As the use of herbal medicine continues to rise, cultivating an awareness of potential interactions between pharmaceuticals and herbs has become more important than ever, in order to inform doctors and healthcare professionals in their practice (1). Similarly, it is important for herbalists to understand the subtleties of herb-drug interactions, as often a herb and a pharmaceutical drug will interact but that does not translate into an immediate contraindication.
Herbalists and doctors who are able to distinguish between pharmacokinetic (how the body affects a substance) and pharmacodynamic (how a substance affects the body) interactions will be able to make better clinical judgement on the concomitant use of a herb with a drug. They can discern whether to adjust the dosage of the herb or drug or stop the use of either completely (2).
A thorough assessment of the patient history, and open communication with the patient, are essential. During patient consultations, herbal medicine and supplement use are an important part of their drug history to discuss. Patients may fear that their doctor will disapprove of their use of non-allopathic medicine, so by enquiring in a non-judgemental manner, the practitioner can ease patients’ reluctance to share with their doctors what herbs they are taking (3).
Often patients themselves are unaware of the potential risks and benefits there are when taking herbs and drugs concomitantly, so educating them and encouraging them to disclose the herbal medicines and supplements they are taking is important for patient and practitioner. Herbalists and doctors alike have a responsibility to provide information on potential interactions and refer to herb-drug interaction checkers for guidance (3).
Understanding herb-drug interactions
There are different important aspects to take into consideration when looking at herb-drug interactions.
1. Pharmacokinetic Interactions
Pharmacokinetic interactions involve changes in the absorption, distribution, metabolism, or excretion (ADME) of drugs. It is crucial to consider how herbs may affect the bioavailability and elimination of pharmaceuticals. The risk of a pharmacokinetic interaction happens when a herbal medicine and a concurrently administered drug, use the same mechanisms of ADME (4). The potential competition for shared ADME pathways between the herbal supplement/medicine and the drug, can lead to alterations in the concentration of the drug at its target site. This interaction can influence the effectiveness and outcomes of the drug in the body (4). An example of this could be when a herb and a drug are metabolised or excreted via the same pathway (5). For example, grapefruit juice inhibits the metabolism and increases the absorption of the anti-arrhythmic drug amiodarone, subsequently increasing amiodarone plasma levels by 50% (6).
Cytochrome P450 Enzymes and herb–drug metabolism
Understanding metabolic pathways of commonly used herbs is important. Some herbs may compete for the same metabolic pathway as pharmaceuticals, leading to altered drug concentrations. Many drugs are metabolised by cytochrome P450 enzymes. These six CYP enzymes account for the metabolism of 80% of all prescribed drugs: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 (2, 7).
For example, grapefruit juice inhibits the metabolism of certain drugs. Grapefruit juice contains compounds known as furanocoumarins, which can inhibit the activity of CYP3A4 (8). Statins (simvastatin, atorvastatin) are a commonly used medication to lower cholesterol levels that can interact with grapefruit juice as they are metabolised by CYP3A4 (8). When consumed with grapefruit juice, the inhibition of CYP3A4 by the juice can lead to increased blood levels of some statins. This heightened concentration may amplify the drug’s effects, potentially increasing the risk of statin side effects, including muscle-related complications such as myopathy or rhabdomyolysis, as reported in isolated case reports (9).
Certain herbs, such as St. John’s wort and echinacea, can induce or inhibit CYP enzymes, influencing drug metabolism and potentially altering therapeutic levels (2). An example of this is the interaction between St John’s wort and the blood thinner warfarin. St John’s wort contains various active compounds, including hyperforin and hypericin, which can induce the activity of several CYP450 enzymes, particularly CYP3A4 and CYP2C9 (5). Warfarin is also metabolised by the liver enzyme CYP3A4. This means that if St John’s Wort induces the activity of CYP3A4, it may lead to increased metabolism and clearance of warfarin from the body. This can result in reduced efficacy of warfarin, potentially leading to a decrease in its anticoagulant effect and an increased risk of blood clot formation (10). St John’s wort can also affect the metabolism of P-glycoprotein (P-gp) substrate drugs (2). P-gp is an efflux pump meaning it ejects foreign substances (including medicines) outside of a cell. As St. John’s wort induces intestinal P-gp, this causes a decreased absorption and therefore lowered plasma concentrations of some drugs including digoxin, talinolol, and fexofenadine (2).
When a herb induces a particular CYP enzyme, it can decrease the efficacy of the drug that is metabolised by that enzyme, and when the herb inhibits a liver enzyme, it generally increases the plasma concentration of the drug that is metabolised by the same enzyme.
2. Pharmacodynamic Interactions
Pharmacodynamic interactions involve direct effects on drug receptors or physiological processes. Herbs may have similar or opposing effects to pharmaceuticals, leading to enhanced or reduced therapeutic outcomes (2, 5). An example of this would be the use of hawthorn together with beta-blockers, a drug class used to control and decrease heart rate. The use of beta-blockers like bisoprolol with hawthorn is not contraindicated, however, as hawthorn can also decrease heart rate by attaching to beta receptors in the heart, their co-administration can have a mild to moderate additive effect (11). Another example of drugs and herbs that can have an interaction by acting via the same pathway is the potential interaction between warfarin and ginkgo. Warfarin is commonly prescribed to prevent blood clots, and its anticoagulant effects are carefully monitored to maintain a balance between preventing clots and avoiding excessive bleeding. Ginkgo is a medicinal plant that is used for many indications, including cognitive enhancement and improved blood circulation. Ginkgo contains ginkgolide B, a constituent that displaces platelet-activating factor (PAF) from its binding sites, decreasing blood coagulation, and therefore also having blood-thinning properties (2). When warfarin and ginkgo biloba are used together, there is a potential for an additive anticoagulant effect, increasing the risk of bleeding (12). Some suggest PAF is a weak platelet activator and there is conflicting research as to whether the effect could be significant (13). A large medical record database indicated that the simultaneous use of ginkgo and warfarin was associated with a 38% higher risk of experiencing a bleeding adverse event (12).
Frequently used medicinal plants and their drug interaction potential
Turmeric
Human studies have shown no effect of turmeric on several CYP enzymes, including CYP2C9 and CYP3A4 (14). A single study showed that turmeric induces CYP1A2, which could decrease levels of some antidepressant and antipsychotic medications, but this should be interpreted with caution (15). There is one study showing that curcumin increased plasma levels of the drug sulfasalazine in vivo (16). This does not mean it has to be avoided when used concomitantly with sulfasalazine, but it can be useful information when prescribed simultaneously.
Echinacea
Echinacea does not appear to inhibit or induce CYP2D6, CYP2C9, or P-gp in human studies. There are conflicting and limited results about its effects on CYP1A2 and CYP3A4 (17).
St. John’s wort
St. John’s wort has been shown in multiple human studies to be a potent inducer of CYP3A4 and P-gp. Clinical studies have found St. John’s wort to reduce plasma levels of cyclosporine, tacrolimus, warfarin, protease inhibitors, irinotecan, theophylline, digoxin, venlafaxine, and oral contraceptives, amongst others (18).
Garlic
Human studies have shown garlic extract to decrease concentrations of drugs that are transported by P-gp, so garlic extract in high doses should be used with caution when taken simultaneously with drugs that are transported by P-gp like colchicine, digoxin, doxorubicin, quinidine, rosuvastatin, tacrolimus and verapamil (19).
Ginkgo
Ginkgo inhibits platelet aggregation, which could increase bleeding risk, especially in combination with antiplatelet or anticoagulant drugs (2). Co-administration of ginkgo and warfarin should be closely monitored. Several human clinical trials have demonstrated no clinically important effects on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 (20).
Milk thistle
Milk thistle does not have inhibitory or inductive effects on CYP1A2, CYP2D6, CYP2E1, CYP3A4, or P-gp, as demonstrated in multiple human studies (21) .
Valerian
Valerian does not induce nor inhibit CYP1A2, CYP2D6, CYP2E1, or CYP3A4, and, therefore, is unlikely to have effects on medications that are metabolised by those enzymes (22). Valerian is a central nervous system sedative, so it should be used with caution with drugs like benzodiazepines or other central nervous system depressants, due to their additive effects.
Herb-drug interaction resources
Databases
The Natural Medicines Comprehensive Database (NATMED) is an authoritative resource available on herbal medicine and dietary supplements. The interaction checker they have is very useful.
Medscape also has its own interaction checker, which can be accessed on the Medscape website. You will need to subscribe to Medscape to access it, but Medscape membership is free.
Websites
On the Memorial Sloan Kettering Cancer Center’s About Herbs page, there is helpful and user-friendly evidence-based information on herbs and their interactions. You can access it on mskcc.org.
Stockleys Herbal Medicine Interactions is also a helpful resource, and so is NatMed Pro.
Peer-Reviewed Journals and books
It is important to stay updated on the latest research in pharmacognosy and herb-drug interactions by referring to peer-reviewed journals. Journals like the Journal of Ethnopharmacology and the Journal of Herbal Medicine provide valuable insights. There are systematic and meta-analysis studies covering herb-drug interactions.
An example of a useful one is titled: Interaction of herbal products with prescribed medications: A systematic review and meta-analysis, by Awortwe et al., 2019 (5).
The Essential Guide To Herbal Safety by Simon Mills is a valuable resource which shares a variety of information on herbal safety and potential drug interactions, as well as in-depth explanations about the nuances of herbal safety.
Summary: General rules
If the patient is taking herbs and drugs for the same indication at the same time then it may be best to stop one.
If the patient is taking herbs and drugs with opposite indications/effects at the same time then it may be best to stop one.
If a herb or supplement or drug does not have any reported interactions it means that we do not know if it is safe yet so caution applies.
Isolated clinical cases and preclinical data in animals are warnings but may not be significant at population level so do not panic.
Good communication between doctors and herbalists is important, as is an awareness of possible symptoms of herb-drug interactions which should be assessed on a case-by-case basis. As shared in this article, one can research the metabolic pathways of a pharmaceutical or herb to assess safety and check for interactions.
References
- WHO (2004) WHO Guidelines on Safety Monitoring of Herbal Medicines in Pharmacovigilance Systems. Geneva, Switzerland: World Health Organization.
- Asher, G. N., Corbett, A. H., & Hawke, R. L. (2017). Common herbal dietary supplement–drug interactions. American family physician, 96(2), 101–107.
- Vickers, K. A., Jolly, K. B., & Greenfield, S. M. (2006). Herbal medicine: women’s views, knowledge and interaction with doctors: a qualitative study. BMC complementary and alternative medicine, 6(1), 1–8.
- Rombolà, L., Scuteri, D., Marilisa, S., Watanabe, C., Morrone, L. A., Bagetta, G., & Corasaniti, M. T. (2020). Pharmacokinetic interactions between herbal medicines and drugs: their mechanisms and clinical relevance. Life, 10(7), 106.
- Awortwe, C., Bruckmueller, H., & Cascorbi, I. (2019). Interaction of herbal products with prescribed medications: A systematic review and meta-analysis. Pharmacological research, 141, 397–408.
- Libersa, C. C., Brique, S. A., Motte, K. B., Caron, J. F., Guedon-Moreau, L. M., Humbert, L., Vincent, A., Devos, P., and Lhermitte, M. A. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol 2000;49(4):373–378
- 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.
- Lilja, J. J., Kivistö, K. T., & Neuvonen, P. J. (1998). Grapefruit juice—simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG‐CoA reductase inhibitors. Clinical Pharmacology & Therapeutics, 64(5), 477–483.
- Dreier, J. P., & Endres, M. (2004). Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology, 62(4), 670–670.
- Ge, B., Zhang, Z., & Zuo, Z. (2014). Updates on the clinical evidenced herb-warfarin interactions. Evidence-Based Complementary and Alternative Medicine, 2014.
- Salehi, S., Long, S. R., Proteau, P. J., & Filtz, T. M. (2009). Hawthorn (Crataegus monogyna Jacq.) extract exhibits atropine-sensitive activity in a cultured cardiomyocyte assay. Journal of natural medicines, 63, 1–8.
- Stoddard, G. J., Archer, M., Shane-McWhorter, L., Bray, B. E., Redd, D. F., Proulx, J., & Zeng-Treitler, Q. (2015). Ginkgo and warfarin interaction in a large veterans administration population. In AMIA Annual Symposium Proceedings (Vol. 2015, p. 1174). American Medical Informatics Association.
- Koch, E. (2005). Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications after oral intake of Ginkgo biloba extracts. Phytomedicine, 12(1–2), 10–16.
- 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.
- 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.
- 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.
- 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.
- Henderson, L., Yue, Q. Y., Bergquist, C., Gerden, B., & Arlett, P. (2002). St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. British journal of clinical pharmacology, 54(4), 349–356.
- Hajda, J., Rentsch, K. M., Gubler, C., Steinert, H., Stieger, B., & Fattinger, K. (2010). Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans. European journal of pharmaceutical sciences, 41(5), 729–735.
- 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.
- Kawaguchi-Suzuki, M., Frye, R. F., Zhu, H. J., Brinda, B. J., Chavin, K. D., Bernstein, H. J., & Markowitz, J. S. (2014). The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metabolism and Disposition, 42(10), 1611-1616.
- Kelber, O., Nieber, K., & Kraft, K. (2014). Valerian: no evidence for clinically relevant interactions. Evidence-Based Complementary and Alternative Medicine: eCAM, 2014.
