Kavain is a psychoactive compound produced by the pepper plant kava or kava kava (also known as Piper methysticum), which is found to grow in the Pacific Islands. It is the principal kavalactone present in the kava plant roots [1]. For centuries, this plant has been used to prepare "kava," a non-alcoholic psychoactive beverage traditionally consumed during religious rituals [1]. It was also used in traditional medicine for its anxiolytic and sedative effects [2,3]. You can read more about kava as a whole in our dedicated blog here, or you can learn more about its effects on anxiety here. In this article, we'll be focusing more on kavain, the main kavalactone found mostly in the roots of the kava plant.
Kavain’s mechanism of action
Kavapyrones, also known as kavalactones, are a group of lipophilic compounds with similar chemical structures responsible for kava properties [4]. Kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are the six major kavalactones extracted from kava plant roots [5]. Despite the deep therapeutic interest in these extracts alleviating anxiety, the active constituents of kava among the kavalactone compounds and their mechanisms of action are still to be established. Many proteins are possible molecular targets for these compounds, including GABA or γ-aminobutyric acid type A, dopamine D2, opioid (μ and δ), and histamine (H1 and H2) receptors [6].
A study published in 2016 unraveled kavain’s ability to bind to GABA type A (GABA-A) receptors [5]. GABA-A receptors are expressed in the central nervous system and, along with GABA — the principal inhibitory neurotransmitter — play an essential role in the brain. Together, they maintain the balance between excitatory and inhibitory neuronal activity. GABA-A receptors are pentameric assemblies from a selection of 19 possible subunits: six α (α 1-6), three β (β 1-3), three γ (γ 1-3), three ρ (ρ 1-3), and one each of the δ, ε, π, and θ subunits [7]. Combinations of these 19 subunits produce numerous receptor isoforms, each with unique localization patterns and distinct physiological and pharmacological properties.
Kavain, the principal anxiolytic kavalactone, binds to human recombinant GABA-A receptors expressed in Xenopus oocytes in vitro. It binds to different subunit combinations of GABA-A receptors, such as α1β2, β2γ2L, αxβ2γ2L (x being α isoform 1, 2, 3, or 5), α1βxγ2L (x being α isoform 1, 2 and 3) and α4β2δ [5]. Using the two-electrode voltage clamp technique, scientists demonstrated that kavain positively modulates all these GABA-A receptors regardless of their subunit composition. However, their degree of enhancement varies. Interestingly, kavain’s effects are unaffected by flumazenil, an allosteric modulator of GABA-A receptors at the benzodiazepine site [5], indicating that kavain does not bind to this site. The asparagine mutation in position 265 of the β3 subunit into a methionine significantly reduces kavain effects [5]. Therefore, kavain may contribute to kava’s anxiolytic effects by activating GABA-A receptors [8]. Other in vitro and in vivo studies highlighted other mechanisms. Kavain inhibits sodium and calcium channels [9] and monoamine oxidase B [10]. It also reduces the reuptake of neuronal dopamine [11] and noradrenaline [12] (also known as norepinephrine).
Kava extracts for the treatment of anxiety
Many clinical trials assessed the efficacy of kava extracts for the treatment of anxiety, and two systematic reviews and meta-analyses were published in 2003 [13] and 2005 [14], respectively. Both studies included six randomized-controlled trials and concluded that kava showed significantly greater anxiolysis than placebo.
Since then, other randomized-controlled studies have been conducted, yielding varied results. A 3-week, placebo-controlled, double-blind crossover trial published in 2009 evaluated the anxiolytic and antidepressant efficacy of an aqueous kava extract. This trial involved 60 adults who received 250 mg of kavalactones per day. The results showed significant anxiolytic and antidepressant activity and raised no safety concerns at the dose and duration studied [15].
However, a study published in 2009 assessed the efficacy of Saint John’s wort combined with kava (150 mg of kavalactones per day) for the treatment of major depressive disorder with anxiety. The randomized-controlled, double-blind study with a crossover design involved 28 adults and found some evidence of antidepressant effects but no significant effects on anxiety. Potential interaction with Saint John’s wort, depression comorbidity, or an inadequate dose of kava were the three possible explanations for the absence of anxiolysis, according to the authors of the study [16].
Another randomized with a crossover design study published in 2012 compared the effects of kava extracts (one acute dose of 180 mg of kavalactones) with benzodiazepines (oxazepam, 30 mg) in 22 participants moderately anxious and found no anxiolytic effect with kava [17]. These results were consistent with a third randomized, double-blind, placebo-controlled study involving 171 patients diagnosed with generalized anxiety disorder who received 240 mg of kavalactones per day for 16 weeks [18].
The composition of kava extracts may partly explain the efficacy variability observed in clinical trials. Indeed, the amount of plant material used and the extraction method (in water, alcohol, acetone, coconut milk, etc.) employed impact the composition and concentration of the various kavapyrones in the final product [19]. Interestingly, a double-blind, placebo-controlled trial conducted in Germany compared the efficacy of D,L-kavain (Neuronika) with oxazepam, a benzodiazepine indicated for the treatment of anxiety. The study, involving 38 patients, concluded that both substances were equivalent as judged using the Anxiety Status Inventory and the Self-Rating Anxiety Scale [2].
The efficacy and safety of kava extracts
In clinical trials, kava extracts are generally well tolerated. However, several reports of kava-induced hepatotoxicity have led to their withdrawal or the issuance of warnings in several countries [20-22]. Since then, due to the lack of direct causal evidence linking kava to liver injury, Germany has lifted the ban on its use [21]. Subsequent research has suggested that hepatotoxicity may be related to the composition and quality of kava extracts and individual risk factors [23]. The hepatotoxicity risk appears low with the use of well-characterized aqueous extracts at the recommended doses. However, individuals with liver conditions or those taking medications that affect liver function should exercise caution with kava products [24].
The comparison between kava and placebo groups in clinical trial settings did not identify withdrawal or addiction with kava [25]. That said, a case report published in 2024 describes an acute kava withdrawal with hyperactive delirium in a heavy kava user [26].
Heavy kava drinkers can acquire a reversible ichthyosiform eruption, called kava dermopathy [27]. A case report published in 2024 describes a diffuse ichthyosiform rash in a newborn (similar to descriptions of kava ichthyosiform dermopathy in adults) caused by maternal kava use during pregnancy [28].
Finally, several studies have shown that kavapyrones inhibit one cytochrome enzyme responsible for drug metabolism before elimination [29,30]. Therefore, kavapyrones potentially interact with many other drugs, altering their metabolism, efficacy, and toxicity.
Conclusion
In the Pacific Islands, the kava plant has been used for centuries to prepare "kava," a non-alcoholic psychoactive beverage with anxiolytic and sedative properties. There is a long-standing interest in the use of kava extracts for the treatment of anxiety, and many clinical trials assessed their efficacy. Despite variability in extract quality and composition, meta-analyses have confirmed kava's efficacy in treating anxiety. Kavain, the major anxiolytic kavalactone produced in the kava plant roots, binds to and activates GABA-A receptors in vitro, which may contribute to the anxiolytic activity of kava extracts.
References
[1] Lindstrom, L. (2004) Kava: From Ethnology to Pharmacology [Internet]. 1st ed. CRC Press. https://doi.org/10.1201/9781420023374
[2] Lindenberg, D. and Pitule-Schödel, H. (1990) [D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness]. Fortschritte Der Medizin, 108, 49–50, 53–4. [Article in German]
[3] Tsutsui, R., Shinomiya, K., Takeda, Y., Obara, Y., Kitamura, Y. and Kamei, C. (2009) Hypnotic and Sleep Quality–Enhancing Properties of Kavain in Sleep-Disturbed Rats. Journal of Pharmacological Sciences, 111, 293–8. https://doi.org/10.1254/jphs.09167FP
[4] Cairney, S., Maruff, P. and Clough, A.R. (2002) The Neurobehavioural Effects of Kava. Australian & New Zealand Journal of Psychiatry, 36, 657–62. https://doi.org/10.1046/j.1440-1614.2002.01027.x
[5] Chua, H.C., Christensen, E.T.H., Hoestgaard-Jensen, K., Hartiadi, L.Y., Ramzan, I., Jensen, A.A. et al. (2016) Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. Barnes S, editor. PLOS ONE, 11, e0157700. https://doi.org/10.1371/journal.pone.0157700
[6] Dinh, L.D., Simmen, U., Berger Bueter, K., Bueter, B., Lundstrom, K. and Schaffner, W. (2001) Interaction of Various Piper methysticum Cultivars with CNS Receptors in vitro. Planta Medica, 67, 306–11. https://doi.org/10.1055/s-2001-14334
[7] Zhu, S., Noviello, C.M., Teng, J., Walsh, R.M., Kim, J.J. and Hibbs, R.E. (2018) Structure of a human synaptic GABAA receptor. Nature, 559, 67–72. https://doi.org/10.1038/s41586-018-0255-3
[8] Savage, K., Firth, J., Stough, C. and Sarris, J. (2018) GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence. Phytotherapy Research, 32, 3–18. https://doi.org/10.1002/ptr.5940
[9] Gleitz, J., Tosch, C., Beile, A. and Peters, T. (1996) The Protective Action of Tetrodotoxin and (±)-Kavain on Anaerobic Glycolysis, ATP Content and Intracellular Na + and Ca 2+ of Anoxic Brain Vesicles. Neuropharmacology, 35, 1743–52. https://doi.org/10.1016/S0028-3908(96)00106-2
[10] Prinsloo, D., Van Dyk, S., Petzer, A. and Petzer, J.P. (2019) Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum). Planta Medica, 85, 1136–42. https://doi.org/10.1055/a-1008-9491
[11] Baum, S.S., Hill, R. and Rommelspacher, H. (1998) Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 22, 1105–20. https://doi.org/10.1016/S0278-5846(98)00062-1
[12] Seitz, U., Schüle, A. and Gleitz, J. (1997) [3 H ]-Monoamine Uptake Inhibition Properties of Kava Pyrones. Planta Medica, 63, 548–9. https://doi.org/10.1055/s-2006-957761
[13] Pittler, M.H. and Ernst, E. (2003) Kava extract versus placebo for treating anxiety. Cochrane Common Mental Disorders Group, editor. Cochrane Database of Systematic Reviews,. https://doi.org/10.1002/14651858.CD003383
[14] Witte, S., Loew, D. and Gaus, W. (2005) Meta-analysis of the efficacy of the acetonic kava-kava extract WS®1490 in patients with non-psychotic anxiety disorders. Phytotherapy Research, 19, 183–8. https://doi.org/10.1002/ptr.1609
[15] Sarris, J., Kavanagh, D.J., Byrne, G., Bone, K.M., Adams, J. and Deed, G. (2009) The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology, 205, 399–407. https://doi.org/10.1007/s00213-009-1549-9
[16] Sarris, J., Kavanagh, D.J., Deed, G. and Bone, K.M. (2009) St. John’s wort and Kava in treating major depressive disorder with comorbid anxiety: a randomised double‐blind placebo‐controlled pilot trial. Human Psychopharmacology: Clinical and Experimental, 24, 41–8. https://doi.org/10.1002/hup.994
[17] Sarris, J., Scholey, A., Schweitzer, I., Bousman, C., LaPorte, E., Ng, C. et al. (2012) The acute effects of kava and oxazepam on anxiety, mood, neurocognition; and genetic correlates: a randomized, placebo‐controlled, double‐blind study. Human Psychopharmacology: Clinical and Experimental, 27, 262–9. https://doi.org/10.1002/hup.2216
[18] Sarris, J., Byrne, G.J., Bousman, C.A., Cribb, L., Savage, K.M., Holmes, O. et al. (2020) Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study. Australian & New Zealand Journal of Psychiatry, 54, 288–97. https://doi.org/10.1177/0004867419891246
[19] White, C.M. (2018) The Pharmacology, Pharmacokinetics, Efficacy, and Adverse Events Associated With Kava. The Journal of Clinical Pharmacology, 58, 1396–405. https://doi.org/10.1002/jcph.1263
[20] Centers for Disease Control and Prevention (CDC). (2002) Hepatic toxicity possibly associated with kava-containing products--United States, Germany, and Switzerland, 1999-2002. MMWR Morbidity and Mortality Weekly Report, 51, 1065–7.
[21] Kuchta, K., Schmidt, M. and Nahrstedt, A. (2015) German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics. Planta Medica, 81, 1647–53. https://doi.org/10.1055/s-0035-1558295
[22] Ulbricht, C., Basch, E., Boon, H., Ernst, E., Hammerness, P., Sollars, D. et al. (2005) Safety review of kava ( Piper methysticum ) by the Natural Standard Research Collaboration. Expert Opinion on Drug Safety, 4, 779–94. https://doi.org/10.1517/14740338.4.4.779
[23] Teschke, R., Sarris, J. and Lebot, V. (2011) Kava hepatotoxicity solution: A six-point plan for new kava standardization. Phytomedicine, 18, 96–103. https://doi.org/10.1016/j.phymed.2010.10.002
[24] Yeom, J.W. and Cho, C.-H. (2024) Herbal and Natural Supplements for Improving Sleep: A Literature Review. Psychiatry Investigation, 21, 810–21. https://doi.org/10.30773/pi.2024.0121
[25] Sarris, J., Stough, C., Teschke, R., Wahid, Z.T., Bousman, C.A., Murray, G. et al. (2013) Kava for the Treatment of Generalized Anxiety Disorder RCT: Analysis of Adverse Reactions, Liver Function, Addiction, and Sexual Effects. Phytotherapy Research, 27, 1723–8. https://doi.org/10.1002/ptr.4916
[26] Cassidy, R.M., Burdick, K., Anesi, T. and Daunis, D. (2024) Kava Withdrawal Treated With Phenobarbital—A Case Report and Literature Review. Journal of Addiction Medicine, 18, 599–601. https://doi.org/10.1097/ADM.0000000000001314
[27] Norton, S.A. and Ruze, P. (1994) Kava dermopathy. Journal of the American Academy of Dermatology, 31, 89–97. https://doi.org/10.1016/S0190-9622(94)70142-3
[28] Spungen, H.H., Mody, K., Micetic, B., Wade, C. and Kang, A.M. (2024) Neonatal and Maternal Ichthyosiform Dermopathy in Association with Kava Use during Pregnancy. Journal of Medical Toxicology, 20, 308–13. https://doi.org/10.1007/s13181-024-01016-x
[29] Wang, P., Zhu, J., Shehu, A.I., Lu, J., Chen, J., Zhong, X. et al. (2019) Enzymes and Pathways of Kavain Bioactivation and Biotransformation. Chemical Research in Toxicology, 32, 1335–42. https://doi.org/10.1021/acs.chemrestox.9b00098
[30] Nascimento, M.D.L., Do Nascimento, S.B., Lima, E.D.S.P., De Oliveira, F.M., Dos Santos, R.R., Cesar, I.D.C. et al. (2024) Evaluation of the Effects of Extracts Containing Valeriana officinalis and Piper methysticum on the Activities of Cytochrome P450 3A and P-Glycoprotein. Planta Medica, 90, 792–800. https://doi.org/10.1055/a-2360-4808
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