention.
In animal studies, milk thistle was found to have a protective effect on rat cardiomyocytes exposed to doxorubicin comparable to that of dexrasoxane.101
Milk thistle usually is tolerated well, with some minor GI (nausea, vomiting, diarrhea,
dyspepsia, bloating) and allergic adverse effects. Although evidence is not conclusive,
caution should be used when combining milk thistle with medications metabolized
through the CYP450 system.102
Probiotics

The WHO defines probiotics as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Probiotics normally are found in
the GI tract or as components of foods and beverages. They should be differentiated
from prebiotics, which are complex carbohydrates that stimulate the growth or activity
of beneficial bacteria already in the colon. Most probiotics are either Lactobacillus or
Bifidobacterium and their different species and strains (eg, Lactobacillus acidophilus
and Bifidobacterium bifidus). Other common probiotics are yeasts (eg, Saccharomyces boulardii).
Probiotics are thought to reinforce the integrity of the intestinal lining as a protective
barrier to prevent harmful organisms and in keeping harmful bacteria or yeast under
control. Probiotics are available as tablets, powders, capsules, and in beverages
such as yogurt or juice.
Probiotics offer a safe and effective method to prevent travelers diarrhea (TD). Several probiotics (Saccharomyces boulardii and a mixture of Lactobacillus acidophilus
and Bifidobacterium bifidum) show significant efficacy. A meta-analysis of current
studies indicates that probiotics significantly prevent TD (RR 5 0.85, 95% CI 0.79
to 0.91, P < .001).103,104
In a meta-analysis of current studies, DSouza and colleagues found that the odds ratio in favor of active treatment over placebo in preventing diarrhea associated with antibiotics was 0.39 (95% CI 0.25 to 0.62; P < .001) for the yeast and 0.34 (CI 0.19 to 0.61; P
< .01 for lactobacilli). The combined odds ratio was 0.37 (0.26 to 0.53; P < .001) in favor
of active treatment over placebo.105,106 A recent randomized study using 100 g of a drink
containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophilus taken twice daily during 1 week after a course of antibiotics reduced the incidence
of antibiotic-associated diarrhea and Clostridium difficile- associated diarrhea.107
Ulcerative colitis

The best evidence for the use of probiotics in ulcerative colitis (UC) comes from the
use of a combination of lactobacilli, bifidobacteria and Streptococcus thermophilus
(VSL#3) taken daily in the primary. Secondary prevention of pouchitis maintains remission in 85% of patients.108,109 Other studies reported that Lactobacillus GG or bifidobacteria, alone or in combination with mesalazine, showed no difference in relapse
rate at 6 (P 5 .44) and 12 months (P 5 .77) among the treatment groups. The treatment
with Lactobacillus GG (18  10(9) viable bacteria/d), however, is more effective than
standard treatment with mesalazine (2400 mg/d) in prolonging relapse-free time
(P < .05).110
Crohns disease

The evidence for the use of probiotics in the maintenance of remission in Crohns disease is not as supportive. Although some studies did show a positive outcome,111

Dietary Supplements Commonly Used for Prevention

most of the studies were small and lacked statistical power to draw any major
conclusions.112
Two Cochrane reviews looking at the prevention of allergic disease and food hypersensitivity in infants found positive evidence (studies using Lactobacillus rhamnosus)
in favor of atopic dermatitis prevention.113 When the review was restricted to atopic
dermatitis or to the use of prebiotics alone, however, findings were not statistically significant.114 A recent literature review looking at the use of probiotics for preventing
nosocomial pneumonia in critically ill patients found insufficient evidence of efficacy
because of the small study samples and poor design.115
Resveratrol

Resveratrol is a polyphenol identified in many plant species including grapes, nuts,

mulberries, pine trees, and red wine. Animal and laboratory studies have identified
antioxidant, anticancer, antiproliferative, and antibacterial effects. Recently, attention
has been directed toward resveratrol for its chemopreventive activities against several
cancers116119 and for its potential health benefits against coronary artery disease
(CAD).120122
Cancer

laboratory studies suggest that resveratol regulates proliferation, cell cycle, apoptosis,
and angiogenesis through regulation of multiple signaling pathways. Moreover, it
inhibits growth of several cancer lines and potentiates the apoptotic effects of cytokines, chemotherapy, and gamma-radiation.116,123 Clinical studies to verify laboratory
findings are pending.
Cardiovascular

Resveratrol exerts its cardioprotective effects through inhibition of platelet aggregation both in vitro and in vivo,124,125 strongly inhibiting NO generation in macrophages
while stimulating NO synthesis in endothelial cells and inhibiting cyclooxygenase2 generation116,126 and tumor necrosis factor (TNF)-a induced NF-kappa B activation
and inflammatory gene expression.127,128 As a general rule, 4 oz of red wine provide
approximately 320 mg of resveratrol. In most cases, when consumed in its natural
sources, resveratrol has no evidence of toxicity.
EVALUATING EVIDENCE FOR PATIENTS

The Natural Standard10 and Natural Medicine Comprehensive databases are comprehensive resources of use to physicians and patients to maintain updated knowledge of
supplements (doses, preparations, and forms) and evidence supporting or refuting
their use, and citing potential harms. There are an increasing number of systematic reviews available in the Cochrane Database of Systematic reviews and in journals that
clinicians should consult before advising their patients on the latest evidence. A principle of first do no harm is a sound guide, and clinicians should balance this principle
with evidence of benefit for wellness and health maintenance when discussing or assessing supplements. Respect for the patients own values and beliefs, and appreciation for limited patient resources for purchasing the supplements versus other
therapies with greater evidence of efficacy are important principles to recognize and
consider. By including supplements and herbals among the many forms of treatment
(such as exercise, meditation, yoga, and consulting shamans) patients already use,
clinicians can give sound advice and play a pivotal role in providing a holistic approach
to health care that improves adherence and overall health maintenance.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge the contributions of Jennifer Encinas, BA, for
technical assistance and manuscript preparation.
FURTHER READINGS

National Center for Complementary and Alternative Medicine (NCCAM): http://nccam.

nih.gov/ NCCAM provides a great scientific review of common therapies and dietary supplements, and offers the opportunity for online training in specific areas.
It also highlights excellent resources of information.
Natural Medicine Comprehensive Database: http://www.naturaldatabase.com/ This is
a comprehensive database that provides evidence-based, clinical information on
natural products. It is designed for medical professionals and updated regularly.
Product search is available by scientific name, common name, brand name or
ingredient.
Natural Standard: http://www.naturalstandard.com/ This database allows one to review information by product, medical condition, brand name, or modality. The information is reviewed and updated regularly. Levels of scientific evidence for
each herbal supplement and condition are outlined and easy to follow.
Office of Cancer Complementary and Alternative Medicine (OCCAM): http://www.
cancer.gov/cam/ Established in 1998, it provides evidence-based CAM practice
and the sciences that support it as well as the availability of high-quality information for the health care community, researchers, and the general public.
Office of Dietary Supplements (ODS): http://ods.od.nih.gov/ The ODS provides information about the potential role of dietary supplements to improve health care,
promotes scientific research, and disseminates research results. One of its services is the International Bibliographic Information on Dietary Supplements
(IBIDS) database (http://ods.od.nih.gov/Health_Information/IBIDS.aspx).
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