Update on BCAAs, glutamine and PEM

[Mary]

Well, after 6 weeks of not crashing, I finally crashed on Easter. I'd gone to a baby shower on Saturday involving a 2-hour ride each way, plus the shower. I was glad I went, saw a niece I had not seen in a long time and other people and just had a good time. Actually I felt remarkably well that Saturday. So - the BCAAs and glutamine didn't prevent the crash, although recovery was still markedly shorter than just a year ago.

I've figured there's a couple of possibilities for why I crashed:
(1) I finally reached my new energy threshold on the BCAAs and glutamine. My prior threshold was 3-1/2 hours of light activity.
(2) I'd had an intestinal bug for 2 weeks prior to the shower, and maybe it prevented absorption of the BCAAs etc.
(3) I'd taken about a teaspoon of chia seeds a couple of nights in a row. Chia is very high in tryptophan, and according to the articles I read about BCAAs and crashing, PEM has to do with high tryptophan-low leucine ratio, so maybe that was a factor; and
(4) maybe none of the above.

I still have more energy than prior to starting the BCAAs, I also re-started DMG (one 125 mg. capsule a day). This stuff is strong, I can feel it. But I seem to be doing okay with it. I did some reading about DMG and CFS and found a post by Richvank where someone asks him about it, and he says it helps the methionine synthase - I didn't really understand the chemistry but think it essentially helps with methylation. I wish Rich had mentioned DMG in his protocol. TMG did nothing for me.

Anyways, I'm still taking the BCAAs and glutamine, and now DMG, and will see how much I can do now. My digestive tract is finally (!) getting back to normal. I was taking inosine, which also helped my energy, but the DMG seems to be better. I may try both soon, but one thing at a time.

 

[SOC]

...PEM has to do with high tryptophan-low leucine ratio...

That's new information to me. Do you have a reference?

 

[Mary]

That's new information to me. Do you have a reference?

Here are links to some articles that got me started taking BCAAs and glutamine last November. I started taking the glutamine incidentally as it was part of the BCAA combo I initially took, and then read so many good things about glutamine, I include it as well.

http://www.ncf-net.org/forum/Fword.htm
http://jn.nutrition.org/content/136/2/544S.full
http://www.ncbi.nlm.nih.gov/pubmed/11310928
http://www.dynamicchiropractic.com/mpacms/dc/article.php?id=41341 (see item 4)

Here's a thread I did about this in January, though I am only now taking one 125 mg. cap of DMG, not 3 (the DMG is separate obviously from the BCAAs, just wanted to clarify this)

http://forums.phoenixrising.me/index.php?threads/bcaas-reducing-pem.34719/

 

[SOC]

Here are links to some articles that got me started taking BCAAs and glutamine last November.

I get that bit. I'm wondering specifically about

...PEM has to do with high tryptophan-low leucine ratio...

I didn't realize we had any real knowledge that PEM is directly related to tryptophan and leucine. Do you have a reference specific to that information?

Glad you're having such good luck with BCAAs, btw. I hope it continues for you.

 

[Mary]

@SOC - This article talks about something called "central fatigue" which has nothing to do with muscle fatigue, which sounded an awfully lot like PEM: http://www.ncf-net.org/forum/Fword.htm - I drew the inference that PEM is central fatigue. This article talks about "5) an increase in the plasma concentration ratio of free tryptophan to branched-chain amino acids" in connection with central fatigue, and CFS.

This article also talks about the ratio of tryptophan to BCAAs and central fatigue: http://www.ncbi.nlm.nih.gov/pubmed/11310928

The other articles I linked talk about this too. This is all the information I have, and my experience is that the BCAA s are definitely increasing my endurance and reducing recovery time after crashing, though it has not been eliminated altogether (at least not yet!

 

[Mary]

@SOC - actually, here is where I first made the link between the tryptophan/leucine ratio and PEM. This article mentions tryptophan/BCAA ratio. I can't remember exactly where I read tryptophan-leucine ratio, as opposed to BCAAs - I don't think it really matters.

"If the tryptophan to BCAA ratio is too high, neurotransmitters made from tryptophan increase, causing physical and mental fatigue.4 When patients first contract CF, the body activates a metabolic pathway that increases the rate of conversion of ATP to cyclic AMP, which is used for immune system stimulation. It seems that CF patients have difficulty turning this pathway off when it is no longer required. The inability to properly regulate this pathway leads to losses of ATP in times of inadequate production. Branch chain amino acids can down-regulate this ATP to cyclic AMP process.5 " http://www.dynamicchiropractic.com/mpacms/dc/article.php?id=41341

This sounded like the anaerobic metabolism mess that people with CFS have. It also ties in anaerobic metabolism and immune system irregularities. So then I did some searching and found the other articles.

 

[SOC]

@SOC - This article talks about something called "central fatigue" which has nothing to do with muscle fatigue, which sounded an awfully lot like PEM: http://www.ncf-net.org/forum/Fword.htm - I drew the inference that PEM is central fatigue.

Ah, I see. I don't think central fatigue is the same thing as PEM, although it wouldn't surprise me if many PWME do have central fatigue and/or exercise intolerance (another exercise/fatigue-related symptom people confuse with PEM) in addition to PEM.

Anything that helps with symptoms of ME/CFS, including central fatigue and exercise intolerance, is worth looking into. I hope the benefits you are getting from BCAAs continue. Please keep us updated.

 

[Mary]

@SOC - did you read my second post, with the quote from Dynamic Chiropractic (which originated with Dr. Cheney)?

 

[SOC]

@SOC - did you read my second post, with the quote from Dynamic Chiropractic (which originated with Dr. Cheney)?

Yes, I did. I still don't believe central fatigue and PEM are the same thing. For starters, the descriptions aren't the same... going by the ICC description of PEM, that is. PEM is not just fatigue. Also, the chiropractor is talking about chronic fatigue which is not the same thing as ME/CFS. Lots of people have chronic fatigue. MDD patients have chronic fatigue which is probably central fatigue, for example. That's not PEM.

That doesn't mean that many PWME don't have central fatigue in addition to PEM. Treatment for central fatigue could greatly improve the quality of life of some ME/CFS patients. I suspect it doesn't cure PEM, though.

 

[Mary]

@SOC - I didn't see the chiropractor's article (from Dr. Cheney) talking about central fatigue. Yes, it mentions fatigue in general, and I completely agree that fatigue does not equal PEM.

What really intrigued me though was the statement about the metabolic pathway which increases the rate of conversion of ATP to AMP, which I think very well could be anaerobic metabolism, which I think directly correlates with PEM.

 

[Hip]

This is a very interesting vein of research on fatigue, @Mary. Thanks for posting this.

I don't think central fatigue is the same thing as PEM

Warning: Pedantry Alert For My Following Post!

When the CCC talks about post-exertional symptoms, it defines them as comprising the following:

Post-exertional symptoms include:
Post exertional malaise (PEM)
Post exertional fatigue
Post exertional pain
Post exertional brain fog (deterioration of cognitive function)
Post exertional various other symptoms

This comes from the following quote in the CCC definition of ME/CFS:

Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed.

Most people on this forum, myself included, erroneously use to the term "PEM" to mean all the post-exertional symptoms; but strictly speaking, as you can see, PEM only refers to the malaise that can appear after exertion, but not to the fatigue, pain, brain fog or other symptoms.

The dictionary defines malaise as: "a condition of general bodily weakness or discomfort, often marking the onset of a disease." So malaise is really that feeling you get when coming down with the flu, etc.


Anyway, fatigue is part of the post-exertional symptoms that ME/CFS patients can get; and this post-exertional fatigue may well be one and that same as central fatigue (although this would be a hypothesis at this stage).



In terms of the nature of central fatigue, it seems that this term is used to refer to fatigue in the brain and nervous system, and contrasts to peripheral fatigue, which is defined as fatigue in the muscles.

This paper which Mary cited earlier says:

Physical fatigue is defined as the inability to maintain power output. The fatigue can be either central or peripheral in its origin.

Several factors have been identified as a cause of peripheral fatigue (e.g., depletion of muscle glycogen or phosphocreatine, accumulation of protons, and failure of neuromuscular transmission), whereas the factors underlying central fatigue are less well known.

Central fatigue is demonstrated experimentally when the maximal effort that can be achieved voluntarily is less than that which can be achieved when the muscle is stimulated directly by electrical stimulation of the motor nerve.

Several mechanisms, which are not mutually exclusive, have been proposed to explain central fatigue; these include:

(1) An increase in the level of key compounds in muscle during physical activity, such as protons, K+-ions, bradykinin, phosphate, prostaglandins that could, via binding to specific fatigue receptors in muscle, transmit information via sensory nerves from muscle to brain;

(2) A decrease in the blood glucose level and hence the level in the brain could restrict glucose utilization by some neurons in some parts of the brain that are involved in control of motor activity. Fatigue has been reported during endurance events, such as ultra marathons, at a time when the blood glucose level is low;

(3) An increase in the concentration of tryptophan in the blood and hence the neurotransmitter 5-hydroxytryptamine (5-HT) in some neurons, which are involved in control of motor activity in the brain, could lead to central fatigue.

The third mechanism of central fatigue mentioned above, where there is an increase in tryptophan in the blood and an increase in 5-HT (serotonin), is the one I believe Mary is focusing on.

 

[Mary]

@Hip - Pedantry alert indeed! - Thanks for the heads up!

It's my theory that someone a long time ago used the extremely inadequate word "malaise" to refer to the bone-deep complete exhaustion, etc. that comprise post-exertional symptoms. They had no clue what they were talking about and so used the word "malaise", which doesn't begin to describe what happens to us post-exertion.

Having said that, it makes so much sense to me that central fatigue might be the fatigue which occurs in PEM (I'm using the term PEM loosely here to refer to all PE symptoms!), when such severe incapacitating symptoms can occur after so little exertion. It's definitely not a muscular or peripheral fatigue. My experience with BCAAs seems to bear this out, how my PEM lessened so much after starting the BCAAs, and how I recover so much quicker.

Yes, I am referring to the increase in tryptophan, and also how it correlates to the level of BCAAs, as mentioned in the articles.

 

[Hip]

@Mary
Some ME/CFS patients talk about the appearance of viral symptoms in the post-exertional period, which generally appears to be the recurrence of the same flu-like or gastrointestinal viral symptoms they experienced when they first caught the virus that triggered their ME/CFS.

So possibly (and I am just speculating here) post-exertional malaise was originally referring to these post-exertional viral symptoms, since the word malaise refers to the feeling you get at the onset of an illness such as flu. But then people started using the term "PEM" to signify all the post-exertional symptoms.

In my case, I don't get any viral symptoms at all after exertion, even though my ME/CFS was triggered by a virus. I mainly just get the post-exertional brain fog and the post-exertional fatigue.

Anyway, back to branch chain amino acids (BCAA), the tryptophan / leucine ratio, serotonin, and the alleviation of post-exertional fatigue:



My Experience With L-Leucine And Its Ability To Reduce ME/CFS Fatigue

I should mention that while I was reading this thread, I suddenly remembered that a few years ago I was using leucine (which is the main amino acid in BCAA) on a regular basis to alleviate my fatigue. I used to take a slightly heaped teaspoon (around 4 grams) of leucine each day, and found this would reduce my ME/CFS fatigue a bit. And the effect was quick: the reduction in fatigue would appear within around 24 hours of beginning this leucine regimen.

At the time, I had no idea why leucine reduce my fatigue; I'd bought leucine for an entirely different purpose, and just happened to notice that while I was taking it, I had a bit more energy. Nothing spectacular, but nevertheless noticeable. But now reading what you posted on the connection between the tryptophan / leucine ratio and fatigue, this seems like a likely explanation for the energy improvements I obtained from leucine.



Raised Serotonin: The Cause Of The Fatigue?

This study which you cited earlier says:

Studies in human subjects have shown that the plasma ratio of free tryptophan/BCAA increases during and, particularly, after sustained exercise. This would favour the transport of tryptophan into the brain and also the synthesis and release of 5-HT which may lead to central fatigue.

So it seems that raised serotonin is behind the fatigue. However, since there are 14 known types of serotonin receptor, presumably it's the effect of raised serotonin on certain specific serotonin receptors that will be responsible for the fatigue.



The Serotonin 5-HT3 Receptor Is Implicated In Fatigue States

In fact a while ago I became interested in some research indicating that drugs which antagonise the 5-HT3 receptor might alleviate fatigue. See this paper for example:

• 5-HT3 receptor antagonists ameliorate fatigue: so much potential, so little knowledge!​

So I wonder if the 5-HT3 receptor is responsible for the fatigue produced by raised serotonin. This 5-HT3 finding has been examined in the context of ME/CFS: the following two pilot studies on 5-HT3 antagonists for ME/CFS looked interesting, and both showed positive results in reducing ME/CFS fatigue levels:

• Treatment of chronic fatigue syndrome with 5-HT3 receptor antagonists -- preliminary results
• The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients -- a pilot study​

However, unfortunately a larger-scale clinical trial 5-HT3 antagonists for ME/CFS found no benefits of in terms of fatigue reduction:

• The effect of ondansetron, a 5-HT3 receptor antagonist, in chronic fatigue syndrome: a randomized controlled trial​

However, a large scale trial of HT3 antagonists for treating the fatigue of chronic hepatitis C did yield good results:

• Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study​

Interestingly, the ondansetron dose used in the hepatitis C trial was half that used in the ME/CFS trial (8 mg daily of ondansetron in the hep C trial, versus 16 mg in the ME/CFS trial).

Now it just so happens that there is a bell-shaped dose-response curve for 5-HT3-receptor antagonists, such as ondansetron (see here). This means that if you take either too little or too much of a 5-HT3-receptor antagonist drug, you lose the effect. So you have to get the dose just right, within narrow ranges. Thus it's possible that too much ondansetron was used in the large scale ME/CFS trial, and better results might have been obtained with a lower dose.



My Experiments With A Serotonin 5-HT3 Receptor Antagonist

I did myself do some experiments with a 5-HT3-receptor antagonist. I used lemon (Citrus limonum) essential oil, as this is a potent 5-HT3-receptor antagonist. Ginger is another 5-HT3-receptor antagonist, but lemon essential oil is much more potent than ginger.

I used a daily dose of 10 drops of lemon essential oil, mixed into 15 ml of cooking oil and taken internally. I also experimented with doses of 5 drops daily. I cannot say that I noticed much, except perhaps a reduction in anxiety, which 5-HT3-receptor antagonists are known to produce. However, I have no idea what the right dose is for lemon essential oil, and as mentioned, due to the bell-shaped dose-response curve, you have to get the dose just right in order to get the effect.



Serotonergic Activation In ME/CFS

In terms of whether serotonergic activation is generally high or low in ME/CFS patients:

Experts are split, however, as to whether serotonin levels are high or low in people with chronic fatigue syndrome. Some studies show that the problem in ME/CFS may lie in low serotonin-receptor activity, which could mean that the brain isn't using serotonin properly, even if plenty is available. A newer study suggests a possible autoimmune reaction to serotonin.

Source: here.

The article on the autoimmune reaction to serotonin is worth reading. Here's an excerpt:

Researchers compared serotonin antibodies in people with ME/CFS, those with chronic fatigue who don't meet ME/CFS criteria, and healthy controls. They found that autoimmune activity against serotonin was more than four times what it was in chronic fatigue, and twelve times higher than in healthy people.

Serotonin autoimmunity was linked to more severe hyperalgesia (pain amplification,) fatigue, brain fog, autonomic symptoms, sadness, and flu-like symptoms.

The autoimmune study referred to in the above quoted article is this one.

 

[SDSue]

Thanks so much for the update, @Mary. The Chia/tryptophan thing is interesting, as I put chia in a lot of foods. It always seems to come back to "everything in moderation" for me.

 

[serg1942]

Interesting subject! I remember I studied this in class last year and it brought my attention, as it has now... If you think about it, it makes perfect sense. After exercise (and after catabolizing therefore), you need to rest, and let the body repair. Well, it is a wise mechanism to use the high proteins delivered to the bloodstream, in this case, the tryptophan and its derivative, serotonin, in order to produce central fatigue and force us to rest after exertion.

But fatigue is a feeling mediated by many other mechanisms. Our fatigue is probably caused by an ongoing immune reaction. Again, it would make sense if you think of a regular flu. Your body needs energy to raise your metabolism and not to feed your muscles, and for that very purpose, some pro-inflammatory cytokines have shown to produce fatigue.

So, I don't really see the serotonin ratio as a clue to understand or treat the fatigue of ME/CFS, although it may very well explain the benefits of BCAAs. I work out at the gym regularly--just anaerobic--, and I take BCAA almost everyday, and the combo of anaerobic exercise and BCAAs does help.

Just thinking out loud!
Best,
Sergio

 

[Mary]

@Hip - thanks for your detailed (as always!) reply. to be honest, it's hard for me to absorb all the chemistry. I just go with major concepts or points. I did look up one of the studies you cited which used Zofran as a 5-HT3 receptor antagonist and found that Zofran can cause birth defects. Whenever at all possible, I strongly prefer nutritional remedies rather than drugs. It would have been interesting to see what would have happened with those 5-HT3 receptor antagonist studies if they had used BCAAs instead of Zofran.

You could be right about raised serotonin causing fatigue. What the studies I read found was that it was the ratio of tryptophan to leucine which was important. It's interesting that leucine helped your energy a little. Maybe the full BCAA complement would help you more. That's interesting that we might have an autoimmune reaction to serotonin. The only thing I know for sure is that the BCAAs and glutamine have helped me so much with PEM, so I'm sticking with them.

 

[Mary]

Thanks so much for the update, @Mary. The Chia/tryptophan thing is interesting, as I put chia in a lot of foods. It always seems to come back to "everything in moderation" for me.

My sister told me about chia seeds being high in tryptophan and they are. I have no idea if the chia seeds were a factor in my crashing (after not crashing for several weeks). There's no way to tell right now but I'm laying off them for awhile. Maybe in a couple of weeks if I do well, I'll try them again and see what happens as I think they helped with sleep but it's not worth it if they also help me crash!

 

[Mary]

Interesting subject! I remember I studied this in class last year and it brought my attention, as it has now... If you think about it, it makes perfect sense. After exercise (and after catabolizing therefore), you need to rest, and let the body repair. Well, it is a wise mechanism to use the high proteins delivered to the bloodstream, in this case, the tryptophan and its derivative, serotonin, in order to produce central fatigue and force us to rest after exertion.

But fatigue is a feeling mediated by many other mechanisms. Our fatigue is probably caused by an ongoing immune reaction. Again, it would make sense if you think of a regular flu. Your body needs energy to raise your metabolism and not to feed your muscles, and for that very purpose, some pro-inflammatory cytokines have shown to produce fatigue.

So, I don't really see the serotonin ratio as a clue to understand or treat the fatigue of ME/CFS, although it may very well explain the benefits of BCAAs. I work out at the gym regularly--just anaerobic--, and I take BCAA almost everyday, and the combo of anaerobic exercise and BCAAs does help.

Just thinking out loud!
Best,
Sergio

Nothing wrong with thinking out loud! But you're referring to the fatigue of CFS, when PEM (not fatigue per se) is the hallmark of CFS.

I keep coming back to this quote, which definitely points to the serotonin ratio as a possible factor in PEM:

"If the tryptophan to BCAA ratio is too high, neurotransmitters made from tryptophan increase, causing physical and mental fatigue.4 When patients first contract CF, the body activates a metabolic pathway that increases the rate of conversion of ATP to cyclic AMP, which is used for immune system stimulation. It seems that CF patients have difficulty turning this pathway off when it is no longer required. The inability to properly regulate this pathway leads to losses of ATP in times of inadequate production. Branch chain amino acids can down-regulate this ATP to cyclic AMP process.5 " http://www.dynamicchiropractic.com/mpacms/dc/article.php?id=41341

It talks about activating a metabolic pathway which increases the rate of conversion of ATP to AMP - this sounds a lot like the anaerobic metabolism of CFS which leads to PEM. There are a lot of threads about low anaerobic threshold and PEM. So when it says that "branch chain amino acids can down-regulate this ATP to cyclic AMP process", I take that to mean that BCAAs can lessen or even eliminate PEM. I've also considered that the statement which refers to immune system stimulation which apparently doesn't get shut off, could possibly explain the Th2 dominance in CFS.

Nothing helped my PEM until I started the BCAAs and glutamine so that makes me think that the tryptophan/ leucine ratio really might be very important in CFS.

 

[SDSue]

@Mary I was reading this and your first thread on BCAA's and am confused on one point.

You began with BCAA's that included glutamine, then stopped the glutamine because of concerns about detox. (I hope I got that right!)

How long were you on the non-glutamine BCAA's before you added back the glutamine? Also, how and why did you add it back? Did you notice a difference when you took it out, and again when you put it back?

Thanks so much. I hope those questions make sense!

 

[Mary]

@SDSue - Your questions make perfect sense and you stated things correctly - the glutamine initially did cause a detox reaction for me and I did stop it for awhile, though I continued with the plain BCAAs. I had the same detox reaction to inositol and glycine when I first took them. I later found out that these amino acids are involved in phase II liver detoxification.

I don't remember when I started to add the glutamine back in. I think I read about glutamine and how important it is, how it can help repair leaky gut plus help with exercise recovery, and I also noticed that I was tolerating glycine and inositol better (I use both for sleep) so at some point - but I can't remember when - I gradually added the glutamine back in and found I was tolerating it better. Also, muscle testing indicated it was very good for me.

I'm now taking two 1,000 mg. glutamine caps a day with no problem. My detox system just seems overall to be working much better than before, and I can't tell you why. I did persist in trying to take glycine and inositol because they did help with sleep and somehow I finally began to tolerate them, but it took awhile.

When you ask did I notice a difference when I stopped the glutamine - the biggest thing was the detox symptoms stopped. In terms of energy or PEM recovery, I really don't know how much of a difference the glutamine is making. I've just gradually improved since last November when I first started the BCAAs, and muscle testing indicates the glutamine as well as the BCAAs are very good for me, so I'm still taking them.

The BCAAs alone did help me - there's no question about that. I think the glutamine probably just adds another layer of benefit but I can't quantify it - I hope this makes sense!