Skip to main content
Log in

Extracts of kava (Piper methysticum) induce acute anxiolytic-like behavioral changes in mice

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Recent clinical trials suggest that kava has therapeutic value for the treatment of anxiety. Demonstration of kava's anxiolytic effects in animals under controlled conditions would provide additional support for its clinical potential as an anxiolytic and would facilitate investigation of its mechanism(s) of action.

Objectives

This study systematically characterized the acute dosage-dependent anxiolytic and sedative effects of kava extract in well established quantitative murine behavioral assays and compared kava- and diazepam-induced behavioral changes.

Methods

Various doses of an ethanolic extract of kava root or diazepam were administered intraperitoneally to BALB/cByJ inbred mice. Behavioral changes were measured in the mirrored chamber avoidance assay and elevated plus-maze assay. Reduced latency to enter and increased time spent in a normally avoided environment operationally defined anxiolysis. Sedation was defined by a significant decrease in locomotor activity in a circular arena.

Results

Kava extract produced statistically significant dose-dependent anxiolytic-like behavioral changes in both assays of anxiolysis. ED50 values for kava-induced increases in time spent inside the mirrored chamber and on the open arms of the plus maze were 125 mg/kg and 88 mg/kg, respectively. Kava extract also caused a profound decrease in locomotor activity (ED50 of 172 mg/kg). Flumazenil, a competitive benzodiazepine receptor antagonist, blocked both the anxiolytic and sedative effects of diazepam, but had no effect on kava's behavioral actions.

Conclusions

Kava extracts produce significant murine anxiolytic-like behavioral changes and sedation that are not mediated through the benzodiazepine binding site on the GABAA receptor complex.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A, B.
Fig. 2A, B.
Fig. 3A, B.
Fig. 4.
Fig. 5A, B.

Similar content being viewed by others

References

  • Backhauß C, Krieglstein J (1992) Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol 215:265–269

    CAS  PubMed  Google Scholar 

  • Baum SS, Hill H, Rommelspacher H (1998) Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry 22:1105–1120

    Article  CAS  PubMed  Google Scholar 

  • Boonen G, Häberlein H (1998) Influence of genuine kavapyrone enantiomers on the GABAA binding site. Planta Med 64:504–506

    CAS  PubMed  Google Scholar 

  • Bowers BJ, Collins AC, Tritto T, Wehner JM (2000) Mice lacking PKC gamma exhibit decreased anxiety. Behav Genet 30:111–21

    Article  CAS  PubMed  Google Scholar 

  • Carola V, D'Olimpio F, Brunamonti E, Mangia F, Renzi P (2002) Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav Brain Res 134:49–57

    Article  PubMed  Google Scholar 

  • Cao W, Burkholder T, Wilkins L, Collins AC (1993) A genetic comparison of behavioral actions of ethanol and nicotine in the mirrored chamber. Pharmacol Biochem Behav 45:803–809

    CAS  PubMed  Google Scholar 

  • Crawley JN (1981) Neuropharmacological specificity of a simple animal model for behavioral actions of benzodiazepines. Pharmacol Biochem Behav 15:695–699

    CAS  PubMed  Google Scholar 

  • Darragh A, Lambe R, Kenny M, Brick I, Taaffe W, O'Boyle C (1982) RO 15-1788 antagonizes the central effects of diazepam in man without altering diazepam bioavailability. Br J Clin Pharmacol 14:677–682

    Google Scholar 

  • Davies LP, Drew CA, Duffield P, Johnston GAR, Jameison DD (1992) Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol 71:120–126

    CAS  PubMed  Google Scholar 

  • Dharmaratne HR, Nanayakkara NP, Khan IA (2002) Kavalactones from Piper methysticum, and their 13C NMR spectroscopic analyses. Phytochemistry 59:429–433

    Article  CAS  PubMed  Google Scholar 

  • Dinh LD, Simmen U, Bueter KB, Bueter B, Lundstrom K, Schaffner W (2001) Interaction of various Piper methysticum cultivars with CNS receptors in vitro. Planta Med 67:306–311

    Article  CAS  PubMed  Google Scholar 

  • Duffield AM, Lidgard RO (1986) Analysis of kava resin by gas chromatography and electron impact and methane negative ion chemical ionization mass spectrometry. Biomed Mass Spectrom 13:621–626

    CAS  Google Scholar 

  • Duffield AM, Lidgard RO, Low GK-C (1986) Analysis of the constituents of Piper methysticum by gas chromatography methane chemical ionization mass spectrometry. Biomed Mass Spectrom 13:303–313

    Google Scholar 

  • Duffield PH, Jamieson DD, Duffield AM (1989) Effect of aqueous and lipid-soluble extracts of kava on the conditioned avoidance response in rats. Arch Int Pharmacodyn Ther 301:81–90

    CAS  PubMed  Google Scholar 

  • Feger B, Boonen G, Haberlein H, Kuschinsky K (1998) In vivo microdialysis study of (±)-kavain on veratridine-induced glutamate release. Eur J Pharmacol 347:211–214

    PubMed  Google Scholar 

  • Friese J, Gleitz J (1998) Kavain, dihydrokavain and dihydromethysticin non-competitively inhibit the specific binding of [3H]-batrachotoxinin-A20-α-benzoate to receptor site 2 of voltage-gates Na+ channels. Planta Med 64:458–459

    CAS  PubMed  Google Scholar 

  • Gallup GG Jr (1968) Mirror-image stimulation. Psychol Bull 70:782–793

    PubMed  Google Scholar 

  • Ganzera M, Khan IA (1999) Analytical techniques for determination of lactones in Piper methysticum Forst. Chromatographia 50:649–653

    CAS  Google Scholar 

  • Garrett KM, Niekrasz I, Haque D, Parker KM, Seale TW (1998) Genotypic differences between C57BL/6 and A inbred mice in anxiolytic and sedative actions of diazepam. Behav Genet 28:125–136

    Google Scholar 

  • Gleitz J, Friese J, Beile A, Ameri A, Peters T (1996) Anticonvulsive action of (±)-kavain estimated from its properties on stimulated synaptosomes and Na+ channel receptor sites. Eur J Pharmacol 315:89–97

    Article  CAS  PubMed  Google Scholar 

  • Griebel G, Belzung C, Perrault G, Sanger DJ (2000) Differences in anxiety-related behaviors and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology 148:164–170

    CAS  PubMed  Google Scholar 

  • Handley SL, Mithani S (1984) Effects of alpha-adrenoreceptor agonists and antagonists in a maze exploration model of "fear"-motivated behavior. Naunyn-Schmiedeberg's Arch Pharmacol 327:1–5

    Google Scholar 

  • Houri D (1986) Effects of central acting drugs on the mirror staircase test. Nippon Yaturigaku Zasshi 87:135–142

    CAS  Google Scholar 

  • Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516

    CAS  PubMed  Google Scholar 

  • Jamieson DD, Duffield PH (1990) The antinociceptive actions of kava components in mice. Clin Exp Pharmacol Physiol 17:495–508

    CAS  PubMed  Google Scholar 

  • Jamieson DD, Duffield PH, Cheng D, Duffield AM (1989) Comparison of the central nervous system activity of the aqueous and lipid extract of kava (Piper methysticum). Arch Int Pharmacodyn Ther 301:66–80

    CAS  PubMed  Google Scholar 

  • Jussofie A, Schmiz A, Hiemke C (1994) Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of the brain. Psychopharmacology 116:469–474

    CAS  PubMed  Google Scholar 

  • Kaul PN, Joshi BS (2001) Alternative medicine: Herbal drugs and their critical appraisal—Part II. Prog Drug Res 57:1–75

    CAS  PubMed  Google Scholar 

  • Keledjian J, Duffield PH, Jameison DD, Lidgard RO, Duffield AM (1988) Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 77:1003–1006

    CAS  PubMed  Google Scholar 

  • Keller K, Klohs MW (1963) A review of the chemistry and pharmacology of the constituents of Piper methysticum. Lloydia 26:1–15

    CAS  Google Scholar 

  • Kretzschmar H, Meyer HJ, Teschendorf HJ (1970) Strychnine antagonistic potency of pyrone compounds of the kavaroot (Piper methysticum Forst.). Experientia 26:283–284

    CAS  PubMed  Google Scholar 

  • Lembert EM (1967) Secular use of kava in Tonga. Q J Stud Alcohol 28:328–341

    PubMed  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  PubMed  Google Scholar 

  • Maura EI, Kopanitsa MV, Gleitz J, Peters T, Krishtal OA (1997) Kava extract ingredients, (+)methysticin and (±)kavain inhibit voltage-operated Na+-channels in rat CA1 hippocampal neurons. Neuroscience 81:345–351

    Article  PubMed  Google Scholar 

  • Martin HB, Stofer WD, Eichinger MR (2000) Kavain inhibits murine airway smooth muscle contraction. Planta Med 66:601–606

    Article  CAS  PubMed  Google Scholar 

  • McDowall A, Owen S, Robin AA (1966) A controlled comparison of diazepam and amylobarbitone in anxiety states. Br J Psychiatry 112:629–631

    CAS  PubMed  Google Scholar 

  • Mohler H, Okada T (1977) Benzodiazepine receptor: demonstration in the central nervous system. Science 198:849–851

    PubMed  Google Scholar 

  • National Institutes of Health (1996) Guide for the Care and Use of Laboratory Animals. National Academies Press

  • Montgomery KC (1958) The relation between fear induced by novel; stimulation and exploratory behavior. J Comp Physiol Psychol 48:254–260

    Google Scholar 

  • Norton SA (1998) Herbal medicines in Hawaii from tradition to convention. Hawaii Med J 57:382–385

    CAS  PubMed  Google Scholar 

  • O'Hara MJ, Kinnard WJ, Buckey JP (1965) preliminary characterization of aqueous extracts of Piper methysticum (kava, kava kava). J Pharm Sci 54:1021–1025

    CAS  PubMed  Google Scholar 

  • Patel JB, Martin C, Malick JB (1982) Differential antagonism of the anticonflict effects of typical and atypical anxiolytics. Eur J Pharmacol 86:295–298

    Article  CAS  PubMed  Google Scholar 

  • Pellow S, Chopin P, File SE (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 14:149–167

    CAS  PubMed  Google Scholar 

  • Pittler MH, Ernst E (2000) Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 20:84–89

    Google Scholar 

  • Rex A, Morgenstern E, Fink H (2002) Anxiolytic-like effects of kava-kava in the elevated plus maze test—a comparison with diazepam. Prog Neuropsychopharmacol Biol Psychiatry 26:855–860

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ, Johnson JT (1995) Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol Biochem Behav 52:297–303

    CAS  PubMed  Google Scholar 

  • Schirrmacher K, Busselberg D, Langosch JM, Walden J, Winter U, Bingmann D (1999) Effects of (±)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats. Eur Neuropsychopharmacol 9:171–176

    Article  CAS  PubMed  Google Scholar 

  • Seale TW, Garrett KM (1995) Genotype-dependent heterogeneity in basal activity and benzodiazepine-induced alteration in anxiety-like behaviors. Behav Genet 25:287

    Google Scholar 

  • Seale TW, Niekrasz I, Garrett KM (1996) Anxiolysis by ethanol, diazepam and buspirone in a novel murine behavioral assay. Neuroreport 7:1803–1808

    CAS  PubMed  Google Scholar 

  • Seitz U, Schüle A, Gleitz J (1997) [3H]-Monoamine uptake inhibition properties of kava pyrones. Planta Med 63:548–549

    CAS  PubMed  Google Scholar 

  • Shulgin AT (1973) The narcotic pepper—the chemistry and pharmacology of Piper methysticum and related species. Bull Narc 25:59–74

    CAS  Google Scholar 

  • Singh YN (1992) Kava: an overview. J Ethnopharmacol 37:13–45

    CAS  PubMed  Google Scholar 

  • Smith KK, Ranjith H, Dharmaratne W, Feltenstein MW, Broom SL, Roach JT, Nanyakkara NP, Khan IA, Sufka KJ (2001) Anxiolytic effects of kava extract and kavalactones in the chick social separation-stress paradigm. Psychoparmacology 155:86–90

    Article  CAS  Google Scholar 

  • Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734

    CAS  PubMed  Google Scholar 

  • Toubas PL, Alba KA, Cao W, Seale TW (1990) Latency to enter a mirrored chamber: a novel behavioral assay for anxiolytic agents. Pharmacol Biochem Behav 35:121–126

    Article  CAS  PubMed  Google Scholar 

  • Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1–7

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Presbyterian Health Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kennon M. Garrett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garrett, K.M., Basmadjian, G., Khan, I.A. et al. Extracts of kava (Piper methysticum) induce acute anxiolytic-like behavioral changes in mice. Psychopharmacology 170, 33–41 (2003). https://doi.org/10.1007/s00213-003-1520-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1520-0

Keywords

Navigation