Series by Kathleen Kendall-Tackett, Ph.D. (St. John’s Wort #2)

This article is the second in a five-part series on St. John’s Wort, an herb with antidepressant properties. 






Part 2, Mechanism for Efficacy and Dosage.


Mechanism for Efficacy

Researchers still do not understand the exact mechanism for St. John’s wort’s antidepressant effect.  Linde et al. (1996) noted that hypericum extracts have at least 10 constituents that likely cause its pharmacological effects.  St. John’swort is standardized by percentage of hypericin, one of the active constituents.  Hypericin was once considered the primary antidepressant component.  Researchers no longer believe that this is true (Bratman & Girman, 2003).  More recently, researchers have recognized hyperforin as the possible antidepressant constituent (Lawvere & Mahoney, 2005; Muller, 2003; Wurglies & Schubert-Zsilavecz, 2006; Zanoli, 2004).  Hyperforin appears to inhibit the reuptake of the monoamines and GABAergic activity (Kuhn & Winston, 2000; Werneke et al., 2006).  It may relieve depression by preventing the reuptake of serotonin, the same mechanism as the selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline).  Indeed, Muller (2003) noted that only hyperforin (and its structural analogue, adhyperforin) inhibit neurotransmitter re-uptake.


St. John’swort, and particularly hyperforin, also appears to be anti-inflammatory (Balch, 2002; Dell’Aica et al., 2007; Kuhn & Winston, 2000; Wurglies & Schubert-Zsilavecz, 2006).  It also modulates cytokine production (Werneke et al., 2006). Hyperforin has anti-nociceptive (anti-pain) and anti-inflammatory effects in animal studies (Abdel-Salam, 2005).  It inhibits the expression of another inflammatory marker—intercellular adhesion molecule (Zhou et al., 2004).  In vitro effects show that St. John’swort is anti-oxidant, anti-cyclooxygenase-1, and anti-carcinogenic (Zanoli, 2004).


Only recently has St. John’s wort been shown to specifically lower levels of the proinflammatory cytokines involved in depression—and it wasn’t in a study of depression (Hu et al., 2006).  The study used an animal model to test whether St. John’s wort could counter the toxic side effects of chemotherapy.  The investigators specifically investigated whether St. John’swort had an impact on the levels of proinflammatory cytokines, including IL-1β, IL-2, IL-6, IFN-γ, and TNF-α.  They found that St. John’swort did protect rats receiving chemotherapy by inhibiting proinflammatory cytokines and intestinal epithelium apoptosis.  Although not a study of depression, it was the first to demonstrate that St. John’swort inhibits the cytokines that are high in depression.








The dosage of St. John’swort is 900 mg per day (300 mg/three times per day), standardized to 0.3% hypericin and/or 2% to 4% hyperforin (Lawvere & Mahoney, 2005).  It generally takes four to six weeks to take effect (Bratman & Girman, 2003; Ernst, 2002; Kuhn & Winston, 2000).  Dosage information is summarized in Table 9.

Table 9: Dosage and Safety Information on St. John’s wort


Dosage: 300 mg, three times a day


Standardized to: 0.3% hypericin or 2% to 4% hyperforin



Where to Go for Information on Herbs and Herb Safety (rates quality of nutritional products through independent testing)


Institute for Natural Products Research:


Humphrey, S. (2003) Nursing mothers’ herbal. Minneapolis: Fairview Press.


Herbs for Health magazine:


The Complete German Commission E Monographs available online and for purchase from the American Botanical Council,


National Center for Complementary and Alternative Medicine (NCCAM)


Mayo Clinic St. John’s Wort Patient Sheet



St. John’s wort reaches peak level in the plasma in five hours, with a half-life of 24 to 48 hours.  Herbalists often combine it with other herbs to address the range of symptoms that depressed people have.  Some of these herbs include lemon balm, kava, schisandra, rosemary, black cohosh, and lavender (Humphrey, 2007; Kuhn & Winston, 2000). 


Unfortunately, it can be challenging for women to know if a brand of herbs they purchase is of good quality.  As of this writing, the U.S. Pharmacopeia does not verify brands of St. John’s wort, but a USP monograph on St. John’swort is due out in 2008. However, does rate brands of herbs.  For a small subscription fee, women can access this resource.  There is also information that consumers can look for on supplement labels that give some indication of quality.  This information is listed in Table 10.

Table 10: What to Look for on a Supplement Label


Standards for Herbal Preparations

Statement of % standardization of the extract

Statement describing which compounds are standardized

Statement describing which parts of the plant are used in the formulation

Extract ratio (the ratio of extract concentration to crude plant materials, e.g., 1:4)

Recommended daily dosage

Weight and number of capsules or tablets per package

Substantiated structure/function claims

Product expiration date to confirm freshness

A toll-free number and/or Website address for company information and contact

USP: Notation that the manufacturer followed standards of the U.S. Pharmacopeia.



Source: Institute for Natural Products Research (2000). Pocket Reference Guide to Botanical and Dietary Supplements. Marine on St. Croix, MN: Institute for Natural Products Research.




Be sure to read tomorrow’s post,

Part 3, Safety Concerns


Part 4, St. John’s Wort and Breastfeeding

Part 5, Summary

















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