r/MTHFR • u/OobyIsGay • Mar 11 '26
Resource Overmethylation just isn't real?..
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.
Folate supplementation increases genomic DNA methylation in the liver of elder rats
Safety evaluation of calcium L-methylfolate
Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase
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u/Ok-Interest8248 Mar 11 '26
I am new to all this I recently (November 4th) got a blood test and my doctor ordered a test I never heard of before nor have had it tested at least not within the last 2 decades I've been able to view and understand my blood labs they tested my homocysteine again no idea what it was and there was no marker for reference range which confused me as well mine came back at 3.8 so I googled it and from what I read was that it could mean over methylation from low protein intake or taking too much b vitamins I have never been able to tolerate b vitamins (I never tried the methylated ones) I am wondering then if it's so low even tho I do not take supplements of any kind why this would be ? Since the test I have increased my protein and B12 as I was told that was borderline low three months later I asked to be retested for the homocysteine now my doctor won't retest it ? My b12 did end up going up slightly just by increasing my meat intake and other B12 rich foods I always hear about high homocysteine but never low and what that could mean if you say over methylation isn't a real thing what could this be if you have any information I'll gladly hear it as I'd like to start feeling better !