Evaluation of Documented Drug Interactions and Contraindications Associated With Herbs and Dietary Supplements

A Systematic Literature Review

H.-H. Tsai; H.-W. Lin; A. Simon Pickard; H.-Y. Tsai; G. B. Mahady


Int J Clin Pract. 2012;66(11):1056-1078. 

In This Article


In this study, we summarised the evidence of HDS–drug interactions and contraindications that have been reported in the primary and tertiary literature. The existing evidence suggests that some HDS products/ingredients have potentially harmful drug interactions that are predominately moderate in their severity. HDS products containing St John's Wort, magnesium, calcium, iron, and ginkgo had the greatest number of documented interactions with drugs. Medications affecting the CNS and cardiovascular system tended to have more documented interactions with these HDS. Of all listed medications, warfarin was documented to have the greatest number of HDS interactions. HDS products containing herbal remedies were more likely to have documented interactions with medications and the contraindications than vitamins, minerals and other types of dietary supplements.

Some of the commonly used herbal remedies such as echinacea, flaxseed, ginkgo and St John's Wort have featured more prominently in industry or government sponsored clinical trials, academic studies and official monographs.[114,115] Some of these HDS entities have undergone more rigorous scientific evaluations. The clinical evidences for HDS are often mixed in terms of their support for efficacy and/or effectiveness. The benefits of HDS treatment must be balanced against the potential harmful effects including adverse events, and the potential for drug interactions or disease state contraindications. Furthermore, there often may be just a self-medicating 'indication creep', where patients who have a certain disease or condition unrelated to the supportive therapy with these HDS. For example, WHO monographs listed that echinacea products could be used in supportive therapy of colds and infections but were contraindicated for patients with autoimmune diseases.[116] Even though the evidence to support the immunological effects of echinacea was still controversial,[117] 6.4% of patients with arthritis/lupus reportedly used echinacea in the 2002 NHIS.[4] Thus, patients need to understand that advantages of using echinacea products are outweighed by the potential harm if they have a specific disease state.

Patients using medications that have a narrow therapeutic range (i.e. warfarin, digoxin) were at greater risk for adverse outcomes because of HDS–drug interactions.[20] This was particularly important for patients on anticoagulants (i.e. warfarin) who concomitantly took HDS products that had antiplatelet or anticoagulant effects (e.g. danshen, dong quai, garlic, ginger and ginkgo).[70,75] In particular, HDS products that contained vitamin K or metabolites related to vitamin K (e.g. coenzyme Q10) had the potential to reduce the effects of warfarin.[75] However, some conflicting information regarding warfarin–HDS interactions was observed when the evidence was retrieved from different literature sources. For instance, in a case study, the international normalised ratio (INR) decreased in patients when ginseng was administered with warfarin in some case reports,[12,66,118] but other in vitro studies demonstrated that several components of Panax ginseng had anticoagulant effects.[12] Furthermore, a controlled clinical trial of healthy subjects revealed that there was no significant interaction when ginseng was administered with warfarin.[12,17,20,31,64] This discrepancy may be attributed to the fact that there are several different species of ginseng on the market [i.e. Asian ginseng (Panax ginseng), American ginseng (Panax quinquefolius), Siberian ginseng (Eleutherococcus senticosus)], different extract types and different doses used. Another interesting example is the concomitant use of warfarin with green tea. Some studies suggested that green tea may enhance the anticoagulant effects of warfarin.[19,75] However, much of the literature suggested that the content of vitamin K in green tea might antagonise the effect of warfarin.[16,17,68,70,75] Regardless, it is important to regularly monitor the INR levels of warfarin users who also use HDS products that might influence the anticoagulation effect.

In addition, patients on a digoxin regime who have been taking an HDS should check to ensure that their plasma concentration of digoxin is indeed within the therapeutic ranges. If this is not the case, then the pharmacist usually should recommend to their patients to stop taking these HDS or have their digoxin dose adjusted by their healthcare providers; for example, as digoxin serum concentrations are usually measured by fluorescence polarisation immunoassay or microparticle enzyme immunoassay, which may be influenced by ginseng and danshen (Salvia miltiorrhiza).[20,58] False digoxin levels may confuse laboratory results and result in inappropriate patient management. Furthermore, aloe vera (Aloe barbadensis), buckthorn (Rhamnus catartica), cascara (Rhamnus purshiani), licorice (Glycyrrhiza glabra) and senna (Cassia senna) may cause hypokalaemia and result in digoxin toxicity.[16,17,33,47] As a result, digoxin users should be told to avoid taking the aforementioned herbal remedies.

In this study, the documented evidence of HDS–drug interactions and contraindications were systematically reviewed from the published literature. This was done because healthcare professionals, in general, use only textbooks, journal and review articles, as well as Internet as their major information source for HDS.[119] Although the NCCAM and Office of Dietary Supplements are the two most commonly used, free online resources about HDS,[120] only limited information is available related to HDS interactions and contraindications on these sites. Furthermore, only 59% of documented HDS–drug interactions could be identified with either their mechanisms and/or severity in either of the two common drug interaction resources (i.e. MicroMedex® and NMCD®). Among them, over 40% of the interactions differed in their severity rating, which is likely to create confusion among healthcare providers about the potential harmful effects associated with a given HDS–drug interactions. Concerns about disagreements across literature resources and databases for drug interactions have been raised before,[121] and these increase the difficulty in implementing an evidence-based clinical practice for HDS products in clinical care. The intention of this review was to evaluate the evidence of HDS interactions and contraindications and to assist clinical practitioners in identifying patients with specific disease states and drug regimens that are more susceptible to these HDS–drug interactions and contraindications.

One of the limitations of this review was that it included all relevant information identified in the literature, regardless of the evidence types or quality of the studies. Although some HDS–drug interactions with little or no clinical significance were included in this study, their severity grading was based upon the available version of MicroMedex® and NMCD®. In order to reduce any personal bias, only those pairs of interactions with evidence retrieved from the aforementioned two databases were included to categorise the corresponding mechanisms and the severity rating. Consequently, we were unable to evaluate 41% of the interaction pairs for the corresponding mechanisms and severity in this study. Another limitation was the concern of publication bias, which might arise as only HDS products and medications that have been published in the literature on the basis of evidence-based medicine. Therefore, there are many potential HDS–drug or disease interactions that may exist but are simply without documented outcomes. Lastly, only reports, books or articles published in English were included in this review. Those evidence regarding traditional herbal medicine or folk therapies, which were published in other languages (e.g. Chinese, Japanese), might be missing. Thus, it is very likely that the amount of documented HDS–drug interactions and/or contraindications in this review might be under-reported.