dihydromethysticin

Dihydromethysticin is one of the six major kavalactones found in the kava plant. It is known for its anxiolytic, analgesic, and anticonvulsant properties. It induces the liver enzymes CYP1A1 and CYP3A through mechanisms involving the aryl hydrocarbon receptor and potentially pregnane X receptor-independent transcriptional activation. Dihydromethysticin acts synergistically with other kavalactones, modulates NMDA receptors and voltage-dependent calcium channels, and functions as a GABAA receptor positive allosteric modulator and monoamine oxidase B inhibitor. Dihydromethysticin shows high systemic exposure and rapid absorption in humans, suggesting it is a major contributor to kava’s effects.

==Pharmacology== Individual kavalactones affect the liver enzyme CYP3A (specifically, CYP3A23 in rats) and activate the pregnane X receptor (PXR). Among six tested kavalactones, dihydromethysticin and desmethoxyyangonin were the only ones that significantly induced CYP3A23 expression (about 7-fold). The induction was greatly reduced or eliminated when either of these two compounds was removed from kavalactone mixtures, suggesting they are essential for the effect. Their activity was enhanced by other kavalactones, indicating a possible synergistic or additive interaction. Both compounds increased CYP3A23 mRNA levels, but only weakly activated rat or human PXR, unlike the strong activator pregnenolone 16α-carbonitrile (PCN). This suggests that dihydromethysticin and desmethoxyyangonin induce CYP3A23 via transcriptional activation, likely through a PXR-independent or indirect PXR-related pathway.