Kennedy (2007)^∗ (n = 23,393 adults)	ConsumerLab.com^† (n = 3226)	Kaufman et al.^‡ (n = 2590)
1. Back pain	1. General health (67%)	1. “To supplement the diet” (45%)
2. Neck pain	2. Colds (53%)	2. General health (16%)
3. Joint pain (5.2%)	3. Osteoarthritis (39%)	3. Arthritis (7%)
4. Arthritis (3.5%)	4. Energy enhancement (37%)	4. Memory impairment (6%)
5. Anxiety (2.8%)	5. Cholesterol control (29%)	5. Energy (5%)
6. Cholesterol (2.1%)	6. Cancer prevention (28%)	6. Immune system enhancement (5%)
7. Head/chest cold (2.0%)	7. Allergies (27%)	7. Other joint issues (4%)
8. Other musculoskeletal conditions (1.8%)	8. Weight management (25%)	8. Sleep aid (3%)
9. Severe headache or migraine (1.6%)		9. Prostate problems (3%)

As often occurs with complementary and alternative/integrative medicine (CAM) modalities, use is most common for disorders (often chronic) that Western medical approaches may not be able to treat as safely or effectively.

∗ National Health Information Survey of reasons for CAM use in general, 2008.

† In 2002 study on reasons for supplement use, 54% of respondents indicated they were taking supplements for four or more simultaneous conditions. Respondents could give multiple reasons for taking supplements. Respondents were users of the ConsumerLab.com website and likely high-frequency herb users.

‡ Results are based on a 2002 telephone survey of why people take supplements. The definition of “supplement” used for respondents excluded vitamins and minerals; 25% answered either “don’t know” or “no reason specified” when asked about supplement use. Respondents could give multiple reasons for taking supplements.

Only in recent decades have more scientifically based studies of supplement efficacy and safety been conducted. With the development of the National Center for Complementary and Alternative Medicine (NCCAM) in October 1998 within the National Institutes of Health (NIH), supplement research funding in the United States has grown dramatically. In other countries, groups such as the European Scientific Cooperative on Phytomedicines (ESCOP, www.escop.com) and Edzard Ernst’s team at the University of Exeter have been gathering and analyzing data from hundreds of well-designed randomized trials. It is no longer legitimate during a patient encounter to make sweeping statements discouraging supplement use because, “We just don’t know enough about them.” To state that all supplements are dangerous is just as inaccurate as claiming, as many manufacturers do, that dietary supplements are consistently safe and effective. Some supplements have shown great promise in helping to prevent or treat various illnesses. Others have been proven harmful enough that their use should be discouraged. Ideally, physicians should be as informed and actively involved in patients’ decisions regarding dietary supplements as they are with their decisions regarding prescription medications. Box 52-1 offers guidelines for discussing supplements with patients.

Box 52-1 Considerations When Evaluating Supplement Safety

Data from Blumenthal M. American Botanical Council. The ABC Clinical Guide to Herbs. New York, Thieme, 2003; Brinker F. Herb Contraindications and Drug Interactions, 3rd ed. Sandy, Ore, Eclectic Publications, 2001; NIH Office of Dietary Supplements, 2009; Natural Medicines Comprehensive Database, 2009; and Rotblatt M, Ziment I. Evidence-Based Herbal Medicine. Philadelphia, Hanley & Belfus, 2002.

Recognize that patients often do extensive research regarding supplements and may often be quite knowledgeable about indications for use and safety risks.

It is acceptable to offer to review supplements’ safety after the visit and discuss its use further with a patient in follow up, if there is uncertainty about a particular product or if clinic visit time is limited.

Although severe complications from using herbs are rarely reported, “natural” does not always mean “safe.” Many natural products can be quite dangerous.

If a supplement has the potential to interact with serum levels of a medication, this should be discussed with the patient.

Some supplements (e.g., St. John’s wort, grapefruit) can alter the activity of cytochrome P-450 enzymes in the liver, affecting other drug levels. Others can affect coagulation, serum glucose, and blood pressure (see Boxes 52-3 to 52-5).

The effects of supplement use on the environment must be considered.

Some herbs, such as American ginseng, slippery elm, and goldenseal, are endangered in the wild.

The U.S. Dietary Supplements Health and Education Act (DSHEA) effectively gave the Food and Drug Administration (FDA) the burden of proving that a given supplement is unsafe. Good manufacturing practices have been required for large companies since 2007 and all companies as of 2010.

As a general rule, many of the mass-produced herb brands seem to score better in product quality than those from small-scale industries, but this is variable.

Finding reliable products and knowledgeable vendors is important; it may help to become familiar with a few manufacturers so that a few specific, reliable products can be recommended.

Some supplements actually improve the body’s ability to metabolize or tolerate certain medications.

For example, milk thistle has been found in some studies to protect the hepatocytes from damage secondary to hepatotoxins (Blumenthal, 2003).

Supplements, particularly herbs, should be used with caution in pregnant or lactating women and children. (See Brinker, 2001, for additional guidelines in special patient populations.)

Many supplement prescribers prefer to recommend products made by companies who have actually invested in research related to efficacy and safety. Manufacturers and product names are often mentioned in the “Methods” sections of randomized controlled trials (RCTs).

Supplement Safety

Key Points

• It is as inappropriate to generalize about supplements being dangerous or having unknown effects as to assume that all supplements are safe because they are “natural.”

• Although rarely observed, physicians must still be aware of herb-drug interactions and adverse supplement effects.

• Supplements can affect blood pressure, serum glucose levels, and coagulation, which can be therapeutically useful or dangerously adverse.

• Use supplements with caution in certain patient populations, including pregnant and lactating women, children, patients taking warfarin, and those with renal or hepatic failure.

Until 2007, supplement manufacturers had few requirements for evaluating the safety of their products. In late 2007, it was mandated that all dietary supplement-related adverse events must be reported to the FDA. Deadlines were set for when companies of various sizes would be required to evaluate the identity, purity, strength, and composition of their products. The last deadline, for companies with 20 or fewer employees, was set for June 2010. However, there is no requirement that the FDA verify efficacy of herbal supplements. Proponents of natural remedies often hold that it is reasonable to keep regulation loose, claiming that “natural” products are, as a general rule, safer than pharmaceuticals. Although this seems true, more than 25% of medications are based on compounds derived from natural substances (Schulz et al., 2001). The line between what is “natural” and what is a “drug” is often blurred. Many herbal products are key ingredients in over-the-counter (OTC) drugs, including capsicum from hot peppers (for herpes skin outbreaks), witch hazel (hemorrhoid treatments), and psyllium seed (laxatives). Conversely, some natural compounds can be highly poisonous, such as daffodil bulbs, oleander leaves or branches, and castor beans (just one or two beans can kill an adult, even though castor oil is relatively safe and often used).

When advising patients regarding herb safety, it must be remembered that pharmaceutical use is itself associated with significant morbidity and mortality. For example, data from 39 prospective studies estimated that adverse drug reactions are implicated in more than 100,000 inpatient deaths per year (Lazarou et al., 1998). In contrast, adverse event reports are much less common for herbs (Brinker, 2001). In 2008, 6 months after supplement adverse event reporting began, the FDA had received 600 adverse event reports; this is in contrast to the 482,154 reports it had received for pharmaceuticals during a 1-year period (Perez, 2008). It is unclear whether this relatively low number of reports is caused in part by limitations in reporting mechanisms. A significant portion of available supplement safety data is based on isolated case reports or extrapolations from pharmacokinetic, in vitro, or animal data.

Patients should be encouraged to bring the supplements they are taking with them to clinic visits. They should be reminded to list supplements whenever they list their medications, particularly on hospital admission. Often, patients will hand their physician the packaging for a particular product; Box 52-2 discusses how to evaluate a product’s quality based on its packaging information.

Box 52-2 Considerations When Reviewing a Supplement’s Packaging

It should be clear what ingredients the product contains.

For botanicals, Latin names of component plants should be listed, because many species have multiple common names.

Use caution with Chinese and Ayurvedic herbs that do not clearly state their ingredients’ names in English or Latin.

According to the U.S. Dietary Supplements Health and Education Act (DSHEA), a supplement’s label may make “structure/function claims” provided they are not misleading and have been validated by some form of scientific research.

Examples of such claims include “supports digestive health” or “helps maintain prostate health.”

Products may not claim to cure, treat, or prevent disease and must state on the label that any claims “have not been evaluated by the FDA.”

If a product does not follow these guidelines, avoid it.

For herbal remedies, note the type of formulation, such as tincture versus crude herb versus infusion. These formulations can have different properties and effects (see Table 52-3).

The numbers of tablets or capsules in the package and the weight of each, as well as a breakdown of nutritional content of the supplement, should be listed.

Look for how the product’s contents are standardized.

Many botanicals will be standardized to a specific percentage content of one particular chemical.

For example, ginseng may be standardized by ginsenoside content and horse chestnut extract by level of aescin.

Different companies may standardize for the same herb using different chemical compounds; for example, St. John’s wort may be standardized to either hypericin or hypericum levels.

In many cases the chemical component used for standardization is not a known physiologically active constituent of the product.

For combination products, the amount of each component of a supplement must be listed, unless the product is a proprietary blend (as many herbals are).

With a proprietary brand, only the total amount of the blend is legally required to be listed.

Use of combination products requires additional caution. Some supplements (including many megavitamins, which add herbs or nonvitamin nutrients to the usual array of vitamins they contain) can contain dozens of individual ingredients.

Consider each ingredient individually for safety and efficacy.

Expiration dates on supplement packaging are assigned by the manufacturer and are often arbitrarily set at 2 years after the manufacture date for herbal remedies.

The manufacturer’s name and address should be seen on the label.

For herbals, where a plant was grown may influence its potency, and the user may not be able to determine this by reading the label.

Supplements containing various organ tissues (e.g., thymus, gonads, adrenals) should be used with caution, given the potential risks of electrolyte disturbances or prion-borne disease.

Typically, patients taking multiple supplements will not be aware that they may be exceeding safe intake levels for certain compounds.

In particular, note cumulative doses of vitamin A, vitamin E, vitamin B₆, selenium, magnesium, and calcium. Keep recommended upper intake levels in mind.

This is also important for supplements that affect serum glucose levels, blood pressure, or coagulation status.

Pay close attention to price, which need not always correlate with quality.

Some supplements can be as expensive as drugs, if not more so.

The challenges associated with placing the burden of proof for product safety on the FDA surfaced with the events leading to the April 2004 ban on ephedra, a naturally derived, amphetamine-like stimulant. Only after linking ephedra to 155 deaths, including the death of a well-known athlete, and dozens of heart attacks and strokes was the FDA finally able to justify putting the ban into effect (Natural Database, 2009; Wong, 2009). Ephedra has been used in various forms in China for thousands of years, but not at the high dosage levels found in many of the products linked to harmful outcomes. Many of the negative effects of ephedra were associated with its use in combination with other compounds, such as caffeine. Some supplement manufacturers seem to assume that “if a little bit is good, more is even better.” Table 52-2 summarizes some herbal supplements that, based on the current level of research, should be avoided or used only under professional supervision.

Table 52-2 Potentially Dangerous Supplements ^∗

Herb Names	Why Avoid
Herbs that Are Generally Contraindicated
Birthwort (Aristolochia spp.) Other names: snakeroot, snakeweed, serpentary, sangrel, sangree root	Contains aristolochic acid, a carcinogen and known cause of renal failure. Deaths have been attributed to consumption
Wild ginger (Asarum canadense)	Banned in seven European countries, Egypt, Japan, and Venezuela
Comfrey (Symphytum spp.) Other names: ass ear, black root, blackwort, bruisewort, consound, gum plant, knitback, salsify, slippery root, wallwort	Liver damage FDA advised removal from market in 2001
Chaparral (Larrea tridentata, L. divaricata) Other names: creosote bush, greasewood, jarilla	Liver damage Death FDA warning issued in 1992
Germander (Teucrium chamaedrys)	Liver damage Banned in France and Germany
Kava (Piper methysticum) Other names: ava, awa, gea, gi, intoxicating pepper, kao, kawa pfeffer, kew, long pepper, malohu, milik, sakau, tonga, yagona	Safety controversial (use only with experience) Has antianxiety and sedative properties, and can reduce coordination and judgment Liver damage; but as is often the case, this was likely caused by a specific product that contained adulterants. FDA warning issued 2002 Banned in Canada, Germany, Singapore, South Africa, Switzerland
Ephedra (Ephedra sinica or E. equisetum) Other names: ma huang, amsania, Brigham tea, budshur, chewa, Chinese joint fur, desert herb, epitonin, horsetail, hum, huma, khama, mao, mao-kon, natural ecstasy, phok, popotillo, sea grape, shrubby, squaw tea, teamster’s tea, yellow astringent	Arrhythmia CNS excitation Hypertension MI Stroke
Herbs Rated as Likely Hazardous (Adverse Event Reports or Theoretic Risk)
Bitter orange (Citrus aurantium) Other names: green orange, kijitsu, neroli oil, Seville orange, shangzhou zhiqiao, zhi xi	Hypertension Increased arrhythmia risk Risk of cardiac or cerebrovascular events
Lobelia (Lobelia inflata) Other names: asthma weed, bladder pod, gagroot, Indian tobacco, pukeweek, vomit wort	Breathing difficulty Tachycardia Hypotension Diarrhea Dizziness and tremor
Pennyroyal oil (Hedeoma pulegioides) Other names: lurk-in-the-ditch, mosquito plant, piliolerial, pussing grass, squawmint, stinking balm, tickweed	Renal and hepatic failure Nerve damage and convulsions Abdominal and throat pain
Skullcap (Scutellaria spp.) Other names: blue pimpernel, helmet flower, hoodwort, mad weed, mad-dog herb, quaker bonnet	Liver damage
Yohimbe (Pausinystalia yohimbe) Other names: johimbi, yohimbehe, often in “herbal Viagra” formulations	Altered blood pressure Arrhythmias, risk of MI Respiratory depression

FDA, U.S. Food and Drug Administration; CNS, central nervous system; MI, myocardial infarction.

∗ Herbs listed are still widely available in several over-the-counter products. Many of these herbs have been used safely for millennia by skilled herbalists providing individualized care. Should not be used without supervision by a knowledgeable herbalist or other skilled professional.

Data from Twelve Supplements You Should Avoid. Consumer Reports, May 2004, p 15; Basch EM, Ulbricht CE. Natural Standard Herb and Supplement Handbook: The Clinical Bottom Line. Boston, Elsevier-Mosby, 2005; and Brinker F. Herb Contraindications and Drug Interactions, 3rd ed. Sandy, Oregon, Eclectic Publications, 2001.

Advising patients regarding supplement safety can be difficult. For example, vitamin E has been widely touted as having a number of potential health benefits, including cancer prevention, lowering heart disease risk, slowing age-related macular degeneration, and reducing dementia progression; results of some studies have been quite favorable (Natural Database, 2009). However, a significant body of research questions vitamin E supplementation. A Johns Hopkins meta-analysis concluded that dosing over 400 international units (IU) daily “may increase all-cause mortality and should be avoided” (Miller, 2005). Other research suggests a potential link between vitamin E consumption and risk of heart failure in patients with vascular disease or diabetes (Lonn et al., 2005). In the Women’s Health Study, vitamin E supplementation did not seem to affect the incidence of cancer or major cardiovascular events, although cardiovascular mortality in younger women was reduced (Lee et al., 2005). For Parkinson’s disease, vitamin E appears beneficial for prevention if eaten in the diet, but not taken as a supplement (Zhang et al., 2002). It is frequently argued that the types of tocopherols taken (alpha vs. gamma vs. mixed) can alter vitamin E’s efficacy and safety.

How does the family physician weigh the risks and benefits of a supplement when faced with such a hodgepodge of information? First, it is important to encourage patients to obtain as many nutrients as possible directly through the foods they eat. If they choose to take additional supplements, patients should keep intake at a reasonably safe range (e.g., no more than 400 IU of vitamin E daily). Keep informed. As with hormone replacement therapy (HRT) and use of cyclooxygenase-2 (COX-2) inhibitors, recommendations regarding supplements may also change dramatically with emerging research findings. Ultimately, decisions about supplement use must be informed by knowledge of individual patients’ circumstances and personal preferences, once they are made fully aware of potential risks and benefits.

Herb-Drug Interactions

An important concern for many clinicians is the possibility of herb-drug interactions. Fugh-Berman and Ernst (2001) compiled case reports and other data from three research databases and contacted 10 supplement manufacturers, ranking studies according to a 10-point scoring system, based on how clearly the report accounted for comorbidities and adequately described the circumstances surrounding the interactions. Of 108 reported interactions, 14 were classed as “likely to exist,” 20 were deemed “possible,” and 74 were classed as “unevaluable.” Many of the most likely herb-drug interactions involved St. John’s wort, an herb used in the treatment of depression. This botanical affects the cytochrome P-450 3A4 system, potentially lowering the serum levels of several drugs, including oral contraceptives and cyclosporine (Brinker, 2001).

One of the most common adverse effects of many herbal remedies is alteration of coagulation. Levels of warfarin, heparin, or antiplatelet agents are altered by some herbs. Box 52-3 lists common supplements that affect coagulation and fibrinolysis. Box 52-4 lists herbs that may affect serum glucose levels, and Box 52-5 lists herbs with potential effects on blood pressure. A recent review of available case studies summarizes possible interactions among several popular herbal remedies, including echinacea, garlic, ginkgo, ginseng, kava, saw palmetto, and St. John’s wort (Izzo and Ernst, 2009).

Box 52-3 Effects of Common Herbs on Coagulation ^∗

Data from Basch EM, Ulbricht CE. Natural Standard Herb and Supplement Handbook: The Clinical Bottom Line. Boston, Elsevier-Mosby, 2005; Brinker F. Herb Contraindications and Drug Interactions, 3rd ed. Sandy, Ore, Eclectic Publications, 2001; and Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Accessed November 2009.

Increased Potential for Hemorrhage

Decreased Prothrombin

Baikal skullcap root

Pau d’arco bark

Sweet clover

Increased Heparin or Warfarin Effect

Black currant seed oil, Evening primrose seed oil

Borage seed oil	Garlic
Danshen root	Ginkgo leaves
Devil’s claw	Papain (papaya)

Dong quai

Decreased Fibrin (or Increased Fibrinolysis)

Algae (e.g., Irish moss red, kelp brown, spiral wrack brown)

^∗ All information is for herbs taken at recommended standard doses. Herbs that can increase hemorrhage risk should be stopped several weeks before surgery.

Box 52-4 Supplements that Can Alter Serum Glucose Levels ^∗

Data from Basch EM, Ulbricht CE. Natural Standard Herb and Supplement Handbook: The Clinical Bottom Line. Boston, Elsevier-Mosby, 2005; and Brinker F. Herb Contraindications and Drug Interactions, 3rd ed. Sandy, Ore, Eclectic Publications, 2001.

Supplements that May Raise Blood Glucose

Arginine	Ephedra (when with caffeine)
Cocoa	Melatonin

Dehydroepiandrosterone (DHEA)

^∗ Includes the most frequently used herbs; list is not comprehensive. Derived from expert opinion, case reports, preliminary trial evidence, and anecdote. Note that these effects can potentially have therapeutic benefit in diabetic or hypoglycemic patients.

Box 52-5 Herbs that May Alter Blood Pressure ^∗

Raise Blood Pressure

Types of Supplements

Key Points

• Supplements can be classified as herbal remedies, vitamins and minerals, nutraceuticals, or combination products.

• Primary care physicians should be familiar with the most popular products and, when necessary, be able to find additional information on indications, safety, and efficacy.

• When discussing the safety of combination products, consider each component individually.

• Marketing information frequently outpaces the information available through good-quality scientific research.

• Price does not necessarily correlate with quality for many products.

Supplements fall into four overall classes: Herbals, vitamins and minerals, nutraceuticals, and combination remedies. In 2007 the nonvitamin, nonmineral products used by adults in the 30 days prior to the survey were fish oil/omega 3 fatty acids, glucosamine, echinacea, flax oil or pills, and ginseng (Barnes et al., 2008).

Herbal Remedies

Herbal remedies, or botanicals, are supplement preparations made from various plant components. Herbals typically contain numerous chemical compounds. One study found that 34% of the U.S. population used herbal remedies at least once, and 14% took at least one herbal remedy consistently from June 2002 to June 2003 (Rogers, 2005). Chinese herbs, Ayurvedic herbs, and Latin American herbs are frequently used, but the great number of available herbs from around the world is not the only issue to discuss with patients. A given remedy’s potency and efficacy are influenced by where an herb was grown, the particular species used in the formulation, how the plant products were processed, which plant parts were used, and which compounds were used for chemical standardization. Table 52-3 lists common forms of herbal preparations. Table 52-4 lists some of the most common individual herbs, with indications, efficacy, and potential adverse effects and drug interactions.

Table 52-3 Types of Herbal Formulations^∗

Table 52-4 Popular Herbal Remedies^∗

Vitamins and Minerals

A 2002 Journal of the American Medical Association review of vitamin use in chronic disease concluded, “We recommend that all adults take one multivitamin daily. This practice is justified mainly by the known and suspected benefits of supplemental folate and vitamins B₁₂, B₆, and D in preventing cardiovascular disease, cancer, and osteoporosis and because multivitamins at that dose are safe and inexpensive” (Fairfield and Fletcher, 2002a, 2002b). At least 84% of U.S. residents use vitamin supplements regularly, and they probably need them. Only 20% to 30% of the American population met the goal of at least five servings of fruits and vegetables daily (Flood and Schatzkin, 2000).

Table 52-5 lists several vitamins and minerals, their uses, contraindications, and efficacy information when available. Dose recommendations for vitamins and minerals are now referred to as reference daily intakes (RDIs) and continue to be debated, especially for certain trace minerals. (For a full list of RDIs and food sources of various nutrients, see Mahan et al., 2004.)

Table 52-5 Vitamin and Mineral Supplements ^∗

Name	Indications/Evidence	Effects/Interactions/Comments
Vitamins
Biotin Considered a vitamin Stored in mitochondria Carboxylation reactions	Brittle nails Deficiency (A) Depression Diabetes Hair loss Malnutrition Peripheral neuropathy Seborrheic dermatitis of infancy	No intake levels set No adverse effects known Absorption decreased with carbamazepine, phenobarbital, phenytoin, primidone
Folic acid (sometimes called vitamin B₉) “Folate” takes multiple forms (pteroylmono-glutamic acid is used in most products) Part of coenzymes involved with DNA synthesis; reduces DNA damage, cell death rate Conversion of homocysteine to methionine May improve endothelial function in atherosclerosis Deficiency common in depression	Alzheimer’s disease Anti-aging Cancer prevention (breast, colorectal) CAD Chronic fatigue (parenteral) Deficiency (A) Depression Fragile X syndrome (−) Gingival hyperplasia High homocysteine (A) Insomnia Megaloblastic anemia (A) Methotrexate toxicity Neural tube defect prevention (A) Neuropathy Osteoporosis Vitiligo	Supplementation in breakfast cereal only raises intake by 100 μg Consider supplementation in alcoholics Well tolerated at <1000 μg/day Doses over 5 mg daily can cause GI distress and rash; over 15 mg/day can lead to altered sleep, overactivity, confusion, psychotic behavior, seizures, zinc depletion Large doses increase neuropathy in vitamin B₁ deficiency May reduce toxicity of methotrexate (caution with chemotherapy) May reduce effectiveness of anticonvulsants; folate levels are decreased by phenytoin and phenobarbital Levels decreased by antacids, PPIs, H₂ blockers, antibiotics, aspirin, carbamazepine, bile acid sequestrants, pancreatic enzymes, sulfasalazine, trimethoprim, and perhaps diuretics
Vitamin A (retinol) Name refers to family of molecules known as retinoids. Retinol is the most potent form; carotenoids are its precursors. Retinol seems to speed wound healing. Retinoic acid regulates structural protein gene expression and immune activities. May induce retinoic acid genes, leading to tumor suppression	Cancer prevention and treatment Deficiency states (A) Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: The Family Physician Gynecology Allergy Care of the Newborn Urinary Tract Disorders Gastroenterology Stay updated, free articles. Join our Telegram channel Tags: Textbook of Family Medicine Oct 3, 2016 \| Posted by admin in MANUAL THERAPIST \| Comments Off on Herbs and Other Dietary Supplements Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access