Target symptoms treated with Hypericum extract, i.e. somatisation, fatigue and depression could be related to an increased activity of glucocorticoids in the brain. One potential mechanism is the increased permeability of the blood-brain barrier for glucocorticoids. Hypericum extract LI160 reduces intracerebral glucocorticoid concentration possibly by its action to induce the expression of the transport protein P-glycoprotein (P-gp). To test this hypothesis directly, we performed a randomised double-blind crossover study to examine the effect of intravenously administered cortisol on auditory evoked potentials (AEPs) and salivary cortisol concentration. Nineteen healthy subjects were treated for 2 weeks with 300 mg LI160 twice a day or placebo. On the 14th day, AEPs were recorded every 30 min, at times -60, -30 and 0 min before the start of the infusion and at +30, +60 and +90 min after starting the infusion. The rate of infusion was 20 mg cortisol/h. No changes in the AEP, especially the N1-P2 component, could be observed under cortisol infusion and consequently no modification with the treatment of Hypericum extract. The salivary concentration of cortisol under cortisol infusion was slightly but significantly decreased in the Hypericum condition compared to placebo. The results of the present study are therefore inconclusive with respect to the influence of LI160 treatment on the expected cortisol-induced AEP changes, but support the concept of an action of Hypericum on P-gp function by the observed changes in salivary cortisol.