Taken daily, this herb cut total exposure to a transplant drug by 52% and to an HIV drug by 57%. Those are measurements from trials, not a precautionary label.
PubMed holds 862 records on its interactions, and 70 of them are trials.
Quick Answer: What Does St. John's Wort Interact With?
St. John's Wort switches on CYP3A4 and P-glycoprotein, the enzyme and pump that clear many drugs, so those drugs fall to lower levels. Documented examples include the pill, warfarin, digoxin, cyclosporine, tacrolimus, HIV drugs and simvastatin. With antidepressants the risk is serotonin syndrome instead. The effect fades about 7 days after stopping.
Key Takeaways
- PubMed holds 862 records on its interactions, and 70 are trials.
- Hyperforin switches on CYP3A4, which handles over 50% of drugs.
- Cyclosporine exposure fell 52% on a high-hyperforin product in 1 trial.
- Indinavir, an HIV drug, lost 57% of its exposure in volunteers.
- The induction fades roughly 7 days after the last dose.
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How One Herb Changes So Many Drugs
Most herb warnings are theoretical. This one has a mechanism, a receptor and a list of trials behind it.
- Step 1: Hyperforin binds a receptor called PXR.
- Step 2: PXR switches on CYP3A4 in the liver and gut.
- Step 3: P-glycoprotein pumps more of some drugs back out.
- The result: Lower drug levels, sometimes below the level that works.
The mechanism was pinned down in 2000, when hyperforin proved a potent ligand for PXR and induced CYP3A4 in human liver cells. That enzyme handles more than half of all drugs.[1]St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor — PNAS (2000) View source
What the plant is, and why people take it, is in our overview of the herb.
The Documented List
These are interactions measured in people, not predicted from a laboratory.
| Medicine | What happened | Study |
|---|---|---|
| Cyclosporine (transplant) | Exposure down 52%, and 65% higher doses needed | 10 kidney transplant patients |
| Indinavir (HIV) | Exposure down 57%, trough level down 81% | Healthy volunteers |
| Digoxin (heart) | Exposure down 25% after 10 days | Controlled trial, 25 volunteers |
| Warfarin (blood thinner) | Faster clearance, weaker effect on INR | 12 healthy men |
| Simvastatin (cholesterol) | Active form's exposure roughly halved | Crossover study, 8 men on simvastatin |
| Combined pill | More breakthrough bleeding, probable ovulation in 1 study | 4 small trials |
The transplant data are the clearest. A high-hyperforin product cut cyclosporine exposure by 52%, while a low-hyperforin product did not change it significantly.[2]Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction — Clinical Pharmacology and Therapeutics (2004) View source
In volunteers, indinavir exposure fell by 57% and its 8-hour trough by 81%, enough to risk drug resistance.[3]Indinavir concentrations and St John's wort — Lancet (2000) View source
The Pill and Antidepressants
Two interactions deserve pages of their own, because the consequence is more than a lower drug level.
- The pill: Breakthrough bleeding, and a risk of unintended pregnancy.
- Antidepressants: Serotonin syndrome from combined serotonin effects.
- Who it affects: Exactly the people most likely to try this herb.
The numbers for the pill are in the contraceptive trials.
Warfarin, Digoxin and Statins
These 3 are worth a closer look, because the direction surprises people.
- Warfarin: The herb weakens it, so clotting protection can drop.
- Digoxin: About 25% lower exposure, through the P-glycoprotein pump.
- Simvastatin: Its active form falls, while pravastatin was unaffected.
- The common thread: Less drug, not more.
In 12 healthy men, warfarin was cleared faster and its effect on INR fell, which means less protection rather than more bleeding.[4]Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects — British Journal of Clinical Pharmacology (2004) View source
Digoxin exposure fell by 25% after 10 days but not after a single dose, which shows the effect builds over time.[5]Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum) — Clinical Pharmacology and Therapeutics (1999) View source
How Long the Effect Lasts
Stopping the herb does not end the interaction that day.
- Build-up: Over days, not after 1 dose.
- Recovery: About 7 days after the last capsule.
- Estimated recovery half-life: About 46 hours.
- Practical point: Tell prescribers you took it recently, not just currently.
After 14 days on the herb, CYP3A activity took about 7 days to return to its starting level.[8]The recovery time-course of CYP3A after induction by St John's wort administration — British Journal of Clinical Pharmacology (2008) View source Moving between the herb and an antidepressant has its own hazard, set out in why it must never be combined with an SSRI.
Why the Product Matters
The size of the interaction tracks hyperforin, not hypericin, and products vary widely in how much they contain.
| Product, per day | Hyperforin | Cut in midazolam exposure |
|---|---|---|
| High-hyperforin extract | 41 mg | 79.4% |
| Whole-herb powder, 2.7 g | 12 mg | 47.9% |
| Powder almost free of hyperforin | 0.13 mg | 21.1% |
A 2006 trial in 42 men used midazolam as a marker drug for CYP3A. The effect grew with hyperforin dose and did not track hypericin at all.[6]The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose — European Journal of Clinical Pharmacology (2006) View source
A 2019 review linked products giving no more than 1 mg of hyperforin a day to fewer major interactions, without ruling them out.[7]Understanding drug interactions with St John's wort (Hypericum perforatum L.): impact of hyperforin content — Journal of Pharmacy and Pharmacology (2019) View source
Before You Take It
The practical rule is short, and it applies to every form of the herb.
- Show your list: Every medicine, to a pharmacist, first.
- Include the rest: Over-the-counter drugs and other supplements.
- Count blends: Our own Depression Tamer contains St. John's Wort too.
- Tell every prescriber: Including before any surgery.
If a pharmacist clears it, our St. John's Wort capsules are a single-herb formula with nothing else added to the herb.
Check With a Pharmacist Before Taking St. John's Wort If
- You take any prescription medicine, because this herb speeds up how the body clears many of them
- You take an antidepressant or any other medicine that acts on serotonin
- You rely on the pill or another hormonal method to prevent pregnancy
- You take warfarin, digoxin, cyclosporine, tacrolimus or any HIV medicine
- You are pregnant or breastfeeding, or have ever had a manic episode
- You have any thought of self-harm, which needs same-day help: call or text 988 in the US
Frequently Asked Questions
What medications cannot be taken with St. John's Wort? +
Documented examples include cyclosporine, tacrolimus, indinavir, digoxin, warfarin, simvastatin and the pill. Antidepressants are a 2nd category, because of serotonin syndrome.
What should you avoid when taking St. John's Wort? +
Unchecked prescription medicines, other serotonin-acting products and strong sun. Those are the 3 practical rules.
Can I take St. John's Wort and Magnesium together? +
No interaction between the 2 appears in the studies we reviewed. The pairing to check is the herb with your prescription medicines.
Can you take vitamin D with St. John's Wort? +
No trial in our review tested the 2 together, and vitamin D is not on the documented list. Your prescription medicines are the thing to check.
What foods should I avoid when taking St. John's wort? +
No food interaction is established in the trials we reviewed. The documented problems involve medicines, more than 50% of which pass through the same enzyme.
How long after stopping St. John's Wort do interactions last? +
In 1 study, enzyme activity took about 7 days to return to normal after 14 days of use.
Does St. John's Wort affect warfarin? +
Yes. In 12 healthy men it sped up warfarin clearance and weakened its effect on INR, which means less protection, not more bleeding.
Why does one herb interact with so many drugs? +
Its constituent hyperforin switches on CYP3A4, which handles more than 50% of drugs, and the P-glycoprotein pump as well.
Is a low-hyperforin product safe with medicines? +
Lower risk is not 0 risk. A 2019 review linked under 1 mg of hyperforin a day to fewer major interactions, without ruling them out.
Does St. John's Wort interact with HIV medicines? +
Yes. In volunteers it cut exposure to the protease inhibitor indinavir by 57%, enough to risk resistance.
Related Reading
- Does St. John's Wort Work for Depression?
- Side Effects Beyond the Interactions
- Dosage, Hypericin and Hyperforin Explained
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