**Serum Concentrations after single 200mg dose of racemic kavain resulted in concentrations of 18ng/ml (.1um) after 1 hour**
-This is important to understand as many of these studies perform research on concentrations in vitro (outside of living organisms) that are far higher than anything we might see in a living system. Keep an eye on what they use for dosages throughout the following studies.
Standard dosages range from 3mg/kg to 10mg/kg in a traditional kava drinking scenario. This of course will depend on the drinkers level of comfort. 3mg/kg will end up being around 250mg of kavalactones, where 10mg/kg will end up being somewhere around 800mg of kavalactones. This should give you a reference as to what we normally see.
Tarbah, F., H. Mahler, B. Kardel, W. Weinmann, D. Hafner, and Th Daldrup. 2003. “Kinetics of Kavain and Its Metabolites after Oral Application.” Journal of Chromatography B 789 (1): 115–30. https://doi.org/10.1016/S1570-0232(03)00046-1. |
The kavalactones are given numbers based on their retention time in HPLC in increasing time order.
Figure Source: Lebot, V. and J. Levesque. “The origin and distribution of kava piper methysticum forst. f. piperaceae a phytochemical approach.” (1989).
1.
Desmethoxyyangonin (DMY) - Generally the scarcest of the 6 kavalactones in most kava root and not much is known about its effects or pharmacology. Induces CYP2A23 activity. Potent inhibitor of CYP1A2, and CYP2C19. May play a role in the increasing and decreasing rate of metabolism of some specific compounds. Has shown in invitro studies to increase dopamine levels.
Sources:
Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats
Study Link:
https://www.sciencedirect.com/science/article/abs/pii/S0278584698000621
Desmethoxyyangonin and dihydromethysticin are two major pharmacological kavalactones with marked activity on the induction of CYP3A23
Study Link:
https://pubmed.ncbi.nlm.nih.gov/15282211/
Effects of Kava (Kava-kava, ‘Awa, Yaqona, Piper Methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes.
Study Link:
https://pubmed.ncbi.nlm.nih.gov/15185840/
2.
Dihydrokavain (DHK) - First isolated by Winzheimer in 1908. "heavy" kavalactone. Found highest concentrations in the leaves of the plant, but also readily found in the roots. Effects include sedation, muscle relaxation; moderately long-lasting. Plays major role in anxiety reduction. No significant changes in dopamine levels are reported with this kavalactone.
Sources:
Klohs, M W. “Chemistry of kava.”
Psychopharmacology bulletin vol. 4,3 (1967): 10.
Kavalactones and dihydrokavain modulate GABAergic activity in a rat gastric-brainstem preparation
Study Link:
https://pubmed.ncbi.nlm.nih.gov/12494336/
Anxiolytic effects of kava extract and kavalactones in the chick social separation-stress paradigm
Study Link:
https://link.springer.com/article/10.1007/s002130100686
Effect of Kava Extract and Individual Kavapyrones on Neurotransmitter Levels in the Nucleus Accumbens of Rats.
Study Link:
https://doi.org/10.1016/s0278-5846(98)00062-1
Inhibition of TNFα-Induced Activation of Nuclear Factor κB by Kava (Piper Methysticum) Derivatives.
Study Link:
https://doi.org/10.1016/j.bcp.2005.12.032.
3.
Yangonin (Y) - First isolated by Reidel in 1904. This is the only kavalactone known to drastically
decrease dopamine in research. Known to be a ligand at the CB1 cannabinoid receptor, but whether this plays a role in subjective effects is unknown. Clearly inhibits CYP1A2, and CYP2C19 isoforms, but had no effect on CYP2D6 or CYP2E1. Also shown to have the most potent MAOI activity of the 6 kavalactones. Also plays a role as an anti-oxidant. Protective effect on cholestasis or when the flow of bile from the liver is blocked or reduced. Decreases synthesis of bile acids. Induces autophagy and sensitizes bladders cancers cells to FKA. Shown to protect against non-alcoholic fatty liver disease. May play a significant part in dopamine modulation. Several studies have shown a sharp decrease in dopamine levels followed by a steady return to baseline. Generally accounts for 10%-20% of total kavalactones, and only found in significant concentrations in the roots
Sources:
Klohs, M W. “Chemistry of kava.”
Psychopharmacology bulletin vol. 4,3 (1967): 10.
Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand
Study Link:
https://pubmed.ncbi.nlm.nih.gov/22525682/
Protective effects of yangonin from an edible botanical Kava against lithocholic acid-induced cholestasis and hepatotoxicity
Study Link:
https://www.researchgate.net/public...c_acid-induced_cholestasis_and_hepatotoxicity
Effects of Kava (Kava-kava, ‘Awa, Yaqona, Piper Methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes.
Study Link:
https://pubmed.ncbi.nlm.nih.gov/15185840/
Kava and Dopamine Antagonism.
Study Link:
https://doi.org/10.1136/jnnp.58.5.639
Interaction of Various Piper Methysticum Cultivars with CNS Receptors in Vitro.
Study Link:
https://doi.org/10.1055/s-2001-14334
Effect of Kava Extract and Individual Kavapyrones on Neurotransmitter Levels in the Nucleus Accumbens of Rats.
Study Link:
https://doi.org/10.1016/s0278-5846(98)00062-1
Kavalactone Yangonin Induces Autophagy and Sensitizes Bladder Cancer Cells to Flavokawain A and Docetaxel via Inhibition of the mTOR Pathway.
Study Link:
https://doi.org/10.7555/JBR.31.20160160
Yangonin Protects against Non-Alcoholic Fatty Liver Disease through Farnesoid X Receptor.
Study Link:
https://doi.org/10.1016/j.phymed.2018.09.006
4.
Kavain (K) - the main heady kavalactone. Kicks in quickly and for a short duration, effects are mental relaxation, euphoria, feelings of well-being. Shown to enhance ligand binding in GABA receptors but at an atypical site (not the GABA nor benzodiazepine binding site). Known to block voltage-gated fast-acting sodium and calcium channels. Anti-inflammatory effects, cancer reduction, and neuroprotection. Shown to reduce glutamate release. Has shown to increase levels of dopamine in the brain. Increases sleep time and decrease sleep latency. Shown in studies to markedly increase delta brainwave activity in sleep disturbed rats.
Sources:
Kinetics of kavain and its metabolites after oral application
Study Link:
https://www.sciencedirect.com/science/article/abs/pii/S1570023203000461
Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism
Study Link:
https://doi.org/10.1371/journal.pone.0157700
Kavain inhibition of LPS-induced TNF-α via ERK/LITAF
Study Link:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764096/
Therapeutic potential of kava in the treatment of anxiety disorders
Study Link:
https://pubmed.ncbi.nlm.nih.gov/12383029/
Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)
Study Link:
https://pubmed.ncbi.nlm.nih.gov/31539917/
Neuroprotective effects of (+/-)-kavain in the MPTP mouse model of Parkinson's disease
Study Link:
https://pubmed.ncbi.nlm.nih.gov/11170221/
Magura, E. I. 1996. “Effects of (±)-Kavain on Inactivation of Voltage-Operated Na+ Channels.”
Study Link:
https://doi.org/10.1007/BF02262780
Effect of Kava Extract and Individual Kavapyrones on Neurotransmitter Levels in the Nucleus Accumbens of Rats.
Study Link:
https://doi.org/10.1016/s0278-5846(98)00062-1
Hypnotic and Sleep Quality–Enhancing Properties of Kavain in Sleep-Disturbed Rats.
Study Link:
https://doi.org/10.1254/jphs.09167FP.
In Vivo Microdialysis Study of (±)-Kavain on Veratridine-Induced Glutamate Release.
Study Link:
https://doi.org/10.1016/S0014-2999(98)00234-9
5.
Dihydromethysticin (DHM) - First isolated by Winzheimer in 1908. Found concentrated highest in kava leaves. very sedating and long-lasting, can cause nausea. The likely culprit behind the next-day sluggishness after a large kava session. DHM is generally pretty low in noble kavas since it's generally the most undesirable kavalactone and has been selected against over the hundreds (or thousands) of years of kava domestication. Along with methysticin, this KL has been seen to induce CYP1A1 enzymes. Likely the KL that causes the analgesic (pain relief) effect. Affects cyclooxygenase enzymes and has been found that 120mg/kg DHM were equal to 200mg/kg pain relief actions of aspirin. Can block the effects of strychnine poisoning. Also may block some carcinogenesis (cancer formation) by reducing DNA damage in tobacco consumers. Also may work together with methysticin to exhibit neuroprotective effects in strokes.
Sources:
Methysticin and 7,8-Dihydromethysticin are Two Major Kavalactones in Kava Extract to Induce CYP1A1
Study Link:
https://doi.org/10.1093/toxsci/kfr235
Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice
Study Link:
https://pubmed.ncbi.nlm.nih.gov/25053626/
Cyclooxygenase enzyme inhibitory compounds with antioxidant activities from Piper methysticum (kava kava) roots
Study Link:
https://pubmed.ncbi.nlm.nih.gov/11924763/
Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents
Study Link:
https://www.sciencedirect.com/science/article/abs/pii/0014299992900375
Inhibition of TNFα-Induced Activation of Nuclear Factor κB by Kava (Piper Methysticum) Derivatives.
Study Link:
https://doi.org/10.1016/j.bcp.2005.12.032.
Klohs, Murle W. 1967. “Ethnopharmacologic Search for Psychoactive Drugs.” In Chemistry of Kava, 126–32.
6.
Methysticin (M) - The first kavalactone to be isolated in research by Cuzent in 1861. Known to act a sodium channel blocker/antagonist (along with kavain). Known as a potent CYP1A1 inducer at the gene expression level, protein expression level, and enzymatic activity. Possible inhibitor of CYP2C19. Shows moderate inhibition at CYP1A2, CYP2C9 and CYP2E1 in vitro. Shows anti-oxidant activity. Anti-convulsant and neuroprotective properties have been shown. This KL blocks all forms of induced epilepsy. Protects against oxidative stress, and inflammation. Also improved long term memory models in mice with induced Alzheimer's disease.
Sources:
Klohs, M W. “Chemistry of kava.”
Psychopharmacology bulletin vol. 4,3 (1967): 10.
Effects of methysticin on three different models of seizure like events studied in rat hippocampal and entorhinal cortex slices
Study Link:
https://pubmed.ncbi.nlm.nih.gov/7630425/
Methysticin and 7,8-Dihydromethysticin are Two Major Kavalactones in Kava Extract to Induce CYP1A1
Study Link:
https://academic.oup.com/toxsci/article/124/2/388/1685738?login=true
Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention
Study Link:
https://doi.org/10.1186/1471-2407-9-187
Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease
Study Link:
https://www.sciencedirect.com/science/article/pii/S2213231717302471
Effects of Kava (Kava-kava, ‘Awa, Yaqona, Piper Methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes.
Study Link:
https://pubmed.ncbi.nlm.nih.gov/15185840/