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Kavain

Kavain is a naturally occurring , a lipophilic α-pyrone derivative, that serves as the major active constituent in the roots of the kava plant (Piper methysticum), a native to the South Pacific islands traditionally used in ceremonial beverages for its calming and effects. With the C14H14O3 and a molecular weight of 230.26 g/mol, kavain is a chiral typically isolated in its (+)- form from extracts. Pharmacologically, kavain exerts effects primarily by modulating GABAA receptors in the , enhancing inhibitory neurotransmission without significant sedation at therapeutic doses. It also demonstrates properties through inhibition of voltage-dependent sodium and calcium channels, contributing to muscle relaxation and reduced neuronal excitability. Additionally, kavain influences vascular contractility by blocking calcium influx, and it has shown potential by regulating pathways such as TNF-α expression in response to endotoxins. While kava extracts containing kavain have been studied for therapeutic applications in anxiety disorders, concerns over potential associated with prolonged or high-dose use have led to regulatory restrictions in some countries.

Chemistry

Chemical Structure

Kavain is a naturally occurring characterized by the molecular formula C14H14O3 and a of 230.263 g/mol. Its systematic IUPAC name is (6R)-4-methoxy-6-[(E)-2-phenylethenyl]-5,6-dihydro-2H-pyran-2-one, reflecting the specific and configuration of its substituents. The core structure of kavain consists of an α-pyrone ring, a six-membered featuring a conjugated system that contributes to its UV absorbance and . This ring is substituted with a (-OCH3) at the 4-position and a trans-styryl (-CH=CH-C6H5) at the 6-position, where the in the side chain adopts the E (trans) configuration. The molecule contains a single chiral center at the 6-carbon, which bears the R absolute configuration in the naturally occurring . In comparison to other kavalactones, kavain is distinguished by its unsaturated styryl ; for instance, dihydrokavain features a saturated propylphenyl at the equivalent position, lacking the and altering its and spectral properties. Yangonin, another prominent , features a fully unsaturated 2H-pyran-2-one core with a at the 4-position and a (E)-2-(4-methoxyphenyl)ethenyl at the 6-position.

Physical and Chemical Properties

Kavain is typically obtained as a to off-white crystalline , often described as a light yellow solid in purified forms. The compound has a reported of 105 °C. It exhibits low , with a estimated at approximately 433 °C at standard pressure, though practical handling occurs well below this due to risks. Kavain demonstrates moderate solubility in organic solvents, dissolving readily in (up to 20 mg/mL), , and acetone, which facilitates its extraction and analysis. In contrast, its in water is limited, approximately 0.016 mg/mL at 25 °C, classifying it as sparingly soluble and contributing to its poor aqueous without formulation aids. Regarding stability, kavain is sensitive to and , necessitating storage in vials under inert atmospheres to prevent degradation. It remains stable under neutral conditions but can degrade in strong acidic or basic environments due to potential of its ring. Spectroscopic supports : kavain shows a characteristic UV absorption maximum at 245 nm, useful for chromatographic detection. reveals key peaks, including the carbonyl stretch at approximately 1717 cm⁻¹ and aromatic C=C vibrations around 1626 cm⁻¹.

Natural Occurrence and Production

Natural Sources

Kavain is primarily found in the roots and rhizomes of Piper methysticum G. Forst. (Piperaceae), commonly known as the kava plant, where it typically constitutes 20–37% of the total kavalactones present in the lipid extract. The kavalactones, including kavain, are concentrated in the rootstock, with the six major compounds accounting for approximately 96% of the extractable lipids. Concentrations of kavain vary by plant part, with the highest levels occurring in lateral roots at approximately 2 mg/g dry weight, while leaves and stems contain substantially lower amounts, often less than 0.1 mg/g dry weight. These variations are influenced by factors such as plant age, type (e.g., vs. non-noble varieties), and growth conditions, with younger lateral roots generally exhibiting elevated kavain content compared to the main or aerial parts. Piper methysticum is native to the tropical Pacific Islands, including , , and , where it grows as a in shaded, moist environments. The plant is also cultivated in other tropical regions with comparable climates, such as parts of and , to meet demand for traditional and commercial uses.

Biosynthesis

Kavain, a principal kavalactone in Piper methysticum, is biosynthesized through a specialized pathway originating from the . The process begins with the of to form trans-cinnamic acid, catalyzed by (PAL). This intermediate undergoes activation to a thioester, followed by iterative chain via a type III (PKS) known as styrylpyrone synthase (SPS), which extends the chain with three units to form the styrylpyrone scaffold. Subsequent lactonization closes the pyrone ring, establishing the core structure of kavain. Tailoring modifications further diversify the kavalactone profile, including O-methylation at the C4 position of the pyrone ring by O-methyltransferases (OMTs) and steps mediated by enzymes. For kavain specifically, PmKLR1 (a reductase) stereospecifically reduces the precursor to the (+)- at the chiral center, while related enzymes like PmCYP719A26 handle modifications such as the methylenedioxy bridge in other . Yangonin synthase, a specialized variant, contributes to the formation of related compounds like yangonin but shares ancestry with the kavain pathway enzymes, all derived from synthase-like PKSs. These enzymes are encoded within clusters in the P. methysticum , spanning approximately 270 kb on scaffolds (NCBI : MK058492–MK058514), enabling coordinated expression for efficient metabolite production. Biosynthesis of kavain is predominantly localized in the root tissues of plants and is regulated by environmental cues. Expression of the pathway genes is upregulated in response to mechanical wounding or treatment with microbial elicitors, such as , which mimic attack and enhance kavalactone accumulation as a mechanism. This inducible regulation underscores the role of kavain in responses, with transcript levels of key PKS and P450 genes increasing up to 10-fold under conditions.

Isolation and Synthesis

Extraction Methods

Kavain, a major in (Piper methysticum), is primarily isolated from the and rhizomes through extraction techniques that target lipophilic compounds. Traditional methods involve aqueous or ethanolic of ground kava . In aqueous extraction, fresh or dried are shredded (0.1–3 mm), soaked in warm water (approximately 45°C) at a 1:3 weight-to-volume ratio, agitated, filtered, and the process repeated to maximize recovery, followed by evaporation to concentrate the extract. Ethanolic maceration uses 95% as the , where ground are mixed (1:8 ratio), extracted under at 60°C for about 1 hour, filtered, and evaporated under reduced pressure to yield a crude extract rich in including kavain. These methods are simple and align with historical preparation of kava beverages but often result in lower purity due to co-extraction of polar impurities. Modern extraction techniques enhance efficiency and purity, particularly (CO₂) extraction, which produces solvent-free isolates suitable for pharmaceutical applications. In this process, ground roots are loaded into an extraction vessel, and supercritical CO₂ (at 30–50°C and 200–400 bar) is passed through, optionally modified with 5–15% to improve yields of polar like kavain; the extract is then separated by depressurization. This method yields high-purity fractions, with kavain comprising a significant portion, and avoids residual solvents. As of October 2025, commercial supercritical CO₂ extracts, such as Super. Kavaton, are available in the and , produced without solvent residues. Solvent partitioning with (DCM) is another approach, where crude aqueous or ethanolic extracts are partitioned against DCM to selectively recover non-polar into the organic phase, which is then dried and concentrated. Purification of kavain from crude extracts typically involves chromatographic techniques. on (200–400 mesh) is commonly used, eluting with mixtures of and (e.g., 9:1 to 8:2 ratios) to isolate kavain-rich fractions. For analytical and preparative separation, (HPLC) employs reversed-phase C18 columns with a -water (e.g., 40–80% methanol over 30 minutes) as the mobile phase, detecting kavain at 240 nm UV absorbance. Yield optimization focuses on selection and conditions, with acetone at elevated temperatures proving most effective for recovery. Ground roots are extracted with acetone (1:10 ratio) at 50°C under or , filtered, and evaporated, achieving up to 28.6% w/w total from dry roots—higher than (10.9%) or (2.3%) due to acetone's superior solvency for . Accelerated variants further boost by applying and (e.g., 100–150°C, 100 ) in short cycles.

Chemical Synthesis

Kavain has been synthesized through various laboratory routes, with classical methods relying on straightforward condensations and cyclizations, while modern approaches emphasize asymmetric induction for the natural (R)-. One classical route involves a modified Reformatsky reaction using and an α-bromo ester in the presence of , followed by cyclization, methylation, and dehydration to form the α-pyrone ring and styryl side chain. This method affords kavain in yields several times higher than earlier procedures, typically around 30% overall. Modern asymmetric syntheses have enabled the preparation of enantiomerically pure (R)-kavain, often employing in reminiscent of Evans' methodology. For instance, N-acetyl thiazolidinethione serves as the in an with an appropriate , followed by malonate displacement, , and lactonization, completing the synthesis in 8–10 steps from common precursors like or malic acid derivatives. This route provides (R)-kavain in good enantioselectivity and moderate overall yields, such as 25–64% depending on optimization. A pivotal step in several syntheses is the Wittig olefination to construct the styryl side chain, where a derived from a benzyl halide reacts with a δ-valerolactone precursor. Stabilized ensure favoring the thermodynamically preferred E-isomer, essential for matching configuration. These synthetic methods facilitate the preparation of kavain analogs for structure-activity relationship () studies and isotopically labeled variants for metabolic investigations, bypassing reliance on natural extraction.

Pharmacology

Mechanism of Action

Kavain exerts its primary pharmacological effects through modulation of ion channels in neuronal membranes. It inhibits voltage-dependent sodium (Na⁺) channels by interacting with site 2 on the channel, as evidenced by dose-dependent suppression of [³H] binding with an IC₅₀ of 88 μM in rat brain synaptosomes. This blockade reduces sodium influx, thereby suppressing the 4-aminopyridine-induced increase in intracellular sodium concentration to 38% of control levels at 400 μM. Additionally, kavain blocks L-type calcium (Ca²⁺) channels, attenuating KCl- and veratridine-induced elevations in intracellular calcium and glutamate release in cerebrocortical synaptosomes, with significant inhibition at 400 μM, reducing KCl-evoked elevations in intracellular calcium to approximately 75% of control. These actions collectively diminish neuronal excitability. Kavain also influences neurotransmitter systems by potentiating GABA_A receptors, particularly at extrasynaptic sites containing α4β2δ subunits, where it enhances influx as a positive at concentrations of 10–300 μM. This effect is independent of the binding site, as demonstrated by lack of antagonism by , and is more pronounced on α4β2δ receptors compared to synaptic α1β2γ2 subtypes. Furthermore, kavain inhibits (MAO) enzymes, reducing the breakdown of serotonin and ; it shows potent reversible inhibition of MAO-B (IC₅₀ = 5.34 μM) and weaker activity against MAO-A (IC₅₀ = 19.0 μM) in recombinant enzymes. Beyond neuronal targets, kavain exhibits anti-inflammatory properties via inhibition of (COX) enzymes, suppressing and synthesis in human platelets with IC₅₀ values of 71 μM and 86 μM, respectively—comparable to aspirin's potency on these pathways. It also antagonizes the () efflux pump, a key ATP-binding cassette transporter, with an f₂ value of 17 μM in P388 cell lines, indicating moderate inhibition of drug efflux. Recent preclinical studies (as of 2024) have identified additional mechanisms, including inhibition of the HIF-1α/VEGF-A/VEGFR2 signaling pathway, reducing expression of (VEGF) and markers (e.g., TNF-α, IL-6) in models of , and suppression of signaling with alterations in cancer metabolism (e.g., reduced glucose shunting to the ) in urothelial tumorigenesis models. These molecular interactions culminate in reduced neuronal firing and enhanced inhibitory signaling, contributing to kavain's and effects observed in preclinical models, such as diminished population spikes in hippocampal slices (without affecting ).

Kavain exhibits rapid absorption following , primarily through passive in the intestines, with peak concentrations typically achieved within 1 to 2 hours post-dose. In studies involving a single oral dose of 800 mg, the time to maximum concentration (T_max) was approximately 1.8 hours, and maximum concentrations ranged from 10 to 40 ng/mL. Oral in humans has not been directly quantified but is inferred to be moderate based on detectable systemic exposure and animal data indicating around 50% in rats. The compound's high , characterized by a value of approximately 3.2, facilitates extensive tissue distribution, including penetration into the . In pharmacokinetic models, the volume of distribution is estimated at about 2.7 L/kg, reflecting broad distribution beyond plasma volume. Metabolism of kavain occurs predominantly in the liver via enzymes, including and , leading to oxidation products such as p-hydroxykavain, the primary metabolite. These metabolites undergo subsequent to form conjugates suitable for excretion. Excretion is primarily renal, with kavain itself not detected unchanged in ; instead, approximately 70% of the dose is eliminated as metabolites within 24 hours. The elimination in humans is about 9 hours, contributing to its relatively short duration of action.

Therapeutic Uses

Traditional Uses

preparations rich in kavain, a principal from the Piper methysticum root, have been integral to ceremonies for over 3,000 years, originating in northern and spreading across the region through Polynesian migration. In , these beverages facilitate social bonding and relaxation during formal yaqona ceremonies, which accompany significant events like weddings, political gatherings, and religious rituals, promoting communal harmony without the aggression associated with . In traditional Pacific medicine, kava serves ethnopharmacological roles in addressing anxiety, insomnia, and muscle tension, with root extracts prepared as aqueous infusions to induce calming and sedative effects. These remedies, consumed orally, typically deliver 100–300 mg of kavain equivalents per serving, derived from grinding and straining 20–50 grams of dried root in water, allowing for gradual absorption during evening rituals. Practices exhibit regional variations; in , is ritualistically shared among men in nakamals—communal meeting spaces—for and life-cycle events like marriages, often incorporating multiple alongside kavain for purported benefits to enhance sociability and intimacy, with applications extending to oral ingestion or topical use for localized relaxation. Kavain itself was first isolated in the as part of early chemical analyses of resin, yet its traditional applications in these cultures extend millennia prior to European documentation in the late .

Modern Research and Clinical Applications

research on kavain, the primary in extracts, has focused on its and sedative properties, drawing from clinical trials of standardized preparations where kavain constitutes a significant portion (typically 30-40%) of the active . A key phase II-equivalent randomized, double-blind, multi-center trial involving 129 outpatients with demonstrated that extract LI 150, administered at 400 mg/day (yielding approximately 120 mg total , including kavain), was comparably effective to (10 mg/day) and (100 mg/day) in alleviating anxiety symptoms over 8 weeks, as measured by the , while exhibiting fewer adverse effects such as drowsiness or gastrointestinal upset. This supports kavain's role in and anxiety relief at doses equivalent to 100-200 mg/day of total in extract form, though isolated kavain trials remain scarce. Beyond anxiety, preclinical investigations have highlighted kavain's potential in other therapeutic areas. In models, kavain displayed activity by inhibiting voltage-operated sodium channels in CA1 hippocampal neurons, reducing neuronal excitability at concentrations relevant to therapeutic exposure. Similarly, kavain analogs have shown effects in models; for instance, Kava-241, a synthetic of kavain, significantly reduced , inflammatory cell infiltration, and COX-mediated production in a murine gingivalis-induced model, suggesting kavain's involvement in inhibition pathways. Human clinical data on kavain remain limited, with no FDA-approved formulations available to date. A small pilot trial with 21 active smokers reported that one week of supplementation (225 mg /day, kavain-enriched) lowered and urinary cortisol equivalents, potentially linking kavain to . Larger randomized controlled trials are needed to validate these findings and explore long-term efficacy. Preclinical ion channel data further indicate promise for kavain as an adjunct in therapy, warranting targeted human studies. A 2024 preclinical study found that , including kavain, supported motivation to engage in during intensive training in mice, suggesting potential applications in performance enhancement and reduction.

Safety Profile

Toxicity and Adverse Effects

Kavain exhibits low in animal models, with an oral LD50 value exceeding 1000 mg/kg in mice, indicating a wide margin of compared to typical therapeutic doses of extracts containing kavain, which range from 70 to 250 mg of daily. At these human-equivalent doses, no significant adverse effects have been observed in short-term studies, underscoring the compound's generally favorable profile when used appropriately. Regarding hepatotoxicity, kavain demonstrates minimal direct cytotoxic effects on hepatocytes, as evidenced by low lactate dehydrogenase release and cell viability reduction in HepG2 cell assays, in contrast to flavokavains A and B, which potently induce liver through mechanisms independent of cytochrome P450 (CYP) enzyme inhibition. Unlike flavokavains, which exhibit strong inhibitory activity against and other isoforms potentially contributing to metabolic disruptions and , kavain shows substantially reduced CYP inhibition, further limiting its role in kava-associated . Common adverse effects of kavain, primarily observed through its prominence in kava preparations, include drowsiness and mild , particularly at doses exceeding 300 mg of , though these are typically transient and resolve upon discontinuation. Rare dermatological reactions, such as kava dermopathy manifesting as dry, scaly skin, have been reported with chronic exposure, but these are infrequent and reversible with cessation of use. In long-term studies, extracts containing kavain have demonstrated carcinogenic effects in . The National Toxicology Program (NTP TR 571) found clear evidence of carcinogenic activity in male rats () and male mice ( and alveolar/bronchiolar ), some evidence in female rats (), and equivocal evidence in female mice (). The human relevance of these findings remains uncertain due to high doses used. In 2015, the International Agency for Research on Cancer (IARC) classified extract as possibly carcinogenic to humans (Group 2B). However, prolonged high-dose use of , where kavain is a major component, carries a potential for mild , characterized by symptoms like anxiety upon abrupt cessation, though this risk remains low compared to conventional anxiolytics.

Drug Interactions and Contraindications

Kavain, as a major constituent of , inhibits 3A4 (), potentially leading to pharmacokinetic interactions by reducing the of coadministered drugs that are CYP3A4 substrates, such as certain statins (e.g., simvastatin) and benzodiazepines (e.g., ). This inhibition may result in elevated plasma levels of these medications, necessitating monitoring of therapeutic effects and adverse reactions when kavain is used concurrently. Pharmacodynamically, kavain exhibits additive sedative effects with and other (CNS) depressants, including benzodiazepines and barbiturates, due to its modulation of GABA_A receptors, which can enhance overall CNS depression and increase risks of drowsiness, impaired coordination, and respiratory depression. Kavain is contraindicated in patients with , as kava-derived compounds, including kavain, have been associated with that could exacerbate existing hepatic impairment. It is also contraindicated during due to limited safety data and potential risks, although no direct evidence of teratogenicity has been established in animal models. Caution is advised with monoamine oxidase inhibitors (MAOIs), as kavain reversibly inhibits MAO-A (Ki = 7.72 μM) and MAO-B (Ki = 5.10 μM), potentially leading to additive effects on monoamine levels and an increased risk of . For elderly patients or those on anticoagulants, dose adjustments and close monitoring are recommended, given kavain's antiplatelet activity, which inhibits arachidonic acid-induced platelet aggregation ( = 78 μmol/L) and synthesis, potentially heightening bleeding risk when combined with agents.

Regulatory Status

Legal Regulations

Kavain, a principal found in ( methysticum), is subject to regulations primarily through controls on kava products rather than the isolated compound itself. In the , kava was effectively banned as a food and in medicinal products in 2002 following reports of associated with its use, leading to the suspension of marketing authorizations across member states. This measure targeted kava extracts containing kavain and other due to concerns over liver safety, though isolated kavain has not been specifically prohibited. Recent developments, including a 2024 German court ruling, have allowed the marketing of certain kava-derived medicinal products from varieties (those high in kavain and low in potentially hepatotoxic flavokavains), potentially paving the way for limited reintroduction in parts of the EU. In the United States, kavain-containing kava is permitted as a dietary ingredient under the Dietary Supplement Health and Education Act (DSHEA) of 1994, but the (FDA) has issued consumer advisories warning of potential severe liver injury risks. The FDA does not classify kava as a , allowing its sale in supplements and beverages, though manufacturers must include labeling on liver risks, and it remains under surveillance for safety. Country-specific restrictions vary: In the , is prohibited for use in medicinal products under the Medicines for Human Use (Kava-kava) (Prohibition) Order 2002 and banned in foods under separate regulations, with no authorized products currently available, though a UK Kava Coalition was launched in August 2025 to champion Pacific Island culture and 's traditional use. In , regulates as a natural health product requiring a Natural Product Number (NPN) for sale, restricting it to licensed formulations for therapeutic use while prohibiting unauthorized supplements due to hepatotoxicity concerns. Australia similarly confines to pharmaceutical and traditional cultural uses under the , with a 2023 review by Food Standards Australia New Zealand permitting varieties in limited quantities (up to 250 mg per dose) for non-medicinal purposes; in October 2025, the Australian government confirmed a ban on the of within the country due to concerns over potential . These regulations generally focus on whole kava extracts rather than pure kavain, reflecting broader safety evaluations of the plant material. The (WHO) has assessed traditional use—typically involving noble varieties prepared from peeled roots—as safe when consumed in moderation, attributing past issues to poor-quality extracts or non-traditional preparations rather than kavain specifically.

Availability and Commercial Use

Kavain is primarily available as a component of (Piper methysticum) extracts rather than in isolated form, with commercial products typically standardized to contain 30-70% total , including kavain as a major constituent. These extracts are commonly marketed in capsules (50-250 mg per dose, equivalent to 75-225 mg ), tinctures, and powders for oral consumption, often promoted for relaxation and stress relief. Pure kavain, however, remains rare outside research settings, where it is used in pharmaceutical-grade formulations for clinical investigations, such as standardized capsules delivering specific doses in anxiety trials. In the market, kava extracts containing kavain are sold as dietary supplements primarily in Pacific Island regions like and , where they originate, as well as through online retailers and health stores in the United States, , and . , a leading exporter, supplies a significant portion of global kava products, with noble cultivars selected for their high kavain content to meet international demand. Pharmaceutical-grade versions, such as those used in clinical trials for , are produced under controlled conditions but are not widely available to consumers. Quality control for kavain-containing products is guided by reference standards from organizations like the (USP), which provides powdered extract references for identity, strength, and purity testing in dietary supplements, though specific kavain purity thresholds are not universally mandated beyond general content (e.g., at least 3% kavain in raw roots). Contamination risks, including and microbial pathogens from poor sourcing in non-noble cultivars, persist despite these standards, prompting industry guidelines for testing limits on , , and toxins. The global kava root extract market, encompassing kavain-rich products, was valued at approximately $1.61 billion in 2024 (as of 2024 data) and is projected to reach $5.45 billion by 2032, driven by demand in nutraceuticals and beverages. Exports favor kavain-rich noble cultivars from and , which command premium prices due to their balanced profiles and compliance with international safety regulations.