St. John's Wort, a traditional herbal medicine obtained from the extract of Hypericum perforatum, has been used in the treatment of mild depression. Its mechanism of action remains to be established. The present study confirmed that Hypericum extract exhibited very weak inhibitory activities towards MAO. Mouse brain MAO activities was unchanged following either acute or chronic treatment with Hypericum extract. 5-HIAA levels were found to be significantly increased in the cerebral cortex, hypothalamus, hippocampus and caudate 3 h after treatment with the Hypericum extract at a dose as low as 10 mg/Kg. An increase of 5-HT levels was also observed in hypothalamus and hippocampus. The increase of brain 5-HIAA was not further enhanced following chronic administration of the herb. The Hypericum extract significantly reduced the plasma tryptophan levels, the precursor of 5-HT. The action of Hypericum extract is consistent with the notion that serotonergic system is involved. The effect of Hypericum extract on the brain 5-HIAA and 5-FIT levels appeared to be quite different from the effect of classical 5-HT re-uptake blockers.