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Cited by 165Complementary and Alternative Medicine StudiesPharmacogenetics and Drug MetabolismPhytochemistry Medicinal Plant Applications

The DOI matches its Crossref record; 404 of the 404 references it cites were found in a registry or an index; none of the 342 sources its claims cite is checked for support yet.

Pharmacokinetic Herb-Drug Interactions (Part 2): Drug Interactions Involving Popular Botanical Dietary Supplements and Their Clinical Relevance

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Gurley, Bill, Fifer, Espero, Gardner, Zoë·2012·Planta Medica
DOI 10.1055/s-0031-1298331
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Abstract

In Part 2 of this review, a critical examination of the pertinent scientific literature is undertaken in order to assess the interaction risk that popular dietary supplements may pose when taken concomitantly with conventional medications. Botanicals most likely to produce clinically important herb-drug interactions are those whose phytochemicals act as mechanism-based inhibitors of cytochrome P450 enzyme activity (e.g., Hydrastis canadensis, Piper nigrum, Schisandra chinensis ) or function as ligands for orphan nuclear receptors (e.g., Hypericum perforatum ). In addition, several external factors unrelated to phytochemical pharmacology can augment the drug interaction potential of botanical supplements. Key Words herb-drug interaction - plant secondary metabolites - cytochrome P450 enzymes - transferases - ATP-binding cassette transporters - solute carrier membrane transport proteins - botanical dietary supplements - black cohosh - Echinacea - garlic - Ginkgo biloba - ginseng - goldenseal - kava - black pepper - piperine - Schisandra - milk thistle - St. John's wort - methylenedioxyphenyl-containing compounds

Overview

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Written from the paper’s full text.

TL;DR

This review critically assesses clinical evidence for herb-drug interactions of popular botanical supplements, concluding most pose low risk at recommended doses while goldenseal, black pepper/piperine, Schisandra, and St. John’s wort pose high risk. Risk is driven mainly by mechanism-based CYP inhibition from methylenedioxyphenyl phytochemicals or nuclear receptor activation by hyperforin/PXR.

Key findings

  • Black cohosh, Echinacea, garlic, ginkgo at ≤240 mg/day, ginseng, kava, and milk thistle were rated low interaction risk; goldenseal, black pepper/piperine, Schisandra, and St. John’s wort were rated high risk.
  • Goldenseal: 14 days of supplementation (~209 mg isoquinoline alkaloids daily) significantly increased midazolam AUC, Cmax, and elimination half-life, with effects proportional to clarithromycin 1000 mg daily; hydrastine inhibited CYP3A4 with IC50 = 25 µM versus berberine IC50 = 400 µM.
  • Black pepper/piperine: every prospective human trial showed improved oral bioavailability, with mean AUC increases of phenytoin 16–133%, rifampicin 69%, propranolol 103%, theophylline 96%, and nevirapine 170%; concern is greatest with CYP3A and/or ABCB1 substrates and piperine/piperamides >10 mg.
  • St. John’s wort: hyperforin is a potent PXR activator with EC50 = 23 nM, below usual human plasma concentrations of ~100–300 nM; >70% of prescription medications are susceptible, and extracts with <1% hyperforin are less likely to produce clinically relevant interactions.
  • Schisandra: clinical AUC increases were 1.5-fold for talinolol, 2.1-fold for tacrolimus, and 2.0-fold for midazolam; gomisins B, C, and G inhibited human CYP3A4 with IC50 values <1.5 µM.
  • Ginkgo: among 29 prospective clinical trials, 23 observed no significant effects on drug disposition, 5 observed modest inhibition, and 3 showed evidence of CYP3A4, CYP2C9, or CYP2C19 induction; doses >240 mg/day may increase interaction prospects.
  • Garlic: garlic oil inhibited human CYP2E1 by almost 40% in young adults and 25% in elderly adults; garlic powder reduced saquinavir mean AUC, 8-hour trough concentrations, and Cmax by 50%; a standardized garlic extract increased duodenal ABCB1 expression by 31%.
  • Milk thistle: standard extracts had no observable effects on many drugs; silymarin increased talinolol AUC by 36% and reduced metronidazole AUC by 29%; in CYP2C9*1/*1 subjects, silymarin produced a 2-fold increase in losartan AUC and Cmax, but not in CYP2C9*1/*3 subjects.

Methods

  • Narrative critical review of published clinical and nonclinical literature on selected popular botanical dietary supplements, presented as Part 2 of a two-part review.
  • For each botanical, the paper assesses in vitro, animal, and human pharmacokinetic interaction data, focusing on cytochrome P450 enzymes, transferases, ABC transporters, and solute carrier transporters, and assigns a qualitative interaction risk rating.
  • No new primary data are reported; no systematic search strategy or meta-analysis is described.

Limitations

  • The paper states that phytochemical profiles and label claims for “standardized” botanical products can vary considerably, which can affect interpretation of efficacy and herb-drug interaction studies.
  • The paper states that most botanicals have not been evaluated clinically and that no clinical assessments of botanical extracts using novel bioavailability-enhancing formulations have been reported.
  • The paper notes methodological concerns in specific studies, such as the Yuan et al. ginseng-warfarin trial being underpowered, using inadequate sampling for AUC, and using a non-stereoselective assay; evident from the text, the review’s risk ratings are qualitative and not based on formal meta-analysis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1055/s-0031-1298331

Cites

404 of 404 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

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Show all 156 claims

  • It may state two separate claims as one. 67
  • The quote only partly states this claim. 16
  • Probably not a substantial claim. 15
96 of 96

  • The paper relies on this without support.

    The products and doses used in the cited clinical studies are representative of commercially available botanical supplements when taken as recommended.

    “most commercially available garlic supplements pose only a limited risk”

  • The paper relies on this without support.

    Most St. John's wort extracts are currently standardized to contain 3% hyperforin.

    “Most SJW extracts are currently standardized to contain 3% hyperforin, yet many brands may possess amounts well below this value.”

  • The paper relies on this without support.

    Many brands of St. John's wort may contain hyperforin amounts well below 3%.

    “Most SJW extracts are currently standardized to contain 3% hyperforin, yet many brands may possess amounts well below this value.”

  • The paper relies on this without support.

    Few St. John's wort products are specifically labeled as having low hyperforin content.

    “Unfortunately for consumers, few SJW products are specifically labeled as having low hyperforin content.”

  • The paper relies on this without support.

    PXR is polymorphic, and certain mutations produce significant functional defects in CYP3A transcription.

    “Like many CYPs, PXR is polymorphic, and certain mutations produce significant functional defects in terms of CYP3A transcription.”

  • The paper relies on this without support.

    Poor dissolution characteristics are major obstacles to phytochemical bioavailability and efficacy.

    “Recognizing that poor dissolution characteristics represent major obstacles to phytochemical bioavailability and efficacy, several dietary supplement manufacturers have recently incorporated novel methods of formulating botanical extracts as a means of improving oral absorption [387,388].”

  • The paper relies on this without support.

    No clinical assessments of the herb-drug interaction potential of botanical extracts incorporating novel formulations have been reported to date.

    “To date, no clinical assessments of the herb-drug interaction potential of botanical extracts incorporating these novel formulations have been reported.”

  • The paper relies on this without support.

    The vast majority of botanical supplements have not been evaluated in a clinical setting.

    “Not surprisingly, the vast majority of these botanicals have yet to be evaluated in a clinical setting.”

  • The paper relies on this without support.

    Hyperforin is a principal mediator of St. John's wort's antidepressive action.

    “Hyperforin, a principal mediator of SJWʼs antidepressive action, lies at the heart of the herbʼs drug interaction potential.”
9 of 9

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Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting descriptions of typical ginkgo study doses

    Major

    The paper says the majority of clinical studies used 240 mg twice daily, or 480 mg/day, but later says most human studies used 240 mg/day or less.

1 of 1

Citations

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Metadata

Authors
Gurley, B., Fifer, E., & Gardner, Z.
Affiliations
  • University of Arkansas for Medical Sciences (US)
  • University of Massachusetts Amherst (US)
ORCID
Gurley, Bill
Venue
Planta Medica
Publisher
Georg Thieme Verlag KG
Published
2012-05-07
Volume
78
Issue
13
Pages
1490-1514
ISSN
  • 0032-0943 (ISSN-L)
  • 1439-0221
DOI
10.1055/s-0031-1298331
OpenAlex
W1983168442
Cited by
165
References
404
Citations by year
2026: 8 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 16 · 2021: 10 · 2020: 8 · 2019: 16 · 2018: 16 · 2017: 16 · 2016: 13 · 2015: 15 · 2014: 10 · 2013: 12 · 2012: 1
FWCI
2.80
Type
journal article
Language
en
Open access
Locations
  • Planta Medica (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytochemistry Medicinal Plant Applications
Keywords
herb-drug interactions, herbal supplements, cytochrome P450 inhibition, phytochemicals, orphan nuclear receptor, black cohosh, Echinacea, garlic, Ginkgo biloba, ginseng, goldenseal, kava, black pepper, piperine, Schisandra, Silybum marianum, Hypericum perforatum, methylenedioxyphenyl compounds
MeSH terms
Adenosine Triphosphate, Cytochrome P-450 Enzyme System, Humans, Pharmacokinetics, Transferases, Dietary Supplements, Magnoliopsida, Membrane Transport Proteins, Plant Preparations, Herb-Drug Interactions

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