Recipe for NAD (and ATP)

[alex3619]

Ok, my protocol at the time of the conference was this:

The theoretically sufficient hypercitricemia daily protocol is currently:

4-8g alanine (depending on body mass) in two doses twelve hours apart.
2-4 g glycine (depending on body mass) in two doses twelve hours apart.
High dose vitamin B complex (optimal dosage not yet determined).
Magnesium and Potassium Phosphates (optimal dosage not yet determined).
Magnesium (chelated - optimal dosage not yet determined).

The alanine is to inhibit PK. It should not be taken close to bedtime. The dose
should start off small and be pyramided in 2-4g increments every 3-4 days.
The more severely affected the patient is, the smaller the increments should
be. This is because the initial effect of the alanine is to induce an
increase in hemolysis. This effect should be neutralized once citric acid
levels decline.

The glycine is a nutritional supplement but also to assist cell membrane
survival under low ATP conditions. The B complex is a general supplement and
includes many cofactors for the affected pathways. It may be preferable to
change this to a high dose multi-vitamin and mineral supplement, but so far
this has not proved necessary. The phosphates are to boost PFK and
G3PD activity, as well as slow the degeneration of 2,3 BPG. Magnesium is
included as a cofactor for PFK as well as a nutritional supplement to help
restore magnesium levels. Potassium is primarily included as a supplement to
help restore potassium levels. It may be necessary to include vitamin D3 if
there is any evidence of phosphate diabetes.

Individual nutritional requirements may necessitate the use of other
supplements. Otherwise, other supplements seem to be optional, at least
theoretically. However, personal experience using alanine shows that it has
minimal or no effect unless other factors are present and most of these have
already been mentioned. Other cofactors are still under investigation.

The treatment is expected to produce significant initial results, but will
have to be maintained to continue producing these results. It is hoped that
eventually this treatment might lead to a permanent correction of the problem,
but it might not. The concern is that although 2,3 BPG levels can be boosted,
restoring tissue oxygen supplies, many non-erythrocytic tissues will have
elevated PFK. This means that these tissues will continually overproduce citric
acid to block the PFK. Some of this will still flow over to block PFK in
erythrocytes. Over time this problem might be self-correcting, as improved
oxygen supply should reduce the rate of PFK synthesis. However, it is also
possible that permanent changes in PFK levels may result in a permanent
tendency to hypercitricemia.

During this general time frame I was also using a range of other factors, including B1 and B3, chromium picolinate, a range of antixoxidants including C, E and (I think) lipoic, pycnogenol (the original), and a bunch of other stuff (edit: including CoQ10). What I discussed in the paper was an attempt to minimize my protocol, rather than the full protocol I had found by experiment. I will have to sort through my notes.

The chief side effect was severe and intractable daily headaches. Nothing touched them. What use is more energy if you cannot get out of bed with an intense headache? Fatigue was also not improved by my protocol. Fatigue and energy are only weakly correlated in my view. You can fix one without the other being fixed. Our fatigue and lack of energy are not the same.

I was also taking folic acid not methyl folate. The whole methyl folate issue was not even on my radar then.

I will be very busy today so might not have much time available till mid week to do more.

 

[alex3619]

One important issue, that might have affected things, is that all this was done on a low arachidonic acid diet.

 

[Kimsie]

"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.
.

Well, here is my hypothesis about that:
Sulfite oxidase is inhibited through a vicious cycle which began with oxidative stress. The original condition which started the vicious cycle may have resolved, but the inhibition of sulfite oxidase (or the molybdenum cofactor) continues because the ratio of sulfite to cysteine is higher than normal, and sulfite interferes with the availability of pyruvate, and has the potential to interfere with enzymes which have a critical sulfhydryl group in the active site, of which there are many, and because the level of sulfate, which is required is reduced for sulfation.

A study has shown that a high cysteine to sulfate ratio is associated with many illnesses, including CFS, ME, MS, RA, IBS, fibromyalgia and some others. This high cysteine to sulfate ratio could be caused by sulfite oxidase inhibition, although apparently sulfite was not monitored in this study. But whether the sulfite oxidase enzyme is inhibited or the high cysteine/sulfate ratio is caused by something else, there is something wrong with cysteine metabolism.

This sulfite is what is inhibiting the ETC either directly or indirectly, according to my hypothesis, and the inhibition of the ETC is what causes a low NAD/NADH ratio which inhibits the TCA cycle especially at the AKG dehydrogenase complex, causing low levels of succinyl-CoA and interfering with the synthesis of heme and catalase. Since heme is needed for the ETC, this is part of the vicious cycle. There must be a lot of other effects, too, some of which I have ideas about, but I am trying to keep to the most salient points.

So that is my hypothesis. It is the inhibition of the ETC which causes the low NAD/NADH ratio and inhibits the TCA cycle. If you can increase the NAD/NADH ratio, the ATP production should increase.

 

[Kimsie]

Ok, my protocol at the time of the conference was this:
4-8g alanine (depending on body mass) in two doses twelve hours apart.
2-4 g glycine (depending on body mass) in two doses twelve hours apart.
High dose vitamin B complex (optimal dosage not yet determined).
Magnesium and Potassium Phosphates (optimal dosage not yet determined).
Magnesium (chelated - optimal dosage not yet determined).

Well, I would guess that the glycine was causing the headache, especially since you were taking folic acid, instead of better forms of folate. When we first started suddenly taking large doses of P5P, every one of us (6 out of 6) got a terrible headache but taking more folate stopped the headache. So how does that relate to glycine? Glycine is metabolized by folate and while I would expect large doses of glycine to improve your symptoms, I would also expect it to make you need more folate, unless you were already taking a generous amount of either methylfolate or folinic acid. I have no idea what pathways cause the headache, I just know that the folate stops the headache. (I wouldn't count the folic acid, even if you took a lot, because we don't know if you were able to use it.)

The alanine is to inhibit PK. It should not be taken close to bedtime. The dose
should start off small and be pyramided in 2-4g increments every 3-4 days.
The more severely affected the patient is, the smaller the increments should
be. This is because the initial effect of the alanine is to induce an
increase in hemolysis. This effect should be neutralized once citric acid
levels decline.

The glycine is a nutritional supplement but also to assist cell membrane
survival under low ATP conditions. The B complex is a general supplement and
includes many cofactors for the affected pathways. It may be preferable to
change this to a high dose multi-vitamin and mineral supplement, but so far
this has not proved necessary. The phosphates are to boost PFK and
G3PD activity, as well as slow the degeneration of 2,3 BPG. Magnesium is
included as a cofactor for PFK as well as a nutritional supplement to help
restore magnesium levels. Potassium is primarily included as a supplement to
help restore potassium levels. It may be necessary to include vitamin D3 if
there is any evidence of phosphate diabetes.

I gather that the idea was to try to inhibit PK to lower the amount of citrate? But why weren't you looking at aconitase and trying to make it work better to lower the citrate? I believe that aconitase is inhibited because the iron-sulfur clusters are affected. However, fairly new research has shown that folate if required for iron-sulfur repair or synthesis, so folate may help there.

...
During this general time frame I was also using a range of other factors, including B1 and B3, chromium picolinate, a range of antixoxidants including C, E and (I think) lipoic, pycnogenol (the original), and a bunch of other stuff (edit: including CoQ10). What I discussed in the paper was an attempt to minimize my protocol, rather than the full protocol I had found by experiment. I will have to sort through my notes.

The chief side effect was severe and intractable daily headaches. Nothing touched them. What use is more energy if you cannot get out of bed with an intense headache? Fatigue was also not improved by my protocol. Fatigue and energy are only weakly correlated in my view. You can fix one without the other being fixed. Our fatigue and lack of energy are not the same.

I understand what you are talking about, except which one would you call a crash,.. fatigue?

I was also taking folic acid not methyl folate. The whole methyl folate issue was not even on my radar then.

I will be very busy today so might not have much time available till mid week to do more.

Well, I wouldn't say that you had tried anything much like the NAD recipe. Also, the fact that you were taking folic acid instead of a better form of folate could have nixed the whole thing, even if you had been taking the other items, depending on how well you can metabolize folic acid.

 

[alex3619]

Your recipe was, according to post one, B3, glycine, aspartate, glutamate, D-ribose, folate, B12, magnesium, and B6. The only thing missing in my protocol was ribose, though as I said this was before I was aware that folic acid is probably better considered a toxin. I should add that I was eating a lot of protein - most aminos were covered. The aminos I boosted as a supplement were few and far between, but included alanine.This protocol also included additional minerals, antioxidants etc, including lipoic and CoQ10. My protocol was very broad, and I have since labelled it the Shotgun Protocol, though that's more about the approach than the specific protocol.

The paper referred to a theoretical protocol based on what I presented in the paper, which was based on a now disproved model of CFS causation, though I still think aspects of it affect pathophysiology. What I was actually on was one based on what I had tested for about two years, but included what was in the paper The only other thing that would have been different was dosage - most Bs for example I was dosing at about 200mg.

The reason I was not more clear is that my notes are scattered over hundreds of pages in several notebooks, and it will take time to piece them together. I have also still not found one of the notebooks. When I do I can give some idea of doses, though I probably did not record specific doses in multi supplements.

I think any NAD protocol would benefit from lipoic, CoQ10, C and E.

 

[alex3619]

I gather that the idea was to try to inhibit PK to lower the amount of citrate? But why weren't you looking at aconitase and trying to make it work better to lower the citrate? I believe that aconitase is inhibited because the iron-sulfur clusters are affected. However, fairly new research has shown that folate if required for iron-sulfur repair or synthesis, so folate may help there.

I was an expert on aconitase back then - just don't ask me much now. I spent many hours debating this. In fact I think our aconitase might be misfolded ... one of those mystery misfolded proteins we keep hearing about. Its not commonly appreciated that aconitase, like a number of proteins in the mitochondria, is not actually made in the mitochondria but imported from the cell. I still do not know though if its imported denatured and folded in the mitochondria.

One of my debating partners maybe two years later was Marty Pall.

The model I was working on was basically a hypoxia model, in which there was an alteration in the oxygen dissociation curve. The hypothesis was that our blood cells were not dumping enough oxygen, but preferred to retain it, and the paper was about mechanisms. This was later shown to be incorrect (based on resting not exercising patients). Our hypoxia is not due to lack of oxygen dumping from RBCs, at least not due to alterations in basic RBC chemistry, though this does not rule out poor circulation or other factors. One we should be thinking about is transient oxygen dumping problems due to alterations in pH, especially during a crash. I do wonder if the findings that disproved my model might not hold during a crash. Indeed, its entirely possible that my model may have been partially right all along, but we would need data from patients in severe metabolic crash, especially RBC 2,3 bisphosphoglycerate. However this interpretation cannot be the whole story but only a piece.

I understand what you are talking about, except which one would you call a crash,.. fatigue?

Fatigue is a peripheral symptom in a crash in my view. Theoretically a crash can occur without any overt fatigue, if you were resting aggressively you might not notice fatigue. Its about energy, hormones, cell signalling etc in my view. Now try to push yourself in a crash and fatigue will be obvious.

 

[Kimsie]

Your recipe was, according to post one, B3, glycine, aspartate, glutamate, D-ribose, folate, B12, magnesium, and B6. The only thing missing in my protocol was ribose, though as I said this was before I was aware that folic acid is probably better considered a toxin. I should add that I was eating a lot of protein - most aminos were covered. The aminos I boosted as a supplement were few and far between, but included alanine....

The only other thing that would have been different was dosage - most Bs for example I was dosing at about 200mg.

The reason I was not more clear is that my notes are scattered over hundreds of pages in several notebooks, and it will take time to piece them together. I have also still not found one of the notebooks. When I do I can give some idea of doses, though I probably did not record specific doses in multi supplements.

I think any NAD protocol would benefit from lipoic, CoQ10, C and E.

I'm not sure if you are saying that you were taking aspartate and glutamate but forgot to mention them, or that eating a lot of protein would be the same as supplementing them, or that the alanine was a substitute for the malic acid because it can be made into pyruvate. Also, I think that the D-ribose and the glycine are the two most important of these sugar and amino acid supplements and the ones most likely to be insufficient, so it is possible that the other amino acids were covered by the protein, but not the D-ribose.

200 mg should be enough for the B's except not even close for the B3. Lipoic, CoQ10 and C and E are good. We have used all of them at times and always the C. It's hard to tell if the E is doing anything, but we have seen noticeable temporary improvements with the lipoic acid and the CoQ10.

I am amazed that you can find the protocol at all after so many years, so you're doing good.

 

[Kimsie]

Fatigue is a peripheral symptom in a crash in my view. Theoretically a crash can occur without any overt fatigue, if you were resting aggressively you might not notice fatigue. Its about energy, hormones, cell signalling etc in my view. Now try to push yourself in a crash and fatigue will be obvious.

So a crash is a lack of energy?

 

[alex3619]

Glutamate is abundant in protein, so no supplementation is necessary unless you have reason to decrease meat or quality protein intake, such as vegetarians or low protein diets. I tried lots of aminos in isolation,but only alanine created a noticeable effect in isolation. Offhand I do not recall data on the aspartate content of high protein foods. Supplementation of any amino should not be necessary in many cases, though it does depend on specific aminos and meat content. Lowish alanine content in most meat is in part why I added it. However, and this is stretching my memory more than a little, specific substances are known to help in hypoxia and I think alanine is one.

I think I heard about methyl folate and the possible importance of ribose for ME less than a decade ago, maybe circa 2005, and for methyl folate that was probably from Rich van Konyenburg. Ribose is in my current view a critical rate limiting substrate in nucleotide synthesis.

Vitamin E probably wont do much by itself in ME patients. Some of us have undetectable vit E though. Its primary use is in protecting lipoic and CoQ10. Its part of the standard cellular antioxidant network. With low vit E the entire antioxidant network might be compromised. Its the lipoic and the CoQ10 that have highest importance here.

 

[alex3619]

So a crash is a lack of energy?

I think its a crash in energy production, or at least that is my current hypothesis. With this goes a cascade of additional secondary effects. However some of what I think are effects may in fact be causes ... we simply don't know enough. Brain and muscle are both affected, but the evidence is also that vascular regulation is affected. I would have to go back and reread stuff to say much more.

One thing I find telling is that if Julia Newton is right, and the abnormalities she finds in biopsied muscle tissue are typical, then there is definitely something wrong with muscle tissue itself, quite aside from blood vessels or neurological or hormonal impact, including cytokines. Isolated muscle from ME patients is stuffed.

Are you familiar with the research at Workwell, or the Lights, or Julia Newton?

 

[Kimsie]

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.

They are regulated but if there is not enough ingredients for making them, then you can't make more even if the body is trying to make more.

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.

I wouldn't expect that. I do think that high AKG is a sign that AKG dehydrogenase is inhibited, but the opposite wouldn't prove that it was not inhibited, because other things could drain AKG or inhibit the synthesis of AKG, but maybe a person is more likely to have the tired feeling kind of fatigue if AKG is high. I was just wondering if all people with CFS have high AKG.

My son, S, who never has any kind of fatigue, has low AKG, but he has to have high niacin. My son, D, has had the tired feeling kind of fatigue, that would make him just lay down on the floor because he felt too tired to sit or stand or walk to his room, maybe his AKG is high, but we never have had it checked. Taking lots of folate cured that kind of fatigue, but then after a few months, he was depressed instead, so that's one example about what you are talking about how of taking lots of one supplement can have negative effects, and he was taking other supplements at the time, too. He was fatigued for over a year without getting any worse, but when he started 5 mg of methylfolate a day, something else must have gotten drained. This protocol is really helping him now that we added the ribose and glycine (we tried them both before separately, but the ribose didn't seem to do anything, and the glycine only worked for 1 day.)

The improvement we often get from more CoQ10, which in some cases is dramatic, suggests the problem might not be entirely with NADH,

(But I said in my very first post that the NAD/NADH ratio is low because the electron transport chain is inhibited which explains why CoQ10 can help. CoQ10 would help even if it was not deficient because it would help the reactions go.)

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.

There certainly could be a CoQ10 deficiency contributing to the problem.

 

[alex3619]

One we should be thinking about is transient oxygen dumping problems due to alterations in pH, especially during a crash.

Actually this might explain a delayed crash. During exercise our decreased muscle pH will induce higher oxygen dumping, but then this shifts (empirically, see the link I provide in a bit) to an increased muscle pH. This will lead to lower muscle oxygen dumping, depriving them of oxygen.

See the discussion on Julia Newton's research here:
http://forums.phoenixrising.me/inde...went-up-a-tad-and-sjogrens.23477/#post-359676

Potentially this could mean there was a programmed response to shut down muscle metabolism. I wonder if this whole thing might be treated best by something like sodium bicarb after exercise, and regular vinegar in water at rest, to assist shifting the pH balance toward normal?

Has anyone looking into optimal pH for NAD and ETC metabolism?

 

[Kimsie]

Glutamate is abundant in protein, so no supplementation is necessary unless you have reason to decrease meat or quality protein intake, such as vegetarians or low protein diets. I tried lots of aminos in isolation,but only alanine created a noticeable effect in isolation. Offhand I do not recall data on the aspartate content of high protein foods. Supplementation of any amino should not be necessary in many cases, though it does depend on specific aminos and meat content. Lowish alanine content in most meat is in part why I added it. However, and this is stretching my memory more than a little, specific substances are known to help in hypoxia and I think alanine is one.
.

I know that you felt that alanine was helping in a different way, but are you aware that alanine is used to make glycine? I wonder if that wasn't why it helped you. The following is from this study.

"The main pathways of glyoxylate metabolism in humans are shown in figure 5... Alanine-glyoxylate transaminase ... catalyses the main reaction of that route, working in the direction of glycine production,"

This is the reaction: L-alanine + glyoxylate

pyruvate + glycine, so alanine actually helps produce pyruvate, although it inhibits pyruvate synthesis from the glycolysis pathway.

It is not likely that anyone gets enough glycine from their diet. If you take a look at the study listed above you will see that even for a healthy person it can be a challenge to have enough glycine. Around 10 grams are needed for collagen production alone.

 

[alex3619]

Thanks for that link @Kimsie. I will have to look into it ... later - too busy and too many good leads at the moment. I would like to point out though that it does not state 10 g of glycine is needed for collagen, but that the diet is typically 10g short. So its worse than that. Interesting.

Glycine and CFS have been long connected, though this is disputed. I am looking up my old references, including a text on hypoxia. I have a suspicion the other amino linked to hypoxia tolerance is glycine, which is why it was in my protocol. I have simply forgotten.

PS. My position fifteen or more years ago does not even reflect my position just thirteen years ago. At the moment I am most intrigued by evidence for cortisol resistance in us, in which we have almost normal levels of cortisol but it appears this has little effect.

 

[heapsreal]

At the moment I am most intrigued by evidence for cortisol resistance in us, in which we have almost normal levels of cortisol but it appears this has little effect.

Cortisol resistance is probably the reason why many have high cholesterol. The liver increases cholesterol production to compensate for low cortisol and cholesterol is the start of the hormone stream. I also think my experience using pregnenolone is why my cholesterol has come down and shot right up when not using pregnenolone. I have read that in adrenal dysfunction that there probably is a problem with enzymes needed to convert cholesterol to pregnenolone which then flows down to make all other hormones.

Is there a type of burn out or down regulation of cortisol production in cfs/me who have been ill longer, maybe due to initial elevated cortisol levels initially seen in cfs/me??

 

[alex3619]

Is there a type of burn out or down regulation of cortisol production in cfs/me who have been ill longer, maybe due to initial elevated cortisol levels initially seen in cfs/me??

I saw you had already seen this video thread: http://forums.phoenixrising.me/inde...ockholm-dr-bansals-talk-youtube-nov-19.33978/

My own concern with low cortisol response is that the mitochondrial function will be impaired, plus there will be exaggerated inflammatory eicosanoid synthesis, and possibly increased mitochondrial oxidative stress (though that one is a long argument related to eicosanoids).

I am sure there will be other impacts. However prototypical corticosteroid resistance, the kinds previously researched, produce a syndrome only superficially like ME. I am suspicious its only part of the story. We do not see lots of ladies with hirsuitism in ME, which is common (iirc) in traditional corticosteroid resistance. It does however closely resemble Addison's disease. It also explains why many of us (pick me, pick me!, aren't I lucky) do not respond properly to cortisol therapies.

On the other hand, mutations in cortisol binding globulin that decrease or destroy the functional capacity of CBG produce a syndrome very very similar to ME.

 

[adreno]

I have tried most, if not all, supplements mentioned. Most of them give me adverse effects. Glycine for example, makes me extremely fatigued and brain fogged. This is not unexpected, as glycine is an inhibitory neurotransmitter. It also lowers cortisol (which I can't tolerate).

Glutamine gives me symptoms of excitotoxicity, malic acid gives me stomach pain, D-ribose crashes my blood sugar aso. The point is that in practice, most of these supps makes me worse, not better. IME, a shotgun approach rarely seems to work.

 

[Sidereal]

We do not see lots of ladies with hirsuitism in ME, which is common (iirc) in traditional corticosteroid resistance.

It does happen. There was a thread about it just a few days ago:

http://forums.phoenixrising.me/index.php?threads/hirsutism-thyroid-and-hormone-profile.33801/

 

[Kimsie]

I have tried most, if not all, supplements mentioned. Most of them give me adverse effects. Glycine for example, makes me extremely fatigued and brain fogged. This is not unexpected, as glycine is an inhibitory neurotransmitter. It also lowers cortisol (which I can't tolerate).

Glutamine gives me symptoms of excitotoxicity, malic acid gives me stomach pain, D-ribose crashes my blood sugar aso. The point is that in practice, most of these supps makes me worse, not better. IME, a shotgun approach rarely seems to work.

You tried them together, along with extra niacin or niacinamide? They work together as a group. As a minimum ribose, glycine and some form of niacin would have to be taken together, or I wouldn't necessarily expect it to be helpful, depending on what a person is already deficient in. If a person isn't taking enough magnesium, that would also interfere, but from what I have read here, most are already taking magnesium.

Malic acid can substitute for glutamine, since it can be made from alpha-ketoglutarate. The acidity can bother the stomach so we always mix it with some baking soda to partially neutralize the acidity at a ratio of 1/4 teaspoon of soda to 1 tsp of malic acid.

 

[alex3619]

It does happen. There was a thread about it just a few days ago:

http://forums.phoenixrising.me/index.php?threads/hirsutism-thyroid-and-hormone-profile.33801/

Thanks @Sidereal. I added a comment on that thread.