Overmethylation Or Undermethylation & B-vitamins

[Orangeyouglad]

What is the difference and how can one tell if they are over-methylating or under-methylating?

The reason I ask is that B vitamins seem to be tricky for me - sometimes after taking them I have trouble breathing, almost like I need to take a deep breath or the feeling of "can't catch a breath". Someone suggested I might have a methylation issue.

Thoughts on how once could tell and signs and symptoms of either?

 

[Joyjoy]

I’m also interested in replies to this, as I’ve been experiencing the same thing.

 

[redsun]

What is the difference and how can one tell if they are over-methylating or under-methylating?

The reason I ask is that B vitamins seem to be tricky for me - sometimes after taking them I have trouble breathing, almost like I need to take a deep breath or the feeling of "can't catch a breath". Someone suggested I might have a methylation issue.

Thoughts on how once could tell and signs and symptoms of either?

There is symptoms of each you can look up on google. Some would think its bogus which isnt entirely wrong, its not that clear cut. B vitamins will increase methylation, even more so if you were to take an active B vitamin complex or if you take extremely high doses. Ive taken active Bs before and I get higher adrenaline and higher energy (which is best described as nervous energy and antsy and adrenaline-fueled obviously) and it can be problematic for mental disorders by exacerbating anxiety or even creating it. Methylation will increase SAM-e which is used to convert NA to adrenaline. Especially if you are already an "overmethylator" you can have these issues. Increasing methylation will obviously help an "undermethylator" and make them feel better.

Overmethylators usually mean high adrenaline and noradrenaline (because of copper excess), low histamine. So things that increase methylation will raise adrenaline more and lower histamine (by methylating it, deactivating it).

The low histamine state is considered to be mostly about excess copper breaking down histamine more than normal. I dont recall the exact details but I know histamine is involved in breathing and the lungs. But if you take B complex(especially if active) in generous amounts for long periods of time you can end with a similar higher adrenal hormones/low histamine state because histamine will be more quickly deactivated by methylation because you'll have more SAM-e. Stopping Bs will reduce methylation and the issue should go away with time.

In this context, extra B vitamins, which you can easily pop daily because they are cheap and very available can have unintended consequences of lowering histamine/raising adrenaline via increased methylation. As I already said, some may need this and find benefit from it if they are histadelic (high histamine). This is why methionine supplementation is used for reducing histamine, by increasing SAM-e which can then methylate histamine.

If Bs are giving you these problems you probably dont need them they are just increasing methylation too much, your histamine is borderline low or low already and Bs are killing it even more.

 

[SOMO]

Thiamine/B1 in high doses has helped me curb my ravenous appetite.

I wish Ray Peat would discuss the interactions between the various B-Vitamins and also whether "overdosing on B-Vitamins" is possible due to their supposed water-solubility.

 

[Mito]

DON’T Use Histamine Levels to Assess Methylation Status | Chris Masterjohn, PhD

 

[magnesiumania]

Its a confusing concept as you can overmethylate, say dopamine and undermethylate something else at the same time. However red light help the methyltransferase enzymes work properly. Aslo remember folate us a photoreceptor. Stay away from too much fake light.

 

[FitnessMike]

There is symptoms of each you can look up on google. Some would think its bogus which isnt entirely wrong, its not that clear cut. B vitamins will increase methylation, even more so if you were to take an active B vitamin complex or if you take extremely high doses. Ive taken active Bs before and I get higher adrenaline and higher energy (which is best described as nervous energy and antsy and adrenaline-fueled obviously) and it can be problematic for mental disorders by exacerbating anxiety or even creating it. Methylation will increase SAM-e which is used to convert NA to adrenaline. Especially if you are already an "overmethylator" you can have these issues. Increasing methylation will obviously help an "undermethylator" and make them feel better.

Overmethylators usually mean high adrenaline and noradrenaline (because of copper excess), low histamine. So things that increase methylation will raise adrenaline more and lower histamine (by methylating it, deactivating it).

The low histamine state is considered to be mostly about excess copper breaking down histamine more than normal. I dont recall the exact details but I know histamine is involved in breathing and the lungs. But if you take B complex(especially if active) in generous amounts for long periods of time you can end with a similar higher adrenal hormones/low histamine state because histamine will be more quickly deactivated by methylation because you'll have more SAM-e. Stopping Bs will reduce methylation and the issue should go away with time.

In this context, extra B vitamins, which you can easily pop daily because they are cheap and very available can have unintended consequences of lowering histamine/raising adrenaline via increased methylation. As I already said, some may need this and find benefit from it if they are histadelic (high histamine). This is why methionine supplementation is used for reducing histamine, by increasing SAM-e which can then methylate histamine.

If Bs are giving you these problems you probably dont need them they are just increasing methylation too much, your histamine is borderline low or low already and Bs are killing it even more.

could insomnia from 500mg b3 be a sign of methylation? for instance due to noradrenaline? i don't feel like i have a stress response, especially when going to bed but maybe noradrenaline is up as a result of the high b3 dose?

 

[yerrag]

Energy deficiency affects methylation, by CMJ:

How Energy Deficiency Hurts Methylation

I'm increasingly seeing this pattern in my consulting practice.

open.substack.com

In my consulting practice, I’ve been increasingly seeing patterns on the Genova Methylation Panel that suggest energy deficiency as the primary methylation problem rather than any problem with the standard methylation nutrients.

I don’t have a large enough sample to say for sure whether this phenomenon is actually increasing or whether I’m seeing this as a result of selection bias or random variation over time.

However, it’s a pattern very much worth noting.

The energy-deficient pattern I am seeing is an accumulation of methionine and S-adenosylhomocysteine (SAH), with low or low-normal levels of S-adenosylmethionine (SAM) and homocysteine.

The basic energy currency of the cell is ATP. Under typical conditions, 90% of ATP is complexed with magnesium, and the magnesium-ATP complex is what enzymes use for energy. So when we say “ATP” fuels something, we always mean magnesium-ATP.

ATP is adenosine triphosphate, and it consists of adenosine connected to three phosphates strung together. The energy it provides for cellular fuel is contained in the chemical bonds between the phosphates. Most enzymes will use the energy from one of those phosphate bonds, generating ADP. More rarely, some will use the energy from two, and generate adenosine monophosphate or AMP. Regardless, some AMP will be produced when energy is used because the enzyme adenylate kinase will move a phosphate from one molecule of ADP to another, generating ATP and AMP.

AMP can be further broken down to adenosine with the enzyme 5’-nucleotidase. Adenosine is ultimately broken down in multiple steps to uric acid.

The regeneration of ATP is usually tightly matched to its use for fuel. This occurs by taking energy from food and using it to join the third phosphate back to ADP. Most of this occurs in the mitochondria’s electron transport chain, while some of it occurs during the breakdown of glucose in glycolysis. Creatine can diffuse much more quickly through the cell than ATP or ADP, so it often acts as an intermediary in this process.

To methylate anything, the amino acid methionine must first be activated. The activated form is S-adenosylmethionine (SAM). The adenosyl refers to the addition of adenosine. Magnesium-ATP provides the energy for this as well as the adenosine.

Once SAM methylates something, it leaves behind S-adenosylhomocysteine (SAH). SAH must then be hydrolyzed (broken down with water) to free the adenosine. In that process, it becomes homocysteine. Homocysteine can then either be broken down or it can be recycled to methionine.

As I noted above, the energy-deficient pattern I am seeing is an accumulation of methionine and SAH, with low or low-normal levels of SAM and homocysteine.

This pattern represents deficient conversion of ADP to ATP because ATP is needed for the activation of methionine to SAM, and adenosine inhibits the hydrolysis of SAH to homocysteine.

One extremely important point about this pattern is you would never, ever see it from measuring homocysteine alone. Less SAH is produced because there is less SAM to methylate things, and what SAH is produced tends to be trapped as SAH rather than being hydrolyzed to homocysteine. Homocysteine will therefore be normal, or perhaps even low.

This is not the only place where ATP enters the methylation cycle. After a meal, when extra methyl groups are buffered by glycine, many of them are later harvested in the mitochondria during the fasting state, generating formate. ATP is needed to glue formate to folate as the first of four steps needed to turn formate into the methyl group of methylfolate, the last of which is catalyzed by the all-too-famous MTHFR.

So, energy deficiency is also likely to hurt the recycling of homocysteine by lowering methylfolate levels. However, you are not likely to see this elevate homocysteine. Since homocysteine production is much lower, a failure to recycle it to methionine is most likely just going to make it look normal instead of low.

Where you would see it is in the sarcosine and dimethylglycine levels on the Genova Methylation Panel. Since methylfolate is the off switch for the glycine buffer system in the fasting state and whenever methyl groups run low, deficient production of methylfolate will lead to the overactivation of the glycine buffer system. Glycine is methylated once to sarcosine and a second time to dimethylglycine. However, chronic overactivation of this system could ultimately lower glycine levels. If glycine runs low, which you would see on the panel, it could restrain the elevation in sarcosine and dimethylglycine and mask this phenomenon.

However, there are many other reasons you could have lowered methylfolate production, such as folate deficiency or a sluggish MTHFR.

Thus, the primary energy deficiency pattern — an accumulation of methionine and SAH, with low or low-normal levels of SAM and homocysteine — is the central way to infer that energy deficiency is the primary problem limiting methylation. If the energy deficiency pattern occurs alongside signs of low methylfolate, energy deficiency is likely a cause, or the cause, of the low methylfolate.

While seeing a high ratio of methionine to SAM without seeing an accumulation of SAH might suggest low ATP levels, it could also be explained by low magnesium levels. This is because the activation of methionine depends on magnesium but the hydrolysis of SAH does not. It may also be explained by genetics, although I do not believe the variations in the relevant enzyme (methionine adenosyl transferase, MAT) have been characterized well enough to use them for interpreting this.

When methionine and SAH accumulate together at the expense of SAM and homocysteine, this becomes a clearer picture suggesting deficient ATP production.

When probing the possible involvement of magnesium, it is essential to measure serum and red blood cell magnesium together. Measuring one without the other will lead to conclusions that are much more often false than true. If serum and red blood cell magnesium agree that you have too much or too little, then you most likely have too much or too little. But if serum is normal or high and red blood cell is low, this suggests magnesium is not being effectively transported into the cells, which requires insulin, salt, and… *drumroll* … since magnesium is retained in cells largely in a complex with ATP, ATP.

So if you see the energy deficiency pattern on the methylation panel and you also see that serum folate runs low but RBC folate does not, while RBC magnesium runs low and serum magnesium does not, you are not primarily dealing with a folate problem or a magnesium problem but rather you are dealing with an energy problem.

That is, you must now completely exit the world of methylation to begin understanding the methylation problem.

You must now enter the world of energy metabolism. This requires looking at thyroid, adrenal, and insulin function; at the collection of inborn errors of metabolism that are each rare on their own but are rather common in total, including many of those dismissed by conventional medicine as “benign” because they don’t cause seizures in infants, or of “carrier” status for the same reason; and the nutrients centrally involved in energy metabolism such as the rest of the B vitamins, iron, copper, and sulfur.

For this reason, Testing Nutritional Status: The Ultimate Cheat Sheet (free for Masterpass members here) redirects someone from the methylation section to the energy metabolism section once this pattern is observed.

In my recent article, High Protein? You Need More Biotin, I provided evidence suggesting suboptimal biotin status is actually widespread. If I am right, it might be a widespread cause of sluggish ATP levels. This would be an otherwise unexpected reason that something like biotin could play a central role in methylation. I am doing some metabolic experiments on myself that I believe will shed insight on this and I will publish them once completed, likely in late November.

The Bottom Line
If you just measure homocysteine, you will completely miss the energy deficiency pattern impacting methylation. This can be seen on a Genova Methylation Panel, where methionine and SAH accumulate at the expense of SAM and homocysteine. This could also lower methylfolate production and intracellular magnesium accumulation, which would be seen separately as low serum folate and low RBC magnesium, with normal or high levels of RBC folate and serum magnesium. The low methylfolate would be seen on the Genova Methylation Panel as elevated sarcosine and/or dimethylglycine, unless it had brought glycine levels low enough to mask this elevation. This energy deficiency pattern should take the focus away from the methylation pathway and on to the spectrum of disorders and nutrient deficiencies that impact the generation of ATP from ADP. That is, the focus should move from methylation to energy metabolism, because in this case energy metabolism is what is driving the methylation problem.

 

[redsun]

could insomnia from 500mg b3 be a sign of methylation? for instance due to noradrenaline? i don't feel like i have a stress response, especially when going to bed but maybe noradrenaline is up as a result of the high b3 dose?

Could be a sign of undermethylation but it could just be because of the effects of niacinamide in high doses. It will acutely inhibit methylation (deactivation) of histamine, norepinephrine, reduce serotonin conversion to melatonin, and this can contribute to insomnia. It will also deplete choline which can reduce parasympathetic activity, which also leads to trouble with sleep since the parasympathetic system helps us wind down and calm down the body and brain to fall asleep.

 

[FitnessMike]

Could be a sign of undermethylation but it could just be because of the effects of niacinamide in high doses. It will acutely inhibit methylation (deactivation) of histamine, norepinephrine, reduce serotonin conversion to melatonin, and this can contribute to insomnia. It will also deplete choline which can reduce parasympathetic activity, which also leads to trouble with sleep since the parasympathetic system helps us wind down and calm down the body and brain to fall asleep.

choline is not a problem as i eat 6 yolks a day, any idea how to counter this reduction in methylation? thats probably whats causing the sleeping problems.

 

[redsun]

choline is not a problem as i eat 6 yolks a day, any idea how to counter this reduction in methylation? thats probably whats causing the sleeping problems.

Its not just the reduction in methylation but also the neurotransmitter enhancing effects of niacinamide. It has been shown to reduce choline transport out of the nervous system leading to a build up in choline in your brain that would otherwise not happen, which will then strongly enhance acetylcholine synthesis. Increased acetylcholine will then stimulate glutamate activity.

Glutamate will then increase release of other excitatory neurotransmitters such as dopamine, histamine, serotonin that will keep you awake. So its not just the issue of reduced methylation of these neurotransmitters, but also enhanced neurotransmitter release. This is probably an even stronger effect because you consume so much choline from eggs.

Your body cannot shut down the arousal system because there is too much neurotransmitter activity that is overpowering GABA signals to get you to fall asleep. This same thing happens also from taking stimulants at night. The effects on neurotransmitters are different based on which stimulant you use but the result is the same. You can also have genetic predispositions that affect neurotransmitter metabolism making you have more activity of certain neurotransmitters than "normal". For example, having slow COMT means your already break down dopamine and norepinephrine slower than normal, niacinamide in high doses would make that even worse.

The solution would be to stick to low doses of niacinamide (50-100mg) a day.

 

[FitnessMike]

Its not just the reduction in methylation but also the neurotransmitter enhancing effects of niacinamide. It has been shown to reduce choline transport out of the nervous system leading to a build up in choline in your brain that would otherwise not happen, which will then strongly enhance acetylcholine synthesis. Increased acetylcholine will then stimulate glutamate activity.

Glutamate will then increase release of other excitatory neurotransmitters such as dopamine, histamine, serotonin that will keep you awake. So its not just the issue of reduced methylation of these neurotransmitters, but also enhanced neurotransmitter release. This is probably an even stronger effect because you consume so much choline from eggs.

Your body cannot shut down the arousal system because there is too much neurotransmitter activity that is overpowering GABA signals to get you to fall asleep. This same thing happens also from taking stimulants at night. The effects on neurotransmitters are different based on which stimulant you use but the result is the same. You can also have genetic predispositions that affect neurotransmitter metabolism making you have more activity of certain neurotransmitters than "normal". For example, having slow COMT means your already break down dopamine and norepinephrine slower than normal, niacinamide in high doses would make that even worse.

The solution would be to stick to low doses of niacinamide (50-100mg) a day.

Thanks for in depth response, much appreciated.

Oh well i wish i could make it work out for me at 500mg dose, my brain works so much better and pulse of course too. Ill try other ways to increase NAD+ suggested here like MB along with low doses of niacinamide.

 

[redsun]

Thanks for in depth response, much appreciated.

Oh well i wish i could make it work out for me at 500mg dose, my brain works so much better and pulse of course too. Ill try other ways to increase NAD+ suggested here like MB along with low doses of niacinamide.

You may get the same cognitive enhancing effects from niacinamide at low dose but without the side effect of insomnia if the major reason is actually methylation and COMT related.

 

[FitnessMike]

You may get the same cognitive enhancing effects from niacinamide at low dose but without the side effect of insomnia if the major reason is actually methylation and COMT related.

Sorry as it's not related to the methylation, but the question I would have would probably be whether there is a potential metabolic benefit coming from higher doses of niacinamide, beyond cognitive enhancement.

"Of the 32 molecules of ATP produced from one glucose, about 80% are from the various mechanisms that use NAD"

Getting such a positive response (amazing pulse, heat production) with 500mg-1g niacinamide, made me think whether there actually might be a deficiency in NAD or something related to the b3. It also made me think about whether there are sometimes needed "therapeutical" doses of certain nutrients, to give the body a kickstart so it can start functioning optimally again.

 

[FitnessMike]

Increased acetylcholine will then stimulate glutamate activity.

Glutamate will then increase release of other excitatory neurotransmitters such as dopamine, histamine, serotonin that will keep you awake. So its not just the issue of reduced methylation of these neurotransmitters, but also enhanced neurotransmitter release. This is probably an even stronger effect because you consume so much choline from eggs.

This bit about enhancing excitatory neurotransmitters makes sense and it literally feels like that would be the case, I wonder whether lifting weights speeds up to break down of these neurotransmitters because last weekend I took 500mg of niacinamide and this day went gym and had no problem falling asleep that night.

 

[redsun]

This bit about enhancing excitatory neurotransmitters makes sense and it literally feels like that would be the case, I wonder whether lifting weights speeds up to break down of these neurotransmitters because last weekend I took 500mg of niacinamide and this day went gym and had no problem falling asleep that night.

You took 500mg last weekend and today you went to the gym and had no issues falling asleep. By then the niacinamide would have left your system mostly.

If you mean you took it the day you went the gym and you could fall asleep it could be the increased mental activity caused by niacinamide was reduced by physical exercise. Its possible it makes you mentally restless and you can't shut off at night but if you exercise you are alright.

 

[FitnessMike]

You took 500mg last weekend and today you went to the gym and had no issues falling asleep. By then the niacinamide would have left your system mostly.

If you mean you took it the day you went the gym and you could fall asleep it could be the increased mental activity caused by niacinamide was reduced by physical exercise. Its possible it makes you mentally restless and you can't shut off at night but if you exercise you are alright.

i meant i took 500mg the day i went gym and i could fall asleep, i will try to replicate it this weekend, thanks.

 

[Kray]

There is symptoms of each you can look up on google. Some would think its bogus which isnt entirely wrong, its not that clear cut. B vitamins will increase methylation, even more so if you were to take an active B vitamin complex or if you take extremely high doses. Ive taken active Bs before and I get higher adrenaline and higher energy (which is best described as nervous energy and antsy and adrenaline-fueled obviously) and it can be problematic for mental disorders by exacerbating anxiety or even creating it. Methylation will increase SAM-e which is used to convert NA to adrenaline. Especially if you are already an "overmethylator" you can have these issues. Increasing methylation will obviously help an "undermethylator" and make them feel better.

Overmethylators usually mean high adrenaline and noradrenaline (because of copper excess), low histamine. So things that increase methylation will raise adrenaline more and lower histamine (by methylating it, deactivating it).

The low histamine state is considered to be mostly about excess copper breaking down histamine more than normal. I dont recall the exact details but I know histamine is involved in breathing and the lungs. But if you take B complex(especially if active) in generous amounts for long periods of time you can end with a similar higher adrenal hormones/low histamine state because histamine will be more quickly deactivated by methylation because you'll have more SAM-e. Stopping Bs will reduce methylation and the issue should go away with time.

In this context, extra B vitamins, which you can easily pop daily because they are cheap and very available can have unintended consequences of lowering histamine/raising adrenaline via increased methylation. As I already said, some may need this and find benefit from it if they are histadelic (high histamine). This is why methionine supplementation is used for reducing histamine, by increasing SAM-e which can then methylate histamine.

If Bs are giving you these problems you probably dont need them they are just increasing methylation too much, your histamine is borderline low or low already and Bs are killing it even more.

On another thread you posted that one who is high in histamine should not add l-histidine IIRC. I had tried histidine for dermatitis, not considering any related factors to high/low histamine status, just to see if it would help dermatitis. Anybody here really cured histamine intolerance?

On this thread you had recommended TMG, assuming I was high-histamine. I tried it for a while and I didn't notice much difference in skin status. I am confused about histamines and what to do, si

If I understand jWithout histamine testing (which I believe isn't really conclusive), would you suggest reintroducing TMG, high zinc foods, etc vs l-histidine

Could be a sign of undermethylation but it could just be because of the effects of niacinamide in high doses. It will acutely inhibit methylation (deactivation) of histamine, norepinephrine, reduce serotonin conversion to melatonin, and this can contribute to insomnia. It will also deplete choline which can reduce parasympathetic activity, which also leads to trouble with sleep since the parasympathetic system helps us wind down and calm down the body and brain to fall asleep.

Hi redsun- I want to clarify something. If I am an overmethylator, then I don't want to add TMG to the mix, right? As well as limiting B vitamins? Thanks-