Giving up on methylation.

[xinamatusx]

The last month of my life has been the worst in a long time. I know I did things incorrectly and that's on me, but I wish I never started methylation. I have wasted so much time and money and feel absolutely terrible.

Due to recurring histamine intolerance and anemia, I decided to try methylation. I did genetic testing and found MTHFR and MTRR mutations. I hadn't read anything yet on here about it and started to take 680 mcg of folate as well as 500 mcg of methylcobalamin. I took this successfully for about 2 months. Obviously, knowing what I know now this has likely induced a donut hole deficiency or paradoxical folate deficiency.

I started to get shallow breathing every time I took folate or b12. It progressed to sleep apnea. I had to stop all supplements. However, the shortness of breath would randomly occur out of nowhere, now accompanied by a racing heart, tightness in my chest, extreme weakness like paralysis, and tingling. These episodes got worse over the next two months. I went to the ER twice. A third time yesterday. The second time, they told me my potassium was low. They gave me some supplements and I did feel better for the next two days only. The episodes resumed. Potassium does help with the shortness of breath most of the time. However, there have been episodes where it doesn't help me at all and I have to sit and breath through all the symptoms. It's absolutely terrifying. The third time I went to the hospital they said I had a low fever and slightly elevated RBC and hematocrit. Yet, couldn't determine the cause.

In the past week, new symptoms have occurred such as feeling very inflamed throughout my body. A constant dull headache. My calves feel swollen (but look normal). My arms feel heavy. I have severe palpitations. Horrible horrible spells of weakness and feeling like I will pass out. I just want all of this to stop but I do not want to touch b12 or folate again in order to get out of this hole because then I'd have to continue to take them and I'm not in a place mentally to continue methylation and handle the roadblocks along the way. Maybe I can try again in a few years the right way but right now I just want all of this to stop. I know there is nothing else going on health wise because I had cancer in the past and am monitored very closely by doctors throughout the year. I do not have heart issues or anything of the sort.

I wish I could go back in time before all of this. If anyone has suggestions as far as this folate deficiency I've induced in myself, please please advise. I need my quality of life back even though it wasn't that great before anyway it was definitely better than this.

 

[Eastman]

Have you considered a thiamine/vitamin B1 deficiency? Many of your symptoms fit those for that condition. See here for more info.

If you look around the forum, you would be able to find reports from several members who found that supplementing with thiamine helped with problems that arose after methylation treatment. See, for examples, here and here.

Also, there have been cases where thiamine supplementation helped resolve problems with electrolyte imbalance, including low potassium. See here.

 

[xinamatusx]

Have you considered a thiamine/vitamin B1 deficiency? Many of your symptoms fit those for that condition. See here for more info.

If you look around the forum, you would be able to find reports from several members who found that supplementing with thiamine helped with problems that arose after methylation treatment. See, for examples, here and here.

Also, there have been cases where thiamine supplementation helped resolve problems with electrolyte imbalance, including low potassium. See here.

That is very interesting and you may be on to something. I see that thiamine deficiency can be caused by hyperthyroidism which I have (intentionally for thyroid cancer). I also have a few swollen lymph nodes in my throat (benign) which is listed as a symptom. I’m definitely going to look into this further. Thank you so much.

 

[nerd]

In my opinion - I know other members will disagree with this - the significance of B12 for the CFS/ME overmethylation is overrated. I think B12 deficiency is a predisposing factor but not the causality for the methylation issues. I would try SAMe or betaine (TMG, not Betaine HCL which is for stomach acid). Betaine recycles homocysteine without B12 and folic acid and is also a methyl group donor itself, so it compensates for the overdemand of methylation.

B12 doesn't only play a part in the methylation cycle. This can cause adverse effects in the other metabolisms, potentially overactivating the dopaminergic pathway. Moreover, B12 can supposedly cause potassium efflux, though I still don't know the mechanism for this phenomenon. Unfortunately, many B supplements overdose B12 to excessive amounts, originally intended for people who can't resorb B12.

I wish I could go back in time before all of this. If anyone has suggestions as far as this folate deficiency I've induced in myself, please please advise. I need my quality of life back even though it wasn't that great before anyway it was definitely better than this.

Regarding folate deficiency, do you mean active folate or inactive one (folic acid)? They usually test only one of the two, which means that you might not have a folate deficiency but a severe folate cycle dysbalance. This can be caused by BH4 deficiency (or biopterins in general), or by oversupply or undersupply of B12. Assuming you have a folate cycle blockage, any B12 supplementation in the world couldn't fix your methylation blockage. Have you been tested for intracellular B12 (from whole blood) or homocysteine levels?

Nevertheless, methylation doesn't define CFS/ME as a disease. CFS/ME has many other pathologies to it. Taking B12 will not solve CFS/ME. If B12 supplementation completely fixes someone's CFS/ME symptoms, they actually had a B12 deficiency, which is a diagnosis on its own.

 

[xinamatusx]

In my opinion - I know other members will disagree with this - the significance of B12 for the CFS/ME overmethylation is overrated. I think B12 deficiency is a predisposing factor but not the causality for the methylation issues. I would try SAMe or betaine (TMG, not Betaine HCL which is for stomach acid). Betaine recycles homocysteine without B12 and folic acid and is also a methyl group donor itself, so it compensates for the overdemand of methylation.

B12 doesn't only play a part in the methylation cycle. This can cause adverse effects in the other metabolisms, potentially overactivating the dopaminergic pathway. Moreover, B12 can supposedly cause potassium efflux, though I still don't know the mechanism for this phenomenon. Unfortunately, many B supplements overdose B12 to excessive amounts, originally intended for people who can't resorb B12.



Regarding folate deficiency, do you mean active folate or inactive one (folic acid)? They usually test only one of the two, which means that you might not have a folate deficiency but a severe folate cycle dysbalance. This can be caused by BH4 deficiency (or biopterins in general), or by oversupply or undersupply of B12. Assuming you have a folate cycle blockage, any B12 supplementation in the world couldn't fix your methylation blockage. Have you been tested for intracellular B12 (from whole blood) or homocysteine levels?

Nevertheless, methylation doesn't define CFS/ME as a disease. CFS/ME has many other pathologies to it. Taking B12 will not solve CFS/ME. If B12 supplementation completely fixes someone's CFS/ME symptoms, they actually had a B12 deficiency, which is a diagnosis on its own.

By folate deficiency I was referring to the paradoxical folate deficiency/donut hole insufficiency that I am assuming I got myself into due to the low doses I was taking.

 

[Judee]

I think it's Dr Axe on Yt that talks about niacin and glycine to clear extra methyl groups. He compares them and favors the glycine. Dr Ben Lynch also talks about niacin when someone is overmethylated.

Not sure if that would help you out of the "donut hole" you find yourself in. I don't understand a lot of that methylation stuff and when I use L-Methylfolate and b12 too often, I don't really feel great.

I would try SAMe or betaine (TMG,

Not sure why but SAMe and especially TMG don't work well for me. The TMG actually makes me very aggressive. I have found that DMG calms me though. Not sure why.

EDIT: oops - it was Dr Chris Masterjohn that talked about the niacin and glycine; not Dr Axe. Sorry about that. Hope I didn't send someone on a wild goose chase.

 

[Oberon]

By folate deficiency I was referring to the paradoxical folate deficiency/donut hole insufficiency that I am assuming I got myself into due to the low doses I was taking.

Having myself gone through an extremely rough time due to trialing methylation by reading too much in to some of the information available on the internet I can tell you with confidence that it will get better if you do nothing and give it time. It may suck for a few weeks to even months but it will get better.

Be careful with the advice you're seeing in regards to methylation online. Please remember that these are all theories by people on a web forum and they aren't scientifically validated. This includes paradoxical folate deficiency/donut hole insufficiency which in my case and others caused much more harm than good going down that rabbit hole.

Have you considered a thiamine/vitamin B1 deficiency? Many of your symptoms fit those for that condition. See here for more info.

If you look around the forum, you would be able to find reports from several members who found that supplementing with thiamine helped with problems that arose after methylation treatment. See, for examples, here and here.

Also, there have been cases where thiamine supplementation helped resolve problems with electrolyte imbalance, including low potassium. See here.

If you really want to try anything I would go down the path @Eastman suggested, i.e. it's more logical to me that you created a nutritional imbalance like Thiamine or Potassium, then that you've entered, "paradoxical folate deficiency/donut hole insufficiency". In my case I can tell you thiamine did end up helping but it doesn't necessarily mean it will work for you. For many others potassium helped but made me substantially worse.

Good luck and it will get better!

 

[Judee]

Went to see if Dr Masterjohn had anything on DMG and why it calms me and found this video of his:

 

[gbells]

Due to recurring histamine intolerance and anemia, I decided to try methylation. I did genetic testing and found MTHFR and MTRR mutations. I hadn't read anything yet on here about it and started to take 680 mcg of folate as well as 500 mcg of methylcobalamin. I took this successfully for about 2 months. Obviously, knowing what I know now this has likely induced a donut hole deficiency or paradoxical folate deficiency.

If you have MTHFR mutation you can only supplement with active B12 and active folic acid. Anything else won't work. MTR in addition to the MTHFR doesn't change the treatment.

The Methylation Myths: MTR & MTRR - MTHFRSupport Australia

 

[xinamatusx]

Having myself gone through an extremely rough time due to trialing methylation by reading too much in to some of the information available on the internet I can tell you with confidence that it will get better if you do nothing and give it time. It may suck for a few weeks to even months but it will get better.

Be careful with the advice you're seeing in regards to methylation online. Please remember that these are all theories by people on a web forum and they aren't scientifically validated. This includes paradoxical folate deficiency/donut hole insufficiency which in my case and others caused much more harm than good going down that rabbit hole.



If you really want to try anything I would go down the path @Eastman suggested, i.e. it's more logical to me that you created a nutritional imbalance like Thiamine or Potassium, then that you've entered, "paradoxical folate deficiency/donut hole insufficiency". In my case I can tell you thiamine did end up helping but it doesn't necessarily mean it will work for you. For many others potassium helped but made me substantially worse.

Good luck and it will get better!

Thank you ❤ I appreciate the kind words.

 

[nerd]

The TMG actually makes me very aggressive. I have found that DMG calms me though.

Did you take large doses of B12 at the same time or none at all?

Aggressiveness is often attributed to neurotransmitter activation and dysregulation, for which COMT plays a role, but also methylation in general. For example, certain MAO and COMT genotypes predispose for aggressive behavior. As I described in this post, the system is complex and there are different ways COMT overactivation can happen. Other than that, thiamine deficiency could also contribute to this phenomenon since glutamate and GABA regulate dopaminergic VTA activation.

If it happens within a day or so after taking TMG, I suspect a SAH buildup. In this case, Niacin and other NAD+ precursors might help to a certain extent, but NAD+ buffer and balance is the most difficult thing to regulate because it also involves sirtuin activation. Moreover, the B12 dosage should be lowered when taking TMG so that there isn't an overcompetition for homocysteine.

TMG can not compensate for B12 deficiency. It's only a redundant methionine recycling system to prevent homocysteine buildup, which also causes a SAH buildup and a methylation blockage.

Lastly, there is also the possibility of a low methylation buffer. This can happen when you take large doses of B6 and would reflect in high cysteine levels. Methionine and SAMe can help with that, but only if the NAD+ buffer is in an equilibrium with the methylation buffer. Otherwise, you'd only be increasing the potential of the methylation dysbalance once methylation is triggered by excitation.

 

[seamyb]

Did you take large doses of B12 at the same time or none at all?

Aggressiveness is often attributed to neurotransmitter activation and dysregulation, for which COMT plays a role, but also methylation in general. For example, certain MAO and COMT genotypes predispose for aggressive behavior. As I described in this post, the system is complex and there are different ways COMT overactivation can happen. Other than that, thiamine deficiency could also contribute to this phenomenon since glutamate and GABA regulate dopaminergic VTA activation.

If it happens within a day or so after taking TMG, I suspect a SAH buildup. In this case, Niacin and other NAD+ precursors might help to a certain extent, but NAD+ buffer and balance is the most difficult thing to regulate because it also involves sirtuin activation. Moreover, the B12 dosage should be lowered when taking TMG so that there isn't an overcompetition for homocysteine.

TMG can not compensate for B12 deficiency. It's only a redundant methionine recycling system to prevent homocysteine buildup, which also causes a SAH buildup and a methylation blockage.

Lastly, there is also the possibility of a low methylation buffer. This can happen when you take large doses of B6 and would reflect in high cysteine levels. Methionine and SAMe can help with that, but only if the NAD+ buffer is in an equilibrium with the methylation buffer. Otherwise, you'd only be increasing the potential of the methylation dysbalance once methylation is triggered by excitation.

What do you mean by methylation buffer?

 

[nerd]

What do you mean by methylation buffer?

The total amount of metabolites in the methylation cycle. A small buffer means increased dysregulation sensitivity to methylation triggers. A large buffer means decreased dysregulation sensitivity but NAD+-dependant.

 

[Judee]

I don't think I was taking it with other things.

For example, certain MAO and COMT genotypes predispose for aggressive behavior.

I think that might include me. I have some polymorphisms in these areas.

Any idea why DMG might be calming? I was thinking of starting it again soon. It is also suppose to help with oxygenation.

Also have you seen this video where Dr Masterjohn talks about glycine helping to balance methylation?

 

[nerd]

Any idea why DMG might be calming?

I presume you just experience the effects of sarcosine on brain receptors.

Also have you seen this video where Dr Masterjohn talks about glycine helping to balance methylation?

Credits: 10.1038/hr.2011.133

His focus seems to be "what do to with excessive methyl groups". This is relevant for athletes, but this isn't exactly the problem with CFS/ME. Of course, glycine can get rid of methyl groups because glycine needs to be methylated to become sarcosine. And the serine-glycine-sarcosine cycle can indirectly buffer methyl groups in the folate cycle. The folate cycle is coupled with the methylation cycle in a B12-dependant manner. But this mechanism is very indirect. DMG comes from the choline pathway which is also methionine-dependant. Hence, an increased methylation buffer will eventually increase the glycine buffer. For what it's worth, the folate cycle is also a methyl group buffer. But there is a difference between methyl group buffering and methylation buffering. One is direct and the other is indirect to methylation availability.

Besides, for the breakdown of SAH, there is still the Niacin/NAD dependency in the methylation cycle regardless of glycine levels (not shown in the figure above). This is why Niacin is important for methylation. It's not supposed to buffer methyl groups in the first place.

I wonder why he presumes that methylation can only be fixed by Niacin or Glycine. Why not fix it in the methylation cycle itself? And I also don't understand his differentiation of Niacin and Glycine. He assumes that Niacin methylation is the only mechanism of Niacin. In that case, you could as well eat something histamine rich and have the same effect. It ends up in the urine all the same. Sure, glycine has a buffering purpose. But Niacin does as well via the NAD cycles. I think he overlooked this aspect. Biochemically, there is no difference between glycine methylation and niacin methylation. The difference comes from the intake. If you take high doses of Niacin, it's the high concentration that grants it methylation priority. The same could be applied to glycine, although glycine has some additional interaction in the folate cycle which might reduce the methylation activity more quickly.

Either way, I would rather take lecithin or betaine for folate-mediated methylation recycling because you'd still be DMG-dependant even with increased glycine buffering. Moreover, glycine metabolites alter brain receptor excitability. I wouldn't mess with brain receptors unless there is reason to believe that it compensates for pathological alterations. I don't know of any evidence of altered GlyR activation in CFS/ME patients.

 

[xinamatusx]

I presume you just experience the effects of sarcosine on brain receptors.

Credits: 10.1038/hr.2011.133

His focus seems to be "what do to with excessive methyl groups". This is relevant for athletes, but this isn't exactly the problem with CFS/ME. Of course, glycine can get rid of methyl groups because glycine needs to be methylated to become sarcosine. And the serine-glycine-sarcosine cycle can indirectly buffer methyl groups in the folate cycle. The folate cycle is coupled with the methylation cycle in a B12-dependant manner. But this mechanism is very indirect. DMG comes from the choline pathway which is also methionine-dependant. Hence, an increased methylation buffer will eventually increase the glycine buffer. For what it's worth, the folate cycle is also a methyl group buffer. But there is a difference between methyl group buffering and methylation buffering. One is direct and the other is indirect to methylation availability.

Besides, for the breakdown of SAH, there is still the Niacin/NAD dependency in the methylation cycle regardless of glycine levels (not shown in the figure above). This is why Niacin is important for methylation. It's not supposed to buffer methyl groups in the first place.

I wonder why he presumes that methylation can only be fixed by Niacin or Glycine. Why not fix it in the methylation cycle itself? And I also don't understand his differentiation of Niacin and Glycine. He assumes that Niacin methylation is the only mechanism of Niacin. In that case, you could as well eat something histamine rich and have the same effect. It ends up in the urine all the same. Sure, glycine has a buffering purpose. But Niacin does as well via the NAD cycles. I think he overlooked this aspect. Biochemically, there is no difference between glycine methylation and niacin methylation. The difference comes from the intake. If you take high doses of Niacin, it's the high concentration that grants it methylation priority. The same could be applied to glycine, although glycine has some additional interaction in the folate cycle which might reduce the methylation activity more quickly.

Either way, I would rather take lecithin or betaine for folate-mediated methylation recycling because you'd still be DMG-dependant even with increased glycine buffering. Moreover, glycine metabolites alter brain receptor excitability. I wouldn't mess with brain receptors unless there is reason to believe that it compensates for pathological alterations. I don't know of any evidence of altered GlyR activation in CFS/ME patients.

@nerd I originally started methylation by trying to follow Chris Masterjohn’s protocol. That is why I was only taking the smallest amount available of folate. However, I couldn’t tolerate any of the other things he suggested such as choline, glycine, or tmg. They all made me feel bad and gave me a headache.

 

[nerd]

@nerd I originally started methylation by trying to follow Chris Masterjohn’s protocol. That is why I was only taking the smallest amount available of folate. However, I couldn’t tolerate any of the other things he suggested such as choline, glycine, or tmg. They all made me feel bad and gave me a headache.

Then I suspect that there is a secondary deficiency involved. Thiamin has already been mentioned. But it could also be biopterin cycle deficiency/dysbalance, or NAD+ deficiency/dysbalance. There are laboratory tests for all of these things, though not every insurance and health plan covers it inexplicably.

I noticed in my other post that you mention whether to take B12. Yes, B12 is still necessary in combination with folate. Normally, B12 is even more important than folate, but it depends on your test results if you have any.

Regarding NAD+, do you take Q10 already?

 

[seamyb]

This is why Niacin is important for methylation. It's not supposed to buffer methyl groups in the first place.

So would you recommend supplementing niacin alongside such things as B12 and folate? I know your theory is somewhat different to the B12/folate model, but I've had good success so far with this. Is niacinamide the same in your opinion?

 

[xinamatusx]

Then I suspect that there is a secondary deficiency involved. Thiamin has already been mentioned. But it could also be biopterin cycle deficiency/dysbalance, or NAD+ deficiency/dysbalance. There are laboratory tests for all of these things, though not every insurance and health plan covers it inexplicably.

I noticed in my other post that you mention whether to take B12. Yes, B12 is still necessary in combination with folate. Normally, B12 is even more important than folate, but it depends on your test results if you have any.

Regarding NAD+, do you take Q10 already?

@nerd Would you mind telling me which lab tests you are referring to? Also, I don’t know anything about biopterin cycle or NAD+. Where would be a good starting point for me to learn about them?

I am waiting for my thiamine blood test result to come back this week. Because of how bad I am feeling, I am nervous to take anything knew without testing first.

No, I do not take Q10. The only things I was taking were methylfolate (680 mcg), methyl b12 (500 mcg), fish oil, creatine, iron, vitamin D, and vitamin A.

 

[nerd]

So would you recommend supplementing niacin alongside such things as B12 and folate? I know your theory is somewhat different to the B12/folate model, but I've had good success so far with this. Is niacinamide the same in your opinion?

I take Niacin only in low doses because of severe adverse effects at a certain threshold. In the context of the IDO trap, I would recommend taking low doses of Niacin, Niacinamide, Nicotinamide riboside, or any other Niacin metabolite that helps to support the NAD+ buffer. But most importantly, and I often don't remember to mention this because I assume it's common knowledge, I take Coenzyme Q10.

Would you mind telling me which lab tests you are referring to? Also, I don’t know anything about biopterin cycle or NAD+. Where would be a good starting point for me to learn about them?

There exist mRNA tests that can screen the whole range of metabolites at once. But not many laboratories offer this. I'm from Germany, so maybe someone else knows where to test this in the US. For instance, I found this US laboratory that offers something similar, though not complete. Just make sure that homocysteine is also tested if it isn't included. I think this is the most important marker. If you also have methionine, cysteine, SAH, or SAMe levels, this allows for better profiling of the methylation status.

This website explains the extended methylation cycle in simple terms. Regarding NAD, I'd refer to this Wikipedia article.

No, I do not take Q10. The only things I was taking were methylfolate (680 mcg), methyl b12 (500 mcg), fish oil, creatine, iron, vitamin D, and vitamin A.

Is there any particular reason why you take creatine? For Q10, there is a blood test available as well.