Although SJW has been investigated extensively in scientific studies, there are still many questions about its pharmacology and mechanisms of action.

Collectively, the data show that SJW extract exerts significant pharmacological activity within several neurochemical systems believed to be implicated in the pathophysiology of depression.

Inhibits synaptic reuptake of several neurotransmitters Preclinical animal studies have found that SJW inhibits the synaptic reuptake system for serotonin, noradrenaline and dopamine (Nathan 1999, Wonnemann et al 2001). Studies using specific isolated constituents have demonstrated potent uptake inhibition of GABA and L-glutamate in vivo (Bilia et al 2002, Chatterjee et al 1998). These effects appear to be non-competitive, dose-dependent and mediated via sodium channels (Roz & © 2007 Elsevier Australia

Rehavi 2004). Studies with hyperforin have shown it acts by reducing the pH gradient across the synaptic vesicle membrane, resulting in diffusion of uncharged monoamines out of the vesicular compartment into the cytoplasm. The increase in cytoplasmic concentration in turn decreases the transmembrane gradient of the neurotransmitters causing an 'apparent' inhibition of synaptosomal uptake by hyperforin. This is a novel mechanism of action, which differs from conventional antidepressant drugs.

Although hyperforin is the main constituent responsible for these effects, tests now show that a number of others are also involved (Gobbi et al 2001), such as adhyperforin, which has demonstrated a strong inhibitory effect on neurotransmitter uptake, and the oligomeric procyanidins fraction, which has demonstrated weak to moderate effects (Wonnemann et al 2001).

GABA receptor binding SJW extracts have been shown to bind at GABA-A and -B receptors, to inhibit GABA reuptake, to evoke GABA release from synaptosomes and to exert an anxiolytic effect that is blocked by the benzodiazepine antagonist flumazenil (Perfumi et al 2002).

Upregulation of serotonin receptors SJW significantly up-regulates both 5-HT1A and 5-HT2A receptors and has a significant affinity for opiate sigma-receptors, which may contribute to the antidepressant effect (Teufel-Mayer & Gleitz 1997). Dopamine beta-hydroxylase inhibition Studies on isolated constituents showed that hypericin and pseudohypericin can inhibit the enzyme dopamine-beta-hydroxylase in vitro (Bilia et al 2002).

Inhibition of catechol-o-methyltransferase This has been demonstrated in test tube studies (Thiede & Walper 1994).

Suppresses IL-6 synthesis Various extracts from SJW produce a potent and dose-dependent inhibition of substance-P-induced IL-6 synthesis (Fiebich et al 2001), which may also contribute to the herb's overall antidepressant effect. Monoamine oxidase (MAO) inhibition Inhibition of MAO by hypericin demonstrated in vitro was believed to be the primary mode of action; however, this has not been confirmed in several subsequent studies that have shown only weak inhibitory activity at doses in excess of usual therapeutic levels (Di Carlo et al 2001).

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