St. John’s wort appears to have multiple potential mechanisms of action, some of which have yet to be clarified.
HP (and more specifically one of its main active compounds, hyperforin) can inhibit the reuptake of serotonin, norepinephrine, and dopamine. Although the exact mechanism is still unclear, it seems that HP does not inhibit their reuptake by blocking the presynaptic transporters, as SSRIs do. One hypothesis is that hyperforin instead works by increasing the intracellular concentration of sodium,[1] resulting in an increased concentration of monoamines available to interact with their postsynaptic receptors. This increased neurotransmitter activity is associated with improved mood and relief of depression symptoms.[2]
Additionally, both in vivo and in vitro studies have found that HP also works by activating the pregnane-X-receptor (PXR) cytochromes, which play a role in regulating the expression of certain enzymes of the cytochrome P450 system (specifically the CYP3A4 enzyme) and the P-glycoprotein (responsible for transporting drugs and other substances out of cells). The activation of the CYP pathway and/or the P-glycoprotein by HP may contribute to the interactions between HP and other drugs metabolized through these pathways.[2]