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Summary

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

Background and Aims:  The use of herbs and dietary supplements (HDS) alone or concomitantly with medications can potentially increase the risk of adverse events experienced by the patients. This review aims to evaluate the documented HDS-drug interactions and contraindications.

Methods:  A structured literature review was conducted on PubMed, EMBASE, Cochrane Library, tertiary literature and Internet.

Results:  While 85 primary literatures, six books and two web sites were reviewed for a total of 1,491 unique pairs of HDS-drug interactions, 213 HDS entities and 509 medications were involved. HDS products containing St. John’s Wort, magnesium, calcium, iron, ginkgo had the greatest number of documented interactions with medications. Warfarin, insulin, aspirin, digoxin, and ticlopidine had the greatest number of reported interactions with HDS. Medications affecting the central nervous system or cardiovascular system had more documented interactions with HDS. Of the 882 HDS-drug interactions being described its mechanism and severity, 42.3% were due to altered pharmacokinetics and 240 were described as major interactions. Of the 152 identified HDS contraindications, the most frequent involved gastrointestinal (16.4%), neurological (14.5%), and renal/genitourinary diseases (12.5%). Flaxseed, echinacea, and yohimbe had the largest number of documented contraindications.

Conclusions:  Although HDS-drug interactions and contraindications primarily concerned a relatively small subset of commonly used medications and HDS entities, this review provides the summary to identify patients, HDS products, and medications that are more susceptible to HDS-drug interactions and contraindications. The findings would facilitate the health-care professionals to communicate these documented interactions and contraindications to their patients and/or caregivers thereby preventing serious adverse events and improving desired therapeutic outcomes.


Review criteria

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

We conducted a structured literature search on tertiary literature, web resources and primary literature, which were focusing on MEDLINE (via PubMed), EMBASE and the Cochrane Library. All evidence related to drug interactions or contraindications for herbal remedies and dietary supplements were selected and all relevant data were extracted using standardised checklists. Possible mechanisms and severity ratings of documented HDS–drug interactions were identified using MicroMedex® and Natural Medicines Comprehensive Database®.

Message for the clinic

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

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.

Introduction

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

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.

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.

Methods

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

Evidence resources and literature search

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.

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.

Data extraction and synthesis

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.

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.

Results

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

Literature search

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).

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Figure 1.  Flow chart of primary literature search

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Table 1.   Summary of the included animal studies to retrieve information about HDS–drug interactions
ReferenceHDSMedicationAnimal model (number)Study designOutcome measuresDose dependentMajor findings
  1. HDS, herbs and dietary supplements; AUC, area under concentration curve.

Chiang et al. (61)Water extract of crude Pueraria lobata (oral)Methotrexate (oral and intravenous)Rats (7 in each group)Parallel designPharmacokinetic parametersYes Pueraria lobata significantly decreased the elimination of methotrexate
Jan et al. (67)1. Extract of dry Evodia rutaecarpa (Wu-Chu-Yu) 2. Commercial herbal extract preparation of Wu-Chu-Yu-Tang (gastrogavage).Theophylline (intravenous)Rats (6 in each group)Randomised parallel designPharmacokinetic parametersYesTheophylline level was significantly decreased
Tang et al. (83)Commercial extract of Ginkgo biloba (oral)Theophylline (oral and intravenous)Rats (6 in each group)Randomised parallel designPharmacokinetic parametersYesGinkgo significantly increased the total clearance, and significantly reduced the AUC of theophylline
Okonta et al. (94)Extract of fresh ginger (oral)Metronidazole (oral)Rabbit (5)Crossover studyPharmacokinetic parametersNo dataGinger significantly increased the absorption and plasma half-life, and significantly decreased the elimination rate constant and clearance of metronidazole
Chang et al. (100)Silymarin, silibinin dissolved in ethanol and PEG2000 (oral)Trazodone (intravenous)Rats (6 in each group)Randomised parallel designPharmacokinetic parameters Biliary excretionYesNo marked effects of silymarin and silibinin on the pharmacokinetics of trazodone under normal daily doses
Chien et al. (109)Extract of crude Andrographis paniculata and major components (oral)Theophylline (intravenous)Rats (9 in control group and 6 in each studied group)Randomised parallel designPharmacokinetic parameters. Major component of HDS.YesAndrographis paniculata increased elimination of theophylline, and chronic use of A. paniculata could elevate the concentration of theophylline
Table 2.   Summary of the included observational studies to retrieve information about HDS–drug interactions
ReferenceHDSMedicationStudy designPopulation (number of participants)Outcome measuresEvidence resources of interactionsResults related to HDS–drug interactions
  1. HDS, herbs and dietary supplements; CAM, complementary and alternative medicine; MAOI, monoamine oxidase inhibitors.

Barone et al. (34)St John’s wortCyclosporineCase reportTransplant recipients (n = 2)_No mentionCyclosporin concentrations were consistently subtherapeutic
Rogers et al. (38)HerbsGeneralSurveyEmergency department patients with heart disease, diabetes, psychiatric disorders and/or hypertension (n = 944)Prevalence and occurrence of sever herb–drug interactionsNo mentionSix patients were identified at risk for seven known herb–drug interactions
Dergal et al. (40)Herbal medicinesPrescription and over-the-counter drugsSurveyOlder adults (≧65 years) attending a memory clinic (n = 195)The frequency of potential interactions between herbal medicines and conventional drug therapiesBook, medical literature identified in MEDLINEThere were 11 potential herb–drug interactions in nine patients
Ly et al. (41)Dietary supplementsPrescription drugsSurveyVeterans ≧65 years (n = 285)The frequency of dietary supplement use and to identify potential interactionsNo mentionThere were 15 patients taking at least one combination that could cause an interaction
Peng et al. (52)Dietary supplementsPrescription drugsSurveyVeteran outpatients (n = 458)The incidence and severity of potential interactions between prescription medications and dietary supplementsTertiary references, newsletters, textbooks, internet web pages and medical literatureThere were 89 patients who had a potential for drug–dietary supplement interactions
Sood et al. (96)Dietary supplementsPrescription drugsCross-sectional, point-of-care surveyPatients in 6 different specialty clinics (n = 1818)The frequency of clinically significant interactions between dietary supplements and prescription medicationMEDLINE database, Natural Medicines Comprehensive Database, published textbookThere were 107 interactions with potential clinical significance identified
Goldman et al. (101)VitaminsPrescribed or over-the-counter medicationsCross-sectional study (survey)Children aged 0–18 years (n = 1804)The frequency and types of potential interactions between vitamins and medicationsPubMed database, MEDLINE Plus, Drug digest and the database of the University of Maryland Medical CenterThere were 193 children with a potential vitamin–drug interaction identified
Lapi et al. (104)Herbal drugs and dietary supplementsSynthetic drugsCross-sectional study (survey)Patients during preoperative anaesthesiological visit (n = 478)The predictors of potential interactions among drugs, HDS and/or other CAM medicationsNo mentionThere were 88 patients detectable for potential interactions evaluation
Simmons and Schneir (113)Commercial supplement products (Atrophex®)PhenelzineCase report24-Year-old male with hypertension (n = 1)_No mentionHypertensive crisis associated with an MAOI interaction with beta-phenylethylamine
Table 3.   Summary of the included clinical trials to retrieve information about HDS–drug interactions
ReferenceHDSDose schedule of HDSMedicationStudy designCountryPopulation (number of participants)Outcome measures
  1. HDS, herbs and dietary supplements; Cmax, maximum plasma concentration; Tmax, time to reach Cmax; CYP, Cytochrome P450; VKORC1, vitamin K epoxide reductase subunit 1; INR, international normalised ratio.

Wang et al. (44)Commercial product of St John’s wort (oral)Single dose and long term for 14–15 daysFexofenadine (oral)Open-label, fixed-schedule studyUSAHealthy subjects (n = 12)Pharmacokinetics (Cmax, Tmax)
Gurley et al. (49)Commercial products of Citrus aurantium, Echinacea purpurea, Milk thistle, Saw palmetto (oral)28 daysMidazolam, caffeine, chlorzoxazone, debrisoquin (oral)Randomised open-label studyUSAHealthy subjects (n = 12)Phenotypic ratio
Yin et al. (53)Commercial Ginkgo biloba product (oral)12 daysOmeprazole (oral)Open-label sequential studyHong KongHealthy subjects genotyped for CYP2C19 (n = 18)Pharmacokinetics (Cmax, Tmax)
Yoshioka et al. (54)Commercial product of Ginkgo biloba (oral)Single doseNifedipine (oral)Randomised crossover studyJapanHealthy subjects (n = 8)Pharmacokinetics (Cmax, Tmax), Pharmacodynamics (blood pressure).
Gurley et al. (62)Commercial products of St John’s wort, garlic oil, Panax ginseng and Ginkgo biloba (oral)28 daysMidazolam, caffeine, chlorzoxazone and debrisoquine (oral)Randomised open-label studyUSAHealthy older subjects who were extensive metabolisers of CYP2D6 (n = 12)Phenotypic metabolic ratios, serum concentration
Gurley et al. (63)Commercial products of goldenseal, kava kava, black cohosh and valerian (oral)28 daysCaffeine, midazolam, chlorzoxazone, debrisoquin (oral)Randomised open-label studyUSAHealthy subjects who were extensive metabolisers of CYP2D6 (n = 12)Phenotypic ratio
Gurley et al. (71)Commercial products of milk thistle, black cohosh (oral)14 daysDigoxin (oral)Randomised open-label studyUSAHealthy young adults (n = 16) Pharmacokinetic analysis, ABCB1 (MDR1) genotyping
Jiang et al. (73)Commercial products of St John’s wort, Asian ginseng, Ginkgo biloba or ginger (oral)7 or 14 daysWarfarin (oral)Two randomised, open-label, controlled, crossover studiesAustraliaHealthy subjects (n = 24)Population pharmacokinetic and pharmacodynamic parameter
Gurley et al. (78)Commercial products of goldenseal, kava kava (oral)14 daysDigoxin (oral)Randomised open-label studyUSAHealthy subjects (n = 20) Pharmacokinetic analysis, phytochemical analyses
Fan et al. (86)Commercial product of baicalin (oral)14 daysRosuvastatin (oral)Randomised crossover studyChinaHealthy subjects who were CYP2C9*1/*1 with different OATP1B1 haplotypes (n = 18) Plasma concentration and pharmacokinetic parameters
Gurley et al. (88)Commercial products of goldenseal, kava kava (oral)14 daysMidazolam (oral)Randomised open-label studyUSAHealthy subjects (n = 16)Pharmacokinetic parameters, phenotypic ratios
Gurley et al. (89)Commercial products of black cohosh, echinacea, goldenseal, kava kava, milk thistle and St John’s wort (oral)14 daysDebrisoquine (oral)Randomised open-label designUSAHealthy subjects who were extensive metabolisers of CYP2D6 (n = 16) Phenotypic ratios, phytochemical analysis and disintegration times
Gurley et al. (90)Commercial products of St John’s wort, echinacea (oral)14 daysDigoxin (oral)Randomised open-label studyUSAHealthy young adults (n = 18) Pharmacokinetic parameters, phytochemical analysis and disintegration times
Mohammed Abdul et al. (91)Commercial products of garlic, cranberry (oral)14 daysWarfarin (oral)Randomised open-label crossover studyAustraliaHealthy subjects of known CYP2C9 and VKORC1 genotype (n = 12)Pharmacokinetic parameters, pharmacodynamics (INR)
Kim et al. (110)Commercial product of Ginkgo biloba (oral)Single doseTiclopidine (oral)Randomised open-label, crossover studyKoreaHealthy subjects (n = 24)Pharmacokinetic parameters, pharmacodynamics (bleeding times)
Nieminen et al. (111)Commercial product of St John’s wort (oral) 15 daysOxycodone (oral)Randomised, balanced, placebo-controlled, crossover studyFinlandHealthy subjects (n = 12)Pharmacokinetic parameters, pharmacodynamics (behavioural and analgesic effects); adverse effects

Quantity of retrieved evidence

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.

HDS–drug interactions

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).

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Figure 2.  Herbs and dietary supplements tended to have documented interactions with medications in each caterory. VMA, vitamin/mineral/amino acid; DS, dietary supplements; DHEA, dehydroepiandrosterone

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Figure 3.  Distribution of medications that might have interactions with herbs and dietary supplements. ATC, anatomical therapeutic chemical. The number of total medications was 509

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Figure 4.  Medications with the largest number of interactions with herbs and dietary supplements. HDS, herbs and dietary supplements

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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 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®.

Table 4.   The HDS–drug interactions with major severity* (other than St John’s Wort)
HDSDrugsPotential consequences/reactions†
  1. *Any HDS–drug interactions with severity rated as contraindicated or major in either database of MicroMedex® or NMCD® were included in this table.

  2. †Potential consequences or reactions were documented according to either aforementioned database with severity rating as major or contraindicated. [UPWARDS ARROW], increasing; [DOWNWARDS ARROW], decreasing.

5-HydroxytryptophanFluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine (17)[UPWARDS ARROW]Risk of serotonin syndrome
AcaciaAmoxicillin (98)[DOWNWARDS ARROW]Absorption of amoxicillin
AlfalfaWarfarin (21,33,43,75)[DOWNWARDS ARROW]The effect of warfarin
Aloe veraDigoxin (16,21,33,45)[UPWARDS ARROW]Digoxin toxicity
American ginsengWarfarin (16,70,75)[DOWNWARDS ARROW]The effect of warfarin
ArginineEnalapril, nitroglycerin (21)[UPWARDS ARROW]Hypotensive effects
Spironolactone (21)[UPWARDS ARROW]Risk of hyperkalemia
Bitter orangePhenelzine (22,98)[UPWARDS ARROW]Risk of hypertensive crisis
CowhageMethyldopa (98)[UPWARDS ARROW]Hypotensive effects
DanshenAspirin, ticlopidine, warfarin (17,20,21,31,35,43,47,64–66,68,70,75,77,81,92,97,98)[UPWARDS ARROW]Risk of bleeding
Digoxin (20,21)[UPWARDS ARROW]Digoxin toxicity
DigitalisBendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, methyclothiazide, metolazone, polythiazide, trichlormethiazide (17,20)[UPWARDS ARROW]Digoxin toxicity
Digoxin (17)[UPWARDS ARROW]Digoxin toxicity
Dong quaiAspirin, heparin, ticlopidine, warfarin (16,17,20,21,31,33,35,38,43,47,64–66,70,72,75,77,92)[UPWARDS ARROW]Risk of bleeding
Evening primroseWarfarin (18,75,98)[UPWARDS ARROW]Risk of bleeding
GarlicRitonavir (16,64,97,103)[DOWNWARDS ARROW]The effect of ritonavir
Saquinavir (16,22,51,64,65,77,81,85,97,98,103)[DOWNWARDS ARROW]The effect of saquinavir
Warfarin (16–19,31,33,35,36,41,43,47,51,52,64–66,68,75,77,80,81,85,87,96,98)[UPWARDS ARROW]Risk of bleeding
GinkgoAspirin, cilostazol, clopidogrel, dipyridamole, heparin, ibuprofen, naproxen, ticlopidine, warfarin (12,16–22,30,31,33–36,38,40,47,51,52,55,60,64–66,68,75,77,80,81,85,87,98,103,105,110)[UPWARDS ARROW]Risk of bleeding
Risperidone (20,103)[UPWARDS ARROW]Risk of risperidone adverse effects
Trazodone (12,17,20,21,35,36,40,47,60,64,65,77,81,87,103)Excessive sedation and potential coma
GlucosamineWarfarin (20,75,96)[UPWARDS ARROW]Risk of bleeding
Green teaEphedrine (17,21)[UPWARDS ARROW]Risk of stimulatory adverse effects
GuaranaEphedrine (16)[UPWARDS ARROW]Risk of stimulatory adverse effects
HawthornDigoxin (16,21,33,98)[UPWARDS ARROW]Digoxin toxicity
HenbaneChlorpheniramine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, promethazine (17)[UPWARDS ARROW]Risk of anticholinergic side effects
KavaAlprazolam, chlordiazepoxide, clonazepam, diazepam, estazolam, flurazepam, lorazepam, midazolam, morphine, oxazepam, henobarbital, quazepam, temazepam, triazolam (16–20,30,35,36,42,57,64,65,69,72,80,81,85,103)[UPWARDS ARROW]Central nervous system depression
Droperidol (21,98)[UPWARDS ARROW]Central nervous system depression
LicoriceWarfarin (16,43,68,75) [UPWARDS ARROW]Risk of bleeding
l-TryptophanCitalopram, duloxetine, fluoxetine, fluvoxamine, isocarboxazid, paroxetine, phenelzine, selegiline, sertraline, sibutramine, tranylcypromine, venlafaxine (17,20,51)[UPWARDS ARROW]Risk of serotonin syndrome
Zolpidem (17)[UPWARDS ARROW]Zolpidem-induced side effect
MelatoninZolpidem (21)[UPWARDS ARROW]Sedative effects
N-acetylcysteineNitroglycerin (17)Severe hypotension, intolerable headaches
NiacinAtorvastatin, cerivastatin, lovastatin, rosuvastatin, simvastatin (19,20,82,84,112)[UPWARDS ARROW]Risk of myopathy or rhabdomyolysis
PABADapsone, sulfamethoxazole (17,20)[DOWNWARDS ARROW]Antibacterial effects
Pleurisy rootDigoxin (17)[UPWARDS ARROW]Digoxin toxicity
PotassiumAmiloride, benazepril, captopril, enalapril, fosinopril, indomethacin, lisinopril, moexipril, quinapril, ramipril, spironolactone, trandolapril, triamterene (17,19,20,52,82)[UPWARDS ARROW]Risk of hyperkalemia
Red yeast riceCyclosporin (21,65,98)[UPWARDS ARROW]Creatine phosphokinase values
S-adenosylmethionineClomipramine (16)[UPWARDS ARROW]Risk of serotonin syndrome
Scotch broomHaloperidol (98)[UPWARDS ARROW]The potential toxicity
Phenelzine (17)[UPWARDS ARROW]Risk of hypertensive crisis
ValerianAlprazolam, phenobarbital (16,20,42)[UPWARDS ARROW]Central nervous system depression
Vitamin AAcitretin, bexarotene, etretinate, isotretinoin, tretinoin (17,19,51,82,84,101,112)[UPWARDS ARROW]Risk of vitamin A toxicity
Vitamin B6Altretamine (84)[DOWNWARDS ARROW]Response to altretamine
Vitamin EDicumarol (84)[UPWARDS ARROW]Risk of bleeding
Vitamin KWarfarin (17,19,20,23,43,47,75,82,84,112)[DOWNWARDS ARROW]Effect of warfarin
WillowDiclofenac, ibuprofen, naproxen, ticlopidine, warfarin (16,17,47,68,75)[UPWARDS ARROW]Risk of bleeding
Table 5.   The St John’s Wort-drug interactions with major severity*
HDSDrugsPotential consequences/reactions†
  1. *Any HDS–drug interactions with severity rated as contraindicated or major in either database of MicroMedex® or NMCD® were included in this table. †Potential consequences or reactions were documented according to either aforementioned database with severity rating as major or contraindicated. [UPWARDS ARROW], increasing; [DOWNWARDS ARROW], decreasing. MAOI, monoamine oxidase inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; NNRTI, non-nucleoside reverse transcriptase inhibitors.

St John’s wortAmiodarone (20,37)[DOWNWARDS ARROW]Effect of amiodarone
Benzodiazepine: alprazolam, clonazepam, diazepam, midazolam, triazolam (20,36,37,49,59,62,64,65,76,77,80,81,87,93,97,99,103)[DOWNWARDS ARROW]Benzodiazepine effectiveness
Bupropion, buspirone, eletriptan, meperidine, trazodone (17,31,37,39,65,69,99,103)[UPWARDS ARROW]Risk of serotonin syndrome
MAOI: isocarboxazid, phenelzine, tranylcypromine (17,33) 
SSRI: citalopram, duloxetine, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, venlafaxine (12,16–18,20,31,32,35–37,47,52,59,64,65,69,72,77,81,87,99,103) 
TCA: amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine (12,16,17,20,36,37,59,64,65,69,72,76,77,80,81,85,87,93,97,99,103) 
Busulfan (39)[DOWNWARDS ARROW]Effect of busulfan
Calcium channel blockers: diltiazem, felodipine, nicardipine, nifedipine, nitrendipine, verapamil (16,20,37,59,65,76,79–81,99,102,103)[DOWNWARDS ARROW]Effect of calcium channel blockers
Carbamazepine (32,37,99)[DOWNWARDS ARROW]Effect of carbamazepine
Cyclophosphamide (16,37,93)[DOWNWARDS ARROW]Effect of cyclophosphamide
Cyclosporin (12,16–18,20–22,30–32,34–37,47,49–51,59,64,65,69,72,76,77,79–81,92,93,97,99,102,103)[DOWNWARDS ARROW]Effect of cyclosporine
Dapsone (37)[DOWNWARDS ARROW]Effect of Dapsone
Dexamethasone (39)[DOWNWARDS ARROW]Effect of dexamethasone
Digoxin (12,16–18,20,22,30–32,34,36,37,47,51,59,64–66,69,72,76,77,79–81,87,90,92,93,97,99,102,103)[DOWNWARDS ARROW]Effect of digoxin
Docetaxel (39,74)[DOWNWARDS ARROW]Effect of decetaxel
Dolasetron (39)[DOWNWARDS ARROW]Effect of dolasetron
Doxorubicin (39,81)[DOWNWARDS ARROW]Effect of doxorubicin
Erlotinib (20)[DOWNWARDS ARROW]Effect of erlotinib
Erythromycin (103)[DOWNWARDS ARROW]Effect of erythromycin
Estrogens/progestogens: estradiol, gestodene, levonorgestrel, norethindrone (37,39,50,72)[DOWNWARDS ARROW]Effect of contraceptive
Etoposide (39,81)[DOWNWARDS ARROW]Effect of etoposide
Exemestane (20)[DOWNWARDS ARROW]Effect of exemestane
Fentanyl, Morphine, Oxycodone (21,37,99,111)[UPWARDS ARROW]Sedation
Fexofenadine (20,44,59,64,65,76,77,79,80,93,97,99,103)[DOWNWARDS ARROW]Effect of fexofenadine
Finasteride (39)[DOWNWARDS ARROW]Effect of finasteride
Flutamide (32,39)[DOWNWARDS ARROW]Effect of flutamide
Gliclazide (103)[DOWNWARDS ARROW]Effect of gliclazide
Haloperidol (37)[DOWNWARDS ARROW]Effect of haloperidol
Ifosfamide (39)[DOWNWARDS ARROW]Effect of ifosfamide
Imatinib (20,59,76,77,79,80,97,99,103)[DOWNWARDS ARROW]Effect of imatinib
Irinotecan (12,16,20–22,49,59,64,65,76,77,80,81,97,103)[DOWNWARDS ARROW]Effect of irinotecan
Ivabradine (103)[DOWNWARDS ARROW]Effect of ivabradine
Ixabepilone (20)[DOWNWARDS ARROW]Effect of ixabepilone
Lapatinib (20)[DOWNWARDS ARROW]Effect of lapatinib
Lidocaine (37)[UPWARDS ARROW]Risk of cardiovascular collapse
Loperamide (21,30,35,36,64,77,99,103)[DOWNWARDS ARROW]Effect of loperamide
Maraviroc (20)[DOWNWARDS ARROW]Effect of maraviroc
Mephenytoin (76,97,99,103)[DOWNWARDS ARROW]Effect of mephenytoin
Methadone (20,21,37,64,65,77,92,93,99,103)[DOWNWARDS ARROW]Effect of methadone
NNRTI: delavirdine, efavirenz, nevirapine (16,18,20,32,37,69,76,77,80,99,103)[DOWNWARDS ARROW]NNRTI concentrations
Omeprazole (17,20,65,76,77,80,92,93,103)[DOWNWARDS ARROW]Effect of omeprazole
Ondansetron (39)[DOWNWARDS ARROW]Effect of ondansetron
Paclitaxel (37,39)[DOWNWARDS ARROW]Effect of paclitaxel
Phenprocoumon (12,18,31,35–37,47,65,66,77,80,81,97,103)[DOWNWARDS ARROW]Effect of phenprocoumon
Phenytoin (32)[DOWNWARDS ARROW]Effect of phenytoin
Piroxicam, rasagiline, risperidone, tetracycline, tolbutamide, tretinoin (20,37,39,77,102,103)[UPWARDS ARROW]Photosensitivity reactions
Propofol, sevoflurane (20,99,103)[UPWARDS ARROW]Risk of cardiovascular collapse
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir (12,16–22,32,34,36,37,47,49,51,64,65,69,72,76,77,79–81,93,97,103)[DOWNWARDS ARROW]Effect of protease inhibitor
Quetiapine (37)[DOWNWARDS ARROW]Effect of Quetiapine
Quinidine (37)[DOWNWARDS ARROW]Effect of Quinidine
Sildenafil (37,50,93)[DOWNWARDS ARROW]Effect of Sildenafil
Sirolimus (20)[DOWNWARDS ARROW]Effect of Sirolimus
Sunitinib (20)[DOWNWARDS ARROW]Effect of sunitinib
Tacrolimus (12,16,20,37,59,64,65,76,77,79–81,92,93,97,99,103)[DOWNWARDS ARROW]Effect of tacrolimus
Tamoxifen (16,37,39)[DOWNWARDS ARROW]Effect of tamoxifen
Temsirolimus (20)[DOWNWARDS ARROW]Effect of sirolimus, the active metabolite of temsirolimus
Teniposide (39)[DOWNWARDS ARROW]Effect of teniposide
Tramadol (96)[DOWNWARDS ARROW]Effect of tramadol
Vinblastin (37,39,81)[DOWNWARDS ARROW]Effect of vinblastin
Vincristine (39)[DOWNWARDS ARROW]Effect of vincristine
Voriconazole (20,76,77,99,103)[DOWNWARDS ARROW]Effect of voriconazole
Warfarin (16–18,20,22,32,35–37,43,47,51,59,64–66,69,70,72,73,75–77,79–81,85,87,97,99,102,103)[DOWNWARDS ARROW]Effect of warfarin

HDS contraindications

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).

image

Figure 5.  Common contraindications for HDS use. *Other contraindications of gastrointestinal diseases included fecal impaction for aloe vera and oesophageal stricture for flaxseed. †Other contraindications of neurologic disorders included multiple sclerosis for echinacea and posttraumatic stress disorder for yohimbe. HDS, herbs and dietary supplements

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Discussion

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

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.

Conclusions

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

This review provides a structured summary of the evidence of the most widely documented HDS interactions and contraindications with medications. Although our findings primarily concern with a relatively small subset of commonly used medications and HDS entities, it is recommended that healthcare professionals should be paid more attention towards those pairs of interactions between any HDS products that contain St John’s Wort, magnesium, calcium, iron and ginkgo, and medications that affect the CNS or the cardiovascular system. These findings should be helpful for healthcare professionals to identify the priority areas where communication regarding HDS usages has the greatest potential to prevent adverse events and to improve patient’s therapeutic outcomes.

Acknowledgements

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

The authors express their gratitude to Jun-Fon Wang, Yi-Ling Chen, Ying-Hung Lu, Po-Ming Hung, Tang-Ping Shih, Chung-Hui Ku, Shan-Chieh Wu and Yi-Zhu Chen for their help on data management, and Dr Chao-Ling (David) Chen, Daniel Lee, Vincent Lee and Matthias C. Lu for their insights and comments for the manuscript. This work was partially supported by the National Science Council (NSC 99-2320-B-039-031-MY3), China Medical University Hospital (DMR-99-140) and Committee on Chinese Medicine and Pharmacy, Department of Health, Executive Yuan, Taiwan, R.O.C. (CCMP99-RD-016).

Author contributions

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

HHT, HWL and ASP participated in designing the review. HHT and HWL searched databases and retrieved the articles. HHT extracted and managed the data, while HWL validated it. HYT helped to resolve the disagreements in evidence abstraction. HHT wrote the manuscript, HWL, ASP, HYT and GBM reviewed and revised the manuscript. All authors read and approved the final manuscript.

References

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

Appendices

  1. Top of page
  2. Summary
  3. Review criteria
  4. Message for the clinic
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusions
  10. Acknowledgements
  11. Author contributions
  12. References
  13. Appendices

Appendix 1 Summary of included books to retrieve information about HDS–drug interactions and contraindications.

ReferenceYearHDS–drug interactionsMedicationFormatSeverity rating of interactionsContraindicationsHDSCited referencesWebsite
  1. HDS, herbs and dietary supplements.

Cassileth (16)2003YesDrug class or individual drugBy HDSNoYesHerbal remedies, other dietary supplements and non-mainstream producted promoted as cancer treatmentsYesYes
Gaby (17)2006YesIndividual drugBy drug and by HDSNoNoHerbs, deitary supplements, foods and alcoholAccessed onlineYes
Mahady (18)2001YesDrug class or individual drugBy HDSNoYesHerbsYesNo
Mason (19)2001YesDrug class and/or individual drugBy HDSNoYesVitamins, minerals and natural oils, natural substances, enzymes, amino acidYesNo
Tatro (20)2010YesDrug class with individual drugBy drugYesNoVitamins, electrolytes and few common used herbsYesYes
Ulbricht (21)2005YesDrug class or individual drugBy HDSNoYesHerbs and supplementsYesYes

Appendix 2 Summary of review articles to retrieve information about HDS–drug interactions and contraindications.

ReferenceReview typeHDSMedicationsDatabasesSearching period
  1. HDS, herbs and dietary supplements; CYP, Cytochrome P450; P-gp, P-glycoprotein.

Coxeter et al. (12)Narrative reviewHerbsGeneralNo mentionNo mention
Ernst (30)Narrative reviewHerbsConventional drugsNo mentionNo mention
Fugh-Berman (31)Narrative reviewHerbsGeneralMEDLINE; EMBASEMEDLINE: 1966–1998; EMBASE: 1994–1999
McIntyre (32)Narrative reviewSt John’s wortGeneralNo mentionNo mention
Semaan (33)Narrative reviewHerbal medicineGeneralNo mentionNo mention
Fugh-Berman and Ernst (35)Systematic reviewHerbsConventional drugsMEDLINE (via PubMed), EMBASE, the Cochrane Library, CISCOMTheir inception to 2000
Izzo and Ernst (36)Systematic reviewHerbal medicinesPrescribed drugsMEDLINE (via PubMed), EMBASE, Cochrane Library and PhytobaseTheir inception to 2000
Markowitz and DeVane (37)Narrative reviewSt John’s wortGeneralMEDLINE, Current contents and PSYCINFO1966–2000
Block and Gyllenhaal (39)Narrative reviewNatural inhibitors and inducers of CYP450Cancer chemotherapy drugs, adjunctive drugsNo mentionNo mention
Lyons (42)Narrative reviewHerbal medicineDrugs used in anaesthesiaNo mentionNo mention
Myers (43)Narrative reviewComplementary medicinesWarfarinNo mentionNo mention
Buehler (45)Narrative reviewHerbal productsConventional medicinesNo mentionNo mention
Chavez et al. (46)Narrative reviewHerbsGeneralNo mentionNo mention
Williamson (47)Narrative reviewHerbsPrescription medicinesEMBASE, MEDLINEEMBASE: 1980–2003; MEDLINE: 1966–2003
Zhou et al. (48)Narrative reviewHerbsSubstrates of CYP enzymesNo mentionNo mention
Huang and Lesko (50)Narrative reviewDietary supplementsGeneralNo mentionNo mention
Ohnishi and Yokoyama (51)Narrative reviewDietary supplementsGeneralNo mentionNo mention
Bartlett and Eperjesi (55)Narrative reviewOcular nutritional supplementsGeneralPubMed, Web of Science1980–2004
Bressler (56)Narrative reviewSaw palmettoPrescription medicationsNo mentionNo mention
Bressler (57)Narrative reviewKavaPrescription medicationsNo mentionNo mention
Bressler (58)Narrative reviewGinsengPrescription medicationsNo mentionNo mention
Bressler (59)Narrative reviewSt John’s wort Prescription medicationsNo mentionNo mention
Bressler (60)Narrative review Ginkgo biloba General (prescription drugs)No mentionNo mention
Hu et al. (64)Narrative reviewHerbal medicinesGeneral (prescription drugs)MEDLINE, Biological Abstracts, Cochrane Library, AMED, Biosis Previews and EMBASETheir inception to 2005
Izzo (65)Narrative reviewHerbal remediesGeneral (prescription drugs)No mentionNo mention
Izzo et al. (66)Systematic reviewHerbal medicinesCardiovascular drugsMEDLINE1966–2003
Marder (68)Narrative reviewDietary supplementsAntithrombotic agentsNo mentionNo mention
Singh (69)Narrative reviewKava and St John’s wortGeneral (prescription drugs)No mentionNo mention
Daugherty and Smith (70)Narrative reviewDietary supplementsWarfarinNo mentionNo mention
Haller (72)Narrative reviewHerbal and dietary supplementsGeneralNo mentionNo mention
Meijerman et al. (74)Narrative reviewHerbsAnticancer drugNo mentionNo mention
Nutescu et al. (75)Narrative reviewHerbal and dietary supplementsWarfarinNo mentionNo mention
Venkataramanan et al. (76)Narrative reviewHerbalGeneralNo mentionNo mention
Yang et al. (77)Narrative reviewHerbsGeneralNo mentionNo mention
Marchetti et al. (79)Narrative reviewP-gp modulators (e.g. St John’s wort)ABCB1 substrates, e.g. digoxin, cyclosporin A, tacrolimusNo mentionNo mention
Nekvindova and Anzenbacher (80)Narrative reviewDietary constituents affecting CYPsCYP substratesNo mentionNo mention
Skalli et al. (81)Systematic reviewCommon herbalGeneralMEDLINE via PubMed, Allied and Complementary, Medicine Database, Healthstar, AMBASE, CINHAL, Cochrane Library1966–2006
Sulli and Ezzo (82)Narrative reviewVitamins and mineralsGeneralNo mentionNo mention
Yetley (84)Narrative reviewMultivitamin and multimineral dietary supplementsGeneralNo mentionNo mention
Cranwell-Bruce (85)Narrative reviewHerbsGeneralNo mentionNo mention
Gardiner et al. (87)Narrative reviewHerbs, vitaminsAnticoagulants, cardiovascular medications, psychiatric medications, laxatives, diabetes medications or medications for human immunodeficiency virus (HIV) infectionNo mentionNo mention
Nowack (92)Narrative reviewHerbsCYP3A4 and transport-protein dependent drug, anticoagulants or antiplatelets, antidiabetics, antihypertensive agentsNo mentionNo mention
Nowack (93)Narrative reviewHerbsImmunosuppressive drugsNo mentionNo mention
Samuels et al. (95)Narrative reviewHerbal medicineAntiepileptic drugNo mentionNo mention
Tomlinson et al. (97)Narrative reviewHerbsCYP3A4/P-gp substratesNo mentionNo mention
Ulbricht et al. (98)Systematic reviewHerbsGeneralMEDLINE, EMBASE, the Cochrane Library, CINAHL, Napralert, International Pharmaceutical Abstracts, CANCERLIT, CISCOM, HERBMEDNo mention
Borrelli and Izzo (99)Narrative reviewSt John’s wortGeneralNo mentionNo mention
Holcomb (102)Narrative reviewHerbsGeneralNo mentionNo mention
Izzo and Ernst (103)Systematic reviewHerbsGeneralMEDLINE (via PubMed), EMBASE and Cochrane LibraryTheir inception to 2009
Shord et al. (105)Narrative reviewHerbsGeneralNo mentionNo mention
Toselli et al. (106)Narrative reviewEchinaceaCYP450 substrateNo mentionNo mention
Abad et al. (107)Narrative review Ginkgo biloba GeneralNo mention2000–2008
Cheng et al. (108)Narrative reviewHerbsAnticancer drugsOvid OLDMEDLINE, Ovid MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Database of Systematic Reviews (CDSR), ACP Journal Club, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CCTR), Health TechnolUntil November 2009
Rogovik et al. (112)Narrative reviewVitaminsGeneralMEDLINE/PubMed, MEDLINE Plus, Drug Digest, Natural Medicine Comprehensive Database and the database of the University of Maryland1966–2009

Appendix 3 PRISMA checklist.

Section/topicNo.Checklist itemReported on page no.
Title
 Title1Identify the report as a systematic review, meta-analysis or both.P1
Abstract
 Structured summary 2Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration numberP2
Introduction
 Rationale3Describe the rationale for the review in the context of what is already knownP4
 Objectives4Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes and study design (PICOS)P4
Methods
 Protocol and registration 5Indicate if a review protocol exists, if and where it can be accessed (e.g. Web address), and, if available, provide registration information including registration numberN/A
 Eligibility criteria 6Specify study characteristics (e.g. PICOS, length of follow-up) and report characteristics (e.g. years considered, language, publication status) used as criteria for eligibility, giving rationaleP5
 Information sources 7Describe all information sources (e.g. databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searchedP5
 Search8Present full electronic search strategy for at least one database, including any limits used, such that it could be repeatedP5
 Study selection 9State the process for selecting studies (i.e. screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis)P5
 Data collection process 10Describe method of data extraction from reports (e.g. piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigatorsP6
 Data items 11List and define all variables for which data were sought (e.g. PICOS, funding sources) and any assumptions and simplifications madeP6
 Risk of bias in individual studies 12Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesisN/A
 Summary measures 13State the principal summary measures (e.g. risk ratio, difference in means)N/A
 Synthesis of results 14Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g. I2) for each meta-analysis N/A
 Risk of bias across studies 15Specify any assessment of risk of bias that may affect the cumulative evidence (e.g. publication bias, selective reporting within studies)N/A
 Additional analyses 16Describe methods of additional analyses (e.g. sensitivity or subgroup analyses, meta-regression), if done, indicating which were prespecifiedN/A
Results
 Study selection 17Give numbers of studies screened, assessed for eligibility and included in the review, with reasons for exclusions at each stage, ideally with a flow diagramP7, P48 (Figure1)
 Study characteristics 18For each study, present characteristics for which data were extracted (e.g. study size, PICOS, follow-up period) and provide the citationsP28–37 (Table 1–3); P53–62 (Appendix 1–2)
 Risk of bias within studies 19Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12)N/A
 Results of individual studies 20For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plotN/A
 Synthesis of results 21Present results of each meta-analysis done, including confidence intervals and measures of consistencyN/A
 Risk of bias across studies 22Present results of any assessment of risk of bias across studies (see Item 15)N/A
 Additional analysis 23Give results of additional analyses, if done [e.g. sensitivity or subgroup analyses, meta-regression (see Item 16)]N/A
Discussion
 Summary of evidence 24Summarise the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g. healthcare providers, users and policy makers)P11–14
 Limitations 25Discuss limitations at study and outcome level (e.g. risk of bias), and at review level (e.g. incomplete retrieval of identified research, reporting bias)P14
 Conclusions 26Provide a general interpretation of the results in the context of other evidence, and implications for future researchP14–15
Funding
 Funding 27Describe sources of funding for the systematic review and other support (e.g. supply of data); role of funders for the systematic reviewP15