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John S. Markowitz, PharmD; Jennifer L. Donovan, PhD; C. Lindsay DeVane, PharmD; Robin M. Taylor, BS; Ying Ruan, MD; Jun-Sheng Wang, MD, PhD; Kenneth D. Chavin, MD, PhD

JAMA. 2003;290:1500-1504.

Context  St John's wort is a popular herbal product used to treat depression but it has been implicated in drug interactions.

Objective  To assess the potential of St John's wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism.

Design, Setting, and Participants  Open-label crossover study with fixed treatment order conducted March 2002 to February 2003 in a US general clinical research center involving 12 healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after 14 days of administration of St John's wort.

Intervention  Participants were given probe drugs (30 mg of dextromethorphan and 2 mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After a minimum 7-day washout period, participants began taking one 300-mg tablet 3 times per day. After 14 days of St John's wort administration, participants were given the probe drugs along with 1 St John's wort tablet to establish postadministration CYP activity; the St John's wort dosing regimen was continued for 48 hours.

Main Outcome Measures  Changes in plasma pharmacokinetics of alprazolam as a probe for CYP 3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan, in urine as a probe for CYP 2D6 activity.

Results  A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St John's wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St John's wort administration (P = .26).

Conclusions  A 14-day course of St John's wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications.

Author Affiliations: Department of Pharmaceutical Sciences (Dr Markowitz), Department of Psychiatry and Behavioral Sciences (Drs Donovan, DeVane, Ruan, and Wang and Ms Taylor), and Department of Surgery, Division of Transplantation (Dr Chavin), Medical University of South Carolina, Charleston.

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