St John’s wort is one of the few herbal medicines that has been subjected to controlled studies in order to determine the significance of its interaction with numerous drugs. Although this can be reassuring, the clinical significance of many interactions is still unpredictable because of the variable chemical composition of products.
It is important to note that interactions due to CYPand P-gp induction do not appear significant with low hyperforin extracts (ZE 117).
- 1 Clinical note— Mechanisms responsible for reported interactions
- 2 ALPRAZOLAM
- 3 AMITRIPTYUNE
- 4 ANTIDEPRESSANTS
- 5 ANTICONVULSANTS
- 6 ANTINEOPLASTIC DRUGS
- 7 CYCLOSPORIN
- 8 DIGOXIN
- 9 HIV NON-NUCLEOSIDE TRANSCRIPTASE INHIBITORS
- 10 HIV PROTEASE INHIBITORS
- 11 METHADONE
- 12 MIDAZOLAM
- 13 OMEPRAZOLE
- 14 ORAL CONTRACEPTIVES
- 15 PUVA THERAPY
- 16 SIMVASTATIN
- 17 TACROLIMUS
- 18 VERAPAMIL
- 19 WARFARIN
Clinical note— Mechanisms responsible for reported interactions
Based on the herb’s pharmacology, there are several mechanisms by which it may interact with drugs. Considering St John’s wort has significant serotonin reuptake inhibitor activity and significantly upregulates both 5-HT1A and 5-HT2A receptors, concomitant use of drugs that elevate serotonin levels, such as tricyclic antidepressants or SSRIs, may result in additive or synergistic effects and increase the risk of serotonergic syndrome. As the constituent hyperforin has a significant and selective induction effect on CYP3A4 and 2C19 activity and induces the drug transporter P-glycoprotein, a number of pharmacokinetic interactions are possible with those drugs that are substrates for CYP3A4 or 2C19 and/or rely on P-gp transport. Refer to Chapter for further information on interactions with herbs and natural supplements.
Decreases serum levels of alprazolam via CYP induction — monitor for signs of reduced drug effectiveness and adjust the dose if necessary.
Although St John’s wort decreases serum levels of amitriptyline via CYP induction in vivo, theoretically it could also induce increases in serotonin availability, which has an opposite effect; the clinical outcome of these two interacting mechanisms is unknown — monitor for signs of changed drug effectiveness and adjust the dose if necessary or avoid concurrent use.
Increased risk of serotonin syndrome possible; however, increased antidepressant activity also possible with appropriate doses — avoid concurrent use unless under medical supervision, so that doses may be altered appropriately.
Phenobarbitone, phenytoin: St John’s wort may increase drug metabolism resulting in reduced drug efficacy — avoid concurrent use unless under medical supervision, so that doses may be altered appropriately.
Irinotecan, imatinib mesylate etc. which are P-gp and/or CYP3A4 substrates — avoid (see Chapter for more information on safety of complementary medicines and cancer).
Decreases plasma levels of cyclosporin significantly within 3 days of concomitant use via CYP induction — avoid concurrent use.
A pharmacokinetic study with kidney graft recipients suggests the effect is not significant when low hyperforin products are used.
Decreases serum digoxin levels significantly within 10 days of concomitant use, chiefly due to induction of the P-glycoprotein — monitor patient for signs of reduced drug effectiveness and adjust the dose if necessary or avoid concurrent use.
HIV NON-NUCLEOSIDE TRANSCRIPTASE INHIBITORS
Decreases serum levels — avoid concurrent use.
HIV PROTEASE INHIBITORS
Decreases serum levels — avoid concurrent use.
Decreases serum levels via CYP induction — avoid concurrent use.
Decreases serum levels of midazolam via CYP induction — monitor for signs of reduced drug effectiveness and adjust the dose if necessary.
Decreases serum levels via CYP induction — monitor for signs of reduced drug effectiveness and adjust the dose if necessary.
Breakthrough bleeding has been reported, which can indicate decreased effectiveness of oral contraceptives. In 2003, a controlled study confirmed that standard doses of St John’s wort cause an induction of ethinyl oestradiol-norethindrone metabolism consistent with increased CYP3A activity — use this combination with caution.
In 2002, a pharmacokinetic study found no significant interaction between low hyperforin St John’s wort and low-dose oral contraceptives — appears to be safe.
High-dose hypericin may increase sensitivity to UV radiation — caution is advised.
Decreases serum levels of simvastatin via CYP induction — monitor for signs of reduced drug effectiveness and adjust the dose if necessary (no interaction is expected with pravastatin).
Decreases serum levels of tacrolimus via CYP induction — avoid this combination.
Decreases serum levels of verapamil via CYP induction — monitor for signs of reduced drug effectiveness and adjust the dose if necessary.
Metabolism of warfarin is chiefly by CYP2C9, and a minor metabolic pathway is CYP3A4, so theoretically it may interact with St John’s wort. A clinical study found no change to INR or platelet aggregation, but there are case reports suggesting St John’s wort may lower the INR— caution is advised.