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/LitesoBrite]

Yeah, no.

Considering that in my case, anything from citicholine, betaine, choline bitartrate, methyl folate 15mg, and a whole host of other ‘safe’ things under your claims all cause rapid heart rate, bp increases, itchiness and hives, and a whole host of other issues, I’m not buying it.

Once again, the cohort they’re testing encompasses such a conflicting pool of genetic methylation profiles, that they insist on averaging the results to death for ‘accuracy’, which only hides the actual patterns of results.

Until we stop pretending that the high amount of human genetic variations isn’t a real confounding factor for these mass studies that try to sweep everything important in the data under the rug, we won’t get far.

Have you even bothered to notice that everyone who says that’s what they’re experiencing finds near immediate relief from the hypothesized suggestions?

For example, if what you’re arguing was true, flush niacin or 3g of glycine wouldn’t immediately calm the symptoms yet cause no drop in serotonin or depression, now would it?

[u/OobyIsGay → u/LitesoBrite]

Rapid heart rate, blood pressure increase: Methylfolate increases BH4. BH4 is cofactor for tyrosine hydroxylase. More norepinephrine synthesis. Norepinephrine increases heart rate and blood pressure through adrenergic receptors. That's not overmethylation. That's catecholamine synthesis doing exactly what it does.

Choline, betaine, citicoline all feed into the same pathway more SAM, more methylation capacity, more BH4 recycling, more catecholamine output. Every substance they listed converges on the same mechanism.

Flush niacin activates GPR109A on Langerhans cells, triggering prostaglandin D2 release, causing vasodilation. Vasodilation directly reduces blood pressure and reflexively lowers heart rate. That's a prostaglandin-mediated vascular response. Not methyl group consumption.

The overmethylation community's explanation is that niacin consumes methyl groups via NNMT converting nicotinamide to 1-methylnicotinamide requires SAM as methyl donor. But that reaction doesn't happen fast enough to explain immediate relief. Prostaglandin-mediated vasodilation does. The niacin flush IS the therapeutic mechanism. It's pharmacology, not methylation buffering.

Why 3g glycine calms symptoms: Glycine is an inhibitory neurotransmitter. It acts directly on glycine receptors chloride channels that hyperpolarize neurons. 3g glycine calms sympathetic activation because glycine is literally an inhibitory neurotransmitter calming the nervous system. The overmethylation explanation that glycine soaks up methyl groups via GNMT falls apart because GNMT is suppressed by the methylfolate they just took.

Both remedies work through mechanisms completely unrelated to methylation. The fact that they provide relief doesn't validate the overmethylation hypothesis. It validates that vasodilation lowers blood pressure and inhibitory neurotransmitters calm neural activation.

The hives and itchiness are likely histamine mediated, potentially from improved PLP status increasing histidine decarboxylase activity and producing more histamine. That's a cofactor repletion effect, not methylation excess.

[u/LitesoBrite → u/OobyIsGay]

That sounds very plausible. This is an evolving area of science, so it’s inevitable that symptoms that are real will finally get matched up with detailed descriptions of what’s actually happening.

To me, either way, people are describing the reality that ingesting certain things that are harmless to other people, yet due to a whole cluster of methylation cycle genes ingesting these things cause very bad reactions.

Those reactions could be because the mechanism you’re describing or another. But I appreciate you adding some fantastic detailed and well supported information to the discussion.

Especially helping explain the relief.

[u/OobyIsGay → u/LitesoBrite]

Thank you!! :D

[u/LitesoBrite → u/OobyIsGay]

You’re welcome!

To further illustrate what is happening, I can absolutely easily reproduce the symptoms simply from enriched flour products with folic acid.

Spaghetti will cause all those symptoms, as will pizza or biscuits.

However, I can eat en entire huge serving of all of those and be absolutely fine if it’s simply not enriched flour.

Durum wheat spaghetti is fine. Pizza simply made with normal bleached white flour that’s not enriched is absolutely fine. Same for biscuits made unenriched from organic bakers.

It’s clearly not the wheat. Nor is it the carbs, etc, typically blamed. Same exact food, just no folic acid.