Glutathione causing anxiety/irritability

godlovesatrier

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I'd be sure you're taking glutathione too.

I started the new glutathione product which did not contain any choline and I didn't get any side effects.

I take it for 3 days after a 3 week break and it knocks me out, I sleep really well. Then on the 3rd day it will start to stimulate me and keeps me awake for a few hours. Haven't noticed any anxiety really. So it could be the type of Glutathione.
 

Shanti1

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Does anyone have a hypothesis of why glutathione / NAC causes many of us generalized anxiety, insomnia, etc?
It just seems like the amounts I take have such a disproportionately great effect, it really baffles me.
I have been pondering this myself because I am also extremely sensitive to NAC and glutathione. Here are the theories that are out there:
  • Sulfite sensitivity: The sulfur compounds in NAC and glutathione get metabolized into sulfites. Those who have trouble metabolizing sulfites (possibly due to SNPs in sulfite oxidase (SUOX)), or due to a molybdenum deficiency, may be sensitive to NAC/Glutathione. https://education.seekinghealth.com/dgp-episode-9-n-acetyl-cysteine-nac/#problem
  • Detox reaction: This is often cited as the reason for glutathione/NAC reaction. I have always wondered about this one because glutathione is involved in phase II detox, so it seems it would take more toxic compounds and change them into less toxic compounds, thereby helping us to feel better. There is the idea that it helps to mobilize toxins, but I haven't ever seen evidence of this, which doesn't mean it isn't possible. There is also the concept that, in the case of mercury, glutathione loosely binds to it and could redistribute it to areas like the nervous system if someone has a high mercury burden.
  • Biofilms: NAC may break up biofilms, which could result in an immune reaction to microbes
I don't feel like my personal reaction is accounted for by the above and I suspect there are other mechanisms. Would love to know if anyone has any other theories.
 

Pyrrhus

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I don't feel like my personal reaction is accounted for by the above and I suspect there are other mechanisms. Would love to know if anyone has any other theories.
Yeah, I also don't feel like any of those theories adequately account for the hellish start-up symptoms I had the first 8-12 weeks that I took NAC.

I'm curious about other theories, too. The only other theory I know of is the one that posits that restoration of intracellular glutathione allows the cell to begin utilizing B12 again:
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")





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

Shanti1

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@Pyrrhus So the idea is that the sudden increase in movement of B12 to it's methyl and adenosyl forms could lead to surges in other pathways that previously had low activity, including methylation, leading to temporary anxiety?
 

Pyrrhus

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@Pyrrhus So the idea is that the sudden increase in movement of B12 to it's methyl and adenosyl forms could lead to surges in other pathways that previously had low activity, including methylation, leading to temporary anxiety?
Yes, exactly, although I might phrase the theory slightly differently:

"The sudden increase in utilization of B12 by cells that previously were depleted in glutathione could lead to surges in other pathways that previously had low activity, including methylation, leading to temporary anxiety."
 

Shanti1

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@Pyrrhus So even if someone was taking high doses of B12 (in any form), they could still have a "functional" vitamin B12 deficiency. Most people don't check MMA, but I would think MMA would be elevated in these cases since CbID is needed to prepare B12 to move into the mito and MMA is metabolized by adenocylcobalamin in the mito. Also, mutations in the MMACHC gene that codes for CbID can lead to high MMA (https://www.ncbi.nlm.nih.gov/books/NBK1328/). Am I thinking about this correctly?

I did recently have an MMA and it was on the low side, so I'm trying to rule this out as the cause for my glutathione sensitivity.
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I am also interested in this because of labs/cases I have collected over time where people have very high serum B12 and high MMA. All the people in these cases were taking high dose Methylcobalamin and it was resolved with adenosylcobalamin. This is odd in itself because the ME/OH/AD/CN is removed in the cytosol and then reconstituted in the mito. I plan on making a separate post at some point.
 

Pyrrhus

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So even if someone was taking high doses of B12 (in any form), they could still have a "functional" vitamin B12 deficiency.
Yes, and with regard to intracellular oxidative stress (which implies low glutathione), here's one paper:

Supraphysiological vitamin B12 serum concentrations without supplementation: the pitfalls of interpretation (Vollbracht et al., 2020)
https://academic.oup.com/qjmed/article/113/9/619/5524896
Excerpt:
Vollbracht et al 2020 said:
Elevated serum B12 levels may also be associated with a functional deficiency of the vitamin. Functional deficiency has been described despite high B12 concentrations and is due to a failure of cellular uptake or intracellular processing, trafficking or utilization.
[...]
Recent findings in diseases associated with oxidative stress have revealed that intracellular oxidative stress results in local functional B12 deficiency.8 Insufficient intracellular processing of B12 due to oxidative stress has been reported in diabetes mellitus or in Alzheimer’s disease,9,10 where it has been postulated to be a significant pathophysiological factor.9 Intracellular reduction of the central cobalt atom is essential for the formation of the metabolically active forms of B12. This process requires reduced glutathione and the hydroquinone form of flavin adenine dinucleotide (FADH2), it is therefore compromised by oxidative stress.9 In such conditions treatment with glutathione and/or vitamin C, a key physiological regenerator of intracellular glutathione, may provide therapeutic benefit. This warrants further investigation.

And to add another complication, people can have a B12 deficiency in one part of the body, and not in another. For example, there is the possibility of B12 deficiency in the brain, but with normal B12 levels in the blood:

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia (Zhang et al., 2016)
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0146797&type=printable
Excerpt:
Zhang et al 2016 said:
Here we report novel findings suggesting that levels of vitamin B12, especially its MeCbl form, decrease with age in frontal cortex of control human subjects. Since serum Cbl levels do not show a similar decrease with age, our results further suggest that vitamin B12 status in the brain compartment is distinctly regulated from the rest of the body and dynamic changes in brain MeCbl across the lifespan may play an important functional role in methylation-dependent processes, including epigenetic regulation of gene expression.

I would think MMA would be elevated in these cases since CbID is needed to prepare B12 to move into the mito and MMA is metabolized by adenocylcobalamin in the mito. Also, mutations in the MMACHC gene that codes for CbID can lead to high MMA (https://www.ncbi.nlm.nih.gov/books/NBK1328/). Am I thinking about this correctly?
Yes, that sounds correct, although you might not see an elevated MMA because:
  1. You may be looking in the blood instead of in the brain.
  2. Only a small part of the body may be experiencing a functional B12 deficiency, which would not be sufficient to alter MMA levels noticeably.


I am also interested in this because of labs/cases I have collected over time where people have very high serum B12 and high MMA. All the people in these cases were taking high dose Methylcobalamin and it was resolved with adenosylcobalamin. This is odd in itself because the ME/OH/AD/CN is removed in the cytosol and then reconstituted in the mito.
Yes, it sounds a bit odd. Perhaps the high doses overwhelmed the ability of the cell to remove the adenosyl group and some adenosylcobalamin found its way into the mitochondrion intact? Perhaps the adenosylcobalamin replenished depleted adenosine in the mitochondria? ...It's always hard to speculate about what happens in the case of supraphysiological doses. And, of course, the science on intracellular B12 processing is still incomplete.
 

Shanti1

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Thank you for taking the time and for the additional info.

And to add another complication, people can have a B12 deficiency in one part of the body, and not in another. For example, there is the possibility of B12 deficiency in the brain, but with normal B12 levels in the blood:
Yes, that sounds correct, although you might not see an elevated MMA because:
  1. You may be looking in the blood instead of in the brain.
  2. Only a small part of the body may be experiencing a functional B12 deficiency, which would not be sufficient to alter MMA levels noticeably.
Yeah, it actually makes more sense to me that this would happen in a select area of the body instead of body-wide, which would mean it wouldn't show on MMA.

Yes, it sounds a bit odd. Perhaps the high doses overwhelmed the ability of the cell to remove the adenosyl group and some adenosylcobalamin found its way into the mitochondrion intact? Perhaps the adenosylcobalamin replenished depleted adenosine in the mitochondria? ...It's always hard to speculate about what happens in the case of supraphysiological doses. And, of course, the science on intracellular B12 processing is still incomplete.
I'm thinking the high doses of methylcobalamin perhaps overwhelmed the absorption of adenosylcobalamin into the cell leading to an intracellular deficiency in adenosyl groups, or it is some unknown mechanism. My data is sparse, but where I have it, the homocysteine and MCV were normal, indicating the methylcobalamin is still getting into the cell, but adenosylcobalamin is not forming in the mitochondria. I should clarify, MMA normalized once people either switched to adenosyl or added adenosylcobalamin to the methylcobalamin in a 1:1 ratio. I didn't actually talk to these individuals (they were cases shared with me), but one had documented neuropathy on high dose methylcobalamin which resolved with adenosyl, along with the high MMA.

Interestingly, here is a case of this reported on the forum: https://forums.phoenixrising.me/threads/two-forms-of-b12-at-once-no-absorption.82147/ and another likely similar situation: https://forums.phoenixrising.me/thr...if-sensitive-to-b12.80981/page-2#post-2370742

I also had an odd experience where I had a hemifacial spasm for 6months and was taking 1mg methylcobalamin per day. Then one day, I purchased a supplement with a mix of methyl and adenosyl and took around 60mg. The spasm disapeared and never came back (but I still use a combo B12), which is what spured my interest in this topic.
 
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Thanks for the detailed and thoughtful hypotheses!
@Pyrrhus
I did recently have an MMA and it was on the low side, so I'm trying to rule this out as the cause for my glutathione sensitivity.
What was your MMA concentration? Mine was 0.08 nmol/mL, which is within Mayo's single upper limit (<=0.40). Serum B12 normal (430 pg/mL).

AFAIK, methylmalonic acid is clinically tested only to rule out high levels, which implies lack of available B12 cofactor for MMA metabolism. But your speculation about low levels is interesting.

A completely different possible explanation I've wondered about is glutamate excitoxicity:

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6377501/
The glutathione cycle shapes synaptic glutamate activity
[...] Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate and could influence synaptic excitability. We find that drugs that inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory postsynaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter.
This article makes it seem like glutathione helps regulate the availability of glutamate, rather than just always upregulating it. In this case, it seems very odd that glutathione would cause us weeks of start-up symptoms, since it should accelerate glutamate homeostasis rather than aggravate it.

Another article I found, particularly interesting to me as I've had histologically diagnosed gastritis (idiopathic, H-pylori negative) since I was a teenager:
https://www.nature.com/articles/srep20169
Oral glutathione supplementation drastically reduces Helicobacter-induced gastric pathologies
Helicobacter (H.) suis causes gastric pathologies in both pigs and humans. Very little is known on the metabolism of this bacterium and its impact on the host. In this study, we have revealed the importance of the glutamate-generating metabolism, as shown by a complete depletion of glutamine (Gln) in the medium during H. suis culture. Besides Gln, H. suis can also convert glutathione (GSH) to glutamate and both reactions are catalyzed by the H. suis γ-glutamyltranspeptidase (GGT). Both for H. pylori and H. suis, it has been hypothesized that the degradation of Gln and GSH may lead to a deficiency for the host, possibly initiating or promoting several pathologies. Therefore the in vivo effect of oral supplementation with Gln and GSH was assessed. Oral supplementation with Gln was shown to temper H. suis induced gastritis and epithelial (hyper)proliferation in Mongolian gerbils. Astonishingly, supplementation of the feed with GSH, another GGT substrate, resulted in inflammation and epithelial proliferation levels returning to baseline levels of uninfected controls. This indicates that Gln and GSH supplementation may help reducing tissue damage caused by Helicobacter infection in both humans and pigs, highlighting their potential as a supportive therapy during and after Helicobacter eradication therapy.
This made me wonder whether a latent gastric infection might be converting glutathione into glutamate and disturbing homeostasis. But I'm not sure how likely this is compared to other explanations.

Yeah, I also don't feel like any of those theories adequately account for the hellish start-up symptoms I had the first 8-12 weeks that I took NAC.
Did you have any trick, other than the Ativan, for getting to sleep during these weeks? The insomnia I get from NAC/glutathione supplementation is the worst part.

Also, could you list the main specific improvements you achieved after this startup period?

Thanks :)
 

Pyrrhus

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This article makes it seem like glutathione helps regulate the availability of glutamate, rather than just always upregulating it. In this case, it seems very odd that glutathione would cause us weeks of start-up symptoms, since it should accelerate glutamate homeostasis rather than aggravate it.
:monocle: Hmm- another potential theory?

Did you have any trick, other than the Ativan, for getting to sleep during these weeks? The insomnia I get from NAC/glutathione supplementation is the worst part.
Nope, none of my regular sleeping pills worked at all. Just the Ativan.

Also, could you list the main specific improvements you achieved after this startup period?
Mostly improvements in cognition, as well as more strength in the legs.
 

Shanti1

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@bob800
What was your MMA concentration? Mine was 0.08 nmol/mL, which is within Mayo's single upper limit (<=0.40). Serum B12 normal (430 pg/mL).
I should have been more clear. I was thinking that my low/normal MMA would rule out the proposed mechanism in myself that low glutathione was leading to an intracellular issue with B12 utilization and that glutathione was causing a sudden activation of the utilization of B12, leading to temporary anxiety. But when Pyrrhus pointed out that the B12 utilization issue due to low glutathione probably happens only in small areas of the body, I realized that low MMA doesn't rule it out as a mechanism. To my knowledge, there is no pathology associated with low MMA. I had urinary MMA done, it was within range, but at the low end.

A completely different possible explanation I've wondered about is glutamate excitoxicity:
This article makes it seem like glutathione helps regulate the availability of glutamate, rather than just always upregulating it. In this case, it seems very odd that glutathione would cause us weeks of start-up symptoms, since it should accelerate glutamate homeostasis rather than aggravate it.
I went down this rabbit hole too and concluded the same. While it seems a possibility, most literature I looked at indicated that glutathione either ameliorates glutamate toxicity or actually decreases glutamate activity at the NMDA receptor. However, the relationship of glutamate, glutathione, and NMDA receptors seems complex, so still could be something there.
 
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The recent discoveries re: vasoregulative GCPR adrenergic autoantibodies in long covid and CFS got me wondering if there is a connection here. Especially because I seem to get the high heart rate and pseudo shortness-of-breath that is constantly discussed on long covid forums, but only after taking strong antioxidant supplements.

Found an interesting article that might tie this together:

Cysteine redox state regulates human β2-adrenergic receptor binding and function
[...] We have previously shown that β2AR agonism generates intracellular ROS, an effect that is required for receptor function, and which post-translationally oxidizes β2AR cysteine thiols to Cys-S-sulfenic acids (Cys-S-OH). [...] The aim of this study was to examine the vitality of β2AR-ROS interplay and the resultant functional consequences of β2AR Cys-redox in the receptors native, oxidized, and redox-deficient states [...] On the contrary, redox-deficient β2AR states exhibit decreased ability to signal via either Gαs or β-arrestin. Together, our results demonstrate a β2AR-ROS redox axis, which if disturbed, interferes with proper receptor function.

The specifics of this are beyond me, but I will do some more reading.
 
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Can chronic NAC supplementation bring some negative effects? I’m taking 600 mg a day and it was the only supplement that helped significantly with nerve/muscle burning/fatiguability. I’m don’t want to stop taking it but I wonder is there any downsides from taking it for more than several months?
Also I’m curious wouldn’t it be more beneficial to take NAC with glycine?
 

Pyrrhus

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is there any downsides from taking it for more than several months?
Since cysteine is a natural part of the human diet, and a typical diet can easily contain 1000mg of cysteine per day, it's hard to see how it could hurt. Personally, I have taken 1000mg NAC per day for a couple years.

wouldn’t it be more beneficial to take NAC with glycine?
It might be worth a try. But cysteine is usually the rate-limiting ingredient in the body's synthesis of glutathione, so the additional glycine might not help. And there might be significant start-up symptoms with glycine. But some people do take glycine to boost glutathione.

Hope this helps.
 
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@Pyrrhus Did you ever experience ever a sense of mental "grogginess" during your NAC start-up symptoms?

I finally was able to work my way up to 250mg glutathione a day without insomnia or anxiety, but now I get this grogginess instead, which sleep has absolutely no effect on.

For what it's worth, I get the same grogginess the days after taking valacyclovir, ranitidine, or cimetidine. The association is highly repeatable and always fades away if I stop taking these.

It's unfortunate because each of these drugs makes me feel much better for ~24 hours, before the grogginess sets in.
 

Pyrrhus

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I finally was able to work my way up to 250mg glutathione a day without insomnia or anxiety, but now I get this grogginess instead, which sleep has absolutely no effect on.

For what it's worth, I get the same grogginess the days after taking valacyclovir, ranitidine, or cimetidine. The association is highly repeatable and always fades away if I stop taking these.

It's unfortunate because each of these drugs makes me feel much better for ~24 hours, before the grogginess sets in.
Well, that's certainly very interesting. I really don't know what to make of that. :monocle:

Personally, after I got over the start-up effects from NAC, I did not notice any further side effects from NAC...