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Styrylpyrones

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).

Silymarin may be used in many cases of liver disease and injury,


though it still remains peripheral to mainstream medicine. It can
offer particular benefit in the treatment of poisoning by the death
cap fungus. These agents appear to have two main modes of action.
They act on the cellular membrane of hepatocytes inhibiting
absorption of toxins, and secondly, because of their phenolic nature,
they can act as antioxidants and scavengers for free radicals which
cause liver damage originating from liver detoxification of foreign
chemicals. Derivatives of silybin with improved water-solubility
and/or bioavailability have been developed, e.g. the bis-
hemisuccinate and a phosphatidylcholine complex.
Ubiquinones (coenzyme Q) are found in almost all organisms and function as electron carriers for the
electron transport chain in mitochondria. The length of the terpenoid chain is variable (n = 112), and
dependent on species, but most organisms synthesize a range of compounds, of which those where n =
710 usually predominate. The human redox carrier is coenzyme Q10. They are derived from 4-
hydroxybenzoic acid , though the origin of this compound varies according to organism. Thus, bacteria
are known to transform chorismic acid by enzymic elimination of pyruvic acid, whereas plants and
animals utilize a route from phenylalanine or tyrosine via 4-hydroxycinnamic acid.
Tocopherols are also frequently found in the chloroplasts and constitute members of the vitamin E
group. Their biosynthesis shares many of the features of plastoquinone biosynthesis, with an additional
cyclization reaction involving the p-quinol and the terpenoid side-chain to give a chroman ring. Thus, the
tocopherols, e.g. -tocopherol and -tocopherol, are not in fact quinones, but are indeed structurally
related to plastoquinones. The isoprenoid side-chain added, from phytyl diphosphate, contains only four
isoprene units, and three of the expected double bonds have suffered reduction. Again, decarboxylation of
homogentisic acid cooccurs with the alkylation reaction. C-Methylation steps using SAM, and the
cyclization of the p-quinol to -tocopherol, have been established. Note once again that one of the nuclear
methyls is homogentisate-derived, whilst the others are supplied by S-adenosylmethionine (SAM).
The phylloquinones (vitamin K1) and menaquinones (vitamin K2) are shikimate-derived naphthoquinone
derivatives found in plants and algae (vitamin K1) or bacteria and fungi (vitamin K2).
Hallucinogenic plants, fungi, and animals

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.

Magic mushrooms (except Fly Agaric) are usually eaten raw


but are also dried out and stored for later use. They can also
be cooked into food or made into a tea or infusion and drunk.
20 - 30 liberty caps would be regarded as a full dose, but
only one or part of a Fly Agaric would be required. Psilocybe semilanceata
(Liberty Cap )
A huge number of hallucinogenic plants and fungi were used
by ancient tribes and civilisations usually as a means of
entering the spiritual world.
Fly agaric mushrooms were used by medicine men or
'shamans' of north east Asia and Siberia.

Liberty caps were seen as sacred intoxicants by the Aztecs


of Mexico at the time of the Spanish invasion in the 1500s.
They do not seem to feature much in European history,
although pagan witches used hallucinogenic plants from the
Psilocybin
potato family, especially Deadly Nightshade and Henbane.
Fly agaric use is more likely to result in unpleasant effects,
including nausea and vomiting, stiffness of joints and lack of
co-ordination. Strong doses (anything more than one fly Amanita muscaria
agaric mushroom) may result in intense disorientation, (Fly Agaric)
convulsions and in some cases death.
Hallucinogen

Cacti
(mescaline), 3,4,5-trimethoxybenzeneethanamine

The peyote experience is different from that of


pure mescaline - the former experience more
intense and complex. This is due to the presence
of many more alkaloids that affect mind and body
such as hordenine, pellotine, anhalinine,
anhalonine and tyramine. Some of these chemicals
in combination apparently potentiate the effects of
the mescaline and definitely alter some of the
San Pedro cacti
characteristics of the experience. The cacti's
effects are in some ways similar to LSD, but
longer lasting and more physical. Users typically
vomit before entering a dreamlike state where
sound and scale distort and visions appear. The
trip can last up to 12 hours with the user deep in
trance and detached from the world around them. mescaline

2CB
4-bromo-2,5-dimethoxyphenethylamine
-demethylDOB, Nexus, bromo,toonies,
herox, sunergy, venus, eros

A flowering peyote cactus


Hallucinogen

DMT (dimethyltriptamine)
(Phalaris aquatica)

similar to LSD though its effects are said to be more


powerful. It can be injected, smoked or sniffed and the
effects rarely last more than two hours.

PCP (phenylcyclidine), angel dust, elephant, hog

PCP is an anaesthetic which has hallucinatory effects. It


is regarded as a very powerful drug that can have
disturbing effects including distortion of the senses,
mood and experience of time, dreamlike states,
euphoria or depression, panic attacks, paranoia and
aggressive, sometimes violent behaviour. Deaths have
been recorded from heart or lung failure
Hallucinogen

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.

During the 1950s, the American military experimented with a


whole range of drugs, including ecstasy, for use in chemical
warfare, to extract information from prisoners and to immobilise
armies. In the 1960s, the drug was rediscovered' by an American
research chemist Alexander Shulgin who experimented with it
on himself. Ecstasy is a stimulant drug which also has mild
hallucinogenic effects. It has been described as being like a mix Ecstasy pills
of amphetamine and a weak form of LSD. The effects of taking
a moderate dose start after 20-60 minutes (longer if on a full
stomach) and can last for up to several hours.
The pupils become dilated, the jaw tightens and there is often
brief nausea, sweating, dry mouth and throat. The blood
pressure and heart rate increases and loss of appetite is common.
After taking ecstasy users may feel very tired and low and need
a long period of sleep to recover. This may last up to three or
four days, known as a comedown.
Regular use may lead to sleep problems, lack of energy, dietary
problems (including anorexia nervosa) and feeling depressed or
type 'Mitsubishies'
anxious. Increased susceptibility to colds, flu, sore throat etc
may follow.
Hallucinogen
Ergot of rye is produced by a lower fungus (Claviceps purpurea) that grows
parasitically on rye and, to a lesser extent, on other species of grain and on
wild grasses. Kernels infested with this fungus develop into light-brown to
violet-brown curved pegs (sclerotia) that push forth from the husk in place
of normal grains. Ergot of rye (Secale cornutum) is the variety used
medicinally.

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

LSD (Lysergic acid diethylamine), Acid, 'Cid, Sid, Bart


Simpsons, Barrels, Tabs, Blotter, Heavenly blue, "L",
Liquid, Liquid A, Lucy in the sky with diamonds, Micro
dots, Mind detergent, Orange cubes, Orange micro,
Owsley, Hits, Paper acid, Sacrament, Sandoz, Sugar,
Sugar lumps, Sunshine, Tabs, Ticket, Twenty-five,
Wedding bells, Windowpane, etc.

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.

17:00: Beginning dizziness, feeling of anxiety, visual distortions, symptoms of


paralysis, desire to laugh.
The dizziness and sensation of fainting became
so strong at times that I could no longer hold
myself erect, and had to lie down on a sofa. My
surroundings had now transformed themselves in
more terrifying ways. Everything in the room
spun around, and the familiar objects and pieces
of furniture assumed grotesque, threatening
forms. They were in continuous motion,
animated, as if driven by an inner restlessness.
The lady next door, whom I scarcely recognized,
brought me milk - in the course of the evening I
drank more than two liters. She was no longer
Dr Albert Hofmann, Mrs. R., but rather a malevolent, insidious witch
with a colored mask."

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