Methylation: Are We Supplementing Too Much?

[apod]

This was a fascinating podcast with Chris Kresser & Kara Fitzgerald from a while back on Methylation:
https://chriskresser.com/methylation-ar ... itzgerald/



"The ease of access to genetic testing and the ability to look at things like the MTHFR gene have led many people to be concerned about their methylation status, or their body’s ability to detoxify. However—as with many things in functional medicine—genes don’t tell the full story."

My last B12 serum test looked a little on the high-side with just 1mg/d (albeit, that's a daily dose of 16,667% of the required intake.) In doing a little more research, it seems as though RBC/intracellular b12 or MMA is what I would want to look at rather than serum b12, should I ever get around to looking at that more closely.

Dr. Fitzgerald mentioned treating patients with a "methylation diet" (probably something fairly similar to what most of us eat around here?) Interestingly, she seems to have success with getting patients with former hyperhomocysteinaemia off of the methyl donors after a sort of intervention period.

When I was supplementing b12+b9+b6+b2+tmg, I felt like I was overdoing it. So, I backed off to just b12+b9 and felt fine, then added b6+b1+b2 back on (sans the tmg) -- I'm now thinking it might be the b6 (or b6+b2) that I don't tolerate as well as the others, so I might swap those back out on the next go around. Tricky stuff.

"We introduce the methylation diet and lifestyle principles to our patients immediately, and then transition them onto that more and more. So, we’ll move through the heavy therapeutic phase, which can include methyl donors, but they’re transitioning into the methylation diet and lifestyle principles, and we’re stopping the methyl donors."

Curcumin was mentioned to be a sort of "Methylation Adaptogen."

[circular]

Thanks for posting this Apod. I heard it too and kept meaning to post it. I think it's an important interview for anyone thinking about methylation to listen to.

[SusanJ]

Yep.

[SusanJ]

Ok, my longer answer is that IMHO, most people take way too high of doses of B vitamins if they see a MTHFR snp without testing blood levels and looking at other health symptoms. And as they say in the video, as you improve your gut, adopt healthier diets and lifestyle, the need will likely go down further.

We're just complex buggers and over-pushing one area almost always causes problems in another. Homocysteine is an example. Some people just need a bit of B12 and folate to reduce it. Others, like Katie and I have other variants at play and need some TMG, but not choline, because we have choline conversion snps that don't work as well and end up pushing other parts of the choline cycle, producing too much acetylcholine - can you say overstimulated?

But I'd also say, for some, it might never go to zero. Being a homozygote MTHFR C677T with many other methylation snp issues including the main enzyme that converts food folate to active folate, I know I'll likely be on methyl-Bs for the rest of my life. I have, however, reduced the amounts I need to take by half over time, as my health has improved.

I always say start low and titer up, because you never know what other thing you'll be pushing, often in the wrong direction. Take, test and repeat. Monitor for side effects. It's the only way to know.

[Bettylacy]

Good advice Susan. Being a 677C/T hetero, I too have needed the addition of TMG, B12 2,000u/day, B6 100, and LMethyl Folate 1000mg, to get my Homocysteine down to 7.3 currently from 9.4. Vit D supplementation might have helped too since that was low and now optimized. The jury is still not totally in on hyper verses hypo methylation. I hear rumbling of + and - of both but lean more into supplementation with inflammatory markers elevated and SNPS evident. Watching for signs of hyperactivity, ie insomnia, and anxiety, when adding and using the motto "start low go slow".

[apod]

Good advice Susan. Being a 677C/T hetero, I too have needed the addition of TMG, B12 2,000u/day, B6 100, and LMethyl Folate 1000mg

I'm guessing that there are more SNPs or epigenetic factors to the story besides the usual suspects. Here's my Methylation panel, full of homozygous red blocks:

mthfr.png

1mg of B12 + 800mcg of B9 last measured 7.4 umol/L of homocysteine -- Although, I wasn't eating much meat leading up to the test (practically vegan-mode.) I'd be curious how this looks with a heavier methionine intake. I do get a ton of folates in from plants.

Has anyone played with the new StrateGene site?

[SusanJ]

I've done Strategene and found it pretty reasonable. It shows visually where in each pathway the genes lie, includes co-factors and agonists and antagonists. Lynch also points out where the research is conflicting.

I get a lot of folate from plants, too, but my conversion might not be so hot. I'm homozygote on MTHFD1, which could be about a third less effective in converting food forms.

apod, since you're wondering about methionine, Strategene looks at the parts of that pathway. It might help you fine tune your stack. The only caveat is what I said about choline. If you're not converting choline, the TMG will be necessary. I recently posted about that here viewtopic.php?f=16&t=2965&p=35519&hilit=rs9001#p35519

[apod]

apod, since you're wondering about methionine, Strategene looks at the parts of that pathway. It might help you fine tune your stack. The only caveat is what I said about choline. If you're not converting choline, the TMG will be necessary. I recently posted about that here viewtopic.php?f=16&t=2965&p=35519&hilit=rs9001#p35519

Very cool, I might have to check that out.

On 23andme, I'm seeing 'No genes or markers found matching "rs12676".' and a T/T @ rs9001. I'm not sure if that's the risk allele or if I'm in the clear there. I'll have to give TMG another try over the b12+b9 stack without the P5P/R5P/TPP.

The other day, I was trying to lookup TMG's effects on glutathione (thinking the extra glycine / methyl donors would boost it.) I came across this article, but didn't find too much else or much on long-term TMG supplementation over HFLC: https://www.ncbi.nlm.nih.gov/pubmed/15885362

I've tried aGPC, CDP-Choline, and ALCAR a few times. In general, I don't notice too much with these. I find ALCAR a little more stimulating, while the others might be a little more relaxing. Lately, I've been doing ~2 soft-boiled eggs 4-5x/wk for a natural choline supplement.

[SusanJ]

T/T on rs9001 is the risk allele (T=A). But if you can take forms of choline without the buzz, you're probably converting okay to TMG.

I'd guess as long as you aren't oversupplementing TMG, or even B vitamins, the methylation cycle will balance itself out to make sure excess Hcy ends up going down the transsulfuration path. When SAM is too high, the CBS enzyme is upregulated to flush out excess Hcy, which eventually ends up converting to glutathione, among other things.

[apod]

Speaking of methylation / b6, this was an interesting new article:
http://www.ergo-log.com/vitamin-b6-help ... y-fit.html

B-Vitamin Intake and Biomarker Status in Relation to Cognitive Decline in Healthy Older Adults in a 4-Year Follow-Up Study (Nutrients 2017): http://www.mdpi.com/2072-6643/9/1/53

I'm surprised to see that low B6 intake and low serum P5P had a more dramatic odds ratio increase for cognitive decline than MTHFR TT, Low Folate, or Low Folate Intake. Granted, the ideal B6 intake here only seemed just higher than say 4mg/d. On cronometer, it looks like I'm often hitting ~2mg/d (occasionally around 1mg, sometimes around 4mg.)

Maybe if I trade out my morning B1+B2+B6+B9+B12 via homocysteX to morning B9+B12+TMG and evening B6 (low dose P5P or pyridoxine?) maybe stacked with Zinc + Magnesium, I'll be closer to my target.

It's actually kind of hard to find a standalone low-dose B6 (I think 5-10mg would be ideal.) I wish there was more info on pyridoxamine and ideal low doses for that one (I'm only seeing these huge under-researched 100-200mg tablets.) Tricky.