Chapter Three: Chemistry Active Principles and Their Effects

Physiological Effects of Kava

Explanation of the Potency

Identification of the Active Principles

Molecular Structure of the Isolated Compounds

Physiological Activity of the Kavalactones

Chemical Structure of the Kavalactones

Absorption and Metabolism of Kava Extracts

Numerous chemical and pharmacological studies of kava have been published over the past 140 years, producing a wealth of data. However, the results of these efforts have often been tentative, fragmentary, and contradictory This chemical research has had a dual aim: (1) to identify the active principles responsible for kava's psychoactive effects and (2) to analyze the physiological activity of those ingredients. In this chapter we first describe the psychoactive effects of kava drinking and then present a chronological review of scientific research focusing on the chemistry of P. methysticum. We do not discuss the neurological mechanisms that underlie kava's psychoactive effects on human emotions. Significant research into kava's alteration of brain chemistry has yet to be undertaken.

Physiological Effects of Kava

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Fresh kava rootstock, when prepared by mastication, pounding, or grinding, Yields a greenish milky potion that is considerably stronger than the grayer mixture obtained from dry roots. Before L. Lewin began his scientific research on the plant in Germany during the nineteenth century, it was generally believed that the method of preparation was the only factor that determined the strength and kind of kava's physiological effects. It was assumed that saliva, mixed in during the mastication process, converted starches contained in kava rootstock into sugar, which produced alcohol when fermented. Lewin (1886a) concluded more than a century ago that "this theory is incorrect in every respect."

Steinmetz (1960) was the first to point out that the main factor determining the psychoactive impact of kava is the degree of separation in water of the resinous active ingredients. Van Veen (1939) had noted that for kava to be most effective, rootstock must be emulsified very finely in water, saliva, lecithin, or oil to disperse the active ingredients. Mastication transforms rootstock mass into tiny particles, releasing the resin stored in the cell tissues. The active substances in this resin, insoluble in water, become available to the drinker after emulsification. This, rather than the action of saliva, explains why kava drink prepared by grinding or pounding rootstock often has less physiological effect than that produced from finely chewed, emulsified rootstock.

Infused kava is an emulsion of lipidlike compounds suspended in water. The resinous compounds present in each cell of the rootstock as microscopic drops are dispersed when the root tissues are macerated and infused. When the beverage is ingested, thousands of these microscopic particles transit rapidly through the stomach membrane to the bloodstream. If the emulsion is rich in active resinous compounds, this will induce a rapid and pronounced psychoactive effect.

Of all the scientists who have studied the physiological effects experienced by a drinkers, Lewin has provided some of the most eloquent descriptions. In 1886 he noted that "a well-prepared kava potion drunk in small quantities proces only pleasant changes in behavior. It is therefore a slightly stimulating drink which helps relieve great fatigue. It relaxes the body after strenuous efforts, clarifies the mind and sharpens the mental faculties. If a certain quantity of these active elements is absorbed they produce special narcotic effects" (Lewin 1886a). later publication (Lewin 1927) offers a more detailed description of kava's effects on the human mind and body:

When the mixture is not too strong, the subject attains a state of happy unconcern, well-being and contentment, free of physical or psychological excitement. At the beginning conversation comes in a gentle, easy flow and hearing and sight are honed, becoming able to perceive subtle shades of sound and vision. Kava soothes temperaments. The drinker never becomes angry, unpleasant, quarrelsome or noisy, as happens with alcohol. Both natives and whites consider kava as a means of easing moral discomfort. The drinker remains master of his conscience and his reason. When consumption is excessive, however, the limbs become tired, the muscles seem no longer to respond to the orders and control of the mind, walking becomes slow and unsteady and the drinker looks partly inebriated. He feels the need to lie down. The eyes see the objects present, but cannot or do not want to identify them accurately. The ears also perceive sounds without being able or wanting to realize what they hear. Little by little, objects become vaguer and vaguer. The drinker is prey to exhaustion and feels the need to sleep more than any other sensation. He is overcome by somnolence and finally drifts off to sleep. His sleep is similar to that induced by alcoholic inebriation and the subject comes out of it grudgingly. When the mixture is of moderate strength the effect is felt twenty to thirty minutes following its absorption. The effect lasts for about two hours, sometimes longer and up to eight hours. How long the effect lasts depends on the drinker's level of inurement. When the mixture is concentrated, i.e., when it contains a lot of resinous elements, the effect is felt much more quickly. Drinkers can be found prostrate at the place where they have drunk their kava. Before falling asleep, they could have suffered slight nervous trembling. During their sleep, sensitivity is reduced. No excitement precedes these symptoms. (Translation by R. M. Benyon in Lebot and Cabalion 1988).

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A more recent but equally graphic description of kava's effects is provided Gregory, who writes from his own experience with the drug:

Kava seizes one's mind. This is not a literal seizure, but something does change in the processes by which information enters, is retrieved, or leads to actions as a result. Thinking is certainly affected by the kava experience, but not in the same ways as are found from caffeine, nicotine, alcohol, or marijuana. I would personally characterize the changes I experienced as going from lineal processing of information to a greater sense of "being" and contentment with being. Memory seemed to be enhanced, whereas restriction of data inputs was strongly desired, especially with regard to disturbances of light, movements, noise and so on. Peace and quiet were very important to maintain the inner sense of serenity. My senses seemed to be unusually sharpened, so that even whispers seemed to be loud while loud noises were extremely unpleasant. (Gregory and Cawte 1988)

To explain the potency and action of the drug, Steinmetz (1960) suggested that kava affects the nervous system through a reduction of spinal (rather than cerebral) activity followed by muscular stimulation and then paralysis that particularly affects the lower limbs. It reduces the cardiac rhythm, and first stimulates and then slows down respiration. Unlike alcohol, kava does not influence drinkers' capacity to think clearly before they are overcome by sleep. Some drinkers, like Gregory, even claim that kava consumption can help clarify their thought processes.

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As is often reported, kava drinking also causes pupil dilation and reduced light reflexes if an excessively strong dose is absorbed. Immoderate drinkers sometime suffer from photophobia. Cases of diplopia (double vision) are also known, manifesting temporary oculomotor paralysis (Frater 1952). Garner and Klinger (1985) conducted an experiment on a thirty-year-old male who had not previously ingested kava. The beverage increased his pupil diameter and disturbed his oculormotor balance. The mechanisms responsible for these symptoms were difficult to pinpoint, but Garner and Klinger concluded that the disturbance of oculomotor balance must be caused by the general effects of kava on the central nervous system.

Half a coconut shell (approximately 100- 150 ml) of certain varieties of kava is strong enough to put a drinker into a deep, dreamless sleep within 30 minutes. On average, such an emulsion contains 1.0- 1.5 g of psychoactive resin (Lebot 1988). This is excellent performance for a soporific drug. The next day the drinker awakens having fully recovered normal physical and mental capacities. Kava produces no aftereffects comparable to those of alcohol when reasonable quantities of the drug are consumed. Contrary to Lewin's claims (1886a) that " from the point of view of its moral influence on the individual this passion is like alcoholism, morphine -addiction and other yearnings," obvious chemical addiction to kava does not occur (Lebot, personal observation, 1981-87; Lindstrom, personal obtion, 1978-89).

Although Lewin believed kava was addictive, he denied that it was "responsible the skin diseases of the Pacific Islanders, especially a state of scaly exfoliation giving the skin a shrivelled appearance" (Lewin 1886a). This affliction is in fact documented side effect of chronic kava consumption. Very heavy drinking may cause skin lesions and drying of the skin, producing an advanced exanthema of itchy urticarial patches (Lebot, field observations, 1985).

Kava drinkers are thus sometimes recognizable by their bloodshot eyes and erous skin. These symptoms occasionally are wrongly diagnosed as ichthyosarcotoxism, or ciguatera (fish poisoning), which is an occasional health problem in South Pacific. Such reactions are only found in heavy drinkers and can be ibuted to the properties of kava's active constituents, lactones. The lactones in kava are related to sesquiterpenical lactones- "allergens capable of causing severe eczemas ... what provokes the aggressiveness of these substances is the presence an alpha - methylene -butyrolactone group which enables them to attach themeselves to the skin proteins thus easily forming complete antigens, which are responsible for the series of biological reactions, which finally lead to the stage of allergy" (Benezra and Dupuis 1983). Skin lesions, called kani kani in Fiji (Frater 2), disappear if kava. consumption is reduced. Kani kani seems to affect only those drinkers who are susceptible to the allergens.

A second side effect of heavy kava consumption is an occasional state of apathy reportedly affects some drinkers, preventing them from eating adequately.  In areas where kava is prepared by grinding dried rootstock rather than masticating rootstock, these side effects are less common because grinding dried root stock yields a drink with weaker physiological potency. Furthermore, if kava, chewed or pounded, fresh or dried, is drunk in moderation, it has no toxic consequences or other deleterious side effects.

Identification of the Active Principles

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Analysis of the composition of kava rootstock indicates that fresh material on average is 80% water. When dried, rootstock consists of approximately 43.0% starch, 20.0% fibers, 12.0% water, 3.2% sugars, 3.6% proteins, 3.2% minerals, 15.0% kavalactones, although the kavalactone component can vary between and 20% of rootstock dry weight depending on the age of the plant and the cultivar (Lebot and Uvesque 1989; see table 3. 1). Those who have attempted to isolate the active principles have taken two approaches: some have studied watersoluble fractions of kava rootstock, whereas others have analyzed fractions of kava extracted by organic solvents. Although research remains to be done regarding the chemistry of water-soluble fractions, it is now clear that the active principles
of kava are mostly, if not entirely, contained in its resin. These molecules are a series of lactones-that is, organic compounds containing oxygen, with similar structures. These are alpha-pyrones bearing a methoxyl group at carbon 4 and an aromatic styryl moiety at carbon 6 (Hiinsel 1968).

Kava resin has been investigated using several analytical techniques, including thin-layer chromatography, gas chromatography, and high-performance liquid chromatography (Lebot and Uvesque 1989). Some methods of extraction, isolation, and analysis can encourage the formation of artifacts, or substances that are naturally absent from the plant; the composition of a lipid extract thus may vary according to the type of extraction process used, distorting observed activity. If the drink or extract is prepared by infusion or decoction in hot water, for example, enzymes may be destroyed, whereas if an extract is prepared by maceration in cold water, enzymes may be preserved.

The emergence of information about kava chemistry over the past 100 years has been laborious and contentious. During the last half of the nineteenth century, controversy surrounded the issue of who first isolated and described the inebriating substance of kava and the basis of its psychoactivity. On 10 April 1857, while serving as a pharmacist in the French navy, Cuzent isolated an apparently pure crystalline substance he named "kavahine .... to perpetuate the name of kava given to P. methysticum by the Polynesians" (Cuzent 1857). Meanwhile, Gobley had obtained what he labeled "methysticin" from a sample supplied by Cuzent to 'Rorke, another pharmacist who had just traveled around the world via Polynesia uzent 1857 [10 May]). Gobley (1860) proposed the name methysticin for "the inebriating substance in the drink." He analyzed the composition of hot-air-dried kava rootstock as 26% cellulose, 1% crystalline methysticin, 49% starch, 2% resin combined with an essential oil lemon yellow in color), 15% water, and 7% substances of lesser importance (including 1% potassium chloride and 3% caIcium carbonate combined as ash).

Various authors have suggested that the two compounds isolated by Cuzent and Gobley, kavahine and methysticin, are the same and correspond to methysticin as it is known today (see figure 3.1). However, the percentage analysis of carbon (C), hydrogen (H), and oxygen (0) given by Cuzent (1861a) for kavahine 5.85% C, 5.64% H, and 28.51% 0) is closer to the composition of didromethysticin (65.21 % C, 5.84% H, 28.95 % 0) than to that of methysticin 5.69% C, 5.15% H, 29.17% 0, calculated in Lebot and Cabalion 1986). The melting point of kavahine, 120-130 C, is also nearer to that of dihyromethysticin (116-118 °C, Winzheimer 1908; 117-118 °C, Borsche and Bodenstein 1929; 118 °C, Joessang and Molho 1970) than to that of methysticin 132-135 °C, Sauer and Haensel 1967; 136-137 °C, Rasmussen et al. 1979; 139-140 °C, Borsche and Peitzsch 1929a; see also Duve 1981). The differences bserved between these figures would be easy to explain if Cuzent had actually obtained and analyzed pure syncrystals, but the 10 °C variation in the melting point of his kavahine indicates that the substance he analyzed was contaminated. Our best guess is that Cuzent's kavahine was a mixture of dihydromethysticin and methysticin.

The so-called methysticin isolated by Gobley contained 1.12% nitrogen (Cuzent 1983) and therefore was probably also impure, though of different comosition from Cuzent's kavahine. Seernarm (1868), probably quoting Gobley, also wrongly cited 1.12% as the nitrogen content of the "chemical constituents" of kava, suggesting that methysticin represented I% of the dry weight.

When Lewin published his monograph on kava in 1886, he claimed to have been the first to isolate the active components of kava, but he was overlooking the earlier work of Cuzent (1861b), Gobley (1860), O'Rorke (1856), and Noelting and Kopp (1874), who had already isolated yangonin in 1874. Lewin isolated yangonin and also methysticin, concluding correctly, as had Gobley, that kava's active substance was in its resin. This he broke down into alpha resin and beta resin using a process that involved the use of fat solvents, such as petroleum ether, chloroform, and benzene (Lewin 1886a).

Although Lewin did not find any new active ingredients (kavalactones) in 1886, his pharmacological research and the favorable publicity he gave P. methysticum encouraged many scientific teams, especially in Germany, to investigate the drug from both chemical and pharmacological viewpoints. Major chemical substances were isolated from kava rootstock and their structures determined, but a detailed picture of the main active ingredients remained elusive for years. Borsche admitted in the conclusion of his last publication that "these observations have not been very helpful in attempting to answer the original question because they did not lead to the discovery of a well-defined chemical substance which could be considered as the principle vector of kava's effect" (Borsche and Lewinsohn 1933). However, the foundation for discovery of kava's psychoactive principles was laid by chemists working with Borsche, who, between 1913 and 1933, isolated a series of compounds they called kavalactones, including kavain, methysticin, dihydrokavain, and dihydromethysticin.

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Methysticin was first obtained in a pure state by Pomeranz in 1889 after its original isolation by Gobley, Cuzent, and Noelting and Kopp. It was found to yield methysticic acid (C₁₅H₁₂0₅; Pomerang 1889). A second kavalactone, yangonin, was isolated by Reidel in 1904 and a third, dihydromethysticin, by Winzheirner in 1908. Borsche and Gerhard (1914) determined the formulas of these kavalactones: methysticin, C₁₅H₁₄0₅; yangonin, C₁₅H₁₄0₄; and dihydromethysticin, C₁₅H₁₆0₅.

Borsche isolated an additional kavalactone, kavain (C₁₄H₁₄0₃), and converted it into kavaic acid by alkaline treatment and to dihydrokavain by hydrogenation. He attempted unsuccessfully to confirm the structure of kavain by synthesis and concluded wrongly that none of the substances he isolated possessed an identifiable physiological activity. He thus failed to recognize the important psychoactive role of kavalactones, especially dihydrokavain. Still, the meticulous and methodical research carried out by Borsche's team produced 14 dissertations that helped clarify the chemistry of kava (see Bibliography).

Not until 1938, when Van Veen applied the adsorption column technique, was a kavalactone readily isolated in crystalline form by combining the extraction method with chromatographic analysis. Van Veen named this crystallizable substance marindinin (C₁₄H₁₆0₃) after the Marind-anim people of southeastern Irian Jaya, where the kava sample he analyzed was collected. He claimed incorrectly that marindinin (which is actually dihydrokavain) is the only substance in kava that affects the nervous system (Van Veen 1939).

Other research efforts have been directed toward chemical synthesis to address issues of availability and quality of experimental material, variations in natural composition, and purity of active substances. Steinmetz (1960) reported that kavain and dihydrokavain were synthesized for the first time in 1942. Borsche and Peitzsch (1929a, 1929b) synthesized d,l-dihydromethysticin in 1929, and Klohs, Keller, and Williams (1959) were the first to synthesize d,l-methysticin. After Klohs's work (1967), the Riker laboratories in Northridge, California, registered a tent protecting the synthesis of d,l-methysticin and d,l-dihydromethysticin. Haensel, Sauer, and Rimpler (1966) have added four new kavalactone compounds the alpha-pyrone series with the isolation of 5,6-dehydromethysticin, demethoxy-yangonin, 11-methoxy-yangonin, and 11 -methoxynoryangonin. The structures of these compounds have been confirmed by synthesis.

Although such kavalactones as kavain and methysticin can now be synthesized, these synthetics do not induce the same physiological effects as the natural raw extract. The efficacy of kava evidently does not stem from a single active substance but rather from a mixture, a blending of several kavalactones that results in a synergistic physiological effect. Some kava constituents may be of secondary importance but are nonetheless required to induce the whole suite of psychoactive effects. Each kavalactone so depends on the presence of the others that unaltered extracts produce more potent psychoactive results than does any single isolated substance (Steinmetz 1960).

Molecular Structures of Isolated Compounds

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Alkaloids

A number of scientists claim to have found alkaloids among the substances extracted from kava root. Some of the physiological effects of kava are close enough to those produced by alkaloids (e.g., the anesthetic effect of cocaine and the scle relaxation caused by papaverine) that the temptation to seek alkaloid structures is understandable. However, nitrogen, an alkaloidal constituent, is absent in chemical products obtained from kava resin. Some authors have claimed that the presence of alkaloid compounds in kava is demonstrated by reactions in thin layer chromatography; but Hansel (1968) has challenged these claims, arguing at the reagents used in chromatographic analysis are not specific to alkaloids. He also recognized that lactones, which are nitrogen-free compounds, can react like alkaloids when analyzed chromatographically (Farnsworth, Pilewski, and Draus 62).

Achenbach and Karl (1970a), using more sophisticated methods of analysis, succeeded in isolating two alkaloids from kava rootstock. However, these alkaloids are not part of the resinous extract responsible for kava's physiological effect.  Smith (1979) identified in kava leaves a third alkaloid, specific to P. methysticum, which he named pipermethystin.

Lactones

The skeletons of the lactonic molecules isolated from kava rootstock are generally 4-methoxy-2-pyrones with phenyl or styryl substituents at the 6- position (figure 3. 1). They consist of thirteen carbon atoms, six of which form a benzene ring attached by a double bond to an unsaturated lactone. Fifteen lactones, have been isolated from kava rootstock (Hansel 1968), nine of which have been fully identified. The following six compounds are present in the highest concentrations: yangonin, methysticin, dihydromethysticin (synonym pseudomethysticin), kavain, dihydrokavain (synonym lewinin), and demethoxy-yangonin. Nine other compounds are of minor importance in the rootstock: dehydrokavain, cis-5-hydroxykavain, 7,8-dihydroyangonin, 5,6-dihydroyangonin, 5,6-dehydro-methysticin, I I -methoxy-yangonin, I I -hydroxy-yangonin, I I -methoxy- 1 2-hydroxy-dehydrokavain, and 10-methoxy-yangonin (Duve 1981).

Some researchers have tried to classify kavalactones by reference to common characteristics. The simplest method of grouping is one suggested by Hansel (1968), which sorts the molecules according to the presence or absence of double bonds at the 5,6 and 7,8 positions and divides them into two major groups: the enolides, with one double bond, and the dienolides, with two double bonds. This system recognizes that primary chemical differences among the kavalactones involve the presence or absence of these double bonds as well as the presence or absence of substituent groups in the phenyl ring.

It has been established that biogenetic activity is essentially similar in the various parts of kava's vegetative system but produces different chemical compositions in the stump, roots, and leaves (R. M. Smith 1983). After Hansel (1968), Joessang and Molho (1970) attempted to explain the formation of kavalactones by two biosynthetic processes: one starting from cinnamic acid and resulting in styrylpyrones like dehydrokavain; and the other beginning with the alcohol corre sponding to a given styrylpyrone, which develops into styryldihydropyrones like kavain. Kavain is notably absent from the leaves of the kava plant; this is explained by the immediate reduction of one double bond (7,8) by ascorbic acid. Yangonin and dehydrokavain are found in the leaves, but only in traces. Both major and minor kavalactones are present in variable concentrations in different parts of the plant. For example, Duve (1981) determined that together they compose 10.44% of the lateral roots and 5.28% of the rootstock (average of six samples). Concentrations of kavalactones are typically highest in the lateral roots and decrease progressively toward the aerial parts of the plant. In studies of kava from Vanuatu, Lebot (1988) found that when the kavalactone concentration was near 15% in the roots, it decreased to approximately 10 % in the stump and 5 % in the basal stems. These concentrations varied according to the cultivar (Lebot and Uvesque 1989).

Physiological Activity of Kavalactones

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A team of scientists from the Freiburg University Institute of Pharmacology in Germany, led by H. J. Meyer, conducted the first comprehensive study of the physiological activity of the various kavalactones during the 1950s and 1960s. This research determined that the main properties of kavalactones are:

(1) potentiation of barbituric narcosis (Klohs et al. 1959; Meyer 1962)
(2) analgesic effect (Briiggemann and Meyer 1963)
(3) local anesthesia (Meyer 1964; Kretzschmar and Meyer 1965)
(4) muscular relaxation (Meyer 1965)
(5) antimycotic activity (Hansel, Weiss, and Schmidt 1966).

Meyer also attempted to account for the central nervous system and peripheral effects experienced by humans who consume kava. His Freiburg team was the first to document variation in the physiological effects of the major kavalactones. Absorption of kavain and dihydrokavain in the gastrointestinal tract, for example, was remarkably rapid. Methysticin and dihydromethysticin, in contrast, have a longer induction period and a more lengthy duration of action. Although Hansel (1968) states that in animal experiments dienolides, kavalactones of the yangonin type, are pharmacodynamically inert compared with enolides, kavalactoncs of the kavain type, Meyer and his team had demonstrated earlier that all kavalactones are physiologically active. Their experiments showed that the six major kavalactones (kavain, dihydrokavain, yangonin, demethoxy-yangonin, methysticin, and dihydromethysticin) arc pharmacologically effective and that differences in their action are quantitative as well as qualitative. These findings help explain why different chemical compositions of crude kava extracts have different physiological effects on human subjects both in the laboratory and in the field.

Potentiation of Barbituric Narcosis

Haensel (1968), quoting Meyer (1962), noted that among the kavalactones, dihydromethysticin (DHM) has the greatest potentiating effect on barbituric narcosis. He cited an experiment in which Meyer injected white mice with 150 mg/kg of hexobarbital sodium, causing the animals to sleep for an average of 2 hours. Meyer then repeated the experiment, adding 240 mg/kg of DHM to the same dose of hexobarbital sodium, and observed that the animals slept for 27 hours. Hansel concluded that the potentiating activity of DHM on barbituric narcosis is particularly pronounced. Furthermore, he demonstrated that 50-200 mg/kg of dihydrokavain (DHK) or DHM administered to the stomach put a mouse to sleep in 20 minutes. He noted that DHK, which is not soluble in water, is 95 percent luble in ground-nut oil at 37 C and in gastric juices. Like Van Veen (1939), Haensel concluded that DHK and DHM are the most active elements of kava.

Klohs et al. (1959) confirmed that DHK and DHM are the kavalactones with e most active potential, and Meyer and Kretzschmar (1966, 1969) ascertained at potentiation by these two lactones is similar to the narcotic effect of nitrogen otoxide and ether. Notably, traditional forms of potentiation occur in various kava-consurning societies. For example, on Pentecost, Vanuatu, to overinebriate a preetentious kava drinker, a lichen (Usnea sp.) is mixed with the rootstock before grinding. The potent effects of this drink may be explained as a synergy between the kavalactones and certain lactonic acids contained in the lichen (Molho, personal communication, 1984).

Analgesic Effect

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Bruggermann and Meyer (1963) performed comparative tests to measure the analsic effect of kava's two most powerful, and therefore therapeutically promising, lactones: DHK and DHM.

Local Anesthesia

When fresh kava is prepared by mastication, kavalactones produce local anesthesia the chewer's mouth. Van Veen (1939) observed this phenomenon, but Meyer provided the most detailed scientific description of the effect. He noted that, of the many kavalactones that induce anesthesia, kavain is particularly effective in surface anesthesia and that the superficial anesthesia effects of kavain are equivalent to and last as long as those of cocaine. Meyer reported that the kavalactones are particularly interesting as superficial anesthetics because they manifest no toxicity in the tissues.

Baldi (1980) observed that a subcutaneous injection of an alcoholic kavain solution induces a local anesthesia for several hours and sometimes for several days. He found, however, that if the injected dose was high enough it caused paralysis of the peripheral nerves, and concluded that kavain is unsuitable as a local anesthetic, except perhaps in very moderate doses.

Anticonvulsive and Muscle-Relaxant Action

Meyer's Freiburg team demonstrated that DHM and DHK inhibit nervous and muscular contractions. Meyer and Kretzschmar (1966) observed that the length and intensity of effect of these compounds are comparable to those of the best synthetic products of phenobarbital, pyrimidin, and diphenyhydantoin in current use (Hansel 1968; Joessang and Molho 1970). Kretzschmar (1970) described the "excellent psychopharmacological activity" of kavain, which produces "emotional and muscular relaxation, stabilization of the feelings and stimulation of the ability to think and act." Klohs et al. (1959) noted that kavalactones inhibit convulsions caused by strychnine and are a more effective countermeasure than mephenesin, the conventional antidote. Furthermore, a clinical test found antiepileptic action in DHM, which might also be used to treat schizophrenia (Klohs and Keller 1963). J6ssang and Molho (1970), drawing on Meyer and Kretzschmar (1965), pointed out that DHM and DHK are muscular relaxants superior to substances normally used for such purposes (e.g., propanediol, benzazoles, and benzodiazepines).

According to Singh (1983), kavalactones act less by inhibition of neuromuscular transmission than by a direct effect on muscular contractibility:the postsynaptic depression is similar to that caused by lignocain and other local anesthetics. Hansel (1968) observed that the effects of DHM and DHK on muscles are similar to those of papaverine. After experimenting on frogs, Singh suggested that kava acts on the ionic mechanisms that produce muscular contractions. It may be that kava also acts on the control of muscle relaxation by the central nervous system, as do barbiturates and tranquilizers (Bruce Morton, University of Hawaii, personal communication, 1990).

Antimycotic Activity

Hansel (1968) took a special interest in the antimycotic activity of kava when he realized he had never observed kava extracts attacked by yeasts, bacteria, or fungi. Any regular visitor to the urban nakamals (kava bars) of Vanuatu will observe the same phenomenon in kava prepared several days in advance. Haensel, Weiss, and Schmidt (1966) have suggested that although kavalactones possess remarkable ntimycotic properties, they can not be classified as bactericides. However, acording to Steinmetz (1960), Marpmann had demonstrated much earlier that kavain does possess bactericidal properties, especially against gonococcus, the specific pathogenic agent of gonorrhea, and against colon bacillus and blennorrhea. Flavokavin C has been reported to have antibacterial activity against Salmoella typhi.

Haensel (1968) added that although the number of known bactericides is high, ubstances capable of stopping the growth of dermatophytic mycoses are rare. He quoted as an example the case of griseofulvine, a substance commonly used to treat dermatophytic mycoses. Griseofulvine has no effect on strains of Aspergillus niger, but DHK is the perfect remedy because it completely inhibits the growth of A. niger. Haensel believed that kava extracts could be used to prepare orally consumed antimycotics and suggested that clinical tests be carried out on pathogenic fungal strains affecting humans. Duve (1976) has proposed that the potential of these extracts as food preservatives be studied, for most alternative agents can be used only in limited concentrations because of their toxic effects.

Absorption and Metabolism of Kava Extracts

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Researchers have attempted to elucidate the absorption and metabolism of kalactones in animals. Rasmussen et al. (1979), for example, studied the metabolism of dihydrokavain, methysticin, yangonin, and 7,8-dihydroyangonin, admintered orally and peritoneally, in rats. The metabolites were identified by gas chromatography, mass spectrography, and the two techniques combined. The researchers found melting points of the metabolites to be much higher than the norm for kavain, 145-146 C instead of 106-107 C, and DHK 7l-73 C instead of 55-57 C. The team also found that lipophilic kavalactones have extremely low solubility in water, which probably reduces their oral absorption rates and may be responsible for the variable and often low observed metabolism.

Duffield et al. (1986) detected the presence of kava compounds in the urine of drinkers. They analyzed the urine of 80 Aboriginal people from the Northern Territory of Australia and found that individuals who had recently drunk kava had remarkedly higher concentrations of kavalactones in their urine than those who had not consumed the beverage for some time. When 40 mg/kg of DHK was orally ministered, 50 percent was found in the urine within 48 hours in the form of hydroxylated (approximately 67 percent) and other derivatives. The fact that only 50 percent was found in the urine after 48 hours results from the opening of the 6-dihydro-alpha-pyrone ring, which produces nine metabolites, including hippuric acid. Methysticin does not seem to undergo any modification of its pyrone ring, providing only hydroxylated derivatives. Dihydrokavain has its hydroxyl in the meta position of the benzene ring and dihydroxydihydrokavain has it in the para position. The same studies have identified 10 metabolites resulting from oral kavain consumption. Yangonin and 7,8-dihydroyangonin each yield two O-demethylated derivatives in the para position.

Although Rasmussen et al. (1979) found only a very small amount of DHK in feces, they reported large concentrations of kavain and methysticin. According to these authors, unsaturated 7,8 kavalactones, like kavain, methysticin, and yangonin, are not absorbed and metabolized as well as the saturated compounds at the same position. Only the last are modified in their alpha-pyrone cycle.

Keledjian et al. (1988) measured the quantitative uptake of four kavalactones into mouse brains-kavain, dihydrokavain, demethoxy-yangonin, and yangoninafter intraperitoneal injection of 120 mg/kg. Their research established that kavain and dihydrokavain attain their maximal brain concentration within five minutes, whereas the other two compounds enter the brain more slowly and achieve lower peak concentrations. When an extract containing several kavalactones was used, the peak concentrations of kavain and yangonin were markedly higher than when isolated kavalactones were inj ected- supporting evidence for the greater strength of natural kava extracts. In one experiment (Keledjian et al. 1988), the administered extract was designed to resemble natural kava drink as much as possible. Unfortunately, the relative concentrations of kavain and dihydrokavain were not determined, and the "kava" content was expressed only in terms of mass of powder per unit of solution.

According to Keledjian et al. (1988), the synergistic effect observed in brain tissue penetration suggests that ingestion of other drugs like alcohol may affect the concentration of kavalactones in the brain. Kavain and dihydrokavain are the two kavalactones that pass the blood-brain barrier the most easily. Identification of the neuron receptors affected by kavalactones will be essential in understanding the pharmacology of kava.

Less research has been carried out on aqueous extracts of kava. This is not surprising, given that traditional aqueous infusions of plant rootstock are really emulsions of suspended kava resin in water. Furgiule et al. (1965) studied the physiological properties of a steam distillate of kava. They observed that their extract depressed motor activity and reduced irritability in rats. Notably, however, some of their distillate fractions contained kavalactones with known physiological effects (DHK and DHM). It is therefore difficult to conclude that aqueous (as opposed to lipid) kava extracts contain, in addition to kavalactones, unidentified compounds with significant physiological properties.

Duffield and Lidgard (1986) compared pharmacological activity in rats given aqueous kava extracts with and without kavalactones and found that the kavalactone extract had a much wider range of activity. A dose of 250 mg/kg of the extract without kavalactones did, however, cause some loss of spontaneous activity in rats without a reduction in muscle tone and produced some analgesic action and a very slight anticonvulsant effect without hypnosis. Duffield and Lidgard concluded that aIthough there are substances with pharmacological effects in aqueous kava extracts, their effects are insignificant when compared with those of resin fractions. The psychoactivity of kava, as prepared for human consumption, is clearly due to he insoluble resin components, the kavalactones.

Pictorial Presentation of Kava

Chapter 1 Introduction

Chapter 4 Ethnobotany: Cultivation, Classification, Preparation, and Medicinal Use

Chapter 7 Kava: A World Drug?

Bibliography

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