Dihydromethysticin

Dihydromethysticin at a Glance

Dihydromethysticin, usually abbreviated DHM, is one of the six major kavalactones (styryl-pyrones) that carry most of the activity of kava (Piper methysticum). Structurally it is the 5,6-dihydro analog of methysticin — the same molecule with the pyrone ring’s 5,6-double bond reduced — and, like its parent, it carries a methylenedioxyphenyl group. It makes up roughly 8.7-13% of the total kavalactone fraction of kava root ^{8Reference 8Wang et al. · 2015Kavalactone content and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varietiesView study →}.

DHM has two quite different research signatures. The older one is anticonvulsant: the 5,6-hydrogenated kava pyrones (DHM and dihydrokavain) suppress chemically- and electrically-induced seizures in classic rodent work ^{7Reference 7Kretzschmar et al. · 1969Kretzschmar, R., & Meyer, H. J. (1969). [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum: antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning] [animal]. Arch Int Pharmacodyn Ther. https://pubmed.ncbi.nlm.nih.gov/5371178/View study →}. The newer one is cancer chemoprevention: in a focused body of mouse studies, dietary DHM is a remarkably potent blocker of tobacco-carcinogen (NNK)-induced lung tumorigenesis ^{1,2Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 2Hu et al. · 2020AnimalOral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]View study →}.

The single most useful thing to add to kava’s contested safety story is a negative result. When researchers dissected which kava constituent drives the herb’s liver-toxicity signal, DHM was exonerated — the hepatotoxic synergism tracked the chalcone flavokawain B, not the kavalactones ^{6Reference 6Narayanapillai et al. · 2014AnimalFlavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]View study →}. Nearly all of the evidence here is preclinical and much of it comes from a single research programme, so read the per-application basis carefully.

A Kava Pyrone With Two Distinct Signatures

DHM is unusual among the kavalactones in that its two best-evidenced activities sit in almost unrelated fields.

The anticonvulsant pyrone. DHM belongs to the 5,6-hydrogenated subset of kava pyrones. In classic pharmacology these dihydro pyrones antagonised strychnine poisoning and suppressed electroshock/chemically-induced convulsions in rodents ^{7Reference 7Kretzschmar et al. · 1969Kretzschmar, R., & Meyer, H. J. (1969). [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum: antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning] [animal]. Arch Int Pharmacodyn Ther. https://pubmed.ncbi.nlm.nih.gov/5371178/View study →}, and the effect is usually read alongside the broader kavalactone-class actions on voltage-gated sodium channels (well characterised for the parent methysticin and for kavain) and on the GABA-A binding site ^{9,10Reference 9Boonen et al. · 1998In vitroInfluence of genuine kavapyrone enantiomers on the GABA-A binding site [in vitro]View study →Reference 10Magura et al. · 1997AnimalKava extract ingredients (+)-methysticin and (±)-kavain inhibit voltage-operated Na⁺-channels in rat CA1 hippocampal neurons [animal]View study →}. This places DHM in kava’s sedative-anticonvulsant-antispasmodic lineage rather than making it a stand-alone anxiolytic drug.

The lung-chemopreventive lead. In A/J mice given the tobacco-specific nitrosamine NNK, dietary (+)-DHM at 50 ppm reduced lung adenoma multiplicity by ~97% — and synthetic (±)-DHM was equally potent, while the structurally similar dihydrokavain had no activity, a sharp in-vivo structure-activity relationship ^{1Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →}. Follow-up work traced the mechanism to reduced formation of the promutagenic DNA adduct O6-methylguanine, increased glucuronidation of the NNK metabolite NNAL, and a DNA-damage-independent arm involving suppression of protein kinase A signalling ^{2,3,4,5Reference 2Hu et al. · 2020AnimalOral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]View study →Reference 3Narayanapillai et al. · 2016Dihydromethysticin (DHM) blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced O6-methylguanine in a manner independent of P450 enzyme activity [animal]View study →Reference 4Narayanapillai et al. · 2016AnimalDietary dihydromethysticin increases glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in A/J mice [animal]View study →Reference 5Bian et al. · 2022Suppressing the activation of protein kinase A as a DNA damage-independent mechanistic lead for dihydromethysticin prophylaxis of NNK-induced lung tumorigenesis [animal]View study →}.

Which Kava Constituent Is Hepatotoxic?

Kava’s central safety controversy is rare but real idiosyncratic liver injury associated with some (mostly ethanolic/acetonic, and non-noble or aerial-part) preparations. For years the field asked which molecule is responsible — and the kavalactones, as the pharmacologically active fraction, were an obvious suspect. DHM is a clean test case for that question, and the answer is instructive.

In a controlled mouse experiment, kava constituents were tested for their ability to potentiate acetaminophen (APAP)-induced hepatotoxicity — a sensitised model of drug-induced liver injury. The chalcones flavokawain A and flavokawain B recapitulated kava’s hepatotoxic synergism with APAP (higher serum transaminases, worse liver lesions), whereas dihydromethysticin had no such effect ^{6Reference 6Narayanapillai et al. · 2014AnimalFlavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]View study →}. Consistent with that, in the lung-chemoprevention work DHM produced no adverse effects at ten times the effective dose ^{1Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →}, and in vitro the kavalactones are markedly less cytotoxic to HepG2 hepatocytes than the leaf/stem-peeling alkaloid pipermethystine ^{16Reference 16Nerurkar et al. · 2004In vitroIn vitro toxicity of kava alkaloid pipermethystine in HepG2 cells compared to kavalactones [in vitro]View study →}.

The upshot: kava’s hepatotoxicity signal points away from the kavalactones and toward minor chalcones (flavokawain B) and the wrong-plant-part alkaloid (pipermethystine) ^{6,14,16Reference 6Narayanapillai et al. · 2014AnimalFlavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]View study →Reference 14Teschke et al. · 2011ReviewHerbal hepatotoxicity by kava — update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits [review]View study →Reference 16Nerurkar et al. · 2004In vitroIn vitro toxicity of kava alkaloid pipermethystine in HepG2 cells compared to kavalactones [in vitro]View study →}. This does not make kava products safe by fiat — the herb still carries its liver-injury caution at the product level — but it does mean DHM itself is not the culprit, and it is exactly why DHM could be advanced as a chemopreventive lead.

What It's Used For

DHM’s evidence base is preclinical and lopsided: a deep, single-programme body of mouse lung-chemoprevention work on the isolate, plus older class-level anticonvulsant/CNS pharmacology in which DHM is one of several dihydro pyrones. There are no efficacy trials of isolated DHM in humans.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. All scores here are preclinical by design (no human isolate trials), and the chemoprevention data, while striking, come largely from one research programme.

01Lung cancer chemoprevention (tobacco NNK)Promising46%Multiple in-vivo mouse studies of the isolate; ~97% adenoma reduction + defined mechanism, but single-lab and preclinical ^{1,2,3,4,5Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 2Hu et al. · 2020AnimalOral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]View study →Reference 3Narayanapillai et al. · 2016Dihydromethysticin (DHM) blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced O6-methylguanine in a manner independent of P450 enzyme activity [animal]View study →Reference 4Narayanapillai et al. · 2016AnimalDietary dihydromethysticin increases glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in A/J mice [animal]View study →Reference 5Bian et al. · 2022Suppressing the activation of protein kinase A as a DNA damage-independent mechanistic lead for dihydromethysticin prophylaxis of NNK-induced lung tumorigenesis [animal]View study →}

02Anticonvulsant / antispasmodicShaky30%Classic rodent work on the 5,6-hydrogenated pyrones; Na⁺-channel action shown for the parent methysticin ^{7,10Reference 7Kretzschmar et al. · 1969Kretzschmar, R., & Meyer, H. J. (1969). [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum: antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning] [animal]. Arch Int Pharmacodyn Ther. https://pubmed.ncbi.nlm.nih.gov/5371178/View study →Reference 10Magura et al. · 1997AnimalKava extract ingredients (+)-methysticin and (±)-kavain inhibit voltage-operated Na⁺-channels in rat CA1 hippocampal neurons [animal]View study →}

03Sedative / anxiolytic (kavalactone class)Shaky24%GABA-A binding-site modulation by kavapyrones; DHM is one of six lactones in whole-kava anxiety data ^{9Reference 9Boonen et al. · 1998In vitroInfluence of genuine kavapyrone enantiomers on the GABA-A binding site [in vitro]View study →}

Mechanisms

The chemoprevention mechanism is the best-resolved part of DHM’s biology — it works on both the “block the carcinogen” (adduct/glucuronidation) and “block the signalling” (PKA) sides. The CNS actions are largely inferred from the kavalactone class rather than mapped for DHM alone.

Pharmacokinetics

Human PK of isolated DHM is not established. What exists is preclinical and class-level: kavalactones are moderately-to-well permeable across a Caco-2 intestinal monolayer ^{13Reference 13Matthias et al. · 2007In vitroPermeability studies of kavalactones using a Caco-2 cell monolayer model [in vitro]View study →}, and are metabolised by hepatic cytochrome P450 in rat liver microsomes ^{12Reference 12Fu et al. · 2012In vitroKavalactone metabolism in rat liver microsomes [in vitro]View study →}; kava extracts and kavalactones are also inhibitors of CYP3A4, the practical basis for kava’s drug-interaction caution ^{11Reference 11Unger et al. · 2002In vitroInhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (kava-kava) [in vitro]View study →}. The chemoprevention studies dosed DHM orally (dietary or gavage) and showed activity, so oral exposure reaches relevant tissue in mice ^{1,2Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 2Hu et al. · 2020AnimalOral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]View study →} — but a Cmax, half-life and oral-bioavailability figure for the pure compound in humans is not on record, and the effective mouse dietary dose is well above kava-beverage exposure. Treat any systemic-effect claim for DHM cautiously until human isolate PK is characterised.

Clinical Trials

There are no clinical trials of isolated dihydromethysticin. Human evidence involving DHM is indirect — it is a constituent of the standardised whole-kava extracts studied in generalised-anxiety RCTs, where the intervention is total-kavalactone, not DHM. The lung-chemoprevention programme is preclinical (A/J mouse), though it has been explicitly framed as a lead toward future prevention studies ^{1,2Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 2Hu et al. · 2020AnimalOral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]View study →}.

Last checked: July 2026.

Isolate vs. Plant Studies

DHM’s evidence base splits by field. The chemoprevention work is unambiguously the isolate — natural (+)-DHM and synthetic (±)-DHM tested as pure compounds in defined mouse diets, with a structure-activity comparison against isolated dihydrokavain ^{1Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →} — which is a genuine methodological strength, even though it remains single-programme and preclinical. The CNS/anticonvulsant evidence is more class- and plant-flavoured: the anticonvulsant data are for the dihydro-pyrone pair ^{7Reference 7Kretzschmar et al. · 1969Kretzschmar, R., & Meyer, H. J. (1969). [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum: antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning] [animal]. Arch Int Pharmacodyn Ther. https://pubmed.ncbi.nlm.nih.gov/5371178/View study →}, the best-mapped sodium-channel mechanism was shown for methysticin and kavain ^{10Reference 10Magura et al. · 1997AnimalKava extract ingredients (+)-methysticin and (±)-kavain inhibit voltage-operated Na⁺-channels in rat CA1 hippocampal neurons [animal]View study →}, and the human anxiolytic record is for whole kava extract, within which DHM is one of six active lactones ^{9Reference 9Boonen et al. · 1998In vitroInfluence of genuine kavapyrone enantiomers on the GABA-A binding site [in vitro]View study →}. So: strong isolate data for chemoprevention, largely class/whole-plant data for the CNS effects — do not read the two as interchangeable.

Prevalence in Nature

DHM is essentially a kava-specific molecule. It occurs in the root and rhizome of Piper methysticum, where the six major kavalactones together make up roughly 3-20% of the dried root and DHM contributes about 8.7-13% of that kavalactone fraction ^{8Reference 8Wang et al. · 2015Kavalactone content and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varietiesView study →}. Its share, like the whole kavalactone profile, shifts markedly between cultivars and chemotypes — noble vs. two-day (tudei) and wichmannii types differ in lactone ratios (and, separately, in their load of the safety-relevant chalcone flavokawain B) — and root vs. rhizome and the extraction solvent change what ends up in a preparation ^{8Reference 8Wang et al. · 2015Kavalactone content and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varietiesView study →}. Outside kava, DHM is reported only in trace amounts, if at all, in a few other Piper species; there is no significant non-kava dietary source.

Discovery & Synthesis

DHM is one of the six major kavalactones named as the kava pyrones were resolved in mid-20th-century phytochemistry; a precise first-isolation record for dihydromethysticin specifically is not well documented. Its earliest distinct pharmacology comes from Kretzschmar and Meyer’s 1969 work on the natural 5,6-hydrogenated kava pyrones, which set DHM (with dihydrokavain) apart from the unsaturated lactones by its anticonvulsant, strychnine-antagonising action ^{7Reference 7Kretzschmar et al. · 1969Kretzschmar, R., & Meyer, H. J. (1969). [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum: antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning] [animal]. Arch Int Pharmacodyn Ther. https://pubmed.ncbi.nlm.nih.gov/5371178/View study →}. Modern interest revived it from a different direction entirely: the University of Minnesota chemoprevention programme prepared and tested both natural (+)-DHM and synthetic (±)-DHM, confirming the synthetic racemate matched the natural compound’s anti-tumorigenic potency and running iterative structure-activity analogue work around the scaffold ^{1,15Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 15Puppala et al. · 2017AnimalPilot in vivo structure-activity relationship of dihydromethysticin in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced O6-methylguanine and lung tumor formation in A/J mice [animal]View study →}. Manufacture today is accordingly two-track — extraction from kava root for the natural (+)-enantiomer, and total synthesis for research-grade (±)-DHM and analogues — with no large-scale commercial production of the isolate as a stand-alone product.

Patents: not yet researched.

Toxicity & Safety

DHM carries a low flag as an isolated molecule. It is the kava constituent that, when specifically tested, did not potentiate acetaminophen liver injury and showed no adverse effects at ten times its effective chemopreventive dose in mice ^{1,6Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 6Narayanapillai et al. · 2014AnimalFlavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]View study →}. The cautions below are mostly kava-class issues that attach to any kavalactone-containing product rather than to DHM in isolation, and they are why exposure decisions belong on the kava herb page, where intake is actually chosen.

Safety at a Glance

✅ Low / no toxicitySedating

• The exonerated kavalactone. In the study that asked, DHM did not drive kava’s liver-toxicity signal — that tracked the chalcone flavokawain B — and DHM was well tolerated at 10× its effective dose in mice ^{1,6Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →Reference 6Narayanapillai et al. · 2014AnimalFlavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]View study →}.
• Kava-class hepatotoxicity is a product-level caution. Rare idiosyncratic liver injury is associated with some kava preparations; the culprits implicated are flavokawain B and the aerial-part alkaloid pipermethystine, not DHM, but anyone using kava products should heed the herb-level warning ^{6,14,16Reference 6Narayanapillai et al. · 2014AnimalFlavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]View study →Reference 14Teschke et al. · 2011ReviewHerbal hepatotoxicity by kava — update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits [review]View study →Reference 16Nerurkar et al. · 2004In vitroIn vitro toxicity of kava alkaloid pipermethystine in HepG2 cells compared to kavalactones [in vitro]View study →}.
• CYP3A4 inhibition → drug interactions. Kavalactones inhibit CYP3A4, so kava can raise levels of co-administered CYP3A4 substrates; this is a class effect relevant wherever DHM is taken as part of kava ^{11Reference 11Unger et al. · 2002In vitroInhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (kava-kava) [in vitro]View study →}.
• Additive sedation. As part of kava’s sedative pyrone set, DHM plausibly adds to alcohol and other CNS depressants — a class caution more relevant to whole-kava intake than to trace exposure.

Pregnancy/lactation is a per-herb decision and is not adjudicated on this molecule page; it belongs to the kava monograph, where intake is decided. No isolate-specific reproductive dataset for DHM is characterised here.

Dosage

There is no established or recommended human dose for isolated dihydromethysticin. The best-characterised figures are preclinical: dietary (+)-DHM at 0.05 mg/g of diet (50 ppm) blocked NNK-induced lung tumorigenesis in mice, with no adverse effects at ten times that level ^{1Reference 1Narayanapillai et al. · 2014AnimalDihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]View study →}, and oral dosing ahead of the carcinogen was effective in the prophylactic schedule ^{2Reference 2Hu et al. · 2020AnimalOral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]View study →}. These are mouse research doses, not convertible to human self-dosing.

Human exposure to DHM is indirect — it comes as one of six kavalactones in whole-root kava preparations standardised to total kavalactones, not as an isolated dose. These are doses studied in research and are not a personal recommendation.

References

1. Narayanapillai, S. C., Balbo, S., Leitzman, P., et al. (2014). Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differential regulation of DNA damage in A/J mice [animal]. Carcinogenesis. https://pubmed.ncbi.nlm.nih.gov/25053626/
2. Hu, Q., Corral, P., Narayanapillai, S. C., et al. (2020). Oral dosing of dihydromethysticin ahead of tobacco carcinogen NNK effectively prevents lung tumorigenesis in A/J mice [animal]. Chem Res Toxicol. https://pubmed.ncbi.nlm.nih.gov/32476407/
3. Narayanapillai, S. C., Lin, S. H., Leitzman, P., et al. (2016). Dihydromethysticin (DHM) blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced O6-methylguanine in a manner independent of P450 enzyme activity [animal]. Chem Res Toxicol. https://pubmed.ncbi.nlm.nih.gov/27728767/
4. Narayanapillai, S. C., Leitzman, P., Upadhyaya, P., et al. (2016). Dietary dihydromethysticin increases glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in A/J mice [animal]. Drug Metab Dispos. https://pubmed.ncbi.nlm.nih.gov/26744252/
5. Bian, T., Ding, H., Wang, Y., et al. (2022). Suppressing the activation of protein kinase A as a DNA damage-independent mechanistic lead for dihydromethysticin prophylaxis of NNK-induced lung tumorigenesis [animal]. Carcinogenesis. https://pubmed.ncbi.nlm.nih.gov/35353881/
6. Narayanapillai, S. C., Leitzman, P., O’Sullivan, M. G., & Xing, C. (2014). Flavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice [animal]. Chem Res Toxicol. https://pubmed.ncbi.nlm.nih.gov/25185080/
7. Kretzschmar, R., & Meyer, H. J. (1969). [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum: antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning] [animal]. Arch Int Pharmacodyn Ther. https://pubmed.ncbi.nlm.nih.gov/5371178/
8. Wang, J., Qu, W., Bittenbender, H. C., & Li, Q. X. (2015). Kavalactone content and chemotype of kava beverages prepared from roots and rhizomes of Isa and Mahakea varieties. J Food Sci Technol. https://pubmed.ncbi.nlm.nih.gov/25694734/
9. Boonen, G., & Häberlein, H. (1998). Influence of genuine kavapyrone enantiomers on the GABA-A binding site [in vitro]. Planta Med. https://pubmed.ncbi.nlm.nih.gov/9776662/
10. Magura, E. I., Kopanitsa, M. V., Gleitz, J., et al. (1997). Kava extract ingredients (+)-methysticin and (±)-kavain inhibit voltage-operated Na⁺-channels in rat CA1 hippocampal neurons [animal]. Neuroscience. https://pubmed.ncbi.nlm.nih.gov/9300426/
11. Unger, M., Holzgrabe, U., Jacobsen, W., et al. (2002). Inhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (kava-kava) [in vitro]. Planta Med. https://pubmed.ncbi.nlm.nih.gov/12494328/
12. Fu, S., Rowe, A., & Ramzan, I. (2012). Kavalactone metabolism in rat liver microsomes [in vitro]. Phytother Res. https://pubmed.ncbi.nlm.nih.gov/22807255/
13. Matthias, A., Blanchfield, J. T., Penman, K. G., et al. (2007). Permeability studies of kavalactones using a Caco-2 cell monolayer model [in vitro]. J Clin Pharm Ther. https://pubmed.ncbi.nlm.nih.gov/17489874/
14. Teschke, R., Qiu, S. X., & Lebot, V. (2011). Herbal hepatotoxicity by kava — update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits [review]. Dig Liver Dis. https://pubmed.ncbi.nlm.nih.gov/21377431/
15. Puppala, M., Narayanapillai, S. C., Leitzman, P., et al. (2017). Pilot in vivo structure-activity relationship of dihydromethysticin in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced O6-methylguanine and lung tumor formation in A/J mice [animal]. J Med Chem. https://pubmed.ncbi.nlm.nih.gov/28806079/
16. Nerurkar, P. V., Dragull, K., & Tang, C. S. (2004). In vitro toxicity of kava alkaloid pipermethystine in HepG2 cells compared to kavalactones [in vitro]. Toxicol Sci. https://pubmed.ncbi.nlm.nih.gov/14737001/

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