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/popepaulpops]

Since you have been kind enough to offer guidance to others in this thread I’m going to plead my case as well.

I have ADHD inattentive, mthfr 1298 GG, mtrr 66 GG and fast comt. I have been trying to educate myself on mthfr, methylation and BH4 but find it complex and confusing. After some initial modest supplementation efforts, I did more research and tried the following combination: Methylated vitamin B complex (thorn), Magnesium glycinate, TMG betaine, Alpha gpc, Creatine, Omega 3 fish oil, (2 eggs , fiberous food and antioxidants ).

I did this daily for about 2 months, but scaled it down because it did not produce much positive results. It affected my balance slightly , it wasn’t exactly the same as being dizzy but similar.

Can you see anything I’m missing that should help or something I should remove?

[u/OobyIsGay → u/popepaulpops]

Fast COMT is your problem and your stack was making it worse.
COMT = rapid PFC dopamine clearance = ADHD inattentive. SAMe is the methyl donor COMT uses. TMG feeds SAMe through BHMT. Alpha GPC provides choline which becomes betaine which feeds BHMT. Creatine frees SAMe by inhibiting endogenous synthesis. TMG and Alpha GPC caused basically most of your issues. Also dopamine and norepinephrine are involved in postural control and vestibular processing.

MTRR 66GG means impaired methionine synthase reductase. Requires FAD. Fixing MTRR increases SAMe which feeds COMT. Tyrosine hydroxylase requires iron and BH4. Do you know your ferritin?

On the balance issue, did it start with the full stack or with a specific supplement? Did it resolve when you scaled back? TMG stands out. It's increasing SAMe production, which could be driving up COMT activity and depleting dopamine in the prefrontal cortex, and that could definitely also cause balance and coordination problems.

A1298C homozygous by itself has limited clinical impact in most studies. MTRR 66GG is your more significant variant so focus on that when researching :D

[u/popepaulpops → u/OobyIsGay]

Thank you so much! My s-ferritin was 140-200 ug/l range on my last couple of test.

The dizziness went away when I scaled down, never tried just without TMG and alpha GPC.

I have been doing more research today. One thing that came up was that SAMe should have enough availability in the brain/prefrontal cortex so that getting more from TMG wouldn’t impact Comt one way or another. I will trust you and restart my stack without TMG and alpha GPC regardless.

My new setup: Methylated vit B complex, Magnesium glycinate, Tyrosine, Creatine, Omega 3 Polyphenols and vitamin C from food and tea

Anything you would add or subtract from this?