Research Breakdown on Kava
Kava, also known as Kava root or Kava Kava, is a herb native to the Southern Pacific islands that has traditional usage as a hypnotic, psychotropic, and anxiolytic (anxiety reducer). It is reported to have pleasant and mild psychoactive and hypnotic effects when the roots are brewed into a beverage, and is sometimes paired with alcohol and treated in a manner similar to alcohol, being a social drug of potential abuse; the combination is common.
It originates from the islands located around Fiji, and was found in mainland Australia; both places may be referred to 'traditional usage' of Kava as both places consumed Kava via beverages. Kava appears to be used as a ceremonial beverage in Fiji, commonly given to the Head of State.
It is an anxiety reducing agent (anxiolytic) with potency rivaling some pharmaceuticals, with a reported 350,000 prescriptions annually in Germany in 2002, which appears to be on a downward trend from a reported 547,000 prescribed in 1993. Despite increasing popularity in the US, benzodiazepines are more commonly prescribed due to a lack of enforced control over the quality of Kava products. Additionally, Kava possesses some drug-drug interactions that make it undesirable for multi-drug usage.
It is infrequently called Herbal Ecstasy, which given its properties is quite an inaccurate comparison.
Traditionally used herb, typically drunk, that originated in the tropics. Has been used as a hypnotic, sedative, and anxiety reducing agent in manners (and effects) similar to modern usage of alcohol
Kava root is a herb, and thus contains a variety of bioactives. It should be noted that the following are the root, otherwise known as the rhizome. These include:
A collection of 6 bioactives known as kavalactones or kavapyrones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) which are commonly seen as the main 'active ingredients' and comprise 96% of all lactones by weight Yangonin is highest (around 42%) followed by dihydrokawain (35%) and kawain (9%) dihydromethysticin (4%) methysticin (3%) and 5,6-dehydrokawain (2%) The two kawain molecules have higher ranges of possible content, due to being interconverted in the Kava plant
12 other lesser lactones that comprise 4% of total kavalactones by weight
Small amounts of Alkalones, such as Awaine, Pipermethystine, and 3α,4α-Epoxy-5β-pipermethystine
Derivatives of Kavain called Flavokavains, A B and C
Glutathione, which appears to reduce toxicity of select kavalactones
In contrast to the rhizome, aerial parts (leaves, usually) consist of:
Despite the rough ratio of the 6 primary kavalactones to total lactones, the actual lactone content of the root can vary from 3-20% by weight and their effects in vitro, if not standardized prior, can vary dramatically due to varying contents of the above molecules. Standarization of the sources and lactone content would be prudent to increase reliability.
When assessing Kava supplements, the rhizome (vertical root) may be safer than having a supplement made of aerial parts or stems
Pictured below are the six bioactive components (with structural similarity to resveratrol) that are seen as the main compounds in Kava. They are either classified (chemically) as α-pyrones or substituted 5,6-dihydro-α-pyrones. In either case, they are colloquially referred to as either Kavalactones (lactones from Kava) or Kavapyrones (Pyrones from Kava), and the two terms are used interchangeably.
Some ambuguity exists in naming the structures, as is seen with 'Kava extract' and 'Kawa extract' (both accepted terms) so are 'Kavain' and 'Kawain' both accepted terms, and should be seen as interchangeable.
The similarities between the yagonin compounds and Kawain components are exemplified by the compound 5,6-dehydrokawain and desmethoxyyagonin, which are two names for the same molecule.
Kavalactones tends to be highly insoluble in water, and tend to be located in any ethanolic or fat-soluble extraction such as Kava Resin (a term used to refer to the lactone component of Kava) oral ingestion of Kava at 120mg/kg demonstrates accumulation in brain tissue and seemingly at higher levels relative to injections. Accumulation in the brain occurs approximately 45 minutes after ingestion, After oral ingestion in humans significant psychoactive effects are seen within one hour.
Kavalactones readily cross the blood brain barrier and after oral ingestion can exert effects in under an hour Some of the Dihydrokawain had its 3,4-double bond saturated during metabolism (producing an unnamed metabolite), and two methylenedioxy substituted metabolites of unknown origin (although thought to be from tetrahydroyagonin) were found in the urine that were not in the original beverage. A metabolite derived from yagonin or desmethoxyyagonin was also identified and termed C-12-desmethylyagonin. A study conducted in rats noted opening of pyrone rings after oral administration of Kava, but this was not replicated in the human study. 6-phenyl-3-hexen-2-one has been identified as a urinary metabolite of Kava in humans after (theoretically) interacting with Phase II metabolize and glutathione reductase enzymes. although they appear to enhance GABA(A) signalling vicariously through other ligands, by increasing the amount of binding sites. These effects appear to be mostly mediated through the kavapyrone known as dihydromethysticin, with methysticin having less potent effects and others having no effects on sedation. When injected into rats, as little as 20mg/kg mixed kavalactones is able to induce sedative effects and interactions with the GABA receptors appear to not be the cause for anti-anxiety effects of Kava, as coingestion with benzodiazepine blockers fail to abolish the effects of Kava on anxiety as assessed by time spent in the Open Arms test in rats. In this study, dopamine's metabolite (DOPAC) was not significantly affected by the two lower doses, although homovanillic acid (HVA, catecholamine metabolic) increased by 20% with the lowest dose, while the two higher doses fluctuated around baseline nonsignificantly. When Kava was fed to mice at 250-500mg/kg bodyweight (30% Kavapyrones, LI 158), a decrease in dopamine levels was seen with minimal changes in the HVA metabolite. Isolated Kawain, however, has been implicated in decreasing levels of dopamine to 50% of control levels after injection of 30, 60, and 120mg/kg. High doses (120mg/kg) of Yagonin also was capable of this yet was much more variable, while dihydrokawain and both methylsticin compounds had no effect. Dihydrokawain appeared to induce a small but steady rise of dopamine during the 8 tested hours, and desmethoxyyangonin also possessed this effect. When looking at the receptors, methanolic extracts of the leaf and the root (the latter of which is seen as the desirable supplement source) both show inhibition of dopamine D2 receptors, but with IC50 values ranging from 1-100mcg/mL. Along these lines, some case studies have been reported where the clinical signs of dopamine antagonism exist after Kava ingestion.
The variable content of active kavalactones based on source paired with seemingly opposing effects of some kavalactones make the effects of Kava on dopamine quite unpredictable, although a case can be made for both sides this lack of significance was due to high interindividual variability as half of the group experienced an increase of both while the other showed no change. Isolated dihydromethysticin was able to increase serotonin levels after injection with reduced metabolite levels (suggestive of less metabolism) while desmethoxyyagonin appeared to reduce serotonin. This was also seen with whole Kava extract, and was attributed to those two components as other kavapyrones showed no protective effects. Correct recognitions as assessed by Sperling partial report test were also significantly increased while incorrect asssessments were decreased, with no effect on omissions. Improved reaction time was seen in another acute study following 120mg LI 150 extract (30% kavapyrones) but was not significantly different than the improvement in placebo from stress and not different from Valerian at 600mg.
Some small studies suggest it improves reaction speed and improves quality of processing during the speed enhancement, but the possibility of this being secondary to a reduction in stress cannot be ruled outIn a test of word recollection, the WS 1490 extract of Kava has shown efficacy in improving performance and acute recollection more than placebo. At least one study has introduced Kava at 50mg (WS 1490 extract) when current Benzodiazepine dosage is reduced by 50%, to later replace the benzodiazepines with 300mg WS 1490 extract daily. This substitution appeared to be effective, and Kava does not appear to be significantly more or less effective than some standard drugs used to treat anxiety. As assessed by animal studies using injections, the anti-anxiety effects of Kava and its kavalactones can be very rapid and occur as soon as it hits the brain. A range of 210-240mg has been established in a meta-analysis for Kava being more effective than placebo at reducing short term (1-24 week) anxiety. This dose is usually with using a standardized extract of Kava, sometimes the LI 150 extract (30% kavapyrones) or more commonly the WS 1490 extract (70% kavalactones). In regards to potency, at least one study has noted that Kava (specifically, the LI 150 extract at 400mg) was not significantly different than Opirpramol or Buspirone (two pharmaceuticals) in treating Generalized Anxiety Disorder, although the trends suggested Kava a bit less effective. No significant side-effects or dependence was seen in any group. Studies that come back negative report that 150mg kavalactones in an aqueous extract (paired with St.Johns Wort) was effective at reducing depression but with no significant influence on anxiety and one study that found no differences between Kava and placebo in DSM-IV diagnosed Generalized Anxiety disorder, and no significant differences between Kava and Venlafaxine (active control). One study using an internet-based approach (mailing supplements, report results online) with a rather large sample of 1551 found Kava and placebo to be equally effective in reducing anxiety.
For the most part, it appears to be quite potent and reliable in reducing anxiety when used at around the dose of 250-300mg WS 1490 (an extract with a high percentage kavalactones) and able to reduce other adverse effects of anxiety (depression, impaired sleep) through the anxiety reduction Kava intoxication and high (440g or more of the root extract weekly) usage of Kava via beverages is associated with lower body weight. The dose used was 1.8g of the flowering tops of St.Johns wort paired with 2.66g aqueous Kava rhizome (vertical root) taken 3 times a day; 990mcg hypericin (St.Johns wort bioactive) and 50mg kavalactones per capsule. This study noted significantly reduced depressive rates with no statistically significant influence on anxiety, and was not suited to answer the question as to whether the herbs were synergistic or additive. Even by itself, Kava is able to induce a state of drunkedness known as Kava intoxication; although this is only reported with the brew. When paired with alcohol, Kava WS 1490 extract at 300mg (70% kavalactones) demonstrated no negative (acute) multiplicative effects of the combination, yet increase concentration. Another study found that Kava (lipid soluble fragment) was able to amplify the negative effects of alcohol, and increase the state of drunk and hypnosedative effects of both compounds appear to be synergistic. However, the risk of liver damage from Kava may be increased when combining.
It appears the water-soluble fragment may take the edge off alcohol and improve concentration, while the lipid-soluble fragment can exacerbate drunkedness; minimal studies on both sides though, and the risk for liver toxicity needs to be taken into account These results depended on co-ingestion, as loading the kavalactones for 7 days and then taking isolated Kawain on day 8 had no effect.  It is a mono-extract of acetone from the dried roots of the plant and is standardized to 70% kavalactones.  This was associated with multiple adverse event reports (in the range of 78 to 82) and some reported case studies where Kava root was suspected in causing hepatotoxicity, hepatitis, and death by hepatic failure. However, one systemic review noted that out of 82 case studies from 1990 to 2002 (from the German Federal Institute for Drugs and Medical Device) that 20 were unrelated to Kava and 7 doubtfully related to Kava while 31 did not have sufficient evidence to suspect Kava, 21 were confounded (and probably related) to coingested medications, and 5 case studies (of which 11 papers were published) were reasonably related to Kava. At December of 2001, the FDA claimed 26 cases of liver toxicity in Europe associated with Kava. These case studies appear to be idiosyncratic (immune system mediated) and out of 78 case studies assessed in this review 23 were potentially linked to Kava intake with coingested compounds while another 4 are probably linked to the isolated kavalactones.
Many reported adverse events, but a few of them do appear to be related to either Kava itself (and some unforeseen prior condition to the person's liver) or the combination of Kava with something else; causation has not been placed, but it would be prudent to assume a link for nowWhen looking at animal studies, the ethanolic extract at doses of up to 73mg/kg bodyweight for 6 months has failed to exert any toxic effects and 500mg/kg of isolated lactones (aqueous extract) in rats for 4 weeks caused no abnormalities in liver enzymes. Hepatocellular hypertrophy (enlarged liver cells) has been see with 2g/kg bodyweight, elevated γ-glutamyltransferase after 1g/kg bodyweight, and no adverse effects with 0.25g/kg bodyweight of kava lactones for 14 weeks. Combining the results of these animal trials, it appears the longer periods combined with the higher doses may be needed for liver damage, although due to the idiosyncratic nature of the case studies the above may only be 'general' toxicological information and not predictive of the case studies. When establishing an LD50 for Kavalactones, it was found to be approximately 300-400mg/kg daily.
Animal studies suggest Kava usage is quite safe, and liver growth (but not failure) can only be induced by very high doses of Kava. However, the mechanisms seen in human case studies differ from animal models and the two may be unrelatedAll current human trials using Kava (the majority using the WS 1490 extract, and most under 4 weeks in length) have no reported significant adverse effects from Kava supplements, suggesting a range of safe usage of Kava (with dosages around 200-300mg of kavalactones via concentrated extracts). It should be noted that these studies tend to control for co-ingested drugs via inclusion criteria. Studies in humans consuming Kava the traditional way note that Kava intoxication (a state of drunkedness like alcohol but reportedly without aggression and higher levels of happiness associated with consuming 205g kava powder, approximately 140 to 150-fold higher than a clinical dose) note increased liver enzymes (gamma glutamyl transferase, alkaline phosphatase) alongside saccadic dysmetria, saccadic slowing, and reduced accuracy performing a visual search task. Prolonged usage of Kava was associated with lower body weight and depressed immune markers, similar to those seen in alcoholics.
No controlled human trial has noted liver toxicity with Kava in isolation when used at moderate dosages, although not too many assess liver enzymes while most assess clinical signs of liver toxicity. Overdosing on Kava gives clinical effects similar to alcohol intoxication, and seems to give some liver damage as well
It appears to be safe if taken within the demonstrated limits of human interventions (ie. 200-300mg WS 1490 or LI 150 extracts taken for periods not to exceed 2 months). Conclusions about safety beyond those limits cannot conclusively be made which tends to only occur infrequently and in populations that drink Kava daily, in which case it has been reported to affect 14.5% of sampled persons. This has traditionally been thought to be a niacin deficiency, but at least one trial found no benefit of niacin supplements in treating the disease. Modern usage of Kava, resulting in Kava dermopathy, has been seen with usage of 400mg isolated kavapyrones daily and has been reported in some case studies. All cases appear reversible upon cessation of Kava.
Appears to be a concern with high doses of Kava taken for prolonged periods of time, but is reversible upon cessation Tests were performed in human liver microsomes at 100uM total kavalactones, and at 10uM of isolated lactones the CYP2C9 and CYP3A4 enzymes appear to be inhibited by three different kavalactones (desmethoxyyangonin, methysticin, and dihydromethysticin) whereas CYP2C19 and CYP2D6 were only inhibited by dihydromethysticin and methysticin, respectively. These enzymatic inhibition potentials have been seen elsewhere in vitro with IC50 values at around 10uM. When investigating P-glycoprotein, an efflux protein that ejects molecules from cells and the body, Kava was found to inhibit P-gp in vitro. CYP2A6, CYP2C8, and CYP2E1 appear to be unaffected, and the kavalactone Kawain does not appear to inhibit any enzymes. Additionally, when tested after oral administration in humans Kava was found to not influence CYP3A when ingested at 1227mg over 14 days and was not found to influence digoxin parameters, suggesting Kava does not influence P-glycoprotein in vivo. Gastrointestinal side effects (upset stomach) appear to be infrequent, but sometimes noted to occur more with Kava supplementation than in placebo. When assessing the genotoxicity of the compounds, both Kava root per se and the isolated desmethoxyyangonin have not shown genotoxicity in the Micronucleus and Ames test (respectively) and Kava root did not show genotoxicity in vivo in mice.
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