keeron
Kava Enthusiast
Moderator Note: Below are hypotheses on kava toxicity, proposed by member Keeron.
These hypotheses was forwarded to Dr. Mathias Schmidt and Dr. Chengguo (Chris) Xing and their responses to the hypotheses are included in the post in bold red.
Keeron's post is un-edited and as it was at the time it was forwarded to the above researchers.
Since Dr. Xing's response was more broad, it will be included at the top.
Hope this helps to give further information on the subject to the rest of our members.
_____________________________________________________________________
Dr. Chengguo (Chris) Xing:
"[...] my view of the statement was it was a simple collection and speculation of literature/personal communications without the context and careful analysis.
I know this is the fact because I have discussed with someone during a conference break that some compounds in kava might deplete GSH, which remains to be fully tested in animal models while it was stated herein as "Dr. Xing mentioned Tudei contains higher levels of a chemical that depletes glutathione".
[Moderator note: Keeron got this information from Dr. Xing's video interview with Steve Myers (Senior Editor at Natural Products Insider Magazine) at the 13th annual Oxford International Conference on the science and regulation of botanicals at the University of Mississippi. The full transcript, link and video can be found here:http://www.kavaforums.com/forum/threads/dr-xing-hepatotoxic-risk-due-to-wrong-cultivar-and-that-cultivar-is-tudei-kava.2557/]
This is a serious problem for kava and many dietary supplements - speculation and hypothesis, through several reiterations, becomes "the fact"."
Hi guys,
I've studied scientific literature on Kava and tried to study the people who got liver damage or hepatotoxicty from Kava.
The problem with theories on the mechanisms of kava hepatotoxicity is the assumption of the existence of such a toxicity. If you take a look at the case reports there is only a very small number of reports from Switherland and Germany (and only from there, which should trigger questions about the quality used in these cases), so there is as yet not even a strong signal for liver toxicity by kava. With just three more or less secured case reports, and one of them a case of an allergy against the product (not necessarily against kava) the data is insufficient to build a case, and much less so to discuss mechanisms.
Certain studies, came to conclusions that Kava can be Hepatotoxic and mostly Hepatoxic in Europe is because, 12%–21% of Caucasians are poor metabolizers of CYP2D6 enzymes compared to less than 1% for Asians/Pacific Islanders, which may contribute to the lower incidence of kava hepatotoxicity in the Pacific.
I am well aware of this hypothesis, because it was my idea in the first place. I had found the fact that one patient was 2D6 deficient in the paper of Russmann, who had merely mentioned this as a finding. I had discussed this as a potential association with liver toxicity in one of my first publications, but abandoned the hypothesis pretty quickly for the reasons given below. Unfortunately the idea had already been cited by others.
CYP2D6 enzymes are responsible for hydroxylation and demethylation of kavalactones.. So kavalactone metabolism can be different, in westerners compared to the Indigenous Pacific islanders. Which is not surprising considering how long Kava has been used in the south pacific.
Research is suggestive that cholestasis rather than hepatocellular damage is associated with Kava, Which is why i recommend Milk Thistle, and why i take S-adenosylmethionine (SAMe).
Wrong. There is an incidence of 10% deficiency of CyP 2D6 in Caucasians, and 0% in Melanesians, which would mean that around 10% of all Causacians would have trouble with metabolizing kava. Now do the math: we had 450 million doses of kava extract preparations sold only in Germany between 1990 and 2000. Toxicity based on a deficiency of metabolization would be an obligatory form of toxicity: if not sufficiently metabolizing kavalactones would render them toxic, all patients having a 2D6 deficiency should react in some way. 10% of 450 million doses is still 45 million doses, and even if only 1 in 1000 shows the reaction, we would have had a flood of toxicity cases. Where are these cases? Quite obviously the CyP 2D6 theory is not good enough to explain what happened. By the way: Liver toxicity potentially related to kava also occurred in New Caledonia, and possibly in the context of the use of Tudei kava. New Caledonians have not CyP 2D6 deficiency, so why was anything observed there?
Inflammation appears to be involved in both forms of Hepatotoxicity induced by Kava and may be a result from activation of liver macrophages (Kupffer cells). A burst Of Kupffer cells could be a cause of Kava's Toxicity.
So one might want to inhibit Kupffer Cells, which can be done Safely and easily with Glycine, An Amino Acid. Glycine is also Hepapoprotective.
http://www.ncbi.nlm.nih.gov/pubmed/22546493 And can protect from potential liver injuries. I take Glycine sometimes before bed. It also improves sleep quality.
This is built on mere assumptions: an activation of Kupffer cells by kava has never been demonstrated. In fact, all experiments trying to find hints to liver toxic effects (with noble kava) have failed.
However Milk thistle can Inhibit Kupffer Cells too : http://www.ncbi.nlm.nih.gov/pubmed/8666328.
So you can now see why i recommend you to take Milk Thistle. Not only that, but Jarrow's Milk Thistle. (Highest Quality ive Found)
And you can see why Milk Thistle and your liver are so important when consuming Kava, not because Kava is Toxic, but because of whether your Body can actually metabolize Kava or not. If it cant due to lack of P450 activity in your body, then this is were the problem can start.
Is this a marketing story? Do I now have to buy a plethora or other supplements only to counter the vague chance of a kava toxicity?
We also may want to Increase CYP2D6 activity, this may lead to greater demethylating of the Kavalactones.
We might want to increase the rest of the CYP450 enymes also, CYP450 enzymes are also responsible for metabolizing Kava.
CyP 2D6 is a Cytochrome P450 enzyme. So CyP450 is not "also responsible“, this is mere a question of subtypes. And no: we do not want to increase CyP450 activity in general, because this would lead to herb-drug interactions as we have seen with Saint John’s Wort artificially enriched with hyperforin.
So basically you want to up-regulate the CYP450 enymes, which includes CYP2D6 and all the other enzymes which metabolize Kava.
Ginkgo biloba increases the activity of CYP3A4 and CYP2D6 and CYP1A2 and 2D6. So Ginkgo Biloba can be extremely useful. As it Increases activity of 3 Major P450 Enzymes involved in kava metabolism.
Ginkgo is not a potent inducer for Cytochrome P450 enzymes. In addition, there is a discussion about potential toxicity of certain constituents.
Apiaceous vegetables decrease CYP450 enzymes, such as celery, fennel, parsley, parsnip and carrot.
Brassica vegetables increase CYP450, such as cabbage, cauliflower, broccoli, Brussels sprouts, Collard Greens & Kale.
So Eat loads of Broccoli, Cauliflower, Cabbage and sprouts and limit celery, parsnip and fennel etc.
None of these plants would have a relevant clinical effect, this only works in experiments and in vitro. These plants contain furocoumarins, and the only furocoumarin plant with significant effect is grapefruit. Grapefruit inhibits CyP 3A4, which leads to higher blood levels of concomitantly taken drugs. The veggies mentioned here won’t do anything alike.
If you dont like veg, simply buy Broccoli Powder and down it, or mix it in a drink.
Still eat a varied diet, but boost the amount of Broccoli, Cabbages, Sprouts etc.
Biotin (Vitamin B7) also increases Expression of the Cytochrome P450. (CP450)
Abstracts from Studies & Research :
''Based on observations of poor debrisoquine ( Anti-hypertensive drug) metabolism in two individuals reporting symptoms of liver damage following kava ingestion,Russmann S postulated that CYP2D6 deficiency is a risk factor for kava hepatotoxicity.''
This was a misunderstanding, because Russmann had examined the same patient as Strahl. It was not two, but merely one single patient.
A reason why tudei can be Hepatotoxic:
''Among the cultivars characterized was a variety known in the vernacular of Vanuatu as tudei (“two days”). This cultivar was found to contain particularly high concentrations of methysticin (M) and dihydromethysticin (DHM), kavalactones that contain a methylenedioxyphenyl functional group....... Present studies are indicating the inactivation of P450 enzymes.''
This indication has been proven, Kava Inactivates P450 Enzmes. http://www.ncbi.nlm.nih.gov/pubmed/12386118
The studies mentioned in proof are in vitro experiments. They are worthless. In fact, the human studies have never confirmed this effect, and such studies were performed.
''Since DMY, as well as DHM and M, caused the most pronounced enzyme inhibition, it may be that competitive inhibition is a major contributor to the overall inhibition of P450 activities.''
This Means that Tudei itself could not be toxic, but DMY, DHM and M drastically Inhibit P450 Enzymes, which prevent the Metabolism and Methylization of Kava, which could lead to the Hepatoxicity of Kava.
So Tudei could be actually non-toxic, but the inhibition of the P450 Enzymes, is what can cause the Toxicity, due to the high DHM, DMY and M levels in the Tudei strain, which causes a massive drop in P450 enzymes, due to inhibition. ( I bring FKB into the equation soon)
DMY, DHM and Y are clearly not the best kavalactones. They have also been related to skin scaling and yellow coloring, but never to liver toxicity. If this hypothesis were true, we would see a lot of toxicity in the South Pacific, because that is where these kavalactones are regularly consumed. This assumed effect on CyP enzymes would also work for Melanesians, but quite obviously it does not.
I also think Tudei is safer to ingest aswell as Noble, if your P450 Enymes are being modulated and have increased activity, by using things such as Ginkgo Biloba, Broccoli, Sprouts.
P450 Enymes are involved in Liver function and Detoxification. So it is wise to promote liver health so the P450 Enzymes aswell as your liver, can do their job correctly.
Not sure whether I read correctly: Is this a recommendation for the use of Tudei??? In any case this is a rather wild hypothesis, built in bits of random information, for which the clinical consequences have not been shown. This is playing with the health of the consumers!
So if one Inhibit's Kupffer Cells with Glycine and Milk Thistle. We can prevent Inflammation which is involved in the Hepatoxicity of Kava,
As it is believed to be the increase in Kupffer Cells that causes the Inflammation from Kava, and Not the Kava itself.
But if kava does not cause inflammation (there is absolutely no evidence for pro-inflammatory effects!) the whole hypothesis is void.
And if we Up-regulate our P450 Enzymes, with Ginkgo & Broccoli, we can prevent the Hepatoxicty from the Tudei, mainly due to the DHM, DMY and M levels.
Please Note : These studies have ''shown'' and ''hypothesized'' , Except for some that have been proven. You could say that it is proven but only in a few case studies.
And the People who conducted this study, also believe that the P450 Inhibition is the Risk factor in Kava hepatotoxicty.
More studies are going to be done regarding Kava and the P450 Enzyme family.
Kava is a potent P450 Inhibitor, and this is the reason why it can cause Drug Interactions.
So if you raise and up-regulate your P450 Enzymes, the chance of Kava inhibiting P450 to dangerous Low levels, should be reduced.
Sorry, but now things become quite blurred. Now the hypothesis is that kava inhibits CyP enzymes. Where is the evidence? And if so, why didn’t we see toxicity much more frequently? Many patients who used kava in Europe were taking concomitant medication.
As for Tudei, i think its safe to ingest, the only real danger i have seen in studies, is The DHM & DMY inactivating your P450 Enzymes. Which prevents your Liver from Metabolizing the DHM/DMY correctly.
Dangerous nonsense. The kavalactones are not the only constituents of kava!
From Reading Scientific Data, i conclude that Kava Hepatotoxicty, could not be due to the Wrong Cultivar, Tudei.
But more to do with how your own body can metabolize and demethylate the Kavalactones and Chalcones.
Dr. Xing mentioned Tudei contains higher levels of a chemical that depletes glutathione which is true. But mentioned nothing of the P450 Enzyme family.
He also did not mention how this Chemical (FKB) Reduces Glutathione (GSH) levels, i think he and the rest of the scientist or doctors do not know, but i think they may have conclusions about this . Personally i think the reduced GSH involves the P450 enzymes, which i will mention why at the end.
Well, I’d recommend studying the basics first before making such assumptions. GSH is for detoxification in phase II reactions!
If the only problem was glutathione deficiency, then one could simply use NAC, Milk Thistle to boost glutathione levels in the liver.
If noble kava caused GSH deficiency, this would be a mechanism applicable to anyone using it. It would mean that overdosing is potentially lethal (as with acetaminophen). You cannot kill yourself with kava.
I don't think you should stop drinking tudei from these findings, i think you should take steps towards improving your health.
Mainly your Liver and Kidney function. By doing this Kava poses much less of a threat.
Does the author really want to take responsibility for such a recommendation? It is like: You do not need to stop smoking, eat healthy and the cancer will spare you. What if it doesn’t? What if FKB really is liver toxic? In this case all the recommendations for additional supplements won’t lead you anywhere!
However, if one was to stop drinking Tudei Or Kava in general, it would be because of the Flavokawain B.
But yet again, this is no real reason. Why ?
Because this hepatoxic chalcone Flavokawain B , suppresses Cancer Growth, is a anti-cancer, anti-tumor & a chemopreventative compound.
The chemopreventive substance is mainly FKA, not FKB, although I must admit that there are reports. But then, cancer prevention is unrelated to liver toxicity. Of course I could also prevent cancer through death by liver failure…
Evidence is still lacking about toxicty of FKB : Several kava components, including kavalactones, pipermethystine, flavokawain B and contaminant hepatotoxins, have been claimed by different studies to be responsible for the reported kava hepatotoxicity [17], [18], [19] and [20]. However, convincing evidence regarding kava hepatotoxicity is still lacking.
That's true – maybe there is no kava liver toxicity. But if so, I do not need the Cyp hypotheses and the additional supplements.
Safety report on Flavokawaiin A here : http://www.sciencedirect.com/science/article/pii/S2214750014000055
The question is not FKA, but FKB.
I think the last major question is, how toxic is Flavokawain B ? Which has still not been studied.
I have no idea why they have done a safety report on Flavokawaiin A and not Flavokawaiin B.
This safety report on Flavokawaiin B could of answered so many questions, but i guess we still have to wait around for more studies.
I’d love to see toxicity studies on FKB myself, but by now the ones we have must do, and they show liver toxicity in rodents.
Noble Kava is safe, imo.
From the data up till now in 2014, Tudei kava only poses a true threat if you have low Glutathione levels.
Low GSH poses a threat on your health regardless of using Kava.
The logic is flawed, because it focusses only on GSH.
Now im going to Predict something here. This has not been proven, so im going off a hunch here, so bare with me.
Take a look at this : ''findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. ''
A bit crude: Acetaminophen does not simply deplete GSH, the metabolite is detoxified by reaction to GSH. More exactly: The acetyl group is cleaved from acetaminophen, then the molecule is oxidized by Cytochrome P450 3A4 to a hydroquinone derivative, which would be toxic if not bound to GSH. This means the high doses of acetaminophen would deplete GSH levels by simply using all GHS available, and anything in excess becomes toxic. This is called a mandatory toxicity: It works for anyone taking doses of acetaminophen exceeding the metabolic clearance by GSH. Such a mechanism has never been observed with kava, you cannot overdose kava.
So as you know Paracetamol Or acetaminophen is known to be Hepatotoxic and very damaging to the liver.
So if you pay close attention to how acetaminophen actually causes liver damage, it fits the exact mechanism of Kava, not only Kava.
See above. The mechanism is not the same, or otherwise we’d have a dose-dependent toxicity.
But more specifically the Flavokawaiin B. Flavokawaiin B depletes glutathione. But How ???
If FKB depletes GSH (which I find a hypothesis worth following up) it would simply be a question of dose and effect. How much FKB is provided with Tudei, and where is the threshold for such an effect? This is known for acetaminophen, you’d need approximately 10 g to render it toxic. How much for FKB – provided FKB is toxic? This shows that the recommendation to use Tudei is potentially dangerous, because there is 10 times as much FKB in Tudei than in noble kava.
I have a feeling its the same way acetaminophen does, by being activated by CYP450 Enzymes to create a metabolite that depletes GSH.
Even if Flavokawaiin B does not do the exact same thing as acetaminophen. FKB still results in the exact same effects, which is Depleted Glutathione.
So if we are not worried about acetaminophen & paracetamol, then why are we worried about Tudei, or FKB ??
A simple antidote for Tudei, like the study suggests for acetaminophen is N-Acetyl-Cysteine. Combine this with milk thistle and what real threat is there?
But we are worried about acetaminophen – just follow the recent discussions! And anyway, the comparison acetaminophen/FKB cannot be made without any knowledge about metabolic pathways. Even if we assume that FKB is toxic, we do not know whether it would be FKB itself or a metabolite. If a metabolite is toxic, we still do not know, which enzyme is involved in the toxification, or the chemical structure of the potential GSH metabolite resulting from this phase I reaction.
The actual studies that have backed up my theories, this last part about FKB is all speculation.
As there is no 100% proof about FKB and hepatotoxity, it could be wise to Minimize Tudei drinking, however looking at the present findings, FKB is far less damaging than a Paracetmol pill.
How do you know that? A paracetamol pill has 500 mg is is perfectly safe, as it would not exceed the coupling capacity of GSH. In contrast there is some evidence that kava drinking in New Caledonia and the extracts with relatively small quantities in Europe were sufficient to trigger toxicity. So how can anyone make the assumption that Tudei is safer than paracetamol?
Put it this way, would you rather consume a herb that nature made that has anti-cancer, anti-tumour ,chemo-preventative properties, whilst relieving anxiety and tension headaches for some, but has shown hepatotoxic findings with lack of evidence to prove it 100% .
Natural does not mean no adverse effects, but that’s mot the issue here. The issue is the benefit-risk ratio. If you can show that kava is anticancer (and you’ll need double-blind trials for that) a low level risk for liver toxicity is perfectly acceptable. Same for anti-anxietey, but here the regulatory people told us that the efficacy had only been demonstrated for doses exceeding the dose recommended in the European kava extract products. Without this argument, we’d have seen kava back to the market years ago.
Or would you rather consume a pill that is man-made, that gets rid of headaches and mild pain, whilst proven to damage your liver ?
And Paracetamol has caused more liver failure in one year, than Kava ever has. And is currently the Leading cause of acute liver failure. Just a thought for you
.
Maybe, but mostly intentional abuse. You cannot compare suicidal use with regular use. How many cases do you know from regular use?
Heres a scary fact : ''Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year''
Again, yes: overdose. Right, you cannot kill yourself with kava, so no overdose and clearly an advantage. But that dos not say that Tudei kava cannot cause toxicity on repeated intake. This is not about overdosing, this is a question of repeated dose toxicity and potential accumulation.
The last part of my Post about Flavokawaiin B is just my interpretation, you don't have to agree. You have your mind to decide. This is just how ive interpreted the Scientific Data.
Sorry, but this is not an "interpretation of scientific data“, it is just picking what suits you and mixing things that don’t belong together.
These hypotheses was forwarded to Dr. Mathias Schmidt and Dr. Chengguo (Chris) Xing and their responses to the hypotheses are included in the post in bold red.
Keeron's post is un-edited and as it was at the time it was forwarded to the above researchers.
Since Dr. Xing's response was more broad, it will be included at the top.
Hope this helps to give further information on the subject to the rest of our members.
_____________________________________________________________________
Dr. Chengguo (Chris) Xing:
"[...] my view of the statement was it was a simple collection and speculation of literature/personal communications without the context and careful analysis.
I know this is the fact because I have discussed with someone during a conference break that some compounds in kava might deplete GSH, which remains to be fully tested in animal models while it was stated herein as "Dr. Xing mentioned Tudei contains higher levels of a chemical that depletes glutathione".
[Moderator note: Keeron got this information from Dr. Xing's video interview with Steve Myers (Senior Editor at Natural Products Insider Magazine) at the 13th annual Oxford International Conference on the science and regulation of botanicals at the University of Mississippi. The full transcript, link and video can be found here:http://www.kavaforums.com/forum/threads/dr-xing-hepatotoxic-risk-due-to-wrong-cultivar-and-that-cultivar-is-tudei-kava.2557/]
This is a serious problem for kava and many dietary supplements - speculation and hypothesis, through several reiterations, becomes "the fact"."
Hi guys,
I've studied scientific literature on Kava and tried to study the people who got liver damage or hepatotoxicty from Kava.
The problem with theories on the mechanisms of kava hepatotoxicity is the assumption of the existence of such a toxicity. If you take a look at the case reports there is only a very small number of reports from Switherland and Germany (and only from there, which should trigger questions about the quality used in these cases), so there is as yet not even a strong signal for liver toxicity by kava. With just three more or less secured case reports, and one of them a case of an allergy against the product (not necessarily against kava) the data is insufficient to build a case, and much less so to discuss mechanisms.
Certain studies, came to conclusions that Kava can be Hepatotoxic and mostly Hepatoxic in Europe is because, 12%–21% of Caucasians are poor metabolizers of CYP2D6 enzymes compared to less than 1% for Asians/Pacific Islanders, which may contribute to the lower incidence of kava hepatotoxicity in the Pacific.
I am well aware of this hypothesis, because it was my idea in the first place. I had found the fact that one patient was 2D6 deficient in the paper of Russmann, who had merely mentioned this as a finding. I had discussed this as a potential association with liver toxicity in one of my first publications, but abandoned the hypothesis pretty quickly for the reasons given below. Unfortunately the idea had already been cited by others.
CYP2D6 enzymes are responsible for hydroxylation and demethylation of kavalactones.. So kavalactone metabolism can be different, in westerners compared to the Indigenous Pacific islanders. Which is not surprising considering how long Kava has been used in the south pacific.
Research is suggestive that cholestasis rather than hepatocellular damage is associated with Kava, Which is why i recommend Milk Thistle, and why i take S-adenosylmethionine (SAMe).
Wrong. There is an incidence of 10% deficiency of CyP 2D6 in Caucasians, and 0% in Melanesians, which would mean that around 10% of all Causacians would have trouble with metabolizing kava. Now do the math: we had 450 million doses of kava extract preparations sold only in Germany between 1990 and 2000. Toxicity based on a deficiency of metabolization would be an obligatory form of toxicity: if not sufficiently metabolizing kavalactones would render them toxic, all patients having a 2D6 deficiency should react in some way. 10% of 450 million doses is still 45 million doses, and even if only 1 in 1000 shows the reaction, we would have had a flood of toxicity cases. Where are these cases? Quite obviously the CyP 2D6 theory is not good enough to explain what happened. By the way: Liver toxicity potentially related to kava also occurred in New Caledonia, and possibly in the context of the use of Tudei kava. New Caledonians have not CyP 2D6 deficiency, so why was anything observed there?
Inflammation appears to be involved in both forms of Hepatotoxicity induced by Kava and may be a result from activation of liver macrophages (Kupffer cells). A burst Of Kupffer cells could be a cause of Kava's Toxicity.
So one might want to inhibit Kupffer Cells, which can be done Safely and easily with Glycine, An Amino Acid. Glycine is also Hepapoprotective.
http://www.ncbi.nlm.nih.gov/pubmed/22546493 And can protect from potential liver injuries. I take Glycine sometimes before bed. It also improves sleep quality.
This is built on mere assumptions: an activation of Kupffer cells by kava has never been demonstrated. In fact, all experiments trying to find hints to liver toxic effects (with noble kava) have failed.
However Milk thistle can Inhibit Kupffer Cells too : http://www.ncbi.nlm.nih.gov/pubmed/8666328.
So you can now see why i recommend you to take Milk Thistle. Not only that, but Jarrow's Milk Thistle. (Highest Quality ive Found)
And you can see why Milk Thistle and your liver are so important when consuming Kava, not because Kava is Toxic, but because of whether your Body can actually metabolize Kava or not. If it cant due to lack of P450 activity in your body, then this is were the problem can start.
Is this a marketing story? Do I now have to buy a plethora or other supplements only to counter the vague chance of a kava toxicity?
We also may want to Increase CYP2D6 activity, this may lead to greater demethylating of the Kavalactones.
We might want to increase the rest of the CYP450 enymes also, CYP450 enzymes are also responsible for metabolizing Kava.
CyP 2D6 is a Cytochrome P450 enzyme. So CyP450 is not "also responsible“, this is mere a question of subtypes. And no: we do not want to increase CyP450 activity in general, because this would lead to herb-drug interactions as we have seen with Saint John’s Wort artificially enriched with hyperforin.
So basically you want to up-regulate the CYP450 enymes, which includes CYP2D6 and all the other enzymes which metabolize Kava.
Ginkgo biloba increases the activity of CYP3A4 and CYP2D6 and CYP1A2 and 2D6. So Ginkgo Biloba can be extremely useful. As it Increases activity of 3 Major P450 Enzymes involved in kava metabolism.
Ginkgo is not a potent inducer for Cytochrome P450 enzymes. In addition, there is a discussion about potential toxicity of certain constituents.
Apiaceous vegetables decrease CYP450 enzymes, such as celery, fennel, parsley, parsnip and carrot.
Brassica vegetables increase CYP450, such as cabbage, cauliflower, broccoli, Brussels sprouts, Collard Greens & Kale.
So Eat loads of Broccoli, Cauliflower, Cabbage and sprouts and limit celery, parsnip and fennel etc.
None of these plants would have a relevant clinical effect, this only works in experiments and in vitro. These plants contain furocoumarins, and the only furocoumarin plant with significant effect is grapefruit. Grapefruit inhibits CyP 3A4, which leads to higher blood levels of concomitantly taken drugs. The veggies mentioned here won’t do anything alike.
If you dont like veg, simply buy Broccoli Powder and down it, or mix it in a drink.
Still eat a varied diet, but boost the amount of Broccoli, Cabbages, Sprouts etc.
Biotin (Vitamin B7) also increases Expression of the Cytochrome P450. (CP450)
Abstracts from Studies & Research :
''Based on observations of poor debrisoquine ( Anti-hypertensive drug) metabolism in two individuals reporting symptoms of liver damage following kava ingestion,Russmann S postulated that CYP2D6 deficiency is a risk factor for kava hepatotoxicity.''
This was a misunderstanding, because Russmann had examined the same patient as Strahl. It was not two, but merely one single patient.
A reason why tudei can be Hepatotoxic:
''Among the cultivars characterized was a variety known in the vernacular of Vanuatu as tudei (“two days”). This cultivar was found to contain particularly high concentrations of methysticin (M) and dihydromethysticin (DHM), kavalactones that contain a methylenedioxyphenyl functional group....... Present studies are indicating the inactivation of P450 enzymes.''
This indication has been proven, Kava Inactivates P450 Enzmes. http://www.ncbi.nlm.nih.gov/pubmed/12386118
The studies mentioned in proof are in vitro experiments. They are worthless. In fact, the human studies have never confirmed this effect, and such studies were performed.
''Since DMY, as well as DHM and M, caused the most pronounced enzyme inhibition, it may be that competitive inhibition is a major contributor to the overall inhibition of P450 activities.''
This Means that Tudei itself could not be toxic, but DMY, DHM and M drastically Inhibit P450 Enzymes, which prevent the Metabolism and Methylization of Kava, which could lead to the Hepatoxicity of Kava.
So Tudei could be actually non-toxic, but the inhibition of the P450 Enzymes, is what can cause the Toxicity, due to the high DHM, DMY and M levels in the Tudei strain, which causes a massive drop in P450 enzymes, due to inhibition. ( I bring FKB into the equation soon)
DMY, DHM and Y are clearly not the best kavalactones. They have also been related to skin scaling and yellow coloring, but never to liver toxicity. If this hypothesis were true, we would see a lot of toxicity in the South Pacific, because that is where these kavalactones are regularly consumed. This assumed effect on CyP enzymes would also work for Melanesians, but quite obviously it does not.
I also think Tudei is safer to ingest aswell as Noble, if your P450 Enymes are being modulated and have increased activity, by using things such as Ginkgo Biloba, Broccoli, Sprouts.
P450 Enymes are involved in Liver function and Detoxification. So it is wise to promote liver health so the P450 Enzymes aswell as your liver, can do their job correctly.
Not sure whether I read correctly: Is this a recommendation for the use of Tudei??? In any case this is a rather wild hypothesis, built in bits of random information, for which the clinical consequences have not been shown. This is playing with the health of the consumers!
So if one Inhibit's Kupffer Cells with Glycine and Milk Thistle. We can prevent Inflammation which is involved in the Hepatoxicity of Kava,
As it is believed to be the increase in Kupffer Cells that causes the Inflammation from Kava, and Not the Kava itself.
But if kava does not cause inflammation (there is absolutely no evidence for pro-inflammatory effects!) the whole hypothesis is void.
And if we Up-regulate our P450 Enzymes, with Ginkgo & Broccoli, we can prevent the Hepatoxicty from the Tudei, mainly due to the DHM, DMY and M levels.
Please Note : These studies have ''shown'' and ''hypothesized'' , Except for some that have been proven. You could say that it is proven but only in a few case studies.
And the People who conducted this study, also believe that the P450 Inhibition is the Risk factor in Kava hepatotoxicty.
More studies are going to be done regarding Kava and the P450 Enzyme family.
Kava is a potent P450 Inhibitor, and this is the reason why it can cause Drug Interactions.
So if you raise and up-regulate your P450 Enzymes, the chance of Kava inhibiting P450 to dangerous Low levels, should be reduced.
Sorry, but now things become quite blurred. Now the hypothesis is that kava inhibits CyP enzymes. Where is the evidence? And if so, why didn’t we see toxicity much more frequently? Many patients who used kava in Europe were taking concomitant medication.
As for Tudei, i think its safe to ingest, the only real danger i have seen in studies, is The DHM & DMY inactivating your P450 Enzymes. Which prevents your Liver from Metabolizing the DHM/DMY correctly.
Dangerous nonsense. The kavalactones are not the only constituents of kava!
From Reading Scientific Data, i conclude that Kava Hepatotoxicty, could not be due to the Wrong Cultivar, Tudei.
But more to do with how your own body can metabolize and demethylate the Kavalactones and Chalcones.
Dr. Xing mentioned Tudei contains higher levels of a chemical that depletes glutathione which is true. But mentioned nothing of the P450 Enzyme family.
He also did not mention how this Chemical (FKB) Reduces Glutathione (GSH) levels, i think he and the rest of the scientist or doctors do not know, but i think they may have conclusions about this . Personally i think the reduced GSH involves the P450 enzymes, which i will mention why at the end.
Well, I’d recommend studying the basics first before making such assumptions. GSH is for detoxification in phase II reactions!
If the only problem was glutathione deficiency, then one could simply use NAC, Milk Thistle to boost glutathione levels in the liver.
If noble kava caused GSH deficiency, this would be a mechanism applicable to anyone using it. It would mean that overdosing is potentially lethal (as with acetaminophen). You cannot kill yourself with kava.
I don't think you should stop drinking tudei from these findings, i think you should take steps towards improving your health.
Mainly your Liver and Kidney function. By doing this Kava poses much less of a threat.
Does the author really want to take responsibility for such a recommendation? It is like: You do not need to stop smoking, eat healthy and the cancer will spare you. What if it doesn’t? What if FKB really is liver toxic? In this case all the recommendations for additional supplements won’t lead you anywhere!
However, if one was to stop drinking Tudei Or Kava in general, it would be because of the Flavokawain B.
But yet again, this is no real reason. Why ?
Because this hepatoxic chalcone Flavokawain B , suppresses Cancer Growth, is a anti-cancer, anti-tumor & a chemopreventative compound.
The chemopreventive substance is mainly FKA, not FKB, although I must admit that there are reports. But then, cancer prevention is unrelated to liver toxicity. Of course I could also prevent cancer through death by liver failure…
Evidence is still lacking about toxicty of FKB : Several kava components, including kavalactones, pipermethystine, flavokawain B and contaminant hepatotoxins, have been claimed by different studies to be responsible for the reported kava hepatotoxicity [17], [18], [19] and [20]. However, convincing evidence regarding kava hepatotoxicity is still lacking.
That's true – maybe there is no kava liver toxicity. But if so, I do not need the Cyp hypotheses and the additional supplements.
Safety report on Flavokawaiin A here : http://www.sciencedirect.com/science/article/pii/S2214750014000055
The question is not FKA, but FKB.
I think the last major question is, how toxic is Flavokawain B ? Which has still not been studied.
I have no idea why they have done a safety report on Flavokawaiin A and not Flavokawaiin B.
This safety report on Flavokawaiin B could of answered so many questions, but i guess we still have to wait around for more studies.
I’d love to see toxicity studies on FKB myself, but by now the ones we have must do, and they show liver toxicity in rodents.
Noble Kava is safe, imo.
From the data up till now in 2014, Tudei kava only poses a true threat if you have low Glutathione levels.
Low GSH poses a threat on your health regardless of using Kava.
The logic is flawed, because it focusses only on GSH.
Now im going to Predict something here. This has not been proven, so im going off a hunch here, so bare with me.
Take a look at this : ''findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. ''
A bit crude: Acetaminophen does not simply deplete GSH, the metabolite is detoxified by reaction to GSH. More exactly: The acetyl group is cleaved from acetaminophen, then the molecule is oxidized by Cytochrome P450 3A4 to a hydroquinone derivative, which would be toxic if not bound to GSH. This means the high doses of acetaminophen would deplete GSH levels by simply using all GHS available, and anything in excess becomes toxic. This is called a mandatory toxicity: It works for anyone taking doses of acetaminophen exceeding the metabolic clearance by GSH. Such a mechanism has never been observed with kava, you cannot overdose kava.
So as you know Paracetamol Or acetaminophen is known to be Hepatotoxic and very damaging to the liver.
So if you pay close attention to how acetaminophen actually causes liver damage, it fits the exact mechanism of Kava, not only Kava.
See above. The mechanism is not the same, or otherwise we’d have a dose-dependent toxicity.
But more specifically the Flavokawaiin B. Flavokawaiin B depletes glutathione. But How ???
If FKB depletes GSH (which I find a hypothesis worth following up) it would simply be a question of dose and effect. How much FKB is provided with Tudei, and where is the threshold for such an effect? This is known for acetaminophen, you’d need approximately 10 g to render it toxic. How much for FKB – provided FKB is toxic? This shows that the recommendation to use Tudei is potentially dangerous, because there is 10 times as much FKB in Tudei than in noble kava.
I have a feeling its the same way acetaminophen does, by being activated by CYP450 Enzymes to create a metabolite that depletes GSH.
Even if Flavokawaiin B does not do the exact same thing as acetaminophen. FKB still results in the exact same effects, which is Depleted Glutathione.
So if we are not worried about acetaminophen & paracetamol, then why are we worried about Tudei, or FKB ??
A simple antidote for Tudei, like the study suggests for acetaminophen is N-Acetyl-Cysteine. Combine this with milk thistle and what real threat is there?
But we are worried about acetaminophen – just follow the recent discussions! And anyway, the comparison acetaminophen/FKB cannot be made without any knowledge about metabolic pathways. Even if we assume that FKB is toxic, we do not know whether it would be FKB itself or a metabolite. If a metabolite is toxic, we still do not know, which enzyme is involved in the toxification, or the chemical structure of the potential GSH metabolite resulting from this phase I reaction.
The actual studies that have backed up my theories, this last part about FKB is all speculation.
As there is no 100% proof about FKB and hepatotoxity, it could be wise to Minimize Tudei drinking, however looking at the present findings, FKB is far less damaging than a Paracetmol pill.
How do you know that? A paracetamol pill has 500 mg is is perfectly safe, as it would not exceed the coupling capacity of GSH. In contrast there is some evidence that kava drinking in New Caledonia and the extracts with relatively small quantities in Europe were sufficient to trigger toxicity. So how can anyone make the assumption that Tudei is safer than paracetamol?
Put it this way, would you rather consume a herb that nature made that has anti-cancer, anti-tumour ,chemo-preventative properties, whilst relieving anxiety and tension headaches for some, but has shown hepatotoxic findings with lack of evidence to prove it 100% .
Natural does not mean no adverse effects, but that’s mot the issue here. The issue is the benefit-risk ratio. If you can show that kava is anticancer (and you’ll need double-blind trials for that) a low level risk for liver toxicity is perfectly acceptable. Same for anti-anxietey, but here the regulatory people told us that the efficacy had only been demonstrated for doses exceeding the dose recommended in the European kava extract products. Without this argument, we’d have seen kava back to the market years ago.
Or would you rather consume a pill that is man-made, that gets rid of headaches and mild pain, whilst proven to damage your liver ?
And Paracetamol has caused more liver failure in one year, than Kava ever has. And is currently the Leading cause of acute liver failure. Just a thought for you
.Maybe, but mostly intentional abuse. You cannot compare suicidal use with regular use. How many cases do you know from regular use?
Heres a scary fact : ''Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year''
Again, yes: overdose. Right, you cannot kill yourself with kava, so no overdose and clearly an advantage. But that dos not say that Tudei kava cannot cause toxicity on repeated intake. This is not about overdosing, this is a question of repeated dose toxicity and potential accumulation.
The last part of my Post about Flavokawaiin B is just my interpretation, you don't have to agree. You have your mind to decide. This is just how ive interpreted the Scientific Data.
Sorry, but this is not an "interpretation of scientific data“, it is just picking what suits you and mixing things that don’t belong together.
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