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

Box 52-1 Considerations When Evaluating Supplement Safety

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 popularity of shark cartilage in the 1990s contributed to sharp declines in shark populations. 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).

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.

(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.

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.

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,

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 herb-als 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.

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.

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.

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