Common Herbal Dietary Supplement–Drug Interactions

 

Nearly 25% of U.S. adults report concurrently taking a prescription medication with a dietary supplement. Some supplements, such as St. John's wort and goldenseal, are known to cause clinically important drug interactions and should be avoided by most patients receiving any pharmacologic therapy. However, many other supplements are predicted to cause interactions based only on in vitro studies that have not been confirmed or have been refuted in human clinical trials. Some supplements may cause interactions with a few medications but are likely to be safe with other medications (e.g., curcumin, echinacea, garlic, Asian ginseng, green tea extract, kava kava). Some supplements have a low likelihood of drug interactions and, with certain caveats, can safely be taken with most medications (e.g., black cohosh, cranberry, ginkgo, milk thistle, American ginseng, saw palmetto, valerian). Clinicians should consult reliable dietary supplement resources, or clinical pharmacists or pharmacologists, to help assess the safety of specific herbal supplement–drug combinations. Because most patients do not disclose supplement use to clinicians, the most important strategy for detecting herb-drug interactions is to develop a trusting relationship that encourages patients to discuss their dietary supplement use.

Estimates show that between 40% and 60% of U.S. adults with chronic disease use dietary supplements, and among patients taking prescription medications, an estimated 20% to 25% concurrently use a dietary supplement.13 Accordingly, there has been increasing concern over the potential for dietary supplements, particularly herbal dietary supplements, to interact with prescription medications. The National Center for Complementary and Integrative Health defines dietary supplements as a variety of products, including herbs, vitamins and minerals, and probiotics. This review focuses on drug interactions with herbal dietary supplements, which are defined as supplements containing whole plant or plant extracts that are consumed as powder, capsule, tablet, or liquid formulations.

 Enlarge     Print

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferencesComments

Clinicians should ask patients who take over-the-counter or prescription medications about their use of dietary supplements.

C

5, 46, 47

Many patients use dietary supplements, yet few discuss supplement use with their physicians.

Drug interactions with the following herbal supplements are unlikely or very limited: black cohosh, cranberry, ginkgo, American ginseng, milk thistle, saw palmetto, and valerian. With specific exceptions (e.g., ginkgo and warfarin [Coumadin]), clinicians should have low concern for drug interactions with these herbal supplements.

C

711, 1317, 22, 24, 2730, 4143, 45

Numerous clinical trials report consistent findings.

Drug interactions with goldenseal and St. John's wort are highly likely, and clinicians should counsel patients to avoid concurrent use with over-the-counter or prescription medications.

C

12, 13, 15, 23, 44

Several clinical trials report consistent findings.


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferencesComments

Clinicians should ask patients who take over-the-counter or prescription medications about their use of dietary supplements.

C

5, 46, 47

Many patients use dietary supplements, yet few discuss supplement use with their physicians.

Drug interactions with the following herbal supplements are unlikely or very limited: black cohosh, cranberry, ginkgo, American ginseng, milk thistle, saw palmetto, and valerian. With specific exceptions (e.g., ginkgo and warfarin [Coumadin]), clinicians should have low concern for drug interactions with these herbal supplements.

C

711, 1317, 22, 24, 2730, 4143, 45

Numerous clinical trials report consistent findings.

Drug interactions with goldenseal and St. John's wort are highly likely, and clinicians should counsel patients to avoid concurrent use with over-the-counter or prescription medications.

C

12, 13, 15, 23, 44

Several clinical trials report consistent findings.


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Pharmacokinetic vs. Pharmacodynamic Interactions

The Authors

show all author info

GARY N. ASHER, MD, MPH, is an associate professor in the Department of Family Medicine, adjunct associate professor in the Gillings School of Global Public Health, and director of integrative medicine services for the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill....

AMANDA H. CORBETT, PharmD, BPCS, FCCP, is an associate professor at the Eshelman School of Pharmacy and the global pharmacology coordinator for the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill.

ROY L. HAWKE, PharmD, PhD, is an assistant professor and director of graduate education for the Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill.

Address correspondence to Gary N. Asher, MD, MPH, University of North Carolina, 590 Manning Dr., CB #7595, Chapel Hill, NC 27599-7595 (e-mail: gasher@med.unc.edu). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

REFERENCES

show all references

1. Miller MF, Bellizzi KM, Sufian M, Ambs AH, Goldstein MS, Ballard-Barbash R. Dietary supplement use in individuals living with cancer and other chronic conditions: a population-based study. J Am Diet Assoc. 2008;108(3):483–494....

2. Gardiner P, Phillips R, Shaughnessy AF. Herbal and dietary supplement—drug interactions in patients with chronic illnesses [published correction appears in Am Fam Physician. 2008;78(7):808]. Am Fam Physician. 2008;77(1):73–78.

3. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337–344.

4. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–141.

5. Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002–2012. Natl Health Stat Report. 2015;(79):1–16.

6. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;(12):1–23.

7. Fuchikami H, Satoh H, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y. Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2006;34(4):577–582.

8. Patel NM, Derkits RM. Possible increase in liver enzymes secondary to atorvastatin and black cohosh administration. J Pharm Pract. 2007;20(4):341–346.

9. Stoddard GJ, Archer M, Shane-McWhorter L, et al. Ginkgo and warfarin interaction in a large veterans administration population. AMIA Annu Symp Proc. 2015;2015:1174–1183.

10. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled trial. Ann Intern Med. 2004;141(1):23–27.

11. Han Y, Guo D, Chen Y, Chen Y, Tan ZR, Zhou HH. Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers. Eur J Clin Pharmacol. 2009;65(6):585–591.

12. Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH. St John's wort: effect on CYP3A4 activity. Clin Pharmacol Ther. 2000;67(5):451–457.

13. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther. 2005;77(5):415–426.

14. Gurley BJ, Barone GW, Williams DK, et al. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos. 2006;34(1):69–74.

15. Gurley BJ, Swain A, Hubbard MA, et al. Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Mol Nutr Food Res. 2008;52(7):755–763.

16. Lilja JJ, Backman JT, Neuvonen PJ. Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolam—probes of CYP2C9, CYP1A2, and CYP3A4. Clin Pharmacol Ther. 2007;81(6):833–839.

17. Mellen CK, Ford M, Rindone JP. Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients. Br J Clin Pharmacol. 2010;70(1):139–142.

18. Chen Y, Liu WH, Chen BL, et al. Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers. Ann Pharmacother. 2010;44(6):1038–1045.

19. Kusuhara H, Furuie H, Inano A, et al. Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol. 2012;166(6):1793–1803.

20. Volak LP, Hanley MJ, Masse G, et al. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2013;75(2):450–462.

21. Gorski JC, Huang SM, Pinto A, et al. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther. 2004;75(1):89–100.

22. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto [published correction appears in Clin Pharmacol Ther. 2005;77(5):456]. Clin Pharmacol Ther. 2004;76(5):428–440.

23. Gurley BJ, Swain A, Williams DK, Barone G, Battu SK. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res. 2008;52(7):772–779.

24. Gurley BJ, Gardner SF, Hubbard MA, et al. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging. 2005;22(6):525–539.

25. Hajda J, Rentsch KM, Gubler C, Steinert H, Stieger B, Fattinger K. Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans. Eur J Pharm Sci. 2010;41(5):729–735.

26. Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34(2):234–238.

27. Jiang X, Williams KM, Liauw WS, et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005;59(4):425–432.

28. Zadoyan G, Rokitta D, Klement S, et al. Effect of Ginkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers. Eur J Clin Pharmacol. 2012;68(5):553–560.

29. Andrade AS, Hendrix C, Parsons TL, et al. Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir. BMC Complement Altern Med. 2008;8:50.

30. Lee LS, Wise SD, Chan C, Parsons TL, Flexner C, Lietman PS. Possible differential induction of phase 2 enzyme and antioxidant pathways by American ginseng, Panax quinquefolius. J Clin Pharmacol. 2008;48(5):599–609.

31. Malati CY, Robertson SM, Hunt JD, et al. Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants. J Clin Pharmacol. 2012;52(6):932–939.

32. Anderson GD, Rosito G, Mohustsy MA, Elmer GW. Drug interaction potential of soy extract and Panax ginseng. J Clin Pharmacol. 2003;43(6):643–648.

33. Jiang X, Williams KM, Liauw WS, et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects [published correction appears in Br J Clin Pharmacol. 2004;58(1):102]. Br J Clin Pharmacol. 2004;57(5):592–599.

34. Donovan JL, Chavin KD, Devane CL, et al. Green tea (Camellia sinensis) extract does not alter cytochrome p450 3A4 or 2D6 activity in healthy volunteers [published correction appears in Drug Metab Dispos. 2004; 32(11):1331]. Drug Metab Dispos. 2004;32(9):906–908.

35. Werba JP, Giroli M, Cavalca V, Nava MC, Tremoli E, Dal Bo L. The effect of green tea on simvastatin tolerability. Ann Intern Med. 2008;149(4):286–287.

36. Knop J, et al. Inhibitory effects of green tea and (–)-epigallocatechin gallate on transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein. PLoS One. 2015;10(10):e0139370.

37. Misaka S, Yatabe J, Müller F, et al. Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther. 2014;95(4):432–438.

38. Gurley BJ, et al. Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos. 2007;35(2):240–245.

39. Gurley BJ, Swain A, Hubbard MA, et al. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Clin Pharmacol Ther. 2008;83(1):61–69.

40. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos. 2002;30(11):1153–1157.

41. Gurley B, Hubbard MA, Williams DK, et al. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol. 2006;46(2):201–213.

42. Kawaguchi-Suzuki M, Frye RF, Zhu HJ, et al. The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos. 2014;42(10):1611–1616.

43. Markowitz JS, Donovan JL, Devane CL, et al. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther. 2003;74(6):536–542.

44. Wang LS, Zhou G, Zhu B, et al. St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther. 2004;75(3):191–197.

45. Donovan JL, DeVane CL, Chavin KD, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects of CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Dispos. 2004;32(12):1333–1336.

46. AARP; National Center for Complementary and Alternative Medicine. Complementary and Alternative Medicine: What People Aged 50 and Older Discuss With Their Health Care Providers. 2010. https://nccih.nih.gov/sites/nccam.nih.gov/files/news/camstats/2010/NCCAM_aarp_survey.pdf. Accessed May 17, 2017.

47. Shelley BM, Sussman AL, Williams RL, Segal AR, Crabtree BF; Rios Net Clinicians. ‘They don't ask me so I don't tell them’: patient-clinician communication about traditional, complementary, and alternative medicine. Ann Fam Med. 2009;7(2):139–147.

 

 

Copyright © 2017 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions

CME Quiz

More in AFP


Editor's Collections


Related Content


More in Pubmed

MOST RECENT ISSUE


Nov 15, 2017

Access the latest issue of American Family Physician

Read the Issue


Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.

Sign Up Now

Navigate this Article