Pharmacological Toxicological Effects 51 Neurological Effects

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.

A randomized, 25-week, placebo-controlled study by Volz and Kieser showed a significant benefit from the use of kava-kava extract WS 1490 over placebo in treating anxiety disorders of nonpsychotic origin. The study included 101 patients suffering from agoraphobia, specific phobia, generalized anxiety disorder, or adjustment disorder with anxiety—as per the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised—who were randomized to placebo or WS 1490 containing 90-100 mg dry extract per capsule three times daily. The main outcome criterion, the patients' score on the Hamilton Anxiety Scale, was significantly better (p < 0.001) for the WS 1490 patients compared to placebo at 24 weeks. Few adverse effects were judged to be related or possibly related to kava administration. Two patients in the WS 1490 group experienced stomach upset, two noted vertigo, and one experienced vertigo and palpitations. These results support use of kava as an alternative to antidepressants and benzodiazepines (10).

Pittler and Ernst (11) conducted a review of double-blind, randomized, placebo-controlled trials of kava extract monotherapy for treatment of anxiety. They reviewed 14 such studies and three were determined suitable for metaanalysis. They concluded that kava extract was not only relatively safe but superior to placebo in the treatment of anxiety.

Another study compared the cognitive effects of this same kava extract at a dose of 200 mg three times daily for 5 days to oxazepam 15 mg, followed by 75 mg on the experimental day (12). The results suggest that kava is less likely to affect cognitive function than oxazepam, but the oxazepam dosing regimen used was not typical of that seen in practice. Nevertheless, kava is purported to promote relaxation and sleep without dampening alertness, causing heavy sedation, or causing a "hangover" effect the morning after consumption (13). The limbic structures of the brain might represent the site of action of kava, explaining its ability to promote relaxation and sleep without cognitive effects (14).

The mechanism of the anxiolytic effect of kava is unclear. Studies of kava's effects in vitro, in vivo, and ex vivo report conflicting results in regard to kava's effects on benzodiazepine or y-aminobutyric acid (GABA) receptors (5,14,15). This disparity may be explained by differences in GABA receptor subtypes among the different regions of the brain studied (14). It is thought that kavapyrones elicit a tranquilizing effect by enhancing GABA binding in the amygdala, but do not act directly as agonists at GABA receptors (14).

One study has suggested that a nonstereoselective inhibition of [3H]noradrenaline uptake may be responsible for, or at least contribute to, kava's anxiolytic effect (16). This investigation tested the effects of naturally occurring (+)-kavain, (+)-methysticin, and a synthetic racemic mixture of kavain on synaptosomes from the cerebral cortex and hippocampus of rat brains.

Both forms of kavain inhibited [3H]noradrenaline uptake more than methysticin, but the concentrations necessary to achieve this effect were approx 10 times higher than those in mouse brains after a dose of kavain high enough to cause significant sedation. This indicates that inhibition of noradrenaline uptake is probably only part of the psychotropic effects of kava. No effects were seen on the uptake of [3H]serotonin. A subsequent study (17) in rats showed that (+)-kavain and other kavapyrones affect serotonin levels in the mesolimbic area. The authors postulated that this effect could explain kava's hypnotic action. Dopamine levels in the nucleus accumbens were decreased by yangonin and low-dose (+)-kavain, but were increased by higher doses of (+)-kavain and desmethoxyyangonin. The investigators attributed kava's anxiolytic and euphoric effects to its action on mesolimbic dopaminergic pathways.

A study conducted in Germany indicates that kava may have neuroprotective properties, primarily owing to its constituent methysticum and dihydromethysticum (18). The investigators studied the effects of kava extract WS 1490 and the individual pyrones kavain, dihydrokavain, methysticin, dihydromethysticin, and yangonin on the size of infarction in mouse brains. The extract as well as the individual pyrones methysticin and dihydromethysticin showed significant reductions in infarct area similar to those produced by memantine, an anticonvulsive agent known to have neuroprotective qualities (18).

Kava lactones are also centrally acting skeletal muscle relaxants (19). A study by Kretzschmar et al. compared the antagonistic effects of kavain, dihydrokavain, methysticin, and dihydromethysticin to those of mephenesin and phenobarbital in preventing convulsions and death caused by strychnine. All the kava pyrones showed an antagonistic effect, with methysticin being the most potent; however, kavain and dihydrokavain doses required to produce an effect approached the toxic range (20). In contrast to mephenesin and phenobarbital, all the pyrones tested protected against strychnine at doses up to 5 mg/kg without causing impairment of motor function. Gleitz et al., in their studies on the antiseizure properties of kavain, conclude that the inhibition of voltage-dependent Ca++ and Na+ channels by kavain resembles that of local anesthetics. They suggest kava pyrone accumulation in neuronal cell membranes may explain the antieleptic affects of kava (21).

Kava also produces analgesic effects that appear to be mediated through a nonopiate pathway. A study conducted by Jamieson and Duffield compared the activity of an aqueous and a lipid extract of kava as well as eight purified pyrones on two tests for antinociception in mice. Both the aqueous and lipid extracts were effective analgesics, as were four of the eight purified pyrones (lactones): methysticin, dihydromethysticin, kavain, and dihydrokavain (22). In hopes of discovering the mechanism of analgesia, the investigators attempted to antagonize the effects of kava with naloxone, a known inhibitor of opiate-

mediated pathways of analgesia. Naloxone failed to inhibit kava's effects at doses high enough to inhibit the action of morphine, indicating that kava works through a nonopiate pathway to produce analgesia.

In humans, kava is reported to produce a mild euphoria characterized by happiness, fluent and lively speech, and increased sensibility to sounds (1). It has also been reported to cause visual changes such as reduced near-point accommodation and convergence, increase in pupil diameter, and oculomotor balance disturbances (23). It might even have an antipyretic effect (19).

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).

Kava's effects on the peripheral nervous system are limited to a local anesthetic effect, resulting in numbness in the mouth if kava is chewed (1). Lipid-soluble kava extract, or resin, is also capable of causing anesthesia of the oral mucosa, whereas the water-soluble fraction is not (9).

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