St John's wort substantially lowers cyclosporine levels and has caused documented transplant rejection.
What's happening
Hyperforin, the primary CYP-active constituent of St John's wort, activates the pregnane X receptor (PXR) and strongly induces cytochrome P450 3A4 and P-glycoprotein. Cyclosporine is a narrow-therapeutic-index immunosuppressant metabolized by CYP3A4 and effluxed by P-gp. Inducing both pathways accelerates cyclosporine clearance and produces clinically meaningful under-exposure — which after a transplant means rejection. Published case reports span multiple organ types: two heart transplant recipients developed acute rejection after self-starting SJW (Ruschitzka 2000). A 4-patient case series (2001, Am J Kidney Dis) reported 2 heart, 1 kidney, and 1 pancreas transplant recipients whose cyclosporine levels fell 25-62% within 3-4 weeks of starting SJW, with graft rejection in all four. Cyclosporine levels returned to therapeutic range after SJW was stopped and rejection was treated — but graft function can be permanently reduced by a rejection episode, and not every rejection is successfully treated. Standard retail SJW products (600-900 mg/day high-hyperforin) have caused the interaction. Low-hyperforin products may trigger less PK induction but are not reliable for transplant patients given the non-reversible consequence. The same mechanism applies to tacrolimus and sirolimus.
Recommendation
If you have had an organ transplant and take cyclosporine, tacrolimus, or sirolimus, do not take St John's wort under any circumstance. This applies to every product form: capsules, teas, tinctures, combination mood supplements listing hypericum as an ingredient. If you are currently taking both, contact your transplant center today — not your next routine appointment — and stop the SJW. Your cyclosporine levels need to be rechecked quickly. For mood symptoms, your transplant team can discuss alternatives.
Timing
Spacing doses does not help. CYP3A4 induction is transcriptional, taking days to develop and 1-2 weeks to resolve. No timing workaround.
Sources
— PMID:10683008 — Acute heart transplant rejection due to Saint John's wort. 2000.
— PMID:11684566 — Interaction between cyclosporine and Hypericum perforatum after organ transplantation. Am J Kidney Dis 2001.
— PMID:17486092 — Borrelli F, Izzo AA. St John's wort: drug interactions and clinical outcomes. CNS Drugs 2007.
— PMID:31943241 — Nicolussi S et al. Clinical relevance of St John's wort drug interactions revisited. Br J Pharmacol 2020.
How it works
Hyperforin activates the pregnane X receptor (PXR) and strongly induces CYP3A4 and P-glycoprotein. Cyclosporine is a narrow-therapeutic-index immunosuppressant metabolized by CYP3A4 and effluxed by P-gp. Inducing both pathways accelerates cyclosporine clearance and produces clinically meaningful under-exposure — which after a transplant means rejection. Documented cyclosporine level drops of 25-62% within 3-4 weeks of SJW initiation.
Who should be careful
All organ transplant recipients on cyclosporine, tacrolimus, or sirolimus — contraindicated.
Patients on other narrow-therapeutic-index CYP3A4 substrates — class-general concern.
Patients tapering immunosuppression — even low-dose regimens are at risk; induction effect is disproportionate at low levels.
What we don't know
Onset time of clinically relevant induction varies (days to weeks). Genetic variation in PXR/CYP3A4 likely modulates individual susceptibility but is not used clinically to stratify risk. Whether any low-hyperforin formulation is truly safe in transplant recipients has not been tested and would be unethical to test given documented harm.
Why this severity
DANGER. Transplant rejection is non-reversible and potentially life-threatening. Multiple published cases across heart, kidney, and pancreas transplants. Unanimous transplant-medicine contraindication.
Evidence quality (GRADE): high
Frequently Asked Questions
Can I take cyclosporine and st johns wort together?
St John's wort substantially lowers cyclosporine levels and has caused documented transplant rejection.. If you have had an organ transplant and take cyclosporine, tacrolimus, or sirolimus, do not take St John's wort under any circumstance. This applies to every product form: capsules, teas, tinctures, combination mood supplements listing hypericum as an ingredient. If you are currently taking both, contact your transplant center today — not your next routine appointment — and stop the SJW. Your cyclosporine levels need to be rechecked quickly. For mood symptoms, your transplant team can discuss alternatives.
How should I time cyclosporine and st johns wort?
Spacing doses does not help. CYP3A4 induction is transcriptional, taking days to develop and 1-2 weeks to resolve. No timing workaround.
Is this interaction dangerous?
This interaction is rated “Danger” by Formulate. Hyperforin, the primary CYP-active constituent of St John's wort, activates the pregnane X receptor (PXR) and strongly induces cytochrome P450 3A4 and P-glycoprotein. Cyclosporine is a narrow-therapeutic-index immunosuppressant metabolized by CYP3A4 and effluxed by P-gp. Inducing both pathways accelerates cyclosporine clearance and produces clinically meaningful under-exposure — which after a transplant means rejection. Published case reports span multiple organ types: two heart transplant recipients developed acute rejection after self-starting SJW (Ruschitzka 2000). A 4-patient case series (2001, Am J Kidney Dis) reported 2 heart, 1 kidney, and 1 pancreas transplant recipients whose cyclosporine levels fell 25-62% within 3-4 weeks of starting SJW, with graft rejection in all four. Cyclosporine levels returned to therapeutic range after SJW was stopped and rejection was treated — but graft function can be permanently reduced by a rejection episode, and not every rejection is successfully treated. Standard retail SJW products (600-900 mg/day high-hyperforin) have caused the interaction. Low-hyperforin products may trigger less PK induction but are not reliable for transplant patients given the non-reversible consequence. The same mechanism applies to tacrolimus and sirolimus.
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