St John’s wort (SJW) has repeatedly been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP34A isoform. Dutch scientists determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP34A. Five cancer patients were treated with irinotecan (350 mg/m², intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomised crossover study. The plasma levels of the active metabolite SN-38 decreased by 42% [95% confidence interval (CI) = 14–70%] following SJW co-treatment with 1.0 μM × h (95% CI = 0.34 μM × h to 1.7 μM × h) versus 1.7 μM × h (95% CI = 0.83 μM × h to 2.6 μM × h). These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.