Editing Kava (section)

==Pharmacology==

===Constituents===
[[File:Kavalactone General Structure.PNG|frame|right|The general structure of the kavalactones, without the R<sub>1</sub>-R<sub>2</sub> -O-CH<sub>2</sub>-O- bridge and with all possible C=C double bonds shown.]]

A total of 18 different kavalactones (or kavapyrones) have been identified to date,<ref name=drugs/> at least 15 of which are active.<ref name="pmid21073405">{{cite journal | vauthors = Sarris J, LaPorte E, Schweitzer I | title = Kava: a comprehensive review of efficacy, safety, and psychopharmacology | journal = Aust N Z J Psychiatry | volume = 45 | issue = 1 | pages = 27–35 | year = 2011 | pmid = 21073405 | doi = 10.3109/00048674.2010.522554 | s2cid = 42935399 }}</ref> However, six of them, including [[kavain]], [[dihydrokavain]], [[methysticin]], [[dihydromethysticin]], [[yangonin]], and [[desmethoxyyangonin]], have been determined to be responsible for about 96% of the plant's pharmacological activity.<ref name="pmid21073405" /> Some minor constituents, including three [[chalcone]]s{{Mdash}}[[flavokavain A]], [[flavokavain B]], and [[flavokavain C]]{{Mdash}}have also been identified,<ref name="pmid21073405" /> as well as a toxic alkaloid (not present in the consumable parts of the plant<ref>{{Cite journal|last1=Bunchorntavakul|first1=C.|last2=Reddy|first2=K. R.|date=2013-01-01|title=Review article: herbal and dietary supplement hepatotoxicity|journal=Alimentary Pharmacology & Therapeutics|language=en|volume=37|issue=1|pages=3–17|doi=10.1111/apt.12109|pmid=23121117|s2cid=6949220|issn=1365-2036|doi-access=free}}</ref>), [[pipermethystine]].<ref name="pmid21506562">{{cite journal | vauthors = Olsen LR, Grillo MP, Skonberg C | title = Constituents in kava extracts potentially involved in hepatotoxicity: a review | journal = Chem. Res. Toxicol. | volume = 24 | issue = 7 | pages = 992–1002 | year = 2011 | pmid = 21506562 | doi = 10.1021/tx100412m }}</ref> [[Alkaloid]]s are present in the roots and leaves.<ref name="drugs">{{cite web|url=https://www.drugs.com/npp/kava.html|title=Kava|date=3 January 2018|publisher=Drugs.com|access-date=12 January 2018}}</ref>

===Pharmacodynamics===
The following [[pharmacology|pharmacological]] actions have been reported for kava and/or its major active constituents:<ref name="pmid12383029">{{cite journal | vauthors = Singh YN, Singh NN | title = Therapeutic potential of kava in the treatment of anxiety disorders | journal = CNS Drugs | volume = 16 | issue = 11 | pages = 731–43 | year = 2002 | pmid = 12383029 | doi = 10.2165/00023210-200216110-00002| s2cid = 34322458 }}</ref>
* Potentiation of [[GABAA receptor|GABA<sub>A</sub> receptor]] activity (by kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin).
* [[Reuptake inhibitor|Inhibition]] of the [[reuptake]] of [[norepinephrine]] (by kavain and methysticin) and possibly also of [[dopamine]] (by kavain and desmethoxyyangonin).
* Binding to the [[CB1 receptor|CB<sub>1</sub> receptor]] (by yangonin).<ref name="pmid22525682">{{cite journal | vauthors = Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V | title = Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand | journal = Pharmacol. Res. | volume = 66 | issue = 2 | pages = 163–9 | year = 2012 | pmid = 22525682 | doi = 10.1016/j.phrs.2012.04.003 }}</ref>
* Inhibition of [[voltage-gated sodium channel]]s and [[voltage-gated calcium channel]]s (by kavain and methysticin).
* [[Monoamine oxidase B]] reversible inhibition (by all six of the major kavalactones).

Leaf extracts of Hawaiian kava cultivars demonstrated stronger and more potent binding inhibition than root extracts at multiple CNS receptors, including the main GABA<sub>A</sub> binding site, [[D2 receptor|dopamine D2 receptor]], [[μ-opioid receptor|μ-]] and [[δ-opioid receptor]]s, and [[H1 receptor|histamine H1]] and [[H2 receptor|H2]] receptors, despite containing lower levels of major kavalactones.<ref>{{cite journal | vauthors = Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W | title = Interaction of various Piper methysticum cultivars with CNS receptors in vitro | journal = Planta Med. | volume = 67 | issue = 4 | pages = 306–11 | year = 2001 | pmid = 11458444 | doi = 10.1055/s-2001-14334 | bibcode = 2001PlMed..67..306D | s2cid = 260281694 }}</ref><ref>{{cite book | author1=Amitava Dasgupta | author2=Catherine A. Hammett-Stabler | title=Herbal Supplements: Efficacy, Toxicity, Interactions with Western Drugs, and Effects on Clinical Laboratory Tests | url=https://books.google.com/books?id=oNrIvxlFG1sC&pg=PA57 | date=2011 | publisher=John Wiley & Sons | isbn=978-0-470-92275-0 | page=57 }}</ref> Weak binding to [[5-HT6 receptor|serotonin 5-HT6]] and [[5-HT7 receptor|5-HT7]] receptors and the [[benzodiazepine site]] of the GABA<sub>A</sub> receptor was also observed.<ref>{{cite journal | vauthors = Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W | title = Interaction of various Piper methysticum cultivars with CNS receptors in vitro | journal = Planta Med. | volume = 67 | issue = 4 | pages = 306–11 | year = 2001 | pmid = 11458444 | doi = 10.1055/s-2001-14334 | bibcode = 2001PlMed..67..306D | s2cid = 260281694 }}</ref> Thus, other bioactive compounds beyond kavalactones may contribute to the pharmacological effects of kava leaves, with notable variation among cultivars.<ref>{{cite journal | vauthors = Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W | title = Interaction of various Piper methysticum cultivars with CNS receptors in vitro | journal = Planta Med. | volume = 67 | issue = 4 | pages = 306–11 | year = 2001 | pmid = 11458444 | doi = 10.1055/s-2001-14334 | bibcode = 2001PlMed..67..306D | s2cid = 260281694 }}</ref>

Heavy, long-term use of kava has been found to be free of association with reduced ability in [[saccade]] and [[cognitive test]]s, but has been associated with elevated liver enzymes, indicating liver injury.<ref name=drugs/><ref name="pmid12589393">{{cite journal | vauthors = Cairney S, Clough AR, Maruff P, Collie A, Currie BJ, Currie J | title = Saccade and cognitive function in chronic kava users | journal = Neuropsychopharmacology | volume = 28 | issue = 2 | pages = 389–96 | year = 2003 | pmid = 12589393 | doi = 10.1038/sj.npp.1300052 | doi-access = free }}</ref>

===Detection===
Recent usage of kava has been documented in forensic investigations by quantitation of kavain in blood specimens. The principal urinary metabolite, conjugated 4'-OH-kavain, is generally detectable for up to 48 hours.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 803–804.</ref>