St John's Wort for Depression

St John's wort is a well-known herbal remedy that has been traditionally used to alleviate depressive symptoms. Its proposed antidepressant properties are primarily attributed to active compounds like hyperforin, which are believed to modulate neurotransmitter activity. Modern clinical trials have investigated its effectiveness across various forms of depression, ranging from major to mild and minor presentations, to better understand its potential as a safe and natural treatment alternative.

Protocols Studied in Research

Effectiveness of St John's wort in Major Depression [1]

• Protocol: In a multicenter, randomized, double-blind, placebo-controlled trial conducted between November 1998 and January 2000 at 11 U.S. academic centers, 200 adult outpatients with major depression (HAM‑D score ≥20) underwent a 1‑week placebo run‑in, then were randomized to receive either a standardized St John's wort extract (initially 900 mg/d, increased to 1200 mg/d if needed) or placebo for 8 weeks. Multiple outcomes—including HAM‑D, BDI, HAM‑A, GAF, and CGI scores—were assessed over the treatment period.
• Outcome: While both groups improved over time, no significant treatment effect was observed on the primary outcome (HAM‑D change), with only a modestly higher remission rate in the St John's wort group (14.3% vs 4.9%, P = .02). Overall, St John's wort was safe and well tolerated but did not demonstrate clear efficacy for major depression.

The Treatment of Minor Depression with St. John's Wort or Citalopram [2]

• Protocol: In a three‑arm, 12‑week randomized clinical trial targeting patients with minor depression, participants received either 810 mg/day of St John's wort, 20 mg/day of citalopram, or placebo. Depressive symptom severity, quality of life, and overall well‑being were measured to assess treatment efficacy.
• Outcome: A high placebo response was observed on all outcome measures, and neither St John's wort nor citalopram showed significant benefit over placebo. Additionally, both active treatments were associated with a notable burden of side effects, indicating that alternative approaches for minor depression may be needed.

St. John's Wort in Mild to Moderate Depression: The Relevance of Hyperforin [3]

• Protocol: In a randomized, double‑blind, placebo‑controlled multicenter study of 147 outpatients with mild to moderate depression, patients underwent a placebo run‑in and were then randomized to receive one of two Hypericum extracts—WS 5573 (300 mg, 0.5% hyperforin) or WS 5572 (300 mg, 5% hyperforin)—or placebo for 42 days. Efficacy was measured by changes in the 17‑item Hamilton Rating Scale for Depression (HAM‑D), a depression self‑rating scale, and the Clinical Global Impression (CGI) scale.
• Outcome: Patients receiving WS 5572 (5% hyperforin) experienced the greatest reduction in HAM‑D scores (mean decrease of 10.3 ± 4.6 points) and were significantly superior to placebo (p = 0.004), while the WS 5573 group showed effects comparable to placebo. These results indicate that the antidepressant efficacy of St John's wort depends on its hyperforin content.

Long‑Term Effects of St. John's Wort (Ze 117) in Mild to Moderate Depression [4]

• Protocol: In an open, multicentre safety study, 440 outpatients with mild to moderate depression (ICD‑10 criteria) were treated with 500 mg/day of St John's wort extract Ze 117 for up to 1 year. Safety was evaluated via adverse event monitoring, clinical chemistry, and electrocardiograms, while depression was tracked using HAM‑D and CGI scales over the treatment period.
• Outcome: Over the one‑year period, 49% of patients reported adverse events (with 6% considered possibly or probably treatment‑related), predominantly gastrointestinal and skin complaints. No significant changes were observed in clinical chemistry, ECG readings, or BMI. Depression scores improved steadily (HAM‑D decreased from 20.58 at baseline to 11.18 at week 52), supporting the long‑term safety and effectiveness of Ze 117 for treating mild to moderate depression and its potential role in relapse prevention.

Research Interpretation: Summary and Conclusion

Across several studies, the effectiveness of St John's wort in treating depression has shown a variable profile. In a multicenter trial for major depression, patients receiving a standardized extract experienced a modestly higher remission rate compared to placebo, although the primary outcome (change in HAM D scores) was not significantly different, indicating limited overall efficacy. In another trial focusing on minor depression, neither St John's wort nor citalopram offered benefits beyond those seen with placebo, and both treatments were associated with notable side effects. Conversely, a study in mild to moderate depression highlighted that an extract with a higher hyperforin content (WS 5572) led to a significant reduction in depression scores compared to placebo, suggesting that the antidepressant effect may depend on the formulation's hyperforin concentration. Additionally, a long-term safety study of the Ze 117 extract confirmed its sustained effectiveness and safety over one year, with gradual improvements in depressive symptoms and only mild adverse events reported.

In simple terms, while St John's wort appears to be a safe treatment option for depression, its efficacy varies with formulation and patient characteristics, underscoring the need for careful selection and further research to optimize its therapeutic potential.

Publications

[1] Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM, Halbreich U. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA. 2001 Apr 18;285(15):1978-86. doi: 10.1001/jama.285.15.1978. PMID: 11308434.

[2] Rapaport MH, Nierenberg AA, Howland R, Dording C, Schettler PJ, Mischoulon D. The treatment of minor depression with St. John's Wort or citalopram: failure to show benefit over placebo. J Psychiatr Res. 2011 Jul;45(7):931-41. doi: 10.1016/j.jpsychires.2011.05.001. Epub 2011 May 31. PMID: 21632064; PMCID: PMC3137264.

[3] Laakmann G, Schüle C, Baghai T, Kieser M. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998 Jun;31 Suppl 1:54-9. doi: 10.1055/s-2007-979346. PMID: 9684948.

[4] Brattström A. Long-term effects of St. John's wort (Hypericum perforatum) treatment: a 1-year safety study in mild to moderate depression. Phytomedicine. 2009 Apr;16(4):277-83. doi: 10.1016/j.phymed.2008.12.023. Epub 2009 Mar 18. PMID: 19299116.