EBM Consult

Herbal or Natural Supplements Known to Inhibit Cytochrome P450 (CYP) 3A4


  • Many known drug interactions with prescription medications are mediated through CYP3A4.
  • Not only are herbal or natural medicines also on the rise, but the identification of natural medicines that are known inhibitors of CYP3A4 are also increasing in number.
  • As such, clinicians should be aware of common herbal or natural medicines available over-the-counter (OTC) and on the internet that can result in clinically relevant herb-drug interactions thereby putting patients at increased risk for clinically relevant side effects.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015


  • It is well known that the cytochrome (CYP) P450 enzyme system is involved in drug metabolism of many medications used in clinical practice and have been implicated in the causing clinically relevant drug-drug interactions.1,2  There are a number of CYP450 enzymes involved in mediating drug interactions and commonly include CYP1A2, 2C9, 2C19, 2D6, and 3A4.1  Of these CYP enzymes, CYP3A4 is not only the most prevalent CYP enzyme in the liver, but is used by more than 50% of medications on the market for their metabolism and elimination from the body.1  If the number and level of complexity were not enough with prescription medications alone, the addition of a growing increase in the use of natural and herbal medicines, which are now known to inhibit CYP enzymes as well, is only going to make it worse.3  In fact, the number of herbal or natural medicines that are known to inhibit CYP3A4 is growing and is of clinical importance when assessing the potential etiologies in adverse drug events that appear to be from a drug-drug interaction (see the table below).4-14  As such, all clinicians, regardless of specialty or level of training, need to be aware of the list natural medicines found in the table provided at EBM Consult.

    To see the online drug and herbal reference table for inhibitors of CYP3A4 .... Click Here

    It is evident from the table that most of these herbal products appear to directly inhibit the activity of CYP3A4 instead of influencing the gene transcription.4-14  In addition, many appear to be mechanism-based inhibitors.  Mechanism-based inhibition of CYP3A4 can be an inhibition or inactivation of existing CYP3A4 via the formation of a metabolite intermediate complex.  This can be an important form of inhibition since it can result in the irreversible inhibition of CYP3A4 in a concentration and time-dependent manner.  As such, medications depending on the activity and presence of functional CYP3A4 enzyme may then not be metabolized until the body turns on gene transcription to make more of the enzyme.  Since the effect of gene transcription is not acute, it could take days to regenerate the needed CYP3A4 enzyme to metabolize the accumulating medication.  This can obviously put the patient at significant risk for drug related side effects and/or toxicities.


    1. Rendic S, Ci Carlo FJ.  Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors.   Drug Metab Rev  1997;29:413-580.
    2. United States Food and Drug Administration.  Guidance for Industry.  Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling.  September 2006. Clinical Pharmacology. Accessed last on 5/19/2009.
    3. Busti AJ, Nuzum DN, Daves B, McKeever GC.  Why should healthcare providers learn the pharmacology of natural or herbal medicines?  PW Nat Med Newsl  2009;1(1):1-3.  
    4. Subehan, Usia T, Iwata H et al.  Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants.  J Ethnpharmacol  2006;105:449-55.  
    5. Budzinki JW, Foster BC, Vandenhoek S et al.  An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures.  Phytomedicine  2000;7:273-82.  
    6. Tsukamoto S, Aburantani M, Ohta T.  Isolation of CYP3A4 inhibitors from the Black Cohosh (Cimicifuga racemosa) Evid Based Complement Alternat Med  2005;2:223-226.  
    7. Usia T, Watabe T, Kadota S et al.  Metabolite-cytochrome P450 complex formation by methylenedioxyphenyl lignans of Piper cubeba: mechanism based inhibition.  Life Sci  2005;76:2381-91.  
    8. Iwata H, Tezuka Y, Kadota S et al.  Mechanism-based inactivation of human liver microsomal CYP3A4 by rutaecarpine and limonin from Evodia fruit extract.  Drug Metab Pharmacokinet  2005;20:34-45.  
    9. Kupferschmidt HH, Ha HR, Ziegler WH et al.  Interaction between grapefruit juice and midazolam in humans.  Clin Pharmacol Ther  1995;58:20-8. 
    10. Hukkinen SK, Varhe A, Oikkola KT et al.  Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice.  Clin Pharmacol Ther  1995;58:127-32.  
    11. Usia T, Watabe T, Kadota S et al.  Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum.  Biol Pharm Bull  2005;28:495-9. 
    12. Chan WK, Delucchi AB.  Resveratrol, a red wine constituent, is a mechanism-based inhibitor of cytochromeP450 3A4.  Life Sci  2000;67:3103-12.  
    13. Polli JW, Jarrett JL, Studenberg SD et al. Role of P-Glycoprotein on the CNS Disposition of Amprenavir (141W94), an HIV Protease Inhibitor.  Pharm Res  1999;16:1206-12.  
    14. Iwata H, Tezuka Y, Kadota S et al.  Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract.  Drug Metab Dispos  2004;32:1351-8.  
    15. Tsukamoto S, Tomise K, Miyakawa K et al.  CYP3A4 inhibitory activity of new bisalkaloids, dipiperamides D and E, and cognates from white pepper.  Bioorg Med Chem  2002;10:2981-5.

MESH Terms & Keywords

  • Cytochrome, P450, CYP450, CYP3A4 Inhibitors, Herbal Supplements, Herbal Drug Interactions