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St. John's Wort - Hypericum perforatum

St. John's Wort (Hypericum perforatum) is one of the most extensively researched medicinal herbs, with a long history of traditional use and substantial modern clinical investigation. This review examines current evidence for its efficacy, safety profile, and pharmaceutical applications based on peer-reviewed scientific literature.

Image source and license: https://commons.wikimedia.org/wiki/File:Hypericum_perforatum_Dziurawiec_zwyczajny_2020-07-12_05.jpg.
Modified by Peter Jorgensen.

Nomenclature and Identification

The primary botanical name is Hypericum perforatum L., belonging to the Hypericaceae family. Common names include St. John's Wort, Goatweed, Klamath weed, Tipton weed, and Rosin rose. It should not be confused with other Hypericum species (such as H. calycinum, H. androsaemum, or H. balearicum) which share the "St. John's Wort" common name but have different phytochemical profiles and potential effects.

Active Constituents

The primary bioactive compounds in St. John's Wort include hypericin and pseudohypericin (naphthodianthrones), hyperforin (a phloroglucinol), flavonoids (rutin, quercetin, hyperoside), and xanthones. Standardized extracts typically contain 0.3% hypericin and/or 3-5% hyperforin, with the latter now considered more relevant for antidepressant effects.

Evidence-Based Therapeutic Applications

The strongest clinical evidence exists for the following conditions:

• Mild to moderate depression: Multiple meta-analyses have found efficacy comparable to some conventional antidepressants, with fewer side effects.
• Seasonal affective disorder (SAD): Several clinical trials suggest benefit, though the evidence is less robust than for general depression.
• Wound healing: Topical preparations show promise for improving wound healing rates and reducing scar formation.
• Somatic symptom disorders: Some trials indicate benefit for psychosomatic complaints.

Conditions with limited, preliminary, or conflicting evidence:

• Anxiety disorders: Mixed results, with some positive findings for generalized anxiety and social anxiety.
• Premenstrual syndrome: Limited evidence suggests possible benefit.
• Menopausal symptoms: Small studies indicate potential for reducing hot flashes and improving mood.
• Viral infections: In vitro studies show antiviral properties, but clinical evidence is lacking.
• Neuropathic pain: Preliminary animal studies are promising, but human trials are inadequate.

Claims lacking substantial scientific evidence:

• Cancer treatment: Despite some intriguing laboratory studies showing cytotoxic effects against certain cancer cell lines, there is insufficient clinical evidence to support its use in cancer therapy.
• ADHD: Limited trials with methodological limitations.
• Alcoholism and substance dependence: Preliminary studies only.
• Chronic fatigue syndrome: Insufficient evidence for efficacy.

Dosage and Administration

For depression, the most widely supported therapeutic application, clinical evidence supports:

• Standardized extract (0.3% hypericin): 300 mg three times daily, or 600-900 mg once daily
• Standardized extract (3-5% hyperforin): 300-600 mg daily
• Duration: Typically 4-6 weeks minimum for initial assessment of efficacy; maintenance therapy may continue for 6 months or longer under medical supervision

For topical applications (wounds, inflammation): 1-5% cream or oil preparations applied 1-3 times daily.

Safety Profile and Adverse Effects

Generally well-tolerated with a lower side effect profile than many conventional antidepressants. Common side effects include:

• Photosensitivity (increased sensitivity to sunlight), particularly in fair-skinned individuals
• Gastrointestinal disturbances: nausea, abdominal discomfort, diarrhea, constipation
• Dizziness, confusion, and fatigue
• Dry mouth
• Headache
• Allergic skin reactions (rare)

Higher doses have not demonstrated increased efficacy for depression in clinical trials, but may increase the risk and severity of side effects, particularly photosensitivity reactions. No clear additional benefits have been established for doses exceeding 1800 mg daily of standardized extract. Studies investigating doses above this threshold are limited, representing a knowledge gap in the literature.

Drug Interactions

St. John's Wort is known for significant drug interactions, primarily through induction of cytochrome P450 enzymes (particularly CYP3A4, CYP2C9, and CYP1A2) and P-glycoprotein. These interactions constitute the most serious safety concern:

• Serotonergic drugs (SSRIs, SNRIs, MAOIs, triptans): Risk of serotonin syndrome
• Oral contraceptives: Reduced efficacy with potential for unintended pregnancy
• Anticoagulants (warfarin): Reduced efficacy
• Immunosuppressants (cyclosporine, tacrolimus): Reduced blood levels and potential organ rejection
• Antiretroviral medications: Reduced efficacy in HIV treatment
• Anticancer drugs: Potential reduction in therapeutic levels
• Digoxin: Reduced blood levels
• Statins: Reduced efficacy

Contraindications

St. John's Wort should be avoided in:

• Pregnancy and lactation due to insufficient safety data
• Bipolar disorder (may trigger manic episodes)
• Severe depression or suicidal ideation
• Patients undergoing organ transplantation
• Patients taking medications with significant interaction potential
• Patients undergoing phototherapy or scheduled for surgery

Commercial Pharmaceutical Products

Several standardized pharmaceutical-grade preparations are available in various countries:

• Jarsin® (Lichtwer Pharma): Standardized to 0.3% hypericin, approved for depression in Germany
• Perika® (Nature's Way): Standardized to both hyperforin (3-5%) and hypericin (0.3%)
• Remotiv® (Flordis): Standardized extract available in Australia

In contrast to these standardized pharmaceutical products, many over-the-counter supplements lack standardization, quality control, or efficacy testing.

Research Gaps and Future Directions

Current research gaps include:

• Long-term safety and efficacy studies beyond 12 months
• Optimal hyperforin vs. hypericin standardization for specific conditions
• Effects on pediatric and geriatric populations
• Comprehensive pharmacokinetic studies
• Investigation of possible benefits for neurological conditions
• Exploration of other Hypericum species and their potential therapeutic applications

Conclusions

St. John's Wort has established efficacy for mild to moderate depression with a favorable safety profile compared to many conventional antidepressants. However, significant drug interactions and limited evidence for other conditions warrant caution. Standardized pharmaceutical-grade preparations should be preferred over unregulated supplements when used therapeutically. Consultation with healthcare providers is essential, particularly for patients on other medications or with complex health conditions.

References

Barnes, J., Anderson, L. A., & Phillipson, J. D. (2001). St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. Journal of pharmacy and pharmacology, 53(5), 583-600.

Canenguez Benitez, J. S., Hernandez, T. E., Sundararajan, R., Sarwar, S., Arriaga, A. J., Khan, A. T., ... & Benitez, G. A. (2022). Advantages and disadvantages of using St. John's wort as a treatment for depression. Cureus, 14(9), 29468.

Nobakht, S. Z., Akaberi, M., Mohammadpour, A. H., Moghadam, A. T., & Emami, S. A. (2022). Hypericum perforatum: Traditional uses, clinical trials, and drug interactions. Iranian journal of basic medical sciences, 25(9), 1045.

Scholz, I., Liakoni, E., Hammann, F., Grafinger, K. E., Duthaler, U., Nagler, M., ... & Haschke, M. (2021). Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. British journal of clinical pharmacology, 87(3), 1466-1474.

Zhao, X., Zhang, H., Wu, Y., & Yu, C. (2023). The efficacy and safety of St. John’s wort extract in depression therapy compared to SSRIs in adults: A meta-analysis of randomized clinical trials. Advances in Clinical and Experimental Medicine, 32(2), 151-161.

Zirak, N., Shafiee, M., Soltani, G., Mirzaei, M., & Sahebkar, A. (2019). Hypericum perforatum in the treatment of psychiatric and neurodegenerative disorders: Current evidence and potential mechanisms of action. Journal of cellular physiology, 234(6), 8496-8508.