St. John's Wort: Why This "Natural" Supplement Can Be Medically Dangerous

David S. Klein, MD FACA FACPM
3 days ago
4 min read

St. John’s wort is often perceived as a gentle, plant-based option for mood support. Because it is sold over the counter and labeled as “natural,” many patients assume it is inherently safe. From a physician’s perspective, that assumption is not only incorrect—it can be dangerous.

St. John’s wort is one of the most clinically significant drug-interacting supplements in widespread use today, capable of reducing the effectiveness of numerous prescription medications, sometimes with serious or life-threatening consequences.¹⁻³

St. John’s wort can dangerously reduce the effectiveness of many prescription drugs. Learn why this “natural” supplement carries serious interaction risks. — St. John's Wort can cause drug interactions

What Is St. John’s Wort?

St. John’s wort (Hypericum perforatum) is an herbal preparation traditionally used for mild to moderate depression, anxiety, and mood symptoms. Its primary active constituents include hyperforin and hypericin, compounds that exert effects on neurotransmitters such as serotonin, dopamine, and norepinephrine.¹,²

While these properties explain its antidepressant effects, they also underpin its high risk for drug interactions.

The Core Problem: Potent Enzyme Induction

St. John’s wort is a strong inducer of hepatic and intestinal drug-metabolizing enzymes, particularly:

Cytochrome P450 3A4 (CYP3A4)
Cytochrome P450 2C9 and 2C19
P-glycoprotein (P-gp) transporters

These systems are responsible for the metabolism and transport of a large proportion of commonly prescribed medications. When St. John’s wort induces these pathways, it accelerates drug clearance, often lowering blood levels below therapeutic thresholds.³⁻⁵

Importantly, this effect is not subtle—it can be profound.

Medications Commonly Affected

Antidepressants and Psychiatric Medications

Combining St. John’s wort with SSRIs, SNRIs, tricyclic antidepressants, or other serotonergic agents increases the risk of serotonin syndrome, a potentially life-threatening condition characterized by agitation, hyperthermia, tremor, and autonomic instability.⁶⁻⁸

This interaction is especially concerning because patients often self-add St. John’s wort without informing their clinician.

Oral Contraceptives

St. John’s wort can significantly reduce estrogen and progestin levels, leading to contraceptive failure and unintended pregnancy.⁹⁻¹¹

Multiple case reports and pharmacokinetic studies have documented breakthrough bleeding and ovulation in women taking oral contraceptives alongside St. John’s wort.¹⁰,¹¹

Anticoagulants and Cardiovascular Drugs

St. John’s wort reduces plasma concentrations of:

Warfarin
Direct oral anticoagulants
Certain antiarrhythmics

This interaction increases the risk of thromboembolic events, including stroke and pulmonary embolism.¹²,¹³

In patients with atrial fibrillation, prosthetic valves, or prior clotting events, this risk is particularly dangerous.

Transplant and Immunosuppressive Medications

Perhaps the most alarming interactions involve immunosuppressive agents, including cyclosporine and tacrolimus.

St. John’s wort has been shown to precipitate acute transplant rejection by lowering drug levels below therapeutic ranges.¹⁴,¹⁵ These interactions are well documented and widely cited in transplant medicine.

Why These Interactions Are Often Missed

Several factors contribute to under-recognition:

Patients do not consider supplements to be “medications”
Clinicians may not routinely ask about herbal products
Effects may appear weeks after initiation
Drug levels decline silently before clinical failure occurs

This makes St. John’s wort uniquely hazardous—it often causes harm without immediate warning signs.

“Natural” Does Not Mean Safe

From a pharmacologic standpoint, St. John’s wort behaves more like a broad-spectrum enzyme-inducing drug than a benign supplement. Its effects are:

Dose dependent
Sustained over time
Clinically unpredictable between individuals

Unlike prescription medications, there is no standardized dosing, formulation, or monitoring.

Who Should Avoid St. John’s Wort Entirely?

St. John’s wort should generally be avoided in patients who:

Take prescription antidepressants
Use hormonal contraception
Take anticoagulants or cardiac medications
Are transplant recipients
Take seizure medications
Are on complex or multiple drug regimens

In these populations, the risks consistently outweigh any potential benefit.³⁻⁶,¹²⁻¹⁵

The Takeaway: St. John's Wort can be dangerous

St. John’s wort is not a harmless herbal remedy. It is a potent modulator of drug metabolism with the ability to reduce medication effectiveness, trigger dangerous interactions, and cause serious clinical harm.

From a physician’s perspective, the most important message is this:Any supplement capable of altering liver enzymes must be treated like a prescription drug.

Patients should never start St. John’s wort without discussing it with a qualified clinician—especially if they take prescription medications. Transparency, careful review, and medical oversight are essential to avoid preventable and potentially life-threatening outcomes.

Taking Supplements Alongside Prescription Medications?Many “natural” products can interfere with critical drug therapies. At Stages of Life Medical Institute, we perform comprehensive medication and supplement reviews to identify hidden risks and prevent dangerous interactions.

👉 Schedule a medication and supplement safety review today.

The medical references cited in this article are provided for educational purposes only and are intended to support general scientific discussion. They are not a substitute for individualized medical advice, diagnosis, or treatment. Clinical decisions should always be made in consultation with a qualified healthcare professional who can account for a patient’s unique medical history, medications, and circumstances.

References:

Barnes J, et al. St John’s wort (Hypericum perforatum): a review of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol. 2001.https://pubmed.ncbi.nlm.nih.gov/11428685/
Linde K, et al. St John’s wort for depression—an overview and meta-analysis. BMJ. 2008.https://pubmed.ncbi.nlm.nih.gov/18669545/
Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs. Drugs. 2009.https://pubmed.ncbi.nlm.nih.gov/19453202/
Markowitz JS, et al. Effect of St John’s wort on cytochrome P450 enzymes. Clin Pharmacol Ther. 2003.https://pubmed.ncbi.nlm.nih.gov/12576308/
Dresser GK, et al. Induction of P-glycoprotein by St John’s wort. Clin Pharmacol Ther. 2003.https://pubmed.ncbi.nlm.nih.gov/12966369/
Mills E, et al. Herb–drug interactions: review. Lancet. 2005.https://pubmed.ncbi.nlm.nih.gov/16023513/
Izzo AA. Herb–drug interactions with St John’s wort. Drug Saf. 2004.https://pubmed.ncbi.nlm.nih.gov/15053437/
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005.https://pubmed.ncbi.nlm.nih.gov/16079372/
Murphy PA, et al. St John’s wort and oral contraceptive failure. Contraception. 2005.https://pubmed.ncbi.nlm.nih.gov/16022849/
Hall SD, et al. The interaction between St John’s wort and oral contraceptives. Clin Pharmacol Ther. 2003.https://pubmed.ncbi.nlm.nih.gov/12891224/
Schwarz UI, et al. St John’s wort induces CYP3A4 and reduces contraceptive efficacy. Clin Pharmacol Ther. 2003.https://pubmed.ncbi.nlm.nih.gov/12709724/
Jiang X, et al. Effect of St John’s wort on warfarin anticoagulation. Br J Clin Pharmacol. 2004.https://pubmed.ncbi.nlm.nih.gov/15151530/
Piscitelli SC, et al. Induction of cytochrome P450 by St John’s wort. Clin Infect Dis. 2000.https://pubmed.ncbi.nlm.nih.gov/10981743/
Ruschitzka F, et al. Acute heart transplant rejection due to St John’s wort. Lancet. 2000.https://pubmed.ncbi.nlm.nih.gov/10920459/
Mai I, et al. Dangerous interaction between St John’s wort and cyclosporine. Br J Clin Pharmacol. 2000.https://pubmed.ncbi.nlm.nih.gov/10930955/