Metabolic Trap//Who got worse on l-tryptophan?

Wishful

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The noticeable effects of mental fatigue and depression only lasted a couple of days.
That was my response to TRP too. The first tablet made my ME symptoms very much worse. I did repeat it a few days later just to verify that it was the TRP responsible. Nasty stuff. 5-HTP caused no problems. Niacin gave me worsened symptoms in general, and made me feel strongly suicidal. I'm pretty sure that was due to its effect on the TRP/kynurenine pathway.
 

HTester

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That would be a question for Robert Phair (@HTester) to answer. I guess there could be a temporary worsening of symptoms like I had, but according to the trap theory, once you are in the trap, you sort of enter a new steady state with the specific cells that are in the trap already being Trp accumulated, so adding a little bit more or less Trp might not alter this steady state much.

It looks like the daily intake of L-tryptophan from food sources can vary from 0.5 g to 2 g in a typical diet, so I think in the long run a little supplemental tryptophan shouldn't make a big difference if you are already in the trapped state.
As others in this thread have said, the role of serotonin in ME/CFS remains unsettled, but I can at least say what is predicted for any cell type in the IDO metabolic trap.

First, let's consider an immune system cell that has all the enzymes of the kynurenine pathway, but does not express the enzymes of the serotonin pathway. Here, you can get into the trap and all the consequences will be caused by the failure to make kynurenine, and ultimately the failure to make NAD. Failure to make NAD strikes many people as important because you need NAD to run central carbon metabolism and make ATP, but if you are getting plenty of niacin in your diet, then NAD produced from Trp is probably not essential. To me, the main danger of the trap is the absence of kynurenine, which normally activates the ligand-activated AHR transcription factor. Hence, all the genes that are normally turned on by an active kynurenine pathway, are turned off. I've also considered that the high cytosolic Trp might drive the mTOR amino acid sufficiency pathway, but that's another story.

Now, let's switch to the serotonergic neurons in the brainstem. These cells, to the best of our knowledge, express both the kynurenine pathway and the serotonin pathway, and as you know, Trp is the first substrate in both pathways. In cell types with both pathways, you not only fail to make kynurenine, but you have further consequences of high intracellular Trp. In particular, you will be maximizing the production of 5-hydroxytryptophan by the enzyme TPH2. This could result in substantially greater serotonin synthesis so that a supplemental dose of 5-hydroxytryptophan could be all you need to get into a serotonin syndrome-like situation. Some scientists think this is actually inconsistent with ME/CFS, but I think it's true that many patients have horror stories around SSRIs, tryptophan, and 5-hydroxytryptophan so I have not ruled this out. Serotonergic neurons project to many parts of brain that are potentially responsible for major CFS symptoms. We can make a plausible case, but as yet we cannot prove these things are happening in CFS brains.

When you think about the trap, please always think about a specific cell type. The events of the trap are taking place inside the cell and it is unlikely that the affected cell type can produce the same changes in the extracellular space or in blood plasma that it produces inside the cell. For example, there are about 10,000 serotonergic neurons in the brainstem, but there are about 1E11 neurons in the brain. That's seven orders of magnitude difference, so even if all 10,000 serotonergic neurons are trapped, there is absolutely no chance you would detect this in cerebrospinal fluid if all the rest of the neurons are making their normal kynurenine, People argue the theory cannot be right because we do not see high Trp and low Kyn in plasma of CFS patients, but those people are assuming that every body cell or at least a large number of body cells is in the trap. I admit it's much harder to test a theory whose mechanism is confined to one cell type, especially if that cell type is a minority cell type, but you will see immediately that if the affected cell type was a majority cell type like skeletal myocytes, we would probably have found a biomarker years ago. To me, the absence of a reliable plasma biomarker, after all these years, is a hint that we should be looking for malfunction of a minority cell type that is part of an important physiological control system.

Our concern about Trp supplements is not about the fate of trapped cells; we are just worried that you could push more cells into the trap and make the disease worse. 5-hydroxytryptophan supplements are even harder to evaluate because cells expressing TPH2 will already be making too much serotonin, but cells expressing TPH1 (which is also substrate inhibited by high Trp, like IDO1) like gut and pineal will be making too little serotonin.

I've written many words here. Hopefully, I've shed some light on the questions posed in this thread. I'm sorry it's so complicated, but no one is arguing that CFS is simple.
 

HTester

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That was my response to TRP too. The first tablet made my ME symptoms very much worse. I did repeat it a few days later just to verify that it was the TRP responsible. Nasty stuff. 5-HTP caused no problems. Niacin gave me worsened symptoms in general, and made me feel strongly suicidal. I'm pretty sure that was due to its effect on the TRP/kynurenine pathway.
@Wishful I just want to be clear on what effect of niacin on the kynurenine pathway you are referring to.
 

Wishful

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@Wishful I just want to be clear on what effect of niacin on the kynurenine pathway you are referring to.
Niacin (in some form) is one end result of TRP metabolism down the kynurenine pathway; it's formed from QUIN. QUIN is known to cause suicidal moods, and I get the impression that it is also responsible some of the symptoms of neuroinflammation (flu-like symptoms). As I see it, my ME produces excess QUIN in my brain cells, some of which gets converted to niacin. If I add niacin to my diet, it probably reduces production of the enzyme that converts QUIN, leaving me with excess QUIN. That's my hypothesis, which I haven't bothered to verify in depth. If you see a flaw in it, let me know.

I seemed to have the same increase in symptoms from TRP and niacin, so they seemed linked. I just avoided both once I figured that out.
 

Wishful

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This could result in substantially greater serotonin synthesis so that a supplemental dose of 5-hydroxytryptophan could be all you need to get into a serotonin syndrome-like situation.
For me, I was quite sensitive to dietary TRP. 5-HTP caused no problems, and only reduced insomnia about the same as melatonin, so I took that to mean that my 5-HTP pathway was working normally. SSRIs didn't affect my ME symptoms, but at higher dosages, made me a bit dizzy. I think my TRP issues involved the kynurenine pathway and didn't involve the 5-HTP one.

BTW, my MIPS1-alpha was elevated, which might be an indication of elevated picolinic acid.
 
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Many take whey which is loaded with high amounts of tryptophan. And they benefit. Some might experience the opposite, but it's not obligatory.

It's also almost impossible to avoid tryptophan due to dietary changes. And quite unhealthy.
This being said, I personally doubt that you can bring more cells into the trap just by nutrition.
Then it would always be a progressive disease which slowly detoriates and everyone ending up being very severe.

Or we all have another disease. Or similar diseases with other pathomechanisms (which could explain why there is still nothing found that helps all of us)

I took high amounts of whey, 5-HTP and also SSRI with no change to my baseline.

Everyone is different. And it seems to be complex indeed.
 

HTester

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Niacin (in some form) is one end result of TRP metabolism down the kynurenine pathway
Thanks for the clarification. I think we are agreed that quinolinate is an endogenous precursor of nicotinate ribonucleotide, and niacin (nicotinic acid) is an exogenous (dietary) precursor of nicotinate ribonucleotide. And nicotinate is a precursor of NAD. Agreed?
 

Wanja

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As others in this thread have said, the role of serotonin in ME/CFS remains unsettled, but I can at least say what is predicted for any cell type in the IDO metabolic trap.

First, let's consider an immune system cell that has all the enzymes of the kynurenine pathway, but does not express the enzymes of the serotonin pathway. Here, you can get into the trap and all the consequences will be caused by the failure to make kynurenine, and ultimately the failure to make NAD. Failure to make NAD strikes many people as important because you need NAD to run central carbon metabolism and make ATP, but if you are getting plenty of niacin in your diet, then NAD produced from Trp is probably not essential. To me, the main danger of the trap is the absence of kynurenine, which normally activates the ligand-activated AHR transcription factor. Hence, all the genes that are normally turned on by an active kynurenine pathway, are turned off. I've also considered that the high cytosolic Trp might drive the mTOR amino acid sufficiency pathway, but that's another story.

Now, let's switch to the serotonergic neurons in the brainstem. These cells, to the best of our knowledge, express both the kynurenine pathway and the serotonin pathway, and as you know, Trp is the first substrate in both pathways. In cell types with both pathways, you not only fail to make kynurenine, but you have further consequences of high intracellular Trp. In particular, you will be maximizing the production of 5-hydroxytryptophan by the enzyme TPH2. This could result in substantially greater serotonin synthesis so that a supplemental dose of 5-hydroxytryptophan could be all you need to get into a serotonin syndrome-like situation. Some scientists think this is actually inconsistent with ME/CFS, but I think it's true that many patients have horror stories around SSRIs, tryptophan, and 5-hydroxytryptophan so I have not ruled this out. Serotonergic neurons project to many parts of brain that are potentially responsible for major CFS symptoms. We can make a plausible case, but as yet we cannot prove these things are happening in CFS brains.

When you think about the trap, please always think about a specific cell type. The events of the trap are taking place inside the cell and it is unlikely that the affected cell type can produce the same changes in the extracellular space or in blood plasma that it produces inside the cell. For example, there are about 10,000 serotonergic neurons in the brainstem, but there are about 1E11 neurons in the brain. That's seven orders of magnitude difference, so even if all 10,000 serotonergic neurons are trapped, there is absolutely no chance you would detect this in cerebrospinal fluid if all the rest of the neurons are making their normal kynurenine, People argue the theory cannot be right because we do not see high Trp and low Kyn in plasma of CFS patients, but those people are assuming that every body cell or at least a large number of body cells is in the trap. I admit it's much harder to test a theory whose mechanism is confined to one cell type, especially if that cell type is a minority cell type, but you will see immediately that if the affected cell type was a majority cell type like skeletal myocytes, we would probably have found a biomarker years ago. To me, the absence of a reliable plasma biomarker, after all these years, is a hint that we should be looking for malfunction of a minority cell type that is part of an important physiological control system.

Our concern about Trp supplements is not about the fate of trapped cells; we are just worried that you could push more cells into the trap and make the disease worse. 5-hydroxytryptophan supplements are even harder to evaluate because cells expressing TPH2 will already be making too much serotonin, but cells expressing TPH1 (which is also substrate inhibited by high Trp, like IDO1) like gut and pineal will be making too little serotonin.

I've written many words here. Hopefully, I've shed some light on the questions posed in this thread. I'm sorry it's so complicated, but no one is arguing that CFS is simple.
thank you for your detailed answer!
so in my case as i went from mild to severe after taking the 5-HTP and Tryptophan Supplement, is there a way i could try to bring me out of the situation? i got recommended to try BCAAs and L-Lysin to counteract... does this makes sense?
 
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When you think about the trap, please always think about a specific cell type. The events of the trap are taking place inside the cell and it is unlikely that the affected cell type can produce the same changes in the extracellular space or in blood plasma that it produces inside the cell. For example, there are about 10,000 serotonergic neurons in the brainstem, but there are about 1E11 neurons in the brain. That's seven orders of magnitude difference, so even if all 10,000 serotonergic neurons are trapped, there is absolutely no chance you would detect this in cerebrospinal fluid if all the rest of the neurons are making their normal kynurenine, People argue the theory cannot be right because we do not see high Trp and low Kyn in plasma of CFS patients, but those people are assuming that every body cell or at least a large number of body cells is in the trap. I admit it's much harder to test a theory whose mechanism is confined to one cell type, especially if that cell type is a minority cell type, but you will see immediately that if the affected cell type was a majority cell type like skeletal myocytes, we would probably have found a biomarker years ago. To me, the absence of a reliable plasma biomarker, after all these years, is a hint that we should be looking for malfunction of a minority cell type that is part of an important physiological control system.
.
@HTester
thank you so much for explaining the central problem with this disease: that is, why its so clinically difficult to identify any problem, and, experimentally why it is difficult to find a biomarker or study the pathophysiology. When people talk about a biochemical alteration in this disease (e.g., redox status), very few talk about what cell type they are referring to and how any dysfunction could cause symptoms, especially given their relapsing-remitting nature.
 

lenora

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Hi @ Eddy M....No, I don't mess around with anything to do with tryptophan and wouldn't unless I knew with great certainty that it works. You're probably much younger and just starting out....I did try multiple things at one time, but those days are past...for the most part. I hope you have some luck. Yours, Lenora..
 

Wishful

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Anyone ever tried a low-tryptophan diet?
Yes, I spent a year on cornstarch (zero TRP) and water. It didn't help. Surprisingly, I didn't notice any symptoms of nutritional deficiencies either, aside from sore gums if I forgot to take a VitC tablet in time.
 
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Hi @ Eddy M....No, I don't mess around with anything to do with tryptophan and wouldn't unless I knew with great certainty that it works. You're probably much younger and just starting out....I did try multiple things at one time, but those days are past...for the most part. I hope you have some luck. Yours, Lenora..
I am just asking, i know it's risky