Kava, an intoxicating beverage prepared from the pepper plant Piper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAA binding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X-100, suggesting that lipid soluble components were involved. No effects were observed on GABAB binding sites in rat brain membranes in vitro. Kava resin and pyrones exerted some weak effects on benzodiazepine binding in vitro but this did not correlate with pharmacological activity. In addition, in ex vivo studies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by greater than 95%. Similar lack of activity was observed in in vivo binding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine-receptor ligand [3H]Ro15-1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding sites.

1. The antinociceptive properties of the aqueous extract of the intoxicating beverage kava, and of the lipid soluble extract (kava resin) were tested in mice, by the tail immersion and abdominal constriction methods. Both extracts showed analgesic effects in both tests. 2. Eight purified pyrones from the lipid soluble extract were also tested for activity in the tail immersion test, and kawain, dihydrokawain, methysticin and dihydromethysticin were found to be very effective in producing analgesia. Using the tail immersion test the time course of action of the extracts of the four effective pyrones of kava were studied. 3. Naloxone, in doses which inhibited morphine-induced analgesia in both tests, was completely ineffective in reversing the antinociceptive activities of the kava extracts, showing that analgesia produced by kava occurs via non-opiate pathways.

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