5 replies to this topic

[Kris111]

Hello everyone!

 

Need your advice on how best to go about tackling my issues that have plagued almost ALL my adult life. 

 

Short background: 48 yrs old male. 

 

Current symptoms: High histamine, chronic fatigue from noon onwards every day, morning stiffness, diagnosed undermethylation, mild depression, mild anxiety, Pure OCD, tinnitus, high cholesterol (but zero calcification score in CT scan)

 

Quick story: Until few years ago, I could not explain any of my symptoms especially fatigue throughout my adult life. Normal blood work wasn't very helpful either. After reading Dr. Walsh's book "Nutrient Power", I reached out to Dr Mensah (a student of Dr. Walsh). He ordered a special whole body histamine test. He concluded I had undermethylation.  Following that, I did genetic testing and homocysteine test.  The elevated homocysteine and the MTHFR expressions dominant in undermethylated individuals further confirmed for me that I have undermethylation.

 

I have been wary of taking supplements given all kinds of toxicities and the need to balance my conflicting illnesses.  But I have finally given up and am open to suggestions.

 

From what I read elsewhere, to improve my methylation, I should first decrease homocysteine levels, and only after that work on improving methylation.  Is that so?  This means I should probably take only B6 first?  I don't know. I also don't know how long should I continue to take it before I start taking other supplements to address methylation, such as methylfolate etc.

 

Regardless, what would you recommend would be a good supplement stack for me?  And do you have any other advice based on above information?

Edited by Kris111, 19 November 2021 - 04:37 PM.

[CarlSagan]

the supps improving methylation also work to decrease homocysteine.

 

Methyl folate & methyl b12 , b6, and maybe most effectively trimethylglycine (TMG aka betaine anhydrous, at 1gram daily), are the standard for this. 

 

but seems dosing too high could tip the balance over to the other side, & might not need all together so takes some trialing.  i.e could try just the TMG, or just the methyl b vits, before combining.  a decent % of people have a gene which impairs their conversion of folate to the active methyl form, which means lower methylation & leads to increased homocysteine. so maybe methyl folate (5-methyltetrahydrofolate)  would be enough who knows, or maybe its better to hit it from a couple angles

 

there is some back & forth about long term safety of high dose folate. idk the level of methyl folate helpful for undermethylators but personally i would keep supplementary intake up to or under 800 mcg. https://ods.od.nih.g...hProfessional/ 

 

High dose methyl b12 looks pretty safe though, 1000 micrograms is a popular high dose so could go a few 100mcg at first to be conservative which is still up there. not sure about b6 dose. 

 

You probably also want to avoid any high dose niacin supplements. nicotinamide & to a lesser degree niacin have been shown to elevate homocysteine a lot (& people can run into methlyation issues with these, overmethylators take it to reduce). I saw nicotinamide riboside did not elevate homocysteine in a study but I'm not convinced, as 1. the study was funded by the people who sell this product, and 2. riboside version increases nicotinamide in the body anyway so it makes sense it would have the same effect.

Edited by CarlSagan, 06 December 2021 - 11:55 AM.

[CarlSagan]

the supps improving methylation also work to decrease homocysteine.

 

Methyl folate & methyl b12 , b6, and maybe most effectively trimethylglycine (TMG aka betaine anhydrous, at 1gram daily), are the standard for this. 

 

but seems dosing too high could tip the balance over to the other side, & might not need all together so takes some trialing.  i.e could try just the TMG, or just the methyl b vits, before combining.  a decent % of people have a gene which impairs their conversion of folate to the active methyl form, which means lower methylation & leads to increased homocysteine. so maybe methyl folate (5-methyltetrahydrofolate)  would be enough who knows, or maybe its better to hit it from a couple angles

 

there is some back & forth about long term safety of high dose folate. idk the level of methyl folate helpful for undermethylators but personally i would keep supplementary intake up to or under 800 mcg. https://ods.od.nih.g...hProfessional/ 

 

High dose methyl b12 looks pretty safe though, 1000 micrograms is a popular high dose so could go a few 100mcg at first to be conservative which is still up there. not sure about b6 dose. 

 

You probably also want to avoid any high dose niacin supplements. nicotinamide & to a lesser degree niacin have been shown to elevate homocysteine a lot (& people can run into methlyation issues with these, overmethylators take it to reduce). I saw nicotinamide riboside did not elevate homocysteine in a study but I'm not convinced, as 1. the study was funded by the people who sell this product, and 2. riboside version increases nicotinamide in the body anyway so it makes sense it would have the same effect.

 

This says a multi pronged approach is optimal:

 

" In addition to folate, a number of other dietary nutrients are required to maintain 1 carbon flux, ensuring normal homocysteine remethylation, SAM formation, and DNA methylation. These nutrients include vitamin B-6 (serine hydroxymethyltransferase activity), riboflavin (MTHFR stability), vitamin B-12 (methionine synthase function), and choline (betaine precursor as a hepatic methyl source via betaine:homocysteine methyltransferase) "

 

https://www.ncbi.nlm...les/PMC3262611/

 

it sounds like taking SAM-E directly wouldn't be a good way as a methyl donor (as feedback kicks in). you want the things mentioned in the post before to form voltron to use up homocysteine (re-methylation) in creating methionine (then SAM) for the normalizing effect.  this way you correct your excess homocysteine with more methylation.

 

" Under the condition of high SAM concentration, MTHFR is inhibited, which reduces the synthesis of 5-methylTHF and hence remethylation of homocysteine. Conversely, when SAM concentrations are low, remethylation of homocysteine is favored. "

 

Something interesting on riboflavin & MTHFR might be worth exploring tho I havent put time into it https://chrismasterj...avin-deficiency

Edited by CarlSagan, 06 December 2021 - 01:24 PM.

[CarlSagan]

more on some of the methyl consumers like niacin & epinephrine https://www.nature.c...icles/hr2011133

 

interestingly folate is listed as a methyl consumer even though it's a critical part of the cycle. mentioned because excessive folate can actually consume methyl. another reason to go for the methyl version 

 

Folic acid, the synthetic oxidized form of folate used for supplementation and fortification, is an unusual methyl consumer. Unlike 5-methyltetrahydrofolate which is the predominant natural form of folate in plants,74 folic acid has to be reduced to tetrahydrofolate, and then further converted to the active form 5-methyltetrahydrofolate in the body (Figure 1). As shown in Figure 1, the formation of 5,10-methylenetetrahydrofolate from tetrahydrofolate requires a one-carbon unit from serine, dimethylglycine, sarcosine or glycine. The latter three compounds may be derived from betaine or its precursor choline. Also, the one-carbon unit for the formation may be derived from SAM through the glycine-sarcosine cycle (Figure 1), which is an important factor in determining the level of SAM.20 Evidently, the formation of 5-methyltetrahydrofolate from folic acid is a process also dependent on SAM and other methyl donors.

Most importantly, excessive folic acid is eliminated through the urine primarily in its metabolic forms,20 especially 5-methyltetrahydrofolate,75 and thus results in a waste of SAM and the methyl donors. Folic acid supplementation and fortification have been found to significantly increase the urinary excretion of 5-methyltetrahydrofolate.75 Theoretically, excessive folic acid may worsen rather than alleviate methyl-group deficiency. In fact, studies have demonstrated that folic acid supplementation neither lowers SAH, nor increases SAM, nor alters SAM/SAH ratio.76 This may explain why folic acid supplementation has generally failed to reduce vascular events in clinical trials,22, 23, 24, 25 or even has potential harmful effect on individuals with high homocysteine at baseline.24 

 

I wonder if this also applies to inactive form of b12 (needs methyl group attached after consumed)

 

more on riboflavin (needed for what converts folate into methyl folate)  https://www.ncbi.nlm.../books/NBK6145/

 

b6 isn't involved with the rest of this stuff so not vital on the methyl donor side, but is involved in an enzyme used in the transsulfuration of homocysteine  (breaks homocysteine down to cystine which is used to raise glutathione, & glutathione has some benefits).  https://www.ncbi.nlm...les/PMC5372852/

 

" The transsulfuration of homocysteine, catalyzed by two vitamin B6- (B6) dependent reactions, consumes one-carbon units and is a major source of cysteine, contributing with about 50% of the cysteine used for glutathione (GSH) synthesis "

Edited by CarlSagan, 06 December 2021 - 04:25 PM.

[CarlSagan]

TL:DR; methyl folate, methyl b12, & betaine [TMG trimethylglycine] (or choline supporting betaine).   

 

riboflavin if want to help ingested folate convert to methyl folate and active b6 (but watch excess folate intake as can use up methyl in conversion),  b6 for bonus homocysteine breakdown & extra cysteine 

 

Right now i am going for the first 3 as an experiment after trying out 500mg / 1gram of nicotinamide and feeling like shit (blunted depressed mood, irritability, anxiety later on) and vaguely remembering i flushed easy on niacin.  with 600mcg methyl folate [short term use used to correct folate deficiencies is up to a couple grams so will consider going a bit higher for experiment time], 300mcg methyl b12 [dont mind higher tho idk if any benefit to going higher], and 1 gram TMG [should be enough, not taking nicotinamide but dose is often matched with nicotinamide intake, so will keep here].  if i respond positively good indicator it's a methylation problem.  good luck

Edited by CarlSagan, 06 December 2021 - 05:08 PM.

[Schulte257]

Are you a daily caffiene user by any chance? Bad sleep?

The first place id start when anyone mentions brainfog would be no caffiene for 12 days to see if that cures it.

Ive been following methylations tuff since 2013 and its still a crapshoot , one srudy will say take hydroxy b12 anorher avoid ir. One will say tou need methyl folate , another avoid it and so on.

Easy start. Glycine (not even tmg just glycine) , then add SAMe and see if that helps , then methylfolate.

But first id just cut out caffiene 100% , youd be surprised.