Methysticin

(2R)-2-[(E)-2-(1,3-benzodioxol-5-yl)ethenyl]-4-methoxy-2,3-dihydropyran-6-one

Overview

Methysticin belongs to Anxiolytics.

Key safety note: Methysticin is a kavalactone consumed as part of kava, not in isolation, and kava is generally mild but carries real cautions.[3][2]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • As part of kava: calmness, relaxation, reduced anxiety and a sociable, talkative phase, typically followed by muscle relaxation and sleepiness, often with a characteristic numbing of the mouth and tongue.
  • Effects are mild and, at moderate doses, reported without much impairment of clear thinking. Higher doses are more sedating and impair coordination and driving.
  • Offset is gentle. Kava is not associated with the marked withdrawal or craving seen with benzodiazepines or alcohol, though heavy chronic use can cause kava dermopathy and apathy.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Not dosed in isolation. Methysticin is taken only as one component of kava: traditionally a water-based root beverage, or as an extract/capsule standardised to total kavalactones.. There is no established dose of methysticin on its own. It is consumed as part of kava, whose strength is expressed as total kavalactone content and varies widely between products. The figure below is rough context for kava, not a dose of pure methysticin or a 'safe' amount. Key harm-reduction points: prefer water-based extracts of noble kava root from a reputable source, avoid alcohol and other hepatotoxic or sedating drugs, don't use it daily for long periods, avoid it entirely with any liver disease, and don't drive after use.

Dose ranges

Kava context (total kavalactones, anxiety)

≈100–250 mg total kavalactones/day (methysticin is only one of six)

Duration

Chemical & Physical Properties
FormulaC15H14O5
Molar mass274.27 g/mol
StateSolid (crystalline)
Melting pointNot reported
Boiling pointNot reported
DensityNot reported
Vapor pressureNot reported
pKaNot reported
LogP2.4 (predicted, XLogP3)
SolubilityNot reported
Refractive indexNot reported
Identifiers & Synonyms
CAS495-85-2
CAS (enantiomer)
PubChem CID5281567
InChIKeyGTEXBOVBADJOQH-FWEMWIAWSA-N
InChIInChI=1S/C15H14O5/c1-17-12-7-11(20-15(16)8-12)4-2-10-3-5-13-14(6-10)19-9-18-13/h2-6,8,11H,7,9H2,1H3/b4-2+/t11-/m0/s1
SMILESCOC1=CC(=O)O[C@H](C1)/C=C/C2=CC3=C(C=C2)OCO3

Synonyms

  • (+)-Methysticin
  • Kavalactone
Pharmacodynamics & Biochemistry

Methysticin is one of the six major kavalactones (kava pyrones) in kava (Piper methysticum), a Pacific-island plant whose root is prepared as a traditional relaxing, mildly sedating anxiolytic beverage. The naturally occurring form is (+)-(6R)-methysticin, and it is one of the constituents that contribute to kava's calming effects. It is a plant constituent rather than a drug used on its own. Like the other kavalactones it works through several low-affinity mechanisms rather than one high-affinity receptor. It is a positive allosteric modulator of the GABA-A receptor that does not bind the benzodiazepine site, (+)-methysticin increases GABA-A ligand ([3H]bicuculline) binding by roughly 18–28%, while kava pyrones as a class block voltage-gated sodium and calcium channels, reversibly inhibit monoamine oxidase B (MAO-B) and inhibit noradrenaline reuptake. Together these actions reduce neuronal excitability and underlie kava's anxiolytic, mild sedative, muscle-relaxant and anticonvulsant effects. These are micromolar functional potencies rather than nanomolar receptor binding, which is why methysticin is not curated in receptor-binding databases and no clean binding table is given here. Methysticin has attracted separate research interest as a cytoprotective compound: it activates the Nrf2/ARE antioxidant pathway and inhibits NF-κB, and oral methysticin reduced neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of Alzheimer's disease. It is also a potent mechanism-based inhibitor of the drug-metabolising enzyme CYP2C9 and an inducer of CYP1A1: relevant both to herb–drug interactions and to the debate over kava's liver toxicity.

Biological targets

  • GABA-A
  • VGCC
Pharmacokinetics
BioavailabilityNot reported
TmaxNot reported
Half-lifeShort (kavalactones ≈1–2 h), pharmacokinetics of isolated methysticin in humans are not well characterised
VdNot reported
Protein bindingNot reported
MetabolismHepatic (kavalactone). Methysticin is a mechanism-based inactivator of CYP2C9 and an inducer of CYP1A1, so it both undergoes and interferes with cytochrome-P450 metabolism.
ExcretionNot reported
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Methysticin is a kavalactone consumed as part of kava, not in isolation, and kava is generally mild but carries real cautions. The most serious is rare but potentially severe liver injury (hepatotoxicity) linked to kava products, which prompted regulatory bans and warnings in several countries. The risk appears higher with poor-quality or organic-solvent extracts, non-noble varieties, heavy or prolonged use, and combination with alcohol or other liver-stressing drugs. Kava causes dose-dependent sedation and impairs coordination and driving, and heavy long-term use can cause a reversible scaly skin condition ('kava dermopathy'). Because methysticin is a potent mechanism-based CYP2C9 inhibitor it can raise the levels of drugs cleared by that enzyme (e.g. warfarin, phenytoin, many NSAIDs). Avoid in liver disease, in pregnancy and breastfeeding, and combine cautiously: its sedation adds to that of alcohol, benzodiazepines and other depressants. It is not physically addictive in the way benzodiazepines are.[3][2]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

Drugs cleared by shared CYP enzymes (e.g. CYP2C9, CYP3A4) A mechanism-based CYP2C9 inhibitor, so it can raise levels of warfarin, phenytoin, many NSAIDs and some sulfonylureas.[2]
Alcohol, Benzodiazepines Additive sedation, and alcohol adds to the hepatotoxicity risk.[3]
Other hepatotoxic drugs Additive risk of liver injury with other potentially hepatotoxic drugs or supplements.[3]
Dopaminergic drugs (levodopa, dopamine agonists) Levodopa: kava has been reported to worsen Parkinsonian symptoms (possible dopamine antagonism).[3]

Contraindications

Kidney or liver impairment liver disease or raised liver enzymes.[3]
Pregnancy or breastfeeding[3]
Combining with alcohol or other CNS depressants concurrent alcohol or other sedatives and depressants.[3]
Settings where impairment or dissociation risks injury (driving, water, heights) before driving or operating machinery.[2]
Usage & Context
  • Not used on its own: methysticin is one of the kavalactones responsible for the effects of kava (Piper methysticum), whose root is traditionally prepared as a water-based beverage across the Pacific islands for its relaxing, sociable, mildly sedating effect.
  • In the West kava is sold as an anxiolytic dietary supplement or (in some countries) a herbal medicine, standardised to total kavalactone content rather than to methysticin specifically.
  • Methysticin itself is mainly of research interest, as a marker kavalactone and, more recently, as a neuroprotective/anti-inflammatory Nrf2 activator studied in preclinical models.
Sources & Evidence

Further Information