The plausibility of NAC inducing b12 deficiency or 'methyl-trap'

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Hello everyone.
I am writing because I am particularly interested in the evidence for NAC inducing b12/b9 deficiency. I have thus far given the forums a cursory perusal and I have gathered that the event of b12 deficiency is plausibly linked to previous NAC supplementation. I had b12 deficiency earlier last year but have since corrected it with adequate daily sublingual supplementation. However, I recently ingested NAC over the course of two days (roughly 1,600mg) and slowly began to develop profound symptoms. What is most striking about my reaction is that it was not an immediate effect but occurred about six hours after the last ingested dose on the second day. This seems to coincide quite well with @Freddd analysis.

The symptoms I experienced were the same symptoms I had presented with when I developed b12 deficiency last year, the most prominent being:
anxiety, depression, depersonalization, irritability, paresthesia, burning nerve pain in legs, visual snow, after images, central scotoma, no appetite, and muscle weakness (among other things).
I am quite confident that these symptoms are not indicative of some coincidental psychiatric episode, especially reading some others' reaction to NAC.

Anyway, I am curious if you all any information regarding the mechanism for NAC inducing b12 deficiency. I have seen some literature that indicates the potential formation of glutathione-cobalamin binding, but this seems to be protective rather than detrimental. Also, there is clinical evidence that while NAC is a powerful glutathione precursor, it does not seem to directly affect the THF cycle (https://www.researchgate.net/figure...or-biosynthesis-of-Glutathione_fig1_321662012), since NAC is a cysteine which presumably skips over, as it were, the THF cycle and is only a few steps removed from glutathione synthesis. To the point, then, although there seem to be ample anecdotal reports regarding negative effects of NAC in b12 deficiency, I am failing to find an actual mechanism that demonstrates that NAC causes b12 deficiency or the so-called 'methyl-trap'.

I do apologize for the lengthy post. I am very much looking forward to any insight anyone might be able to provide; I am hoping to continue to correct the symptoms I am presently exhibiting with @Freddd protocol.
 

Pyrrhus

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Anyway, I am curious if you all any information regarding the mechanism for NAC inducing b12 deficiency. I have seen some literature that indicates the potential formation of glutathione-cobalamin binding, but this seems to be protective rather than detrimental.
Glutathione can attach to B12 when B12 enters the cell and it may even be necessary for B12 to be optimally utilized inside the cell.[1] This glutathionyl-cobalamin may be converted to methyl-cobalamin (or adenosyl-cobalamin) during the actual enzymatic use of B12.[2][3] (I'm skipping a lot of details.)

A problem with people who have low glutathione is that blood tests can theoretically show normal, or even excessive B12 levels despite the presence of symptoms of B12 deficiency. This is because the B12 in the blood might not be fully utilized by the cells lacking glutathione. There is also the possibility of B12 deficiency in the brain, but with normal B12 levels in the blood.[4] (This has been mostly talked about in autism, but may apply equally to ME patients.)

Long story short: It is perfectly natural for an ME patient to have dramatic, sometimes intolerable, start-up effects when starting NAC. Rest assured that these are start-up effects, not permanent side effects. As with many supplements that turn out to be helpful, you can "start low and go slow". For me personally, I could only tolerate a single 500mg dose of NAC the first week I took it. The second week I took a single 500mg dose on Monday and another one on Friday. The third week I took a single 500mg dose on Monday, Wednesday, and Friday. After 2-3 months, I was able to take 500mg every day without any effects whatsoever.

Hope this helps.

EDIT: clarifications and references

REFERENCES:
[1] https://www.ncbi.nlm.nih.gov/pubmed/2357215
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/pdf/42-49.pdf
[3] https://ghr.nlm.nih.gov/gene/MMACHC
[4] https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0146797&type=printable
 
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Pyrrhus, thank you very much indeed for kindly replying.

To be sure, are you suggesting that the introduction of NAC can affect that aforementioned conversion inside the cell and thereby produce b12 deficiency or the so-called methyl-trap? Or should the phenomenon be construed purely as a side effect of NAC (unrelated to b12 deficiency or methyl-trap)?

Thanks again for sharing.
 

Pyrrhus

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Are you suggesting that the introduction of NAC can affect that aforementioned conversion inside the cell and thereby produce b12 deficiency or the so-called methyl-trap? Or should the phenomenon be construed purely as a side effect of NAC (unrelated to b12 deficiency or methyl-trap)?
Yes, the introduction of NAC can restore glutathione in a glutathione-depleted cell, thereby allowing the proper utilization of B12 within that cell. But this would not produce B12 deficiency or a "methylfolate trap" in that cell. If anything, it would reverse that cell's B12 deficiency and remove that cell's "methylfolate trap". So the symptoms you are seeing might be more of a "B12 restoration" than a "B12 deficiency".

It would be difficult, if not impossible, to say with any certainty what exactly causes the start-up effects that are associated with NAC. But the most obvious explanation is that the NAC allows cells that are low in glutathione, and possibly deficient in B12, to suddenly start utilizing the B12 from the blood and to break out of its "methylfolate trap".

Note that by the term "methylfolate trap" I am referring to the reduced methylation found in B12 deficiency. (see https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05913.x ) I am NOT referring to the Yasko/Konynenburg/Freddd methylation traps, which are entirely separate, but related, hypotheses. Most posts on Phoenix Rising that mention "methylation trap" are referring to one of the Yasko/Konynenburg/Freddd hypotheses, not to the basic "methylfolate trap" found in B12 deficiency.

Of course, there are other perfectly plausible explanations for the start-up effects of NAC, but they all relate to the restoration of glutathione activity in glutathione-depleted cells.

Hope this helps. Apologies if I haven't been clear enough.

EDIT: clarifications and reference
 
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According to the Methionine Cycle chart I received from Dr. Ben Lynch any excess cystine/cysteine from food or NAC would suppress the CBS pathway and therefore push more homocysteine to the MTR pathway that feeds into the Folate Cycle (THF). This could also work the BHMT pathway a bit more I would surmise. So any possible deficiency of b9/b12 via NAC would in all actuality be due to b9/b12 being utilized by the MTR pathway. This could theoretically show lower serum b9/b12 values because the cells are utilizing them more. Hope this helps!!
 

Pyrrhus

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So any possible deficiency of b9/b12 via NAC would in all actuality be due to b9/b12 being utilized by the MTR pathway. This could theoretically show lower serum b9/b12 values because the cells are utilizing them more.
That could well be the correct explanation!
 
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Yes, the introduction of NAC can restore glutathione in a glutathione-depleted cell, thereby allowing the proper utilization of B12 within that cell. But this would not produce B12 deficiency or a "methylfolate trap" in that cell. If anything, it would reverse that cell's B12 deficiency and remove that cell's "methylfolate trap". So the symptoms you are seeing might be more of a "B12 restoration" than a "B12 deficiency".

It would be difficult, if not impossible, to say with any certainty what exactly causes the start-up effects that are associated with NAC. But the most obvious explanation is that the NAC allows cells that are low in glutathione, and possibly deficient in B12, to suddenly start utilizing the B12 from the blood and to break out of its "methylfolate trap".

Note that by the term "methylfolate trap" I am referring to the reduced methylation found in B12 deficiency. (see https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05913.x ) I am NOT referring to the Yasko/Konynenburg/Freddd methylation trap, which is an entirely separate, but related, hypothesis. Most posts on Phoenix Rising that mention "methylation trap" are referring to the Yasko/Konynenburg/Freddd hypothesis, not to the basic "methylfolate trap" found in B12 deficiency.

Of course, there are other perfectly plausible explanations for the start-up effects of NAC, but they all relate to the restoration of glutathione activity in glutathione-depleted cells.

Hope this helps. Apologies if I haven't been clear enough.

EDIT: clarifications and reference
Do you (or anyone else 🙂) have any recommendations on using liposomal glutathione vs NAC? My assumption is that glutathione would be able to correct this more immediately / efficiently, but I'm curious if NAC provides some mode of action I'm unaware of?
 

Pyrrhus

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Do you (or anyone else 🙂) have any recommendations on using liposomal glutathione vs NAC? My assumption is that glutathione would be able to correct this more immediately / efficiently, but I'm curious if NAC provides some mode of action I'm unaware of?
I haven't seen much research on oral liposomal glutathione. All the research I have seen has been using NAC.

With that said, here is one pilot study that found that oral liposomal glutathione increases glutathione in the blood:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389332/

It's certainly possible that taking liposomal glutathione is absorbed by the intestines intact, unlike regular glutathione, which is broken down during digestion.

Even if the glutathione is broken down in the intestines, it can sometimes be reformed inside cells, since oral glutathione would contain all three amino acids needed to make glutathione, whereas NAC only provides one. (which is usually the most important one)

But bear in mind that glutathione is primarily an intracellular antioxidant, not an extracellular one. Glutathione is created inside cells and any glutathione that escapes the cells is often broken down in the linings of blood vessels.

So whereas liposomal glutathione may increase both intracellular and extracellular glutathione levels, NAC would primarily boost intracellular glutathione, where it's needed most.
 
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I haven't seen much research on oral liposomal glutathione. All the research I have seen has been using NAC.

With that said, here is one pilot study that found that oral liposomal glutathione increases glutathione in the blood:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389332/

It's certainly possible that taking liposomal glutathione is absorbed by the intestines intact, unlike regular glutathione, which is broken down during digestion.

Even if the glutathione is broken down in the intestines, it can sometimes be reformed inside cells, since oral glutathione would contain all three amino acids needed to make glutathione, whereas NAC only provides one. (which is usually the most important one)

But bear in mind that glutathione is primarily an intracellular antioxidant, not an extracellular one. Glutathione is created inside cells and any glutathione that escapes the cells is often broken down in the linings of blood vessels.

So whereas liposomal glutathione may increase both intracellular and extracellular glutathione levels, NAC would primarily boost intracellular glutathione, where it's needed most.
Thanks for the response Pyrrhus.

When it comes to feeling start up symptoms (especially a sharp rise in potassium and vit c needs, but also increased energy) I do find that NAC causes that, l-gluathione is a bit more pronounced, and liposomal glutathione is an order of magnitude more so.

My experiences align with what you've written on the board about glutathione though. I had previously tried to avoid due to Freddd's suggestions, but it really does seem to be a rate limiting step for me when omitted. I'll continue to try and observe any differences between the two.
 

Pyrrhus

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When it comes to feeling start up symptoms (especially a sharp rise in potassium and vit c needs, but also increased energy) I do find that NAC causes that, l-gluathione is a bit more pronounced, and liposomal glutathione is an order of magnitude more so.
That's very interesting!

I had previously tried to avoid due to Freddd's suggestions
Remember that Freddd may have had an unusual genetic situation that most ME patients don't have:

Freddd himself is not able to tolerate anything that helps to form glutathione, which NAC does. I think this is unusual with respect to ME/CFS, because the depletion of glutathione is what brings on this disorder, in my hypothesis.

I think that the problem in Freddd's case is that he has inherited what is referred to in the published literature as a rare mutation in the CblC complemetation group. This is part of the intracellular B12 processing pathway. Normally, glutathiione helps CblC to process B12. However, in Freddd's case, apparently when glutathione combines with B12 to form glutathionylcobalamin, his cells are not able to access the B12, and this makes his B12 status worse instead of better. Freddd does not believe that this is rare, and I think he has found some others that respond in this same way. I haven't run across other cases like this in the ones I have studied.
 

Pyrrhus

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Glutathione can attach to B12 when B12 enters the cell and it appears to be necessary for B12 to be optimally utilized inside the cell.[1] This glutathionyl-cobalamin appears to be converted to methyl-cobalamin (or adenosyl-cobalamin) during the actual enzymatic use of B12.[2][3] (I'm skipping a lot of details.)
I found a really good paper that explains some of the details of how glutathione is essential for a cell's utilization of B12.[1] It may be a bit hard to read, but there is a more readable paper in reference [2].

In addition to glutathione protecting B12 from degradation inside the cell, it also strips the "methyl-" and the "adenosyl-" from methyl-cobalamin or adenosyl-cobalamin when methyl-cobalamin or adenosyl-cobalamin first enters the cell. (The cell later adds back the "methyl-" or "adenosyl-" if or when it is needed.)

Therefore, if there is insufficient glutathione available inside the cell, methyl-cobalamin or adenosyl-cobalamin might get stuck in the CblC complex (AKA MMACHC), unable to bind the CblD (AKA MMADHC) needed to transport it to the enzymes that use B12.

Here is a diagram from the paper:
("methyl-" or "adenosyl-" is represented by "R-" and B12 is referred to as "cobalamin" or "Cbl")

331D8087-D250-4766-866C-91B27D038D05.jpeg

299712C1-4446-4C87-A97B-6A4352BF090A.jpeg



References:
[1] https://pubmed.ncbi.nlm.nih.gov/23539619/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/
 
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Sophiedw

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Hey, you should be asking @Freddd for sure! He's the most likely to have answer regarding this matter. The original question was what is the mechanism of glutathione induced b12 deficiency? And my furthrr question is what is the genetic defect that makes it a process only in certain individuals?

And @Pyrrhus, I think it depends on your genetics. When I induced this b12 deficiency by taking NAC (one of the things that made me really unwell) I wouldn't have got rid of my brain fog and other symptoms if I hadn't replenished all my b12 and folate.

Take care
 
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Hello guys,

I have suffered from a mild verison of CFS for 4,5 years now. My conition might be due to a chronic Coxsakie infection. I tried a number of antivirals, some of them helping me whereas others didn't.

Now I started taking glutathione, and I think it helped me since I felt good and could exercise moderately. I want to take vitamin b12 and q10 additionally, but I haven't started yet. After 7 days of glutathion I am feeling "sore lungs", Yesterday, I had a caugh, I don't have a fever, but it could be a cold. I don't have a sore throat, which is normally always one of the symptoms when I catch a cold or the flu.

Do you think the sore feeling in lungs could be the result of the intake of glutathione? I also take sodium selenite and finished a three-month-course of Arbidol recently. I take 6 pills of oxymatrine as well, which I tolerate well. I have a hyperresponsive bronchial system, which was the result of a bronchitis in Februar 2018. Every now and then I take a cortisone spray (intermittently), and I haven't had problems for a longe time. I don't feel sick, but my lungs don't feel okay. I don't think it's Covid19 since my girlfriend got tested negatively just the other day (we live in one household).

So what do you think? I am convinced that the glutathione helped me, but I haven't taken vitamin b12 so far. Could that be the reasons?

Best wishes and all the very best to you :)
 

Pyrrhus

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After 7 days of glutathion I am feeling "sore lungs", Yesterday, I had a caugh, I don't have a fever, but it could be a cold.
I also take sodium selenite and finished a three-month-course of Arbidol recently.
I am convinced that the glutathione helped me, but I haven't taken vitamin b12 so far. Could that be the reasons?
I also had a light cough for a few days with N-acetyl Cysteine (NAC), but that went away quickly. Interestingly, some doctors prescribe inhaled NAC as a treatment for bronchitis, since it loosens up the mucus in the lungs. So maybe the glutathione is treating your lingering bronchitis from 2018?

Or it could have nothing to do with the glutathione, and is due to something else, like the Arbidol or the oxymatrine. How did your experiment with Arbidol go?
 

Pyrrhus

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So any possible deficiency of b9/b12 via NAC would in all actuality be due to b9/b12 being utilized. This could theoretically show lower serum b9/b12 values because the cells are utilizing them more. Hope this helps!!
This is probably why some people believe that "glutathione induces B12 deficiency" when it, in fact, increases utilization of B12.

And my furthrr question is what is the genetic defect that makes it a process only in certain individuals?
The genetic defect that @richvank described is called "methylmalonic aciduria and homocystinuria, CblC type". It does not result in B12 deficiency, it just means that the cell has problems converting B12 from one form to another.

NAC does chelate zinc and other essential minerals out
https://pubmed.ncbi.nlm.nih.gov/1529808/
As mentioned in the paper you cite:
"NAC exerts no detectable influence on the metabolism of essential trace metals when used in the above context (i.e. at doses near 600 mg per day)."

NAC is converted into cysteine in the intestines. Cysteine is just an amino acid found in protein. As long as you are using reasonable doses of cysteine, such as the doses normally found in dietary protein, you shouldn't have to worry about cysteine chelating essential minerals. The U.S. recommended combined daily allowance of Methionine+Cysteine is 1140mg, which would correspond to an absolute maximum daily NAC dosage of 1541mg per day.

However, if you use excessive doses of cysteine, or if you inject NAC instead of taking it by mouth, then you might develop a problem of mineral chelation.
 
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@Pyrrhus the Arbidol intake went quite well, no side effect. I think it help me to some extent, but I can't tell for sure. My lungs still feel a bit rough, and I don't know where it comes from. I don't think I am sick.... it's weird. I guess I will start taking Q10 and a vitamin b complex. Maybe that helps...

My symptoms are rahter intermitten and less constant....
 
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Could the effects I am sensing at the moment also be due to a detoxification process?
Is it generally okay to take a vitamin b complex and Q10 together with glutathione?
 

Pyrrhus

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Could the effects I am sensing at the moment also be due to a detoxification process?
Glutathione is indeed very important for the liver's detoxification pathways. It's also important to strong immunity in the lungs. But again, it's really hard to tell if your effects are related to either one of those.

Is it generally okay to take a vitamin b complex and Q10 together with glutathione?
I can't see any fundamental problems with that- they may well complement each other.
Of course, it's always wise to start at a low dosage, and then increase the dosage slowly.

I hope this helps.
 
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Hello @Pyrrhus,

Thank you for your insights, which I really appreciate :)

Today, I got a bit of a headache, but that's life.. I am curious about what will happen in the next few days or weeks. Something is happening in my body after I started glutathione.

As for vitamin b and Q1, I just take one pill each per day (according to the recommended dosage).

Best wishes :)