Herb-Drug Interactions

By Dónal P. O’Mathúna, PhD

The use of herbal remedies has expanded widely in the last decade. Sales of dietary supplements in the United States doubled every two years between 1991 and 1999.1 According to the Natural Marketing Institute, a consulting group that monitors consumer trends, nearly $17 billion was spent on dietary supplements in 2001 in the United States—with herbal remedies estimated to generate $4 billion.2 Izzo and Ernst have estimated that Europe spends nearly $7 billion on herbal therapies.3

Along with this sustained growth in usage has come increasing scrutiny into the safety of herbal remedies. On the one hand, some studies find evidence that certain herbs may be effective for specific conditions. But on the other hand, there is growing evidence that many products available on the U.S. market are of poor quality.4 In addition, several studies have found herbal products that are contaminated with prescription drugs, pesticides, or heavy metals.5 As is the case with pharmaceuticals, even the highest quality herbal remedies have dangers inherent to their use; dangers of which consumers often are unaware. A National Consumers League survey released in 2002 found that 86% of Americans believe that products labeled "natural" are safe.6 Yet if herbal remedies are effective, they must contain biologically active chemicals, which increases the possible risk of side effects and interaction with other drugs.

This article will focus on the interactions between herbal remedies and pharmaceutical drugs. Research in this area has been slow to develop, in part because of a failure to recognize the significance of the problem.

Systematic reviews of the medical literature reveal relatively few case reports.7 Some take this to mean that the risks of herbal remedies are being blown out of proper proportion as a way to distract public attention from the risks of pharmaceuticals.8 Yet there also are many reasons to believe that herb-drug interactions have been under-reported. As one reviewer commented, "Lack of evidence of risks is clearly not the same as evidence of lack of risks."9 However, a number of unexpected bleeding episodes during and after surgery have been linked to interactions between herbal remedies and drugs used during and after surgery, leading the American Society of Anesthesiologists to suggest that patients discontinue all dietary supplements at least two weeks prior to surgery.10

All herbal remedies are complex mixtures of compounds, any number of which might interact with drugs taken at the same time. However, often there is little information on the active ingredient in the remedy, and even less on which ingredient(s) might interact with drugs or other herbs. People taking herbs often are treating themselves for chronic ailments for which they likely are taking prescribed pharmaceutical drugs. Because many patients take herbal remedies without telling their conventional practitioners, the chances are increased that adverse symptoms may not be viewed as interactions between herbs and drugs.

As more case reports become available involving herbal remedies, it will be important to evaluate the quality of reports. Fugh-Berman and Ernst have developed a 10-point scale that allows ready evaluation of the quality of a case report.7

Each case is given one point for each criterion satisfied (see Table 1 below), and then scored according to the following scale:

  • 0-3 points: unevaluable—report contains insufficient information to determine the likelihood of an interaction;
  • 4-7 points: possible interaction—evidence points to an interaction, but other causes may be involved;
  • 8-10 points: likely interaction—report provides reliable evidence for an interaction.7
Table 1
10-point scoring system8
  • Adequate patient history given
  • Concurrent diseases, conditions, or medications associated with the adverse event
  • Concomitant medications documented
  • Adequate description of interactors
  • Obvious alternative explanations have been excluded
  • Chronology complete
  • Time between taking herb and adverse event manifesting itself is reasonable
  • Adverse event is adequately described
  • Event ceases when herb stopped
  • Event recurs upon rechallenge

As additional cases of interactions between herbs and drugs are reported, this scoring system gives providers a handy checklist for evaluating the quality of each report. These same authors went on to review the medical literature and identified 108 case reports of adverse events alleged to involve interactions between herbal remedies and drugs.7 Using the above system, 74 were classified as unevaluable, 20 were possible interactions, and 14 were likely interactions. Warfarin was the drug most commonly involved in adverse event reports, while St. John’s wort was the herb most commonly implicated.

The case of St. John’s wort is a good example of the importance of conducting rigorous research on herbal remedies. Clinical studies have demonstrated that St. John’s wort is as effective as sertraline and imipramine in the treatment of mild depression, but is no more effective than placebo in treating major depression.11 Increased medical attention and widespread popular use of St. John’s wort also has led to it being the herb with the largest number of case reports of herb-drug interactions (85 cases). Of these, 54 involved cyclosporin, 12 involved oral contraceptives, seven involved warfarin, nine with antidepressants, and one each with phenprocoumon, theophylline, and loperamide.7 In addition, four clinical studies have provided more rigorous data about the nature of the interactions.12

Patients taking St. John’s wort also may be taking pharmaceutical antidepressants. Nine case reports have documented symptoms of serotonin syndrome that may have been the result of each substance potentiating the other. A variety of antidepressants were involved, most commonly sertraline, but also including nefazodone and trazodone.12 Some may assume that treating their conditions with both herbal remedies and pharmaceutical drugs will bring added benefits; however, this may increase the likelihood of adverse effects.

Several studies (though not every study) have found evidence that St. John’s wort induces one of the cytochrome P450 enzymes, thus providing a mechanism of action to explain the reports of interactions.13 Yet St. John’s wort contains several biologically active ingredients, and the extent of the reported herb-drug interactions could not be explained by induction of P450 enzymes alone. A recent clinical study demonstrated that after taking St. John’s wort for 32 days, patients had a four-fold increase in the expression of P-glycoprotein.14 This molecular complex functions as a pump to actively eliminate drugs from cells and facilitates the development of resistance to those drugs, which include methotrexate, protease inhibitors, and steroids. Research is ongoing in developing inhibitors of P-glycoprotein that might serve to enhance the effectiveness of other drugs, particularly chemotherapy agents. Clearly, the effectiveness of those drugs would be counteracted by St. John’s wort.

Consumer interest in St. John’s wort has led to research into its effectiveness and safety. This has revealed evidence of both efficacy and drug-herb interactions. As a result, patients can be better advised about the conditions for which St. John’s wort may be most beneficial, and about the drugs that should be avoided or carefully monitored if taken concomitantly.

For most herbs, however, the evidence for herb-drug interactions is of lesser quality. Even with the St. John’s wort case reports, only seven (8%) satisfied enough of Fugh-Berman and Ernst’s criteria to be classified as "likely interactions."7 Given these limitations, Table 2 has been compiled from many sources to give guidance on the types of interactions most likely to occur with commonly used herbs. Many interactions are supported only by a theoretical connection with the herb’s mechanism of action, or a concern based on traditional use.

Unfortunately, due to lack of uniform reporting requirements, the incidence of each interaction is not known.

For these reasons, clinicians merely can alert patients to the fact that herbs may interact with other medications and dietary supplements. Patients should be encouraged to be open about all the substances they are consuming, regardless of whether they view them as drugs. Such openness can be encouraged if clinicians know about the risks and benefits of herbal medicines, including some of the most common herb-drug interactions presented in this article.

Increased surveillance of patients for herb-drug interactions is another important way to develop accurate knowledge in this area. If an interaction between an herb and a drug is suspected, it should be reported to the Food and Drug Administration’s MedWatch program in the same way as drug-drug interactions are reported (1-800-FDA-1088 or www.fda.gov/medwatch).

Table 2 is not exhaustive and will need to be updated as new reports and studies are published. Those seek- ing more detailed information or information on herbs not mentioned in Table 2 are encouraged to consult the articles and general resources listed in the reference below.

Dr. O’Mathúna is Professor of Bioethics and Chemistry at Mount Carmel College of Nursing, Columbus, OH.

References

1. Zeisel SH. Regulation of "nutraceuticals." Science 1999;285:1853-1855.

2. Dietary Supplement Trends Report. Philadelphia, PA: Natural Marketing Institute; March 2002.

3. Izzo A, Ernst E. Interactions between herbal medicines and prescribed drugs. Drugs 2001;61:2163-2175.

4. Larimore WL, O’Mathúna DP. Herbal remedy quality and the role of quality certification programs. Ann Pharmacotherapy. In press.

5. Huggett DB, et al. Organochlorine pesticides and metals in select botanical dietary supplements. Bull Environ Contam Toxicol 2001;66:150-155.

6. National Consumers Release. Natural’ or plant-derived’ labeling can mislead. Jan. 17, 2002.

7. Fugh-Berman A, Ernst E. Herb-drug interactions: Review and assessment of report reliability. Br J Clin Pharmacol 2001;52:587-595.

8. Sørensen J. Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: Mechanisms involved and their medical implications. J Altern Complement Med 2002;8:293-308.

9. Ernst E. Herb-drug interactions: Potentially important but woefully under-researched. Eur J Clin Pharmacol 2000;56:523-524.

10. Norred C, Brinker F. Potential coagulation effects of preoperative complementary and alternative medicines. Altern Ther Health Med 2001;7:58-67.

11. Shelton RC, et al. Effectiveness of St John’s wort in major depression: A randomized controlled trial. JAMA 2001;285:1978-1986.

12. Gold JL, et al. Herbal-drug therapy interactions: A focus on dementia. Curr Opin Clin Nutr Metab Care 2001;4:29-34.

13. Obach RS. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 2000;294:88-95.

14. Hennessy M, et al. St John’s wort increases expression of P-glycoprotein: Implications for drug interactions. Br J Clin Pharmacol 2002;53:75-82.

Other Articles on Herb-Drug Interactions

Brown R. Potential interactions of herbal medicines with antipsychotics, antidepressants and hypnotics. Eur J Herbal Med 1997;3:25-28.

Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355:134-138.

Kuhn MA. Herbal remedies: Drug-herb interactions. Crit Care Nurse 2002;22:22-32.

Lyons T. Herbal medicines and possible anesthesia interactions. AANA J 2002;70:47-51.

Miller LG. Herbal medicinals: Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-2211.

Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22:195-206.

Williamson E. Synergy and other interactions in phytomedicines. Phytomedicine 2001;8:401-409.

General Resources

Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, OR: Eclectic Medical Publications, 1998.

Jellin JM, et al. Pharmacist’s Letter/Prescriber’s Letter: Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Facility, 2002. Also available at www.naturaldatabase.com.

PDR for Herbal Medicines. 2d ed. Montvale, NJ: Medical Economics, 2000.