Some HDS 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 other medications. Drugs affecting the central nervous system and cardiovascular system were documented to have more interactions with HDS. Herbal remedies were more likely to have documented drug interactions and contraindications than other dietary supplements.

A major challenge for healthcare providers in counselling patients about HDS is that the available clinical evidence may be ambiguous and sometimes conflicting for HDS adverse events and drug interactions ( 10 , 11 ). Also, there are often practice‐based barriers to identifying the evidence on HDS–drug interactions ( 12 ), including lack of familiarity or access to HDS‐related textbooks and databases ( 13 , 14 ). In general, fewer and less rigorous studies are available for HDS than that of prescription drugs, particularly with respect to randomised controlled clinical trials ( 15 ). Many available references for HDS list numerous ‘potential HDS–drug interactions’ with little clinical significance or risk. Many reference books are replete with errors that serve only to confuse healthcare practitioners or consumers. The aim of this review was to provide healthcare professionals with a resource that concisely summarises the scientific evidence for HDS–drug interactions and contraindications from 2000 to 2010.

The marketing and consumer use of herbs and dietary supplements (HDS) has risen dramatically in the USA over the past two decades ( 1 , 2 ). It is estimated that > 50% of patients with chronic diseases or cancers ever use HDS ( 3 ), and nearly one‐fifth of patients take HDS products concomitantly with prescription medications ( 4 , 5 ). Despite their widespread use, the potential risks associated with combining HDS with other medications are poorly understood by these consumers. Although many HDS users believe that HDS are safe ( 6 ), HDS products have been reported to be associated with mild‐to‐severe adverse effects such as heart problems, chest pain, abdominal pain and headache ( 2 , 7 , 8 ). Because a majority of patients often fail to disclose that they have taken HDS products to their healthcare providers, e.g. one study estimated only 30% disclosure ( 9 ), patient‐provider communication concerning the risks and benefits of HDS is critically important.

We grouped HDS products/ingredients into three categories: herb/botanical, vitamin/mineral/amino acid (VMA) and others. The most common drugs were grouped according to the Anatomical Therapeutic Chemical (ATC) classification system ( 26 ). Possible mechanisms and the severity ratings of each pair of interactions were retrieved using the Interactions database in MicroMedex ® ( 27 ) and ‘Natural Product/Drug Interaction Checker’ in Natural Medicines Comprehensive Database ® (NMCD ® ) ( 28 ). We categorised the mechanisms for pairs of interactions into four types: pharmacokinetics, pharmacodynamics, both (pharmacokinetics plus pharmacodynamics) and unknown. The severity of each documented interaction was categorised as contraindicated, major, moderate and minor based upon MicroMedex ® , and major, moderate and minor based upon NMCD ® , respectively. The definitions of ‘major’, ‘moderate’ and ‘minor’ were similar in these two databases. For instance, a major interaction may cause life‐threatening damage and/or serious adverse effect(s), and a minor interaction would result in a negligible effect(s). However, contraindicated interactions were rated as ‘major’ severity in NMCD ® . The types of contraindications were categorised based on Goldman: Cecil Medicine ® ( 29 ). All data were compiled and managed using an Excel spreadsheet. Descriptive analyses to define the frequency or proportion of the evidence associated with the interaction pairs, the corresponding mechanisms and severity ratings of interactions and the types of contraindications for certain populations or patients was performed.

Two standardised data abstraction checklists were developed and used to perform the review (one for the HDS–medication interactions and the other for HDS contraindications). All pairs of HDS–drug interactions documented in the retrieved literature sources (except for those interaction pairs with consequences that may benefit to users) were extracted. Because most HDS products or ingredients are not recommended for use during pregnancy or lactation ( 25 ), documented contraindications for these conditions were not further reviewed. All relevant data were extracted, compiled and classified all by one qualified reviewer, and then validated by another. Any disagreements related to the abstraction of data were resolved by consensus.

The primary literature was obtained by searching databases, i.e. MEDLINE (via PubMed), EMBASE and Cochrane Library. Search terms included, but were not limited to the medical subject headings (MeSH terms) or key words that encompassed ‘herb drug interactions’, ‘dietary supplements’ OR ‘vitamins’ OR ‘minerals’ OR ‘amino acids’ OR ‘botanical’ OR ‘herbal medicine’ OR ‘phytotherapy’ combined with ‘contraindications’ OR ‘drug interactions’. The searches were performed in English only for the period of January 2000 to December 2010. The articles were selected based on the titles and abstracts and reviewed independently by two authors (HHT, HWL). Literature without related information, including studies regarding efficacy of HDS, regulation of HDS or methods of assay, was excluded. All relevant articles were selected without restriction for animal studies, clinical trials, observational studies (including case reports) or review articles.

This review of HDS–drug interactions and contraindications focused on the evidence in the primary literature and tertiary literature (i.e. textbooks) related to HDS or drug interactions ( 16 - 21 ). Important online resources about HDS, including the website of National Center for Complementary and Alternative Medicine (NCCAM) ( 22 ), and Office of Dietary Supplements ( 23 ) were also included. The definition of HDS used for this study was the official definition of dietary supplements as stated in the Dietary Supplement Health and Education Act of 1994 (DSHEA) ( 24 ). HDS refers to any herbal product or dietary supplement product containing one of the following ingredients: vitamin, mineral, other botanical, amino acid, or other dietary substance. Thus, traditional foods or fruit products, not listed in the definition (e.g. avocado, grapefruit, and onion, etc.), were not included in this review.

Fifty‐nine HDS from 152 reports were contraindicated for use among patients with specific disease states. The reports were classified into 19 disease states, including gastrointestinal diseases, neurologic disorders, renal/genitourinary diseases, neoplastic disorders, diseases of the liver/gallbladder/bile ducts and cardiovascular diseases ( Figure 5 ). Flaxseed ( Linum usitatissimum ), echinacea ( Echinacea purpurea ) and yohimbe ( Pausinystalia yohimbe ) had the highest number of documented contraindications. For example, flaxseed was documented to have contraindications associated with gastrointestinal disorders such as acute or chronic diarrhoea, oesophageal stricture, inflammatory bowel disease, hypertriglyceridemia and prostate cancer ( 21 ). Echinacea was contraindicated for use among patients with rheumatoid arthritis, systemic lupus erythematosus, leukosis, multiple sclerosis, tuberculosis and HIV infection ( 16 , 18 ). Yohimbe was contraindicated in patients with anxiety, bipolar disorder, depression, mania and schizophrenia, as well as benign prostate hypertrophy and kidney disease ( 21 , 22 ).

Among the 507 documented interaction pairs identified with a severity rating in MicroMedex ® , 69.4% were categorised as the moderate interactions, 17.2% as major interactions, 10.3% as minor interactions and 3.1% were attributable to the contraindications. As for the 763 pairs of documented interactions being identified with the severity rating based on the NMCD ® , the majority documented interaction pairs were categorised as moderate (69.2%), major (26.5%) and minor (4.3%). Approximately, 240 documented HDS–drug interactions were categorised as major severity in either database ( Tables 4 and 5 ). For example, the following pairs of interactions were considered as being contraindicated for concurrent use in MicroMedex ® : l‐Tryptophan vs. MAOI (i.e. isocarboxazid, phenelzine and tranylcypromine) or venlafaxine and St John’s wort vs. protease inhibitors (i.e. amprenavir, fosamprenavir and indinavir), irinotecan, rasagiline or voriconazole, respectively. Among the 390 documented interaction pairs having severity ratings in both databases, 41.3% were inconsistent. For example, the combination of alfalfa ( Medicago sativa ) and warfarin were considered as the minor interaction in MicroMedex ® ; however, it was rated as the major interaction in NMCD ® . The combination of St John’s Wort with quetiapine, quinidine, risperidone or sildenafil gave severity ratings major according to NMCD ® , and no interaction was reported in MicroMedex ® .

Among 882 pairs of interactions with identified mechanisms, a total of 373 pairs (42.3%) were attributable to pharmacokinetic‐related mechanisms, i.e. affected the absorption, distribution, metabolism or excretion of the HDS/drug. Approximately 40.1% of all interaction pairs accounted for pharmacodynamic‐related mechanisms, and 8.5% were attributed to a combination of both mechanisms. No mechanism was identifiable for the remaining 9.1% of pairs. Among the 373 documented HDS interaction pairs that were pharmacokinetic‐related, 87 pairs were associated with St John’s Wort (23.3%), whereas calcium supplements were involved in 47 pairs of documented interactions (12.6%), and iron was involved in 42 pairs of interactions (11.3%). St John’s Wort was documented to reduce the effectiveness of alprazolam, amitriptyline, imatinib, midazolam, nifedipine and verapamil via the CYP (Cytochrome P450) 3A4 pathway, and the plasma levels of fexofenadine and digoxin via PgP (p‐glycoprotein) pathway. Some drugs (i.e. atorvastatin, cyclosporin, indinavir, nevirapine and simvastatin) were documented to interact with St John’s Wort through both pathways ( 37 , 99 ). Among the 354 documented interactions that were pharmacodynamic‐related, kava accounted for 4.8% pairs of interactions (17 pairs). St John’s Wort and ginkgo were both involved in 15 pairs of interactions (4.2%). Risk of additive serotonergic effects were increased when St John’s Wort was used concurrently with monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), or tryptamine‐based drugs causing symptoms of anxiety, dizziness, restlessness, nausea and vomiting ( 16 - 18 , 20 ). As a result of their pharmacological actions on the GABA receptor, synergism in CNS adverse events may result from taking barbiturates or benzodiazepines in combination with kava ( 16 , 20 , 98 ). Furthermore, kava may worsen the extrapyramidal effects associated with the use of droperidol, haloperidol, metoclopramide or risperidone because of a dopamine ( 21 , 98 ).

Among all included interactions between HDS and individual drugs, 166 different herbs/botanical products, 28 VMA and 19 other supplements accounted for 890 pairs (59.7%), 529 pairs (35.5%) and 72 pairs (4.8%) of documented interactions, respectively ( Figure 2 ). The top five herbs/botanical products, which were documented to have the most interactions with individual medications, were St John’s Wort ( Hypericum perforatum ), ginkgo ( Ginkgo biloba ), kava ( Piper methysticum ), digitalis ( Digitalis purpurea ) and willow ( Salix alba ). For example, St John’s Wort, magnesium, calcium, iron and ginkgo have been documented to interact with 147, 102, 75, 71 and 51 individual medications, respectively. Furthermore, a total of 509 unique drugs contributed to the 1491 documented pairs of interactions with HDS. The majority of these medications ( n = 100) were categorised as treatment for central nervous system (CNS), second were those medications affecting the cardiovascular system and then systemic anti‐infective drugs ( n = 90 and 75, respectively) ( Figure 3 ). The medications that most contributed to documented interactions with HDS were warfarin, insulin, aspirin, digoxin and ticlopidine. Not surprisingly, warfarin was documented to have interactions with over 100 HDS entities ( Figure 4 ).

After excluding the evidence regarding HDS not recommended for human use (i.e. anvirzel, belladonna, chaparral, comfrey, ephedra and pennyroyal) ( 16 , 19 , 21 - 23 ) and the duplicates, a total of 1491 unique pairs of documented interactions between HDS and individual drugs were identified. Among these pairs, 814 pairs (54.6%) were retrieved from the primary literature, 1018 pairs (68.3%) from books and only 23 pairs of interactions were identified in the two reviewed web sites. Among these interactions, the corresponding mechanism and severity was determined for 507 pairs (34.0%) using MicroMedex ® and 763 pairs (51.2%) in the NMCD ® online database. In total, 882 pairs (59.2%) of documented HDS–drug interactions were identified for their potential mechanism and severity. In terms of contraindications, there were 128, 15 and 9 documented HDS contraindications retrieved from books, primary articles and web sites, respectively, for a total of 152.

Finally, 461 articles of primary literature were initially identified. Eighty‐five articles with full text, including 54 review articles, other than the 6 books and 2 web sites were selected for further review ( Figure 1 ). The summaries of the animal studies, observational studies and clinical trials to retrieve information about HDS–drug interactions and contraindications for the original studies are listed in Tables 1–3 , respectively. The summaries of the retrieved books and reviewed articles to retrieve information about HDS–drug interactions and contraindications were listed in Appendices 1 and 2 , respectively. Among the original studies ( n = 31), more than half ( n = 16) were clinical trials. All of these articles contained information about HDS–drug interactions ( 12 , 30 - 113 ), but only five articles provided descriptive information about HDS contraindications ( 55 - 57 , 59 , 102 ).

Discussion

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.