Hi all,
Our friends and Forney/Root and Pestle have completed another research project and have asked us to share their findings here. It's certainly a longish piece, but def worth reading if you are interested in kava's pharmacology. I hope you enjoy it!
Disclaimer: Don’t use this post as a basis to determine what’s safe to combine with kava and what isn’t. Consult with a qualified medical practitioner instead.
Notes: Due to technical limitations in posting with Greek characters (such as the names of enzyme subunits and molecular compounds), we’ve used some approximate substitutions. We appreciate your understanding regarding these slight inaccuracies and hope it doesn’t detract too much from the value of the content. Same with formatting. We might try to edit things back in properly, after the fact.
Kava is a fascinating drink. Its incredible psychotropic effects are well documented, yet the captivating biomolecular interactions behind them are often obscured behind repetitions of generic, outdated, or oversimplified summaries or hidden like sparsely sprinkled Easter eggs down long rabbit holes deep into perplexing scientific literature. For those of you who have spent any time investigating this topic, you have probably found comprehensive information to be elusive, scattered, and conflicting; If you have found yourself dissatisfied with superficial explanations like, “kava acts at GABA receptors and ion channels” or tired of sifting through mountains of lengthy technical papers to try to envision a more complete picture of kava’s intricate pharmacology, this post is for you.
Here at Root & Pestle R&D, we are attempting to give you something unique – not just in terms of kava analysis data, but also better information. The aim of this post is to give you a more comprehensive summary on kava’s pharmacology than has been compiled elsewhere, but still a summary, without all of the hundreds (or thousands) of pages of supporting material that would be necessary to troll through in order to find these mechanisms yourself in peer-reviewed papers. In doing so, we’ll be getting much deeper into the esoteric territory of molecular biology than many may want to venture, so we’ll leave it up to you whether this is a journey you feel comfortable embarking upon or not. In any case, please know from the outset that it’s going to be an exploration into a niche topic full of technical jargon, and that this is meant to be more of a list than an explanation; We’re trying to strike a balance between completeness, correctness, and conciseness, and we can’t do that if we get bogged down by too many background details.
For those of you who want to skip this one, we understand, and we still greatly appreciate you. We are happy to meet you at the next topic. For those of you who really do want to understand what’s going on inside your body when you knock back a shell, read on and use this list as a jumping point to guide your investigative discovery.
So, why is kava pharmacology tricky and what contributes to its enigmatic nature?
Kava exerts many of its therapeutic effects (like promoting calmness and a sense of wellbeing) by acting to reduce the excitability of the brain’s limbic system (an integral part of the central nervous system involved in emotions and behaviour), but there is certainly more to it than that. The pharmacology of the active compounds in kava is diverse and can be confusing, and contrary to common misconceptions, not limited to the 6 major kavalactones (Although the complete secondary metabolome of kava has not yet been defined, there are still roughly 100 compounds found in kava which have now been characterised, including at least a dozen other pyrones – the “minor” kavalactones, 3 chalcones – flavokavains A, B, and C, several flavonoids – such as vitexin, orientin, and isoorientin, and the more recently reported isosakuranetin, 2′,4′-dihydroxy-6′-methoxydihydrochalcone and alpinetin, as well as sterols – such as stigmasterol, have been identified in kava, all contributing as part of a molecular orchestra to the symphonic experience of this beautiful beverage), although kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are of course the major players for most of the psychoactive effects and for many of the physiological effects.[1]
Specific cultivar, along with the ratio of rhizome (basal roots or chips) to lateral roots (and subsequent kavalactone ratios and concentrations), the processing and preparation methods (which can lead to variations in overall extraction efficiency or cause some kavalactones (or other compounds) to be extracted preferentially), and other factors (including the physiology and nutritional or therapeutic regime of the imbiber) may all affect pharmacological activity. These variations, even if small, can lead to big differences in effect, as the compounds in kava don’t exert their actions alone, but in mysterious and glorious synergy with each other; It is well established that the biological activity of one kavalactone alone is not the same as when it is administered along with other kavalactones. This quirk means that it cannot be said that because one particular kavalactone was observed to have a particular effect, particularly in vitro, that the same effect will be observed following ingestion of kava. Mechanisms of action are elusive for much of the activity observed with kava, and a complete consensus has not yet been reached, but we will try to give you a summary of some of the more important interactions, as we believe them to be.
A few caveats:
Note that this post, unlike most of our others, is not intended to be aimed at a broad audience nor do we claim that it is either accessible enough for the masses, nor faultless enough in its accuracy for the experts; It is not a scientific article intended for publication in a peer-reviewed journal, but neither is it an editorial to entertain the casual reader, rather this is a unique attempt to collate much of the fundamental pharmacological mechanisms into one free-to-access reference for anyone with a good understanding of (or interest in) pharmacology and more than a passing curiosity in kava, but who is not a professional researcher able to spend countless hours, weeks, or years sifting through the literature to compile a similar list for themselves. Feel free to skip it if it isn’t your jam; While many people are satisfied enough to enjoy kava and its effects without probing too intensely into the technical details, we know there are those amongst you who have been seeking a well-investigated list like this, so we hope for at least a few, we have provided a helpful resource.
We believe the information assembled here to be true in its translation and transcription, and we hope we have parleyed the results gleaned by pharmacologists correctly to our readers, but please don’t crucify us when you discover a result somewhere in your investigative journey that does not corroborate what you read here; We are trying not to be contentious, but to some extent that is impossible for compounds whose mechanisms are still being elucidated and for which much research remains. In other cases, conflicting results have been published – What we have listed here are our best interpretations of what is going on when the molecular machinery in our bodies interacts with the compounds in your kava, so please take this all with a grain of salt and as stimulus to do your own digging; If it is critical that the information you ingest is certain to be error free, this may not be the article for you, although we think we’ve gotten it mostly right.
Another important consideration when you’re considering kava’s mechanisms of action is dosage. Great expense and immense investigative efforts have been applied towards attempts at finding toxicity, although the results virtually always come up either lacking, or (perhaps to the horror of the funding bodies) discover benefits. These efforts have largely been made in attempt to justify otherwise unjustifiable regulatory control or outright bans of kava products worldwide, particularly after the German kava ban in the early 2000s (the “science” which supported it now having been fully debunked, and regulatory agencies worldwide looking more and more favourably upon kava all the time). As such, many published pharmacological interpretations stem from research conducted with concentrations of kavalactones at their potential sites of action far greater than what would likely be expected from recreational use, and without the balance of the full spectrum of molecules present in a typical aqueous extraction – administering pure kavain directly to a cultured Petri dish of cells is not the same as absorbing squeezed kava powder in the form of a beverage through the gastrointestinal tract. Nevertheless, some of the studies we’ve pulled our list from only found activity of compounds within kava at molecular targets in the brain at (sometimes unrealistically) high concentrations, so again, this information should be considered critically – nobody fully understands how kava works its magic on our minds, and many in vitro studies at high molar concentrations are all but irrelevant in the context of drinking kava.
Just to give you a rough idea, pharmacokinetic studies in animal models sometimes administer a single kavalactone at 100 mg/kg, which would be the equivalent of a person weighing 75 kg consuming 7.5 g of one kavalactone. If its relative abundance in the drink is similar to the other kavalactones, that would be a total consumption of about 45 g of pure kavalactones, which is perhaps 65 times more than one would expect to find in a 200 mL shell of strong kava; Studies often cite molar concentrations orders of magnitude higher than what would likely be encountered by people enjoying traditionally prepared kava recreationally, and therefore many results of pharmacological studies may be essentially meaningless in a holistic sense.
With that disclaimer out of the way, let’s get down to business.
First, a few random warm-up concepts and a tiny bit of pharmacological ADME:
Kavalactones are not believed to act through opioid pathways; Their biological activity is unaffected by co-administration of naloxone.
Absorption of kavalactones has been found to be significantly reduced if consumed with food.
Kavalactones are lipophilic and undergo more rapid absorption in the gut than in the upper gastrointestinal tract. They are highly mobile and permeate membranes easily; Permeation rates in order of fastest to slowest are believed to be dihydromethysticin > yangonin > kavain > methysticin > desmethoxyyangonin (ranging from around 0.4 um/s down to about 0.26 um/s). The permeation rate of dihydrokavain was not found in the literature, but based on its chemical structure it is probably similarly swift.
Dihydrokavain and kavain attain high concentrations in the brain very rapidly but are also eliminated rapidly. Desmethoxyyangonin and yangonin reach lower maximum concentrations in the brain but are eliminated slowly. All kavalactones cross the blood-brain barrier readily.
The systemic exposure of the kavalactones after oral dosing has been found to be dihydrokavain > dihydromethysticin > kavain > methysticin > yangonin > desmethoxyyangonin.[2]
Time to reach peak plasma concentrations are generally less than 3 h for orally ingested kavalactones, often much quicker. One study reported that kavain and dihydrokavain reached maximum concentrations in a mouse brain within 5 minutes of intraperitoneal administration.
Higher exposure to kavalactones has been found to occur if a full dose is taken at once rather than split into smaller doses and consumed over a longer period of time. Dividing a large dose into smaller portions consumed over time has resulted in a longer duration of exposure.
There is proportionality in pharmacokinetics with kavalactone doses.
A 225 mg oral dose of combined kavalactones (equivalent to a relatively small/weak shell) has been shown to yield a plasma concentration in the ballpark of 1 to 140 ng/mL for each kavalactone.
Kavalactones are metabolized by CYP450 enzymes (more details on this later).
Metabolic transformations of kavalactones are many, but often involve demethylation of the 4‑methoxy substituent of the alphapyrone ring or reduction of the 3,4-double bond. For yangonin, demethylation of the 12-methoxy has been reported. For desmethoxyyangonin, C-12 has been reported to be hydroxylated. We won’t go into much more depth on metabolism here as the market for recipients of such information is even more niche, and metabolites of kavalactones aren’t that difficult to look up, if you’re interested in such things.
In animal models, kavain has been found to be excreted 77% in urine and 14% in faeces within 72 hours. It seems that other kavalactones and their metabolites are also excreted relatively quickly.
So, what are the molecular targets of kava?
GABAA receptors: gamma-aminobutyric acid (GABA), this receptor’s normal ligand, reduces neuronal excitability in the central nervous system and is the chief inhibitory neurotransmitter in humans. Kavalactones are positive allosteric modulators (PAMs) of GABAA receptors, increasing the activity of the receptor and enhancing the inhibitory effects of GABA. We have seen some evidence to support the idea that kavalactones bind to the benzodiazepine site on GABAA receptors, however, the modulatory effect of kavain has been shown to be unaffected by flumazenil in at least one study, leading to the conclusion that kavain does not enhance GABAA receptors via the classical benzodiazepine binding site. Kavain has, however, been shown by others to bind at a1B2, B2y2L, axB2y2L (x = 1, 2, 3 and 5), a1Bxy2L (x = 1, 2 and 3) and a4B2delta GABAA receptors and to positively modulate all GABAA receptors (to some extent) regardless of the subunit composition, with enhancement greater at a4B2delta than at a1B2y2L GABAA receptors. In addition to their positive allosteric modulation of GABAA receptors, it is believed that the biosynthesis of GABAA receptor antagonist eicosanoid thromboxane A2 is also inhibited by kavalactones.[3]
N-methyl-D-aspartate (NMDA) receptors: Kavalactones have been found to inhibit the activity of NMDA receptors by binding to the receptor at a site distinct from glutamate, which along with glycine, D-serine, and aspartate, is the primary endogenous ligand. Overactivation of this receptor significantly contributes to neural death and has been associated with neurological disorders such as Alzheimer’s, Parkinson’s, Huntington’s, and epilepsy, but the activity of NMDA receptors isn’t all bad – they are important to learning and memory functions by mediating synaptic plasticity. Many psychoactive drugs block NMDA receptor activity, contributing to the analgesic and anaesthetic effects of some of them. Methysticin and yangonin exert their inhibition by directly blocking the NMDA receptor’s ion channel. Although NMDA receptor inhibition by kavalactones seems to be close to consensus, it should be noted that there have been reports that kavalactones may potentiate glycine binding, which enhances NMDA receptor activity.[4],[5],[6],[7]
The GABA and NMDA activity is thought to underlie the anxiolytic and sedative effects of kava, although kava’s effect on GABAergic activity, and even more so, its mechanism, is an ongoing topic of debate in some circles.
Dopamine receptors: Many people hear “dopamine” and automatically synonymise it with “the happy chemical”. It’s a bit more complicated than that, but for the purposes of this post we’ll think of the interactions with dopamine receptors as affecting pleasure and motivational salience. Kavalactones have been found to interact with several dopamine receptor subtypes, including D2, D3, and D4 receptors, and possibly D1 too. The precise mechanisms by which kavalactones modulate dopamine receptor activity are not yet fully understood and may vary between subtype and kavalactone. Changes in dopamine concentration or signalling initiated by kava are certainly not due exclusively to direct interaction with dopamine receptors (inhibition of metabolic enzymes, among other things, also plays a role), but they are involved. Kava’s influence on dopamine concentration seems more to do with preventing a decrease via re-uptake inhibition rather than stimulating an increase, but in any case, kava may prolong or increase the effects of dopaminergic activity.[8] As with all kava pharmacology though, it can get a bit weird here too: Low doses of kavain have been shown to decrease dopamine, while higher doses have been shown to either not substantially affect dopamine’s concentration or to increase it. Yangonin results in a decrease of dopamine levels, so again, the chemotype of the kava being consumed may influence the overall pharmacological effect.[9]
Activation of the mesolimbic dopaminergic neurons may contribute to the euphoria and relaxation that many people report after consumption of kava.[10]
Serotonin receptors: Kavalactones have been found to interact with several serotonin receptor subtypes, including 5-HT1A, 5-HT2A, and 5-HT6 receptors.[11] The effects of kavalactones on these receptors are complex and unsurprisingly may vary depending on the specific receptor subtype and the ratios and concentration of kavalactones; Kavalactones acting at 5-HT1A are partial agonists, but are antagonists of 5-HT2A, to illustrate this point. Some studies have found that kavain decreases serotonin concentrations, while others have found that kavain seems to increase serotonin enrichment and decrease shunting of glucose to the pentose phosphate pathway. This interaction may contribute to its anti-inflammatory properties.[12],[13],[14]
The results of some studies suggest that the sleep-inducing action of kava is due at least in part to changes of activity at clusters of neurons expressing 5-HT receptors.
Voltage-gated ion channels: Kavalactones have been found to interact with several types of voltage-gated ion channels, including calcium channels, sodium channels, and potassium channels. Binding to sodium channels by kavain and methysticin has been reported to occur when the ion channels are in their inactivated state, prolonging inactivation. Some research suggests that binding occurs on the sodium channel at receptor site 2, which is commonly targeted by local anaesthetic agents. In any case, kavalactones have a weak antagonistic effect on Na+ channels, pronounced antagonistic effect on L-type Ca2+ channels, and act as positive modulators of outward K+ current. Inhibition of sodium and calcium ion channels by kavalactones would contribute to diminished excitatory neurotransmitter release, which is in good alignment with kava’s documented muscle relaxant and anticonvulsant properties.[15],[16],[17]
Transient receptor potential (TRP) family of ion channels: Kava is hypothesised to possess non‑kavalactone ligands for TRPs. Although a complete justification for this hypothesis is beyond the scope of this post, it is due in part to the reported observation that immunocytes do not exhibit calcium mobilisation in response to partially purified kava extracts (which still contain kavalactones), but immunocytes do induce these calcium responses upon exposure to traditionally prepared aqueous extracts of kava. Under patch clamp, TRP-like conductances have been observed in cells treated with kava, and it is thought that some of the kava pharmacology may therefore be attributable to TRP-mediated cellular effects.[18]
Noradrenaline: Reuptake inhibition into synaptosomes has been observed in vitro upon exposure to kavalactones. Norepinephrine-induced intracellular calcium influx has also been reported to be inhibited by kavalactones in lung cancer cells. Noradrenaline reuptake inhibition has been proposed as a partial explanation for the anxiolytic capacity of kava and also may contribute to the reported chemoprotective potential against carcinogen induced tumorigenesis.[19],[20]
Cannabinoid receptor type 1 (CB1): Yangonin is the only kavalactone which has been documented to bind to cannabinoid receptors with moderate affinity for CB1 (Ki = 0.72 uM). It has good selectivity over CB2 (Ki > 10 uM), although the functional activity remains unknown. It has been postulated that this interaction with the endocannabinoid system may contribute to the psychopharmacology of kava, however, given that the Ki of delta-9-tetrahydrocannabinol (THC, the main active compound in cannabis) is 0.0041 uM, and taking into account the strong influence kavalactones exert on other molecular targets, it seems that most of the psychoactive effects of kava are likely due to non-cannabinoidergic mediated interactions. Relatedly, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are 2 important metabolic enzymes in the cannabinoid system against which kavalactones have been assessed for their inhibitory potential, and none was found.[21]
Monoamine oxidase enzymes (MAOs): Kavalactones have been found to reversibly inhibit both MAO-A and MAO-B, which are enzymes involved in the metabolism of neurotransmitters such as dopamine and serotonin. The potency of kavalactones at MAO-B is reported to be considerably stronger (approximately 2 to 25 times stronger) than at MAO-A. Of the kavalactones, yangonin has been shown to be the most potent MAO inhibitor, however, one in vitro study determined the order of potency of platelet MAO-B inhibitions to be desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-)-dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain. MAO inhibition is thought to contribute to the mood-elevating effects of kava.[22],[23],[24]
Lysine-Specific Demethylase 1 (LSD1): Kavalactones inhibit LSD1, which is thought to play a role in kava’s reported ability to hinder cancer development and tumorigenesis.[25],[26]
Liver carboxylesterase 1 (hCE-1, CES1, CES1A1, serine esterase 1, SES1, monocyte esterase, cholesterol ester hydrolase, or CEH): This widely distributed enzyme (which is particularly concentrated in the liver and notably poorly concentrated in the gastrointestinal tract) is involved in the metabolism of a huge range of structurally divergent xenobiotics (including methylphenidate, clopidogrel, cocaine, and heroin) and is also responsible for activating many prodrugs, including oseltamivir and dabigatran. It is inhibited by kavalactones (competitively by kavain, dihydrokavain, and desmethoxyyangonin, and mixed competitive-noncompetitively by methysticin, dihydromethysticin, and yangonin), so there is the possibility for drug-drug interactions, however, the inhibition constants for each of the major kavalactones have been reported to range from around 25 – 35 uM (for yangonin, desmethoxyyangonin, and methysticin, respectively) up to around 68 – 105 uM (for dihydromethysticin, kavain, and dihydrokavain, respectively), so considerable (perhaps > 1 g) kavalactone consumption would likely precede clinically relevant inhibition.[27]
Neuromuscular junction (NMJ): There is evidence that the inhibitory-excitatory balance of neurotransmission within the NMJ is disrupted by kavalactones, likely due to their agonism of acetylcholine (ACh) receptors, however, kavain alone is not believed to agonise Ach receptors. Exacerbated Ach signalling induced by kavalactones may be mediated by nicotinic receptor ACR-2, which is expressed in cholinergic motor neurons, however, the jury is still out on this one, as is the hypothesis that increased Ach signalling in response to kavalactones may be due to inhibition of acetylcholinesterase (AChE), the enzyme found in muscles and nerves at postsynaptic neuromuscular junctions which rapidly breaks down ACh. Whatever the exact mechanism, sensitivity to kavalactones has been shown to be greatly altered in animal models (C. elegans) with modifications to genes involved in Ach transmission.[28],[29],[30],[31]
Protein arginine methyltransferase 5 (PRMT5): Flavokavain A has been found to inhibit this potential therapeutic target for bladder cancer by binding to Y304 and F580 of the enzyme, blocking the symmetric arginine dimethylation of histone H2A and H4.[32]
Cyclooxygenase 1 and cyclooxygenase 2 (COX-1 and COX-2): These enzymes, which serve to convert arachidonic acid to prostaglandins, have been reported to be inhibited by yangonin and dihydrokavain.[33] The go-to drugs for treating many kinds of inflammatory conditions, including rheumatoid arthritis, have been Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), which also work by inhibiting cyclooxygenase enzymes. Selective COX-2 inhibitors have been used as anti-pyretics, analgesics, and highly effective anti-inflammatories, so it would make sense that some of the reported anti-inflammatory activity of kava may be due to COX inhibition.
On a side note, some COX inhibitors, like aspirin, inhibit platelet aggregation and act as blood thinners. There have been anecdotal claims (largely from anonymous and non-expert sources on Reddit), that because kava contains compounds like yangonin and dihydrokavain that interact with COX enzymes, it must have a strong blood thinning effect too. To date, there is no substantial evidence in the scientific literature to support this claim, and there are other COX inhibitors (such as celecoxib and meloxicam, among others) which are known not to have blood thinning effects. While kava’s interaction with COX enzymes might contribute to its anti-inflammatory effects, the idea that it has a significant anticoagulant effect is speculative, and we have seen no robust empirical evidence indicating that kava affects blood clotting.
Note too that Flavokavain A has been reported to supress the expression of COX-2 and inducible nitric oxide synthase (iNOS) in macrophages via blockade of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) and activator protein 1 (AP-1) activation (and the subsequent production of nitrous oxide and prostaglandin E2), which could also contribute to the molecular basis for some of kava’s reported anti-inflammatory properties.[34] Further along this path, some of the neuroprotective effects reported of kavalactones are believed to be mediated by the P38/nuclear factor-kappa B /cyclooxygenase 2 signalling pathway, although kavalactone-mediated upregulation of antioxidation enzymes is also believed to be important in this regard.[35]
P-glycoprotein 1 (also called multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 (CD243) or permeability glycoprotein or P-gp or Pgp): kava has been shown in vitro to moderately inhibit this ATP-dependent cell membrane efflux pump, the normal purpose of which is to pump foreign substances out of cells, including exogenous drugs. Inhibition would therefore increase the bioavailability of susceptible drugs (and other kavalactones). On the other hand, a study on digoxin pharmacokinetics conducted on healthy volunteers found no statistically significant modulation of Pgp following a small daily dose (equivalent to 225 mg of kavalactones per day) of kava, suggesting that this molecular target (as is the case with many others) is unlikely to become relevant for potential drug-drug interactions with kava until the extent of exposure is increased considerably.[36]
Human cytochrome P450s: Kavalactones have been shown to inhibit some important hepatic P450 enzymes, including those involved in the metabolism of the large majority of pharmaceutical drugs, however, the majority of CYP inhibition studies as they relate to kava constituents have been done in vitro and often at concentrations which may not be clinically relevant to most consumers.
Inhibition of these enzymes by kava is mostly due to methysticin and dihydromethysticin, and to a lesser extent desmethoxyyangonin, and for some of them the inhibition has been reported to be relatively profound in extent and duration, so drug-drug interactions with kava are conceptually possible, especially for cultivars with relatively high methysticin or dihydromethysticin content, but in a practical sense these suspected drug-drug interactions seem to be reported somewhat infrequently in the clinical setting.
The inhibition capacity of kavain on P450s is seemingly very low, with some reports showing that it does not directly inhibit CYP isoenzymes at all, however, kavalactones on the whole have been shown to inhibit a number of CYPs, sometimes potently, so it is best to err in favour of caution and not consume kava alongside other compounds reliant on these pathways for their metabolism.
Following are the most noteworthy kavalactone/P450 interactions we have found reported in the literature.
CYP2E1 (for which normal substrates include chlorzoxazone, acetaminophen, theophylline, and ethanol) is reportedly inhibited by kavalactones, and unlike most other CYP isozymes has been found to have appreciably decreased activity (around 40%) with chronic ingestion of kava. That said, another study has found 2E1 activity to be unaffected after being incubated for 15 minutes with 100 uM total kavalactones, so perhaps serious drug-drug interactions involving this enzyme may only become significant after prolonged or high levels of exposure.
Percent inhibition of specific CYPs at 100 uM (total kavalactones) incubation for 15 minutes [37]:
CYP1A2 (56%), 2C9 (92%) (2C9 is important for metabolism of barbiturates, NSAIDs, and warfarin), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%).
CYP2A6 and 2C8 activities were unaffected.
Percent inhibition of specific CYPs at incubation with 10 uM of individual kavalactones kavain, desmethoxyyangonin, methysticin, and dihydromethysticin:
CYP2C9, 2C19, 2D6, and 3A4 were not inhibited by kavain.
CYP2C9 by desmethoxyyangonin (42%), methysticin (58%), and dihydromethysticin (69%).
2C19 by dihydromethysticin (76%).
2D6 by methysticin (44%).
3A4 (important in the metabolism of benzodiazepines) by desmethoxyyangonin (40%), methysticin (27%), and dihydromethysticin (54%).
CYP1A2 has been reported to be inhibited most potently by desmethoxyyangonin.
CYP4A11 and CYP2C9 are structurally inhibited by kavalactones. It has been noted that CYP2F22 is structurally similar and may play a role in kava dermopathy, which is sometimes reported following long-term consumption of large doses; It is possible that CYP2F22 becomes reversibly inhibited by kavalactones after long periods of exposure to large amounts. On that note, cinnamic acid bornyl ester has been identified in kava. Mast cell calcium channel TRPA1 is activated by cinnamic acid and has been associated with contact dermatitis. Although the safety of kava has been well established, there have been reports of reversible dermopathies (mostly amongst high-dosing chronic users), and we thought it might be prudent to note these potential relationships, as solutions are usually easier to solve once potential causes have been established. Anyway, back to the P450s…
CYP1A2, CYP3A4, CYP2D6, and CYP2C19 have reportedly been found to be inhibited by kavalactones, so there may be potential for drug-drug interactions with compounds metabolised by these enzymes, however there are also studies which show these enzymes are either only inhibited weakly, or not at all with relatively low doses of kava, and CYP3A4/5, CYP2D6, and CYP1A2, have been reported to be (mostly) unaffected by kava in humans, so although the jury is still out on some of these interactions, it seems at this stage that most CYP interactions with kava are unlikely to be clinically relevant for most consumers.[38]
As an interesting side note, it may be worth pointing out that kavalactones themselves may inhibit the degradation of other kavalactones.
In addition to inhibition, gene expression of P450s may also be altered by regular kava consumption; Rodents of both sexes have experienced increases in the expression of CYP1A1, CYP1A2, CYP2B1, CYP2C2, CYP3A1, CYP3A3 and CYP13A1 and decreases in expression of CYP2C23, CYP2C40, and in females, a decrease in expression of CYP2D1 (human CYP2D6 homolog), following long-term daily consumption. Gene expression of CYP2C9, CYP2C19, CYP2D6, CYP3A4 has also been reportedly inhibited in human hepatic microsomes by kavalactones, and CYP2E1 expression has been reduced by 40% following kavalactone consumption in vivo; Looking at the body of investigative studies holistically, it seems plausible that some of the reported decrease in CYP2E1 activity (or other CYPs for that matter) may have been misattributed to enzyme inhibition rather than a decrease in expression.[39]
Side tracking slightly here (again), but for those of you wondering about kava’s reported reverse tolerance (or sensitisation), if the metabolic pathways are downregulated, the body might retain higher kavalactone levels, requiring smaller amounts to achieve the same effect over time, and as such, the changes in gene expression (in addition to inhibition) of cytochrome P450 enzymes might potentially play a role here. If kavalactones decrease the expression of specific CYP enzymes involved in kavalactone metabolism, the body may gradually metabolise kava more slowly after some (possibly protracted) period of consumption, which could lead to higher levels of kavalactones in the bloodstream during subsequent uses, contributing to an increased sensitivity or enhanced effects. The suppression of enzymes that metabolise kavalactones would result in elevated concentrations of active compounds and extended durations of bioavailability, supporting the notion of reverse tolerance, which we have been witness to on a multitude of occasions, despite the not insignificant amount of refute we’ve seen here about its purported existence. We believe it’s a thing. Feel free to disagree – we can’t please everyone, and maybe we’re wrong (but we suspect not).
The inhibition of CYP1A2 expression has been reportedly confirmed in humans, which has a number of practical implications not only because this enzyme is part of the metabolic pathway for a number of drugs, but perhaps more interestingly because 1A2 is involved in the bioactivation of aflatoxins and other hepatic carcinogens, which means that kava may be implicated in a liver-protective effect, particularly in tropical climates where aflatoxins are more abundant.
A few more random tidbits:
Kavain has been shown to suppress eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) expression (which plays a critical role in cellular processes such as growth, metabolism, and response to stress) and ribosomal protein S6 (rpS6, which is a component of the 40S ribosomal subunit and plays a crucial role in protein synthesis) phosphorylation, which is believed to contribute to kava’s reported anti-cancer properties. Much of the documented anti-cancer action of kava constituents is also attributed to flavokavains A, B, and C, which may induce apoptosis in (and inhibit proliferation of) cancer cells. There are reports that FKB also regulates several receptor tyrosine kinases, regulates the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations, and enhances the levels of interleukin 2 and interferon gamma (IFN-y), but suppresses interleukin 1 beta (IL1B). There is also evidence in the literature that kava reduces NNK-induced DNA damage with preferential reduction of O(6)-methylguanine.
FKC has anti-inflammatory activity on nuclear factor kappa B-dependent nitric oxide production and expression of inducible nitric oxide synthase. It may also prevent inflammation via the mitogen-activated protein kinase (MAPKs) (extracellular-signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK)) pathway, which is one reason kava may one day prove to become a valuable addition to cosmetics.
Yangonin’s reported hepatoprotective capacity is due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and it promotes lipid metabolism and glycogen synthesis. On that note, it also modulates blood glucose homeostasis. Yangonin also inhibits SREBP-1c and SCD1 protein expression, which also helps with hepatoprotection, as does its inhibition of MiR-194. Essentially yangonin is believed to protect against liver injury by regulating the miR-194/FXR axis and inhibiting cellular senescence; Once touted as potentially harmful to the liver, compounds found within kava are now being considered for their treatment potential of liver problems.[40]
Kavalactones downregulate the expression of pro-inflammatory cytokines through the NF-KB, STAT3, and PI3K/Akt/mTOR pathways, which is a believed to be a significant contributor to kava’s anti-inflammatory properties.[41]
Isosakuranetin is a powerful antioxidant free-radical scavenger found in kava.
Alpinetin, another compound found in kava, has been found to be an inhibitor of xanthine oxidase (IC50 of approximately 135 ug/mL), which may make it useful for anti-hyperuricemia activity.[42]
That’s a wrap… For now.
Looking at a list like this and understanding that we've barely touched on kava’s pharmacokinetic parameters (absorption, distribution, metabolism, and excretion), and realising that each of the molecular targets on our list of pharmacodynamic interactions are part of a vastly complex and intertwined network of molecular pathways which are yet to be elucidated in their entirety, it becomes evident that anybody who claims to know everything about kava and how it works should probably just sit down, have a shell, and chill out, and that we should take their pontifications with a large grain of salt. Much has been demystified, but there is still so much to learn. We hope you enjoy the challenge of the journey, if it’s a path you wish to explore further.
Kava gives us a realm where science meets the senses and where complex chemical interactions converge with the simple art of enjoyment. Thank you for joining us on our exploration of this elaborate and mysterious world, where the phytomolecules of the plant perform an intricate dance with our own biomolecular machinery, choreographing a medley of easy sociability, relaxation, and pleasant euphoria.
There is so much more to the pharmacology of kava than we’ve posted here, from pharmacogenetics (genetic variability in CYP450 enzyme expression (particularly CYP2D6, which shows genetic polymorphisms) may contribute to individual differences in subjective effects or sensitivities, for example), to a deeper look at neuroplasticity, reverse tolerance mechanisms, and emerging therapeutic potentials, but whether you choose to immerse yourself in the details and continue your scientific exploration or elect instead to simply revel in kava’s delightful effects, let's collectively raise a shell to this pharmacologically enigmatic elixir that has fascinated over 100 generations before ours.
Malok!
The R&D team at Root & Pestle
References::
[1] Cheung, Cynthia; Baker, Jonathan D.; Byrne, Julianne M.; Perrault, Katelynn A. "Investigating Volatiles as the Secondary Metabolome of Piper methysticum from Root Powder and Water Extracts Using Comprehensive Two-Dimensional Gas Chromatography." Journal of Ethnopharmacology 2022, 294, 115346. https://doi.org/10.1016/j.jep.2022.115346.
[2] Kanumuri, Siva Rama Raju; Mamallapalli, Jessica; Nelson, Robyn; McCurdy, Christopher R.; Mathews, Carol A.; Xing, Chengguo; Sharma, Abhisheak. "Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers." Journal of Ethnopharmacology 2022, 297, 115514. https://doi.org/10.1016/j.jep.2022.115514.
[3] Chua, Han Chow; Christensen, Emilie T. H.; Hoestgaard-Jensen, Kirsten; Hartiadi, Leonny Y.; Ramzan, Iqbal; Jensen, Anders A.; Absalom, Nathan L.; Chebib, Mary. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PloS One 2016, 11 (6), e0157700. https://doi.org/10.1371/journal.pone.0157700.
[4] Ferger, Boris; Boonen, Georg; Häberlein, Hanns; Kuschinsky, Klaus. In Vivo Microdialysis Study of (±)-Kavain on Veratridine-Induced Glutamate Release. European Journal of Pharmacology 1998, 347 (2), 211-214. https://doi.org/10.1016/S0014-2999(98)00234-9.
[5] Gleitz, J.; Friese, J.; Beile, A.; Ameri, A.; Peters, T. Anticonvulsive Action of (+/-)-Kavain Estimated from Its Properties on Stimulated Synaptosomes and Na+ Channel Receptor Sites. European Journal of Pharmacology 1996, 315 (1), 89-97. https://doi.org/10.1016/s0014-2999(96)00550-x.
[6] Gleitz, J.; Gottner, N.; Ameri, A.; Peters, T. Kavain Inhibits Non-Stereospecifically Veratridine-Activated Na+ Channels. Planta Medica 1996, 62 (6), 580-581. https://doi.org/10.1055/s-2006-957981.
[7] Hegazy, Nada Hany; Breitinger, Hans-Georg; Breitinger, Ulrike. Kavalactones from Kava (Piper Methysticum) Root Extract as Modulators of Recombinant Human Glycine Receptors. Biological Chemistry 2019, 400 (9), 1205-1215. https://doi.org/10.1515/hsz-2019-0112.
[8] Sorrentino, L.; Capasso, A.; Schmidt, M. Kava-kava in the Treatment of Generalized Anxiety Disorder: A Double-blind, Randomized, Placebo-controlled Study. Journal of Clinical Psychopharmacology 2006, 26 (4), 473–477.
[9] Schelosky, L.; Raffauf, C.; Jendroska, K.; Poewe, W. Kava and Dopamine Antagonism. Journal of Neurology, Neurosurgery, and Psychiatry 1995, 58 (5), 639-640. https://doi.org/10.1136/jnnp.58.5.639.
[10] Baum, Siedy S.; Hill, Regina; Rommelspacher, Hans. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Progress in Neuropsychopharmacology & Biological Psychiatry, vol. 22, no. 7, October 1998, pp. 1105-1120. DOI: 10.1016/s0278-5846(98)00062-1.
[11] Dinh, L. D.; Simmen, U.; Bueter, K. B.; Bueter, B.; Lundstrom, K.; Schaffner, W. Interaction of Various Piper Methysticum Cultivars with CNS Receptors in Vitro. Planta Medica 2001, 67 (4), 306-311. https://doi.org/10.1055/s-2001-14334.
[12] Gleitz, J.; Beile, A. Neuropharmacological Studies on Ethanolic Kava Extracts and Kavalactones. Pharmacopsychiatry 1993, 26 (3), 93–97. doi:10.1055/s-2007-1014378.
[13] Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; et al. Kavalactone Yangonin Induces Autophagy via the AMPK/ULK1 Pathway and Autophagy Inhibition Enhances Yangonin-Induced Apoptosis in Colorectal Cancer Cells. Cell Death Discovery 2020, 6 (1), 2. doi:10.1038/s41420-019-0242-4.
[14] Sarris, J.; Kavanagh, D. J.; Byrne, G.; Bone, K. M.; Adams, J.; Deed, G. K.; et al. The Kava Anxiety Depression Spectrum Study (KADSS): A Randomized, Placebo-Controlled Crossover Trial Using an Aqueous Extract of Piper Methysticum. Psychopharmacology (Berl). 2009, 205 (3), 399–407. doi:10.1007/s00213-009-1549-9.
[15] Spinella, Marcello. "Herbal Medicines and Epilepsy: The Potential for Benefit and Adverse Effects." Epilepsy & Behavior 2001, 2, 524-532. doi: 10.1006/ebeh.2001.0281.
[16] Grunze, Heinz; Langosch, Jens; Schirrmacher, Karin; Bingmann, Dieter; von Wegerer, Jörg; Walden, Jörg. Kava pyrones exert effects on neuronal transmission and transmembraneous cation currents similar to established mood stabilizers - a review. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2001, 25 (8), 1555-1570. https://doi.org/10.1016/S0278-5846(01)00228-5.
[17] Cairney, Sheree; Maruff, Paul; Clough, Alan R. The Neurobehavioural Effects of Kava. The Australian and New Zealand Journal of Psychiatry 2002, 36 (5), 657-662. https://doi.org/10.1046/j.1440-1614.2002.01027.x.
[18] Shimoda, L. M. N.; Showman, A.; Baker, J. D.; Lange, I.; Koomoa, D. L.; Stokes, A. J.; Borris, R. P.; Turner, H. "Differential Regulation of Calcium Signalling Pathways by Components of Piper methysticum ('Awa)." Phytotherapy Research 2015, 29, 582-590. https://doi.org/10.1002/ptr.5291.
[19] Sarris, Jerome; LaPorte, Emma; Schweitzer, Isaac. "Kava: A Comprehensive Review of Efficacy, Safety, and Psychopharmacology." Australian & New Zealand Journal of Psychiatry 2011, 45(1), 27-35. https://doi.org/10.3109/00048674.2010.522554.
[20] Seitz, U., A. Schüle, and J. Gleitz. 1997. “[3H]-Monoamine Uptake Inhibition Properties of Kava Pyrones.” Planta Medica 63 (6): 548–49. https://doi.org/10.1055/s-2006-957761.
[21] Ligresti, Alessia; Villano, Rosaria; Allarà, Marco; Ujváry, István; Di Marzo, Vincenzo. "Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand." Pharmacological Research 2012, 66(2), 163-169. https://doi.org/10.1016/j.phrs.2012.04.003.
[22] Prinsloo, Denise; van Dyk, Sandra; Petzer, Anél; Petzer, Jacobus P. "Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)." Planta Medica: International Journal of Medicinal Plant Research 2019, 85, 1136-1142. https://doi.org/10.1055/a-1008-9491.
[23] Uebelhack, R.; Franke, L.; Schewe, H. J. "Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava)." Comparative Study Pharmacopsychiatry 1998, 31(5), 187-192. https://doi.org/10.1055/s-2007-979325.
[24] Krum, Bárbara Nunes; Molz de Freitas, Catiuscia; Busanello, Alcindo; Finger Schaffer, Larissa; Fachinetto, Roselei. Ex Vivo and in Vitro Inhibitory Potential of Kava Extract on Monoamine Oxidase B Activity in Mice. African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM / African Networks on Ethnomedicines 2021, July. https://doi.org/10.1016/j.jtcme.2021.07.002.
[25] Li, Xuesen; Song, Liankun; Xu, Shan; Tippin, Matthew; Meng, Shuan; Xie, Jun; Uchio, Edward; Zi, Xiaolin. "Kava root extracts hinder prostate cancer development and tumorigenesis by involvement of dual inhibition of MAO-A and LSD1." Journal of Translational Genetics and Genomics 2021, 5, 163-172. https://doi.org/10.20517/jtgg.2021.22.
[26] Xu, Xia; Tian, Xuejiao; Song, Liankun; Xie, Jun; Liao, Joseph C.; Meeks, Joshua J.; Wu, Xue-Ru; Gin, Greg E.; Wang, Beverly; Uchio, Edward; Zi, Xiaolin. "Kawain Inhibits Urinary Bladder Carcinogenesis through Epigenetic Inhibition of LSD1 and Upregulation of H3K4 Methylation." Biomolecules 2023, 13(3), 521. https://doi.org/10.3390/biom13030521.
[27] Melchert, Philip W.; Qian, Yuli; Zhang, Qingchen; Klee, Brandon O.; Xing, Chengguo; Markowitz, John S. "In vitro inhibition of carboxylesterase 1 by Kava (Piper methysticum) Kavalactones." Chemico-Biological Interactions 2022, 357, 109883. https://doi.org/10.1016/j.cbi.2022.109883.
[28] Kautu, Bwarenaba B.; Phillips, Juliana; Steele, Kellie; Mengarelli, M. Shawn; Nord, Eric A. "A Behavioral Survey of the Effects of Kavalactones on Caenorhabditis elegans Neuromuscular Transmission." Journal of Experimental Neuroscience 2017, 11, 1-7. https://doi.org/10.1177/1179069517705384.
[29] Singh, Y. N. Effects of Kava on Neuromuscular Transmission and Muscle Contractility. Journal of Ethnopharmacology 1983, 7 (3), 267-276. https://doi.org/10.1016/0378-8741(83)90002-8.
[30] Noor, Neveen A. Anxiolytic Action and Safety of Kava: Effect on Rat Brain Acetylcholinesterase Activity and Some Serum Biochemical Parameters. African Journal of Pharmacy and Pharmacology 2010, 4 (11), 823-828. http://dx.doi.org/.
[31] Aughton, Harvey. Kava and Balance: The Effects of Traditionally Influenced Kava Consumption on Human Physiology. The University of Waikato, 2020. Available at: https://researchcommons.waikato.ac.nz/handle/10289/14110.
[32] Liu, Shuangjie; Liu, Zhuonan; Piao, Chiyuan; Zhang, Zhe; Kong, Chuize; Yin, Lei; Liu, Xi. "Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer." Journal of Experimental & Clinical Cancer Research 2022, 41, 293. https://doi.org/10.1186/s13046-022-02500-4.
[33] Wu, D.; Yu, L.; Nair, M. G.; DeWitt, D. L.; Ramsewak, R. S. "Cyclooxygenase enzyme inhibitory compounds with antioxidant activities from Piper methysticum (kava-kava) roots." Phytomedicine 2002, 9, 41-47.
[34] Kwon, Dong-Joo; Ju, Sung Mi; Youn, Gi Soo; Choi, Soo Young; Park, Jinseu. "Suppression of iNOS and COX-2 expression by flavokawain A via blockade of NF-κB and AP-1 activation in RAW 264.7 macrophages." Food and Chemical Toxicology. 2013, 58, 479-486. https://doi.org/10.1016/j.fct.2013.05.031.
[35] Wruck, Christoph J.; Go¨tz, Mario E.; Herdegen, Thomas; Varoga, Deike; Brandenburg, Lars-Ove; Pufe, Thomas. "Kavalactones Protect Neural Cells against Amyloid β-Peptide-Induced Neurotoxicity via Extracellular Signal-Regulated Kinase 1/2-Dependent Nuclear Factor Erythroid 2-Related Factor 2 Activation." Molecular Pharmacology 2008, 73(6), 1785-1795. https://doi.org/10.1124/mol.107.043265.
[36] Gurley, Bill J.; Swain, Ashley; Barone, Gary W.; Williams, D. Keith; Breen, Philip; Yates, C. Ryan; Stuart, Leslie B.; Hubbard, Martha A.; Tong, Yudong; Cheboyina, Sreekhar. "Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans." Drug Metabolism and Disposition, vol. 35, no. 2, 240-245 (2007).
[37] Mathews, James M.; Etheridge, Amy S.; Black, Sherry R. "Inhibition of Human Cytochrome P450 Activities by Kava Extract and Kavalactones." Drug Metabolism and Disposition 2002, 30(11), 1153-1157. https://doi.org/10.755/1918832.
[38] Gurley, Bill J., Gardner, Stephanie F., Hubbard, Martha A., Williams, D. Keith, Gentry, W. Brooks, Khan, Ikhlas A., Shah, Amit. In Vivo Effects of Goldenseal, Kava Kava, Black Cohosh, and Valerian on Human Cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 Phenotypes. Clinical Pharmacology & Therapeutics: Pharmacokinetics and Drug Disposition 2005, Published: 16 May. https://doi.org/10.1016/j.clpt.2005.01.009.
[39] Soares, Rita B.; Dinis-Oliveira, Ricardo Jorge; Oliveira, Nuno G. "An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava." Journal of Clinical Medicine 2022, 11(14), 4039. https://doi.org/10.3390/jcm11144039.
[40] Camporez, João Paulo G.; Asrih, Mohamed; Zhang, Dongyan; Kahn, Mario; Samuel, Varman T.; Jurczak, Michael J.; Jornayvaz, François R. "Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21." Journal of Endocrinology 2015, 226(3), 207-217. https://doi.org/10.1530/JOE-15-0136.
[41] Bian, Tengfei; Corral, Pedro; Wang, Yuzhi; Botello, Jordy; Kingston, Rick; Daniels, Tyler; Salloum, Ramzi G.; Johnston, Edward; Huo, Zhiguang; Lu, Junxuan; Liu, Andrew C.; Xing, Chengguo. "Kava as a Clinical Nutrient: Promises and Challenges." Nutrients 2020, 12(10), 3044. https://doi.org/10.3390/nu12103044.
[42] Minh, Truong Ngoc; Van, Truong Mai; Khanh, Tran Dang; Xuan, Tran Dang. "Isolation and Identification of Constituents Exhibiting Antioxidant, Antibacterial, and Antihyperuricemia Activities in Piper methysticum Root." Foods 2022, 11(23), 3889. https://doi.org/10.3390/foods11233889.
Our friends and Forney/Root and Pestle have completed another research project and have asked us to share their findings here. It's certainly a longish piece, but def worth reading if you are interested in kava's pharmacology. I hope you enjoy it!
Disclaimer: Don’t use this post as a basis to determine what’s safe to combine with kava and what isn’t. Consult with a qualified medical practitioner instead.
Notes: Due to technical limitations in posting with Greek characters (such as the names of enzyme subunits and molecular compounds), we’ve used some approximate substitutions. We appreciate your understanding regarding these slight inaccuracies and hope it doesn’t detract too much from the value of the content. Same with formatting. We might try to edit things back in properly, after the fact.
Kava is a fascinating drink. Its incredible psychotropic effects are well documented, yet the captivating biomolecular interactions behind them are often obscured behind repetitions of generic, outdated, or oversimplified summaries or hidden like sparsely sprinkled Easter eggs down long rabbit holes deep into perplexing scientific literature. For those of you who have spent any time investigating this topic, you have probably found comprehensive information to be elusive, scattered, and conflicting; If you have found yourself dissatisfied with superficial explanations like, “kava acts at GABA receptors and ion channels” or tired of sifting through mountains of lengthy technical papers to try to envision a more complete picture of kava’s intricate pharmacology, this post is for you.
Here at Root & Pestle R&D, we are attempting to give you something unique – not just in terms of kava analysis data, but also better information. The aim of this post is to give you a more comprehensive summary on kava’s pharmacology than has been compiled elsewhere, but still a summary, without all of the hundreds (or thousands) of pages of supporting material that would be necessary to troll through in order to find these mechanisms yourself in peer-reviewed papers. In doing so, we’ll be getting much deeper into the esoteric territory of molecular biology than many may want to venture, so we’ll leave it up to you whether this is a journey you feel comfortable embarking upon or not. In any case, please know from the outset that it’s going to be an exploration into a niche topic full of technical jargon, and that this is meant to be more of a list than an explanation; We’re trying to strike a balance between completeness, correctness, and conciseness, and we can’t do that if we get bogged down by too many background details.
For those of you who want to skip this one, we understand, and we still greatly appreciate you. We are happy to meet you at the next topic. For those of you who really do want to understand what’s going on inside your body when you knock back a shell, read on and use this list as a jumping point to guide your investigative discovery.
So, why is kava pharmacology tricky and what contributes to its enigmatic nature?
Kava exerts many of its therapeutic effects (like promoting calmness and a sense of wellbeing) by acting to reduce the excitability of the brain’s limbic system (an integral part of the central nervous system involved in emotions and behaviour), but there is certainly more to it than that. The pharmacology of the active compounds in kava is diverse and can be confusing, and contrary to common misconceptions, not limited to the 6 major kavalactones (Although the complete secondary metabolome of kava has not yet been defined, there are still roughly 100 compounds found in kava which have now been characterised, including at least a dozen other pyrones – the “minor” kavalactones, 3 chalcones – flavokavains A, B, and C, several flavonoids – such as vitexin, orientin, and isoorientin, and the more recently reported isosakuranetin, 2′,4′-dihydroxy-6′-methoxydihydrochalcone and alpinetin, as well as sterols – such as stigmasterol, have been identified in kava, all contributing as part of a molecular orchestra to the symphonic experience of this beautiful beverage), although kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are of course the major players for most of the psychoactive effects and for many of the physiological effects.[1]
Specific cultivar, along with the ratio of rhizome (basal roots or chips) to lateral roots (and subsequent kavalactone ratios and concentrations), the processing and preparation methods (which can lead to variations in overall extraction efficiency or cause some kavalactones (or other compounds) to be extracted preferentially), and other factors (including the physiology and nutritional or therapeutic regime of the imbiber) may all affect pharmacological activity. These variations, even if small, can lead to big differences in effect, as the compounds in kava don’t exert their actions alone, but in mysterious and glorious synergy with each other; It is well established that the biological activity of one kavalactone alone is not the same as when it is administered along with other kavalactones. This quirk means that it cannot be said that because one particular kavalactone was observed to have a particular effect, particularly in vitro, that the same effect will be observed following ingestion of kava. Mechanisms of action are elusive for much of the activity observed with kava, and a complete consensus has not yet been reached, but we will try to give you a summary of some of the more important interactions, as we believe them to be.
A few caveats:
Note that this post, unlike most of our others, is not intended to be aimed at a broad audience nor do we claim that it is either accessible enough for the masses, nor faultless enough in its accuracy for the experts; It is not a scientific article intended for publication in a peer-reviewed journal, but neither is it an editorial to entertain the casual reader, rather this is a unique attempt to collate much of the fundamental pharmacological mechanisms into one free-to-access reference for anyone with a good understanding of (or interest in) pharmacology and more than a passing curiosity in kava, but who is not a professional researcher able to spend countless hours, weeks, or years sifting through the literature to compile a similar list for themselves. Feel free to skip it if it isn’t your jam; While many people are satisfied enough to enjoy kava and its effects without probing too intensely into the technical details, we know there are those amongst you who have been seeking a well-investigated list like this, so we hope for at least a few, we have provided a helpful resource.
We believe the information assembled here to be true in its translation and transcription, and we hope we have parleyed the results gleaned by pharmacologists correctly to our readers, but please don’t crucify us when you discover a result somewhere in your investigative journey that does not corroborate what you read here; We are trying not to be contentious, but to some extent that is impossible for compounds whose mechanisms are still being elucidated and for which much research remains. In other cases, conflicting results have been published – What we have listed here are our best interpretations of what is going on when the molecular machinery in our bodies interacts with the compounds in your kava, so please take this all with a grain of salt and as stimulus to do your own digging; If it is critical that the information you ingest is certain to be error free, this may not be the article for you, although we think we’ve gotten it mostly right.
Another important consideration when you’re considering kava’s mechanisms of action is dosage. Great expense and immense investigative efforts have been applied towards attempts at finding toxicity, although the results virtually always come up either lacking, or (perhaps to the horror of the funding bodies) discover benefits. These efforts have largely been made in attempt to justify otherwise unjustifiable regulatory control or outright bans of kava products worldwide, particularly after the German kava ban in the early 2000s (the “science” which supported it now having been fully debunked, and regulatory agencies worldwide looking more and more favourably upon kava all the time). As such, many published pharmacological interpretations stem from research conducted with concentrations of kavalactones at their potential sites of action far greater than what would likely be expected from recreational use, and without the balance of the full spectrum of molecules present in a typical aqueous extraction – administering pure kavain directly to a cultured Petri dish of cells is not the same as absorbing squeezed kava powder in the form of a beverage through the gastrointestinal tract. Nevertheless, some of the studies we’ve pulled our list from only found activity of compounds within kava at molecular targets in the brain at (sometimes unrealistically) high concentrations, so again, this information should be considered critically – nobody fully understands how kava works its magic on our minds, and many in vitro studies at high molar concentrations are all but irrelevant in the context of drinking kava.
Just to give you a rough idea, pharmacokinetic studies in animal models sometimes administer a single kavalactone at 100 mg/kg, which would be the equivalent of a person weighing 75 kg consuming 7.5 g of one kavalactone. If its relative abundance in the drink is similar to the other kavalactones, that would be a total consumption of about 45 g of pure kavalactones, which is perhaps 65 times more than one would expect to find in a 200 mL shell of strong kava; Studies often cite molar concentrations orders of magnitude higher than what would likely be encountered by people enjoying traditionally prepared kava recreationally, and therefore many results of pharmacological studies may be essentially meaningless in a holistic sense.
With that disclaimer out of the way, let’s get down to business.
First, a few random warm-up concepts and a tiny bit of pharmacological ADME:
Kavalactones are not believed to act through opioid pathways; Their biological activity is unaffected by co-administration of naloxone.
Absorption of kavalactones has been found to be significantly reduced if consumed with food.
Kavalactones are lipophilic and undergo more rapid absorption in the gut than in the upper gastrointestinal tract. They are highly mobile and permeate membranes easily; Permeation rates in order of fastest to slowest are believed to be dihydromethysticin > yangonin > kavain > methysticin > desmethoxyyangonin (ranging from around 0.4 um/s down to about 0.26 um/s). The permeation rate of dihydrokavain was not found in the literature, but based on its chemical structure it is probably similarly swift.
Dihydrokavain and kavain attain high concentrations in the brain very rapidly but are also eliminated rapidly. Desmethoxyyangonin and yangonin reach lower maximum concentrations in the brain but are eliminated slowly. All kavalactones cross the blood-brain barrier readily.
The systemic exposure of the kavalactones after oral dosing has been found to be dihydrokavain > dihydromethysticin > kavain > methysticin > yangonin > desmethoxyyangonin.[2]
Time to reach peak plasma concentrations are generally less than 3 h for orally ingested kavalactones, often much quicker. One study reported that kavain and dihydrokavain reached maximum concentrations in a mouse brain within 5 minutes of intraperitoneal administration.
Higher exposure to kavalactones has been found to occur if a full dose is taken at once rather than split into smaller doses and consumed over a longer period of time. Dividing a large dose into smaller portions consumed over time has resulted in a longer duration of exposure.
There is proportionality in pharmacokinetics with kavalactone doses.
A 225 mg oral dose of combined kavalactones (equivalent to a relatively small/weak shell) has been shown to yield a plasma concentration in the ballpark of 1 to 140 ng/mL for each kavalactone.
Kavalactones are metabolized by CYP450 enzymes (more details on this later).
Metabolic transformations of kavalactones are many, but often involve demethylation of the 4‑methoxy substituent of the alphapyrone ring or reduction of the 3,4-double bond. For yangonin, demethylation of the 12-methoxy has been reported. For desmethoxyyangonin, C-12 has been reported to be hydroxylated. We won’t go into much more depth on metabolism here as the market for recipients of such information is even more niche, and metabolites of kavalactones aren’t that difficult to look up, if you’re interested in such things.
In animal models, kavain has been found to be excreted 77% in urine and 14% in faeces within 72 hours. It seems that other kavalactones and their metabolites are also excreted relatively quickly.
So, what are the molecular targets of kava?
GABAA receptors: gamma-aminobutyric acid (GABA), this receptor’s normal ligand, reduces neuronal excitability in the central nervous system and is the chief inhibitory neurotransmitter in humans. Kavalactones are positive allosteric modulators (PAMs) of GABAA receptors, increasing the activity of the receptor and enhancing the inhibitory effects of GABA. We have seen some evidence to support the idea that kavalactones bind to the benzodiazepine site on GABAA receptors, however, the modulatory effect of kavain has been shown to be unaffected by flumazenil in at least one study, leading to the conclusion that kavain does not enhance GABAA receptors via the classical benzodiazepine binding site. Kavain has, however, been shown by others to bind at a1B2, B2y2L, axB2y2L (x = 1, 2, 3 and 5), a1Bxy2L (x = 1, 2 and 3) and a4B2delta GABAA receptors and to positively modulate all GABAA receptors (to some extent) regardless of the subunit composition, with enhancement greater at a4B2delta than at a1B2y2L GABAA receptors. In addition to their positive allosteric modulation of GABAA receptors, it is believed that the biosynthesis of GABAA receptor antagonist eicosanoid thromboxane A2 is also inhibited by kavalactones.[3]
N-methyl-D-aspartate (NMDA) receptors: Kavalactones have been found to inhibit the activity of NMDA receptors by binding to the receptor at a site distinct from glutamate, which along with glycine, D-serine, and aspartate, is the primary endogenous ligand. Overactivation of this receptor significantly contributes to neural death and has been associated with neurological disorders such as Alzheimer’s, Parkinson’s, Huntington’s, and epilepsy, but the activity of NMDA receptors isn’t all bad – they are important to learning and memory functions by mediating synaptic plasticity. Many psychoactive drugs block NMDA receptor activity, contributing to the analgesic and anaesthetic effects of some of them. Methysticin and yangonin exert their inhibition by directly blocking the NMDA receptor’s ion channel. Although NMDA receptor inhibition by kavalactones seems to be close to consensus, it should be noted that there have been reports that kavalactones may potentiate glycine binding, which enhances NMDA receptor activity.[4],[5],[6],[7]
The GABA and NMDA activity is thought to underlie the anxiolytic and sedative effects of kava, although kava’s effect on GABAergic activity, and even more so, its mechanism, is an ongoing topic of debate in some circles.
Dopamine receptors: Many people hear “dopamine” and automatically synonymise it with “the happy chemical”. It’s a bit more complicated than that, but for the purposes of this post we’ll think of the interactions with dopamine receptors as affecting pleasure and motivational salience. Kavalactones have been found to interact with several dopamine receptor subtypes, including D2, D3, and D4 receptors, and possibly D1 too. The precise mechanisms by which kavalactones modulate dopamine receptor activity are not yet fully understood and may vary between subtype and kavalactone. Changes in dopamine concentration or signalling initiated by kava are certainly not due exclusively to direct interaction with dopamine receptors (inhibition of metabolic enzymes, among other things, also plays a role), but they are involved. Kava’s influence on dopamine concentration seems more to do with preventing a decrease via re-uptake inhibition rather than stimulating an increase, but in any case, kava may prolong or increase the effects of dopaminergic activity.[8] As with all kava pharmacology though, it can get a bit weird here too: Low doses of kavain have been shown to decrease dopamine, while higher doses have been shown to either not substantially affect dopamine’s concentration or to increase it. Yangonin results in a decrease of dopamine levels, so again, the chemotype of the kava being consumed may influence the overall pharmacological effect.[9]
Activation of the mesolimbic dopaminergic neurons may contribute to the euphoria and relaxation that many people report after consumption of kava.[10]
Serotonin receptors: Kavalactones have been found to interact with several serotonin receptor subtypes, including 5-HT1A, 5-HT2A, and 5-HT6 receptors.[11] The effects of kavalactones on these receptors are complex and unsurprisingly may vary depending on the specific receptor subtype and the ratios and concentration of kavalactones; Kavalactones acting at 5-HT1A are partial agonists, but are antagonists of 5-HT2A, to illustrate this point. Some studies have found that kavain decreases serotonin concentrations, while others have found that kavain seems to increase serotonin enrichment and decrease shunting of glucose to the pentose phosphate pathway. This interaction may contribute to its anti-inflammatory properties.[12],[13],[14]
The results of some studies suggest that the sleep-inducing action of kava is due at least in part to changes of activity at clusters of neurons expressing 5-HT receptors.
Voltage-gated ion channels: Kavalactones have been found to interact with several types of voltage-gated ion channels, including calcium channels, sodium channels, and potassium channels. Binding to sodium channels by kavain and methysticin has been reported to occur when the ion channels are in their inactivated state, prolonging inactivation. Some research suggests that binding occurs on the sodium channel at receptor site 2, which is commonly targeted by local anaesthetic agents. In any case, kavalactones have a weak antagonistic effect on Na+ channels, pronounced antagonistic effect on L-type Ca2+ channels, and act as positive modulators of outward K+ current. Inhibition of sodium and calcium ion channels by kavalactones would contribute to diminished excitatory neurotransmitter release, which is in good alignment with kava’s documented muscle relaxant and anticonvulsant properties.[15],[16],[17]
Transient receptor potential (TRP) family of ion channels: Kava is hypothesised to possess non‑kavalactone ligands for TRPs. Although a complete justification for this hypothesis is beyond the scope of this post, it is due in part to the reported observation that immunocytes do not exhibit calcium mobilisation in response to partially purified kava extracts (which still contain kavalactones), but immunocytes do induce these calcium responses upon exposure to traditionally prepared aqueous extracts of kava. Under patch clamp, TRP-like conductances have been observed in cells treated with kava, and it is thought that some of the kava pharmacology may therefore be attributable to TRP-mediated cellular effects.[18]
Noradrenaline: Reuptake inhibition into synaptosomes has been observed in vitro upon exposure to kavalactones. Norepinephrine-induced intracellular calcium influx has also been reported to be inhibited by kavalactones in lung cancer cells. Noradrenaline reuptake inhibition has been proposed as a partial explanation for the anxiolytic capacity of kava and also may contribute to the reported chemoprotective potential against carcinogen induced tumorigenesis.[19],[20]
Cannabinoid receptor type 1 (CB1): Yangonin is the only kavalactone which has been documented to bind to cannabinoid receptors with moderate affinity for CB1 (Ki = 0.72 uM). It has good selectivity over CB2 (Ki > 10 uM), although the functional activity remains unknown. It has been postulated that this interaction with the endocannabinoid system may contribute to the psychopharmacology of kava, however, given that the Ki of delta-9-tetrahydrocannabinol (THC, the main active compound in cannabis) is 0.0041 uM, and taking into account the strong influence kavalactones exert on other molecular targets, it seems that most of the psychoactive effects of kava are likely due to non-cannabinoidergic mediated interactions. Relatedly, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are 2 important metabolic enzymes in the cannabinoid system against which kavalactones have been assessed for their inhibitory potential, and none was found.[21]
Monoamine oxidase enzymes (MAOs): Kavalactones have been found to reversibly inhibit both MAO-A and MAO-B, which are enzymes involved in the metabolism of neurotransmitters such as dopamine and serotonin. The potency of kavalactones at MAO-B is reported to be considerably stronger (approximately 2 to 25 times stronger) than at MAO-A. Of the kavalactones, yangonin has been shown to be the most potent MAO inhibitor, however, one in vitro study determined the order of potency of platelet MAO-B inhibitions to be desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-)-dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain. MAO inhibition is thought to contribute to the mood-elevating effects of kava.[22],[23],[24]
Lysine-Specific Demethylase 1 (LSD1): Kavalactones inhibit LSD1, which is thought to play a role in kava’s reported ability to hinder cancer development and tumorigenesis.[25],[26]
Liver carboxylesterase 1 (hCE-1, CES1, CES1A1, serine esterase 1, SES1, monocyte esterase, cholesterol ester hydrolase, or CEH): This widely distributed enzyme (which is particularly concentrated in the liver and notably poorly concentrated in the gastrointestinal tract) is involved in the metabolism of a huge range of structurally divergent xenobiotics (including methylphenidate, clopidogrel, cocaine, and heroin) and is also responsible for activating many prodrugs, including oseltamivir and dabigatran. It is inhibited by kavalactones (competitively by kavain, dihydrokavain, and desmethoxyyangonin, and mixed competitive-noncompetitively by methysticin, dihydromethysticin, and yangonin), so there is the possibility for drug-drug interactions, however, the inhibition constants for each of the major kavalactones have been reported to range from around 25 – 35 uM (for yangonin, desmethoxyyangonin, and methysticin, respectively) up to around 68 – 105 uM (for dihydromethysticin, kavain, and dihydrokavain, respectively), so considerable (perhaps > 1 g) kavalactone consumption would likely precede clinically relevant inhibition.[27]
Neuromuscular junction (NMJ): There is evidence that the inhibitory-excitatory balance of neurotransmission within the NMJ is disrupted by kavalactones, likely due to their agonism of acetylcholine (ACh) receptors, however, kavain alone is not believed to agonise Ach receptors. Exacerbated Ach signalling induced by kavalactones may be mediated by nicotinic receptor ACR-2, which is expressed in cholinergic motor neurons, however, the jury is still out on this one, as is the hypothesis that increased Ach signalling in response to kavalactones may be due to inhibition of acetylcholinesterase (AChE), the enzyme found in muscles and nerves at postsynaptic neuromuscular junctions which rapidly breaks down ACh. Whatever the exact mechanism, sensitivity to kavalactones has been shown to be greatly altered in animal models (C. elegans) with modifications to genes involved in Ach transmission.[28],[29],[30],[31]
Protein arginine methyltransferase 5 (PRMT5): Flavokavain A has been found to inhibit this potential therapeutic target for bladder cancer by binding to Y304 and F580 of the enzyme, blocking the symmetric arginine dimethylation of histone H2A and H4.[32]
Cyclooxygenase 1 and cyclooxygenase 2 (COX-1 and COX-2): These enzymes, which serve to convert arachidonic acid to prostaglandins, have been reported to be inhibited by yangonin and dihydrokavain.[33] The go-to drugs for treating many kinds of inflammatory conditions, including rheumatoid arthritis, have been Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), which also work by inhibiting cyclooxygenase enzymes. Selective COX-2 inhibitors have been used as anti-pyretics, analgesics, and highly effective anti-inflammatories, so it would make sense that some of the reported anti-inflammatory activity of kava may be due to COX inhibition.
On a side note, some COX inhibitors, like aspirin, inhibit platelet aggregation and act as blood thinners. There have been anecdotal claims (largely from anonymous and non-expert sources on Reddit), that because kava contains compounds like yangonin and dihydrokavain that interact with COX enzymes, it must have a strong blood thinning effect too. To date, there is no substantial evidence in the scientific literature to support this claim, and there are other COX inhibitors (such as celecoxib and meloxicam, among others) which are known not to have blood thinning effects. While kava’s interaction with COX enzymes might contribute to its anti-inflammatory effects, the idea that it has a significant anticoagulant effect is speculative, and we have seen no robust empirical evidence indicating that kava affects blood clotting.
Note too that Flavokavain A has been reported to supress the expression of COX-2 and inducible nitric oxide synthase (iNOS) in macrophages via blockade of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) and activator protein 1 (AP-1) activation (and the subsequent production of nitrous oxide and prostaglandin E2), which could also contribute to the molecular basis for some of kava’s reported anti-inflammatory properties.[34] Further along this path, some of the neuroprotective effects reported of kavalactones are believed to be mediated by the P38/nuclear factor-kappa B /cyclooxygenase 2 signalling pathway, although kavalactone-mediated upregulation of antioxidation enzymes is also believed to be important in this regard.[35]
P-glycoprotein 1 (also called multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 (CD243) or permeability glycoprotein or P-gp or Pgp): kava has been shown in vitro to moderately inhibit this ATP-dependent cell membrane efflux pump, the normal purpose of which is to pump foreign substances out of cells, including exogenous drugs. Inhibition would therefore increase the bioavailability of susceptible drugs (and other kavalactones). On the other hand, a study on digoxin pharmacokinetics conducted on healthy volunteers found no statistically significant modulation of Pgp following a small daily dose (equivalent to 225 mg of kavalactones per day) of kava, suggesting that this molecular target (as is the case with many others) is unlikely to become relevant for potential drug-drug interactions with kava until the extent of exposure is increased considerably.[36]
Human cytochrome P450s: Kavalactones have been shown to inhibit some important hepatic P450 enzymes, including those involved in the metabolism of the large majority of pharmaceutical drugs, however, the majority of CYP inhibition studies as they relate to kava constituents have been done in vitro and often at concentrations which may not be clinically relevant to most consumers.
Inhibition of these enzymes by kava is mostly due to methysticin and dihydromethysticin, and to a lesser extent desmethoxyyangonin, and for some of them the inhibition has been reported to be relatively profound in extent and duration, so drug-drug interactions with kava are conceptually possible, especially for cultivars with relatively high methysticin or dihydromethysticin content, but in a practical sense these suspected drug-drug interactions seem to be reported somewhat infrequently in the clinical setting.
The inhibition capacity of kavain on P450s is seemingly very low, with some reports showing that it does not directly inhibit CYP isoenzymes at all, however, kavalactones on the whole have been shown to inhibit a number of CYPs, sometimes potently, so it is best to err in favour of caution and not consume kava alongside other compounds reliant on these pathways for their metabolism.
Following are the most noteworthy kavalactone/P450 interactions we have found reported in the literature.
CYP2E1 (for which normal substrates include chlorzoxazone, acetaminophen, theophylline, and ethanol) is reportedly inhibited by kavalactones, and unlike most other CYP isozymes has been found to have appreciably decreased activity (around 40%) with chronic ingestion of kava. That said, another study has found 2E1 activity to be unaffected after being incubated for 15 minutes with 100 uM total kavalactones, so perhaps serious drug-drug interactions involving this enzyme may only become significant after prolonged or high levels of exposure.
Percent inhibition of specific CYPs at 100 uM (total kavalactones) incubation for 15 minutes [37]:
CYP1A2 (56%), 2C9 (92%) (2C9 is important for metabolism of barbiturates, NSAIDs, and warfarin), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%).
CYP2A6 and 2C8 activities were unaffected.
Percent inhibition of specific CYPs at incubation with 10 uM of individual kavalactones kavain, desmethoxyyangonin, methysticin, and dihydromethysticin:
CYP2C9, 2C19, 2D6, and 3A4 were not inhibited by kavain.
CYP2C9 by desmethoxyyangonin (42%), methysticin (58%), and dihydromethysticin (69%).
2C19 by dihydromethysticin (76%).
2D6 by methysticin (44%).
3A4 (important in the metabolism of benzodiazepines) by desmethoxyyangonin (40%), methysticin (27%), and dihydromethysticin (54%).
CYP1A2 has been reported to be inhibited most potently by desmethoxyyangonin.
CYP4A11 and CYP2C9 are structurally inhibited by kavalactones. It has been noted that CYP2F22 is structurally similar and may play a role in kava dermopathy, which is sometimes reported following long-term consumption of large doses; It is possible that CYP2F22 becomes reversibly inhibited by kavalactones after long periods of exposure to large amounts. On that note, cinnamic acid bornyl ester has been identified in kava. Mast cell calcium channel TRPA1 is activated by cinnamic acid and has been associated with contact dermatitis. Although the safety of kava has been well established, there have been reports of reversible dermopathies (mostly amongst high-dosing chronic users), and we thought it might be prudent to note these potential relationships, as solutions are usually easier to solve once potential causes have been established. Anyway, back to the P450s…
CYP1A2, CYP3A4, CYP2D6, and CYP2C19 have reportedly been found to be inhibited by kavalactones, so there may be potential for drug-drug interactions with compounds metabolised by these enzymes, however there are also studies which show these enzymes are either only inhibited weakly, or not at all with relatively low doses of kava, and CYP3A4/5, CYP2D6, and CYP1A2, have been reported to be (mostly) unaffected by kava in humans, so although the jury is still out on some of these interactions, it seems at this stage that most CYP interactions with kava are unlikely to be clinically relevant for most consumers.[38]
As an interesting side note, it may be worth pointing out that kavalactones themselves may inhibit the degradation of other kavalactones.
In addition to inhibition, gene expression of P450s may also be altered by regular kava consumption; Rodents of both sexes have experienced increases in the expression of CYP1A1, CYP1A2, CYP2B1, CYP2C2, CYP3A1, CYP3A3 and CYP13A1 and decreases in expression of CYP2C23, CYP2C40, and in females, a decrease in expression of CYP2D1 (human CYP2D6 homolog), following long-term daily consumption. Gene expression of CYP2C9, CYP2C19, CYP2D6, CYP3A4 has also been reportedly inhibited in human hepatic microsomes by kavalactones, and CYP2E1 expression has been reduced by 40% following kavalactone consumption in vivo; Looking at the body of investigative studies holistically, it seems plausible that some of the reported decrease in CYP2E1 activity (or other CYPs for that matter) may have been misattributed to enzyme inhibition rather than a decrease in expression.[39]
Side tracking slightly here (again), but for those of you wondering about kava’s reported reverse tolerance (or sensitisation), if the metabolic pathways are downregulated, the body might retain higher kavalactone levels, requiring smaller amounts to achieve the same effect over time, and as such, the changes in gene expression (in addition to inhibition) of cytochrome P450 enzymes might potentially play a role here. If kavalactones decrease the expression of specific CYP enzymes involved in kavalactone metabolism, the body may gradually metabolise kava more slowly after some (possibly protracted) period of consumption, which could lead to higher levels of kavalactones in the bloodstream during subsequent uses, contributing to an increased sensitivity or enhanced effects. The suppression of enzymes that metabolise kavalactones would result in elevated concentrations of active compounds and extended durations of bioavailability, supporting the notion of reverse tolerance, which we have been witness to on a multitude of occasions, despite the not insignificant amount of refute we’ve seen here about its purported existence. We believe it’s a thing. Feel free to disagree – we can’t please everyone, and maybe we’re wrong (but we suspect not).
The inhibition of CYP1A2 expression has been reportedly confirmed in humans, which has a number of practical implications not only because this enzyme is part of the metabolic pathway for a number of drugs, but perhaps more interestingly because 1A2 is involved in the bioactivation of aflatoxins and other hepatic carcinogens, which means that kava may be implicated in a liver-protective effect, particularly in tropical climates where aflatoxins are more abundant.
A few more random tidbits:
Kavain has been shown to suppress eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) expression (which plays a critical role in cellular processes such as growth, metabolism, and response to stress) and ribosomal protein S6 (rpS6, which is a component of the 40S ribosomal subunit and plays a crucial role in protein synthesis) phosphorylation, which is believed to contribute to kava’s reported anti-cancer properties. Much of the documented anti-cancer action of kava constituents is also attributed to flavokavains A, B, and C, which may induce apoptosis in (and inhibit proliferation of) cancer cells. There are reports that FKB also regulates several receptor tyrosine kinases, regulates the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations, and enhances the levels of interleukin 2 and interferon gamma (IFN-y), but suppresses interleukin 1 beta (IL1B). There is also evidence in the literature that kava reduces NNK-induced DNA damage with preferential reduction of O(6)-methylguanine.
FKC has anti-inflammatory activity on nuclear factor kappa B-dependent nitric oxide production and expression of inducible nitric oxide synthase. It may also prevent inflammation via the mitogen-activated protein kinase (MAPKs) (extracellular-signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK)) pathway, which is one reason kava may one day prove to become a valuable addition to cosmetics.
Yangonin’s reported hepatoprotective capacity is due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and it promotes lipid metabolism and glycogen synthesis. On that note, it also modulates blood glucose homeostasis. Yangonin also inhibits SREBP-1c and SCD1 protein expression, which also helps with hepatoprotection, as does its inhibition of MiR-194. Essentially yangonin is believed to protect against liver injury by regulating the miR-194/FXR axis and inhibiting cellular senescence; Once touted as potentially harmful to the liver, compounds found within kava are now being considered for their treatment potential of liver problems.[40]
Kavalactones downregulate the expression of pro-inflammatory cytokines through the NF-KB, STAT3, and PI3K/Akt/mTOR pathways, which is a believed to be a significant contributor to kava’s anti-inflammatory properties.[41]
Isosakuranetin is a powerful antioxidant free-radical scavenger found in kava.
Alpinetin, another compound found in kava, has been found to be an inhibitor of xanthine oxidase (IC50 of approximately 135 ug/mL), which may make it useful for anti-hyperuricemia activity.[42]
That’s a wrap… For now.
Looking at a list like this and understanding that we've barely touched on kava’s pharmacokinetic parameters (absorption, distribution, metabolism, and excretion), and realising that each of the molecular targets on our list of pharmacodynamic interactions are part of a vastly complex and intertwined network of molecular pathways which are yet to be elucidated in their entirety, it becomes evident that anybody who claims to know everything about kava and how it works should probably just sit down, have a shell, and chill out, and that we should take their pontifications with a large grain of salt. Much has been demystified, but there is still so much to learn. We hope you enjoy the challenge of the journey, if it’s a path you wish to explore further.
Kava gives us a realm where science meets the senses and where complex chemical interactions converge with the simple art of enjoyment. Thank you for joining us on our exploration of this elaborate and mysterious world, where the phytomolecules of the plant perform an intricate dance with our own biomolecular machinery, choreographing a medley of easy sociability, relaxation, and pleasant euphoria.
There is so much more to the pharmacology of kava than we’ve posted here, from pharmacogenetics (genetic variability in CYP450 enzyme expression (particularly CYP2D6, which shows genetic polymorphisms) may contribute to individual differences in subjective effects or sensitivities, for example), to a deeper look at neuroplasticity, reverse tolerance mechanisms, and emerging therapeutic potentials, but whether you choose to immerse yourself in the details and continue your scientific exploration or elect instead to simply revel in kava’s delightful effects, let's collectively raise a shell to this pharmacologically enigmatic elixir that has fascinated over 100 generations before ours.
Malok!
The R&D team at Root & Pestle
References::
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