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The Glutathione Depletion Cascade

Kimsie

Senior Member
Messages
397
Deplin is sold in 15 mg and in the trials they used up to 60mg of it. That's a great observation between B6 and B9. What about B12? Do you give him any of that at all? If so which form?
I'm sorry I didn't reply to this before. We are now using the hydroxocobalamin form of B12 as a nasal spray (for D) to test it's use as an antioxidant along with methylcobalamin orally.

One thing about B12 that may be even more significant than its use for methylation for people with mitochondrial problems is that it helps change some of the amino acids into succinyl-CoA, which may be depressed in these illnesses, according to my hypothesis.
I think many of the "toxicity" reports, or side effects, with B6/P5P is because it can drain folate. I find that the folate and B6 needs to be balanced. The neurological symptoms with B6 probably happens because folate (and perhaps B12) goes to low. If I get side effects from P5P I take more folate and it usually goes away.
I agree, we found that we all got headaches taking B6 if we didn't take enough folate, too, but that goes away in a day or two as the enzymes adjust. I think this is because if a person is low in B6 and suddenly starts taking a lot of it, the body needs to adjust the amount of the enzymes that use B6 down.

We haven't noticed anything that would make us think that it has been draining B12. The only folate enzyme which uses B6 is SHMT, and that pathway shouldn't affect B12.

I should update here to say that we not longer need to take so much B6, we are using 50 mg of P5P a day now.

Dannybex, none of us has CFS and we are not sensitive to supplements, as are most people with ME/CFS. People with CFS need to change doses very gradually.

I have changed my hypothesis somewhat since I started this thread and I am in the process of trying to figure out the answers to another question which is very important: Does pushing the ETC with the NAD recipe increase oxidative stress and damage to the ETC or not? When I think I have the answer I am going to write up and update my hypothesis both here and on my blog.

I am constantly making adjustments to my hypothesis as I get more data.
 

undcvr

Senior Member
Messages
822
Location
NYC
You're taking 90mg mfolate daily? Damn.

It's lifted the fatigue I don't feel like I have chronic fatigue anymore. I feel like I am weak in general but not fatigued. Somehow somewhere someone dropped the ball, i think we are eventually going to find out that mfolate is therapeutic (and safe) in doses much larger that we thought.
 

Kimsie

Senior Member
Messages
397
It's lifted the fatigue I don't feel like I have chronic fatigue anymore. I feel like I am weak in general but not fatigued. Somehow somewhere someone dropped the ball, i think we are eventually going to find out that mfolate is therapeutic (and safe) in doses much larger that we thought.
How long have you been taking this dose of folate? Do you have PEM or did you have PEM before you started taking such a large dose of folate?
Thanks, Kim
 

undcvr

Senior Member
Messages
822
Location
NYC
Yes i've had PEM before I started taking this dose. I usually ramp up my doses of everything for the winters here anyway, this time I just decided to take much more cos the 15mg dose of it was at least able to to keep the SAD away.
I started in Nov I would say. I nvr believed that methylation was the issue but at these higher doses it virtually eliminated all the chronic fatigue. I take mb12 at a half the amount of whatever mfolate I take and I take p5p too. So i really focus on B6,9,12 all in their active forms. I make sure I take the mfolate freely but I notice that it works out to 90-120mg for me. If you drink a cup of coffee you get about 100mg of methyl groups straight away from caffeine - a methylxanthine. No guarantee that it goes where it is supposed to.
 

Kimsie

Senior Member
Messages
397
Yes i've had PEM before I started taking this dose. I usually ramp up my doses of everything for the winters here anyway, this time I just decided to take much more cos the 15mg dose of it was at least able to to keep the SAD away.
I started in Nov I would say. I nvr believed that methylation was the issue but at these higher doses it virtually eliminated all the chronic fatigue. I take mb12 at a half the amount of whatever mfolate I take and I take p5p too. So i really focus on B6,9,12 all in their active forms. I make sure I take the mfolate freely but I notice that it works out to 90-120mg for me. If you drink a cup of coffee you get about 100mg of methyl groups straight away from caffeine - a methylxanthine. No guarantee that it goes where it is supposed to.
The reason I ask is because this could be helping in 3 ways 1. methylation, which I doubt. 2. purine synthesis to increase ATP and NAD pool, but without extra niacin or niacinamide, it probably isn't making so much difference in the NAD pool, and in our experience, you have to take the other ingredients for purine synthesis for it to keep working or you run low on either glutamine, glycine (probably not glycine if you are taking extra B6) or aspartate, or 3. You are using the folate pathway to produce ATP. There is a danger in using this pathway, but it takes time to do damage so if this is the case with you it might not have had time to change your symptoms, or you may not even get symptoms from it, OR you might not get new symptoms for years. This is all according to my hypothesis, of course, I don't have proof. Take a look at this, maybe you have already seen this because I have posted it before.
Folate cycle energy path.jpg

There are a couple of pathways in the folate cycle that can produce ATP. If you use the SHMT patheway it produces glycine, but might use up B6. This pathway produces 1 NADPH.

If you use this pathway for a while the glycine will be building up and you will start using the glycine decarboxylase pathway (which is only in the mitochondria), but that will increase ammonia, and getting rid of the ammonia takes several ATP. This pathway makes 1 NADPH, too.

If you use the little pathway shown in the enlarged box, you use up 1 NADPH for each ATP produced. You can use this pathway both in the mitochondial matrix and the cytosol, as far as I know. This will drain both the NADPH made by the Pentose Phosphate Pathway, and the NNT enzyme and the other enzymes in the matrix which produce NADPH.

Since NADPH is required to recycle glutathione, oxidative stress will increase, and this will gradually increase the amount of damage to the electron transport chain enzymes, leading to increased dependence on the folate pathway for energy.

Eventually you may start experiencing symptoms that relate to low NADPH, specifically symptoms caused by nonfunctioning catalase, because catalase depends on NADPH to stay in a functional form.

This is especially relevant to you because you experience SAD. NADPH is needed for recycling BH4, and BH4 is needed for synthesis of serotonin and dopamine and the other catecholamines. The folate pathway is one of the main ways that BH4 is recycled, as you can see in the illustration, so taking a lot of it helps. BUT after a while the amount of NADPH being drained through the folate pathway of ATP production becomes high enough to interfere with the dopamine beta-hydroxlyase enzyme which changes dopamine to norepinephrine, and in some people low noripinephrine causes depression, at least I think that is the case with my son D.

After a bout with the Epstien Barr Virus, my son D had extreme fatigue (all the time and without PEM) for well over a year before we started giving him high dose methylfolate. The large dose of folate made his fatigue go away in a few hours, but after 4-6 weeks on high folate he started having symptoms of depression which eventually became very severe. I have spent the last two years working on figuring out why this happened and what I have written above is my conclusion about how it happened.

If you can tolerate it, you might be able to take the NAD recipe to avoid needing so much folate. I am in the process of trying to figure out if this solution also increases damage to the ETC or not.

At this time I think the low norepinephrine is one of the factors that leads to the damage in diseases like Alzheimer's, which probably takes years before symptoms are noticed, so if I am correct, and I don't have proof that I am.
 

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adreno

PR activist
Messages
4,841
Since NADPH is required to recycle glutathione, oxidative stress will increase, and this will gradually increase the amount of damage to the electron transport chain enzymes, leading to increased dependence on the folate pathway for energy.
That doesn't sound good, I hope I haven't done any long term damage with folate. But it does feel kind of addictive, once you're on it. I see a lot of posts where people are literally craving folate.
 

Kimsie

Senior Member
Messages
397
That doesn't sound good, I hope I haven't done any long term damage with folate. But it does feel kind of addictive, once you're on it. I see a lot of posts where people are literally craving folate.
What changes does the folate make for you? How long did it take for it to make those changes? I don't think that the problem is unsolvable. I think the tendency towards neurodegenerative illnesses from this is genetic, so some people might not get that kind of damage, anyway. Do you know of any people with CFS who later got Alzheimer's or MS?

How sensitive to glutamine are you, does it give you detox?
 

undcvr

Senior Member
Messages
822
Location
NYC
That doesn't sound good, I hope I haven't done any long term damage with folate. But it does feel kind of addictive, once you're on it. I see a lot of posts where people are literally craving folate.

Not quite sure I agree with high dose mfolate doing long term damage. In fact I see it as rescuing many pathways that would othewise have trouble proceeding. The way it is helping is nothing like anything else I have tried and at the end of the day methylation is crucial.
 

adreno

PR activist
Messages
4,841
What changes does the folate make for you? How long did it take for it to make those changes? I don't think that the problem is unsolvable. I think the tendency towards neurodegenerative illnesses from this is genetic, so some people might not get that kind of damage, anyway. Do you know of any people with CFS who later got Alzheimer's or MS?

How sensitive to glutamine are you, does it give you detox?
It can't really say exactly. It's all a big mess of symptoms that sometimes improve with folate, sometimes don't. It's impossible for me to get the ratios right. I constantly have to decrease one B vitamin and increase another to keep symptoms under control.

I can't take glutamine. I get anxiety, severe headache, insomnia etc. Feels like high gluatamate, or perhaps ammonia, I don't know. Just a gram causes this.
 
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Kimsie

Senior Member
Messages
397
Not quite sure I agree with high dose mfolate doing long term damage. In fact I see it as rescuing many pathways that would othewise have trouble proceeding. The way it is helping is nothing like anything else I have tried and at the end of the day methylation is crucial.
I'm not sure that it does do long term neurological damage by itself, but it might contribute in people who have a genetic predisposition to those illnesses, but I think usually those people don't need extra folate and they don't experience any unusual fatigue. The main question is whether using the folate pathway as an ATP producing pathway can cause problems in other ways.
 

Kimsie

Senior Member
Messages
397
It can't really say exactly. It's all a big mess of symptoms that sometimes improve with folate, sometimes don't. It's impossible for me to get the ratios right. I constantly have to decrease one B vitamin and increase another to keep symptoms under control.

I can't take glutamate. I get anxiety, severe headache, insomnia etc. Feels like high gluatamate, or perhaps ammonia, I don't know. Just a gram causes this.
It doesn't seem to me that you are using the folate pathway much for ATP synthesis. If you did, I think the improvement would be more dramatic.

I know you take not taking more than 250 mg of niacinamide a day. Can you tell me how much ribose, glycine or serine, and aspartate in any form? Also, how does B6 affect you? How much magnesium do you take and how does it affect you? Have you ever had B6, B3 and mag tested and how did the test come out? Sorry about all the questions, if you don't feel like answering I understand.
 

Kimsie

Senior Member
Messages
397
I don't tolerate anything from your NAD recipe, except niacinamide. I get some glycine from Mg glycinate. I take about 550mg Mg daily (different forms).

You must understand that I haven't had a single day feeling normal in the last 7 years. It feels as though the whole system is out of whack. Temperature changes, paresthesia, tachycardia, headache, anxiety, brain fog, muscle twitching, sleep problems, pain, irritability, shortness of breath, orthostatic intolerance, exercise intolerance, depression, apathy etc.

These symptoms change from day to day, even hour to hour. Sometimes most of the systems improve, but it doesn't last more than a few days, then things get worse again.

Case in point, B6. Sometimes it helps with tachycardia, cold limps, tingling, anxiety, headache, insomnia. But after a while it might drain folate (symptoms I get is shortness of breath and tachycardia coldness, insomnia)...then I increase folate and feel better for a while...then I start to get borderline psychotic from the methyl groups...then I increase B3 and feel ok...then after I while B2 is drained, or B6, or B1...or perhaps folate again...sometimes I go through all of them one at a time until I find the one I need. I try to stay at the dose that worked, but after a few days it's out of whack again.

So I can get some of the same symptoms with different kinds of deficiencies. Example: tachycardia. Sometimes it B6 that helps. Sometimes folate. Sometimes it's B3. Aso.

There are a few tell tale symptoms that are sure...borderline psychotic -> need B3. Shortness of breath -> need folate. But many symptoms I am not sure where the problem is.

The only test I have was an organic acids test I had years ago.
I am curious about what you mean by borderline psychotic. Do you have hallucinations? My son can't tell when he is delusional, but he knows when he hears voices.

Is there anything that helps you that doesn't seem to cause other problems?

Does B12 ever bother you? Vitamin C or other antioxidants? I am sure you have mentioned this, but how much PEM do you have and what is your window of activity? Do you have gut dysbiosis? Did your symptoms start with EBV?
 

adreno

PR activist
Messages
4,841
Not delusional, it's more like mania and loss of control (high DA and NE, I guess).

B12 doesn't seem to bother me, nor vit C or antioxidants in general. Some of them can make me more fatigued and irritable (mostly phenols). PEM is a problem, but the worst for me is OI. I just can't stand up for very long. And I get quickly fatigued doing something physical.

Probably have gut dysbiosis, yes. EBV, I had it, but it don't think it's what started it. It's way to complex to explain my whole back story, and it wouldn't make sense to you anyway.
 
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Kimsie

Senior Member
Messages
397
Not delusional, it's more like mania and loss of control over myself (high DA and NE, I guess).

B12 doesn't seem to bother me, nor vit C or antioxidants in general. Some of them can make me more fatigued and irritable (mostly phenols). PEM is a problem, but the worst for me is OI. I just can't stand up for very long. And I get quickly fatigued doing something physical.

Probably have gut dysbiosis, yes. EBV, I had it, but it don't think it's what started it. It's way to complex to explain my whole back story, and it wouldn't make sense to you anyway.
I was just curious about the EBV because a lot of people here seem to have had their problems start that way.

What you are describing with the mania isn't psychosis; psychosis is having hallucinations and/or delusions, but a lot of people don't realize that. My guess would be that your norepinephrine is low and that contributes to depression and apathy. It sounds to me like you don't have enough NAD+ to get rid of epinephrine, and the epinephrine causes the mania feelings. I think maybe you have a seriously low NAD+ pool.

Since you don't tolerate the NAD recipe maybe there is a way to get around it by taking insosine which can be recycled back to IMP and bypass the part of the purine synthesis pathway that uses aspartate, glutamine and glycine, if your purine salvage pathway is working and if you have D-ribose. If you use small doses, such as about 50 mg insosine at a time by opening the capsule, along with 50 mg of the niacinamide, and 100 mg of D-ribose 1 time a day, and work up to 5 times a day if you are feeling comfortable with it and you might be able to tolerate them better together and at such small doses. I wouldn't expect 1 dose a day to make a noticeable difference in your symptoms, though. How small of a dose of D-ribose have you tried? Do you think that you could tolerate 100mg?
 

adreno

PR activist
Messages
4,841
Thanks, I will consider your ideas.

I could probably tolerate more than 50mg ribose. I haven't tried under 2g, and that was sometimes ok, sometimes not. So I think 500mg would be okay.

It's not realistic for me to do 5x dosing, but I could probably manage 3x daily. Would you recommend splitting all the B vitamins this way? It's a hassle when taking the B vitamins separately, and having to split so many caps.

Here's what I usually take, mostly in the morning :

100mg thiamine
100mg riboflavin
250mg Niacinamide
300mg Pantethine
50mg p5p
3000mcg biotin
1000mcg folate
1000mcg mb12
 
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undcvr

Senior Member
Messages
822
Location
NYC
@adreno omg no not glutamate not even healthy pple can tolerate glutamate in small amounts, its not even therapeutic in anyway. If you are going to try B3 and ribose I suggest you skip all that and take NADH from Enada and from Enada only. It's may help as it skips over all the pathways inbetween to get to NADH which works directly.

Up your mfolate :)
 

Kimsie

Senior Member
Messages
397
Thanks, I will consider your ideas.

I could probably tolerate more than 50mg ribose. I haven't tried under 2g, and that was sometimes ok, sometimes not. So I think 500mg would be okay.

It's not realistic for me to do 5x dosing, but I could probably manage 3x daily. Would you recommend splitting all the B vitamins this way? It's a hassle when taking the B vitamins separately, and having to split so many caps.

Here's what I usually take, mostly in the morning :

100mg thiamine
100mg riboflavin
250mg Niacinamide
300mg Pantethine
50mg p5p
3000mcg biotin
1000mcg folate
1000mcg mb12
I don't think you need to slit any of the B vitamins except the niacinamide. Maybe you could take one capsule and split it into 3 capsules. This is to keep the levels more stable through the day.

Then try adding ribose 500 mg 3 times a day (which will keep it under 2000mg a day) with the niacinamide and see how you tolerate that. Then add a very small dose of glutamine, small enough so you can tolerate it. After whatever number of days you feel comfortable with add in, I know you are going to feel hesitant about it, aspartic acid at a very small dose. We have found that when you take the other things aspartic acid becomes a limiting factor. I think that when you have the niacinamide and the ribose in place, then the body will be able to use the glutamine and aspartic acid for NAD synthesis. If you would like I can send you enough aspartic acid powder to test this, it's expensive to have to buy a lot and then find out it isn't going to work for you.

Once everything is in place, the doses could be raised little by little. Some people might need to take glycine, too. There isn't any way for me to know exactly which things an individual might be the lowest on.

If you don't like the idea, I understand. I am just trying to work out a practical way for people who are sensitive to gradually raise their NAD pool. If anyone else wants to try this I would be willing to send some aspartic acid to them, too, if they just PM their address to me.
 

Kimsie

Senior Member
Messages
397
@adreno omg no not glutamate not even healthy pple can tolerate glutamate in small amounts, its not even therapeutic in anyway. If you are going to try B3 and ribose I suggest you skip all that and take NADH from Enada and from Enada only. It's may help as it skips over all the pathways inbetween to get to NADH which works directly.

Up your mfolate :)
NAD and NADH don't cross the inner mitochondrial membrane. They could help increase the NAD pool in the mitochondria by adding ingredients to some degree by sparing those ingredients, but the synthesis and salvage pathways for NAD consume an ATP for each NAD produced - they don't change it to ADP or even AMP so in order to continue to increase the NAD pool you have to increase the de novo synthesis of ATP, and that is what all of the NAD recipe ingredients, except the niacinamide, are for.

I think that most people with CFS would greatly improve their symptoms if they were able to take such large doses of folate as undcvr takes, and it probably wouldn't hurt to do it for a while, but it is important to understand that if you do that you are most likely exchanging NADPH for ATP, and so you have to weigh the long term costs of having lower levels of NADPH in order to make a decision about whether and how much and how long you want to use the folate pathway in this manner.

If a person could somehow limit the extra folate to the cytosol, so that hopefully the PPP could produce enough NADPH so that they could produce energy and enough NADPH for other functions it probably wouldn't be a problem, but the folate will get into the mitochondria and use up NADPH there, too, and the mitochondria may not be able to produce enough extra NADPH to avoid increasing the oxidative stress inside the mitochondria and increasing the damage to the ETC. The matrix doesn't have the unlimited (technically, and only if the Pentose Phosphate Pathway (PPP) isn't inhibited at all) and cheap access to NADPH that the cytosol has because the PPP is in the cytosol.
 

Kimsie

Senior Member
Messages
397
Sorry, I meant glutamine :eek:
You can't make de novo ATP without changing two molecules of glutamine to glutamate, and making and even recycling NAD consumes 1 ATP, so you can't increase your NAD pool without either making more glutamate or depleting the ATP/ADP/AMT pool. Now that's an interesting thought, I hadn't thought of that before in connection with Sarah Myhill's idea that the ATP/ADP/AMT pool becomes depleted in CFS. I'll have to give that more thought.

There is some evidence that glutamate dehydrogenase is inhibited by sulfite (which I hypothesize is high in these illnesses due to inhibition of sulfite oxidase). This might be why some people with these illnesses have trouble with glutamate. I can't help wondering if the enzyme that changes glutamate to glutamine isn't inhibited also in some people. That reaction also takes ATP so that is another factor against it in people with low ATP.

Another possibility is that B6 is drained and the aminotransferases aren't working correctly.

What might help is making sure you have some of the amino acids that can help with the changing of glutamate to alpha-ketoglutarate through aminotransferases, such as oxaloacetate, and probably the best way of doing that is to take the branched chain amino acids which can enter the TCA cycle as succinyl-CoA.