Kava

Kava (Piper methysticum): A Comprehensive Reference

1. Identity and Botanical Description

Botanical name: Piper methysticum G. Forst., a member of the pepper family Piperaceae. The name Piper methysticum translates from Greek as "intoxicating pepper." The plant is commonly known as kava, kava kava, and in Hawaii as ʻawa.

Kava is an ethnomedicinal shrub native to the Polynesian islands with well-established anxiolytic and analgesic properties. Its main psychoactive principles, kavalactones, form a unique class of polyketides that interact with the human central nervous system.

Kava plants are generally found in Polynesia, Melanesia, and Micronesia. Kava biomass is normally sold as the rhizome, with the periderm and roots removed. The plant is usually harvested when it is about 2–2.5 m in height. The cultivation and selection of kava has produced numerous varieties or cultivars recognized by differences in the internodes, colour of stems, intensity of leaf colour, and quality of the root.

Analysis of the composition of kava rhizome indicates that the fresh material is on average 80% water. When dried, the rhizome consists of approximately 43% starch, 20% fibres, 12% water, 3.2% sugars, 3.6% proteins, 3.2% minerals, and 15% kavalactones, although the kavalactone component can vary between 3% and 20% of the dry weight of the rhizome, depending on the age of the plant and the cultivar.

Chemotyping has identified over 200 variant strains of kava, but the chemical signature can vary between roots, rhizomes, and basal stems.

Common Forms and Preparations

Kava products are available over the counter (OTC) in the U.S. as standardized liquid extracts, tinctures, dried powder, and tablets. The traditional way of preparing kava drink is by chewing or grinding the kava roots and rhizomes into pulp, blending it with water and filtering before drinking it. In the U.S. and western countries, solvents such as acetone or ethanol may be used in kava extraction.

Ethanol has the highest extraction efficiency for the six major kavalactones, whereas hexane gives the lowest extraction efficiency. Historically, the beverage was made from fresh kava; preparation from dry kava emerged in response to the efforts of Christian missionaries in the 18th and 19th centuries to prohibit the drinking of kava.

2. Traditional and Historical Use

Origins and Geographic Spread

Indigenous to the islands of the South Pacific, kava has been cultivated and consumed for at least 3,000 years across Fiji, Vanuatu, Tonga, Samoa, and Hawaii. The exact island where kava was first domesticated remains a topic of debate; it is widely believed to be in Vanuatu, but a few people believe it to be Papua New Guinea.

Historically, island communities were interconnected through substantial trade networks, and kava was taken by seafarers on journeys between islands. This eventually led to the spread of kava throughout other parts of the Melanesian Islands such as Papua New Guinea and the Solomon Islands, the Polynesian Islands including Tonga, Samoa, and the Hawaiian Islands, and the Micronesian Islands.

Traditional Preparation Methods

Traditionally, kava was prepared by cutting the root into small pieces, being chewed by several people, and spat into a bowl, where it was mixed with coconut milk. Traditional preparation also involved pounding or chewing the dried root, mixing it with water, and straining the liquid through fibrous material into a communal bowl. Over time, kava is prepared by grinding the root into a fine powder and mixing it with water to create a tea.

Cultural, Ceremonial, and Medicinal Roles

Kava plays a central and sophisticated role in traditional ceremonies, rituals, and gatherings within Pacific Island communities. Its cultural significance goes beyond being a mere beverage and is deeply intertwined with spiritual beliefs, social interactions, and the preservation of cultural identity. Kava ritual is a ceremonial practice symbolizing community unity and spiritual connection.

Throughout the South Pacific, kava drinking has been part of reverent ceremonies since ancient times. The installation of a new village chief, agreements between communities, or the welcoming of an important visitor always includes a kava ceremony. In Tonga, the installment of the king or a noble title is not complete until they conduct a kava ceremony.

In many Pacific Island cultures, kava was a sacred vessel for communicating with the divine. During religious ceremonies, chiefs, priests, or elders would consume kava to become spiritually receptive, allowing them to speak with ancestors and gods. Chants or invocations would often accompany this ritual, reinforcing the sacred nature of the occasion.

Kava was carried throughout the Pacific by ancient voyaging societies. The most important kava product continues to be the traditional beverage made from the roots and stump of the plant. Modern pharmaceutical uses are based on the psychoactive properties of the kavalactones.

3. Key Constituents and Active Compounds

Kavalactones

The bioactive principles of kava rhizome are mostly, if not entirely, contained in the lipid-soluble resin. The compounds of greatest pharmacological interest are the substituted α-pyrones or kavapyrones, commonly known as kavalactones. At least 15 lactones have been isolated from kava rhizome.

To date, eighteen kavalactones have been identified from the root, six of which account for approximately 95% of the organic extract: namely, kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. The six major kavalactones constitute over 96% of the kavalactone content in the plant rhizome.

Kavain, dihydrokavain, and methysticin are considered to be the most important kavalactones for the effects observed in the central nervous system (CNS). Methysticin is thought to help in neuroprotection against ischemia and, in combination with dihydromethysticin, may reduce brain infarction in mice.

Total kavalactone accounts for 3%–20% dry weight, with the highest concentration in the lateral roots, decreasing gradually towards the aerial plant structures.

More than 40 compounds have been isolated from kava, with the active components present in the lipid-soluble resin containing three chemical classes: (i) arylethylene-α-pyrones, (ii) chalcones and other flavones, and (iii) conjugated diene ketones.

Flavokavains

Kava also produces flavokavains, which are chalconoids with anticancer properties structurally related to kavalactones. Flavokavains A and B have been separately identified; flavokawain pigments are suspected by some researchers to be responsible for hepatotoxic effects, and are commonly removed in the production of commercial extracts, despite the lack of scientific proof.

Metabolism

The main metabolic pathways for kavalactones in humans and rats are hydroxylation of the C-12 in the aromatic ring, breaking and hydroxylation of the lactone ring with subsequent dehydration, reduction of the 7,8-double bond, and demethylation of the 4-methoxyl group. Nineteen different kavalactones have been identified, which can be metabolized in the liver by cytochrome P450 enzymes (CYP450).

4. Mechanisms of Action

Kavalactones are compounds that exhibit direct activity on central nervous system receptors and neurotransmitters, notably through their interaction with GABA-benzodiazepine receptors and the inhibition of noradrenaline uptake, while also modulating voltage-dependent Na⁺ and Ca²⁺ channels.

GABAergic Activity

Numerous proteins including γ-aminobutyric acid type A receptors (GABA_ARs), voltage-gated Na⁺ and Ca²⁺ channels, opioid μ and δ receptors, dopamine type-2 receptor, histamine type-1 and 2 receptors, cannabinoid type-1 receptor, and monoamine oxidase type B have been suggested to be the molecular targets for kavalactones. Due to the paucity of robust evidence, however, a consensus on the pharmacology of kavalactones has not yet been reached, but there is a prevailing view, on the basis of their benzodiazepine-like pharmacological actions, that GABA_ARs are the main target for kavalactones.

One study characterised the functional properties of the major anxiolytic kavalactone, kavain, at human recombinant GABA_ARs expressed in Xenopus oocytes. The researchers found that kavain positively modulated all receptors regardless of the subunit composition, but the degree of enhancement was greater at α4β2δ than at α1β2γ2L GABA_ARs.

None of these studies detected significant affinity of kavalactones for the benzodiazepine binding site, contrary to popular belief. Kavalactones appear to activate GABAergic effects via modulation of GABA channels. Their lipophilic nature allows them to remain in the lipid membrane and potentially influence a variety of cell surface receptors. This influence may include an ability to increase the number of GABA binding sites rather than to change an affinity to bind GABA directly.

Data are consistent with pre-clinical models on kavain as a positive allosteric modulator of the GABA-A receptor outside the typical benzodiazepine site binding. Data also contribute to the evidence of unique GABAergic action with kavalactones, supported by pre-clinical tissue studies.

Limbic System and Monoamine Systems

Reduced excitability of the limbic system, particularly the amygdala complex, appears responsible at least in part for emotion modulation by kavalactones. Inhibition of monoamine oxidase and noradrenaline uptake may also contribute to kava's psychoactivity.

Voltage-Gated Ion Channels and Neuroprotection

Kava has been reported to have neuroprotective effects (mediated via its blocking action on voltage-gated Na⁺ and Ca²⁺ channels) and anxiolytic effects. Recent studies on the mechanisms of action for isolated kavalactones have revealed other neuroprotective activities not directly related to their GABAergic effects. These findings suggest that the use of kava might also be beneficial for the treatment of many degenerative diseases or nervous system conditions. One of the neuroprotective effects of kavalactones is mediated by the P38/nuclear factor-κB/cyclooxygenase 2 (COX2) signaling pathway.

Analgesic Mechanism

Kava has an analgesic action that is not mediated through opioid receptors, because it is not reversed by naloxone. It is most likely that it acts by interacting with GABAergic and monoamine transmitters.

5. Scientific Evidence by Area of Use

5.1 Anxiety

The largest and most robust body of clinical evidence for kava concerns anxiety disorders, particularly generalized anxiety disorder (GAD).

Cochrane Review (Pittler & Ernst, 2003): Twelve trials met the inclusion criteria. The meta-analysis of seven trials suggests a significant treatment effect for the total score on the Hamilton Anxiety Scale in favour of kava extract. Few adverse events were reported in the reviewed trials, which were all mild, transient, and infrequent.

Earlier systematic review and meta-analysis: Superiority of kava extract over placebo was suggested by all seven reviewed trials. The meta-analysis of three trials suggests a significant difference in the reduction of the total score on the Hamilton Rating Scale for Anxiety in favor of kava extract (weighted mean difference, 9.69; 95% confidence interval, 3.54–15.83). These data imply that kava extract is superior to placebo as a symptomatic treatment for anxiety.

2018 systematic review and meta-analysis (Smith & Leiras): Kava Kava was shown to be more effective than placebo in 3 of the 7 trials. A final risk ratio of 1.50 (95% CI: 1.12, 2.01) from responder rates was calculated in favor of the intervention from 5 clinical trials (n = 330). Kava Kava appears to be a short-term treatment for anxiety, but not a replacement for prolonged anti-anxiety use.

Sarris et al. 2013 — 6-week RCT in GAD: A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of kava (120/240 mg of kavalactones per day depending on response) versus placebo. Involving 75 participants with diagnosed GAD (58 randomised to 120 mg daily kavalactones titrated to 240 mg for non-response), a group × time interaction was found (P = 0.046) for a significant reduction in HAM-A scores in favour of kava over placebo. Kava significantly reduced participant anxiety by −4.2, representing a moderate effect size (Cohen's d = 0.63). For participants with moderate-to-severe level anxiety, the treatment effect was more pronounced (P = 0.020), with a larger effect size (d = 0.80).

Sarris et al. 2009 — 3-week crossover RCT: A randomised, double-blind, placebo-controlled, balanced, crossover trial (n = 60) using a water-soluble rootstock extract of a noble kava cultivar, standardised to a dose of 250 mg kavalactones, was conducted. One week of prescribed kava significantly reduced participants' anxiety compared to placebo on the HAMA (Cohen's d = 2.24, p < 0.0001).

Sarris et al. 2020 — 16-week phase III RCT: The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia.

Evidence characterization: The evidence for kava in short-term treatment of anxiety is among the strongest of any herbal supplement, with multiple positive RCTs and a Cochrane meta-analysis. A 2018 systematic review found that kava may produce short-term improvements for anxiety, but is not a replacement for prolonged anti-anxiety use. The reviewers noted that liver toxicity is especially possible if taken longer than 8 weeks. There has been a fair amount of research in people on the use of kava for anxiety, but few studies have been done on other conditions.

5.2 Sleep and Insomnia

Multicenter RCT (Lehrl 2004, WS 1490 extract): In a multicenter, randomized, double-blind clinical study, 61 patients received daily doses of 200 mg WS 1490 or placebo over a period of 4 weeks. Efficacy was measured by the sleep questionnaire SF-B, the Hamilton Anxiety Scale (HAMA), the Bf-S self-rating scale of well-being, and the Clinical Global Impressions (CGI) scale. The confirmatory analysis of the two primary efficacy variables, the differences of sleep questionnaire SF-B sub-scores 'Quality of sleep' and 'Recuperative effect after sleep' after 4 weeks of double-blind treatment compared to baseline, demonstrated statistically significant group differences in favor of kava extract WS 1490 (P = 0.007 and P = 0.018, respectively). Safety and tolerability were good, with no drug-related adverse events or changes in clinical or laboratory parameters. The authors concluded that sleep disturbances associated with non-psychotic anxiety disorders can be effectively and safely treated with kava extract WS 1490.

Other investigations have revealed improvements in sleep quality without impairment of rapid eye movement (REM) sleep. A subsequent, higher quality study found kava to be more effective than a placebo at improving sleep quality and reducing anxiety. Kava's effects on insomnia may stem from its effects on anxiety. Stress-induced insomnia is common in those with anxiety; in cases of insomnia, kava may be treating anxiety, which may then help people sleep better.

Evidence characterization: Kava showed promising results in rats and humans, with decreased sleep latency, better sleep quality, and recuperation after sleep; however, it has raised concern about its potential for hepatotoxicity. The sleep evidence is largely tied to anxiety-related insomnia and is preliminary; better-powered, independent replications are needed.

5.3 Pharmacological and Pharmacokinetic Studies

Properties shown by kavalactones in pharmacological investigations include a positive influence on cerebral information processing, tranquilizing effects, local anesthesia, anticonvulsive, as well as spasmolytic effects. In particular, pharmacological and clinical studies revealed no evidence of any potential for tolerance or dependency.

Several studies have documented a wide spectrum of pharmacological effects of P. methysticum, including anxiolytic, analgesic, muscle relaxant, and mild anaesthetic effects. Other documented actions include sedation, euphoria, and both anticonvulsant and neuroprotective activity.

6. Body Systems and Health Areas

• Central nervous system (anxiety, mood, sleep): The best-studied area. Kavalactones modulate GABA_A receptor function, limbic excitability, and monoaminergic tone, producing anxiolytic and sedative effects that have been confirmed in multiple RCTs.
• Musculoskeletal system: Kavalactones appear to work directly on muscles as a relaxant.
• Neurological/neuroprotection: Recent studies on the mechanisms of action for isolated kavalactones have revealed neuroprotective activities not directly related to their GABAergic effects, suggesting that the use of kava might also be beneficial for the treatment of many degenerative diseases or nervous system conditions.
• Hepatic system: The liver is both the site of kavalactone metabolism via CYP450 enzymes and a documented target of potential toxicity in rare cases (see Safety section below).
• Skin: Heavy or prolonged kava use is associated with a reversible dermopathy (see Safety section below).
• Oncology (preclinical): Kava also produces flavokavains, which are chalconoids with anticancer properties structurally related to kavalactones. This evidence is preclinical only.

7. Dosage Forms and Dosages Reported in Studies

In included double-blind placebo-controlled RCTs, oral kava monopreparations with daily kavapyrone content ranging from 60 to 240 mg were compared with placebo. Doses of kava extract were generally given between two and four times daily. Duration of studies ranged from one night (pre-operative) to 24 weeks.

Key clinical trial dosages documented in the primary literature include:

• A 6-week, double-blind, randomized controlled trial (n = 75) involving chronic administration of kava at one tablet twice per day (120 mg of kavalactones per day), titrated in non-response to two tablets twice per day (240 mg of kavalactones).
• A three-week double-blind, placebo-controlled, crossover RCT (n = 60) used a preparation standardised to a dose of 250 mg kavalactones per day.
• A 16-week phase III RCT administered an aqueous extract of dried kava root twice per day in tablet form, standardised to 120 mg of kavalactones twice per day.
• In a multicenter, randomized, double-blind clinical study, 61 patients received daily doses of 200 mg WS 1490 or placebo over a period of 4 weeks.

Regarding commercial supplement standardization: If one capsule contains 100 mg of kava root extract and is standardized to contain 30% kavalactones, it will contain 30 mg of kavalactones. To reach an effective dose within the range of 70 to 250 mg of kavalactones, multiple capsules may be required. Most extracts of kava root contain 30% to 70% kavalactones.

8. Safety Considerations and Drug Interactions

8.1 Hepatotoxicity

Liver safety is the most scrutinized aspect of kava's safety profile and remains a subject of ongoing scientific debate.

Reports of kava hepatotoxicity first emerged in Germany in 1998, and by the end of 2005, the World Health Organisation had received 91 reports of 189 adverse reactions relating to kava-only products. Fifty-five of those reactions involved liver and biliary system disorders, including three cases of hepatic failure and two cases of hepatic comas. Reported daily doses ranged from 45–1200 mg kavalactones taken for one week to twelve months.

A regulatory ban for ethanolic and acetonic kava extracts was issued in 2002 for Germany on the basis of reports connecting liver disease with the use of kava, but the regulatory causality assessment was a matter of international discussions.

In subsequent studies using a structured, quantitative, and hepatotoxicity-specific causality assessment method in 14 patients with liver disease described worldwide, causality for kava ± co-medicated drugs was highly probable (n = 1), probable (n = 4) or possible (n = 9) regarding aqueous extracts (n = 3), ethanolic extracts (n = 5), acetonic extracts (n = 4), and mixtures containing kava (n = 2). Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements in most of the 14 patients. Hepatotoxicity occurred independently of the used solvent, suggesting poor kava raw material quality as an additional causative factor.

Of major concern was the question whether the solvent used for kava extract preparation might possibly be considered as the culprit for the emerging toxic liver injury following kava use. It is conceivable that the ethanol and acetone extraction procedure may either concentrate or select toxic compounds, or diminish protective ingredients.

Several groups have disputed the evidence for hepatotoxicity, suggesting that responsibility for liver injury lies with adulterants or concomitant drugs or herbals. Furthermore, the literature on liver injury from kava has included several incomplete or overlapping reports, and causality was rarely well shown. Nevertheless, there are a small number of cases of severe hepatic injury arising during therapy that are convincing.

A 2013 randomized controlled trial of 75 participants who received kava extract over a 6-week period found no significant differences across groups for liver function tests, nor any significant adverse reactions associated with kava administration.

8.2 Kava Dermopathy

Kava dermopathy is a condition characterized by dry, cracked, scaly skin particularly focused on the arms, legs, and face. This is not an acute reaction, and is something that develops over weeks and months when regularly consuming larger amounts of kava. This is not a rash.

The rash from kava dermopathy often begins on head, face, and neck, and gradually becomes more generalised. The rash is ichthyosiform (resembling ichthyosis); that is, rough, dry, and scaly. The scales are polygonal in shape. The rash lacks erythema. It may be more evident in areas of skin exposed to the sun. Kava dermopathy may have an associated peripheral neuropathy, resulting in numb or tingling hands and feet.

Regular or daily kava consumption has been theorized to interfere with cholesterol metabolism in skin cells known as keratinocytes. This interaction is thought to reduce production of ceramides secreted by organelles within the cell known as lamellar bodies. Ceramides are a type of long-chain, omega-hydroxylated fatty acid and help maintain skin hydration, facilitate skin-cell shedding, and protect the skin barrier. Decreased ceramides can lead to dry, scaly, and thickened skin.

Kava dermopathy was found to affect 34.6% of kava users in a Pacific Island population. The condition was reversible in 83.3% of cases upon reduction of kava use.

8.3 Other Adverse Effects

Although adverse effects are not expected when kava is used at the recommended dosage, rarely kava has been found to cause side effects such as gastrointestinal upset, headache, dizziness, drowsiness, enlarged pupils, disturbances of oculomotor equilibrium and accommodation, dry mouth, and allergic skin reactions.

A variety of adverse reactions, including visual disturbances, urinary retention, GI discomfort, exacerbation of Parkinson disease, extrapyramidal effects, and rhabdomyolysis, have been reported.

8.4 Drug Interactions

Kava extract can significantly modulate drug-metabolizing enzymes, particularly the cytochrome P450 isozymes, a fact that has been suggested to predispose to drug-induced liver injury. Particularly, kavalactone inhibition of CYP450 enzymes may predispose to relevant pharmacokinetic interactions.

Kava may theoretically increase sedation with sedative drugs. If taken with CYP450 substrate drugs, especially CYP1A2 or CYP2E1, kava may increase both their effects and side effects.

Preliminary evidence suggests kava may inhibit multiple cytochrome P450 subtypes, which could affect the metabolism of a patient's other medications. In addition, kava should not be used concomitantly with central nervous system depressants, such as alcohol or benzodiazepines, because of potentiation of drowsiness.

Case reports exist on interactions with alprazolam, alcohol, barbiturates, and levodopa. Concomitant administration of kava with haloperidol, risperidone, and metoclopramide, among other drugs, may be associated with adverse reactions.

Kava is contraindicated for those with Parkinson's disease, hepatitis (active case or history of disease), depression, and genetic cytochrome P450 2D6 (CYP2D6) isozyme susceptibility, as well as for women who are pregnant or lactating.

Theoretically, using kava along with potentially hepatotoxic drugs, herbs, and nutritional supplements might increase the risk of developing liver damage, particularly in individuals with genetic deficiency in the cytochrome P450 2D6 (CYP2D6) isozyme. Kava can adversely affect the liver in susceptible poor metabolizers, patients whose cytochrome P450 2D6 (CYP2D6) isozyme is underactive.

8.5 Regulatory Status

The use of kava has been banned or restricted in many countries of the world such as Germany, Switzerland, France, Canada, and Great Britain. Kava products are sold in the United States as dietary supplements and in some other countries as drugs or herbal medicines. These products are promoted for anxiety and other health conditions.

The European Medicines Agency (EMA) published a 103-page assessment report in 2017 summarizing all available data, concluding there were no significant hepatotoxicity findings in controlled clinical studies and only mild, reversible transaminase elevations in a few subjects.

References

• Toxicokinetics of Kava — PMC/NIH
• Exposure Data — Some Drugs and Herbal Products (NCBI/NIH Bookshelf)
• The biosynthetic origin of psychoactive kavalactones in kava — PubMed
• Kavalactone content and chemotype of kava beverages — PMC
• Kavain Potentiates GABAA Receptors — PLOS ONE
• Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors — PMC
• Neuroimaging Insights: Kava's Effect on GABA in Generalized Anxiety Disorder — PMC
• Neuroprotective properties of kavalactones — PMC
• Kava extract for treating anxiety — Cochrane
• Efficacy of kava extract for treating anxiety: systematic review and meta-analysis — NCBI Bookshelf (DARE)
• Efficacy of kava extract for treating anxiety: systematic review and meta-analysis — PubMed
• The effectiveness and safety of Kava Kava for treating anxiety symptoms: systematic review — PubMed
• Kava for Generalized Anxiety Disorder: A Review of Current Evidence — Journal of Alternative and Complementary Medicine
• Kava: Usefulness and Safety — NCCIH/NIH
• Anxiety and Complementary Health Approaches — NCCIH/NIH
• Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders — PubMed
• A systematic review of effectiveness and safety of some herbal compounds as treatment for primary insomnia — PMC
• Kava in the Treatment of Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study — ResearchGate
• Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study — ResearchGate
• Kava for the treatment of generalised anxiety disorder (K-GAD): study protocol for a randomised controlled trial — PMC
• Kava Kava — LiverTox, NCBI Bookshelf
• Kava hepatotoxicity: pathogenetic aspects and prospective considerations — Liver International (Wiley)
• Kava hepatotoxicity. A clinical review — ScienceDirect
• Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat — PMC
• An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava — MDPI Journal of Clinical Medicine
• Kava (Piper methysticum) Monograph — Restorative Medicine
• Kava dermopathy — DermNet NZ
• Kava Dermopathy: A Deep Dive — International Kava Organization
• Kava — Memorial Sloan Kettering Cancer Center
• Kava for the Treatment of GAD RCT: Analysis of Adverse Reactions, Liver Function, Addiction, and Sexual Effects — Wiley Phytotherapy Research