Which prescription drugs metabolized by CYP3A4 have documented interactions with herbal supplements?
Executive summary
St. John’s wort, grapefruit (juice), and a range of polyphenol-rich herbal supplements have documented, clinically significant interactions with prescription drugs that are substrates of CYP3A4, altering blood levels and therapeutic effects of immunosuppressants, statins, certain anticancer agents, opioids and other widely used drugs [1] [2] [3]. Many other botanicals (green tea extracts, flavonoid supplements, milk thistle, some commercial herbal preparations) show in vitro CYP3A4 inhibition or induction or variable effects across brands, but clinical relevance is often inconsistent or insufficiently studied [4] [5] [6] [7].
1. The clearest real‑world offenders: grapefruit and St. John’s wort
Grapefruit constituents (furanocoumarins) irreversibly inhibit intestinal CYP3A4 and have a long-established ability to increase systemic exposure to multiple CYP3A4‑metabolized drugs — classic examples include simvastatin (markedly increased levels), cyclosporine (≈38% increase), tacrolimus (≈110% increase) and oxycodone (≈67% increase) after grapefruit exposure, with documented clinical consequences in oncology and transplant medicine [2] [1]. By contrast, St. John’s wort is a potent inducer via the pregnane X receptor and has been shown to decrease plasma levels of CYP3A4 substrates such as the anticancer prodrug irinotecan (≈40% reduction reported) and to lower levels of many tyrosine kinase inhibitors and other CYP3A4‑dependent drugs, producing loss of efficacy [1] [7].
2. Immunosuppressants, statins, opioids and anticancer drugs — high‑risk drug classes
Clinically important CYP3A4 herb–drug interactions concentrate in a few drug classes: calcineurin inhibitors (cyclosporine, tacrolimus) and mTOR/kinase inhibitors used in transplant and oncology, statins metabolized by CYP3A4 (e.g., simvastatin), certain opioids (oxycodone), and chemotherapeutics or targeted anticancer agents (irinotecan; many tyrosine kinase inhibitors such as imatinib, osimertinib, lapatinib) — all are named in reviews noting grapefruit, St. John’s wort or other botanicals as modifiers of systemic exposure [1] [2] [8]. The FDA explicitly lists St. John’s wort and grapefruit among non‑drug substances that alter CYP activity and drug exposure [3].
3. Evidence beyond the headlines: flavonoids, green tea, milk thistle and commercial variability
A wide group of dietary polyphenols and flavonoids inhibit CYP3A4 in vitro, and predictive screens plus experimental studies flag green tea extract, certain flavonoid supplements and milk thistle as modulators of CYP3A4 activity; green tea extract in particular produced marked CYP3A4 inhibition in one comparative study across commercial brands (inhibition ranged widely by product) [5] [9] [4] [6]. However, preclinical inhibition does not always translate to clinical interactions — milk thistle showed inhibitory activity in hepatocyte cultures but clinical trials failed to confirm broad inhibition in humans, highlighting gaps between lab data and patient outcomes [6].
4. Mechanisms matter: induction vs inhibition and the role of transporters
Herbal agents can either inhibit CYP3A4 (raising drug exposure) or induce it via nuclear receptors (lowering exposure); they may also affect drug transporters such as P‑glycoprotein, creating combined effects on absorption and clearance — P‑gp plus CYP3A4 in enterocytes form a barrier that many orally administered drugs must cross, and herbs that modulate both systems (e.g., hyperforin in St. John’s wort) produce especially impactful interactions [10] [11] [7]. This dual mechanism explains why the same herb can change both the peak concentration and overall exposure (AUC) of sensitive drugs [10] [2].
5. Clinical nuance, regulatory gaps and practical implications
The literature repeatedly stresses variability: not all herbs or brands behave identically, clinical studies are limited for many botanicals, and the regulatory framework for supplements allows large compositional differences between products, producing unpredictable interaction risk [4] [12]. Systematic reviews and deep‑learning screens predict many potential CYP3A4 inhibitors among dietary compounds, reinforcing that clinicians and patients should treat supplements as possible interaction partners with drugs metabolized by CYP3A4 until rigorous clinical data prove otherwise [8] [13].
6. Bottom line: who to watch and where evidence is strongest
Strong, clinically established herb–CYP3A4 interactions: grapefruit (simvastatin, cyclosporine, tacrolimus, oxycodone and many others) and St. John’s wort (irinotecan, certain TKIs and numerous CYP3A4 substrates) [2] [1] [3]. Probable or experimentally supported risks: green tea extract, concentrated flavonoid supplements, some commercial herbal formulations and milk thistle (in vitro/variable clinical data) affecting drugs metabolized by CYP3A4 and/or transported by P‑gp [4] [5] [6] [11]. Where direct clinical evidence is absent in provided sources, the reporting is explicit about the limitation and inconsistency of human data [6] [12].