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Interaction of St John's wort with conventional drugs: systematic review of clinical trials

BMJ 2004; 329 doi: (Published 01 July 2004) Cite this as: BMJ 2004;329:27

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Ethical considerations of St. John's wort interaction studies

Dear Editor,

with great interest we read the article by Mills et al.,1 in which
they studied the methodological quality of trials examining drug
interactions with St John’s wort (SJW). According to classic
epidemiological standards, studies employing a crossover design, control
group, blinding, randomisation, and herb analysis were considered to be
superior. We agree that a solid methodology for this kind of study is
essential in order to be conclusive. At the same time, certain
circumstances make it impossible to meet all criteria. In case of our
study,2 the effect of SJW on the pharmacokinetics of irinotecan was
studied in cancer patients. At the time our study was designed,
preliminary data were available that suggested an influence of SJW on
cytochrome P450 3A4 and P-glycoprotein,3 and hence an interaction between
irinotecan and SJW with potentially dramatic consequences was speculated.
Like other anti-neoplastic agents, irinotecan has a small therapeutic
window and is highly cytotoxic, which precluded the use of healthy
volunteers to study this interaction. During an interim-analysis, it was
found that the exposure to irinotecan’s active metabolite was more than
40% reduced. This provided incentive to discontinue the study, as it was
considered unethical to expose additional patients to this drug
combination with the possibility of inactivation of cancer treatment. As
this argument was not taken into account by Mills et al., it was striking
to note that the five studies that enrolled patients instead of volunteers
were among the “worst” studies. In addition, one should wonder whether the
degree of interaction seen in patients is comparible to that seen in
healthy volunteers.
Regardless, although there may currently not be enough high quality
information to guide the decision to use SJW, we would like to stress that
patients should be aware of the possibility for dangerous interactions
with their conventional drug(s).


1 Mills E, Montori VM, Wu P, Gallicano K, Clarke M, Guyatt G.
Interaction of St John’s wort with conventional drugs: systematic review
of clinical trials. BMJ 2004;329:27-30.

2 Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A.
Effects of St John’s wort on irinotecan metabolism. J Natl Cancer Inst

3 Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I.
Pharmacokinetic interaction of digoxin with an herbal extract from St.
John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338-45.

Competing interests:
None declared

Competing interests: No competing interests

27 July 2004
Ron H.J. Mathijssen
Jaap Verweij, MD, PhD, and Alex Sparreboom, PhD
ErasmusMC - Daniel den Hoed Cancer Center, 3008 AE, Rotterdam, the Netherlands