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Quinine Is A Serotonin Antagonist And Inhibits Serotonin Synthesis

Discussion in 'Scientific Studies' started by haidut, Apr 1, 2015.

  1. haidut

    haidut Member

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    Quinine is the original drug used against malaria, and is still used in certain countries to this day. This study shows that quinine does a few very interesting things that potentially explain its beneficial effects against the malaria plasmid and may be of interest to people trying to control serotonin. It seems that quinine is a serotonin "antagonist" at several "receptors" but even more interestingly quinine inhibits tryptophan absorption and also decreases new serotonin synthesis by inhibiting TPH2. Another drug that does this is the well-known pCPA, so the study draws a parallel between the two. I posted a study not long ago showing that inhibiting TPH2 essentially cures obesity and restores metabolism back to youthful rates. You will also notice in the study that serotonin strongly stimulated neuroblastoma growth (as well as several other cancers) and quinine strongly inhibited that growth. So much for serotonin being good for you...
    I am not sure on what human dosage would achieve the effects observed in the study, but some of the effects such as inhibiting tryptophan absorption occurred at concentrations achievable with doses administered to humans for malaria. I suspect that even drinking tonic water may have some effects on tryptophan absorption since it does result in micromolar concentrations of quinine.

    http://www.nature.com/srep/2014/140109/ ... 03618.html

    "...The key novel findings in this paper are that the antimalarial drug quinine can interfere with both production and function of the major neurotransmitter serotonin. This could help to explain certain adverse reactions to QN treatment seen among malaria patients, particularly those with low dietary tryptophan3, 4, 7. The results also raise the possibility that quinine could find application as an antidote against serotonin syndrome, a condition linked to excessive serotonin in patients25. As discussed below, the effect of QN on serotonin production could be attributable to competition between the drug and tryptophan (the substrate for serotonin biosynthesis) at two principal sites: the active site of the rate-limiting enzyme for serotonin biosynthesis (TPH), and transporters responsible for tryptophan uptake by cells.
    To assay potential interactions between QN and serotonin function, we exploited previous reports of serotonin-induced cell proliferation in yeast and tumorigenic cells
    21, 22, 26, 27, as well as the availability of 5-HT2a,2c receptor-expressing cells. Aromatic alcohols act as autoinducers of yeast and tumorigenic cell growth. In nitrogen deficient media, tryptophol, an amino alcohol and tryptophan derivative is synthesized to autoinduce cell proliferation21. Because of the structural similarity between serotonin and tryptophol, serotonin can act as an autoinducer under the same conditions21. In the present study, QN suppressed these proliferative effects of serotonin. Amine alcohol receptors of yeast are poorly understood. In contrast, 5-HT receptors are well described in higher cells, including as therapeutic targets, and previous work indicated that QN inhibits activation of mammalian 5-HT3 receptors expressed in Xenopus oocytes or HEK-293 cells19, 20. In addition, QN has been reported to inhibit active serotonin uptake into rat synaptosomes28 and to affect serotonin-modulated K+-channels29. Here, QN was observed to inhibit calcium signalling at 5-HT2a/2c receptors. This is important as 5-HT2 receptors are linked to a variety of neuropsychological disorders such as anxiety and mood lowering effects16.
    In mammals, serotonin production in the central nervous system is rate-limited by the TPH2 enzyme30. The present in vitro assays suggested that QN competes directly with tryptophan for binding to the active site of TPH2, similar to the known competitive TPH2 inhibitor, pCPA31. pCPA potently decreases serotonin production in the brain31. The inference that QN, similarly, may have the potential to suppress serotonin production by cells was borne out by analysis of serotonin levels in RN46A cells and, in particular, yeast cells. The strong effect in yeast cells was despite relatively low levels of QN uptake ( Fig. 5a ), highlighting the potential potency of QN action in inhibiting serotonin production. However, there was a smaller relative effect on serotonin production in the rat serotonergic cell line RN46A, despite much higher QN uptake. This indicates that the absolute intracellular QN level is not the sole factor that determines inhibition of serotonin production. We propose that another key factor involved here could be cellular tryptophan concentration. Previously we showed that QN and tryptophan compete for uptake via the Tat2p transporter in yeast, leading to tryptophan depletion5. The high level of QN uptake in RN46A cells appears to be through a different type of mechanism, as excess tryptophan did not affect QN uptake. This apparent lack of competition for uptake between tryptophan and QN suggests that QN is unlikely to cause the cellular tryptophan depletion in RN46A that occurs in yeast cells. Therefore, the lesser impact of cellular QN on serotonin production in RN46A cells may at least partly be attributable to relatively high tryptophan levels in these cells, as this would balance the competition for TPH2 binding in favour of the tryptophan substrate ( Fig. 6a ).
    It is evident from the above discussion that the level of competition with tryptophan both for uptake into cells and for TPH2 binding may determine the relative impact of QN on serotonin production. Competition at the point of uptake, in particular, is likely to vary considerably: between cell types as seen here (e.g. depending on the transporters expressed by cells), and between in vivo physiological environments, as affected by interactions between cells, neurotransmitters and hormones as well as organ type. For example, the level of QN within the brains of patients is thought to be lower than in peripheral tissues due to the blood-brain barrier32. Such considerations may mitigate the fact that the effective QN concentrations used in certain of our in vitro experiments with the RN46A cells were higher than the recommended therapeutic dose, approaching QN concentrations that are toxic to mammalian cells. More to the point, the physiological relevance of interactions between QN and tryptophan has already been established in clinical studies, which provided evidence for competition between these molecules in vivo and showed that high plasma tryptophan decreases the incidence of adverse reactions to therapeutic doses of QN in malaria patients7. The present work shows how effects of QN on synthesis and function of the major tryptophan metabolite, serotonin, provides a potential explanation for such previous findings. This rationale has further indirect support, from the similarities in the reported adverse neuropsychological effects of QN and of serotonin imbalance, which include tinnitus, loss of appetite, sleep disturbance and anxiety3, 4, 12, 15, 16. These issues underscore how adherence to the narrow therapeutic index of QN during treatment may avert neurological toxicity and serious adverse effects. Even then, however, several of the effects we report (e.g., Figs. 2, 3, 5) did occur at quinine concentrations that are within the 4–100 μM ranges seen in human organs or plasma during quinine treatment5, 7. The present work also leaves open the possibility that there are interactions between QN and tryptophan at cellular sites additional to those studied to date, which may have in vivo consequences beyond those suggested. For example, tryptophan is also a precursor in the kynurenine pathway, which is known to play a role in cerebral malaria33, 34. A high level of QN uptake by mammalian cells, indicated here, may underpin many effects of this drug."
     
  2. Gl;itch.e

    Gl;itch.e Member

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    Interesting Haidut. What got you looking into Quinine? I only just came across this recently when my sick girlfriend requested tonic water. I had no idea of its existence prior.
     
  3. OP
    haidut

    haidut Member

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    I am looking for natural substances that would block/inhibit tryptophan absorption from food. There are very few of them, unless you consider synthetic drugs. Quinine seems to be unique in that it inhibits all serotonin pathways - it inhibits tryptophan absorption, it inhibits TPH2 and thus new serotonin synthesis, and it also binds to and antagonizes serotonin "receptors". I am not aware of any other substance, natural or synthetic, that does something similar.
     
  4. dd99

    dd99 Member

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    Maybe that's why gin and tonic tastes so good to me!
     
  5. Dean

    Dean Member

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    Interesting. If only there was a tonic water that didn't have junk (high fructose corn syrup, citric acid, etc.) in it.
     
  6. OP
    haidut

    haidut Member

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    Whole Foods in USA sells several brands that seem clean, but they tend to be quite pricey - $7 for 4 tiny bottles. Other than that you can get quinine powder and add to whatever carbonated drink you want. I am thinking it would go well with Coke. Maybe.
     
  7. narouz

    narouz Member

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  8. lexis

    lexis Member

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  9. narouz

    narouz Member

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    Thought I'd give this a bump because
    another thread is discussing tryptophan
    and it seems like this intriguing substance haidut posted about
    might've gotten a little lost....
     
  10. robertf

    robertf Member

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    I got some cinchona bark powder a while back to see if there was any anti-protozoan action. It might have messed up my flora so I stopped, but it's worth trying out again.
     
  11. mt_dreams

    mt_dreams Member

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    It appears eating the bark (or not straining out of the liquid) may have some negative side effects. Not sure how serious this is, but it looks like powerful stuff.

    http://www.alcademics.com/2014/08/poten ... water.html

    Outside of what the article suggested, what would be the best method for trying this stuff out? Should I leave it to the companies who measure the amount in their drinks, rather than trying this myself?
     
  12. robertf

    robertf Member

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    Thanks for the article. I didn't experience anything serious, it was about the same effect as eating pasta, my flora was off for a day and then back to normal the next day. I think a lot of these warnings are totally blown out of proportion, I've done all sorts of drugs, herbs, and things that are supposed to be dangerous and not been aware of anything detrimental. Antibiotics, amalgams, now those are supposed to be safe and they totally screwed me.

    A word about tannins, since people here think they are toxic, I have found at least in drinking black tea that it has a seriously positive effect on gut flora - why? who knows, I have some theories. Tea is the best hydratring drink I've found and it antidotes bad food choices and sets my flora back to normal very fast. I know we're on quinine and not tannins but just thought I'd mention it.
     
  13. aarfai

    aarfai Member

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    This is very interesting. Has anyone explored Quinine yet?
     
  14. Mmmaurshmallows

    Mmmaurshmallows Member

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    Thanks Haidut! This is something I've been very curious about for some time. A few summers ago I found myself literally drinking a double gin and tonic EVERY DAY. Wow! That Christmas is when I started to really fall apart. I always figured all that alcohol was partially to blame (believe me, I had a ton of other symptoms for years prior to that). Now I know why I was craving those delicious treats...quinine (my poor stomach and brain were a mess!), lime juice (very alkalizing), and now I've read that gin (a good one) offers great benefits from the juniper berries.

    This is the article where I read about the gin. I don't have my 'Peat glasses' properly in focus quite yet. What would RP think of gin soaked raisins? I imagine he's not a fan of alcohol in general...but on occasion???

    Which Gin for Gin-Soaked Raisins? - The People's Pharmacy

    I think I'll be revisiting those gin and tonics this weekend! :cheers
     
  15. Mmmaurshmallows

    Mmmaurshmallows Member

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    @haidut Another thing I've been very interested in...the differences and similarities of quinolinic acid and quinine. Maybe their names just sound alike, but I was tested to have high quinolinic acid...and I know that's not good. Any thoughts on these? :thankyou
     
  16. Diokine

    Diokine Member

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    Very good stuff! I've been reading as much as I can about quinine recently, and I think it definitely has a place in therapy. It has traditionally been used to reduce hyperthyroid symptoms, and I can vouch for it's effectiveness in this regard. Also tends to be somewhat calming. I'd like to request any other white paper type articles you have on it, I was left a little lacking in mechanism of action and other information after my searches. Here is some info that I came across - what's the bigger picture?

    The development of aversive responses to quinine in hyperthyroid rats.

    Quinine for nocturnal leg cramps: a meta-analysis including unpublished data.

    Quinine-induced thrombocytopenia in a 64-year-old man who consumed tonic water to relieve nocturnal leg cramps. - this one doesn't even have an abstract but the appearance of thrombocytopenia definitely points to 5-HT2a activity




     
  17. dookie

    dookie Member

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    I have tried quinine, in the form of drinking a lot of Schweppes, and it gave me blurred vision. It disappeared quickly after stopping consumption (was gone in less than a day)
     
  18. marikay

    marikay Member

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    The only quinine powder I can find is the cinchona bark powder that some websites sell to make your own tonic water. It looks like you are supposed to heat and then strain the powder before drinking it. Do you think you could just place a little bit of the powder into coke and drink it? Or do you know of a place/site where you can buy quinine powder that doesn't have to be dissolved in water? Thanks.
     
  19. milk_lover

    milk_lover Member

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    Anybody knows if 7UP has quinine? People in my country, even the old folks, have used it and recommended it for stomach relief. I tried it in the past and it surprisingly worked every single time!
     
  20. Mmmaurshmallows

    Mmmaurshmallows Member

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    I make my own soda using sugar, lemon and lime juices, cinnamon, giner, nutmeg, allspice, almond & vanilla extracts, and Gerolsteiner water. (I hope it's Peaty enough!) I'm going to experiment with using tonic water instead. :D
     
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