Kava resin

Jamieson DD, Duffield PH. (1990). Positive interaction of ethanol and kava resin in mice. Clin Exp Pharmacol Physiol. 17(7) 509-14. 

Although the structures of a series of 6-substituted 4-methoxypyran-2-ones have been established by chemical means, their alternative formulation as derivatives of 2-methoxy-pyran-4-ones was mainly excluded on the basis of an absorption at 1733 cm-1 attributable to the pyran-2-one system (59JA2427). This report concludes that pyran-2-ones exhibit their first carbonyl band at ca. 1725 cm-1, whereas pyran-4-ones absorb at ca. 1667 cm-1. Similarly, absorption at 1724 cm-1 indicated a pyran-2-one structure for yangonin (98), the major constituent of kava resin, and this has been confirmed by an unambiguous synthesis. Pseudoyangonin (99) absorbs at 1667 cm-1, characteristic of a pyran-4-one (60JCS502). Comparison of the spectra of some constituents of the rosewoods with that of yangonin established them as pyran-2-ones. The products from the reaction of malonyl chloride with some 1,3-diketones were identified in part by IR spectroscopy. 

The neurological effects of kava are attributed to a group of substituted dihydropyrones called kava lactones (1). The main bioactive constituents include yangonin, desmethoxyyangonin, 11-methoxyyangonin, kavain (kawain), dihydrokavain, methysticin, dihydromethysticin, and 5,6-dehydromethysticin (8). It is believed that the components present in the lipid-soluble kava extract, or kava resin, are responsible for the central nervous system (CNS) activities of kava including sedation, hypnosis, analgesia, and muscle relaxation (9). Aqueous kava extract was not active orally in mice or rats. 

Tolerance and development of physical dependence by laboratory animals has been investigated for both the aqueous kava extract and kava resin, which contains the pharmacologically active pyrones. Duffield and Jamieson reported tolerance to be evident in mice only after parenteral administration of the aqueous kava extract, but not when given orally. Likewise, tolerance was not seen after daily dosing with kava resin over a 7-week period of time. They concluded tolerance to kava resin was not readily demonstrable (24). 

Other substances isolated from the kava resin include cinnamylidine acetone and... 

Duffield, A.M. and Lidgard, R.O. (1986) Analysis of kava resin by gas chromatography and electron impact and methane negative ion chemical ionization mass spectrometry. New trace constituents of kava resin. Biomedical Environmental Mass Spectrometry, 13,621-626. 

The writhing test was used to determine chemical-induced visceral pain sensitivity. Mice were injected with acetic acid (0.1 ml/kg of 0.8% acetic acid) and the number of writhes with or without pretreatment with kava resin (200 mg/kg po) or aqueous kava extract (200 mg/kg ip) was recorded. The number of pain-dependant reactions per minute was significantly (P < 0.001) reduced, from 22.9 to 11.3 with kava resin and from 22.7 to 3.2 with aqueous kava, indicating a pronounced analgesic effect with both preparations. The authors also raised the possibility that the muscle-relaxant and sedative effects of the extracts might have influenced the analgesic and local anesthetic actions could not be excluded (Jamieson and Duffield, 1990a). 

Spontaneous motility or apomorphine-induced and amphetamine-induced motility in mice were significantly reduced P < 0.005) by aqueous kava extract (62.5-250 mg/kg) and kava resin (120—250mg/kg). In addition, the two preparations produced a significant reversal (f < 0.001) of tetrabenazine-induced ptosis (Duffield etal., 1989a,b). However, the kava elfects were smaller compared to those produced by the standard antipsychotic drugs chlorpromazine and haloperidol. 

Additionally, the kava resin and purified dihydromethysticin, when tested for anticonvulsant activity in humans, provided some control of grand mal seizures in one trial (Pfeiffer etal., 1979). However, other workers (Jamieson etal., 1989) found that the anticonvulsant effect of the aqueous extract against strychnine was very slight. From this and other observations it appears that many of the pharmacological effects of kava appear to be mainly due to the activity of the compounds present in the lipid soluble resin fraction. 

In acute toxicity studies, the LDjq of kava resin given by ip injection to mice, rats, and rabbits ranged from 300 to 400mg/kg. With oral administration, the LDjq in mice was 920mg/kg for dihydrokavain and 1050mg/kg for dihydromethysticin (Meyer, 1962). However, doses of 50mg/kg of dihydromethysticin, administered three times a week for three months to rats, produced no evidence of chronic toxicity (Meyer, 1966). 

Kava resin administered orally to mice produced no loss of righting reflex in doses less than 200mg/kg. Doses between 250 and 300mg/kg produced short-term loss of... 

Foo and Lemon (1997) assessed the acute effects of kava, alone and in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance. This was a placebo-controlled study, with ten subjects in each of four conditions placebo, kava, alcohol, and kava plus alcohol. The placebo was pure fruit juice and fruit juice was added to kava and alcohol as well to maintain double blind conditions. A battery of tests was included to measure outcomes, including subjective measures of impairment and intoxication, and visual-motor and cognitive performance. These measures were performed before (time = 0), and 30, 60 and 90 minutes after consumption of the drinks. Each test trial took about 12 minutes. Kava consumption produced no significant effects on perceived or measured competence, while alcohol caused motor and cognitive impairments. However, when kava and alcohol were combined, kava potentiated both the perceived and measured impairment produced by the alcohol alone. This potentiation effect is in accord with the findings of Jamieson and Duffield (1990) on the positive interaction of ethanol and kava resin in mice. 

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