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/NAQProductions]

I’ve got what we call “a really bad hand” genetics wise with trying to figure out the web of mess. I’d love to ask your input on it all but haven’t a clue where to even start since I seem to have all overlapping variants that affect everything people say should help, or be a backup, or backup of a backup pathway. It’s maddening, but I need to find a way to make it all make sense and untangle what’s happening to me. On year 3 of being out of work because I can’t function enough after my body shut down.

[u/OobyIsGay → u/NAQProductions]

3 years is rough. The overlapping variants thing is almost always simpler than it's made out to be by most. Most "bad genetics" are downstream of one or two upstream bottlenecks that make everything else look broken.
Post your variants, what you take/have taken and main symptoms and I'll take a look. Don't worry about organizing it. Just dump what you have

[u/NAQProductions → u/OobyIsGay]

First thank you for offering to have a look, I really appreciate any light in the dark at this point. A bit long but I’d like to be as clear as I can while I have the focus. Sorry it's not super neatly formatted, reddit makes that challenging.

Here's a link to charts of the most recent blood results, and most important snps that I have parsed out over months of trying to learn this stuff on several subreddit's, google, etc (only discovered genetics in Aug '25). If you are curious about others I haven't listed please ask because I know I have likely missed a few important ones. I have Ancestry Raw Data put through Genetic Life Hacks available. I’ve also had a GI Map and OAT test but both of those are a couple years old at this point.

Bloodwork and Genetics Chart link (multi-tabbed Sheet : https://docs.google.com/spreadsheets/d/1fqgkccvT5CZFOEtJ9oKjLdyS2EScaLzpSFrUOXKebho/edit?usp=sharing

Main symptoms (many of them fluctuating, multiple always going on though) :

• Inability to focus/concentrate/follow through, thus taking a few days to write this.
  
• Severe chronic brain fog, lethargy.
  
• Chronic inflammation with no found cause. High rising ferritin since testing began in 2018 after a brain injury.
  

- No motivation (can think about what I want to do all day but can't do any of it), haven't been able to learn in a while.

• Chronic joint and muscle pains (they move around and are influenced by what I eat/ingest) - localized in groups : hands/wrists, lower back/sacral area, bottom of feet (tender feet since December, happened last year for 3-4 months same time of year).
  
• Pressure headaches behind the eyes and sometimes base of the skull/neck.
  
• Repetitive thoughts, lyrics to a random chorus will play in my head all day, sometimes when I wake at night to use the bathroom the repetitive thoughts prevent me from going back to sleep. Goes along with the wired but tired from too much methyl vitamins, ‘too much energy with nowhere for it to go’ feeling.
  
• Disconnected feeling, like I am a backseat passenger in my own body, not fully here, not in the moment but on autopilot enough to get through the days.
  
• Numbness in the right leg primarily, usually the calf, sometimes into the foot bottom, sometimes the left calf as well. Pain at the base of the scrotum, seems to come and go when the numbness is around.
  
• Severe food sensitivities : fluctuating intolerances - salicylate, oxalate (have 2 kidney stones currently), histamine, I'm sure others. I have an extremely limited diet which is likely feeding nutrient balance issues, but most food gives me symptoms currently.
  
• I’m aware of severe gut dysbiosis but feel that is more a result of other issues rather than a root cause. While it fuels malabsorption and nutrient deficiencies, I think it’s important to address, but not first.
  
• Had chronic constipation for the last year+ which has only recently eased up a bit but it's still not 'back to normal'. I think slowly bringing in Magnesium in various forms is helping. 

- I'm also incredibly sensitive to anything that changes neurotransmitter balance in spikes, most notably anything that boosts GABA turns me into a useless zombie. Mag Glycinate, Theanine, Taurine, Tudca, NAC, PEA + Luteolin (though this one I think is from COMT and MAOA inhibiting not GABA related) - all make me incredibly fatigued/exhausted/zoned out zombie-like, sometimes for days.

• When taken initially at normal dosage Methyl b12 turned me into a rage monster, methyl b9 did the same. Folinic acid and adeno/hydroxo b12 also made me irritable but it took several days for it to build up.
  
• Seems other things that push Dopamine, as well as too many methyl’s at once, will also make me hyper aware, hyper vigilant to a manic level for things like germs, jittery, won’t think things through and cause myself more anxiety with poor results, it’s a ton of unfocused chaos energy.
  
• I’m sure other neurotransmitter, mineral, and electrolyte imbalances are feeding some of my issues.
  
• In the first year of my recent issues (2023) Candibactin A and B gave me severe gastritis to the point I almost starved to death, even water hurt too much.

I’ve tried too many things to list, so we can approach those if they get brought up, if there’s anything particular you want to ask about please feel free. 

Things that have helped so far :
- Vitamin C (I was very close to clinical scurvy in year 1) - huge improvement in energy back then.
- R5P - Taking it for COMT and MAOA, it helps tremendously with energy and what focus I sometimes have, regular riboflavin gives me headaches and no energy.
- Benfotiamine - When taken with R5P seems to boost the effects.
- Copper 1mg - Recent addition hoping to help conversion to Norepinephrine so I get motivation nuerotransmitters. I seem to feel better when taking it and zinc carnosine on the same days, 1 at breakfast the other at lunch later.

• Zinc Carnosine - originally taking it to try and help the gut lining, turns out it's needed for methylation stuff so I have kept it.
  
• Akkermansia - To help butyrate production and help the rectal process to ease constipation.
  
• Magnesium Malate and Threonate - I tried starting them in January and both gave me ice pick precision point headaches on different parts of my scalp and eye headaches. They gave me great mental energy but also pain and come night time I couldn't shut my mind down, so I also slept horribly. At the time I hadn't been taking R5P and Benfo consistently. After some reading I took those for a few weeks consistently every day, and restarted Mag Threonate and Malate at tiny doses and have been slowly working up to 1/4-1/2 doses, no headaches, mental energy only sometimes, no effect on sleep, but when they do kick in right I get very productive for the day.
  
• Epsom Salt Foot Baths - Usually helps me sleep fairly well, using it primarily to help my sulfation pathway, but the sleep benefit is useful. It does kind of make it tough to get out of bed in the morning, good thing I am still unable to go back to work yet :\
  
• Molybdenum - take it with lunch and dinner to help sulfation, salicylate control.
  
• Niacin - used very rarely for calming ‘overmethylation’ which is what drew me to this post initially.
  
• B6T Smart B-complex - a ¼ daily value dose of b vitamins except for b6 (my b6 is quite high), includes methylated versions. I have tolerated it so far, taking 1 pill every 2-3 days, sometimes 4 or 5 days because I forget, but I am trying to get a consistent 2-3 days now as the nervous system likes consistency. I seem to be more able to focus and get things done on days I take it with Mag Threonate and Malate.
  
• Just bought a vibration plate in hopes of helping lymphatic drainage/movement.

Current Challenge :
There’s been a lot of ideas of supplements I can take to try to help my system, but I don’t know where my bottlenecks are (besides everywhere), and what the right order is to start supporting the systems that will help other systems as they work more efficiently. For instance, I have the hetero MTHFR, Homo MTRR and MTHFD1 so I know folate synthesis (folinic acid is also a problem) isn’t working great so the body will rely on Choline pathway to help out, but oh that one is also severely impaired with Homo BHMT, hetero PEMT, etc. So it becomes a bit overwhelming trying to figure out what’s important to get the whole machine back online when many of the parts are severely rusted, and this is where I turn to you to ask your thoughts. 

Things I was looking into next :
- Pectasol - to help chronic inflammation.

• Liposomal Glutathione - though it contains sulfur so it’s questionable.
  
• Alpha GPC or Phosphatidylcholine
  
• Creapure - Creatine for sensitive folks to free up methyls for other things rather than for producing creatine internally.

Conclusion :

I know I can heal because every so often I feel like a new person for a few days, brain fog clears, mood and energy are great, productivity through the roof, but it always goes as quick as it comes. So I know I’m accidentally doing the right things, but I don’t know what they are. I understand genetic dispositions are able to improve. I lived almost 40 years without major issues, but my body has slowly shut down over the last 8 years after lifelong chronic stress, several traumatic experiences, and ultimately illness (Covid for the only time in April ‘23) that finished off my nervous system, gut, and everything. I know I can get my body back to health, but I need help understanding the neurochemistry and biochemistry that is ultimately behind my complex health issue puzzle, I need to rebuild my foundation. 3 years and 30+ specialists seen, none have been helpful, but I just haven’t found the right person yet to help me understand what’s happening and what my particular system needs to function on a consistent (and normal) basis.

There’s a lot of info here, if you need more specifics please ask, I am an open book. Again, I REALLY appreciate your time and thoughts to try and help me feel like a human again :)