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Complementary and Alternative Medicine Series

Herbal Products: Pearls, Perils, and Precautions for the Prescriber

Kristy H. Lucas, PharmD

Given that most patients are now taking some type of herbal preparation and the trend shows no sign of slowing, this overview seeks to provide prescribers with information about the general principles of herbal therapies, including considerations regarding dietary supplement use among patients, regulations, safety concerns, and clinical guidelines for improving safety and minimizing liability when patients incorporate herbal supplements into their health care.

Herbal medications are botanicals used to treat health-related, often chronic, problems or to attain/maintain improved health. The US Food and Drug Administration (FDA) classifies herbal products as nondrug substances called dietary supplements.

HERBAL USE AMONG PATIENTS

The popularity of dietary supplements among American consumers comes as no surprise to most prescribers. A survey conducted in 1997 showed that four out of 10 Americans were using some form of complementary or alternative medicine (CAM) therapy, spending $27 billion annually on such care. These participants reported making 386 visits to primary care physicians versus 629 visits to CAM practitioners, mostly paying out of pocket (few third parties cover CAM therapy).¹ In 2000, Americans spent an estimated $16 billion on dietary supplements alone.² Why are patients so interested in alternatives to traditional medicine? They may be frustrated with the current health care system (eg, third-party insurers, health maintenance organizations), or they may be unable to get timely medical appointments due to physician overbooking. Americans are becoming more Internet-savvy, and are doing online research about their health problems. Often referred to as “natural” products, herbals are frequently misperceived as safer than traditional medications. Although patients may equate “natural” with “safe,” herbal supplements may also lead to untoward adverse effects.

REGULATORY ISSUES

One safety net provided by the FDA is for approval. Medications must be proved effective for their claimed purposes and shown to have a reasonable margin of safety. Neither of these standards is guaranteed with herbal products. Prior to the early 1990s, dietary supplements were regulated by the FDA as food substances. As the popularity and use of these agents grew, it became apparent that they acted more like therapeutic agents. The government’s proposed solution was to remove dietary supplements from the market and reevaluate each of them, using standards set forth for other therapeutic substances such as drugs.

Confronted by the ensuing public outcry against withdrawing supplements from the market, the FDA passed compromise legislation: the Dietary Supplement Health and Education Act of 1994 (DSHEA). Per the DSHEA, the FDA has minimal regulatory control over these agents. The act defines dietary supplements as oral products intended to supplement the diet or increase total dietary intake, containing one or more of the following ingredients: herbs, vitamins, minerals, amino acids, or other botanicals. Further, a dietary supplement may be a concentrate, metabolite, constituent, extract, or combination of these ingredients. In addition to defining dietary supplements, the DSHEA specifies labeling requirements. For example, the label must state from what part of the plant the herbal product is derived (eg, root, stem, seed, leaf).²

The DSHEA also restricts the statements allowed on labels. The label may make three different types of claims. The first is simply a nutrient claim, such as “good source of folic acid.” The second type includes health claims, such as “diets high in calcium may reduce the risk of osteoporosis.” Health claims explain the relationship between the supplement or dietary component and health conditions or diseases. The third type is a structure/function claim, which describes the relationship between the dietary supplement and health maintenance, eg, “promotes bowel regularity.” Although easily confused with this last type, the label may not carry a disease claim, such as “prevents constipation.” Products making structure/function claims must print the following statement on their label: “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.” Manufacturers making structure/function claims must notify the FDA of such claims within 30 days of marketing the product.²

Importantly, the DSHEA places the responsibility for safety on the dietary supplement manufacturers. Whereas drugs are subject to review and approval by the FDA to ensure safety and efficacy prior to marketing, dietary supplements are not. In fact, dietary supplement manufacturers may market their products without prior approval, or even registration, with the FDA. However, if a product is determined to be unsafe, as evidenced by postmarketing surveillance, the FDA does have the authority to remove it from the market. Additionally, if the claims made on any product’s label are found to allege to diagnose, treat, cure, or prevent any disease, the FDA considers that product a drug, and may remove it from the shelves. The product would then be subject to thorough FDA review as a drug.

SAFETY ISSUES

Because postmarketing information is essential for the FDA to protect the public from harmful dietary supplements, adverse event (AE) reporting is a key responsibility of patients and health care practitioners. Although reporting to the FDA is currently voluntary, a proposal was made in April 2001 by the Office of Inspector General of the US Department of Health and Human Resources to mandate that manufacturers of dietary supplements report any AEs associated with their products to the FDA. It is estimated that fewer than 1% of AEs with dietary supplements are actually reported. A Web site has been developed by the FDA Center for Food Safety and Nutrition as a mechanism for voluntary reporting of dietary supplement AEs (http://vm.cfsan.fda.gov/~dms/aems.html).²

Some AEs with herbals that are especially worrisome involve adulterants in marketed products. Prescription drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, diuretics, and corticosteroids, have been found in certain dietary supplement products. Heavy-metal contaminants such as lead, arsenic, and mercury have also been detected. Recently, several dietary supplement products (SPES and PC SPES) were removed from the market due to findings that they contained prescription drugs (alprazolam and warfarin, respectively).³ Other AEs not associated with adulterants are numerous, including serious and fatal events such as stroke, myocardial infarction, and cardiovascular arrhythmia leading to death (multiple weight-loss products containing ephedra), and liver damage (LipoKinetix“, another weight-loss agent).^4,5

Herbal interactions with traditional drugs is a topic of much concern among prescribers. Not only must health care practitioners carefully document and monitor drugs they prescribe, but they must also track their patients’ use of over-the-counter drugs and dietary supplements. Herbals and dietary supplements must be incorporated into the routine medication history. Patients interpret questions from health care workers differently. Thus, it is essential to ask explicitly about the use of nonprescribed substances. This may require specific probing and use of lay terminology, such as “natural therapies,” “products from the health-food store,” and “vitamins,” to describe these preparations. It has been well established that patients feel uneasy about sharing information with their physicians regarding CAM use.⁶ To avoid hindering communication, it is helpful for clinicians to maintain a nonjudgmental attitude and accommodate the patient’s beliefs regarding the use of such therapies. In a 2001 survey, patients revealed they felt physicians know little about dietary supplements, and are biased against them. Interestingly, this survey found that patients generally believe so strongly in the benefits of dietary supplements that they would continue taking them even if the products were scientifically proven ineffective.⁶ Practitioners who unilaterally condemn the use of these products risk driving their patients away and encouraging them to withhold information. By simply informing the patient of facts and potential risks (for example, the lack of approval by the FDA), practitioners are less likely to be perceived as judgmental.

Once a complete medication history is attained, the prudent clinician should screen the list for potential drug interactions. Although clinicians must depend on case reports and the limited clinical trial literature on dietary supplements for information about herbal interactions, a number of theoretical interactions can be postulated based on the proposed mechanisms of various herbs. The bleeding risk posed by substances such as garlic, ginseng, gingko, and ginger is just one example of how a particular mechanism of interaction may be hazardous in a number of settings. For example, if patients are using anticoagulants or antiplatelet drugs, they may experience excessive bleeding if they also take any of these supplements. Should this patient need surgery, the risk could be considerable. In 2001, a review of popular herbal therapies deemed that there were eight notably worrisome herbals that pose a risk to surgical patients.⁷ They cited echinacea for its immunosuppressive quality; garlic, ginkgo, and ginseng for their bleeding anticlotting effects and potential additive properties with other drugs; kava and valerian due to their sedative properties and potential interaction with perioperative medications; St. John’s wort for its potential interaction with many drugs that undergo metabolism via cytochrome P450 system; and ephedra due to its cardiotoxicity and increased risk of stroke or death.

Initially thought to be relatively safe and effective, St. John’s wort enjoyed many years of widespread use and sales. After several articles published in 2000 revealed that multiple drug interactions were not only possible, but had already contributed to several serious AEs in patients, sales dropped by 40%.^8,9 This agent, which is used for depression, was found to induce cytochrome P450 isoenzymes 3A4 and 2C9, contributing to interactions with drugs such as oral contraceptives, protease inhibitors and nonnucleoside reverse transcriptase inhibitors for human immunodeficiency virus (HIV), cyclosporine for preventing transplant rejection, and warfarin.^8-10 Further decreasing the use of St. John’s wort is a recent study from the National Institutes of Health finding this herb equivalent to placebo for treating major depression.¹¹ This example demonstrates the need for both safety testing and well-designed efficacy studies to determine which, if any, herbal preparations should be recommended. More studies of similar quality will further aid the practitioner in caring for patients who use these supplements.

LABELING AND SEALS OF APPROVAL

Other concerns are raised when products making therapeutic claims and resembling medications are not considered drugs and not regulated as such. For example, the lack of standardization allows variations, both interproduct (ie, brand A may not contain the same ingredient as brand B, although their labels reflect identical contents) and intraproduct (ie, batch 1 of brand A’s product may not contain the same ingredients as batch 2). Further, in a bottle of tablets of the same brand and batch, one tablet may have different ingredients than another. Efforts to standardize dietary supplements are underway through several mechanisms. Some companies claim standardization (eg, Centrum“ vitamins “Pharmaprint“ system”), while other organizations are offering testing services to determine which products are more consistent in their ingredients.

Current regulations do not require dietary supplement labeling to include information about proper use or essential cautionary warnings. This allows many products to be misbranded. The quantity of each ingredient need not be displayed on the label. In fact, the only required components on a dietary supplement label are the descriptive name of the product stating that it is a supplement; the name and place of business of the distributor, packer, or manufacturer; a complete list of ingredients; and net contents of the product.¹² Consumers are often forced to rely on the reputation of the manufacturer to select products they trust. There are no guarantees that the label reflects what is in the bottle. Additionally, tablets may vary in contents and strength from tablet to tablet. In an effort to bring a higher level of confidence to dietary supplement purchases and consumption, at least four different agencies have begun their own programs to provide a seal of approval for dietary supplements that meet predetermined criteria. These four groups are the United States Pharmacopoeia (USP), NSF International, ConsumerLab.com, and the Good Housekeeping Institute.

United States Pharmacopoeia

The USP is better known to prescribers for setting standards for prescription and over-the-counter drugs. However, in an effort to provide some basis for evaluating supplements, the USP is now testing selected dietary supplements (based on voluntary manufacturer participation and payment for testing), and giving the “USP” stamp to the labels of those that meet their predefined standards. The USP stamp ensures that the product was manufactured in a clean, professional facility; that the contents are accurately reflected on the label; that no contaminants such as heavy metals, prescription drugs, or pesticides were found in the product; and that proper dissolution occurs with oral administration. Health claims of the product are not verified, however, and this seal, like the other three, does not ensure the product’s safety or efficacy.

NSF International

NSF International is an independent, nonprofit testing organization that has traditionally tested food products for quality. Its seal of approval verifies that the product was manufactured in a clean, professional facility; that the contents are accurately reflected on the label; and that no contaminants were found in the product. Like USP testing, manufacturers must pay for their products to be tested. Once an NSF seal is granted, follow-up testing is performed twice a year, and manufacturing houses are inspected annually.

ConsumerLab.com

ConsumerLab.com performs testing on classes of dietary supplements by selecting from various brands and formulations available to consumers. This organization tests for dissolution, contents reflected on the label (specifically identity, potency, purity, bioavailability, and consistency), and absence of contaminants. Products are not selected for testing based on payment, but the manufacturer may pay to ensure that their product is included in the assessment. Once all testing of selected products is completed, a list of products meeting their standards is generated and published on the company’s Web site. Products failing to meet the standards are not disclosed.

Good Housekeeping Institute

Good Housekeeping began testing select products that are advertised in its magazine. This testing looks for clinical studies to back the product’s claims, and verifies that the label reflects the amount of active ingredient in the bottle. Again, this seal does not ensure safety or efficacy, but it is the only seal requiring clinical studies to back claims.

MALPRACTICE LIABILITY

When prescribers are faced with patients who use CAM, several key considerations may help reduce professional liability, including informed consent and documentation of discussion between the physician and patient about dietary supplement use. The practitioner must consider the level of risk conferred by the therapy based on current and available evidence. Additionally, it is wise to determine what an expert witness would say or be able to prove if litigation arose.

To assign probability of liability regarding CAM therapies, Cohen and Eisenberg¹³ have proposed a framework of four quadrants for potential liability. Quadrant A includes therapies for which evidence supports both safety and efficacy (such as mind-body techniques for chronic pain); the stance assigned to quadrant A therapies is that liability is improbable. Quadrant B involves therapies for which evidence supports safety, but there is inconclusive evidence regarding efficacy (eg, massage therapy for low back pain); for quadrant B therapies, clinicians could conceivably be found liable, but these therapies are probably acceptable. Quadrant C is the area into which most herbal therapies fall, ie, evidence supports efficacy, but safety is inconclusive; the therapeutic posture recommended by the authors is that clinicians should consider tolerating such therapies, advising caution, and closely monitoring patients. Quadrant D represents therapies for which evidence indicates serious risk or inefficacy; the authors recommend avoiding and actively discouraging quadrant D therapies because liability is probable. Examples of quadrant D therapies are known toxic herbs (eg, licorice, ephedra, comfrey)¹⁴ and herbs that are known to interact with existing drug therapy (eg, St. John’s wort use in an HIV patient).⁸ Five proposed “clinical pearls” for minimizing liability with CAM therapies are:

• Determine the clinical risk level using a method such as the quadrant system;
• Document literature that supports the CAM treatment choice;
• Provide and document informed consent, which engages the patient in a clear discussion of the proposed therapy, including risks and benefits;
• Obtain the patient’s express written agreement to use the therapy and keep it in the medical record; and
• Carefully monitor the patient as dictated by disease states and therapies.¹³

CONCLUSION

The relative lack of regulation of dietary supplements by the FDA poses many potential risks to patients and prescribers alike. By carefully considering the therapies used and obtaining meticulous informed consent from patients interested in taking dietary supplements, prescribers can minimize both health risks to the patient and potential liability for themselves. Screening for drug-nutrient interactions, reporting AEs, reading scientific studies of dietary supplement safety and efficacy, following regulatory issues with CAM, incorporating dietary supplements into the routine medication history, documenting discussions of supplement use with patients, monitoring patients using such therapies, and maintaining a nonjudgmental attitude, clinicians can better manage patients as society moves from an allopathic health care system to one integrating CAM therapies.

REFERENCES

1. Eisenberg DM, Ettner SL, Appel S, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575.
2. Hume AL. Herbal products. In: Berardi RR, Newton GD, Oszko MA, et al, eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self Care, vol. 13. Washington DC: American Pharmaceutical Association; 2002:1065-1100.
3. Dietary Supplements PC SPES and SPES Recalled. Fax-Stat on Drugs. St. Louis, Mo:2002;XI:1.
4. Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med. 2002;136:590-595.
5. Samenuk D, Homoud MK, Contreras R, et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc. 2002;77:12-16.
6. Blendon RJ, Benson JM, Brodie M, Altman DE. Americans’ views on the use of dietary supplements. Arch Intern Med. 2001;161:805-810.
7. Ang-Lee MK, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286:208-216.
8. Piscitelli SC, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John’s wort. Lancet. 2000;355:547-548.
9. Ruschitzka F, Turina M, Luscher TF, Noll G. Acute heart transplant rejection due to St. John’s wort. Lancet. 2000;355:548-549.
10. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355: 134-138.
11. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002; 287:1853.
12. FTC Cracks Down on False Dietary Supplement Ads. Am J Health-Sys Pharm. 2001;58:1382-1384.
13. Cohen MH. Potential physician malpractice liability associated with complementary and integrative medical therapies. Ann Intern Med. 2002;136:596-603.
14. Klepser TB. Unsafe and potentially safe herbal therapies. Am J Health-Sys Pharm. 1999;56:125-138.

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