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Recipe for NAD (and ATP)

Kimsie

Senior Member
Messages
397
There have been a couple of threads in the past about how to raise NAD levels. This is something that I have been giving a lot of thought lately and I would like to share what I have come up with.

Often people with CFS and other chronic illnesses find that something helps them quite a lot...for a short while, and then it stops working. For instance, one person took NADH and stopped crashing for 10 days, and then it stopped working.

I would like to suggest that when that happens it is because the person actually needs more of several things, or ingredients. Lets take a recipe. suppose we want to make cookies, and we need 3 cups of item A, 1 cup of item B, and 1 tablespoon of item C. If we have 1 cup of item B but only 1 cup of item A, we can only make 1/3rd of the recipe because we have run out of one of the items.

When a person takes something that helps, they have more of item A, but when they run out of item B that they also need to make the product, they can't make it any more and the supplement they are taking appears to no longer be working, but if they took item B in sufficient amounts to go with item A, then they could keep making the product.

So what is the recipe for NAD?

niacin (or niacinamide) + ATP = NAD

So you see that when we make NAD, we use up a molecule of ATP for every molecule of NAD that we make. So we need to make a lot of ATP (new or de novo synthesis, not recycling) to make our NAD. So what do we need to make ATP?

Glycine + aspartate + glutamine + D-ribose + folate = ATP (these ingredients are for the Adenosine synthesis, the A part)

Folate isn't actually an ingredient, it is part of the mixer.

Aspartate and glutamine can be either taken as a supplement or made indirectly through TCA cycle intermediates by taking L-malic acid. This process requires P5P (B6) for the aminotransferases. If you might be low on B6, then taking aspartate and glutamine might work better, but glutamine and glycine are ingredients for glutathione, so taking glutamine with the glycine can trigger detox.

So if a person takes D-ribose as a supplement, they can still only make as much ATP and NAD as they have enough glycine and glutamine, etc. The D-ribose is no longer the limiting factor. In order to make lots of ATP and NAD (and FAD and coenzyme A, which also consume ATP for synthesis), you have to have lots of all the ingredients at the same time. And of course for NAD you need the addition of lots of niacin or niacinamide.

You also have to have enough of other supporting parts (enzyme cofactors) of the mixer, such as folate, B12, magnesium, B6, etc.

So besides needing more ATP, why do we need so much NAD? Some parts of the following are my hypothesis, they haven't been scientifically proven.

Because when the NAD/NADH ratio gets too low several key enzymes in the TCA cycle are inhibited, especially alpha-ketoglutarate dehydrogenase.

And why would the NAD/NADH ratio be too low? Because the electron transport chain is inhibited. When the electron transport chain (ETC) is inhibited, the NADH levels have to build up high enough to "push" the ETC reactions, so if there isn't enough NADH to "push" the ETC, then you don't have enough energy.

And if you don't have enough NAD to be changed into NADH and still have enough left to keep the NAD/NADH ratio high enough to not inhibit the TCA cycle enzymes, you are in trouble and your body can slip into using 2 ADP to produce one ATP and one AMP for energy production and for each time that happens you have to produce a new ATP de novo, as per Sarah Myhill's article.

So in order to make lots of de novo ATP, and lots of NAD, you have to take glycine, D-ribose, either malate (and enough P5P) or glutamine and aspartate, niacin or niacinamide, and folate and all the other supplements like magnesium that I think most of you already take. The thing is, you have to have enough of all of them, not just D-ribose.

Any increase in the amount of niacin or niacinamide would probably bring an improvement if a person is taking the other items, but in our experience, the amount really needed (to overcome the inhibition of the TCA cycle) is far above what people here at Phoenix Rising are accustomed to taking. And with the niacin more folate and B12 is needed because niacin is metabolized by methylation. I know taking large amounts of niacin or niacinamide goes against what a lot of people believe here, but give it some thought; if you need lots of NAD, you will have to take a lot of niacin or niacinamide.

This post only addresses ATP de novo and NAD synthesis. Other parts of the TCA cycle need support for the best energy production results, such as carnitine or coconut oil to help produce acetyl CoA, etc. If you don't have the NAD production in place any efforts to increase acetyl CoA will only have temporary results.

Just something to think about!

Yes, there have been cases of niacin, especially slow-release niacin, causing liver damage at high doses, so I am mentioning that here, but I think that the safety of niacin or niacinamide could be covered in another post if anyone is interested in the subject. This post is long enough already.

Kim
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Here is one flaw in the argument. I have read, and suspect its true, that we make more weight of ATP in a day than we actually weigh. Mostly that is recycled from AMP, so technically it cannot be counted the myriad times, as this converts back and forth to ATP. The problem is that in straight production terms we make oodles of ATP. Its more complicated than that.

Now increasing AMP might be useful ... more substrate for the whole process to work on. Increasing B3 somewhat is probably a good idea, as it provides more NAD. Having a balanced approach is probably a good idea.

We possibly have enough Acetyl CoA due to our increased glycolysis, but this is an assumption on my behalf. Does anyone know if this is right?

Any argument on these things has to take into account two issues. The first is feedback loops. The second is empirical evidence. Most theoretical ideas sound good but are then later proven wrong. Of course some are found to be sound, or at least useful. Caution is warranted, but that doesn't mean that a new idea should be dismissed.

NAD is also recycled. Some B3 would be good. A lot is probably unnecessary. Its about making the recycling to make ATP operate faster.

Here is one more problem. We do not yet know why we have a problem making ATP. Everything needs to be considered experimental. Some of the research (e.g. Myhil) suggests we may have transporter problems. Now more substrate might well increase the amount transported ... or not.

We might have microvascular problems, particular regulation, so the cells are oxygen deprived. If that is the case then pushing this system might do a lot of damage.

We might have cytokine issues. The wrong push might increase cytokine production. Might, not will.

We might have different subsets with different issues. Some might benefit, some might not, and some might get worse.

Biological systems have multiple feedback loops. We do not know what impact this might have. One of those I worry about is that the wrong method of increasing energy might increase negative hormonal feedback on ATP production.

One thing I would like to see more focus on is how to recycle AMP and NAD faster, and this is not just about the obvious biochemical equations. There is certainly a principle in chemistry, called Le Chateliers Principle, in which adding more substrate increase the rate of reaction. (It says more than that, but that is the message that applies here.) Under that principle, and ignoring the possible effects of the entire biological matrix, then adding more substrate such as AMP and NAD might indeed help.

It might also shut things down due to feedback effects. Deficiency states are not the only thing that can shut reactions down in a biological system. Enzymatic regulation and gene regulation might play a part here.

One risk that always lurks at the back of my thinking is that a sudden increase in burst energy production can induce massive damage to mitochondria. As always, caution should rule.

Ribose really is a special case. Our bodies can process and even make many things needed, but the ribose sugar is a rate limiting substrate. Its a potential bottleneck. Most of these processes are not bottlenecks. So the ribose needs to be in the diet to make more AMP faster.

The mineral I think would be most involved is magnesium. Its needed at multiple steps.

I am not saying this model is wrong. I am not saying don't try to treat our deficits. I am saying we need some caution.

I would really like a lot of our ideas on PR tested on things like the muscle test beds used in UK research (i.e. Newton). It would be nice if we could get a pilot study to test a lot of these ideas. With that behind us we could then organize bigger and more focused studies.

I will write more later if I can get around to it, I am going to be busy the next few days.
 
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alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Let me sum up the first post this way, to see if I got it right. This is about addressing an ATP problem by increasing the size of the AMP and NAD pools. AMP is also needed to make NAD (via ATP) but is returned when NAD is catabolized.

My questions are these: what processes regulate these pools? In other words what feedback loops exist? What factors are not being taken into account? What are the potential downsides? This last I understand will be discussed in a further post.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
One of the things that worries me is that many ME patients have elevated urinary uric acid. This can arise due to AMP breakdown. Is our AMP pool depleted? How would we know? I am not convinced it is, however if this is due to lots of energy going to new AMP synthesis then this would have its own problems.

To me the AMP pool is important as with energy and inorganic phosphate this leads to ADP and ATP, and ATP is used for NAD synthesis.

In case anyone is unaware, when NAD is broken down it can release AMP.

One way to boost AMP would be to decrease its degradation.
 

Gingergrrl

Senior Member
Messages
16,171
Often people with CFS and other chronic illnesses find that something helps them quite a lot...for a short while, and then it stops working.

This has not only been true for me but one step beyond. A medication or treatment can work great the first time and then nearly kill me in subsequent tries (like over-methylation or fluid overload from saline.) I have always wondered why and wish I had the scientific background to understand the rest of this thread but it is light years above my grasp!
 

Kimsie

Senior Member
Messages
397
I am going to put my comments in the quote in bold to make it easier to follow.

Here is one flaw in the argument. I have read, and suspect its true, that we make more weight of ATP in a day than we actually weigh. Mostly that is recycled from AMP, so technically it cannot be counted the myriad times, as this converts back and forth to ATP. The problem is that in straight production terms we make oodles of ATP. Its more complicated than that.

I think that most of the ATP we make each day is recycled from ADP, not AMP. Can you give me a reference about it being recycled mainly from AMP? I mean AMP is the precursor of ATP, but the main recycling of ATP happens in the mitochondria with ATP synthase, which uses ADP as the substrate.

I understand what you are saying, but practical experience has shown me that this protocol is helpful.


Now increasing AMP might be useful ... more substrate for the whole process to work on. Increasing B3 somewhat is probably a good idea, as it provides more NAD. Having a balanced approach is probably a good idea.

We possibly have enough Acetyl CoA due to our increased glycolysis, but this is an assumption on my behalf. Does anyone know if this is right?

Well, this is more complicated. I didn't get into the glycolysis issue because my post was already complicated enough, but it is an important issue. If there isn't a problem with acetyl CoA, when why would carnitine help someone with CFS, as Mary told me it did with her and stopped her from crashing for a few days? It's part of my theory that pyruvate is there, but it is less available because sulfite is forming adducts with it, latching on to it so that it can't enter the TCA cycle. So not all of the pyruvate is able to enter the cycle, and by using alternative routes for making acetyl CoA, the limited pyruvate is able to supply more intermediates through oxaloacetate.


Any argument on these things has to take into account two issues. The first is feedback loops. The second is empirical evidence. Most theoretical ideas sound good but are then later proven wrong. Of course some are found to be sound, or at least useful. Caution is warranted, but that doesn't mean that a new idea should be dismissed.

Well as far as empirical evidence, or perhaps anecdotal evidence would be a better word, Mary told me that D-ribose helps her energy level, and I don't know of any other pathway that it could help her energy level through than the one that makes AMP, ADP ATP, NAD, FAD..... Also, perhaps it won't seem to you to have anything to do with CFS, but my son with depression, D, who also has fatigue issues at times, has responded considerably better to the protocol when I added the NAD recipe, or maybe I should say the AMP or ATP recipe items because we had already tried all kinds of doses of niacin, and it helped, but it didn't help enough without the ribose, glycine, etc. My son S, who has schizophrenia, but no fatigue issues, responds to the protocol without ribose, etc, but he seems to do better with it than without it.

I believe that they have the same problems in the TCA cycle (i.e. the electron transport chain is inhibited) as people with CFS, it is just different genetics that dictates what symptoms a person gets.

NAD is also recycled. Some B3 would be good. A lot is probably unnecessary. Its about making the recycling to make ATP operate faster.

You can't recycle ATP efficiently without enough NAD. We have found that it all just doesn't work without lots of B3, but there is no need to start with a super high dose. A person can slowly build up and stop at the point when they are no longer getting an increase in improvement, but I really don't think it would work very well without the NAD recipe items being taken in generous amounts, too.


Here is one more problem. We do not yet know why we have a problem making ATP. Everything needs to be considered experimental. Some of the research (e.g. Myhil) suggests we may have transporter problems. Now more substrate might well increase the amount transported ... or not.

Sarah Myhill thinks that people with CFS have trouble making ATP.

We might have microvascular problems, particular regulation, so the cells are oxygen deprived. If that is the case then pushing this system might do a lot of damage.

We might have cytokine issues. The wrong push might increase cytokine production. Might, not will.

We might have different subsets with different issues. Some might benefit, some might not, and some might get worse. I am sure that there are various other problem, but I think that the main problem is with ATP.

Biological systems have multiple feedback loops. We do not know what impact this might have. One of those I worry about is that the wrong method of increasing energy might increase negative hormonal feedback on ATP production. Well, that is possible, but we can only find out if some people give it a try.

One thing I would like to see more focus on is how to recycle AMP and NAD faster, and this is not just about the obvious biochemical equations. There is certainly a principle in chemistry, called Le Chateliers Principle, in which adding more substrate increase the rate of reaction. (It says more than that, but that is the message that applies here.) Under that principle, and ignoring the possible effects of the entire biological matrix, then adding more substrate such as AMP and NAD might indeed help.

Adding substrate and cofactors to increase the rate of reaction is exactly what I am suggesting.

It might also shut things down due to feedback effects. Deficiency states are not the only thing that can shut reactions down in a biological system. Enzymatic regulation and gene regulation might play a part here.

It does need testing, we need some testers to find out if it will work for people with CFS.

One risk that always lurks at the back of my thinking is that a sudden increase in burst energy production can induce massive damage to mitochondria. As always, caution should rule.

Of course people with CFS need to gradually raise the amounts of these supplements. With my sons that isn't an issue.

Ribose really is a special case. Our bodies can process and even make many things needed, but the ribose sugar is a rate limiting substrate. Its a potential bottleneck. Most of these processes are not bottlenecks. So the ribose needs to be in the diet to make more AMP faster.

Absolutely, but we found ribose alone didn't do anything. For people with CFS it probably usually does something, but not enough by itself.

The mineral I think would be most involved is magnesium. Its needed at multiple steps.

Yes, I mentioned magnesium in my first post.

I am not saying this model is wrong. I am not saying don't try to treat our deficits. I am saying we need some caution.

As I said, people with CFS need to increase the amounts of supplements gradually, with caution.

I would really like a lot of our ideas on PR tested on things like the muscle test beds used in UK research (i.e. Newton). It would be nice if we could get a pilot study to test a lot of these ideas. With that behind us we could then organize bigger and more focused studies.

I don't really see why a person has to wait for a pilot study, especially a pilot study that will probably never be funded because it uses vitamin supplements that can't be patented. A person can do their own personal study, and report here on PR. If several people do that, you can do your own pilot study. It might take some time to raise the amounts of the supplements because some of them will probably cause detox and have to go slow, such as glycine and glutamine.

I will write more later if I can get around to it, I am going to be busy the next few days.

Thanks for your comments. I really appreciate your taking the time.
 

Kimsie

Senior Member
Messages
397
One of the things that worries me is that many ME patients have elevated urinary uric acid. This can arise due to AMP breakdown. Is our AMP pool depleted? How would we know? I am not convinced it is, however if this is due to lots of energy going to new AMP synthesis then this would have its own problems.

It could be that there is a block somewhere that is causing the purines to be excreted.

One way to boost AMP would be to decrease its degradation.

That would be a good idea. I will try to think about how that might be done.

Probably too much AMP is being made through the 2ADP to AMP + ATP pathway. It sounds contradictory that we want to make more AMP de novo to avoid making it through another pathway, but that's what we want to do.
 

Kimsie

Senior Member
Messages
397
Let me sum up the first post this way, to see if I got it right. This is about addressing an ATP problem by increasing the size of the AMP and NAD pools. AMP is also needed to make NAD (via ATP) but is returned when NAD is catabolized.

Yes. Particularly the NAD pool needs to be increased, but you have to increase the AMP pool to increase the NAD pool sufficiently.

My questions are these: what processes regulate these pools? In other words what feedback loops exist? What factors are not being taken into account? What are the potential downsides? This last I understand will be discussed in a further post.

I will try to look into the feedback loop question.

I imagine that one process that regulates the NAD pool, besides availability of substrate and cofactors, is the NAD/NADH ratio. When the ratio is too low along with low ATP it probably stimulates production of NAD. However, I have checked into this, and no one seems to know how it is regulated, as far as I have been able to find.

I will post on the safety of high dose niacin, too. There could certainly be some factors that I don't know about, and so I can't take them into account.


One helpful thing is that I don't have CFS so I have plenty of energy and time for research.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I think that most of the ATP we make each day is recycled from ADP, not AMP
Correct, my bad. However the AMP pool and the ADP pool appear to have a strong correspondence. What I am unsure of is the kinetics involved. Myhil also postulates that when pushed we destroy ADP if I recall correctly. I have AMP on my brain at the moment because its important in other things I have been investigating.

Sarah Myhill thinks that people with CFS have trouble making ATP.
Yes, but my point was: why? We are still trying to figure that out. I do not think there is much doubt we cannot make enough ATP, but this is only really clear when our body is challenged. When we try to make more ATP to meet increased demand we appear to crash, though the process is so far not well understood and complex.

NAD, AMP and ADP are subject to multiple regulatory loops in the mitochondria. The ratios and amounts appear to be regulated. I am not aware of the full details. It may be difficult to alter this reliably.

I understand there is anecdotal evidence of improvement from B3, NAD, CoQ10, Ribose, etc. What we lack is solid research evidence. That doesn't mean people shouldn't try things, it means we should be cautious.

We might have different subsets with different issues. Some might benefit, some might not, and some might get worse. I am sure that there are various other problem, but I think that the main problem is with ATP.
This is too vague. It could be that the nerves are not regulated right, leading to poor circulation, leading to low aerobic capacity in the mitochondria, at least in a subset. I acknowledge we cannot increase ATP production beyond a low threshold (and this is probably what causes PEM when we push) but we still don't know why, or if its the same why in everyone. It probably isn't the same for everyone.

Well, that is possible, but we can only find out if some people give it a try.
I have no problems with people trying things, I just want everyone to approach it with caution. Here is my lemon rule:

http://forums.phoenixrising.me/index.php?entries/28-rules-of-thumb.941/
22. Most treatments for ME are lemons, they don't suit everyone - but you often wont know if it suits you until you suck it and see. If you see a soured look on my face you will know why.

A big reason I am cautious is that supra-physiological doses of anything can have unpredictable or dangerous results. This may only show up when large numbers of people have been doing it for a while.

Adding substrate and cofactors to increase the rate of reaction is exactly what I am suggesting.
I am aware of this, which is why I commented on the principle. I am also aware this often does not work. Its one thing to do this in a test tube, another to do it in a living system. The system has set points and fights back, and there are often unintended consequences. Hence my suggestion of caution. Sometimes this might not show up until after prolonged use - it can be delayed. While regular chemical reactions, in isolation, follow Le Chateliers Principle, biological systems with enzyme driven reactions can violate the rule to some extent.

One of the issues is that many of these kinds of treatments do work in varying degrees, but only for subsets. It was suggested, I think, that alpha ketoglutarate might be a marker. It would be interesting to see if responders versus non responders can be predicted from alpha ketoglutarate levels.

The improvement we often get from more CoQ10, which in some cases is dramatic, suggests the problem might not be entirely with NADH, though its also possible it can also drive improved NADH metabolism in the electron transport chain. I just do not know. I suspect that adding CoQ10 to the mix might improve the response, at least in a subset. There are a few studies now that have indicated we might have a CoQ10 deficiency which is entirely consistent with the larger picture.

Cross comparison of groups with disorders other than ME can be useful, but also might be misleading.

Unless an improvement is dramatic and in almost everyone then we do need clinical research tests. It was once the case that we couldn't get funding for things like this, but Rich van Konyenburg managed (a folate clinical trial using the simplified methylation protocol), and we now have crowd sourcing as a possible financial mechanism. The funding model needs to change, and natural therapies need to have research funded by patients. Also if some indications are right the FDA and other regulatory agencies in many countries might ban many natural supplements. They have been trying for years, and in some cases succeeded. If that happens then research would be mandatory to gain acceptance.

One thing we could do is establish a dosage that is generally recognized as safe and run a small research pilot study. If improvements are seen and established reliably then follow-up studies can be done.

Please don't misunderstand me, if it can be shown, even anecdotally, that a high percentage of patients make dramatic improvements under this model then I think quite a lot of us will try it, and good luck to them.

For the record I used a protocol similar to this but missing ribose, back in the late 90s. My energy was restored but two weeks later severe side effects set in. It did nothing for fatigue though - but I will take restored energy if I can get it safely.

One of the most important things that needs to be monitored is who, if any, get severe adverse results. Even drug companies fail at this and we don't have anything like their resources.
 
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alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Probably too much AMP is being made through the 2ADP to AMP + ATP pathway.

This is what Myhil suggests. Its not contradictory because the 2ADP pathway is an emergency energy pathway, with the mitochondria destroying ADP to make more energy so you don't die. I do not know the kinetics, or rate, at which AMP is converted to ADP. This might be a rate limited step. I suspect it is.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
One helpful thing is that I don't have CFS so I have plenty of energy and time for research.
That is indeed helpful. :) Its not just energy and time that is a problem for an investigator with ME, its concentration and memory - I keep having to relearn my biochemistry. I used to be able to draw the Krebs cycle and electron transport chain, now I can't remember anything but vague details and need to look it up.

I used to debate this stuff all the time back when I had a better understanding of the topic. I have lost most of that.
 

heapsreal

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Nadh can stimulate dopamine and noradrenaline release, so should have an increase in energy through this mechanism but could also be improving pots/oi symptoms.
just a thought?
 

Kimsie

Senior Member
Messages
397
For the record I used a protocol similar to this but missing ribose, back in the late 90s. My energy was restored but two weeks later severe side effects set in. It did nothing for fatigue though - but I will take restored energy if I can get it safely.
I will respond to the rest of your comments later today, but I wanted to comment on this quickly before I leave. If you didn't take ribose then it wasn't the same protocol. Also, I doubt that you were taking the amount of B3, but that is a moot point without the ribose.

If you have records, I would like to know what the protocol was and what the side effects were because this is exactly the type of information I am looking for. This is what helps me figure the puzzle out and I need more data like this.

I hope you don't think that because we don't agree about everything I don't like your comments. I can see that you have studied these things a lot and I like having a conversation with you because of that.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I will respond to the rest of your comments later today, but I wanted to comment on this quickly before I leave. If you didn't take ribose then it wasn't the same protocol. Also, I doubt that you were taking the amount of B3, but that is a moot point without the ribose.

If you have records, I would like to know what the protocol was and what the side effects were because this is exactly the type of information I am looking for. This is what helps me figure the puzzle out and I need more data like this.

I hope you don't think that because we don't agree about everything I don't like your comments. I can see that you have studied these things a lot and I like having a conversation with you because of that.

The issues about protocols was why I commented specifically on ribose.

I titrated B3 to maximum effect, but I did not need a lot.

I appreciate that people disagree, and that this should even be expected. I consider we are all looking for answers, and one way to approach that is to question everything. Things that survive hard questions tend to be more reliable. I have also done this before, more than once. Indeed I first got involved in debating theories in the late 90s. I have debunked a few theories, had one of my own debunked, and participated in the very early days of what became the simplified methylation protocol years later.

We are all looking for answers. WE as patients and caregivers, have a much greater vested interest in finding answers than most doctors.

I am looking up my old protocols, but they are a mismash .. I had brainfog when I wrote them. I do have something I wrote in a paper for a conference in 1999. I will send it via messaging if I locate it.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I have found a text file version of my old paper. The treatment section is here, but first I will post a comment. Please note the hypercitricemia theory is disproved as a cause, but not as part of pathophysiology (despite rather poor research claiming otherwise).

Increases in size and number type 2 muscle fibers may also be indicative of
hypoxia. This is because type 2 fibers rely on glycolysis and not oxygen. It
is not unreasonable to expect this kind of adaptation in chronic hypoxia. On
the other hand, some researchers (e.g. Behan et. al. [Beha 91], [Vecc 96])
have shown atrophy of type 2 or type 1 fibers, with type 2 atrophy the most
common. Behan et. al. found the unusually large and compartmentalized
mitochondria in these same muscle studies. This would increase the
mitochondrial capacity to absorb oxygen, as this is in part dependent on
surface area. Atrophy of any muscle tissue would be expected under this
theory of hypercitricemia as muscle is probably catabolised as a protein
source.

The CFS finding that lactate is markedly elevated during early exercise but
peaks normally is identical to the hypoxic response. The discovery that VOmax
is reduced in CFS is extremely indicative. The study that apparently
contradicts this should therefore be addressed.

While there is evidence of reduced ATP during intense exercise [Wong 92], it is
difficult to link this to oxygen. Scroop et. al. [Scro 98] demonstrate normal
oxygen consumption during exercise (VOmax). However, there are several points
which can be made about this study:

1. There were only five CFS patients in the study.
2. It is not known how many of these patients exhibited hypercitricemia or
phosphate diabetes.
(This is because these factors were not considered important at the time
of the study.)
3. This study is in apparent conflict with another study [Beck 98] in which
there was an extreme reduction in oxygen consumption (up to 42% less).
4. The study focuses on final lactate results - it puts less emphasis on the
growth rate of lactic acid during exercise. Final lactate production
usually reaches a normal maximum even under hypoxic conditions.
5. The study uses incremental exercise. Most other studies of a similar
nature use continuous exercise. Slowly increasing exercise intensity over
time has been shown to improve performance in PFK deficiency. This is
because increased lactate and blood flow improves total oxygen transfer.

Riley et. al. [Rile 90] also discuss oxygen consumption by 13 patients with CFS
(presumably using the Oxford definition). Peak exertion oxygen consumption
was for CFS patients, on average, 16% below the controls. At rest, oxygen
consumption was only 5% below controls, and this increased faster than normal
to 15% over the controls in the early stages of exercise. Recovery levels of
oxygen consumption were on average 19% lower than in the controls.

In the Riley et. al. study, resting lactate was 8% over the controls, and this
increased to nearly 15% over the controls during early exercise. Final
lactate production was 16% over the controls. They conclude that oxygen
consumption is reduced, and lactate abnormally high. It may also be of
significance that heart rates were abnormally high, although maximal heart
rates were lower than controls.

With regard to mineral and ion balance, numerous studies have shown concern
over potassium, magnesium and calcium in CFS. Watson et. al., in particular,
has shown a possible potassium transport problem which links CFS and Syndrome
X. Both of these findings are consistent with the theory of hypercitricemia.

There are a number of other points arising from this theory that are worth
discussing. These include factors arising out of erythrocyte and neuronal
metabolism, amino acid imbalances and metabolic traps. This is followed by a
discussion of possible triggers for the disorder, specific predictions
arising out of the theory, and possible treatments.