Chapter Seven: Chemistry and Actions

Dried kava contains many ingredients: starch, fibers, sugars, proteins, and minerals. Although a small amount of research has been conducted on the water-soluble component of the rootstock, the majority of the research has been done on the resin, which contains most, if not all, of the active, fat soluble components. These are the kavapyrones or kavalactones (a lactone is an organic compound containing oxygen), which typically make up anywhere from 3% to 20% of kava's dried weight. Other compounds include alkaloids (two from the roots and one, piper methystin, from the leaves), flavokavins, an alcohol, a phytosterol, ketones, and organic acids. The concentration of kavalactones is generally highest in the lateral roots (15%) and decreases progressively toward the aerial part of the plant (10% in the stump; 5% in the basal stems). ¹

Extraction Process

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During the 1700s, a common method of kava preparation involved pounding the rootstock into small pieces, which were then chewed. When the chewing was completed, the chewer put the mouthful of pulp into a large wooden bowl where it was then mixed with cold water, strained, and served, as described in Chapter 6. The other traditional method of preparation was manually grinding and pounding the root, then adding water. The chewing method seems to produce the more potent kava drink. The reason for this was once thought to be related to the enzymes contained in saliva.

In 1939, researcher A.G. Van Veen discovered that for kava to be most effective, the rootstock must be emulsified to disperse the ingredients-in water, saliva, lecithin, or oil.^2,3 It is now accepted that the lipid soluble material is released into aqueous solution through emulsification and that this process is mechanical rather than enzymatic or chemical. Present-day technological extraction methods take this into account. The kava roots destined for export are carefully washed, cut up, and dried before being mechanically ground into a fine powder. The powder is then ready for mixing with water for drinking- in the traditional way, or for extraction and processing.

Whole Kava vs. Extracted or Synthesized "Active Ingredients"

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When confronted with a plant that exhibits healing properties, conventional medicine's response is often to break it down chemically in search of an elusive "active ingredient" that can be extracted or synthesized, and hopefully, patented. But in the case of kava, as with so many other healing herbs, this ignores the power of the whole. Vincent Lebot deserves to be quoted at length on the subject: "Kavalactones can now be synthesized, but these synthetics do not induce the same physiological effects as the natural extract. The efficacy of kava does not stem from a single substance but rather from a mixture, a blend of several kavalactones, that results in a synergistic physiological effect. Each kavalactone so depends on the presence of the others that unaltered extracts produce more psychoactive results than does any single isolated substance."⁴ One study suggested that the human brain absorbs the lactones in whole kava much more readily than it does in the form of isolated kavalactones.⁵

With St. John's wort, for example, it was once thought that the active psychoactive ingredient was hypericin, and that its main mode of action was NIAO inhibition. Later research proved both ideas to be less conclusive, with the activity stemming from a synergistic action among its various compounds and possibly from some other as-yet undiscovered ingredient and mode of action. Similarly, kavalactones may simply be markers for the as-yet undiscovered "real thing." Meanwhile, the different compounds affect different target cells and symptoms, maximizing healing effects while minimizing side effects. just as hypericin as a marker for St. John's wort reflects only a small aspect of the herb's antidepressant and antianxiety qualities, so it is with kava. For maximum effectiveness, standardization must be multifaceted, addressing the potency, activity, species, and part of the plant used.

We have available highly sophisticated means of determining the kavalactone profile.⁶ You might wonder if the wide variety of kava under cultivation (or "cultivars") produces problems in standardizing the product that shows up on North American and European shelves. According to Steven Dentali, a respected consultant to the herbal industry and author of a major safety review of kava, "There is no problem in standardizing for total kavalactone (or more accurately, kavapyrone) content, although the relative concentration of individual kavapyrones may vary. The total amount of kava pyrones in unprocessed underground material is reported to range between 5 and 15%, so standardization can be a matter of making a concentrated extract and ensuring that the finished material meets the desired specifications."

Components of Kava

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In 1973, pharmacologist Alexander Shulgin divided the kava components into three categories: major (dihydrokavain, kavain, and methysticin), minor (yangonin, dihydromethysticin, desmethoxyyangonin, flavokavin A, pinostrobinchalcone, dihydrotectochrysin, aplinetinchalcone, aplinetin, and dihydrooroxylin A), and trace (I I-methoxy~nor-yangonin, I Imethoxyyangonin, and flavokavin B). In these last two categories are flavokavins that may be the source of the yellow skin condition discoloration seen in chronic kava users.⁷

Vincent Lebot later categorized six major kavalactones (kavain, dilrydrokavain, yangonin, dimethoxyyangonin, methysticin, and dihydromethysticin) and nine minor ones, all pharmacologically active. The proportions of these kavalactones vary widely in the different cultivars, grown for human consumption, creating a unique "cocktail" for each cultivar.⁸ Content is also affected by such factors as the age of the plant and specific environmental factors, such as where and how it is grown, the soil conditions, climate, harvesting, drying, and processing methods. Although they were ignorant of modem chemistry and genetics, the Pacific Islanders who first domesticated kava cultivated different varieties for specific purposes, exemplifying an interesting interaction between the human and plant worlds.

Some kava varieties were meant for everyday use by the common folk, and others were reserved for highranking chiefs and princes or were used only for special ceremonies. Some were particularly mild, while one type, "two-day kava," was notorious for its potency and long-lasting effects. For the best psychoactive effect, high kavain and low dihydromethysticin is preferred, since kavain and dilrydrokavain pass the blood-brain barrier most easily. That is, they are absorbed more readily from the bloodstream into the brain.

Kavain and dihydroyangonin predominate in the rootstalk, while dihydrokavain and dihydromethysticin, predominate in the stalks and leaves. Animal studies have shown that dihydromethysticin and dihydrokavain have sleep inducing, anticonvulsant, and muscle-relaxant properties. Some herbal companies are marketing kava extracts made from the aboveground portions of the plant, claiming that the leaf and stem-based products can deliver kava's muscle relaxing effects without producing intoxication. On the other hand, these components are similar to those found in Piper methysticum's wild cousin, Piper wichamanii, and both are often associated with nausea and headaches.

Because of the variability in kavalactone composition and overall activity, testing with high-performance liquid chromatography (HPLC or at least, thin layer chromatography (TLC), is important to ensure the quality of the material sold as bulk herb or finished product.^{9, 10}

How Does It Work?

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Much research on the basics of kava chemistry and how it acts on a living body has already been done. Many of these studies have used laboratory animals, a subject that may be troubling for some. So, without passing judgment on the ethics of the tests themselves, following are some of the findings.

Actions on the Nervous System

Kavalactones have been shown to relieve anxiety and pain and to relax muscles in laboratory animals. An underlying question is the seeming paradox of its actions; it relaxes without sedating at lower doses, while higher doses sedate but in a different way from other known sedatives.

Antianxiety Effects

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Early studies suggested that kava affects the nervous system through a reduction of activity in the spinal part of the nervous system rather than in the higher centers of the brain.¹¹ Later studies show that the limbic system, or emotional center, is also involved. Understanding this effect calls for a brief lesson in brain anatomy and function.

The central nervous system is comprised of the brain, the spinal cord of nerves that carry messages to and from the brain, and the peripheral nerves that connect these to various parts of the body. The brain itself may be divided into three parts based on levels of evolution. The newest part, in evolutionary terms, is the neocortical part, the site of higher thought functions. Next is the limbic system, the emotional control center-which contains the following:

• The pituitary or master gland

• The amygdala, which is the center for registering fear and anger

The hypothalamus, which mediates the stress response as discussed in Chapter 2

Last is the most primitive level-comprised of the brain stem and reticular formation-which joins the brain to the spinal cord. This is the auto-pilot of the brain, governing the basic vital functions such as breathing, heart rate, and digestion.

The effects of drugs on the nervous system will vary according to the target areas. The question is: Where and how does kava work on the nervous system? We do have some idea, although more research is needed for a complete understanding. Besides this anatomical map, we also know that the chemical messengers of the brain-such as neurotransmitters, endorphins, and neurohormones-act in many different locations of the brain and the body (for details, see Candace Pert's Molecules of Emotion). ¹² As in many other fields, the current move is toward a "systems" rather than "linear" way of observation and analysis. All that said, anatomically based research has given us a great deal of valuable information.

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Kava appears to work on the body and brain in a manner different from all known pharmaceuticals that produce sedation and muscle relaxation. For one, kava does not appear to bind to the brain's opiate receptors, meaning that it reduces pain in a manner unrelated to that of morphine and other opiates, or even aspirin. Nor are these pain-relieving effects due to its sedating and muscle-relaxing effects.¹³

A 1991 EEG study showed that kava acted on the limbic system and primarily on the amygdala, the seat of the emotions. This may explain how it can promote sleep even in the absence of sedation. This would also explain the pleasant feelings associated with its use, as feelings of fear and anger are subdued.¹⁴

Effects on GABA, the "Valium" Receptor

GABA, or gamma-aminobutyric acid, is a naturally occurring, calming amino acid. Its plentiful receptors in the brain are the site of action of the benzodiazepines. We might expect that since the actions of kava are similar to the benzodiazepines, it would bind to these receptors. Earlier animal studies, however, indicated that kavalactones bind only weakly, if at all, to these receptors.¹⁵

Later research shows that kavapyrones do mediate sedative effects by way of GABA-receptor binding, with the hippocampus and amygdala showing the highest levels of enhancement. These effects were due to an increase in the number of GABA binding sites rather than to a change in affinity. The authors also observed that when kava was mixed with a barbiturate, kava potentiated its sedating effects. They suggest that the previous study might have seen little effect on GABA:s binding activity for a number of reasons, including: 1) the previous authors looked at areas atypical for kavapyrone effect (frontal cortex and cerebellum) as opposed to the usual target brain centers for its actions (hippocampus, amygdala, and medulla oblongata); 2) only two kavapyrone concentrations (100 M and I mm) were used; 3) investigators used pure compounds of methysticin, dihydromethysticin, kavain, and dihydrokavain rather than a whole extract which more closely estimates its pharmacological effect in vivo. ¹⁶

Muscle-Relaxing, Analgesic, and Anticonvulsant Effects

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The kavalactones are non-sedating muscle relaxants. Moreover, these effects are on both skeletal (striated, voluntary) muscle and smooth or involuntary muscle, such as that of the heart, lungs, and digestive system.

Kavalactones also have strong anticonvulsant effects, as seen in studies of rats pretreated with strychnine, which caused them to convulse. In addition, muscle contractions in isolated smooth muscle in rats also were inhibited by the pyrones. Its analgesic effect is superior to aspirin's, but less marked than that of morphine. ^17,18

In a significant 1982 study, YN. Singh studied the effects of kava. in the muscles and nerve tissue of mice and frogs.¹⁹ His study found that kava differed from other antianxiety drugs by causing a direct action on muscle contractibility, instead of by inhibiting neuromuscular transmission. This makes kava more closely related to local anesthetics in its physiological effects (as anyone who's ever tasted the stuff can attest), and helps explain why very high doses can cause ataxia and temporary paralysis in the lower limbs without loss in consciousness. This, however, was an "in vitro" study; that is, done on a tissue preparation, which doesn't mean it is necessarily a muscle relaxant when taken orally. Kavain substantially inhibited the contractile response in guinea pig ileum (gut) tissues, further confirming kava's relaxant properties on smooth muscle, i.e., the "involuntary" muscles of the gut, heart, and other organs. However, the kavain had no effect on the ileum strips which were subjected to caffeine-induced contractions. The final results suggest that kavain may act in a non-specific way on the smooth muscle membrane. Also, a potential antipathy between kavain and caffeine is suggested. This might mean that you should avoid caffeine if you want to enjoy the full relaxant effects of kava. On the other hand, such conclusions may be stretching it-from caffeine-treated ileum to oral kava and java is a long way.²⁰ Kavalactones inhibit convulsions caused by strychnine, electroshock, and pentylenetetrazole in animals. Here, as in other studies, the authors note that multiple constituents of Piper methysticum have an additive or synergistic effect compared to the individual kavalactones. Peripherally, kavalactones also produce local anesthesia similar to that of procaine. The analgesia of kava is not reversed by "naloxone," a chemical that blocks the action of narcotics. This indicates that the mode of action of kava's pain-killing effects differs from that of the narcotics, such as morphine.²¹. A 1995 rat brain study provides further clues as to the physical mechanisms of kava's relaxation effects. It showed that kavain affects transmission of electrical impulse conduction by inhibition of voltage-dependant sodium channels, a common target of anti-epileptic drugs.²²

The influence of kavain on veratridine-stimulated increases in intrasynaptasomal Na+ concentrations of rat cerebrocortical synaptosomes was investigated.

A recent report suggests that kavain and/or methysticin suppress release of the excitatory amino acid neurotransmitter glutamate, leading to a calming effect.²³

Similar to the anticonvulsant drug memantine, in rodent experiments, methysticin and dihydromethysticin protected the brain cells against damage due to lack of blood supply. It had a similar protective effect on test-tube tissue preparations deprived of oxygen. The effect appears to be by direct action on the neurons.²⁴ Not surprisingly, the effectiveness of whole root extracts appears to be greater than that of isolated kavalactones.²⁵ A 1988 study also found that the kava resin was more effective in animal studies than the individual constituents.²⁶

Conclusion

Science has far more to learn about the mechanisms of kava's action. One consistent finding is that kava worked best as a whole extract. These discoveries in turn may shed new light on the complex interactions between the human body and brain, and afford new, less toxic opportunities for healing. Kava is a safe, effective, and natural treatment for stress, anxiety, and insomnia, as well as a host of other physical and psychological ailments. In the next chapter, we will describe kava's clinical uses and the research that backs it up.

References

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1. Lebot, Vincent, Merlin, Mark, and Lindstrom, Lamont, Kava: The Pacific Elixir. Rochester, VT: Healing Arts Press, (1997).

2. Van Veen, A.G., "Isolation and Constitution of the Narcotic Substance from Kawa Kawa" Receuil des Travaux Chimiques de Pays-Bas (1939): 58: 521-527.

3. Steinmetz, E.F., Kava Kava: Famous Drug Plant of the South Sea Islands. San Francisco, CA: Level Press, (1960, 1961).

4. See note I above.

5. Molts, M.W., et al., "A Chemical and Pharmacological Investigation of Piper Methysticurn Forst" J Me Pharm Chem (1959) 1: 95-103.

6. Cheng, D., Lidgard, R.O., Duffield, P.H., Duffield, A.M., and Brophy, JJ., Biomedical Mass Spectrometry Unit, University of New South Wales, Kensington, Australia.

7. Shulgin, A., The Narcotic Pepper-The Chemistry and Pharmacology of Piper Methsticum and Related Species. Bulletin on Narcotics, (April-June 1973): 25: 59-74.

8. See note I above.

9. Duve R.N., Gas-Liquid Chromatographic Determination Of Major Constituents of Piper Methysticurn Analyst. (1981): 106: 160-165.

10. Smith, et al., "High-Performance Liquid Chromatography of Kava Lactones" Journal of Chromatography (1984): 283: 303-308.

11. See note 3 above.

12. Pert, Candace, Molecules of Emotion. New York, NY. Scribner, (1997).

13. Jamieson, D.D. and Duffield, P.H., "The Antinociceptive Action of Kava Components in Mice" Clinical and Experimental Pharmacology and Physiology (1990): 17:495-508.

14. Holm, E., et al., "Studies on the Profile of the Neurophysiological Effects of D,L-kavain: Cerebral Sites of Action and Sleep-Wakefulness-Rhythm in Animals" Arzneim Forsch (1991): 41: 673-83.

15. Davies, L., Drew, C., Duffield, P., andjamieson, D., "Kavapyrones and Resin: Studies on GABA a, GABA b and Benzodiazepine Receptor Sites in Rodent Brain" Pharmacology and Toxicology (1992): 71(2): 120-126.

16. Jussofie, A., Schmiz, A., Hiemke, C., "Kavapyrone Enriched Extract from Piper Methysticum as Modulator of the GABA Binding Site in Different Regions of Rat Brain" Psychopharmacology (1994): 469-474.

17. Meyer, HJ., and Kretzchmar, R., Klin Wschr (1966): 44, 902.

18. Meyer, HJ., "Pharmakologie der Wirksamen Prinzipien DES Kawa-Rhizoms" Archives Internationales de Pharmacodynamie (1962): 138: 505-536.

19. Singh, Y.N., "Effects of Kava on Neuromuscular Transmission and Muscle Contractility" Journal of Ethnopharmacology (1983): 7: 267-276.

20. Seitz, U., Ameri, A., Pelzer, H., et al., "Relaxation of Evoked Contractile Activity of Isolated Guinea-Pig Ileum by (+/-)-Kavain" Planta Med (1997): 63: 303-306.

21. See note 13 above.

22. Gleitz,J., Beile, A., and Peters, T., "(+/-)-Kavain Inhibits Veratridine-Activated Voltage-Dependent Na(+)Channels in Synaptosomes Prepared from Rat Cerebral Cortex" Neuropharmacology (September 1995): 34(9): 1133-1138.

23. Magura E.I., et al., "Kava Extract Ingredients, (+)-Methysticin and (+/-)Kavain Inhibit Voltage-Operated Na(+)-Channels in Rat CAI Hippocampal Neurons" Neuroscience (1997): 81(2): 345-351.

24. Backhaus, C., Krigelstein,J., "Neuroprotective Activity of Kava Extract (Piper Methysticum) and Its Methysticin Constituents In Vivo and In Vitro" Pharmacology of Cerebral Ischemia; EurJPharmac (1992): 215: 265-269.

25. See note 4 above.

26. Keledjianj., Duffield, P.H.,Jamieson, D.D., et al., "Uptake into Mouse Brain of Four Compounds Present in the Psychoactive Beverage Kava"JPharm Sci (1988):77:1003-1006.