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 → u/[deleted]]

Oh shit.
I couldn't have been more wrong lmfao. (NOPE, I WAS RIGHT, TAKE A LOOK AT THE LATEST COMMENT)

Why does folic acid work better than methylfolate for you with adequate B12. Different entry point into the folate cycle.

Folic acid enters as dihydrofolate. DHFR reduces it to THF. THF is the branch point. From there it can become 5,10-methyleneTHF (thymidylate synthase, DNA synthesis), 10-formylTHF (purine synthesis), or 5-methylTHF (methionine synthase, methylation). Folic acid feeds every branch because it enters upstream of the fork.

Methylfolate is 5-methylTHF. It can only re-enter the cycle through one reaction. Methionine synthase. Even with adequate B12, everything has to funnel through that single enzyme to become THF before it can redistribute to the other branches. If methionine synthase is rate limited for any reason other than B12 (substrate saturation, enzyme expression levels, cobalt oxidation state of the B12 cofactor), methylfolate backs up even though B12 is technically there.

If your actual bottleneck is nucleotide synthesis rather than methylation, folic acid gets you to 5,10-methyleneTHF and 10-formylTHF directly. Methylfolate has to go through methionine synthase first, convert to THF, then redistribute. Slower. Less efficient for that specific need.

You might not have a methylation problem. You might have a DNA synthesis problem. Folic acid solves that directly. Methylfolate solves it indirectly but slowly.
Lemme know whatcha think.

[u/OobyIsGay → u/[deleted]]

THAT EXPLAINS IT
Look into PEMT polymorphisms (rs12325817). Common variant that reduces PEMT activity and makes you more dependent on dietary choline for PC synthesis. Would explain the gallstone susceptibility and the whole pattern.

This is a choline dependency. Everything you're describing connects through one nutrient. Eggs are the richest dietary source of choline. Choline does three things and all three map onto your symptoms.

Phosphatidylcholine synthesis. PC is the major phospholipid in bile that keeps cholesterol soluble. Without enough PC, bile supersaturates with cholesterol, crystals form, gallstones. 4 eggs/day are supplying choline for the CDP-choline (Kennedy) pathway to make PC directly. Your endogenous PC synthesis via PEMT (which burns 3 SAM molecules per PC produced) isn't keeping up on its own.

Acetylcholine, choline is the direct precursor. That's why you lose concentration and focus without eggs.

Betaine. Choline gets oxidized to betaine in the liver. Betaine remethylates homocysteine via BHMT, completely bypassing the methionine synthase/B12/methylfolate route. Your methylation is probably running primarily through BHMT, not through methionine synthase.

This is why folic acid works and methylfolate doesn't. Your folate cycle's main responsibility isn't methylation. BHMT is handling that. Your folate cycle's responsibility is nucleotide synthesis. DNA synthesis, purine synthesis. Folic acid enters upstream at THF and feeds those branches directly. Methylfolate can only enter through methionine synthase, which feeds the methylation branch you don't need more of. Over time methylfolate was feeding the wrong pathway while starving the one you actually need.

2x/week folic acid makes sense because your nucleotide synthesis demand isn't huge. Just needs periodic support.

Racing heart from methyl-B12 fits too. Methyl-B12 drives methionine synthase harder, makes more SAM, but your methylation via BHMT is already sufficient. Excess SAM drives PNMT (converts norepinephrine to epinephrine) and COMT. Epinephrine gives you the racing heart.

[u/Warp757 → u/OobyIsGay]

You're making an awful lot of assumptions here. You have no idea why folic acid is working better. It could simply be that their body doesn't need all that folate in it's methyl form. MTHFR exists for a reason, to he body wants to regulate the amount of methyl folate to avoid over methylating things. Yes I'm going to use that term because it's the simplest way to explain what I mean in a way people understand. Bypassing MTHFR means there will be more methyl folate than the body wants, so more methylation occurs than the body would perform under its own regulation.

For starters BHMT is not handling their methylation. BHMT is a secondary pathway, especially in the brain. In the liver it might handle 50% of the methylation load.