Abstract
Kava is a psychoactive drink prepared from the root of the plant Piper methysticum Forst. f. that has been used for millennia in the Pacific islands. The main pharmacological effects of kava occur through the actions of a lipid soluble group of compounds known as kava lactones, that are also referred to as kava pyrones [1]. Kava lactones will be the preferred terminology throughout this review. Kava lactones have muscle relaxant, local anaesthetic, anxiolytic and anticonvulsive properties [1–4]. Kava can be consumed by drinking an infusion of either the dried powdered parts of the plant or the fresh ground root, or by swallowing the product of a commercial extraction process [5]. In small doses, kava acts as a muscle relaxant [1]. Larger doses of kava can produce ataxia, intoxication, sedation, analgesia and paralysis of the extremities without loss of consciousness, and these effects are completely recoverable [6]. Kava is native to, and has been used ceremonially for thousands of years in the Pacific Island region. The consumption of kava is part of everyday life on islands such as Fiji, Tonga and Vanuatu and occurs during important events or social and relaxing gatherings [7] and in secular drinking [8, 9]. The beverage is prepared within a ‘kava circle’ of people gathering to drink, in rituals that vary somewhat across the Pacific, yet the styles and tempos are similar [5]. In the early 1980s kava was, in part, introduced as a substitute for alcohol among Aboriginal populations in the north of Australia [6, 10] where apparently heavy consumption has since caused considerable debate about its health effects [5, 11, 12]. Due to its muscle relaxant properties, kava or kava derivatives are increasingly popular in European and American markets, in capsule form, for the treatment of anxiety and tension [4, 13, 14]. Despite the widespread and often heavy use of kava, little is known of its psychopharmacological actions. To investigate the neurobehavioural consequences of substance use, it is necessary to consider the pharmacological effects of the substance, the psychological characteristics of its consumers, and the social and physical environment in which it is used [15].
Cultural aspects of kava
The mood-altering effects of kava lactones have been described as hypnotic [16] and different from the deep changes in the experience of reality brought on by the use of more widely recognized psychotomimetics (such as THC or LSD). More than 50 years of anthropological studies in Pacific island societies document the significance of kava in the facilitation of ritual practices, invocation of the supernatural, normative behaviours and social processes [17–20]. Kava is symbolically significant in these regions and since Cook's apotheosis as the Hawaiian god Lono, and his subsequent fall [21], kava has held an important place in the affirmation of Pacific island culture and independence [5].
In Australia, kava was brought by Arnhem Land Aboriginal people to their communities in 1982 [22]. In these societies, traditional cultural and religious practices persist and remain a significant part of everyday life [23]. These practices include mortuary rites and contemporary versions of ritual healing and killing [24, 25]. While not part of traditional systems, many Aboriginal users recognize that the psychopharmacological qualities of kava facilitate the peaceful negotiation of stressful and difficult issues surrounding these kinds of social interaction [Clough A: unpublished observation]. The contrasting impact of alcohol on community amenity has been reported previously [6, 26]. These brief examples indicate the difficulty in using the observed or reported psychological effects of kava in different cultural groups or social settings as clues to the psychopharmacological basis for the action of kava.
Kava preparations
It is difficult to compare the psychopharmacological effects of kava between the published studies as these vary considerably in methods of preparation, means of ingestion, and the potency and quantity of dosages actually consumed by participants. Furthermore, the potency of kava can vary according to the genetics and age of the plant, the soil in which it was grown, the size of the root and the method of preparation [5, 7]. Although there are variations in traditional preparation procedures, most involve soaking the pulverized root in a bowl of water and filtering the mix to produce the brew in a communal bowl. The kava is then drunk from a cup, sometimes a coconut shell, and shared amongst all members of the kava gathering. In parts of Vanuatu and Papua New Ginea today, and in other regions across the Pacific in the past, the root is pulverized through mastication [5]. The resultant mix of kava and saliva is thought to promote narcotic-like effects such as visual and auditory changes, euphoria, loss of appetite and loss of fatigue [20]. This contrasts the more socially relaxed state that occurs when kava is prepared using the ‘Fijian method’ that involves pounding the root rather than chewing it [27]. In Arnhem Land, dried powdered kava imported from Fiji or Tonga, is mixed with water and consumed in a similar style [28]. Thus, potency can vary according to subtleties in the preparation procedure making it difficult to accurately establish the content of kava lactones.
The relaxant effects of kava observed in its social use have initiated more controlled clinical studies to determine the efficacy of kava for reducing anxiety. These studies typically use enriched capsules manufactured under strict guidelines to contain 70% kava lactones, such as the European product WS1490 [29]. These also include Laitan or Kavasporal from Germany, Potter's Antigian tablets from the United Kingdom, Viocava from Switzerland and Mosaro from Austria [30]. In contrast, products available to the general population that are manufactured in the United States contain between 30% and 55% kava lactones [13, 29]. For clinical trials, the usual therapeutic dose is 140–250 mg/day of kava lactones [29]. This dose is small when compared to the amounts ingested in the social or recreational consumption of kava. For example, a recent report estimated that quantities of kava consumed in Australian Aboriginal communities are comparable to those in the Pacific islands, with heavy consumers drinking at least 610 g/week of kava powder [28]. With the estimated lactone content in kava powder averaging 12.5% [31], this equates to approximately 76 g lactones per week [28] or more than 50 times the recommended therapeutic dose. Thus it is important to determine as accurately as possible, the lactone content when comparing these studies. This is more difficult when the crude kava root is used, as the lactone content depends on the region in which it was grown and the social circumstances that surround the mixing of the brew.
Neuropsychiatric and cognitive effects of kava
In humans, kava disrupts motor and coordination systems and has anaesthetic and anxiolytic effects [4, 7]. Additional anticonvulsive effects have been reported and, in the 1960s, kava was used to treat patients with epilepsy [2]. The neuropsychiatric observations following kava use are shown in Table 1. Considerable research has been devoted to establishing the efficacy of kava as an anxiolytic agent. Pittler and Ernst [4] conducted a comprehensive review of 14 double-blind randomly controlled studies, and performed a metaanalysis of those that used the Hamilton Rating Scale for Anxiety. This analysis showed that for the individuals involved, 51 percent of whom met a DSMIII-R [32] diagnosis of anxiety disorder, kava demonstrated superiority over placebo in treating anxiety and tension of a non-psychotic origin. Thus the anxiolytic effects of kava are well-established. It is important to consider drug interactions in the therapeutic use of kava, as its combination with alcohol increased the subjective experiences and performance deficits that occurred when alcohol was administered alone [33] and its combination with benzodiazepine resulted in coma [34]. Although psychotic experiences induced by kava use are reported in the anthropological literature [7, 20, 31], it is important to note that inexplicable visual and auditory changes are not uncommon within these same traditional practices in which the kava was consumed. Of a greater concern are the few cases of sudden involuntary choreoathetosis that occurred following kava consumption [30, 35]. Further investigation is necessary to identify the risk-factors for these severe motor responses.
Neuropsychiatric observations following kava consumption
The effect that kava has on cognitive processes is unclear. A review of the available literature reveals that very few studies have investigated the effect that the acute (n = 6) or chronic (n = 1) use of kava has on cognitive function. The results from these studies are shown in Table 2. In general, studies of the cognitive consequences of kava use involve a variety of kava preparations and mostly use very poor techniques to control dosage levels. Consequently, there are no specific findings of cognitive effects with acute kava use in humans and there also is no understanding of the cognitive consequences of long-term kava use.
Studies of the cognitive effects when humans ingest kava
Chemistry and pharmacology
Kava lactones are characterized by a 5,6-dihydro-α-pyrone ring [36]. When extracted from crude kava resin, the lipid-soluble fraction is high in lactone content and when isolated properly, the water-soluble fraction is considered to be completely lactone free [37]. The water soluble fraction of kava was inactive when given orally in mice and rats, and caused sedation without ataxia or loss of muscle control when administered peritoneally [37]. The potency of kava is attributed predominantly to six lactones in the lipid-soluble fraction. These are kawain, dihydrokawain, methysticin, dihydromethysticin, desmethoxyyangonin and yangonin [1, 3, 36].
Animal studies show that kawain and dihydrokawain are absorbed rapidly into the brain and gastrointestinal tract, with peak concentration levels occurring within 10 min of administration, followed by a rapid decay [1, 3, 38, 39]. The same studies show that brain absorption of methysticin, dihydromethysticin, desmethoxyyangonin and yangonin occurs more slowly, reaching maximum levels within 30–50 min, followed by a slower decay. When animal synaptosomes were treated with crude kava resin, concentration levels of the individual lactones were increased compared to when they were administered individually, suggesting a synergistic effect for multiple lactones [38–41]. Thus to accurately monitor the pharmacological effects of kava, it is necessary to determine proportionate quantities of the individual constituents.
Neurophysiological models of kava
Animal studies have established that kava lactones act to directly alter neuronal excitability through voltagedependent ion (probably Na +) channels, causing a release of muscle tension [42–46]. Inhibition of voltageoperated ion channels can account for the anaesthetic and anticonvulsive pharmacological actions of kava lactones, although it is difficult to link to the psychotropic effects of kava that have been observed in humans. Non–specific interactions have been demonstrated between kava lactones and most neurotransmitter systems. For example, kava lactones were associated with the modulation of both serotonergic [41, 47–49] and glutamatergic systems [50, 51] and also demonstrated dopamine antagonistic properties [37, 52, 53]. In addition, the administration of kava lactones enhanced the binding capacity of GABA receptors [54–56]. However, unlike sedatives such as benzodiazepines, barbiturates and anaesthetic steroids, kava lactones do not appear to act on the GABA receptor complexes directly [55, 56]. Animal studies also provide considerable evidence that kava lactones are most active in the limbic structures, including the amygdala complex, the caudate nucleus and hippocampal regions [54–57]. Moreover, synthetic kavain was capable of modulating excitatory signals in the hippocampus, although there was no alteration on the synaptic plasticity [46] that underlies learning and memory [58]. These studies indicate that while kava clearly disrupts the neurotransmitter systems that underlie behaviour, there is no indication of specific changes in response to kava.
Conclusion
In the acute stages, kava causes the release of muscle tension and is consequently used to induce relaxation and anaesthesia. Less frequently, kava has induced sudden choreoathetosis and, within traditional practices, has been associated with psychotic experiences. There are no obvious cognitive changes with kava use. Despite the consumption of kava in various forms in many countries around the world and its classification as a ‘world drug’ [5], there are no comprehensive models to explain the cognitive or neuropsychiatric consequences of the chronic administration of kava. A systematic neuropsychiatric investigation is therefore necessary to identify the neurological and cognitive processes that are affected by the chronic use of kava.