St. John’s wort (Hypericum perforatum) and warfarin: Dangerous liaisons!

Abstract

An 85-year-old male patient with a history of hypertension, old anterior wall myocardial infarction and atrial fibrillation was placed on warfarin one year previously. However, he did not comply with regular international normalized ratio (INR) measurements, but kept taking warfarin (5 mg) on a daily basis for almost a year without any problems. After watching a television program about herbal remedies, he decided to take St John's wort on his own initiative. One month later, he reported to the emergency service of our hospital with upper gastrointestinal bleeding. Initial blood work revealed hemoglobin (Hb): 7.9 g/dl, hematocrit (htc): 23%, and INR: 6.2. With supportive treatment of fresh frozen plasma and blood transfusions, the bleeding ceased. Later, an esophagogastroduodenoscopy showed no significant pathology. The patient was instructed not to use herbal remedies with prescription medications on discharge.Herbal remedies are frequently used worldwide without medical or government control. Many toxic effects due to herbal remedies have been reported in the medical literature, especially when they are used in combination with prescribed medications. Some have life-threatening side effects, as seen in our patient (1).It is interesting to note that the combined use of St John's wort and warfarin usually causes neutralization of the effect of warfarin by increasing its metabolism via the P450 enzyme system (2). However, in our patient, reverse events occurred: the INR was increased and the patient developed a severe bleeding diathesis, which manifested itself with hematemesis and melena. This is a rare event (3).It is thought that since St John's wort contains many active ingredients, namely hyperforin, flavonols, flavonol glycosides, biflavones, naphthodianthrones, acylphloroglucinols, and phenylpropanes, one or more combinations of these active ingredients might affect the drug metabolism of warfarin in sensitive individuals by potentiating its effect on the clotting cascade (4).Herbal remedies should be considered as toxic as any other drug, and the public should be warned and informed about these effects via accumulation of such reports in the medical literature.

St John’s wort (Hypericum perforatum)-induced psychosis: a case report

“…In particular, hypericin and hyperforin are reported to be respectively CYP1A2 and CYP3A4 inducers [ 7 ]. Thus, attention should be paid when Hypericum is administered in combination with other medications in general [ 12 , 13 ] and more specifically with drugs such as antiretrovirals [ 14 ], cyclosporine [ 15 ], anticoagulants [ 16 ], hormonal contraceptives [ 17 ], and other psychotropic agents such as antidepressants [ 15 ] and antipsychotics [ 18 ]. The number of neurotransmitter systems potentially involved in the mechanism of action of Hypericum is remarkable, encompassing not only monoamines (serotonin, noradrenaline, and dopamine), for which the antidepressant effect is hypothesized, but also glutamate and ion channels [ 19 , 20 ].…”

Updates on the Clinical Evidenced Herb-Warfarin Interactions

“…In a randomized, crossover study in 12 healthy subjects, one tablet of St John's wort (each tablet containing standardized dry extract equivalent to 1 g Hypericum perforatum flowering herb top, 0.825 mg hypericin and 12.5 mg hyperforin) three times daily for two weeks modestly decreased the AUC of both R - and S -warfarin by about 25% after a single 25 mg dose of warfarin [ 91 ]. However, in another case, an 85-year-old patient taking warfarin 5 mg daily was reported to develop upper gastrointestinal bleeding one month after starting St John's wort (without dosage information) [ 122 ]. Until now, the potential interactions between warfarin and St John's wort have not been systemically investigated.…”

Drug‐Drug Interactions Between Warfarin and Psychotropics: Updated Review of the Literature

“…In an open‐label study of healthy subjects, warfarin was demonstrated to induce the clearance of both S‐ and R‐warfarin, with resultant reduction in the effects on INR . In contrast, one case report of supratherapeutic INRs in a patient taking St. John's wort and warfarin concurrently documented the patient's development of a severe bleeding diathesis, manifested by hematemesis and melena . As this is the only such documented interaction predisposing to a bleeding diathesis, one wonders if St. John's wort was responsible for this.…”