Objectives: Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.Methods: Twelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30‐day washout period was interposed between each supplementation phase. Probe‐drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1‐hydroxymidazolam/midazolam serum ratios (1‐hour sample), paraxanthine/caffeine serum ratios (6‐hour sample), 6‐hydroxychlorzoxazone/chlorzoxazone serum ratios (2‐hour sample), and debrisoquin urinary recovery ratios (8‐hour collection), respectively.Results: Comparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P < .0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P = .030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba.Conclusions: Single‐time point phenotypic metabolic ratios may provide a practical means of predicting CYP‐mediated herb‐drug interactions in humans.Clinical Pharmacology & Therapeutics (2002) 72, 276–287; doi: 10.1067/mcp.2002.126913

The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-week-old male B6C3F₁ mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX^® (20 mg/kg). In the acute study, significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST, and total bilirubin were observed for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways associated with lipid and xenobiotic metabolism raises serious concerns about potential drug interactions as well as the safety of CBD.

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.