Repeated administration of berberine inhibits cytochromes P450 in humans
Open accessAbstract
Purpose Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interactions between berberine-containing products and cytochromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses.Methods A two-phase randomized-crossover clinical study in healthy male subjects was performed. After 2 weeks of berberine (300 mg, t.i.d., p.o.) administration, midazolam, omeprazole, dextromethorphan, losartan, and caffeine were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2, respectively.Results A decrease in CYP2D6 activity was observed as the 0-8 h urinary dextromethorphan/dextrorphan increased ninefold (P < 0.01). In addition, losartan/E-3174 ratio doubled (P < 0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the C(max), AUC(0-∞), and AUC(0-12) of midazolam were increased 38% (P < 0.05), 40% (P < 0.01), and 37% (P < 0.05) after BBR treatment, respectively. Compared with the placebo period, the T(max) and T(1/2) of midazolam during BBR administration were prolonged from 3.03 ± 0.27 to 3.66 ± 0.37 h and 0.66 ± 0.08 to 0.99 ± 0.09 h, respectively; the oral clearance of midazolam was decreased 27% (P < 0.05); and the phenotypic indices of 1 h midazolam/1'-hydroxymidazolam increased 59% (P < 0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group.Conclusions Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities. Drug-drug interactions should be considered when berberine is administered.
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Berberine inhibits major cytochrome P450 enzymes and modulates membrane transporters essential to drug disposition.
“Berberine inhibits major cytochrome P450 enzymes and modulates membrane transporters essential to drug disposition [35,36,37]”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
The Conclusion reports that berberine inhibited CYP2D6, CYP2C9, and CYP3A4. The paper does not report that berberine modulates membrane transporters; its References mention a study of P-glycoprotein interaction, but that does not establish the claim for this paper. (LLM, conf=0.90)
Experimental — accuracy not yet measuredHow long CYP2D6 activity stays suppressed in humans after berberine is stopped has not been measured; the clinical duration of this component is inferred from the in vitro mechanism and not observed.
“What nobody has measured is how long CYP2D6 activity stays suppressed in humans after berberine is stopped, which means the clinical duration of this component is inferred from the in vitro mechanism and not observed [35,59].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
The Methods report CYP2D6 probe measurements before and at the end of each treatment phase, with a four-week washout between phases; they do not report measurements tracking how long suppression persists after berberine is stopped. The Discussion proposes substrate competition as a possible mechanism, but does not infer a clinical duration from in vitro findings. That part of the claim is unsupported by this paper. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChronic, repeated administration of berberine lets inhibitory effects accumulate and carries a time-dependent component of CYP2D6 inhibition.
“Chronic, repeated administration, typical of supplement use, lets these inhibitory effects accumulate, and it carries a time-dependent component of CYP2D6 inhibition that we characterize in Section 2.2.1 [35,59].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
The Abstract Conclusions report decreased CYP2D6 activity after two weeks of repeated berberine administration. The paper does not show that inhibition accumulates over successive doses or establish a time-dependent component; the Discussion instead suggests substrate competition as a possible explanation for CYP2D6 inhibition. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLow systemic exposure to berberine coexists with high local concentrations that inhibit CYP3A4/CYP2D6/CYP2C9, can induce CYP3A4 transcriptionally, and modulate P-glycoprotein and organic cation transporters.
“Low systemic exposure coexists with high local concentrations that inhibit CYP3A4/CYP2D6/CYP2C9, and can even induce CYP3A4 transcriptionally, and that modulate P-glycoprotein and organic cation transporters [35,59,65]”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
The Conclusions (page not provided) report that repeated berberine administration decreased CYP2D6, CYP2C9, and CYP3A4 activities. The Discussion says CYP3A4 mRNA expression was suppressed at higher doses, rather than induced. The passages found do not establish low systemic exposure alongside high local concentrations or modulation of P-glycoprotein and organic cation transporters. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAcross the whole field, the paper identified one controlled study in patients (renal-transplant recipients receiving cyclosporine), one probe-cocktail study in healthy volunteers, and one human enzyme-phenotyping study; everything else is preclinical, in vitro or observational.
“Across the whole field we identified one controlled study in patients, in renal-transplant recipients receiving cyclosporine, one probe-cocktail study in healthy volunteers, and one human enzyme-phenotyping study; everything else is preclinical, in vitro or observational.”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Berberine is not a harmless "natural" product but an active pharmacological perpetrator, with an interaction profile predictable from its pharmacology.
“Berberine is not a harmless “natural” product but an active pharmacological perpetrator, with an interaction profile predictable from its pharmacology [35,37,111].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
The Results and Conclusion report that repeated berberine dosing inhibited CYP2D6, CYP2C9, and CYP3A4 in healthy male volunteers and that drug interactions should be considered. This supports describing berberine as pharmacologically active rather than harmless. The Discussion, however, treats some mechanisms as tentative and says the CYP2C9 effect needs further study; it does not establish that berberine’s interaction profile is predictable from its pharmacology. (LLM, conf=0.82)
Experimental — accuracy not yet measuredBerberine is far from inert.
“yet berberine is far from inert”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
Repeated administration of berberine reduced CYP2D6, CYP2C9 and CYP3A4 activity in a clinical study in volunteers.
“In a clinical study in volunteers, repeated administration of berberine reduced CYP2D6, CYP2C9 and CYP3A4 activity, a human enzyme-activity finding, Grade B, that provides the mechanistic basis for the potential interactions discussed below [35].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
A synthesis resting on three human studies cannot support strong statements about effect size in practice, whatever the mechanistic literature suggests.
“A synthesis resting on three human studies cannot support strong statements about effect size in practice, whatever the mechanistic literature suggests [35,83,118].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [35]
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References 17 · Cited by 137
- Authors
- Guo, Y., Chen, Y., Tan, Z.-R., Klaassen, C. D., & Zhou, H.-H.
- Affiliations
- Central South University (CN)
- University of Kansas Medical Center (US)
- Corresponding author
- Klaassen, Curtis D.
- Zhou, Hong-hao
- Venue
- European Journal of Clinical Pharmacology
- Published
- 2011-08-26
- Volume
- 68
- Issue
- 2
- Pages
- 213-217
- ISSN
- 0031-6970 (ISSN-L)
- 1432-1041
- PMC
- PMC4898966
- OpenAlex
- W1985232876
- Cited by
- 137
- References
- 17
- Citations by year
- 2026: 27 · 2025: 10 · 2024: 10 · 2023: 12 · 2022: 6 · 2021: 7 · 2020: 15 · 2019: 8 · 2018: 3 · 2017: 9 · 2016: 4 · 2015: 11 · 2014: 6 · 2013: 5 · 2012: 3
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-081461, R01DK081461)
- National Institute of Environmental Health Sciences (ES009649, ES-019487, R01ES009649, R01ES019487)
- National Center for Research Resources (RR021940, P20RR021940)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Keywords
- berberine, cytochrome P450 inhibition, drug-drug interactions, CYP3A4, CYP2C9, CYP2D6, CYP2C19, CYP1A2, midazolam, dextromethorphan, losartan, omeprazole, caffeine, probe drugs, repeated dosing
- MeSH terms
- Adult, Berberine, Caffeine, Dextromethorphan, Drug Interactions, Drugs, Chinese Herbal, Enzyme Inhibitors, Humans, Male, Midazolam, Omeprazole, Cross-Over Studies, Losartan, Young Adult, Cytochrome P-450 Enzyme Inhibitors
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