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
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.
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
- 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:
U, higelin j, Berger-Buter K et al. Neurochemical studies with St.
John's wort in vitro. Pharmacopsychiatry 2001;34 Suppl 1:S137-42.
- Ebadi M. Pharmacodynamic basis of herbal medicine. 2nd Ed. Taylor & Francis Group. Boca Raton, FL. 2007.
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:
- Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev 2008;4:CD000448
- Butterweck V. Mechanism of action of St John's wort in depression: what is known? CNS Drugs 2003;17:539-62.
- Neary JT, Bu Y. Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Res 1999;816:358-63.
SS, Bhattacharya SK, Wonnemann M et al. Hyperforin as a possible
antidepressant component of hypericum extracts. Life Sci
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.
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.
HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and
hypericin. J Geriatr Psychiatry Neurol 1994;7 Suppl 1:S54-6.