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Kava drinks
Aqueous extracts from the root and rhizome of Piper methysticum (Piperaceae) have long been
consumed as an intoxicating beverage by the peoples of Pacific islands comprising Polynesia,
Melanesia and Micronesia, and the name kava or kava-kava referred to this drink. In herbal medicine,
the dried root and rhizome is now described as kava, and it is used for the treatment of anxiety,
nervous tension, agitation and insomnia. The pharmacological activity is associated with a group of
styrylpyrone derivatives termed kavapyrones or kavalactones, good quality roots containing 58%
kavapyrones. At least 18 kavapyrones have been characterized, the six major ones being the enolides
kawain, methysticin, and their dihydro derivatives reduced in the cinnamoyl side-chain, and the
dienolides yangonin and demethoxyyangonin. Compared with the dienolides, the enolides have a
reduced pyrone ring and a chiral centre. Clinical trials have indicated kava extracts to be effective as
an anxiolytic, the kavapyrones also displaying anticonvulsive, analgesic, and central muscle relaxing
action. Several of these compounds have been shown to have an effect on neurotransmitter systems
including those involving glutamate, GABA, dopamine, and serotonin.
Kava was used throughout Oceania to calm nerves, cause relaxation and sleep, fight fatigue. It was
drank to unclog urinary tracts, to lose weight, relieve asthma and rheumatism. Drinking kava is thought
to be good for headaches, cramps, and to cure syphilis and gonorrhea. Many islanders believe kava to
restore strength, to soothe stomach pains and to cure such ailments as boils.
In addition to drinking the pounded root, some people use kava leaves. Fumigation with the leaves is
believed to treat general illnesses.
Macerated kava as well as external application of the masticated kava stump are other methods of cure,
although drinking it in the traditional way is the most popular method of cure
Kava is a botanical product derived from the rhizome and roots of Piper methysticum, a shrub indigenous
to the South Pacific. In the North America, kava-containing products are sold as dietary supplements and
marketed for the treatment of anxiety, occasional insomnia, premenstrual syndrome, and stress. These
supplements often are in the form of raw plant material or concentrated extracts, which are obtained by
using either acetone or ethanol extraction or cryoprecipitation. Preparations marketed for human
consumption contain a mixture of components collectively known as kava pyrones (i.e., kavalactones).
Kava-containing products might differ based on the absolute amount of kava pyrones present and on the
relative distribution of kava pyrones.
Fulminant liver failure after administration of the herbal antidepressant Kava-Kava. M. Kraft1,
T. W. Spahn, J. Menzel, N. Senninger, K.-H Dietl, H. Herbst, W. Domschke1, M. M., Dtsch med
Wochenschr 2001; 126: 970-972.
History and clinical findings: A 60 year-old woman was admitted to hospital because of jaundice,
fatigue, weight loss over several months and icteric skin. Because of progressive liver failure,
concomitant renal failure and progressive encephalopathy she was transferred to an intensive care unit.
Investigations: Biochemical tests revealed acute liver failure with high levels of total and conjugated
bilirubin (30 mg/dl) as well as aspartate aminotransferase (921 IU/l) and alanine aminotransferase
(1350 IU/l) concentrations. Prothrombin time was less than 10 %. Serological tests could rule out viral
hepatitis, metabolic or autoimmune causes of liver failure. On abdominal computed tomography and
ultrasonography no pathological changes were detected. Above all portal vein thrombosis, ascites, focal
lesions of the liver and extrahepatic cholestasis could be excluded. Liver histology showed extensive
hepatocellular necrosis with intrahepatic cholestasis.
Treatment and clinical course: The patients physical condition deteriorated. She had to be intubated
because of respiratory insufficiency and encephalopathy stage IV. Because of progressive liver failure
under conservative treatment the patient received an orthotopic liver transplant 11 days after admission.
Conclusions: The exclusion of other causes and the histological diagnosis made Kava-Kava as the
cause of acute liver failure most likely. This is the 18th case of Kava-Kava induced liver failure
reported to the European regulatory authorities.
PHARMACOKINETICS AND DISPOSITION OF THE KAVALACTONE
KAWAIN: INTERACTION WITH KAVA EXTRACT AND KAVALACTONES
IN VIVO AND IN VITRO
James M. Mathews, Amy S. Etheridge, John L. Valentine, Sherry R. Black,
Donna P. Coleman, Purvi Patel, James So, and Leo T. Burka. Drug Metab
Dispos.2005; 33: 1555-1563.
Reported adverse drug interactions with the popular herb kava have spurred
investigation of the mechanisms by which kava could mediate these effects. In vivo
and in vitro experiments were conducted to examine the effects of kava extract and
individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The
oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in
rats with and without coadministration of kava extract (256 mg/kg) to study the effect
of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose
eliminated within 72 h, chiefly in urine. Compared with kawain alone,
coadministration with kava extract caused a tripling of kawain AUC08 h and a
doubling of Cmax. However, a 7-day pretreatment with kava extract (256 mg /kg/day)
had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day
pretreatment with kava extract only modestly induced hepatic P450 activities.
The human hepatic microsomal P450s most strongly inhibited by kava extract
(CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree
by a "composite" kava formulation composed of the six major kavalactones
contained in the extract. Ki values for the inhibition of CYP2C9 and CYP2C19
activities by methysticin, dihydromethysticin, and des-methoxy-yangonin
ranged from 5 to 10 M. Kava extract and kavalactones ( 9 M) modestly
stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that
kava can cause adverse drug reactions via inhibition of drug metabolism.
Flavonoids and Stilbenes
Flavonoids are a class of water-soluble plant pigments. Flavonoids are broken down into categories,
though the issue of how to divide them is not universally agreed upon. One system breaks flavonoids into
isoflavones, anthocyanidins, flavans, flavonols, flavones, and flavanones. Some of the best-known
flavonoids, such as genistein in soy, and quercetin in onions, can be considered subcategories of
categories. Although they are all structurally related, their functions are different. Flavonoids also include
hesperidin, rutin, citrus flavonoids, and a variety of other supplements.
While they are not considered essential nutrients, some flavonoids support health by strengthening
capillaries and other connective tissue, and some function as anti-inflammatory, antihistaminic, and
antiviral agents. Quercetin has been reported to block the "sorbitol pathway" that is linked to many
problems associated with diabetes. Rutin and several other flavonoids may also protect blood vessels.
As antioxidants, some flavonoids, such as quercetin, protect LDL ("bad") cholesterol from oxidative
damage. Others, such as the anthocyanidins from bilberry, purple cabbage, and grapes, may help
protect the lens of the eye from cataracts. Animal research suggests that naringenin, found in
grapefruit, may have anticancer activity. Soy isoflavones are also currently being studied to see if they
help fight cancer.
Flavonoids are found in a wide range of foods. For example, flavanones are in citrus, isoflavones in
soy products, anthocyanidins in wine and bilberry, and flavans in apples and tea.
Their polyphenolic nature enables them to scavenge injurious free radicals such as superoxide and
hydroxyl radicals. Quercetin in particular is almost always present in substantial amounts in plant
tissues, and is a powerful antioxidant, chelating metals, scavenging free radicals, and preventing
oxidation of low density lipoprotein. Flavonoids in red wine (quercetin, kaempferol, and
anthocyanidins) and in tea (catechins and catechin gallate esters) are also demonstrated to be effective
antioxidants. Flavonoids contribute to plant colours, yellows from chalcones and flavonols, and reds,
blues, and violets from anthocyanidins. Even the colourless materials, e.g. flavones, absorb strongly in
the UV and are detectable by insects, probably aiding flower pollination. Catechins form small
polymers (oligomers), the condensed tannins, e.g. the epicatechin trimer which contribute astringency
to our foods and drinks, as do the simpler gallotannins, and are commercially important for tanning
leather.
An interesting combination of flavonoid and lignan structures is found in a group of compounds called
flavonolignans. They arise by oxidative coupling processes between a flavonoid and a phenylpropanoid,
usually coniferyl alcohol. Thus, the dihydroflavonol taxifolin through one-electron oxidation may provide
a free radical, which may combine with the free radical generated from coniferyl alcohol. This would
lead to an adduct, which could cyclize by attack of the phenol nucleophile on to the quinone methide
system provided by coniferyl alcohol. The product would be silybin, found in Silybum marianum
(Compositae/Asteraceae) as a mixture of two trans diastereoisomers, reflecting a lack of stereospecificity
for the original radical coupling. In addition, the regioisomer isosilybin, again a mixture of trans
diastereoisomers, is also found in Silybum. Silychristin demonstrates a further structural variant which
can be seen to originate from a mesomer of the taxifolin-derived free radical, in which the unpaired
electron is localized on the carbon ortho to the original 4-hydroxyl function.
The flavonolignans from Silybum (milk thistle) have valuable antihepatotoxic properties, and can provide
protection against liver-damaging agents. Coumarinolignans, which are products arising by a similar
oxidative coupling mechanism which combines a coumarin with a cinnamyl alcohol, may be found in
other plants. The benzodioxane ring as seen in silybin and isosilybin is a characteristic feature of many
such compounds.
silybin
taxifolin
milk thistle
Silybum marianum (Compositae/Asteraceae) is a biennial thistle-
like plant (milk thistle) common in the Mediterranean area of
Europe. The seeds yield 1.53% of flavonolignans collectively
termed silymarin. This mixture contains mainly silybin, together
with silychristin, silydianin, and small amounts of isosilybin.
Both silybin and isosilybin are equimolar mixtures of two trans
diastereoisomers. Silybum marianum is widely used in traditional
European medicine, the fruits being used to treat a variety of hepatic
and other disorders. Silymarin has been shown to protect animal
livers against the damaging effects of carbon tetrachloride,
thioacetamide, drugs such as paracetamol, and the toxins -amanitin
and phalloin found in the death cap fungus (Amanita phalloides).
Ayahuasca (contains DMT and an MAOI, commonly Banisteriopsis caapi with Psychotria viridis)
Deadly nightshade (Atropa belladonna) (contains tropane alkaloids)
Diviner's sage (Salvia divinorum) (contains salvinorin A)
Epen (Virola sp.) (contains 5-MeO-DMT and DMT)
Ergot fungus (Claviceps purpurea) (not hallucinogenic in itself, but contains LSD precursors)
Floripondio (Brugmansia sp.) (contains tropane alkaloids)
Fly Agaric mushroom (Amanita muscaria) (contains muscimol)
Hawaiian baby woodrose (Argyreia nervosa) (contains Ergine)
Henbane (Hyoscyamus niger) (contains tropane alkaloids)
Iboga (Tabernanthe iboga) (contains ibogaine)
Mandrake (Mandragora sp.) (contains tropane alkaloids)
Cannabis (contains THC)
Nutmeg (Myristica fragrans) (questioned hallucinogenic activity)
Ololiuhqui/Coaxihuitl (Turbina/Rivea corymbosa) (contains Ergine)
Peruvian Torch cactus (Trichocereus peruvianus) (contains mescaline)
Peyote cactus (Lophophora williamsii) (contains mescaline)
Psilocybian mushrooms (Psilocybe sp. and some Conocybe, Panaeolus and Stropharia) (contain psilocybin and psilocin)
San Pedro cactus (Trichocereus pachanoi) (contains mescaline)
Sinicuichi (Heimia salicifolia) (questioned hallucinogenic activity)
Thorn Apple/Jimson Weed (Datura sp.) (contains tropane alkaloids)
Tlitliltzin/Badoh Negro (Ipomoea violacea) (contains Ergine)
Among the most well-known animals that secrete hallucinogens are:
Psychoactive toads (Bufo alvarius) (contain 5-MeO-DMT and Bufotenine)
Hallucinogen
magic mushrooms
Psilocybin, shrooms, liberties, magics, mushies, magics, liberty cap,
psilocybe, silocybin, shrooms, amanita, fly agaric, etc.
Cacti
(mescaline), 3,4,5-trimethoxybenzeneethanamine
2CB
4-bromo-2,5-dimethoxyphenethylamine
-demethylDOB, Nexus, bromo,toonies,
herox, sunergy, venus, eros
DMT (dimethyltriptamine)
(Phalaris aquatica)
MDA
(3,4-methylenedioxyamphetamine), Ecstasy, Adam (MDA), brownies,
burgers, disco biscuits, doves, E, eckies, Edward, elephants, essence,
fantasy, love doves, M and Ms, MDMA powder, Mitsi(bushie)s, New
Yorkers, pills, rhubarb and custard, shamrocks, sweeties, tulips, white
doves, X, XTC.
Ergot was first mentioned in the early Middle Ages, as the cause of outbreaks of mass
poisonings affecting thousands of persons at a time. The illness appeared in two
characteristic forms, one gangrenous (ergotismus gangraenosus) and the other
convulsive (ergotismus convulsivus). Popular names for ergotism - such as "mal des
Ergot growing in rye
ardents", "ignis sacer", "heiliges Feuer" or "St. Anthony's fire" - refer to the gangrenous
form of the disease. The patron saint of ergotism victims was St. Anthony, and it was
primarily the Order of St. Anthony that treated these patients. Until quite recently,
outbreaks of ergot poisoning approaching epidemic proportions were recorded in most
European countries including certain areas of Russia. However, in the seventeenth
century it was discovered that ergot-containing bread was the cause of the poisonings.
This, coupled with progress in agriculture, caused the frequency and extent of ergotism
epidemics to diminish considerably. The last great epidemic occurred in certain areas of
southern Russia in the years 1926-27.
Ergotism, a condition sometimes called St. Anthony s Fire, is caused by toxic doses of
alkaloids produced by purple masses of spores called sclerotia. The condition is
characterized by two sets of symptoms -- gangrene with burning pain in the extremities
and convulsions, hallucinations, severe psychosis, and death. It can also cause
miscarriages in both humans and animals.
Ergotamine, another ergot derivative is valuable as a vasoconstrictor (restricting blood
flow to the extremities) and is being used in medicines for the treatment of migraine
headaches.
Hallucinogen
Dose: 15-50 mg
The effects of LSD are unpredictable. They depend on the amount taken,
the user's personality, mood and expectations,
and the surroundings in which the drug is used.