What medications does St. John's wort (Hypericum perforatum) interfere with?

St. John's Wort Drug Interactions

St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein that significantly reduces plasma concentrations of numerous medications, potentially causing treatment failure, organ rejection, unintended pregnancy, and life-threatening complications. 1, 2, 3

Mechanism of Drug Interactions

• St. John's wort induces cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), accelerating drug metabolism and elimination, thereby reducing therapeutic effectiveness of substrate medications 2, 4, 5
• This induction effect is primarily attributed to hyperforin, a major constituent of St. John's wort 5
• The interaction persists for several months after discontinuation due to the herb's long-lasting enzymatic effects 1

Critical Drug Interactions by Category

Immunosuppressants (Highest Risk)

• Cyclosporine and tacrolimus: St. John's wort causes marked reduction in blood concentrations, resulting in subtherapeutic levels, transplant rejection, and graft loss 3, 4, 5
• The FDA drug label explicitly warns against this combination due to documented cases of organ rejection 3
• Multiple case reports and clinical trials confirm this life-threatening interaction 5

Cardiovascular Medications

• Warfarin: Reduced anticoagulant effect increases thrombotic risk; patients must avoid this combination 2, 4, 6
• Digoxin: Decreased plasma concentrations may lead to inadequate heart rate control 4, 6
• Statins (atorvastatin, lovastatin, simvastatin): Significantly reduced levels compromise cholesterol management 2
• Ivabradine: Specifically contraindicated due to reduced effectiveness 2
• Amiodarone with sofosbuvir-based regimens: Life-threatening arrhythmias can occur 1

Oral Contraceptives

• St. John's wort reduces effectiveness of combined oral contraceptives, leading to unintended pregnancies 1, 2, 7
• This interaction is well-documented with multiple reports of contraceptive failure 5, 6

Antidepressants (Contraindicated)

• SSRIs and MAOIs: Concomitant use is absolutely contraindicated due to risk of serotonin syndrome 2, 7, 4
• Serotonin syndrome can manifest as lethargy, confusion, agitation, hyperthermia, and potentially fatal complications 5
• Monitor for 24-48 hours after discontinuing St. John's wort before initiating SSRIs 2

Antiretroviral Medications

• HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir) and non-nucleoside reverse transcriptase inhibitors (nevirapine): Significantly decreased plasma concentrations compromise HIV viral suppression 2, 4, 5

Hepatitis C Direct-Acting Antivirals

• Sofosbuvir and sofosbuvir/velpatasvir: St. John's wort is contraindicated as it reduces drug exposure and may lead to treatment failure 1
• This applies to all potent P-gp inducers including rifampicin, carbamazepine, phenobarbital, and phenytoin 1

Cancer Medications

• Imatinib and dasatinib: Unpredictably decreased plasma concentrations may require dose adjustments or treatment failure 2, 8
• Irinotecan: Reduced concentrations compromise chemotherapy efficacy 4, 5

Anticonvulsants

• Carbamazepine, phenytoin, phenobarbital: St. John's wort may decrease anticonvulsant levels, increasing seizure risk 2, 4

Other High-Risk Medications

• Theophylline: Reduced concentrations may worsen respiratory symptoms 4, 6
• Alprazolam and other benzodiazepines: Decreased efficacy 4
• Methadone: Reduced levels may precipitate withdrawal symptoms 4
• Fexofenadine: Decreased antihistamine effect 4

Clinical Management Recommendations

Absolute Contraindications

• Do not combine St. John's wort with: immunosuppressants (cyclosporine, tacrolimus), MAOIs, SSRIs, HIV medications, hepatitis C antivirals, or oral contraceptives 1, 2, 7, 3

Perioperative Management

• Discontinue St. John's wort at least 2 weeks before surgery due to multiple drug interactions and effects on serotonin levels 2

Monitoring Requirements

• Patients taking St. John's wort with any interacting medication require more frequent monitoring of drug levels or therapeutic effects 2
• Obtain a complete herbal supplement history from all patients 2

Important Regulatory Considerations

• St. John's wort is not FDA-regulated, with no standardization of content or potency in U.S. preparations 2, 7
• European preparations may have better quality control, but drug interactions remain consistent 8

Common Pitfalls to Avoid

• Assuming all herbal products are safe: St. John's wort has one of the highest potentials for serious drug interactions among herbal supplements 4
• Failing to ask about herbal supplements: Patients often do not volunteer this information unless specifically asked 2
• Underestimating interaction duration: Effects persist for weeks to months after discontinuation due to enzymatic induction 1
• Confusing with other herbs: Unlike ginkgo, ginger, and garlic (which inhibit CYP450), St. John's wort induces these enzymes, causing opposite effects 2