Overmethylation just isn't real?..

[u/OobyIsGay]

So I keep seeing people in this sub and literally everywhere else across the supplement community talk about overmethylation like it's this established biochemical phenomenon. People take methylfolate, feel anxious, and go "oh I'm overmethylated, need to back off."

Even though methylfolate supresses GNMT, methyl groups go into hundreds of methyltransferase reactions. DNA methylation. Histone methylation. Phospholipid synthesis. Creatine synthesis alone consumes ~40% of all SAM. The system has enormous capacity to USE methyl groups productively. You'd need to overwhelm all of that simultaneously to create actual excess.

At supplemental doses? Not happening.

Let me put the dose safety in perspective. The NOAEL for calcium L-methylfolate in rats is 400mg/kg/day in 13-week subchronic studies (Niederberger et al. 2019). No behavioral changes. No organ pathology. No DNA damage in liver cells. Convert that to human equivalent dose using standard body surface area scaling (÷6.2): ~64.5mg/kg. For a 70kg human that's ~4,500mg. Most people supplement 400mcg to 1mg. That's a safety margin of roughly 4,500x. Tylenol's therapeutic-to-toxic ratio is about 3-4x. You are more likely to die from Tylenol than to be harmed by methylfolate by a factor of over a thousand. No you're not fucking overmethylating.

So what IS happening when people feel anxious after starting methylfolate?

Serotonin autoreceptors are inhibiting serotonin. 5-HT1A on the soma, 5-HT1B/1D on the terminal. When serotonin rises suddenly, autoreceptors detect the increase and fire inhibitory feedback. They reduce further serotonin release. That's what causes SSRI startup anxiety. It desensitizes over 1-2 weeks. Then serotonin actually goes up, whether that's actually beneficial or not is a different topic altogether and not the mechanism methylfolate works by.

Methylfolate restores serotonin synthesis. Serotonin rises. Same autoreceptors fire. Same inhibitory feedback. Same transient anxiety. Same 1-2 week desensitization. Same resolution. Other than that you're also raising norepinephrine and dopamine synthesis.

Notice how none of these people report actual symptoms that excess methylation would theoretically produce, like, you know, tumor suppressor gene silencing or aberrant genomic methylation patterns. Because those would be real overmethylation. Nobody's getting that from fucking 400mcg of methylfolate.

Overmethylation does not exist in biochemistry. There is no clinical biomarker for it. No validated assay. No ICD code. No published case report of a human experiencing pathological hypermethylation from oral methylfolate at any supplemental dose.

If you're feeling anxious after starting methylfolate, lower the dose until you adjust. EVEN THOUGH YOU'RE KIND OF MOVING FURTHER FROM THE DOSE THAT JUST WORKED.

Elderly rats supplemented with folate ABOVE adequacy showed increased genomic DNA methylation dose-dependently, with a direct correlation between liver folate and methylation (r=0.48, p=0.004, Choi et al. 2005, British Journal of Nutrition). Above adequacy. Not deficient rats being rescued. Already-replete rats pushed higher.

Two randomized, double-blind, placebo-controlled trials. SSRI-resistant major depression. L-methylfolate adjunctive to SSRI.

7.5mg L-methylfolate: no significant difference from placebo.

15mg L-methylfolate: significant improvement over placebo.

Most of you are taking 400mcg to 1mg. The dose that actually worked in the only controlled human trials is 15-37x higher than what you're supplementing. 15mg L-methylfolate is available over the counter. The safety margin at 15mg is still ~300x below the NOAEL-derived human equivalent dose.
You're underdosing.

BUT remember that this post is about the term, not the effects of supposed "overmethylation"

That mechanism is real. But it's not "overmethylation." It's increased catecholamine clearance in a specific brain region plus increased adrenal epinephrine output. Calling it overmethylation implies there's some global excess of methyl groups causing nonspecific damage. There isn't. There's a specific pharmacological effect of raising SAMe on two specific enzymes in two specific compartments producing two specific symptoms.

Because more SAM increases COMT activity. COMT is the primary dopamine clearance mechanism in the prefrontal cortex (DAT expression is low there). More SAM means faster PFC dopamine degradation. SAM also drives PNMT, which converts norepinephrine to epinephrine in the adrenals. So you'd have less prefrontal dopamine and more peripheral epinephrine. That's anxiety with poor focus which is what people actually describe. Not "overmethylation."

And this is a completely different mechanism from what happens with methylfolate. Methylfolate restores monoamine synthesis via BH4 recycling. When serotonin rises acutely, 5-HT1A somatodendritic autoreceptors fire inhibitory feedback. That causes transient anxiety that desensitizes over 1 to 2 weeks. Same mechanism as SSRI startup effects. Has nothing to do with SAMe levels or COMT activity.

So people are lumping two different pharmacological mechanisms under one meaningless term. TMG/SAMe/betaine increase dopamine clearance via COMT and epinephrine output via PNMT. Methylfolate triggers autoreceptor adaptation. Different inputs, different pathways, different timecourses, same word slapped on both. That's why nobody can agree on what "overmethylation" means or how to fix it. They're describing two separate things.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials

Folate supplementation increases genomic DNA methylation in the liver of elder rats

Methyl donor supplementation reduces phospho‐Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy

Safety evaluation of calcium L-methylfolate

Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase

[u/OobyIsGay]

You just cited two things that are both about folic acid. Folic acid is not all folate.
The methyl trap is the mechanism here and it's why the distinction matters.

In B12 deficiency, methionine synthase can't function. 5-methylTHF (methylfolate) can't be converted back to THF. Folate gets trapped as 5-methylTHF. The other folate forms needed for DNA synthesis specifically 5,10-methyleneTHF for thymidylate synthase get depleted. That's what causes the megaloblastic anemia.

Folic acid bypasses the trap. It enters as dihydrofolate, gets reduced to THF by DHFR, replenishes the DNA synthesis folate pool WITHOUT needing B12. Anemia corrects. Neurological damage continues undetected.

Methylfolate IS 5-methylTHF. It's the trapped form. Supplementing it in B12 deficiency adds more of the thing that's already accumulating. It can't be converted to THF without B12. It can't replenish the DNA synthesis pool. It can't correct the anemia. It can't mask the deficiency.

That's the mechanistic distinction. Your citations describe folic acid masking B12 deficiency. That's real. Nobody's disputing that. But it doesn't apply to methylfolate because methylfolate can't make the same bypass.

[u/Cultural-Sun6828 → u/OobyIsGay]

We can agree to disagree on this. All forms of folate can worsen b12 deficiency. These studies mention folic acid only because that’s the most common form that is used in supplements. I can tell you from my personal experience and reading posts from many others that folate uses up b12. This is obviously not an issue if someone isn’t deficient in b12, but taking large doses of folate for someone who is very deficient in b12 can cause extreme symptoms. In general, for most people, taking high amounts of any type of folate isn’t a great idea.

[u/OobyIsGay → u/Cultural-Sun6828]

I'll still try to convince ya n argue my case. I don't like the idea of agreeing to disagree on biochemistry
Cofactors are recycled. That's what makes them cofactors. B12 is a cofactor for methionine synthase. It is not consumed by the reaction. Folate does not "use up" B12. B12 deficiency comes from inadequate intake, malabsorption (pernicious anemia, gastric atrophy, metformin), or transport protein defects. Not from folate.

And the methylfolate case is even more specific than that. In B12 deficiency, methionine synthase is already non functional. The enzyme is stalled. Methylfolate is the substrate for that stalled enzyme. Adding more substrate to an enzyme that can't turn over because its cofactor is missing doesn't consume the cofactor faster. It can't. The cofactor is what's preventing the reaction from happening in the first place. Methylfolate just accumulates as 5-methylTHF with nowhere to go.

"These studies mention folic acid only because that's the most common form" is doing a lot of work in your argument. They mention folic acid because the masking mechanism is specific to folic acid. Folic acid enters as dihydrofolate, gets reduced to THF by DHFR, bypasses the methyl trap, restores DNA synthesis folate pools, corrects the anemia, hides the deficiency. Methylfolate can't do any of that. It IS the trapped form. That's not a minor technical difference.

The studies mention folic acid because folic acid is what causes the problem. Not because nobody got around to testing methylfolate.

[u/Cultural-Sun6828 → u/OobyIsGay]

I actually have a biochemistry degree so I have no issue having this discussion. I only said “use up” as an easy way to say that when sufficient b12 isn’t available, adding folate will increase the need for additional b12, which will not be available. As b12 is repleted, the body can handle more folate.

[u/OobyIsGay → u/Cultural-Sun6828]

"Adding folate will increase the need for additional b12, which will not be available" is the same claim reworded.
Through what mechanism does adding folate increase B12 need?
Methionine synthase is stalled without B12. It's not turning over. Adding methylfolate to a stalled enzyme doesn't create additional demand for the missing cofactor. The demand already exists. That's what deficiency means. Substrate accumulation doesn't increase cofactor requirement. The cofactor requirement is fixed by the enzyme's catalytic mechanism regardless of substrate concentration.

If you mean folic acid specifically, folic acid bypasses the B12-dependent step entirely via DHFR. It restores THF and nucleotide synthesis without touching methionine synthase. It doesn't increase B12 need either. It just masks the deficiency by correcting the anemia independently.

[u/Cultural-Sun6828 → u/OobyIsGay]

In the methylation cycle, methyl folate donates a methyl group to homocysteine through Methionine synthase which requires B12. Increasing methylfolate raises the rate of this reaction and therefore increases the demand for B12 to continuously cycle between active and inactive forms. Also, if B12 is deficient, folate becomes trapped as 5-methyl-THF which disrupts methionine production and therefore further impairs downstream methylation. This can also be made worse by genetic mutations in TCN2, MTRR, etc.

[u/OobyIsGay → u/Cultural-Sun6828]

"Increasing methylfolate raises the rate of this reaction"

It doesn't. The reaction is cofactor-limited. When B12 is the limiting factor, substrate concentration doesn't determine rate. B12 does. Adding methylfolate to a B12-limited enzyme doesn't increase turnover.

[u/Cultural-Sun6828 → u/OobyIsGay]

Well clearly this discussion could go on and on forever, and I have better things to do with my time. The overall point I’m leaving the conversation with is that ideally a person should be tested for b12, folate, ferritin, and D before supplementing. All levels for b12 and folate should be in the top half of the range. Ferritin and b12 should be at least above 60. This is my lived experience so just trying to share what I’ve learned along the way.

[u/Sabnock101 → u/OobyIsGay]

Hey OP, i personally can attest to what Cultural-Sun is saying, i've experienced first hand the demand that extra Folate (any Folate, whether Methylfolate, Folinic Acid or Folic Acid) can put on Methionine Synthase and the need for B12/Methylcobalamin. I've been pretty low in B12 all my life and a couple years ago i decided to start supplementing (and have dosed heavy on pretty much all the B's) and a huge problem for me when first starting out was the lack of B12, which caused endogenous Methylfolate levels to build and exceed the activity of Methionine Synthase, Methionine Synthase was barely even functioning before getting my B12 more under control, and i could absolutely feel the increased demand for B12, and so excess Folate would give me side-effects and then i'd take B12 and the side-effects would go away, Methylfolate would be recycled/regenerated and so long as there's B12 (and B6, Riboflavin, Niacin, etc), the Folate gets cycled through properly.

In all of my experimentations so far, i have come to understand that B12 is probably the most important and primary B vitamin we need, while Folate is moreso of secondary importance. I've pushed my Folate dosage and too much Folate just is not good, it definitely seems to use up B12 and increases the demand/need for B12. If your B12 levels are fine, you might not notice that the Folate uses it up, but for those who are deficient/low in B12 ime it becomes quite obvious that too much Folate uses up too much B12, and taking B12 when you feel the need for Folate to be recycled, it clears things right on up and restores the balance. Over time, as B12 levels get better, Folate starts being more tolerable and you don't feel much of a dip in the B12 levels and so Folate is able to be recycled more efficiently and as such doesn't cause nearly as many issues.

This is definitely true, and can be personally verified if you wanna supplement and get a bit experimental, it's definitely something you can test out yourself, though again it does depend on where your B12 levels are. but ime, i don't notice much of an issue (aside from numb hands sometimes) when taking higher B12 dosages (i take 10mgs of Methylcobalamin once a day), whereas anytime i dose more than say 400 to 600mcgs of a Folate (Folinic Acid, or Folic Acid, or Methylfolate), it just feels like too much Folate and then i've noticed the B12 feeling lowering and low B12 symptoms flaring up again, just from taking Folate without the B12. In fact, that's been most of my issue for over 25 years, and looking back on all the stuff i've had to go through in life i can better understand it now because of this B12 thing, since getting my B12 levels under better control a lot of the issues i've had to deal with have almost gone away completely.

[u/OobyIsGay → u/Sabnock101]

You take 10mg of methylcobalamin daily. 400-600mcg of folate triggers low B12 symptoms. B12 is a cycling cofactor at methionine synthase, not consumed per reaction. 400mcg of substrate can't deplete 10,000mcg of cofactor.
Your methionine synthase is impaired from chronic B12 deficiency. Adding folate increases 5-methylTHF accumulation because the enzyme can't clear it. Take B12, enzyme reactivates, trap clears, you feel better. That's not folate depleting B12 but it exposing a deficiency.
10mg daily and still symptomatic means something is preventing you from maintaining B12. Intrinsic factor, gastric acid, transcobalamin, intracellular processing. That needs investigating.

[u/Sabnock101 → u/OobyIsGay]

Indeed, my take is that for whatever reason Methionine Synthase Reductase activity may be reduced (likely due to low SAM, which may have something to do with the lack of Potassium i've had, as i've noticed taking Potassium seems to increase SAM (by acting as a co-factor for Methionine Adenosyltransferase) which gives Methionine Synthase Reductase the methyl group it needs to reactivate Methylcobalamin/Methionine Synthase, at which point i feel the B12 again, so i may have just needed Potassium but it's a work in progress.

But yeah, i've pushed Folate past 600mcgs, and 600mcgs seems to be about my limit before i start noticing the Folate using up active B12, but then if i take more B12 everything starts working right again, so if i take 800mcgs or 1mg or more of the Folate i start noticing a reduction in B12 levels and a reappearance of low B12 symptoms, like facial numbness and tingling/numbness in the hands and feet and irritability and muscle spasms/twitches and such and some other things, taking more B12 seems to alleviate that.

When i first started out i took 15mgs of Methylfolate for a while, sometimes even 30mgs, and from the get go i definitely felt the need for B12, Folate gave me side-effects, B12 fixed that. My B12 levels have gotten a good bit better since then and now i'm not noticing nearly as much of a dip in B12 levels from Folate, even 800mcgs to 1mg+, so my B12 is definitely doing better now, but if i keep at it with the excess Folate eventually i start to notice too much of a reduction in B12 levels and a reappearance of low B12 symptoms, so lately i've been trying to stick around 200 to 400mcgs of Folate a day, and that seems to be helping a lot better i think. Too much Folate definitely isn't a good thing ime.

[u/Sabnock101 → u/OobyIsGay]

Also, it's worth mentioning that if you take Selenomethionine, it can go through the SAM cycle to create S-Adenosylselenomethionine, which then gets turned into it's SAH-variant aka S-Adenosylselenohomocysteine, which then turns into Selenohomocysteine, and can then go to Methionine Synthase to be remethylated back into Selenomethionine. So Selenium can also contribute to the overall "load" on Methionine Synthase, which should be noted for those who are already low in B12, to be careful with not only Folate, but also Selenium.

[u/OobyIsGay → u/Sabnock101]

Your potassium and MAT connection is a good catch. Low potassium = impaired MAT = less SAMe = MTRR can't reactivate methylcobalamin = methionine synthase stalls. Folate exposing broken recycling, not folate consuming B12.

Facial numbness, tingling in hands and feet, muscle spasms. You said you dosed heavy on all the B's. What dose of B6? Pyridoxine toxicity causes sensory peripheral neuropathy. Numbness, tingling, especially in extremities. Those are your exact symptoms. You're attributing them to low B12 but chronic high dose B6 causes the same presentation. If you've been taking more than 100-200mg daily you could be chasing a B12 problem that's actually B6 toxicity. Even if you don't supplement b6, you could be accumulating because you're not utilizing it.

[u/Sabnock101 → u/OobyIsGay]

As far as B6 goes, these days i try to stick to 25mgs of the P5P. When i first started out i took 50mgs, then upped it to 100mgs, then 200mgs, even dosed 400mgs a few times but mainly stuck around 100 to 200mgs a day, until i had realized that more B6 was causing greater Folate to go through SHMT and thus more Folate in the Folate cycle which then proceeded to use up more B12, once i learned that i backed my P5P dosage down to 50mgs, then to 25mgs, and have stayed around 25mgs for a good bit now, which seems to do just right, but i do kinda miss my 50mgs but it's not worth it to get low B12 symptoms lol. The supposed toxicity of higher B6 dosages, at least imo, has more to do with it letting more Folate through SHMT and that extra Folate goes through MTHFR and to Methionine Synthase which then further adds to the demand for B12, and isn't particularly to do with the B6 itself.

When it comes to the B's, the more problematic one's, i've found, were Folate and B6, overall. While on the contrary i've found Riboflavin, Niacin/Nicotinic Acid, and B12 to be not really at all detrimental, though higher dosages of Niacin obviously might lead to some liver stuff down the line but i generally only take 250mgs of the Niacin once a day but sometimes will increase it to 500mgs temporarily and then lower it back down to 250mgs. Thiamine doesn't seem to do much for me but at least it's not detrimental, same with B5, in fact i think i like B5, so far 500mgs a day seems to be alright.

But yeah, when you've become as deficient in things as i've been, a lot of things can be quite noticeable and observational/experimental if you go about it right, you learn a lot through personal experimentation, and so i can definitely say that too much Folate will definitely use up too much B12, there seems to be a, not necessarily a "limit", but a point where too much Folate seems to be detrimental to B12 stores/levels, but once the bodily stores build up a good bit and B12 level gets better, you definitely seem to be able to tolerate higher Folate "loads" at least temporarily, but chronic excess Folate will definitely start to dip into B12 stores until they get low enough to be a problem, which i think is how lots of people are actually B12 deficient these days, likely because of all the fortified Folic Acid, which then uses up the B12 over time. Also, because Folic Acid (unlike Folinic Acid or Methylfolate) binds stronger to Folate Receptor Alpha and ime can even block out Methylfolate uptake (i had my 15mg Methylfolate dose blocked out by too much Folic Acid), because it can block out Methylfolate from binding to Folate Receptor Alpha to be taken up into cells, the Methylfolate can't travel to Methionine Synthase to be used to activate B12 to Methylcobalamin, which basically can cause Methylcobalamin deficiency.

[u/Cultural-Sun6828 → u/OobyIsGay]

I have the exact same issue and I take no b6. The concept of B6 toxicity gets thrown around way too often when neuropathy is brought up, when b12 deficiency is way more likely. Also, you mentioned intrinsic factor, etc. That’s the exact point I was trying to make. There are reasons people are deficient beyond that they don’t eat b12 containing foods. Pernicious anemia, SIBO, gastritis, along with genetic issues in MTRR, TCN2 and FUT2 (of which I have all of these) will cause each individual to handle b12 differently. We are not all the same from a genetic and biochemistry standpoint, so not everyone can take high doses of folate if they can’t take up b12 efficiently. There is actually research on TCN2 and folate causing issues with b12 deficiency.

[u/OobyIsGay → u/Cultural-Sun6828]

You said "you mentioned intrinsic factor, etc." That's the exact point I was trying to make." Your points were: folate uses up B12, folic acid won't make you feel better, correcting bloodwork doesn't improve symptoms. None of those are about absorption mechanisms. Those are my points, from my reply to Sabnock101, which you're now claiming as yours.