St. John’s Wort / Hypericum perforatum

Hypericum perforatum
Herba Hyperici

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Mechanism of Action of St John’s Wort in Depression

Extracts of Hypericum perforatum L. (St John’s wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John’s wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John’s wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John’s wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John’s wort extract demonstrated significant affinity for adenosine, GABAA, GABAB and glutamate receptors. In vivo St John’s wort extract leads to a downregulation of β-adrenergic receptors and an upregulation of serotonin 5-HT2 receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John’s wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John’s wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John’s wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John’s wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John’s wort and its active constituents with a large body of existing literature.

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A Systematic Review of St. John’s Wort for Major Depressive Disorder

This systematic review evaluated St. John’s wort (SJW) for the treatment of Major Depressive Disorder (MDD). The objectives of this review are to (1) evaluate the efficacy and safety of SJW in adults with MDD compared to placebo and active comparator and (2) evaluate whether the effects vary by severity of MDD. METHODS: We searched PubMed, CINAHL, PsycINFO, CENTRAL, Embase, AMED, MANTIS, Web of Science, and ICTRP and existing reviews to November 2014. Two independent reviewers screened the citations, abstracted the data, and assessed the risk of bias. We included randomized controlled trials (RCTs) examining the effect of at least a 4-week administration of SJW on depression outcomes against placebo or active comparator in adults with MDD. Risk of bias was assessed using the Cochrane Risk of Bias tool and USPSTF criteria. Quality of evidence (QoE) was assessed using the GRADE approach. RESULTS: Thirty-five studies examining 6993 patients met inclusion criteria; eight studies evaluated a hypericum extract that combined 0.3 % hypericin and 1–4 % hyperforin. The herb SJW was associated with more treatment responders than placebo (relative risk [RR] 1.53; 95 % confidence interval [CI] 1.19, 1.97; I2 79 %; 18 RCTs; N = 2922, moderate QoE; standardized mean differences [SMD] 0.49; CI 0.23, 0.74; 16 RCTs; I2 89 %, N = 2888, moderate QoE). Compared to antidepressants, SJW participants were less likely to experience adverse events (OR 0.67; CI 0.56, 0.81; 11 RCTs; moderate QoE) with no difference in treatment effectiveness (RR 1.01; CI 0.90, 1.14; 17 RCTs, I2 52 %, moderate QoE; SMD −0.03; CI −0.21, 0.15; 14 RCTs; I2 74 %; N = 2248, moderate QoE) in mild and moderate depression. CONCLUSIONS: SJW monotherapy for mild and moderate depression is superior to placebo in improving depression symptoms and not significantly different from antidepressant medication. However, evidence of heterogeneity and a lack of research on severe depression reduce the quality of the evidence. Adverse events reported in RCTs were comparable to placebo and fewer compared with antidepressants. However, assessments were limited due to poor reporting of adverse events and studies were not designed to assess rare events. Consequently, the findings should be interpreted with caution.

Key Findings

The existing evidence base suggests that the herb St. Johns Wort (SJW) is as effective as antidepressant medication in improving the symptoms of mild to moderate depression, with fewer adverse events.

Response to treatment did not differ significantly between participants receiving SJW and antidepressants.

The treatment response rate was significantly higher among those receiving SJW (56 percent) in comparison to those receiving placebo (35 percent).

There was insufficient evidence to evaluate the effect of SJW on severe depression.

Findings should be interpreted with caution, as differences were found in effects across studies.


Future studies should evaluate the effect of SJW on severe depression, the comparative effectiveness of specific extracts and dosages of SJW, the effect of concurrent use of SJW and psychotherapy, and the effect of SJW on quality of life. Additionally, systematic assessment of adverse events with SJW use is needed, especially for rare events.

More information:

St. John’s Wort monograph

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