Kavain is the principalkavalactone found in the roots of the kava plant (Piper methysticum), where it contributes significantly to the plant's psychoactive and anxiolytic effects.
Kavain exhibits anticonvulsant properties by modulating voltage-dependent sodium and calcium channels, and it may influence mood and anxiety through reversible inhibition ofmonoamine oxidase A andmonoamine oxidase B, potentially affectingserotonin,dopamine, andnorepinephrine signaling. Although it does not bind to thebenzodiazepine site ofGABAA receptors, kavain potentiates GABA activity at extrasynaptic α4β2δ GABAA receptors and overlaps with the modulatory pathways of certaingeneral anesthetics. It also shows weak sodium antagonism, strong L-type calcium channel blockade, and enhances early potassium currents, suggesting mood-stabilizing effects akin tolamotrigine.
Its precise mechanisms remain under investigation, but its activity across multiple pathways makes it a promising candidate for drug development targeting ion channels,P-glycoprotein,cytochrome P450, andcyclooxygenase enzymes.
However, the precise mechanisms underlying thepsychotropic,sedative, andanxiolytic actions of kavain and related kavalactones are still debated. Direct binding to thebenzodiazepine/flumazenilbinding site of theGABA-A receptor does not occur with kavainenantiomers.[3] Many studies involved kava extracts from different plant parts and are, therefore, not applicable to kavain itself. Kavain directly modulates several human GABAA receptor subtypes—most strongly α4β2δ—via a mechanism independent of the classical benzodiazepine binding site; its reduced efficacy at receptors carrying the β3N265M anesthetic-resistance mutation suggests overlap with the modulatory pathways of certaingeneral anesthetics.[4]
A comparative review ofin-vivo studies with kavain (and related kavapyrones) to commonly usedantiepileptic drugs andmood stabilizers affecting ion fluxes indicates that the kavapyrones are weakly Na+ antagonistic and therefore antiepileptic. They also have pronouncedL- typeCa2+ channel antagonistic properties and act as a positive modulator of the early K+ outward current, which contribute to mood stabilizing properties similar tolamotrigine.[5]
^Grunze, Heinz; Langosch, Jens; Schirrmacher, Karin; Bingmann, Dieter; Von Wegerer, Jörg; Walden, Jörg (2001). "Kava pyrones exert effects on neuronal transmission and transmembraneous cation currents similar to established mood stabilizers - a review".Progress in Neuro-Psychopharmacology and Biological Psychiatry.25 (8):1555–70.doi:10.1016/S0278-5846(01)00208-1.PMID11642654.S2CID41325450.
^Rowe, A.; Narlawar, R.; w. Groundwater, P.; Ramzan, I. (2011). "Kavalactone Pharmacophores for Major Cellular Drug Targets".Mini Reviews in Medicinal Chemistry.11 (1):79–83.doi:10.2174/138955711793564088.PMID21034404.
