Clinical assessment of CYP2D6‐mediated herb–drug interactions in humans: Effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea
Open accessAbstract
Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. John's wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates.
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The actual berberine content, the presence of co-alkaloids such as hydrastine, the chemical form, and "enhanced-bioavailability" formulations determine the effective perpetrator dose the patient receives.
“The actual berberine content, the presence of co-alkaloids such as hydrastine, the chemical form, and “enhanced-bioavailability” formulations determine the effective perpetrator dose the patient receives [71,109,110].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [71]
The Analytical methods section (page unavailable) says the authors measured berberine and hydrastine content in goldenseal. The Discussion (page unavailable) links those alkaloids to CYP2D6 inhibition and notes that berberine has low bioavailability in animal studies. The paper does not assess whether chemical form or “enhanced-bioavailability” formulations determine the effective dose a patient receives. (LLM, conf=0.86)
Experimental — accuracy not yet measured(−)-β-hydrastine appears to be the main alkaloid responsible for time-dependent CYP3A inhibition, and berberine is a weaker CYP3A4 inhibitor.
“In fact, (−)-β-hydrastine appears to be the main alkaloid responsible for this time-dependent inhibition, berberine being a weaker CYP3A4 inhibitor; therefore, the alkaloid profile and botanical identity of the product influence the magnitude of the interaction [71,74].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [71]
The Discussion (page unavailable) compares berberine and hydrastine as inhibitors of CYP2D6, not CYP3A or CYP3A4. Searches for time-dependent CYP3A inhibition and the claimed alkaloid ranking found no passage in our copy addressing either point. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Influential
- Authors
- Gurley, B. J., Swain, A., Hubbard, M. A., Williams, D. K., Barone, G., Hartsfield, F., Tong, Y., Carrier, D. J., Cheboyina, S., & Battu, S. K.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- University of Arkansas at Fayetteville (US)
- University of Mississippi (US)
- Venue
- Molecular Nutrition & Food Research
- Publisher
- Wiley
- Published
- 2008-07
- Volume
- 52
- Issue
- 7
- Pages
- 755-763
- ISSN
- 1613-4125 (ISSN-L)
- 1613-4133
- PMC
- PMC2562884
- OpenAlex
- W2168807338
- Cited by
- 169
- References
- 86
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 12 · 2019: 9 · 2018: 9 · 2017: 7 · 2016: 3 · 2015: 14 · 2014: 14 · 2013: 9 · 2012: 20
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Nutrition & Food Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM071322, GM71322)
- National Center for Research Resources (M01RR014288, RR-14288)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- CYP2D6, herb-drug interactions, herbal supplements, Silybum marianum, black cohosh, goldenseal, kava, Hypericum perforatum, Echinacea, debrisoquine, CYP2D6 inhibition, drug metabolism
- MeSH terms
- Humans, Phytotherapy, Plant Extracts, Cytochrome P-450 CYP2D6, Dietary Supplements, Echinacea, Kava, Hypericum, Silybum marianum, Cimicifuga, Hydrastis, Herb-Drug Interactions
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