Ovarian steroid hormones, estrogen and progestin, affect the function of the serotonin neural system by inhibiting serotonin re-uptake through allosteric interaction with the serotonin transporter (SERT) in a nongenomic mechanism. Blocking or reducing serotonin re-uptake at the synapse alleviates depression. The aim of this study was to test the effect of compounds of the isoflavan and isoflavene groups, subclasses of the flavonoids family, on serotonin re-uptake and to compare the results with the effect of other known phytoestrogens like genistein and daidzein to relate the activity of these compounds to their structure. The effect of these compounds on the re-uptake of radioactive serotonin was assayed in HEK-293 cells stably expressed the recombinant human serotonin transporter (hSERT). The results demonstrated that the isoflavans glabridin and 4'-O-methylglabridin (4'-OMeG) and the isoflavene glabrene inhibited serotonin re-uptake by 60, 53 and 47%, respectively, at 50 microM, whereas resorcinol, the isoflavan 2'-O-methylglabridin (2'-OMeG), and the isoflavones genistein and daidzein were inactive. The inhibition of serotonin re-uptake is dose dependant with glabridin and estradiol. These results emphasize the importance of the lipophilic part of the isoflavans, as well as the hydroxyl at position 2' on ring B. In conclusion, this study showed that several isoflavans are unique phytoestrogens, which like estradiol, affects the serotonergic system and inhibits serotonin re-uptake and, thus, potentially may be beneficial for mild to moderate depression in pre- and postmenopausal women.