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

Back in the mid 1980's, on a doctor's recommendation, I took L-tryptophan for sleep once - and only once. That night, I had the weirdest dream experience of my life. It was like I was rapidly shifting between random images - fragments of dreams which only lasted a second. The worst aspect was that I couldn't get out of the "dream," even though I wanted to. There's a famous animation called "An American Time Capsule" that captures that kind of rapid image change, but I won't link to it here because it's basically an exercise in sensory overload.

I haven't seen the conference video yet - (my internet connection is apparently too slow for live 720), but tryptophan is an essential amino acid and the precursor molecule to tryptophol (there are several steps). Tryptophol is the molecule that trypanosomes produce which seems to be the behind some of the effects of sleeping sickness.

In 1989, the sale of over the counter L-tryptophan was abruptly halted in the US and other countries when 1,500 users of L-tryptophan of came down with Eosinophilia–myalgia syndrome (EMS). Thirty-seven people died. The cause of the "outbreak" was thought to be contaminants introduced into a batch produced by one Japanese manufacturer, but some cases had occurred up to 3 years earlier. The exact link between L-tryptophan and EMS remains unknown. [This paper suggests there is genetic risk factor.]

In the US, the FDA began removing restrictions on L-tryptophan in 2001, lifting the general import ban in 2005.
 
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Forbin said:
That night, I had the weirdest dream experience of my life. It was like I was rapidly shifting between random images - fragments of dreams which only lasted a second. The worst aspect was that I couldn't get out of the "dream," even though I wanted to. There's a famous animation called "An American Time Capsule" that captures that kind of rapid image change, but I won't link to it here because it's basically an exercise in sensory overload.
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I've had that experience with melatonin. Tryptophan is the precursor to melatonin.
 
That's a fascinating paper you linked to @Snow Leopard. I note it's from 1999. Here's the abstract. I've split it into short sections for easy reading:
The role of tryptophan in fatigue in different conditions of stress.
Abstract
Tryptophan is the precursor for the neurotransmitter 5-hydroxytryptamine (5-HT), which is involved in fatigue and sleep. It is present in bound and free from in the blood, where the concentration is controlled by albumin binding to tryptophan.

An increase in plasma free tryptophan leads to an increased rate of entry of tryptophan into the brain. This should lead to a higher level of 5-HT which may cause central fatigue.

Central fatigue is implicated in clinical conditions such as chronic fatigue syndrome and post-operative fatigue.

Increased plasma free tryptophan leads to an increase in the plasma concentration ratio of free tryptophan to the branched chain amino acids (BCAA) which compete with tryptophan for entry into the brain across the blood-brain barrier.

The plasma concentrations of these amino acids were measured in chronic fatigue syndrome patients (CFS) before and after exercise (Castell et al., 1998), and in patients undergoing major surgery (Yamamoto et al., 1997).

In the CFS patients, the pre-exercise concentration of plasma free tryptophan was higher than in controls (p < 0.05) but did not change during or after exercise. This might indicate an abnormally high level of brain 5-HT in CFS patients leading to persistent fatigue.

In the control group, plasma free tryptophan was increased after maximal exercise (p < 0.001), returning towards baseline levels 60 min later.

The apparent failure of the CFS patients to change the plasma free tryptophan concentration or the free tryptophan/BCAA ratio during exercise may indicate increased sensitivity of brain 5-HT receptors, as has been demonstrated in other studies (Cleare et al., 1995).

In post-operative recovery after major surgery plasma free tryptophan concentrations were markedly increased compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased after surgery. Plasma albumin concentrations were decreased after surgery: this may account for the increase in plasma free tryptophan levels.

Provision of BCAA has improved mental performance in athletes after endurance exercise (Blomstrand et al., 1995, 1997). It is suggested that BCAA supplementation may help to counteract the effects of an increase in plasma free tryptophan, and may thus improve the status of patients during or after some clinically stressful conditions.
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Snow Leopard said:
According to the hypothesis, SSRIs would make things worse.

See:
https://www.ncbi.nlm.nih.gov/pubmed/10721121
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This is what I was thinking. While I believe the grief I experienced did have physical consequences I think it is quite possible that the Prozac made things worse. I don’t remember feeling so exhausted before this time.

ETA around the time I started taking Prozac I also started having counselling and this helped me a lot. Unfortunately it wasn’t possible to tell if the effect was purely from the counselling or the Prozac so I ended up continuing Prozac for years. I still have counselling but have ditched the Prozac.

ETA2 when I was looking at the UK researchers involved in the Harvard Group I spotted this link from Prof Janet Lord at Birmingham’s page about the physical impact of grief which is relevant to my experience I was in my 40s so not an older person but my experience was of ongoing grief for Mum who had severe dementia for 15 years before she died. https://www.birmingham.ac.uk/news/latest/2014/09/age-alters-our-immune-response-09-09-14.aspx
 
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Trish said:
That's a fascinating paper you linked to @Snow Leopard. I note it's from 1999. Here's the abstract. I've split it into short sections for easy reading:
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This is really interesting. Also, reading more about tryptophol, I see that it's also present in some alcohols and is created by candida: https://en.m.wikipedia.org/wiki/Tryptophol

Could these convergences explain some of the secondary symptoms (IBS/GI problems, alcohol intolerance, etc)?

Obviously, these are all preliminary findings that need follow-up, but I think it chimes with some of what we know anecdotally. Whether it's a generalised issue or only a factor for a subgroup is yet to be seen.
 
Jaybee00 said:
Hi,

I missed the symposium--I guessed that there was nothing definitive on Cyclophosphamide from Fluge? I see from Cort Johnson's tweets that he infers that there are some positive results.....

Thanks
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They are only at the phase 2 open label trial stage. I think he said they are still assessing whether there is enough evidence to warrant going on to a full sized double blind trial.


adambeyoncelowe said:
This is really interesting. Also, reading more about tryptophol, I see that it's also present in some alcohols and is created by candida
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The amino acid of interest in the metabolic trap hypothesis is tryptophan. I've had a look at the article about tryptophol and it's a different chemical - an alcohol derived from tryptophan by some organisms. There's no mention of it in any of the discussions about ME I've seen, so I'm not sure what relevance it has here. Can you clarify what you meant?
 
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Trish said:
The amino acid of interest in the metabolic trap hypothesis is tryptophan. I've had a look at the article about tryptophol and it's a different chemical - an alcohol derived from tryptophan by some organisms. There's no mention of it in any of the discussions about ME I've seen, so I'm not sure what relevance it has here. Can you clarify what you meant?
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I was responding to Forbin's comment above:
I haven't seen the conference video yet - (my internet connection is apparently too slow for live 720), but tryptophan is an essential amino acid and the precursor molecule to tryptophol (there are several steps). Tryptophol is the molecule that trypanosomes produce which seems to be the behind some of the effects of sleeping sickness.
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Forbin's comment suggested that this metabolic trap might be linked to Ron's other comments about trypanosomes. I was just making huge leaps in logic. :P
 
fossil said:
Could this high tryptophan theory be relevant to the reports of ME/CFS remission during pregnancy?
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I just wanted to ask this very question as well. I vaguely remember reading something about how an increase in IDO is necessary for the maternal immune system to not attack the fetus, and blocking it with 1-methyl-tryptophan leads to a t-cell mediated attack on the fetal tissue. There must be some 'flag' thingy set (or reset) here.

Another obvious question would be why IDO activity is dysregulated in the first place, because we don't want to find out we can easily fix this with an IDO2 inducer and then die to whatever was the reason for this stuff not working in the first place.

I hope someone who knows more about this will chime in...
 
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fossil said:
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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Some Reality check here :

- What percentage of pregnant women with ME/CFS goes into remission?

-Are there women that have an increase of Symptoms or got ME/CFS after/during pregnancy ?

-If lowering levels of Tryptophan during pregnancy is the reason , wouldn’t some of us have an amelioration of symptoms by minimising Tryptophan food sources intake?
 
mariovitali said:
Some Reality check here :

- What percentage of pregnant women with ME/CFS goes into remission?

-Are there women that have an increase of Symptoms or got ME/CFS after/during pregnancy ?

-If lowering levels of Tryptophan during pregnancy is the reason , wouldn’t some of us have an amelioration of symptoms by minimising Tryptophan food sources intake?
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From what I’ve read, 30% get better during the pregnancy (but doesn’t last), 30% feel no difference, and 30% get worse. I’ve seen these numbers many times, but I have no idea where they come from or how accurate they are.

The leading hypothesis is that the increased blood volume helps, but I have a hard time seeing how that could make someone worse.

What happens during pregnancy doesn’t appear to dictate what happens after the pregnancy. Some get better, some get worse, some stay the same. Again, I’ve seen this mention a lot but don’t know what it is based on.
 
I think the variable results in pregnancy have to do with the fact that our basic disease is a problem with energy production. In MS, where the illness is based on an immune problem, pregnancy may cause a remission by it's action on the immune system.

In ME, any improvement caused by the immune system could easily be swamped by the increase in energy needed to cope with, say, throwing up or the increased weight, never mind all the other physical and social problems that pregnancy brings.

Whether pregnancy makes someone feel better or worse is down to a complex interaction of factors which will be very difficult to disentangle.
 
It seems to me that this links to what the CII team found in this paper? https://www.nature.com/articles/s41598-018-28477-9, discussion thread https://www.s4me.info/threads/insig...ehensive-metabolomics-2018-lipkin-et-al.4873/

In it they say
MetaMapp identified perturbations in tryptophan metabolism, carnitine shuttle/energy homeostasis and complex lipids. Metabolites representing the tryptophan and carnitine pathway were decreased in ME/CFS compared to controls. In contrast, threonic acid, amino acids (tyrosine, methionine and lysine), phenylacetylglutamine, pantothenic acid, hexaethylene glycol and ε-caprolactam were enriched in ME/CFS.
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Seems to me that they are talking about the same thing?

They say on the subject of serotonin
Plasma levels of 5-MT, a compound related to tryptophan, serotonin and melatonin metabolism, were decreased in ME/CFS; however, this finding was confounded by the use of selective serotonin reuptake inhibitors (SSRIs) or other antidepressants (serotonin-norepinephrine reuptake inhibitors [SNRIs] and tricyclic antidepressant [TCAs]) in 25 of 50 (50%) ME/CFS subjects vs. 6 of 50 (12%) healthy controls. Prior metabolomic studies have shown reduced levels of plasma 5-MT with chronic, but not acute, SSRI administration36,37. In human cells, 5-MT is an important metabolite involved in two-step conversion pathways between serotonin (5-hydroxytryptamine) and melatonin (N-acetyl-5-methoxytryptamine)38,39. Reduced levels of serotonin transporters, which play a role in regulating serotonin levels at synapses, have previously been reported in ME/CFS
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Andy said:
It seems to me that this links to what the CII team found in this paper? https://www.nature.com/articles/s41598-018-28477-9, discussion thread https://www.s4me.info/threads/insig...ehensive-metabolomics-2018-lipkin-et-al.4873/

In it they say

Seems to me that they are talking about the same thing?

They say on the subject of serotonin
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So what does this mean? Is it likely this is a side-effect of long-term amitriptyline use (or similar)? If not, would long-term use of these drugs worsen the problem?
 
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