Saint John's Wort

NutraPedia - Evidence-Based Supplement Research

Back to Table of Contents
Health Goals: mood stress anxiety

Research Overview

Research on Hypericum perforatum (Saint John’s Wort) has most extensively focused on its phytochemistry, pharmacology, and clinically relevant drug–herb interactions. Multiple lines of work characterize its complex chemical profile (e.g., flavonoids and naphthodianthrones such as hypericin/pseudohypericin) and explore bioactivity in diverse experimental systems, including immunomodulatory and antiviral effects in vitro and in animal models. Beyond medicinal use, compositional studies also examine Saint John’s Wort as a tea/food ingredient, describing volatile compounds, fatty-acid profiles (including omega-3/omega-6 content), and polyphenols; these studies primarily inform nutritional/quality attributes rather than clinical efficacy.

The strongest and most clinically actionable evidence in the provided abstracts concerns safety—specifically, Saint John’s Wort as a potent inducer of drug-metabolizing enzymes and transporters (notably CYP3A and P-glycoprotein), leading to reduced exposure of co-administered medications. A controlled phase I study in healthy volunteers showed marked induction of CYP3A activity and substantial reductions in exposure to CYP3A/P-gp substrates (e.g., rivaroxaban and macitentan), supporting recommendations to avoid certain combinations, particularly with narrow-therapeutic-index drugs or where loss of efficacy is dangerous. By contrast, efficacy signals for new indications in these abstracts are largely preclinical: an ethyl acetate fraction demonstrated anti-infectious bronchitis virus activity in chicken cells and animals, with associated shifts in innate immune signaling (increased type I interferon pathway markers and reduced pro-inflammatory mediators), but these findings do not yet establish human clinical benefit.

Key gaps include the need for rigorous, indication-specific clinical trials where mechanistic plausibility exists but clinical evidence is limited (e.g., migraine: physiological activity is noted, but controlled clinical studies are lacking). Additional research is also needed to identify which constituents or combinations drive specific bioactivities, to standardize preparations, and to define dose–response relationships and safety margins across products. Finally, interaction research would benefit from broader mapping across drug classes and patient populations at higher risk (e.g., polypharmacy, transplant, oncology), integrating real-world outcomes with pharmacokinetic/pharmacodynamic studies to better quantify clinical impact and guide individualized risk management.

1. What conditions has Saint John’s Wort been studied for?

  • Viral infection (infectious bronchitis virus, IBV): Studied in vitro (chicken embryo kidney cells) and in vivo (chickens) using an ethyl acetate extract fraction (HPE).

  • Plaque-type psoriasis: Studied as a topical Hypericum perforatum ointment in a double-blind, placebo-controlled pilot trial.

  • Migraine: Discussed in a review of phytomedicines; Saint John’s Wort is mentioned as having relevant physiological activity but lacking clinical studies for migraine.

  • Willis–Ekbom’s disease (restless legs syndrome): Studied in an open-label pilot trial using 300 mg/day concentrated extract for 3 months.

  • Drug–herb interactions / pharmacokinetics: Studied as a CYP3A4 and P-glycoprotein inducer affecting exposure to drugs (e.g., rivaroxaban and macitentan) in healthy volunteers; also discussed in clinical reviews of drug-food/drug-herb interactions.

  • Nutritional/food context (tea): Saint John’s Wort included among flower/leaf teas assessed for polyphenols, volatile compounds, and fatty acid profiles (nutritional characterization rather than a disease treatment study).

  • Aquaculture stress/immune function (Atlantic salmon): Included as part of a combination plant-extract functional diet evaluated for antioxidant/immune status under crowding stress (not directly human clinical evidence).

  • Cancer metastasis target discovery (SSH inhibitors): A natural-products screen for slingshot phosphatase (SSH) inhibitors is described, but the provided abstract fragment does not clearly confirm Saint John’s Wort as the source of the identified inhibitors.

2. Does it work in treating those conditions? Summarize the evidence.

  • IBV antiviral effects (preclinical; promising but not human evidence):

    • In vitro, the ethyl acetate fraction (HPE) reduced IBV mRNA expression and virus titer and reduced immunofluorescence signal in infected cells.

    • In vivo (chickens), HPE (reported doses 480–120 mg/kg for 5 days) reduced trachea/kidney injury and reduced IBV mRNA in those tissues.

    • Mechanistic signals reported: decreased IL-6, TNF-α, NF-κB mRNA and increased MDA5 pathway/type I interferon (IFN-α/IFN-β) mRNA.

    • Limitation: This is not evidence of efficacy for human viral illnesses; it is a chicken virus model with a specific extract fraction.

  • Plaque psoriasis (human pilot RCT; supportive but small):

    • In a double-blind, placebo-controlled pilot with intraindividual comparison (n=20), topical Hypericum ointment led to significant reductions in TNFα staining in multiple tissue compartments (e.g., dermis p=0.025; endothelial cells p=0.033; dendritic cells p=0.014; epidermis reduction superior to placebo p=0.046).

    • Clinical outcomes: PASI component scores (erythema, scaling, thickness) were significantly improved on treated vs placebo areas (p=0.014, 0.004, 0.003).

    • Limitation: Pilot size; topical preparation studied (not necessarily generalizable to oral products); longer-term outcomes and comparisons to standard therapies were not provided in the abstract.

  • Migraine (insufficient clinical evidence):

    • A review notes Saint John’s Wort has “relevant physiological activity” but lacks clinical studies for migraine, and highlights its hepatic enzyme induction as a practical limitation.

  • Willis–Ekbom’s disease / restless legs syndrome (preliminary, uncontrolled):

    • Open-label pilot (n=21) reported symptom severity reduction in 17/21 patients on 300 mg/day for 3 months.

    • Limitation: No placebo control or blinding; results are highly susceptible to placebo effect and regression to the mean. The abstract itself notes that future blinded placebo-controlled trials are needed.

  • Drug interaction outcomes (evidence of clinically meaningful effects on drug exposure):

    • In a phase I trial in healthy volunteers, Saint John’s Wort strongly increased CYP3A activity (midazolam probe: +272%).

    • It substantially reduced exposure to macitentan (AUC decreased by 48%) and also reduced rivaroxaban exposure; authors conclude the combination with rivaroxaban should be avoided.

3. What health benefits does it have?

  • Anti-inflammatory effects (human evidence in psoriasis):

    • Topical Hypericum perforatum reduced TNFα levels in psoriatic lesions and improved clinical signs (erythema, scaling, thickness) versus placebo in a small double-blind pilot study.

  • Antiviral and immunomodulatory signals (preclinical):

    • In the IBV model, an ethyl acetate extract fraction reduced viral markers and shifted immune signaling toward higher type I interferon pathway markers (MDA5/IFN-α/IFN-β) and lower inflammatory markers (IL-6/TNF-α/NF-κB).

    • Active constituents in that fraction were reported as hyperoside, quercitrin, quercetin, pseudohypericin, and hypericin, with the suggestion that combinations may mediate antiviral activity.

  • Nutritional/food-related properties (tea analysis; not clinical outcomes):

    • Saint John’s Wort tea samples were among flower/leaf teas characterized as potential sources of polyphenolic compounds and showed presence of omega-3 and omega-6 fatty acids (the study quantified omega-3 in mint, Saint John’s Wort, green, blueberry, and lavender samples; omega-6 was high in several including Saint John’s Wort).

    • Limitation: compositional data do not demonstrate clinical benefit.

  • Possible benefit in Willis–Ekbom’s disease (very preliminary):

    • Open-label pilot data suggest symptom improvement in a majority of participants, but confirmation requires blinded controlled trials.

4. Does it have any downsides or side effects?

  • Major downside: clinically important drug interactions (strong evidence):

    • Saint John’s Wort is repeatedly highlighted in the provided reviews as a key cause of drug–herb interactions that can change drug plasma concentrations, potentially decreasing efficacy or causing serious harm—especially in higher-risk settings (older age, polypharmacy, transplant, cancer, HIV, malnutrition, enteral/parenteral feeding) and with narrow therapeutic index drugs (e.g., warfarin, immunosuppressants, anticancer drugs, cardiovascular drugs, opioids, NSAIDs).

    • In the clinical pharmacokinetic trial, Saint John’s Wort induction markedly increased CYP3A activity and reduced exposure to macitentan and rivaroxaban; authors state the combination with rivaroxaban should be avoided (risk: reduced anticoagulant effect and thrombosis).

  • Enzyme induction as a practical limitation in some therapeutic areas:

    • The migraine phytomedicine review specifically notes Saint John’s Wort is a hepatic enzyme inducer, which complicates its use alongside conventional migraine therapies (even aside from the lack of clinical efficacy data for migraine).

  • Other side effects:

    • The provided abstracts focus on interactions and do not detail common adverse effects (e.g., photosensitivity, GI upset, serotonergic effects). Therefore, side-effect conclusions beyond drug-interaction risk cannot be well supported from these abstracts alone.

5. Is it beneficial or harmful for any genetic variations (pharmacogenomics)?

The provided abstracts do not report pharmacogenomic analyses (e.g., outcomes stratified by CYP3A4/3A5, ABCB1/P-gp, or other genotype), so no genotype-specific benefit or harm can be concluded from this set of evidence.

  • Mechanism relevant to pharmacogenomics (but not genotype-tested here): Saint John’s Wort induces CYP3A activity and P-glycoprotein, which can lower exposure to many drugs. In principle, genetic variants affecting these pathways could modify the magnitude of interaction, but this is not evaluated in the abstracts provided.

  • Clinical implication despite lack of genotype data: Because induction effects were large in healthy volunteers (e.g., +272% CYP3A activity; reduced macitentan and rivaroxaban exposure), interaction risk is clinically relevant regardless of genotype, and caution/avoidance with sensitive substrates (notably rivaroxaban per the trial conclusion) is warranted.

References

  1. Antiviral Activity Against Infectious Bronchitis Virus and Bioactive Components ofHypericum perforatumL
    Huijie Chen, Ishfaq Muhammad, Yue Zhang, Yudong Ren, Ruili Zhang (2019)
  2. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort?
    Stéphane Mouly, Célia Lloret-Linares, Pierre-Olivier Sellier, Damien Sene, J-F Bergmann (2017) - Pharmacological research
  3. Chemical Analysis of Various Tea Samples Concerning Volatile Compounds, Fatty Acids, Minerals and Assessment of Their Thermal Behavior.
    Thomas Dippong, Oana Cadar, Melinda Haydee Kovacs, Monica Dan, Lacrimioara Senila (2023) - Foods (Basel, Switzerland)
  4. Phytomedicines in the Treatment of Migraine.
    Thilinie Rajapakse, William Jeptha Davenport (2019) - CNS drugs
  5. Identification of sennoside A as a novel inhibitor of the slingshot (SSH) family proteins related to cancer metastasis.
    Seon Young Lee, Wooil Kim, Young Geun Lee, Hyo Jin Kang, Sang-Hyun Lee, Sun Young Park, Jeong-Ki Min, Sang-Rae Lee, Sang J Chung (2017) - Pharmacological research
  6. Effect of yeast (Xanthophyllomyces dendrorhous) and plant (Saint John's wort, lemon balm, and rosemary) extract based functional diets on antioxidant and immune status of Atlantic salmon (Salmo salar) subjected to crowding stress.
    Sebastián Reyes-Cerpa, Eva Vallejos-Vidal, María José Gonzalez-Bown, Jonathan Morales-Reyes, Diego Pérez-Stuardo, Deborah Vargas, Mónica Imarai, Víctor Cifuentes, Eugenio Spencer, Ana María Sandino, Felipe E Reyes-López (2018) - Fish & shellfish immunology
  7. Efficacy and Safety of Co-Administered St. John's Wort and
    Hantai Kim, Jungho Ha, Hun Yi Park, Yun-Hoon Choung, Jeong Hun Jang (2023) - Journal of clinical medicine
  8. Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided.
    Andrea Huppertz, Lars Werntz, Andreas D Meid, Kathrin I Foerster, Jürgen Burhenne, David Czock, Gerd Mikus, Walter E Haefeli (2018) - British journal of clinical pharmacology
  9. The impact of topical Saint John's Wort (
    P Mansouri, S Mirafzal, P Najafizadeh, Z Safaei-Naraghi, M H Salehi-Surmaghi, F Hashemian (2017) - Journal of postgraduate medicine
  10. [Drug-food interactions in internal medicine: What physicians should know?].
    S Mouly, M Morgand, A Lopes, C Lloret-Linares, J-F Bergmann (2015) - La Revue de medecine interne
  11. Saint John's wort, an herbal inducer of the cytochrome P4503A4 isoform, may alleviate symptoms of Willis-Ekbom's disease.
    José Carlos Pereira, Márcia Pradella-Hallinan, Rosana Cardoso Alves (2013) - Clinics (Sao Paulo, Brazil)
  12. [Effect of Hypericin on the Function of the Neuroretina: An Electroretinographic Study].
    M Alnawaiseh, W Albanna, R Abumuaileq, M R R Böhm, N Eter, T Schneider (2015) - Klinische Monatsblatter fur Augenheilkunde


Want personalized supplement recommendations based on your genetics?
Upload Whole Genome Sequencing (WGS) raw DNA data today!
Or upload raw DNA data to get started with your free analysis!