Metabolic Trap, wouldn't we suffer from serotonin abnormality?

Horizon

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One thing that strikes me as odd is that if the Metabolic Trap is correct shouldn't we all have Serotonin Syndrome if we are very high? We don't generally suffer most of those symptoms.

On the flip if we were too low wouldn't we all be depressed?

Given that 40% of the healthy population has mutations with the gene I'm feeling skeptical
 

Wishful

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I haven't heard of the metabolic trap involving serotonin or a specific gene. Last I heard, the metabolic trap was a hypothesis about some sort of feedback loop, with no specifics.

I don't seem to have low serotonin (supplemental 5-HTP doesn't do anything except counter insomnia). My problem seems to involve the other tryptophan pathway, producing too much of the nastier kynurenines.

I've also heard that there's a lot of marketing effort behind testing for mutations, but that most of those "evil scary, OMG you're doomed!" mutations don't actually have a significant effect on health.
 

Horizon

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I haven't heard of the metabolic trap involving serotonin or a specific gene. Last I heard, the metabolic trap was a hypothesis about some sort of feedback loop, with no specifics.

I don't seem to have low serotonin (supplemental 5-HTP doesn't do anything except counter insomnia). My problem seems to involve the other tryptophan pathway, producing too much of the nastier kynurenines.

I've also heard that there's a lot of marketing effort behind testing for mutations, but that most of those "evil scary, OMG you're doomed!" mutations don't actually have a significant effect on health.
They discuss serotonin a lot in here https://www.healthrising.org/blog/2...on-the-molecular-basis-of-me-cfs-at-stanford/
 

Neunistiva

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One thing that strikes me as odd is that if the Metabolic Trap is correct shouldn't we all have Serotonin Syndrome if we are very high?
My guess, and this is just a guess, is that the level is not nearly high enough to cause Serotonin Syndrome but is high enough to produce these sypmtoms:

The serotonin system is in the midbrain. Phair pointed out six nuclei or neurons in the midbrain which control serotonergic pathways in the brain. Dysfunction in these nuclei could produce a long list of symptoms found in ME/CFS including impaired cognitive function, movement, and smell, dysautonomia, motor neuron problems, air hunger, dopamine production, POTS, and pain.
So far they only tested one type of immune cells. Brain cells are kind of hard to get to :) Please someone correct me if I'm wrong.

Phair also noted, though, that depending on the cell type, serotonin levels could be high or low.

Given that 40% of the healthy population has mutations with the gene I'm feeling skeptica
That is a requirement actually for this hypothesis to be correct. Common among healthy people, present in all ME/CFS patients. The only way to explain the outbreaks and why ME/CFS is 3 times more prevalent than Multiple Sclerosis. Only difference between ME/CFS sufferers and healthy people with that mutation is that we got into a situation where the switch was flipped and they haven't.

I haven't heard of the metabolic trap involving serotonin or a specific gene
I am not sure if you saw it already but there is a thread where metabolic trap is discussed in great detail and Health Rising article from a few days ago.
 

Horizon

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Its hard to find info on symptoms of high serotonin not serotonin Syndrome.

This website says:
  • Shivering
  • Muscle stiffness
  • Confusion
  • Restlessness
  • Agitation
  • Rapid heart rate
  • Sweating
  • Loss of coordination
  • Twitching muscles
https://www.naturalstacks.com/blogs...#Symptoms-of-high-levels-of-serotonin-include

While we do have some of those symptoms we don't have others and our main symptoms aren't really described by this
 

Neunistiva

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@Horizon Ok, I found the answer to your initial question on wikipedia

Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents
So it seems one can't get serotonin syndrome from naturally produced serotonin even if the system is faulty.

While we do have some of those symptoms we don't have others and our main symptoms aren't really described by this
Metabolic trap is not about high serotonin, though. That's just one possible consequence.
 

nandixon

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So far they only tested one type of immune cells.
Did you hear or read what the specific type of immune cell is? I realized a couple of days ago that if they used lymphocytes, for example, that the expression of IDO1 apparently isn't upregulated by interferon-gamma (IFNg) in that type of cell, versus if they simply used the general class of PBMCs (which includes lymphocytes) that IDO1 would be found to be upregulated by IFNg (due to the monocytes in the PBMCs, for example). Knowing what type of cell they used potentially changes the analysis of what they found. Thanks.
 

Hufsamor

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I've got my serotonin level checked ones.
It was part of a test I did for other things.
The level was very low.

I got something to rise the serotonin level, and got a bit more energy for a while.

It's not easy to know if you are high or low on something before you gets it measured
 
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Wishful

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I'm happy to see some research into the IDO pathway, since it seems to be a major part of my ME. I think they're checking the wrong pathway though. While TRP makes my symptoms worse, 5-HTP doesn't, so I believe it's the KYN pathway where the problem lies. The nastier kynurenines, such as quinolinic acid, could explain many of the neurological symptoms.
 

Neunistiva

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@nandixon I believe the tests were done on white blood cells. @Janet Dafoe (Rose49) mentioned white blood cells, but note that for us the issue is with faulty IDO2, not IDO1. Our IDO1 works fine according to the hypothesis.

It's not easy to know if you are high or low on something before you gets it measured
That's true but your serotonin levels were measured in blood not in cells, and serotonin in different types of cells could be high or low, according to Dr. Phair.

Dr. Janet Dafoe said in comments

The way to test if someone is in the trap is to check the tryptophan/kynurinine ratio in white blood cells, not plasma. Regular medical labs are not equipped to do this. Scientists at the genome center are working on a simpler and cheaper method for doing this. Right now it requires a $100,000 – $1,000,000 mass spectrometer.
I think they're checking the wrong pathway though. While TRP makes my symptoms worse, 5-HTP doesn't, so I believe it's the KYN pathway where the problem lies.
From my understanding dietary intake of tryptophan is irrelevant for our cellular levels. I could be wrong.
 

nandixon

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@nandixon I believe the tests were done on white blood cells. @Janet Dafoe (Rose49) mentioned white blood cells, but note that for us the issue is with faulty IDO2, not IDO1. Our IDO1 works fine according to the hypothesis.
Yes, but I'm wondering what type of white blood cells - PBMCs or just the lymphocytes, etc.

Under the hypothesis, IDO2 is completely broken (Edit: or I guess at least mostly broken depending on whether the average of 1.7 damaging IDO2 mutations found in the severe patient study are on one or both alleles in a given patient). So then it comes down to looking at IDO1 and trying to determine whether IDO1 really is inhibited (e.g., by too high a concentration of tryptophan) as the hypothesis requires or if instead IDO1 isn't getting sufficiently upregulated or is getting degraded too quickly, etc.
 
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nandixon

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(In my second paragraph above I'm referring of course to the in vitro tracer experiment results on the 6 patients which showed a poor conversion of tryptophan to kynurenine and which is consistent with Phair's metabolic trap hypothesis but which doesn't prove it by any means since, as implied, there are multiple other possible explanations for the results.)
 
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They measured serotonin in the cells, not the blood (as others have discussed), so I don't know if the serotonin syndrome info would be relevant.
They certainly measured tryptophan in the cells. There are two pathways for tryptophan and their focus has been on the theoretically broken pathway, the kynurenine one. I'm not sure they measured serotonin, did they? They just know that tryptophan breaks down into serotonin and so assumed that if we have abundant tryptophan we'd also get an excess of serotonin.

(This is the main reason they recommend caution in self-experimenting. Ron and Rob are hypothesising that we might have high serotonin levels and have also acclimatised to them, by dialing down our receptors. rapidly reducing tryptophan would cause less serotonin and then we'd feel a dramatic shortage of it because our bodies are (according to this purely hypothetical scenario) used to lots of serotonin.)

fwiw I agree with @Horizon's earlier comment that if this is a sudden switch to high serotonin we'd surely notice it at disease onset, at least. Any dialling down of serotonin receptors would not yet have happened.

@nandixon if you look on rob phair's page on research gate you can see him asking questions about whether pbmcs are a good model for metabolism in the rest of the body. This leads me to believe he is testing pbmcs. (I'm sure I saw something on this elsewhere too, Phair was agonosing over whether it'd be worth pursuing the theory in other cell types if he failed to find evidence for it in PBMCs .)

> A central question in current CFS research is whether every cell in a patient's body is a model for the disease. We often take it as a given that Peripheral Blood Mononuclear Cells (PBMCs) can be studied in lieu of cells (e.g. skeletal myocytes or hepatocytes) whose collection might traumatize the patient. But there is no guarantee. Even if PBMCs are found to have abnormal phenotypes, it remains possible that hepatocytes or myocytes or neurons are the cells affected by CFS, and PBMCs are only abnormal because they live their lives in blood plasma whose composition, as measured by metabolomics, is demonstrably outside normal bounds. We ask this question often. What do you think?
 
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keenly

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One thing that strikes me as odd is that if the Metabolic Trap is correct shouldn't we all have Serotonin Syndrome if we are very high? We don't generally suffer most of those symptoms.

On the flip if we were too low wouldn't we all be depressed?

Given that 40% of the healthy population has mutations with the gene I'm feeling skeptical
If you study the work of Dr Doug Wallce, the worlds leading expert on mitochondria; genetics are vastly overrated. Nearly all diseases are environmental.
 

Moof

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Correct me if I've misremembered, but I seem to recall from one of the presentations that those who have very high serotonin levels have probably just become accustomed to living with them. Which is one of the dangers of experimenting with this pathway – what happens if serotonin levels are suddenly depleted, after decades of people's brains being used to high levels? (I don't know, but I'm guessing it wouldn't be much fun!)
 

Wishful

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@nandixon
From my understanding dietary intake of tryptophan is irrelevant for our cellular levels. I could be wrong.
TRP tablets very definitely made my symptoms much worse. I forget whether the increase was within hours or 'next day'. By that, I'd say that a large increase in dietary TRP does have an effect. However, I tried a low-TRP diet (cornstarch and water) for many months, with no noticeable decrease in symptoms, so even a drastic decrease in dietary TRP seems to have little effect. Maybe the body stores years worth, or switches to an extra-efficient TRP usage mode when necessary.
 

FMMM1

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(In my second paragraph above I'm referring of course to the in vitro tracer experiment results on the 6 patients which showed a poor conversion of tryptophan to kynurenine and which is consistent with Phair's metabolic trap hypothesis but which doesn't prove it by any means since, as implied, there are multiple other possible explanations for the results.)
I think you have a much better understanding of this than I have but here goes.

What you need is lots of data i.e. measurements of intra-cellular tryptophan (and Kynurenine?). OMF are working on methods for measuring intra-cellular tryptophan. Possibly Gulf War veterans, who have severe un-diagnosed fatigue, might get you the combination of public funding and a large population to study.

Substrate inhibition of IDO1 is relatively easy to demonstrate i.e. provided you have IDO1. Add higher levels of tryptophan to (normal levels of) IDO1 and plot the suppression of IDO1. Haven't looked at the presentation for a while but I assume that's what they did.

Getting hold of IDO2 produced by presumed non-functioning genes sounds a little bit more difficult. Really winging it here but CRISPR gene editing appears to have made it possible to edit genes more easily, so maybe it possible to produce IDO2 from these genes and then check its activity. There are now some of the best scientists in the world working on this; I assume it's deliverable i.e. if there's funding.

A method of reducing intra-cellular tryptophan also appears to be necessary i.e. to prove the trap hypothesis. Does the approach used in refeeding syndrome provide a possible way of reducing intra-cellular tryptophan? The drug which is referred to here seems interesting as well. I see OMF are working with Nancy Klimas [https://www.omf.ngo/2017-accomplishments/]; that link (Klimas) might help to get public funding via the Gulf War veterans.

I'm not confident that problems with IDO2 will explain all of ME/CFS but it might just give an insight i.e. to make progress.

@Ben H Anyone looking at a Gulf War veteran study? I assume that many fit the diagnosis for ME/CFS.


Consider writing to your elected representative i.e. to request funding for ME/CFS research including the development of a diagnostic test.
I've written to the European Union Committee on the Environment, Public Health and Food Safety (ENVI) requesting that they lobby for funding for research into ME/CFS including the development of a diagnostic test [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1003111].
Currently the ENVI Committee is lobbying for increased funding for research into Lyme disease and the development of a diagnostic test.
In 2016 the European Commission [European Union civil service] said [regarding Lyme disease] that "Both basic research and the development of new diagnostics, treatments and vaccines for Lyme borreliosis are funded by EU research and innovation framework programmes. The total EU contribution to such projects since 2007 amounts to EUR 33.9 million [US dollars]" [http://www.europarl.europa.eu/doceo/document/E-8-2016-008631-ASW_EN.html].

ME/CFS received no funding from the European Union [http://www.europarl.europa.eu/doceo/document/E-8-2017-006901-ASW_EN.html].
 

Neunistiva

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TRP tablets very definitely made my symptoms much worse.
I think pills don't count as part of a diet. For example, they say it is impossible to get enough vitamin D from a diet, yet it is quite possible to bring vitamin D levels to normal with a supplement.

Anyway, maybe I used the word diet wrong, I was just trying to say that food shouldn't affect our cellular tryptophan levels.

That is what wikipedia says as well

There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet, but consuming purified tryptophan increases the serotonin level in the brain, whereas eating foods containing tryptophan does not.

from https://en.wikipedia.org/wiki/Tryptophan#Use_as_a_dietary_supplement

I personally wouldn't experiment with tryptophan in any way until Dr. Phair and Dr. Davis know more.
 

alex3619

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There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet,
We cannot infer much about this as the trap hypothesis is for intracellular levels. Blood levels are irrelevant.

My concern here is about tissue distribution of IDO2, and what that might mean. There might not be enough of it to make much serotonin unless its really being pumped out, and the biggest organ for that is the liver. However all (this is not confirmed to be all) immune cells will be affected, and many of those reside in the brain. So the local concentrations of serotonin in the blood might be high, rather than total blood serotonin or serotonin concentration on average. It might also occur in bursts, with short very high levels, though I have no idea if this is the case it remains a possibility.

For a summary of a lot of the factors you might look here - https://www.genecards.org/cgi-bin/carddisp.pl?gene=IDO2
You can scroll down for tissue distribution. It is not clear what cell types in the brain contribute to IDO2 expression.

Note the African Sleeping Hypothesis ties into the Tryptophan Trap Hypothesis. I have not investigated this further.

What impresses me is the fact that every single patient in the severe patient study has a problem with this gene. This is very unlikely to be by chance. The abnormal Trp/Kyn is also shown in six out of six patients. We need more data of course, with many more patients, but its looking likely as a contributing factor if not the sole cause.

Its also unlikely to be the only factor in ME. If maybe 40% of the population have an inactivating IDO2 mutation, and less than 1% have ME (possibly more like 0.2%) and only about 10% of patients (sometimes up to 20%) who have a severe infection get ME, then some other factors are involved. One possibility is infections or immune signals rising inside the brain, that is they cross the blood brain barrier.