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German "kava" extracts contained cheaper "synthetic kavain" and not actual kavain?

Discussion in 'Kava News' started by Henry, Feb 14, 2017.

  1. Henry

    Henry . Moderator The Kava Society of New Zealand

    I've found this super strange quote:

    "A poisoning by synthetic enantiomers could also be a possible cause, as a dissertation published in 2011 shows. The drugs produced in Germany (such as, for example, the drug Laitan) contained not only natural substances but also, for cost reasons, synthesized Kavain . [21] Artificially produced Kavain is a racemic mixture of (+) - Kavain and (-) - Kavain (also referred to as DL- Kaavain). Kava Kava contains only (+) - Kavain. The work has shown that the synthetic (-) - kavain is degraded to harmful para-hydroxy compounds. This would explain why hepatotoxic cases have mainly occurred in the German-speaking world, while the hepatotoxicity in the Pacific region is virtually unknown. The present differences to the hepatotoxicity in the scientific literature could also be understood, since the authors do not explicitly state whether the examined kavain is synthetic or originates from the kava kava."

    ?! Has anyone else read about synthetic kavain being used in the manufacturing of the German extracts?
    @verticity ?

    Henry, thanks for posting this, I never ever knew that they were making their own Kavain. I wonder if Dr. Schmidt knows about this?
    I will have to ask him, thanks again for sharing this information. Aloha.

    Chris

    I think this is well known in Germany. There were at least two drugs containing synthetic Kavain:
    Kavaform and Neuronika. As far as I know, Laitan was made of natural Kava. There was also an article in german:
    https://www.deutsche-apotheker-zeitung.de/daz-az/2000/daz-29-2000/uid-6989

    So strange! This seems like a very important piece of info and yet it doesn't even get mentioned in any of these comprehensive lit reviews. I've found another source (in French) claiming that laitan also contained synthetic kavain..

    I have never heard of that. Where did you find that quote, @Henry ?
    In general it is difficult to synthesize enantiomerically pure chemicals using conventional chemistry, but plants and animals naturally do it all the time. Normally one of the enantiomers is biologically active, and the other form is just inert: it doesn't do anything useful, but is very difficult to separate. I have never heard of one enantiomer being toxic while the other one is not. That is indeed very strange.

    OK, there actually was one notorious example of a drug where one optical isomer is a useful drug, but the other one is toxic: thalidomide. (That was also another notorious example of a failure by German pharmaceutical companies.) Unfortunately in that case the two forms can spontaneously interconvert so it is impossible to make a pure form. (That is not the case for kavain: naturally occuring (+)-kavain can't change to (-)-kavain):
    http://www.avericadiscovery.com/blog/why-thalidomide-is-important-to-chiral-separation/

    There is also The Stout Labs" in Canada who have this going-- interesting.
    "Kavalactone biosynthesis in Piper methysticum
    Kava is a beloved plant of the Polynesian peoples because it produces a number of polyketides collectively known as the kava lactones. We are currently testing a number of candidate genes that were sequenced from the PhytoMetaSyn project (http://phytometasyn.ca/) that may encode the biosynthetic enzymes that produce the major kava lactones. "

    There are methods to synthesize pure (+)-kavain. One method uses enzymes. But I don't think any of these methods were known in 2000 when these products were made.
    http://www.sciencedirect.com/science/article/pii/S0040403906019769

    Huh interesting, I think back when the liver concerns first started they were linked to people in Germany having liver failure due to kava.

    It was originally a poor translation from a random German article. But I've found the original source. It was written by Dr Barguil in his PhD thesis (chemistry):

    "Cependant, certains travaux se heurtent à des obstacles méthodologiques : plusieurs étudesutilisent en effet, en complément ou en substitut à l’extrait de kava, le mélange racémique quiconstitue la kavaïne de synthèse. C’est ce mélange de produits naturels et du produit de synthèsequi est le principe actif essentiel d’une série de produits pharmaceutiques allemands autorisésjusqu’en 2000. Or on sait que les isomères (+) des kavalactones (les seuls présents dans la plante)sont actifs sur le plan thérapeutique. Doper l’extrait naturel de kava par un produit synthétiqueétait un moyen économique pour les pharmacologues allemands d’accroître la quantité de produitsactifs (au risque d’y introduire un produit étranger). De plus, l’activité du kava naturel n’est pasdue à une seule kavalactone, mais à la synergie de l’ensemble des kavalactones qui sont présentesen proportions très variables selon le cultivar. Tester un mélange de kava naturel et de kavaïne desynthèse équivaut à tester simultanément des kavalactones naturelles et l’isomère (-) kavaïneétranger à la plante.Il convient donc de rester prudent face aux résultats d’auteurs qui ne précisent pas lanature de l’extrait ou de la substance qu’ils ont utilisés, parfois une kavalactone naturelle pure,parfois une molécule provenant d’une synthèse racémique, parfois même des extraits de kava dontla provenance, le mode de préparation et la concentration en kavalactone(s) ne sont pas précisés.Nous avons chaque fois tenté de connaître la nature du produit utilisé sous le terme de « kava » ousous celui de « kavaïne » "
    https://kavalogue.files.wordpress.com/2011/11/these-doctorat-kava-yann-barguil-2011.pdf

    You can google translate it, should be pretty accurate. But let me know if it's not clear, I can help to translate it.

    He argues that synthetic kavain was present in a range of German products up until 2000.

    Clear enough:
    "Some studies, however, encounter methodological obstacles: several studies use, in addition or as a substitute to the extract of kava, the racemic mixture which synthesizes kavain. It is this mixture of natural products and the synthetic product which is the essential active ingredient of a series of German pharmaceutical products authorized until 2000. It is known that the (+) isomers of kavalactones (the only ones present in the plant) Are therapeutically active. Doping the natural extract of kava with a synthetic product was an economical way for German pharmacologists to increase the quantity of active products (at the risk of introducing a foreign product). Moreover, the activity of the natural kava is not due to a single kavalactone, but to the synergy of all the kavalactones which are present in very variable proportions according to the cultivar. Testing a mixture of natural kava and kavain desynthesis is equivalent to simultaneously testing natural kavalactones and the (-) kavain-strange isomer to the plant. It is therefore advisable to remain cautious with the results of authors who do not specify the nature of the extract Or of the substance which they have used, sometimes a pure natural kavalactone, sometimes a molecule derived from a racemic synthesis, sometimes even kava extracts whose origin, method of preparation and concentration in kavalactone (s) are not Each time we tried to know the nature of the product used under the term "kava" or under the term "kavain""

    But I'm still not finding the research where they find that (-)-kavain is toxic.
    Last edited by a moderator: Apr 7, 2017
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  2. Henry

    Henry . Moderator The Kava Society of New Zealand

    Not sure what's happened with this post lol, but just thought some of our new(er) members who happen to be fluent in French (@Krunkie McKrunkface ?) might find these discussions interesting
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  3. verticity

    verticity I'm interested in things

    @Henry I saw your post of the French dissertation from last night via email, and also recall that we discussed this topic at some length here a while ago. It appears that someone attempted to merge your new post with the old thread on the same topic, but somehow deleted both your post and most of the old thread...

    Hopefully it can be recovered because this is an interesting topic that I don't think enough attention is payed to...

    Looking at the OP here, attributed to @Henry I see some comments that I'm pretty sure that I wrote embedded in there... the part that starts "I have never heard of that. Where did you find that quote, @Henry ? In general it is difficult to synthesize enantiomerically pure chemicals..."

    Looks like the same thing happened with some comments by Chris and others...

    I guess it's sort of all still there?? :confused:
    Last edited: Mar 7, 2019
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  4. Alia

    Alia 'Awa Grower/Collector

    Very odd. This is the first time I have seen this complete Posting. Even though I am quoted as having knowledge of the Canada PhD. That Lab actually visited us while researching kava. The little Laitan 100 Booklet Schwabe folks gave me in 1998 has much to say about this product but clearly claims it only has "110 mg dry extract of Kava-Kava rhizome (11-20:1) corresponding to 70 Kava lactones. Extraction agent: acetone/water."
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  5. Alia

    Alia 'Awa Grower/Collector

    What Paper/Study is this quote from? "I've found this super strange quote:"
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  6. Henry

    Henry . Moderator The Kava Society of New Zealand

    I deleted my new post because I realised I had posted almost the same thing earlier.
    But I have no idea what's happened with this old post. Perhaps it got weirdly merged and mixed up when the content posted by G.S. was removed?

    Anyway, I find it fascicinating that the French language scholarship on kava world appears to be developing indpeendingly to others. E.g. that benzene hypothesis!
  7. verticity

    verticity I'm interested in things

    The benzene reference in French Wikipedia is something I haven't seen anywhere else. This paragraph, right?

    "En premier lieu ils ont utilisé des solvants chimiques, notamment le benzène. En soi celui-ci est porteur d'effets nocifs graves - noter qu'entre autres effets nocifs du benzène il peut amener des tremblements, voire des convulsions (rappelant le syndrome parkinsonien). De plus il peut avoir soit libéré des substances toxiques contenues dans la racine, qui ne sont pas libérées par les méthodes traditionnelles d'utilisation de la plante ; soit empêché l'extraction d'autres substances dans la racine, changeant ainsi la nature et les propriétés de l'extrait[2]."
    https://fr.wikipedia.org/wiki/Kava

    Google translate:

    "In the first place they used chemical solvents, especially benzene. In itself it carries serious harmful effects - note that among other harmful effects of benzene it can cause tremors or convulsions (reminiscent of Parkinson's syndrome). In addition, he may have either released toxic substances contained in the root, which are not released by the traditional methods of use of the plant; it prevents the extraction of other substances in the root, thus changing the nature and properties of the extract[2]."
    The reference cited is a herb and seed vendor:
    https://www.richters.com/show.cgi?page=Issues/kava.html

    Which has this:

    "Why kava products suddenly became suspect as a liver toxin is a matter of speculation. Some argue that the manufactured products are concentrated in a manner that differs greatly from the traditional practice. Commercial kava products are extracted using organic solvents such as benzene, while the traditional extraction involves a process of oral mastication and fermentation in water."
    It is not a scientific paper, and is just saying that organic solvents "such as" benzene were used. I have never heard of benzene being used for extract products, and because benzene is completely non-polar it wouldn't be a very good solvent for kavalactones. I think it is just referring to acetone and ethanol, which are organic solvents "like benzene", not benzene itself. [EDIT: The herb and seed vendor also wrongly states that kava is "fermented", suggesting it's not a very reliable source..]
    Last edited: Mar 8, 2019
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  8. Alia

    Alia 'Awa Grower/Collector

    Oh, never mind I see now the paper you refer to! Right in front of me.
    Also, an example of "French language scholarship on kava world"...developing independently is P. Simeoni Buveurs de KAVA. Great big book, never translated to English.
    Last edited: Mar 7, 2019
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  9. Henry

    Henry . Moderator The Kava Society of New Zealand

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  10. Krunkie McKrunkface

    Krunkie McKrunkface Kava Enthusiast

    Some of the words in the original are lacking a space between them which causes some interesting mistranslation but it's still good enough you get the basic idea. They don't use the term "entourage effects" but that's what they are talking about in comparing grog to the Frankenkrank monster ze Germans came up with.
    Last edited: Mar 7, 2019
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  11. Alia

    Alia 'Awa Grower/Collector

    This is a very interesting subject to return to but I still wonder if it will ever be resolved? There does not seem to be an agreed upon model as to why/how the liver toxicity happened in the 1st place, what exactly caused it, and whether the FDA will ever divide "Dietary Supplement fragmented product" from a water based beverage made from roots and stump.
  12. verticity

    verticity I'm interested in things

    It would be really interesting, but the experiments to answer the question (whether synthetic kavain is toxic) would be very expensive, so there probably is no one with both the interest and research dollars to spend.

    For those wondering what this is all about, here is a good explanation of the difference between optical isomers, and two examples (thalidomide, which was mentioned before, and the antihistimine Seldane) where one isomer is toxic and the other is not. In the case of kavain it's not proven if the unnatural isomer in synthetic kavain is toxic, but it is theoretically possible:
    https://fruiscientia.wordpress.com/2015/01/13/thalidomide-seldane-and-chirality/
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