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


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.