St. John's wort (Hypericum perforatum L.) has been used for centuries to treat a number of common ailments (such as neuralgia, sleep disorders, wound healing, and hemorrhoids), but it is best known for its use in the treatment of mild to moderate depression.1  As it relates to depression, its use is most common in Germany and other areas throughout Europe and is increasing in the United States.2,3  The data supporting the safety and efficacy has been questioned by some government agencies due to a significant degree of heterogeneity and inconsistencies among the clinical trials done.3  Other meta-analysis have also shown a minimal benefit of St. John's wort especially when compared to placebo.4   Regardless, it is clear from a historical perspective that some patients will benefit from St. John's wort for the treatment of mild or moderate depression.  

St. John's wort is known to have several active ingredients which include cyclopseudohypericin, hypericin, hyperforin, isohypericin, protohypericin, pseudohypericin and several other flavonoids.2,5 Each of these active components appear to have differing levels of contribution to its antidepressant properties.5  There also appears to be a number of different mechanisms that have been linked to the antidepressant effects of St. John's wort.  It is unknown if any one of these contributes a greater degree of influence over another.5  As such it is likely that a combination of these ingredients and mechanisms culminate in an antidepressant effect. 

One of the proposed mechanisms of St. John's wort in the treatment of depression is the inhibition of the uptake of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) from the synaptic cleft of interconnecting neurons.6,7  A second contributing mechanism is the ability to bind to the major neuro-inhibitory receptor, gamma aminobutyric acid (GABA-A and GABA-B) receptors, to block the binding of GABA.8,9  This reduction in GABA ligand binding results in decreased central nervous system (CNS) depression.  A third mechanism is an increase in the number or density of 5-HT2 receptors in the frontal cortex of the brain, which is potentially beneficial when treating depression.10  However, the data supporting this effect with St. John's wort is primarily from rats.  A fourth and possibly fifth separate contributing mechanism is St. John's wort ability to inhibit the activity of both monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) enzymes.10,11  When functional or active, both of these CNS enzymes metabolize dopamine precursors into inactive products versus allowing dopamine to metabolized to norepinephrine (NE) in the brain.  Thus, inhibition of these enzymes in the CNS will favor the formation of NE.

As stated earlier, no single effect appears to predominate.5  As such, the overall antidepressant effect appears to be an amalgamation of multiple mechanisms.5  It is possible that the dosage form and/or extract of St. John's wort may influence the biologic effect since the concentration of each active ingredient may be different.  Despite all of these effects on neurotransmitters in the CNS, the clinical trial data suggests that the benefits are minimal and limited to those with mild to moderate depression.  The lack of a consistent and/or significant effect in the treatment of depression may also explain why the side effect profile of St. John's wort is slightly less than standard antidepressant used in clinical practice.

References:

1. National Center for Complementary and Alternative Medicine: National Institutes of Health.  Herbs at a glance: St. John's wort.  Last accessed on 1-27-2009:  
2. Simmen U, higelin j, Berger-Buter K et al.  Neurochemical studies with St. John's wort in vitro.  Pharmacopsychiatry  2001;34 Suppl 1:S137-42.  
3. Ebadi M.  Pharmacodynamic basis of herbal medicine. 2^nd Ed.  Taylor & Francis Group.  Boca Raton, FL. 2007.
4. National Center for Complementary and Alternative Medicine: National Institutes of Health.  What the science says about St. John's wort for depression.  Last accessed on 6/16/2009:  
   
5. Linde K, Berner MM, Kriston L.  St John's wort for major depression.  Cochrane Database Syst Rev  2008;4:CD000448  
   
6. Butterweck V.  Mechanism of action of St John's wort in depression: what is known?  CNS Drugs  2003;17:539-62.  
   
7. Neary JT, Bu Y.  Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes.  Brain Res  1999;816:358-63.  
   
8. Chatterjee SS, Bhattacharya SK, Wonnemann M et al.  Hyperforin as a possible antidepressant component of hypericum extracts.  Life Sci  1998;63:499-510.  
9. Baureithel KH, Buter KB, Engesser A et al.  Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of hypericum.  Pharm Acta Helv  1997;72:153-7.  
10. Muller WE, Rolli M, Schafer C et al.  Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity.  Pharmacopsychiatry  1997;30 Suppl 2:102-7.  
    
11. Thiede HM, Walper A.  Inhibition of MAO and COMT by hypericum extracts and hypericin.  J Geriatr Psychiatry Neurol  1994;7 Suppl 1:S54-6.

St John's wort, Hypericum Perforatum, Mechanism of Action St Johns wort