Quick Reference
RxDrug of choiceNot applicable; St John's Wort is an herbal supplement. For depression, first-line SSRIs like escitalopram 10-20 mg daily are preferred.
AltAlternativesOther antidepressants without CYP induction: escitalopram, sertraline, venlafaxine, mirtazapine, bupropion.
⊘AvoidAbsolute: with MAOIs, SSRIs, SNRIs, triptans, linezolid due to serotonin syndrome. Relative: with warfarin, cyclosporine, tacrolimus, oral contraceptives, antiretrovirals, digoxin, and other CYP3A4/CYP2C9/CYP2C19/P-gp substrates.
DxTest of choiceSerum drug levels of narrow therapeutic index drugs (e.g., cyclosporine, tacrolimus, digoxin, warfarin INR).
ScKey scoreNaranjo Adverse Drug Reaction Probability Scale.
→When to referTo clinical pharmacist for complex drug interaction management; to psychiatrist for alternative antidepressant therapy.
St John's Wort is a potent inducer of CYP3A4, CYP2C9, CYP2C19, and P-gp, causing reduced efficacy of many critical drugs. It should be avoided in patients on medications with narrow therapeutic indices or those metabolized by these pathways. Serotonin syndrome risk with serotonergic drugs.
St John's Wort (Hypericum perforatum) is a widely used herbal supplement for mild-to-moderate depression, but its potent induction of CYP3A4, CYP2C9, CYP2C19, and P-glycoprotein causes numerous clinically significant drug interactions. The bottom line: any patient on a narrow-therapeutic-index drug or serotonergic agent should avoid St John's Wort due to risks of reduced efficacy, organ rejection, thrombosis, contraceptive failure, or serotonin syndrome. Clinicians must routinely ask about herbal supplement use and manage interactions by discontinuing the herb, adjusting drug levels, and selecting alternative antidepressants.
Overview and Recommendations
Key Facts
- •St John's Wort (Hypericum perforatum) is one of the most widely used herbal supplements for mild-to-moderate depression, with an estimated 2-5% of US adults reporting use and a global market exceeding $500 million annually. Its primary antidepressant mechanism is thought to involve inhibition of serotonin, norepinephrine, and dopamine reuptake, but this is clinically overshadowed by its potent enzyme-inducing properties that cause widespread drug interactions.
- •The key pharmacologic concern is induction of cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2C19) and the efflux transporter P-glycoprotein (P-gp), leading to reduced plasma concentrations of numerous co-administered drugs. This induction is mediated primarily by hyperforin, a phloroglucinol derivative that activates the pregnane X receptor (PXR), resulting in upregulation of these drug-metabolizing enzymes and transporters.
- •St John's Wort is available over-the-counter in many countries and is not FDA-approved, leading to variability in product quality, standardization, and content. Most clinical studies use extracts standardized to 0.3% hypericin (e.g., 300 mg three times daily), but hyperforin content can vary widely (0.5-5%), which directly correlates with the magnitude of drug interactions, products with >1% hyperforin pose the greatest risk.
- •The clinical impact of interactions is substantial: breakthrough bleeding and contraceptive failure with oral contraceptives, reduced INR with warfarin leading to thrombosis, graft rejection with cyclosporine and tacrolimus, and virologic failure with antiretroviral therapy. The induction persists for 1-2 weeks after discontinuation of the herb, so interactions cannot be avoided by stopping the herb immediately before a procedure.
- •St John's Wort is also associated with serotonin syndrome when combined with other serotonergic agents (SSRIs, SNRIs, MAOIs, triptans, linezolid), due to additive effects on serotonin reuptake inhibition. This risk is underappreciated because many patients do not disclose herbal supplement use, and the syndrome can be life-threatening.
Clinical Use
- •Suspect use of St John's Wort in any patient presenting with depression, anxiety, or seasonal affective disorder who is also taking conventional medications, especially those with narrow therapeutic indices. Ask specifically about herbal and over-the-counter supplement use using a non-judgmental tone to elicit accurate history, many patients do not consider herbs as medications.
- •Examine the patient for signs of reduced drug efficacy: breakthrough bleeding or spotting in women on oral contraceptives, unexplained increase in INR instability in patients on warfarin, rising creatinine or signs of rejection in transplant recipients on calcineurin inhibitors, or virologic failure in HIV patients on antiretroviral therapy.
- •Order relevant drug levels when available: serum cyclosporine/tacrolimus trough levels, INR for warfarin, digoxin levels, and therapeutic drug monitoring for antiepileptics (e.g., carbamazepine, lamotrigine). A decrease in these levels from baseline or subtherapeutic levels should prompt consideration of St John's Wort interaction.
- •Diagnostic criteria for a St John's Wort drug interaction include: documented use of the herb, co-administration of an interacting drug, temporal relationship between initiation and loss of efficacy or subtherapeutic levels, and exclusion of other causes (nonadherence, dose change, other interacting drugs). Resolution of the interaction upon discontinuation of the herb confirms the diagnosis.
- •Also consider other CYP3A4 inducers (rifampin, carbamazepine, phenytoin, phenobarbital) as potential confounders or additive interactions. St John's Wort is often the hidden cause when no other inducer is identified.
- •Assess for serotonin syndrome in patients also taking serotonergic medications: symptoms include altered mental status, autonomic instability, neuromuscular hyperactivity (clonus, hyperreflexia, tremor). Use the Hunter Serotonin Toxicity Criteria to aid diagnosis.
- •Obtain a complete medication list including prescription, OTC, and herbal supplements. Document the specific St John's Wort product, dose, frequency, and duration of use. Note that patients may not know the exact formulation; ask for the bottle if possible.
- •Consider the patient's risk factors: pregnancy (interaction with oral contraceptives), organ transplant status, HIV, anticoagulation, epilepsy, and psychiatric comorbidities. Polypharmacy increases the risk of multiple interactions.
- •In the emergency department, suspect St John's Wort interaction in any patient with unexplained loss of therapeutic effect, especially if the patient has a history of depression or herbal supplement use. Check serum levels of any narrow therapeutic index drugs the patient is taking.
- •Educate the patient about the interaction: explain that St John's Wort can reduce the effectiveness of their medication, and that it is not a harmless herbal product. Provide written information and alternative treatments.
Safety
- •The first-line management for a clinically significant St John's Wort drug interaction is to discontinue the herb, provided the interacting drug is critical. The induction effect resolves over 1-2 weeks, so drug levels and clinical parameters should be monitored closely during this period, anticipate the need for dose reductions of the interacting drug as the induction wanes.
- •If the patient requires continued antidepressant therapy, switch to a standard antidepressant with minimal CYP induction, such as an SSRI (e.g., escitalopram 10-20 mg daily, starting at 10 mg) or SNRI (e.g., venlafaxine 75-225 mg daily). Avoid using St John's Wort concurrently with these agents due to serotonin syndrome risk.
- •For patients on warfarin and St John's Wort, discontinue the herb and monitor INR daily for the first week, then weekly. The INR may rise as the induction wears off; anticipate a 20- reduction in warfarin dose. The typical induction magnitude is a 30- reduction in INR, so reversal can require careful dose adjustments.
- •For patients on oral contraceptives, discontinue St John's Wort and advise use of a backup method (e.g., condoms) for at least one month. Consider switching to a non-hormonal method or a contraceptive that is less affected by CYP induction, such as an intrauterine device or progestin-only implant.
- •In transplant recipients on cyclosporine or tacrolimus, discontinue St John's Wort and monitor trough levels every 2-3 days until stable. The dose of the calcineurin inhibitor may need to be increased by 50-100% temporarily, then reduced as the induction resolves. Alternatively, consider a non-inducing antidepressant like mirtazapine (15-45 mg daily at bedtime) or bupropion (150-300 mg daily, extended release).
- •For HIV patients on antiretroviral therapy (especially protease inhibitors or NNRTIs), discontinue St John's Wort and check viral load and CD4 count. The drug levels may be subtherapeutic; consider switching to an integrase inhibitor-based regimen which is less affected by CYP induction. Never restart the herb without careful monitoring.
- •Avoid initiating St John's Wort in any patient on medications with a narrow therapeutic index that are substrates of CYP3A4, CYP2C9, CYP2C19, or P-gp. This includes warfarin, acenocoumarol, dabigatran, apixaban, rivaroxaban, cyclosporine, tacrolimus, sirolimus, everolimus, digoxin, amiodarone, quinidine, theophylline, carbamazepine, phenytoin, lamotrigine, oral contraceptives, tamoxifen, irinotecan, imatinib, sunitinib, and many others.
- •Avoid combining St John's Wort with other serotonergic drugs: SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, sertraline), SNRIs (duloxetine, venlafaxine, desvenlafaxine), MAOIs (phenelzine, tranylcypromine, isocarboxazid, selegiline), triptans (sumatriptan, rizatriptan), linezolid, methylene blue, and tramadol. The risk of serotonin syndrome is significant and can be life-threatening.
- •Do not use St John's Wort in patients with bipolar disorder, as it may induce mania or hypomania. It should also be avoided in patients with a history of psychosis or severe depression requiring hospitalization.
- •Monitor for adverse effects of the herb itself: photosensitivity (especially with high doses or fair skin), gastrointestinal upset, dizziness, dry mouth, sedation, and fatigue. These are generally mild, but photosensitivity can be severe in rare cases.
- •Educate patients: St John's Wort is not FDA-approved and labeling often does not include warnings about drug interactions. Advise them to inform all healthcare providers of their supplement use, including dentists and surgeons. Provide a list of interacting medications to avoid.
- •When to refer: to a clinical pharmacist for management of complex drug interactions, to a psychiatrist for alternative antidepressant therapy, to a primary care provider for ongoing monitoring, and to a transplant pharmacist for transplant recipients.
- •Discharge criteria for patients with a resolved interaction: stable drug levels within therapeutic range, no clinical signs of loss of efficacy, and patient education complete. Follow-up in 1-2 weeks to reassess.
- •For patients who insist on continuing St John's Wort, consider a trial of dose adjustment of the interacting drug, but this is risky and requires frequent monitoring. It is generally not recommended.
- •In pregnancy and lactation, advise against St John's Wort due to unknown safety and potential interactions with prenatal vitamins or other medications. Use alternative antidepressants with established safety data, such as sertraline (50-200 mg daily) or fluoxetine (20-80 mg daily) under medical supervision.
Board Review — High Yield
- •CYP3A4 induction, St John's Wort reduces efficacy of oral contraceptives, cyclosporine, tacrolimus, and many antiretrovirals; breakthrough bleeding or graft rejection may occur.
- •P-glycoprotein induction, Reduces absorption of digoxin and dabigatran; monitor levels.
- •Hyperforin, The main active component responsible for CYP induction; products with >1% hyperforin pose the greatest interaction risk.
- •Serotonin syndrome, Potentially life-threatening when combined with SSRIs, SNRIs, MAOIs, triptans, or linezolid; use Hunter criteria for diagnosis.
- •Long-lasting induction, Enzyme induction persists for 1-2 weeks after discontinuation; cannot be stopped acutely to avoid interactions.
- •Warfarin interaction, Reduces INR by 30-; anticipate warfarin dose reduction of 20- when St John's Wort is stopped.
- •Oral contraceptive failure, Breakthrough bleeding and pregnancy risk; advise backup method for at least one cycle.
- •Not FDA-approved, Quality varies; standardized extracts to 0.3% hypericin are commonly used (300 mg TID), but hyperforin content is not regulated.
- •Mania risk, Can induce mania in bipolar patients; avoid if history of hypomania or bipolar disorder.
- •Naranjo scale, Useful for assessing causality of adverse drug reactions involving St John's Wort.