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Pharmacology of Kava and its Constituents.
The first pharmacological evaluation of the kava pyrones was published in Lewin's admirable monograph but because limited quantities of pure compounds -- methysticin and yangonin -- were at his disposal, his data now is deemed of only historical significance.(96) At any rate,they are worth noting. Methysticin was found to be inactive when injected intraperitoneally (i.p.) in doses of up to two grams in both warm- and cold-blooded animals. Yangonin, being available in even smaller quantities, could be tested only in two frogs in oral doses of 0.05 g with no observable effects.

The bulk of Lewin's experiment was carried out on resin remaining after the crystallization of methysticin and yangonin. It produced paralysis in frogs and showed a local anaesthetic action. In experiments with a bat, a sparrow and a pigeon, it caused the loss of use of the wings, the animals appearing to be deeply sedated. Subcutaneous injection of the resin in cats resulted in deep sleep with obvious local anesthetic activity, but when given orally, only salivation and vomiting were noted.

Borsche and Blount came to the conclusion that none of the kava pyrones known at that time (i.e., methysticin, dihydromethysticin [DHM]), yangonin, dihydrokawain [DHK],and kawain), possessed the biological activities reputed to be present in the crude preparation.(97) The possibility that the active principle might be present in the unsaponifiable fraction could not be substantiated, as the solubility characteristics of the fraction did not allow for biological testing. In a pharmacological investigation carried out about this time, Schübel found the kava resin to have a weak sleep-inducing action, to paralyze sensory nerves and to first stimulate, then paralyze smooth muscles.(98) The hydrolysis products of this resin also showed similar actions. The local anesthetic action was attributed to compounds containing benzoic and cinnamic acid residues. In experiments in the isolated frog heart, Schübel showed that incubation of the kava root with human saliva increased th e potency of kava extract. He attributed the increase in activity to the enzymatic breakdown of starch in the root, which in turn led to a more efficient extraction of the active materials. However, Schübel was unable to demonstrate any pharmacological activity when the pure compounds yangonin and methysticin were administered to rabbits, pigeons, or frogs.

Van Veen employed pigeons, monkeys, and rice birds to follow the active principles of kava in his isolation procedures.(99) Preliminary results indicated that rice birds were overly sensitive to the crude extracts, and monkeys too resistant. Pigeons were thereafter used for routine assays. Eight to fifteen minutes after administration of the extract, the pigeons became sleepy and atactic -- unable to coordinate movements. A deep sleep then set in lasting from two to ten hours. The birds appeared to be fully recovered upon awakening. Monkeys required three to five times the dose used in pigeons. An effective dose caused initial loss of limb control,followed by sleep within fifteen to thirty minutes which lasted for 15 hours or longer. Purified fractions gave a maximal effect when administered in an oil or lecithin-water emulsion, suggesting that chewing the root and admixing saliva produced emulsification and thus promoted activity.

Van Veen succeeded in isolating an active fraction from which he reported a crystalline material that he called marindinin. He subsequently demonstrated that marindinin was a slightly impure form of DHK, a compound found by Borsche to be physiologically inactive. Van Veen also tested the purified DHK and showed that the physiological activity he had earlier demonstrated was indeed due to this refined material and not to the impurity.

More recent work has confirmed the activities of the kava pyrones. Hansel and Beiersdorff showed that DHK and DHM both appeared to be active in causing sleep in white mice and white rats when administered orally by a stomach tube as an emulsion.(100) Meyer, Oberdorf, and Seifen reported that DHK and DHM had sedative activity when administered i.p. or orally to mice, rats, rabbits, and cats.(101) Higher doses led to a marked ataxic phase followed by loss of the righting reflex (an animal's ability to regain normal posture on all four limbs when artificially forced onto its back). When administered to mice as peanut oil solutions, both DHK and DHM produced sedation, hypothermia, and a corresponding reduction in total oxygen consumption. Recently, Jussogie and co-workers have suggested that the sedative action of kava pyrones might be mediated through their effects on GABA, receptor binding site.(102) However, Davies et al. detected no significant interaction between kava pyrones a nd GABA or benzodiazepine binding sites.(103) In unanesthetized rabbits, blood pressure was only slightly reduced.(104) These findings, however, could not be duplicated by Keller and Klohs(3) and are reminiscent of the contradictory evidence of Borsche and Van Veen mentioned earlier.(97,99)

Later, Meyer demonstrated that the most characteristic central nervous action of all kava pyrones was their ability to produce a muscular relaxation in all species of laboratory animals.(103) The pyrones have also proved to be considerably more effective than mephenesin in protecting mice from convulsions and death caused by toxic doses of strychnine. Thus, these compounds might represent a new group of potent skeletal muscle relaxants. Larger doses produced ataxia and an ascending paralysis without loss of consciousness, followed by complete recovery. In doses causing muscular relaxation, the pyrones did not possess a curate-like action on the neuromuscular function.(106) Death after large oral or i.p. doses was the result of respiratory failure. In addition,the pyrones reduced experimentally produced edema. Experimentally induced contractions of isolated ileum or uterus were inhibited by the pyrones.(105)

Klohs et al. studied the effects of the ground root of kava, a chloroform extract obtained therefrom, and several of its crystalline constituents on the central nervous system as determined by their ability to antagonize clonic strychnine convulsions and death in mice, cause fall-out in roller cage experiments, and potentiate sodium pentobarbital-induced sleeping time.(107) The crude extract, methysticin, and DHM were particularly effective in affording protection against the lethal effects of strychnine, while yangonin and dihydroyangonin (DHY) were practically without effect. Kawain and DHK were only moderately effective. All of the compounds increased pentobarbital-induced sleeping time with DHM being the most potent agent. Using "fall-out" from revolving (roller) cages as an index, none of the crystalline compounds had significant activity. This was in sharp contrast to the ground root and the crude extract. On the basis of these results, Klohs et al. proposed the presence o f a synergistic action for the individual compounds when administered in combination.(107) An indication of a synergistic effect was also found by testing a mixture of kawain, DHK, methysticin, DHM, yangonin and DHY against strychnine convulsions and death. The amounts of the compounds tested were in the ratio in which they were isolated from the crude extract. The mixture showed a potency similar to that of DHM. Since this agent represented only about 5 percent of the mixture and since the other constituents were less potent or inactive, a synergistic effect of the mixture or increased absorption of individual components are likely explanations. In agreement with Klohs et al., Meyer reported that the activity of yangonin and desmethoxyyangonin (given i.p.) in preventing mice from maximal electroshock seizure was markedly increased when given in combination with the other kava constituents.(107,105) An interesting observation was recently made by Backhauss who found that kava extract, methysticin, and DHM, but not the other pyrones, protected against tissue damage in experimentally induced ischemia in rat and mouse brains.(108)

Recently Keledjian et al. have measured the rate of uptake into mouse brain tissue of kawain, DHK, yangonin, and desmethoxyyangonin,(109) all of which are reported to be active as anticonvulsants against maximal electroshock seizures when tested in mice.(105,110) They found that maximal brain concentrations of kawain and DHK occurred five minutes after their i.p. injection. Previously, Meyer showed that the peak effect of the two compounds in protecting mice from maximal electroshock seizure occurred after 10 minutes.(105) Therefore, the brain concentrations correlated well with the centrally mediated pharmacological actions.

Duffield's group showed that both pyrone-free and lipid soluble kava resin fractions reduced amphetamine-induced hypermotility and conditioned avoidance responses in rats and mice.(111) However, the kava effects were slight compared to that of the standard antipsychotic drugs chlorpromazine and haloperidol. This group also found that the anticonvulsant effect of the aqueous extract against strychnine was very slight.(112) The kava resin produced hypnosis, analgesia, and a local anesthetic action. Overall, the pharmacological effects of kava appeared to be mainly due to the activity of the compounds present in the lipid soluble resin fraction. In the cat, the preferential site of action of the kava extract and the pure compound d,l-kawain appears to be the amygdala complex.(113) According to them, the participation of these structures in modulating emotional processes may explain the promotion of sleep by kava.

Frater also observed the effects of kava on the nervous system of human subjects.(72) Following the consumption of six pints of an infusion (no defined concentrations were mentioned in the studies) over a two-hour period, the subjects looked sleepy, their eyes were slightly bloodshot and definitely watery, with the pupils enlarged and reacting only slowly to light. Speech was only slightly affected. The subjects were able to walk in a straight line and could still run up the stairs two at a time. In an effort to assess the effects on alertness, and on speed of access of information in long-term memory, Russell, Bakker, and Singh showed that kava has no effect on the reaction times or errors in two groups of native drinkers who consumed doses thought usual or greater than those associated with social functions.(114) In a study on the visual effects produced by kava, Garner and Klinger noted a reduced near point of accommodation and convergence, an increase in pupil diameter and d isturbance to the oculomotor balance.(114) However, no changes were recorded in visual or stereoacuity, or in ocular refractive error.

The local anaesthetic action of the pyrones originally observed by Lewin, Schübel, and others early this century has been re-investigated.(96,98) Frater showed that a thin paste of kava powder, when applied to the mucous membrane of the lip, produced a slightly burning sensation and a feeling of numbness.(72) With a pin-prick test there was a slight impairment of feeling as compared with the rest of the lip. When some root was chewed for 15 minutes, however, the degree of anesthesia was greater, leading him to conclude that there was a definite local anesthetic effect. In another study most of the kava pyrones inhibited frog heart contraction.(116) These actions were compared with those of cocaine which showed a similar protection against ventricular fibrillation through its local anesthetic effectiveness. More recently, Singh examined the effects of whole kava extract on muscle contractility and neuromuscular transmission, using twitch tension and electrophysiological tech niques(115). He found that the extract caused muscle paralysis by mechanisms similar to local anesthetics like lidocaine. These observations are supported by the recent finding that kawain, like the common local anesthetics, blocked voltage-dependent sodium ion channels.(118)

The antimycotic (antifungal) properties of some of the pyrones have been investigated.(119,120) A large number of Gram-positive, Gram-negative, pathogenic and non-pathogenic bacteria were found to grow uninhibited in nutrients containing the pyrones, indicating they are not bacteriostatic in nature. However, some of the pyrones showed remarkable fungistatic properties against a wide genera of fungi, including some which are pathogenic to humans.

Since the bulk of the pharmacological work has concentrated on the water-soluble pyrones, Buckley, Furgiuele, and O'Hara investigated the biological activity of the water-soluble fractions of kava obtained by steam distillation.(121) They found that the two fractions so obtained contained biologically active materials which were relatively free of any pyrones. These materials suppressed spontaneous activity in test animals and at higher doses led to muscular relaxation previously seen with the pyrones. In addition, one of the two fractions exhibited an anti-serotonin activity similar to that of DHM.

Recent investigations by Lebot et el. into the relative proportions of the various pyrones in kava has shed a tremendous amount of light on the origin of kava and its chemistry which has been modified through native selection of individual plants. Lebot found that the chemical makeup of kava, and not its outward appearance, correlated with ethnobotanical use. Pharmacologically driven selection appears to have created chemical variations of kava far removed from its wild ancestor.(8)

Article copyright American Botanical Council.

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By Yadhu N. Singh and Mark Blumenthal