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Stanford Community Symposium 2018: Phair, Metabolic traps, Tryptophan trap

Discussion in 'BioMedical ME/CFS News' started by NelliePledge, Sep 30, 2018.

  1. NelliePledge

    NelliePledge Moderator Staff Member

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    This thread has been split from the main Stanford Community Symposium 2018 thread.

    Interesting presentation on metabolic traps focussing on tryptophan/kyneurenine.

    Serotonin

    And a very clear and strong message from Ron Davis that people should not experiment on themselves because he said there are very serious risks of making things much much worse.

     
    Last edited by a moderator: Nov 17, 2018
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  2. strategist

    strategist Senior Member (Voting Rights)

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    More on the metabolic trap:
    mt1.png mt2.png
     
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  3. NelliePledge

    NelliePledge Moderator Staff Member

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    Because serotonin was mentioned Im wondering in my non scientific brain if taking SSRIs would have any relevance to the kynurenine/tryptophan issue - could it potentially contribute to the situation or aggravate it.
     
  4. Trish

    Trish Moderator Staff Member

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    No idea. It seemed that the metabolic trap was affecting the other pathway from tryptophan to kynurenine, not the pathway from tryptophan to serotonin, though I guess there could be a link.

    The particular biological pathway he highlighted was based on a genetic variant of the IDO2 gene observed in the severe ME CFS study patient's genomes. His idea was that since ME sometimes occurs in outbreaks, there must be a common genetic variant that predisposes a lot of people to develop ME. He looked for common genes that occurred more often in the study group and found this particular gene where there are several mutations possible that mean a pathway from tryptophan to kynurenine is disrupted if the tryptophan level rises too high.

    There is another gene for making kynurenine from tryptophan, so having one disrupted is not normally a problem as both pathways combine to produce enough kynurenine.

    But if the tryptophan level rises too high, the pathway under study here switches to producing less kynurenine, more tryptophan builds up, and makes the situation worse, so the biochemistry is trapped in an unhealthy steady state. Hence metabolic trap.

    I don't know why I've tried to explain all that. I hope I've got it right. I found it absolutely fascinating. I wonder whether @Chris Ponting has looked at this gene.

    And the key point for patients that Ron Davis emphasised about this research is not to try messing about with our levels of any of the chemicals involved such as tryptophan. He says that could be very dangerous.
     
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  5. strategist

    strategist Senior Member (Voting Rights)

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    I believe that other pathway is only used by liver cells. The rest of the body does it via IDO1 and 2.
     
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  6. Barry

    Barry Senior Member (Voting Rights)

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    So I think what you are saying here is that what is normally a negative feedback control loop for healthy people, has switched to being a positive feedback loop. So the regulation flips, and as the kynurenine level falls lower than it should be, instead of producing more to restore correct levels, it causes even less to be produced. And so tryptophan builds up as a consequence.

    Negative feedback control loops can be like that in all manner of systems, when something provokes them to switch to positive feedback; causing systems to latch into an abnormal state instead of regulating to their required target value.
     
  7. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    Wasn't there a paper by Sharpe which suggested high serotonin might be involved in 'CFS' (although, notably, his patients met criteria both for Oxford CFS and 'neurasthenia').

    Does the metabolic trap increase serotonin, too, or does the tryptophan stay put? A few weak studies claim SSRIs don't work for us, although, anecdotally, SNRIs or tricyclics might work for some.

    Is any of this connected?
     
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  8. Sid

    Sid Senior Member (Voting Rights)

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    I think he said some might have elevated serotonin and others low depending on receptor adaptations that would take place.
     
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  9. Stewart

    Stewart Senior Member (Voting Rights)

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    I think that Dr Phair touched on this (very) briefly at the start of the panel discussion that followed his talk. From memory, he said that the disruption of the kynureine pathway would have knock-on consequences for the seratonin pathway - although he seemed to say (and again, this is just my recollection - it was late and the stream kept pausing for me) that it could be upregulated or downregulated. He didn't explain in any further detail.

    ETA: Crossposted with Sid, who obviously has a slightly better recollection than me!
     
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  10. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    That makes sense. That would explain why things that work for some people don't work for others.

    Another thing that occurred to me: isn't vitamin B3 connected to tryptophan/serotonin metabolism? There was a weak study which suggested NADH may be helpful, and again anecdotally, some people have low vitamin B3 levels (myself included). Maybe further disruption of B3 pathways would result in higher or lower serotonin, explaining the contradictory findings in patients?
     
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  11. NelliePledge

    NelliePledge Moderator Staff Member

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    The serotonin issue has sparked my interest having been on prozac for 12 years until 18 months ago. May be completely unrelated coincidence but my health started to be worse around that time with frequent flu like illnesses and laryngitis which at the time I put down to being susceptible due to depression diagnosis (persistent low mood due to ongoing grief). Understand why I was prescribed Prozac but it needs to be looked at to see if can have negative effect.
     
  12. ScottTriGuy

    ScottTriGuy Senior Member (Voting Rights)

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    Fluoxetine (a.k.a. Prozac) is effective as an anti-viral, study suggests ...https://www.sciencedaily.com/releases/2012/07/120727171919.htm
     
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  13. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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  14. NelliePledge

    NelliePledge Moderator Staff Member

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    I highlighted Ron Davis warning in #68 on this thread it was a general warning not to try to experiment on this pathway

    (mod note: #68 refers to a post in another thread, numbering has changed after split)
     
    Last edited by a moderator: Oct 6, 2018
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  15. Barry

    Barry Senior Member (Voting Rights)

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    [My bold]

    This again has echoes of a negative feedback control loop that has gone awry and switched to positive feedback. If you take the trivial example of a central heating system (it's simple on/off control but the principle is the same). Suppose it is set to regulate at 20°C. If the room temperature is at 22°C the negative feedback will work to cool the room down, turning off the heating. If the room temperature is at 18°C the negative feedback will work to warm the room up, turning on the heating.

    But if the feedback has changed to positive feedback, the behaviour gets weird.

    If the room temperature is at 22°C the positive feedback will work to heat the room up further, turning on the heating. This condition will latch, and only limit once the temperature has got as hot as it is going to get. But then say the heating system turns off overnight, and the air temperature is at 18°C when it turns back on again the next morning.

    The positive feedback will now work to further cool the room, leaving the heating turned off. This condition will latch, and only limit once the temperature has got as cold as it is going to get - ambient in this case.

    So the positive feedback can drive the system to one extreme or the other, depending on its initial condition. Positive feedback can sometimes be used in this way for switching mechanisms, so some part of a system can be fully driven towards one limit or another. But for regulating to a target value it needs to be negative feedback; if it flips to positive feedback the regulation is lost.

    I lay no claims to medical knowledge, but if there are negative and positive feedback control loops involved then the basic principles are universal. They can of course get much more complex and interactive.
     
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  16. Inara

    Inara Senior Member (Voting Rights)

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    I think this is really important. Those things - metabolism, biochemistry of the body, all the interplay and interaction - are so complex. After peeping into calcium metabolism, too, which is only a very small fraction of what's going on, I am sure one can easily mess things up, and then you might be stuck in a situation where no one can help you because no one understands what's wrong. (That's actually part of what Ron Davis said, too.)

    To me, that makes treatment studies potentially more "dangerous" - can we really "just try" if we can end up in another "trap"?
     
  17. Roy S

    Roy S Senior Member (Voting Rights)

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    Thank you. I think this subject is serious enough that it bears repeating and reinforcing. Since I haven't seen the video yet, this is a direct quote from elsewhere for clarity:

    "Ron Davis himself issues a big warning on not trying to manipulate your own cellular tryptophan. You could give yourself brain damage or die. They think there could be an easy cure but they want to test it properly and are very worried about patients hurting themselves."

    From personal experience , I tried tryptophan for sleep several years ago and I think I only took one capsule before throwing it out because it made me worse . It is widely available over the counter in the United States .
     
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  18. MeSci

    MeSci Senior Member (Voting Rights)

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    I had to stop it very quickly after 2 weeks when I took it in the early days of ME, due to apparent adverse effects: https://forums.phoenixrising.me/ind...-notes-including-suicide-attempt-1995-6.2099/.

    But I was taking several other drugs too, so can't be sure that symptoms were (just) due to prozac/fluoxetine.

    Oh - and I tried to kill myself 3 months later, in case that's relevant.
     
    Last edited: Sep 30, 2018
  19. Barry

    Barry Senior Member (Voting Rights)

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    Very much agree.
    Really glad you didn't manage it.
     
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  20. fossil

    fossil Senior Member (Voting Rights)

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    Could this high tryptophan theory be relevant to the reports of ME/CFS remission during pregnancy?

    "Decreased plasma tryptophan in pregnancy."

    https://www.ncbi.nlm.nih.gov/pubmed/8684760?dopt=Abstract

    Just one study, obviously. Have no idea what I'm talking about and have just over-googled, so need to rest. Hoping someone knowledgeable can comment.
     

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