Kavalactone

Kavalactones are a class of lactone compounds found in kava roots and Alpinia zerumbet (shell ginger)^[1] and in several Gymnopilus, Phellinus and Inonotus fungi.^[2] Some kavalactones are bioactive. They are responsible for the psychoactive, analgesic, euphoric and sedative effects of kava.^[3][4]

The general structure of the kavalactones, without the R₁-R₂ -O-CH₂-O- bridge and with all possible C=C double bonds shown.

Bioactivity

Kava extract interacts with many pharmaceuticals and herbal medications. In human volunteers, in vivo inhibition includes CYP1A2^[5] and CYP2E1^[6] through use of probe drugs to measure inhibition.

Research

Its anxiolytic and hepatotoxic properties have been investigated.^[7][8][9]

The major kavalactones (except for des­methoxy­yangonin) potentiate GABA_A receptors, which may underlie the anxiolytic and sedative properties of kava. Further, inhibition of the reuptake of nor­epi­neph­rine and dopamine, binding to the CB₁ receptor,^[10] inhibition of voltage-gated sodium and calcium channels, and monoamine oxidase B reversible inhibition are additional pharmacological actions that have been reported for kavalactones.^[11]

Toxicity

Several kavalactones (e.g., methysticin and yangonin) affect a group of enzymes involved in metabolism, called the CYP450 system. Hepatotoxicity occurred in a small portion of previously healthy kava users,^[8][12] particularly from extracts, as opposed to whole root powders.

Compounds

See also: Flavokavain

At least 18 different kavalactones are known,^[1] with methysticin being the first identified.^[13] Multiple analogues, such as ethysticin, have also been isolated.^[14] Some consist of a substituted α-pyrone as the lactone, while others are partially saturated.

The average elimination half-life of kavalactones typically present in kava root is 9 hr.^[15]

Name	Structure	R1	R2	R3	R4
Yangonin	1	-OCH3	-H	-H	-H
10-methoxyyangonin	1	-OCH3	-H	-OCH3	-H
11-methoxyyangonin	1	-OCH3	-OCH3	-H	-H
11-hydroxyyangonin	1	-OCH3	-OH	-H	-H
Desmethoxyyangonin	1	-H	-H	-H	-H
11-methoxy-12-hydroxydehydrokavain	1	-OH	-OCH3	-H	-H
7,8-dihydroyangonin	2	-OCH3	-H	-H	-H
Kavain	3	-H	-H	-H	-H
5-hydroxykavain	3	-H	-H	-H	-OH
5,6-dihydroyangonin	3	-OCH3	-H	-H	-H
7,8-dihydrokavain	4	-H	-H	-H	-H
5,6,7,8-tetrahydroyangonin	4	-OCH3	-H	-H	-H
5,6-dehydromethysticin	5	-O-CH2-O-		-H	-H
Methysticin	7	-O-CH2-O-		-H	-H
7,8-dihydromethysticin	8	-O-CH2-O-		-H	-H

Kavalactones: General structures

Structure 1	Structure 2	Structure 3	Structure 4
Structure 5	Structure 6	Structure 7	Structure 8

Biosynthesis

The kavalactone biosynthetic pathway in Piper methysticum was described in 2019.^[16]

See also

• Pipermethystine