Benton Bramwell, ND, and Matt Warnock
There are many ways that herbs and prescription drugs can affect the movement (kinetics) and effects (dynamics) of each other in the body. This includes changes in how each are absorbed, metabolized by enzymes in the liver and other organs, excreted through the kidneys and bowels, and how they interact with receptors that mediate their effects. Most often, unwanted herbal-drug interactions are a focus of interest when an herb is seen as a problem in interfering with the desired effects of a drug. To be fair, it is equally correct to state that a prescription drug may interfere with a well-applied herbal medicine.
Moreover, an optimal evaluation of a drug or an herb’s safety profile is best when it considers the context of an individual patient’s diet. Some drugs, in particular, may have varying safety issues that arise when diets change. For example, the safety profile of the anticoagulant drug warfarin may be significantly altered when vitamin K intake from diet exceeds about 150 mcg/d; therefore, a suggested strategy for reducing the risk of mishaps with warfarin dosing is to carefully maintain a consistent level of vitamin K intake in the diet.[1]
Since most of the data collected to date that is available for review speaks to known interactions of an herb altering aspects of a drug’s action, and since such interactions may lead to catastrophic outcomes clinically, we focus on this data in our review. Still, it is right and fair when a reasonable course of herbal medicine is employed to be aware of potentially interfering effects of prescription medicines.
This area is full of both in vitro data that shows the potential for undesirable interactions as well as in vivo data in animals that is informative and often used to guide recommendations from pharmacists and practitioners. However, human clinical data, to which the greatest weight can be attached, is available in lesser amounts.
For the purposes of this review, we have decided to focus primarily on human data (clinical studies and case reports) exploring the presence of interactions, in order to provide a snapshot of some of the most definitive, and perhaps most applicable, data available at the present time. It has been convenient in most cases to review reported interactions on a per herb basis, though in the case of analgesics/anti-inflammatories the data lends itself nicely to description as a group.
Analgesics (Pain relievers/anti-inflammatories)
Some of the most common pain relievers used are the analgesic acetaminophen and the non-steroidal anti-inflammatory drugs, such as ibuprofen. One of the herbs most commonly studied for its anti-inflammatory effects is Curcumin longa (turmeric), whose main actives, the curcuminoids, are often administered with small amounts of piperine (a constituent of black pepper) to enhance their absorption.
A randomized, controlled and crossover study of 8 subjects examined the effect of several days of pretreatment with curcuminoids and piperine on the pharmacokinetics of acetaminophen and a drug closely related to ibuprofen (flurbiprofen). In this study, short-term pretreatment with curcuminoids and piperine actually did not show any effects on the pharmacokinetics of acetaminophen or flurbiprofen.[2] As noted by the authors, these findings are in contrast to in vitro work from the same team.[3]
Thus, while the results did not provide evidence of an interaction with typical curcuminoid extract given over the short term, we do highlight these results as they provide an important opportunity to better understand why in vitro results that suggest an interaction do not necessarily always correlate with results seen in humans.
In this case, the authors point out that the in vivo levels of curcuminoids are relatively low compared with levels that lead to changes in activity of drug metabolizing enzymes, in vitro. Moreover, the curcuminoids detectable in vivo in this study are mostly conjugated (through glucuronidation or sulfation) and the potential for these conjugated forms to affect drug metabolism is not known. It may be that any effect of curcuminoids on drug-metabolizing enzymes is a dynamic heavily affected by the rate of curcuminoid absorption and how efficiently curcuminoid conjugation is taking place in the gut and/or liver.
In vivo realities of absorption that are essentially concomitant with a biotransformation process that may begin in the gut and continue in the liver exemplify how variables difficult to include in in vitro testing can make translation of basic science research to real world scenarios challenging.
One of the most frequently used herbal medicine combinations in Korea is known as Ojeok-san. From 1990 to 2010 this herbal medicine represented the most commonly used herbal medicine supplied by the National Health Insurance Corporation of Korea, and among its many uses is that of an analgesic.[4] Its formula is composed of small amounts of 17 herbs in combination, including mandarin orange (Citrus reticulata Blanco), ginger, Jujube fruit, licorice, and Chinese peony, among others.[5]
In a human study of 20 subjects, when Ojeok-san and the common anti-inflammatory drug Celecoxib were taken together there was a trend for reduction in maximum and total blood concentrations (Cmax and Area Under the Concentration Time Curve, AUC) of Celecoxib vs when Celcoxib was taken by itself.[6] There was also a tendency for the rate of elimination of Celecoxib to actually be slower when Ojeok-san and Celecoxib were taken together. How the suggested changes in kinetics of Celecoxib would ultimately impact the effectiveness of Celecoxib as a pain reliever is not known from the present data.
One of the most common drugs used to treat neuropathic pain is gabapentin. In terms of dietary-drug interactions, there is an interesting, albeit not necessarily clinically impactful interaction between gabapentin and shitake, a mushroom consumed in the diet (and consumed also in dietary supplements). In healthy subjects, dietary shitake mushroom slightly increased the renal clearance of gabapentin, though this change was not enough to significantly alter the in vivo concentration (AUC) of gabapentin.[7]
Goldenseal
There is evidence from a human study that in acting as an inhibitor of the drug-metabolizing enzyme CYP3A4, goldenseal increases the in vivo concentration of the benzodiazepine drug, midazolam (increased Area Under the Concentration Time Curve, AUC, and maximum serum concentration, Cmax), while slowing its rate of clearance.[8] Additional work in healthy humans shows that goldenseal decreases the metabolism of the drug debrisoquine, a drug used as a marker for CYP2D6 activity.[9] Further, goldenseal is shown in a human study to lower the AUC of metformin.[10] Goldenseal has also been evaluated in humans for its potential to affect action of the cellular drug transporter p–glycoprotein, using digoxin as marker of p-glycoprotein action, and did not produce an observable effect on this important aspect of drug metabolism.[11]
Salvia miltiorrhiza
One of the medicines used in China to improve circulation in cases of heart disease is an extract of the plant Salvia miltiorrhiza. When this herbal medicine is combined with aspirin, there are some interesting effects on the kinetics of both actives identified in the plant extract and also salicylic acid, the active of aspirin. In the case of one of the actives of the herb, salvionolic acid B, its elimination time is prolonged and the total concentration (area under the concentration-time curve, AUC) of salvionolic B decreases when the extract is taken along with aspirin. With respect to the active of aspirin, salicylic acid, its absorption time is shortened and the total amount absorbed is decreased when taken along with the herbal extract.[12] Any impact of these differences on actual clinical effectiveness of both Salvia miltiorrhiza extract and aspirin is less clear.
St John’s Wort
Perhaps no other herb is as extensively studied for potential to interact with drugs as St. John’s wort. At present, most of the information on St. John’s wort is in the context of its ability to increase both the expression of a liver enzyme that metabolizes many drugs (CYP3A4) and also to increase the activity of the drug transporter p-glycoprotein that removes many drugs from a cell’s interior. The combined effects of CYP3A4 induction and increased p-glycoprotein activity underscore the relatively potent potential for St. John’s wort to lower in vivo levels of drugs, and thus potentially lead to changes in pharmacodynamics. Prescription drugs whose blood levels are shown to be decreased when administered with St. John’s wort have largely been reviewed by Zhou.[13] Their findings, as well as those from several additional sources identified in the literature, are summarized below.
Drugs levels reduced by concurrent use with St. John’s wort, based on human data
| Drug Interacting with St. John’s wort | Effect reported | Category of Human data |
| amitriptyline | lower blood concentration | clinical study[14] |
| cyclosporine | lower blood concentration | case report[15] |
| digoxin | lower blood concentration | clinical study[16] |
| fexofenadine | lower blood concentration | clinical study[17] |
| gliclazide | lower blood concentration | clinical study[18] |
| indinavir | lower blood concentration | clinical study[19] |
| methadone | lower blood concentration | clinical study[20] |
| midazolam | lower blood concentration | clinical study[21] |
| nevirapine | lower blood concentration | case series (n=5)[22] |
| oxycodone | lower blood concentration | clinical study[23] |
| phenprocoumon | lower blood concentration | clinical study[24] |
| simvastatin | lower blood concentration | clinical study[25] |
| tacrolimus | lower blood concentration | clinical study[26] |
| theophylline | lower blood concentration | case report[27] |
| warfarin | lower blood concentration | case series (n=7)[28]; clinical study[29], clinical study[30] |
It can be difficult to anticipate if a particular herb-drug interaction might exist, based on interaction data from a drug in the same category, or even based on a single known action on biotransforming enzymes. An example of this is the current differing data regarding interactions between St. John’s wort and fentanyl and St. John’s wort and oxycodone.
In the case of St. John’s wort and fentanyl, there was no pharmacokinetic or pharmacodynamic interaction when human subjects consumed 900 mg of St. John’s wort extract over 30 days and also received fentanyl infusions, nor were there any significant effects on fentanyl’s analgesic effects.[31] This finding is in contrast to the demonstrated interaction between St. John’s wort and oxycodone noted above.
Even though CYP3A4 and p-glycoprotein affect the metabolism of many drugs (CYP3A4, for example, is estimated to affect the metabolism of over half of known drugs because of the low specificity with which it binds to substrates[32]), the effect of CYP3A4 is also dependent on genetic polymorphisms of CYP3A4.[33] Additionally, while induction of CYP3A4 is a predominant effect, there seem to be inhibitory effects of St. John’s wort constituents on other CYP (P450) enzymes.[34] Thus, the overall interaction of St. John’s wort (and likely many other herbs) and any given drug is dependent on the sum effects of multiple aspects of biotransformation. Given the noted disparity that can also occur between results from in vitro/animal testing and human testing, we feel it important to again stress that applicable human data is a potent, though relatively rare, clarifier in the sphere of herb-drug interaction data.
Green Tea
If St. John’s wort is the most studied herb for its interactions with drugs, the catechins from green tea may be a strong second, with multiple human studies accumulating in the last few years. The human data on this topic includes a 2017 open label study of 13 healthy subjects that found that co-administration of single dose of 300 mg epigallocatechin-3-gallate (EGCG) with 20 mg of rosuvastatin resulted in a significant decrease in the area under the concentration-time curve by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67-0.97), compared to baseline administration of rosuvastatin by itself.[35] Interestingly, however, when EGCG was given for ten days prior to dosing with rosuvastatin, there was not a significant reduction in AUC compared to baseline. A similar decrease in AUC after acute dosing with atorvastatin and either 300 mg or 600 mg of dried green tea extract is also reported, from a randomized, double-blind, placebo-controlled trial of 12 healthy subjects, though the effect was not dose-dependent.[36]
Quite striking decreases of nadolol concentration have also been reported with green tea as a beverage when the green tea was consumed either along with, or an hour before, nadolol dosing.[37] With concomitant administration, the geometric mean ratio for AUC of nadolol with green tea vs nadolol alone was 0.371 (90% CI 0.303-0.439); with 1 hour pre-dosing the mean ratio was 0.536 (0.406-0.665).
Significant reductions in the concentration of lisinopril, given after an overnight fast and concomitantly with 300 mg of EGCG in a water solution, have also been reported, suggesting overall lowered absorption of lisinopril.[38] Finally, significant reductions in concentrations of Nintedanib have also been found with concomitant administration of green tea extract, an effect that was most prominent in subjects with a genetic variant of the drug efflux transporter ABCB1 (3435 C>T), a finding that suggests alteration of this transporter’s activity as a plausible mechanism of action contributing to green tea’s effects on pharmacokinetics.[39]
The Ginsengs
Like St. John’s wort, Panax ginseng appears to increase activity of CYP3A4, as evidenced by lower concentrations of midazolam when the two are concurrently administered in healthy subjects.[40] However, the same work did not show an effect of Panax ginseng on inducing p-glycoprotein activity–highlighting again the need of clinical data specific to any particular herb-drug combination. When Panax ginseng, known to increase CYP3A4 activity, is given for two weeks prior to dosing with the protease inhibitor ritonavir, which inhibits CYP3A4 activity, there is not an observable effect on the pharmacokinetics of ritonavir.[41] Nor in the same study is any interaction seen between Panax ginseng and lopinavir, a drug also metabolized by CYP3A4 and formulated with ritonavir in order to slow lopinavir’s metabolism.[42]
With regard to the potential for interaction between Panax ginseng and warfarin, two weeks of their concurrent use led to increases in INR and PT of ischemic stroke patients compared to baseline, but there was not a significant across group difference in INR or PT compared to a group that only received warfarin.[43] An additional study in healthy subjects reported an increase in clearance of warfarin with Panax ginseng intake, but did not find a change in warfarin’s pharmacodynamics that would be clinically relevant.[44]
In subjects with stable coronary heart disease and chronic gastritis, it was found that two months of supplementation with saponins from Panax notoginseng (a species closely related to Panax ginseng) potentiated the antiplatelet effects of aspirin, including inhibiting platelet aggregation. Moreover, the combination of notoginseng and aspirin led to stronger inhibition of platelet production of multiple inflammatory cytokines derived from arachidonic acid as well as improved symptoms of dyspepsia compared to those in the aspirin group alone.[45]
American ginseng (Panax quinquefolius), a third species of the genus Panax, has been shown to significantly reduce concentrations (AUC) of warfarin after two weeks of use. In this case, there was also a measurable decrease in the INR when American ginseng was introduced.[46]
Ginkgo biloba
Ginkgo-drug interactions are also described repeatedly in human studies. In an open-label study of 14 healthy subjects, standardized Ginkgo biloba extract led to a significant reduction in absorption of midazolam (AUC and Cmax) compared to baseline absorption without ginkgo intake.[47] As in other interaction studies, midazolam is used as a marker for effect on the broadly acting metabolizing enzyme CYP3A4. The finding of decreased concentration of midazolam is in contrast to the results seen in another human study of 10 healthy subjects, where Ginkgo biloba extract was seen to significantly increase the absorption of midazolam.[48] The reasons for this discrepancy are not entirely clear. It is noted that several other drugs were included in the first study (lopinavir and ritonavir), though a washout period was included to minimize effects of these drugs. This latter study (Uchida) also showed a decrease in levels of tolbutamide (metabolized by the enzyme CYP2C9) associated with Ginkgo biloba use.
In another small study, in 2 out of 8 healthy subjects, Ginkgo biloba was reported to approximately double the maximal blood concentration of the calcium channel blocker nifedipine, leading to headaches, dizziness, and hot flashes in these subjects.[49] In a further interaction, ginkgo administration has been shown to increase hydroxylation of omeprazole through the CYP2C19 enzyme, leading to decreased blood concentrations of omeprazole in 18 healthy subjects.[50] Interestingly, ginkgo also seemed to slow renal clearance of the hydroxylated form of omeprazole in this study.
Echinacea
Another herb with literature available describing its interactions with drugs in vivo is Echinacea purpurea. Echinacea has been shown to increase the bioavailability of orally administered midazolam (again a marker of affecting metabolism through CYP3A4 activity); to increase blood concentration (area under the curve) of orally administered tolbutamide (marker of affecting metabolism through CYP2C9); and to both slow the rate of clearance of orally administered caffeine while delaying the time to attainment of its maximal concentration.[51] In contrast, there is some evidence of echinacea causing small decreases in concentrations of the anti-HIV protease inhibitor darunavir. While the change was not substantial enough to merit a change in darunavir dosing, monitoring of darunavir levels is warranted with echinacea use.[52] Illustrating that there is sometimes a gap between establishment of a pharmacokinetic interaction and actual observable impact of drug effect, though echinacea has been shown to lower plasma levels of warfarin by increasing clearance, this was not a change that led to an actual change in INR. Nor was a change observed in platelet aggregation.[53]
Dong Quai
It is of course sometimes the case that a probable interaction can be observed clinically though the mechanism of action is not yet understood. So it is with several case reports of interaction between warfarin and Dong Quai. In one case, a patient who had been taken warfarin for ten years after replacement of a mitral valve presented after a month of taking Dong Quai with widespread bruising and an INR of 10.[54] In another case, a female patient who was stabilized on warfarin treatment for atrial fibrillation showed greater than a 2-fold elevation in prothrombin time and INR after a month a taking Dong Quai, and these values returned to her usual level a month after discontinuing the herb.[55]
There is rightful growing awareness of the interactions between herbs, which are often commonly used in the diet, and drugs. Because basic science research may have limited predictive power as to the clinical relevance of an interaction, regularly reviewing the still relatively small but growing collection of human studies and case reports that document herb-drug interactions in humans is highly important, as is clinical monitoring of patients using both herbal medicines and drugs.
[1]. Violi, Francesco MD; Lip, Gregory YH MD; Pignatelli, Pasquale MD; Pastori, Daniele MD. Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True?. Medicine 2016; 95(10):p e2895.
[2]. Volak LP, Hanley MJ, Masse G, Hazarika S, Harmatz JS, Badmaev V, Majeed M, Greenblatt DJ, Court MH. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):450-62. doi: 10.1111/j.1365-2125.2012.04364.x. PMID: 22725836; PMCID: PMC3579260.
[3]. Volak LP, Ghirmai S, Cashman JR, Court MH. Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos. 2008 Aug;36(8):1594-605. doi: 10.1124/dmd.108.020552. Epub 2008 May 14. PMID: 18480186; PMCID: PMC2574793.
[4]. Hyekyung Ha, Jun Kyoung Lee, Ho Young Lee, Chang-seob Seo, Jung-Hoon Kim, Mee-young Lee, Woo Suk Koh, Hyeun Kyoo Shin. Evaluation of safety of the herbal formula Ojeok-san: Acute and sub-chronic toxicity studies in rats. Journal of Ethnopharmacology 2010; 131(2):410-416.
[5]. Ko, Y., Go, HY., Han, IS. et al. Efficacy and safety of Ojeok-san in Korean female patients with cold hypersensitivity in the hands and feet: study protocol for a randomized, double-blinded, placebo-controlled, multicenter pilot study. Trials 19, 662 (2018).
[6]. Park SI, Park JY, Park MJ, Yim SV, Kim BH. Effects of Ojeok-san on the Pharmacokinetics of Celecoxib at Steady-state in Healthy Volunteers. Basic Clin Pharmacol Toxicol. 2018 Jul;123(1):51-57. doi: 10.1111/bcpt.12971. Epub 2018 Mar 15. PMID: 29377603.
[7]. Toh DS, Limenta LM, Yee JY, Wang LZ, Goh BC, Murray M, Lee EJ. Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects. Br J Clin Pharmacol. 2014 Jul;78(1):129-34. doi: 10.1111/bcp.12273. PMID: 24168107; PMCID: PMC4168387.
[8]. Gurley BJ, Swain A, Hubbard MA, Hartsfield F, Thaden J, Williams DK, Gentry WB, Tong Y. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Clin Pharmacol Ther. 2008 Jan;83(1):61-9. doi: 10.1038/sj.clpt.6100222. Epub 2007 May 9. PMID: 17495878.
[9]. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Khan IA, Shah A. 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 May;77(5):415-26. doi: 10.1016/j.clpt.2005.01.009. PMID: 15900287; PMCID: PMC1894911.
[10]. Nguyen JT, Tian DD, Tanna RS, Hadi DL, Bansal S, Calamia JC, Arian CM, Shireman LM, Molnár B, Horváth M, Kellogg JJ, Layton ME, White JR, Cech NB, Boyce RD, Unadkat JD, Thummel KE, Paine MF. Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. Clin Pharmacol Ther. 2021 May;109(5):1342-1352. doi: 10.1002/cpt.2107. Epub 2020 Dec 23. PMID: 33174626; PMCID: PMC8058163.
[11]. Gurley BJ, Swain A, Barone GW, Williams DK, Breen P, Yates CR, Stuart LB, Hubbard MA, Tong Y, Cheboyina S. Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos. 2007 Feb;35(2):240-5. doi: 10.1124/dmd.106.012708. Epub 2006 Nov 1. PMID: 17079360; PMCID: PMC1868501.
[12]. Cao W, Yang Q, Zhang W, Xu Y, Wang S, Wu Y, Zhao Y, Guo Z, Li R, Gao R. Drug-drug interactions between salvianolate injection and aspirin based on their metabolic enzymes. Biomed Pharmacother. 2021 Mar;135:111203. doi: 10.1016/j.biopha.2020.111203. Epub 2021 Jan 3. PMID: 33401223.
[13]. Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John’s wort. J Psychopharmacol. 2004 Jun;18(2):262-76. doi: 10.1177/0269881104042632. PMID: 15260917.
[14]. Johne A, Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, Scholler G, Langheinrich M, Roots I. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort ( Hypericum perforatum ). J Clin Psychopharmacol. 2002 Feb;22(1):46-54. doi: 10.1097/00004714-200202000-00008. PMID: 11799342.
[15]. Rey JM, Walter G. Hypericum perforatum (St John’s wort) in depression: pest or blessing? Med J Aust. 1998 Dec 7-21;169(11-12):583-6. doi: 10.5694/j.1326-5377.1998.tb123424.x. PMID: 9887899.
[16]. Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther. 1999 Oct;66(4):338-45. doi: 10.1053/cp.1999.v66.a101944. PMID: 10546917.
[17]. Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther. 2002 Jun;71(6):414-20. doi: 10.1067/mcp.2002.124080. PMID: 12087344.
[18]. Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ. Effects of St John’s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol. 2008 Apr;153(7):1579-86. doi: 10.1038/sj.bjp.0707685. Epub 2008 Jan 21. PMID: 18204476; PMCID: PMC2437900.
[19]. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John’s wort. Lancet. 2000 Feb 12;355(9203):547-8. doi: 10.1016/S0140-6736(99)05712-8. Erratum in: Lancet 2001 Apr 14;357(9263):1210. PMID: 10683007.
[20]. Eich-Höchli D, Oppliger R, Golay KP, Baumann P, Eap CB. Methadone maintenance treatment and St. John’s Wort – a case report. Pharmacopsychiatry. 2003 Jan;36(1):35-7. doi: 10.1055/s-2003-38090. PMID: 12649774.
[21]. Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther. 2001 Oct;70(4):317-26. PMID: 11673747.
[22]. de Maat MM, Hoetelmans RM, Math t RA, van Gorp EC, Meenhorst PL, Mulder JW, Beijnen JH. Drug interaction between St John’s wort and nevirapine. AIDS. 2001 Feb 16;15(3):420-1. doi: 10.1097/00002030-200102160-00019. PMID: 11273226.
[23]. Nieminen TH, Hagelberg NM, Saari TI, Neuvonen M, Laine K, Neuvonen PJ, Olkkola KT. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain. 2010 Sep;14(8):854-9. doi: 10.1016/j.ejpain.2009.12.007. Epub 2010 Jan 27. PMID: 20106684.
[24]. Maurer A, Johne A, Bauer S, Brockmoller F, Conath I, Roots M, Langheinrich M, Hubner WD. 1999. Interaction of St. John’s wort extract with phenprocoumon [Abstract]. European Journal of Clinical Pharmacology 55:A22.
[25]. Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, Arakawa M, Sakamoto K, Masada M, Miyamori I, Fujimura A. Different effects of St John’s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther. 2001 Dec;70(6):518-24. doi: 10.1067/mcp.2001.120025. PMID: 11753267.
[26]. Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant. 2003 Apr;18(4):819-22. doi: 10.1093/ndt/gfg002. PMID: 12637655.
[27]. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother. 1999 Apr;33(4):502. doi: 10.1345/aph.18252. PMID: 10332544.
[28]. Yue QY, Bergquist C, Gerdén B. Safety of St John’s wort (Hypericum perforatum). Lancet. 2000 Feb 12;355(9203):576-7. doi: 10.1016/S0140-6736(05)73227-X. PMID: 10683030.
[29]. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004 May;57(5):592-9. doi: 10.1111/j.1365-2125.2003.02051.x. Erratum in: Br J Clin Pharmacol. 2004 Jul;58(1):102. PMID: 15089812; PMCID: PMC1884493.
[30]. Jiang X, Blair EY, McLachlan AJ. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol. 2006 Nov;46(11):1370-8. doi: 10.1177/0091270006292124. PMID: 17050802.
[31]. Loughren MJ, Kharasch ED, Kelton-Rehkopf MC, Syrjala KL, Shen DD. Influence of St. John’s Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial. Anesthesiology. 2020 Mar;132(3):491-503. doi: 10.1097/ALN.0000000000003065. PMID: 31794512; PMCID: PMC7029805.
[32]. Zhou S, Yung Chan S, Cher Goh B, Chan E, Duan W, Huang M, McLeod HL. Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet. 2005;44(3):279-304. doi: 10.2165/00003088-200544030-00005. PMID: 15762770.
[33]. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007 Aug 1;76(3):391-6. PMID: 17708140.
[34]. Wang D, Zhao T, Zhao S, Chen J, Dou T, Ge G, Wang C, Sun H, Liu K, Meng Q, Wu J. Substrate-dependent Inhibition of Hypericin on Human Carboxylesterase 2: Implications for Herb-drug Combination. Curr Drug Metab. 2022;23(1):38-44. doi: 10.2174/1389200223666220202093303. PMID: 35114918.
[35]. Kim TE, Ha N, Kim Y, Kim H, Lee JW, Jeon JY, Kim MG. Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers. Drug Des Devel Ther. 2017 May 9;11:1409-1416. doi: 10.2147/DDDT.S130050. PMID: 28533679; PMCID: PMC5431696.
[36]. Abdelkawy KS, Abdelaziz RM, Abdelmageed AM, Donia AM, El-Khodary NM. Effects of Green Tea Extract on Atorvastatin Pharmacokinetics in Healthy Volunteers. Eur J Drug Metab Pharmacokinet. 2020 Jun;45(3):351-360. doi: 10.1007/s13318-020-00608-6. PMID: 31997084.
[37]. Misaka S, Abe O, Ono T, Ono Y, Ogata H, Miura I, Shikama Y, Fromm MF, Yabe H, Shimomura K. Effects of single green tea ingestion on pharmacokinetics of nadolol in healthy volunteers. Br J Clin Pharmacol. 2020 Nov;86(11):2314-2318. doi: 10.1111/bcp.14315. Epub 2020 May 12. PMID: 32320490; PMCID: PMC7576630.
[38]. Misaka S, Ono Y, Uchida A, Ono T, Abe O, Ogata H, Sato H, Suzuki M, Onoue S, Shikama Y, Shimomura K. Impact of Green Tea Catechin Ingestion on the Pharmacokinetics of Lisinopril in Healthy Volunteers. Clin Transl Sci. 2021 Mar;14(2):476-480. doi: 10.1111/cts.12905. Epub 2020 Oct 22. PMID: 33048477; PMCID: PMC7993260.
[39]. Veerman GDM, van der Werff SC, Koolen SLW, Miedema JR, Oomen-de Hoop E, van der Mark SC, Chandoesing PP, de Bruijn P, Wijsenbeek MS, Mathijssen RHJ. The influence of green tea extract on nintedanib’s bioavailability in patients with pulmonary fibrosis. Biomed Pharmacother. 2022 Jul;151:113101. doi: 10.1016/j.biopha.2022.113101. Epub 2022 May 17. PMID: 35594703.
[40]. Malati CY, Robertson SM, Hunt JD, Chairez C, Alfaro RM, Kovacs JA, Penzak SR. Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants. J Clin Pharmacol. 2012 Jun;52(6):932-9. doi: 10.1177/0091270011407194. Epub 2011 Jun 6. PMID: 21646440; PMCID: PMC3523324.
[41]. Calderón MM, Chairez CL, Gordon LA, Alfaro RM, Kovacs JA, Penzak SR. Influence of Panax ginseng on the steady state pharmacokinetic profile of lopinavir-ritonavir in healthy volunteers. Pharmacotherapy. 2014 Nov;34(11):1151-8. doi: 10.1002/phar.1473. Epub 2014 Aug 20. PMID: 25142999; PMCID: PMC5466349.
[42]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021226s018lbl.pdf Accessed 21 Feb 2023.
[43]. Lee SH, Ahn YM, Ahn SY, Doo HK, Lee BC. Interaction between warfarin and Panax ginseng in ischemic stroke patients. J Altern Complement Med. 2008 Jul;14(6):715-21. doi: 10.1089/acm.2007.0799. PMID: 18637764.
[44]. Jiang X, Blair EY, McLachlan AJ. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol. 2006 Nov;46(11):1370-8. doi: 10.1177/0091270006292124. PMID: 17050802.
[45]. Wang W, Yang L, Song L, Guo M, Li C, Yang B, Wang M, Kou N, Gao J, Qu H, Ma Y, Xue M, Shi D. Combination of Panax notoginseng saponins and aspirin potentiates platelet inhibition with alleviated gastric injury via modulating arachidonic acid metabolism. Biomed Pharmacother. 2021 Feb;134:111165. doi: 10.1016/j.biopha.2020.111165. Epub 2020 Dec 25. PMID: 33370633.
[46]. Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M, Moss J. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled Trial. Ann Intern Med. 2004 Jul 6;141(1):23-7. doi: 10.7326/0003-4819-141-1-200407060-00011. PMID: 15238367.
[47]. Robertson SM, Davey RT, Voell J, Formentini E, Alfaro RM, Penzak SR. Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin. 2008 Feb;24(2):591-9. doi: 10.1185/030079908×260871. PMID: 18205997.
[48]. Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H, Umegaki K, Ohashi K, Yamada S. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol. 2006 Nov;46(11):1290-8. doi: 10.1177/0091270006292628. PMID: 17050793.
[49]. Yoshioka M, Ohnishi N, Koishi T, Obata Y, Nakagawa M, Matsumoto T, Tagagi K, Takara K, Ohkuni T, Yokoyama T, Kuroda K. Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Pharm Bull. 2004 Dec;27(12):2006-9. doi: 10.1248/bpb.27.2006. PMID: 15577221.
[50]. Yin OQ, Tomlinson B, Waye MM, Chow AH, Chow MS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004 Dec;14(12):841-50. doi: 10.1097/00008571-200412000-00007. PMID: 15608563.
[51]. Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther. 2004 Jan;75(1):89-100. doi: 10.1016/j.clpt.2003.09.013. PMID: 14749695.
[52]. Moltó J, Valle M, Miranda C, Cedeño S, Negredo E, Barbanoj MJ, Clotet B. Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients. Antimicrob Agents Chemother. 2011 Jan;55(1):326-30. doi: 10.1128/AAC.01082-10. Epub 2010 Nov 15. PMID: 21078942; PMCID: PMC3019656.
[53]. Abdul MI, Jiang X, Williams KM, Day RO, Roufogalis BD, Liauw WS, Xu H, Matthias A, Lehmann RP, McLachlan AJ. Pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. Br J Clin Pharmacol. 2010 May;69(5):508-15. doi: 10.1111/j.1365-2125.2010.03620.x. PMID: 20573086; PMCID: PMC2856051.
[54]. Ellis GR, Stephens MR. Untitled (photograph and a brief case report). BMJ. 1999;319(7210):650.
[55]. Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999 Jul;19(7):870-6. doi: 10.1592/phco.19.10.870.31558. PMID: 10417036.
Published October 7, 2023
About the Authors
Benton Bramwell, ND, is a 2002 graduate of National College of Naturopathic Medicine who practiced primarily in Utah while helping to expand the prescriptive rights of naturopathic physicians in that state. Currently, he owns and operates Bramwell Partners, LLC, providing scientific and regulatory consulting services to both dietary supplement and conventional food companies. He and his wife, Nanette, have six children and two grandchildren; they live in Manti, Utah.
Matt Warnock is an accidental herbalist, who received his MBA and Juris Doctor from BYU, then worked as an attorney, litigator, and business consultant until 2000. He then joined RidgeCrest Herbals, a family business started by his father, and started learning about herbal medicine, focusing especially on complex herbal formulas. He has two U.S. patents for herbal formulations and methods. He lives near Salt Lake City with his wife, Carol; they are the parents of three children and four grandchildren.