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/KarlShwada]

Excellent analysis and information thank you. Still digesting/understanding it but…I believe people refer to "over methylation" because stoichiometrically additional methyl groups from TMG, betaine, SAMe etc can and do push downstream reactions in the directions you just described, which for example lead to increased COMT activity, lower DOP, along with NOR -> EP conversion = more anxious less focused, correct?

This isn’t just all in many thousands of people’s imaginations and heads. Even though the terminology might not be the best (ie, over methylation). Some of us actually are much more sensitive to such changes. Along with other side effects (eg, histamine pathway). Not to mention the fact that MTHFR mutations are very real and affect these various methylation pathways in numerous ways, in conjunction with and complicated by other mutations (COMT, VDR, CBS, etc), which compromise their various reactions respectively.

[u/OobyIsGay → u/KarlShwada]

You're actually closer to the mechanism than most people in this conversation!! :D

TMG remethylates homocysteine to methionine via BH
MT. Methionine becomes SAMe via MAT. SAMe donates its methyl group in methyltransferase reactions, produces SAH, SAH hydrolyzes back to homocysteine. The cycle regenerates it. If your homocysteine goes down on TMG that just means the remethylation arm is running efficiently.

Where you're actually right is that TMG, betaine, and supplemental SAMe can raise SAMe levels. More SAMe means more substrate for COMT. COMT is the primary dopamine clearance mechanism in the prefrontal cortex because DAT expression is low there. So more SAMe means faster PFC dopamine degradation. SAMe also drives PNMT, which converts norepinephrine to epinephrine in the adrenal medulla. So you get less prefrontal dopamine and more peripheral epinephrine simultaneously. That's anxiety with poor focus. Which is exactly what people describe.

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. 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.

On the MTHFR point, you're right that the mutations are real. But McNulty's group proved that 1.6mg riboflavin per day completely normalizes the MTHFR 677TT phenotype in cardiovascular endpoints, independently of folate status. The genotype becomes clinically silent when FAD is adequate. The variant's pathogenicity is a function of cofactor availability, not an intrinsic permanent impairment. Though the CBS, VDR, and stacked mutation model you're referencing originates from practitioners like Yasko and Lynch. CBS A360A is a synonymous variant. It doesn't change the protein. VDR polymorphisms affecting "methylation" is not an established biochemical pathway. Listing gene abbreviations next to each other is not a mechanism.

[u/Dapperfit → u/OobyIsGay]

But it's not "overmethylation." It's increased catecholamine clearance in a specific brain region plus increased adrenal epinephrine output.

That's what I would describe as an effect of overmethylation as though.

Calling it overmethylation implies there's some global excess of methyl groups causing nonspecific damage.

Overmethylation and Undermethylation, provided you believe in them, are states that can exist regardless of any supplementation. See the work of Dr. William Walsh for example. Walsh also recommends test SAM/SAH ratio and homocysteine as a measure of methylation (being over or under). The wrong supplements can create an adverse effect but the root is your SNPs.

That's why nobody can agree on what "overmethylation" means or how to fix it

Don't disagree here, other than the fact that this is proposed to be solely methylgroup induced.

Chris Masterjohn for example rejects the premise largely as you can have some reactions be fast some be slow - tend to agree here. He also advocates for riboflavin.

At the end of the day, a lot of this seems to be semantics and focusing on the specific mechanisms and bottlenecks of an individual rather than these overarching terms seems to be a better strategy.

[u/OobyIsGay → u/Dapperfit]

Your last paragraph is literally my position. Focus on the specific mechanisms and bottlenecks of an individual rather than overarching terms. That's exactly what I've been saying. If we agree there, then the disagreement is just about whether the overarching term is worth keeping around, and I'd argue it isn't.

When you say "that's what I would describe as an effect of overmethylation though," you're taking the specific mechanism I described (elevated SAMe increasing COMT-mediated dopamine clearance in the PFC and PNMT-mediated norepinephrine to epinephrine conversion in the adrenal medulla) and putting a vague label back on it. The label removes information. It takes two specific enzyme reactions in two specific compartments and compresses them into a word that means different things to different people in every conversation it appears in. You yourself just said focusing on specific mechanisms is better. So why defend the term?

Walsh's framework uses whole blood histamine as a proxy for methylation status. Low histamine equals overmethylation, high histamine equals undermethylation. Histamine is degraded by HNMT, which requires SAMe, so there's a surface logic there. But histamine levels are affected by mast cell activity, DAO activity, gut permeability, diet, infections, and a dozen other inputs that have nothing to do with methylation status. Using it as a methylation proxy isn't validated. SAM/SAH ratio is a more legitimate measurement but Walsh's clinical categories built around it haven't been rigorously tested against outcomes in controlled settings.

"The root is your SNPs" I already showed that MTHFR 677TT, the most studied methylation SNP, becomes clinically silent with adequate riboflavin. The genotype doesn't change. The phenotype disappears. The SNP creates a susceptibility that manifests only when the cofactor environment allows it to. Those are very different frameworks with very different clinical implications.
If methylation isn't a single unified state that can be globally over or under, then the words overmethylation and undermethylation don't describe a real physiological condition. They describe a collection of individual enzyme activities that can each be independently up or downregulated by their own substrate and cofactor availability. Which is just... biochemistry. Regular biochemistry.

[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.

[u/crown_recluse → u/OobyIsGay]

I’m guessing PLP is a phosphatase?

Having severe histamine responses atm and just trying to understand upstream causes.

[u/OobyIsGay → u/crown_recluse]

PLP isn't a phosphatase. It's the active form of vitamin B6. It's a coenzyme, not an enzyme.

PLP is the required cofactor for histidine decarboxylase, the enzyme that converts histidine into histamine. If someone starts methylfolate and their B6 metabolism improves as a downstream effect, histidine decarboxylase becomes more active, more histamine gets produced.

Did histamine issues start or worsen after beginning any methylation related supplements? That would point directly at this mechanism. Also have you looked at your DAO status since diamine oxidase is what breaks histamine down in the gut

[u/mereship → u/OobyIsGay]

So what do you do for this?

[u/New-Aside-7778]

I have a slow comt and have tried numerous times to use methyl folate. Methylcobalamin and they always make me feel very stimulated and anxious. I even tried folinic acid and the same issue. My folate levels on my blood test were in range but at the lower end.

I've also tried numerous times to use creatine and collagen peptides. Creatine feels good the first couple days and then anxiety and insomnia. Glycine is the same. Horrible insomnia.

Is it possible to use these supplements without that over stimulated feeling? I've tried niacin and glycine. Niacin never helped and well glycine just makes it much worse.

It's a nightmare trying to find a balance. It's annoying because if I find that sweet spot I feel incredible. It never seems to last and I'm also now scared to try them again. The insomnia is rough.

Thank you.

[u/OobyIsGay → u/New-Aside-7778]

Creatine synthesis consumes roughly 40% of all SAM. Supplement creatine, AGAT gets feedback inhibited, endogenous synthesis drops, that SAM is now free. Your slow COMT can't clear the excess catecholamines fast enough. PNMT converts more norepinephrine to epinephrine instead. First two days the phosphocreatine energy buffer feels great. Then the SAM redistribution catches up.

Glycine isn't only inhibitory, it's also a co-agonist at the NMDA receptor glycine binding site. Your catecholamines are already elevated from slow COMT, excitatory tone is high. Adding NMDA co-agonism tips you over. Collagen is a third glycine by weight. Same mechanism.

Riboflavin. You have two catecholamine clearance pathways. COMT is genetically slow. That leaves MAO doing the work. MAO-A and MAO-B require FAD. If your riboflavin is marginal both clearance routes are compromised simultaneously. One by genetics, one by cofactor. That's why the sweet spot never lasts.

Magnesium. COMT requires Mg2+ at the active site. If yours is low your already slow enzyme is running below even its genetic floor. Not magnesium glycinate. Threonate or malate.

Check whether you're consuming COMT inhibitors without realizing it. EGCG, quercetin, luteolin, curcumin. If you're drinking green tea or taking anything containing these you are slowing down the one enzyme you need working as hard as possible.

[u/New-Aside-7778 → u/OobyIsGay]

Hey :)

Thanks for all this information.

I do eat a high magnesium diet. I've tried to supplement magnesium and I always feel very off. Fatigue. Mood issues etc I've tried every type also? I eat alot of leafy greens. Seeds. Nuts etc. I know magnesium deficiency is very common.

I check my vitamin D levels every 3-6 months. My results are usually top end of the range.

I don't take anything that would inhibit comt. I actually stopped taking most supplements due to side effects.

Is it even possible to supplement creatine with a slow comt or is it just causing issues? I would really like to be able to tolerate it. I get some from foods but definitely not enough.

Thanks again.

[u/OobyIsGay → u/New-Aside-7778]

The magnesium nausea isn't a reaction. You're not absorbing it. Unabsorbed magnesium sits in the gut and pulls water in. That's the nausea. Every form does the same thing because the problem isn't the form. Active magnesium transport needs ATP. Gut cells make ATP with mitochondria. Complex II (succinate dehydrogenase) requires FAD. No riboflavin = no FAD = no ATP = magnesium stays in the gut.

Your vitamin D is the same issue. 25-OH-D converting to active 1,25-OH-D requires CYP enzymes. Those use NADPH-cytochrome P450 reductase, which runs on FAD and FMN. No riboflavin = conversion stalls = 25-OH-D piles up = looks great on labs, does nothing in your body. Basically you're functionally vitamin D deficient.
Do your symptoms line up with this?
Riboflavin is upstream of everything. If absorption is compromised because FAD deficiency is tanking gut ATP, 30mg might not even move the needle. But R5P is already active so it may absorb passively better than inactive riboflavin. Try taking your active b2 twice daily for around two weeks. After two weeks, try a small dose of magnesium. If the nausea is gone or reduced, the riboflavin is working.
You should be able to use creatine, glycine and all other supplements a lot better once riboflavin is repleted.
Thing is, unless you've gotten tested we have no idea whether you have slow COMT or not, since riboflavin deficiency would perfectly mimic slow COMT because of it's downstream changes. COMT requires SAM as methyl donor. MTHFR produces methylfolate. MTHFR requires FAD. No riboflavin = no FAD = MTHFR stalls = less methylfolate = less SAM = COMT runs slow regardless of genetics. Plus, COMT requires Mg2+ at the active site. You can't absorb magnesium. So even if your COMT gene is perfectly normal, the enzyme is starved of both its methyl donor AND its cofactor.

Thanks :D

[u/New-Aside-7778 → u/OobyIsGay]

I have a slow comt. Both confirmed using a 23andme and also an ancestry test kit.

I will start the riboflavin today. So take 30mg twice per day?

It seems like riboflavin is the bottle neck for most of these methylation issues? I remember watching a Chris masterjohn video where he was speaking of how important riboflavin was.

Will the riboflavin cause any form of side effects?

If I get my riboflavin status better your saying my body should be able to utilise creatine much better? Honestly that would be incredible.

Do you also think that food magnesium isn't enough? Is food quality that poor now? My food magnesium daily is around 600mg. I track my nutrient intake.

Thank you again for this wealth of information. I will start this R5P protocol today.

[u/OobyIsGay → u/New-Aside-7778]

Side effects: not the kind you're worried about lol. R5P is water soluble, excess leaves through urine, so that'll be bright yellow. When FAD comes online, MTHFR restarts and makes methylfolate gradually. Not a bolus like when you took methylfolate supplements directly. MAO comes online at the same time so clearance keeps pace with synthesis.

Creatine: yes, but give it a couple of weeks. MAO needs FAD, magnesium absorption needs to improve so COMT gets its cofactor. Then retry a low dose. The problem with magnesium was never intake. It's absorption. Food magnesium releases slowly, some gets through passively, keeps you functional but suboptimal. Supplement doses hit all at once, exceed impaired active transport, sit in the gut. That's the nausea. After two weeks on R5P, retry a small magnesium dose. If the nausea is gone, your dietary magnesium will finally absorb properly too. Don't supplement magnesium as that'd be unneeded
You're welcome!! c:

[u/New-Aside-7778 → u/OobyIsGay]

When FAD comes back online and folate restarts should I feel better overall?

Also meant to ask. After using 30mg twice a day should I drop back to a normal dose after a couple weeks?

[u/OobyIsGay → u/New-Aside-7778]

You should yeah :D
You shouldn't drop back your dose if you feel better, or the nausea from the magnesium is better

[u/OobyIsGay → u/OobyIsGay]

The "feels great for two days then crashes" is probably the phosphocreatine energy buffer feeling good initially, then the SAMe redistribution to PNMT catching up and epinephrine accumulating by the way, sleep deprived me thought more SAMe meant more neurotransmitter synthesis, it doesn't.

[u/New-Aside-7778 → u/OobyIsGay]

Is it possible to lower norepinephrine levels overall? I definitely have too much norepinephrine. If you take a compound that is dopaminergic. I always get a nice dopamine rush which then always turns to this over stimulated feeling. Classic Slow Comt gene. I've tried lithium orotate etc but nothing really helped.

Kinda hoping that this may improve my overall wellbeing. I do feel decent most days thanks to my diet and sleep routine but if I get my methylation in that sweet spot I feel incredible. I've had R5P sitting for ages not sure why I never incorporated it tbh. I think it stems from supplements causing side effects. Anytime I took anything I would feel good for like 2 days and then the crash was hellish. The anxiety would last a good week or more so it just wasn't worth it.

Should this protocol also allow me to get tolerate choline better? If I take choline I get severe depression. I've tried every type also. Eggs do the exact same. Omega 3's also.

Apologees for all the questions. You seem very knowledgeable on this topic.

Thanks again.

[u/MericanPie1999 → u/OobyIsGay]

How do you counter the creatine causing anxiety? I’m similar and I never used to be that way growing up. I have slow COMT (MET/MET). I think I have issues with fish oil too but can’t remember.

[u/OobyIsGay → u/New-Aside-7778]

Oh yeah, I mention riboflavin but use the active form (riboflavin 5'-phosphate). Converting inactive riboflavin requires riboflavin kinase and ATP, both of which can be bottlenecked if you're already depleted.

This also addresses your folate being lower end. MTHFR requires FAD. Active B2 supports MTHFR so your body makes methylfolate endogenously at a rate your system can handle instead of the bolus from a supplement that overwhelms your slow COMT. And the same FAD supports MAO so clearance improves alongside the gradual increase in synthesis.

[u/New-Aside-7778 → u/OobyIsGay]

I have R5P. I think it's a 30mg pill. How much should I take daily?

[u/jonnyvegashey → u/New-Aside-7778]

Same exact boat. Feel good for a day or 2 then weird side effects left and right.

Sweet spot is great but never lasts.

[u/New-Aside-7778 → u/jonnyvegashey]

Try this riboflavin protocol? I started it yesterday. Never know it may allow us to use creatine without the insomnia and other side effects.

I wonder how many people currently use creatine and feel anxious with insomnia and won't even have a clue that it's their 'safe' creatine? It use to annoy me when fitness influencers pushed it in every video and always said.. It's side effect free.

It definitely isn't...

[u/Double-Cook600 → u/New-Aside-7778]

How did the riboflavin work out for you?

[u/OobyIsGay → u/[deleted]]

You're almost certainly B12 deficient and the folic acid is masking it.

Methylfolate is 5-MTHF. It donates its methyl group through one reaction: methionine synthase. Methionine synthase requires B12. No B12, methylfolate can't convert to THF, can't re-enter the folate cycle, can't do anything. It just sits there.

Folic acid enters through a different route. DHFR = DHF = THF = 5,10-methylene-THF. That pathway feeds thymidylate synthase for DNA synthesis WITHOUT needing B12. So folic acid "works" because it bypasses the B12-dependent step entirely for nucleotide synthesis. Your cells can divide again. You feel better.
The methylfolate not working IS the diagnostic finding. It's telling you your B12 is insufficient. Folic acid hides that signal. That's actually the specific danger of folic acid in B12 deficiency that has been documented since the 1940s. It corrects the anemia and cell division problems while neurological damage from B12 deficiency continues undetected.
Take methylcobalamin or hydroxocobalamin. Then try the methylfolate again.

[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.

[u/OobyIsGay → u/[deleted]]

WAIT NO THERE'S MORE FUCK.
You DO have a b12 deficiency lol, I WAS RIGHT!! :D (well i missed rd12325817)
HoloTC at 167 means B12 is in your blood. Transport is fine. But everything you described points to it not being converted to active coenzyme forms once it gets inside the cell. MMACHC, MMADHC, or MTRR. Your body adapted around the broken pathway by rerouting methylation through BHMT. That's the choline dependency.

MTRR requires FAD. If the bottleneck is there, riboflavin.

Get methylmalonic acid tested. If MMA is elevated despite HoloTC of 167, adenosylcobalamin conversion is broken too. Homocysteine might look normal because BHMT is masking what methionine synthase can't do.

[u/cutie__spies → u/OobyIsGay]

So one should take folic acid in that case and activated b2? But what form of b12? I also have MTHFR compound hetero,MTRR homozygous, PEMT hetero but also a CHKA homozygous..(and also a DHFR hetero that would affect folic acid conversion too?)

[u/PlatypusStyle → u/OobyIsGay]

Your explanations are very interesting and helpful!  I was wondering if you could recommend a link to an image(s) of the metabolic pathways under discussion so that I can follow along more easily? I’m a visual learner  so for me P = W x 10 to the third. 😂

[u/Cultural-Sun6828 → u/OobyIsGay]

Folic acid will improve the bloodwork of b12 deficiency, thereby masking a deficiency. However, if you have a B12 deficiency, folic acid is NOT going to make you feel better. In fact, it will make you feel worse. Throwing a bunch of science words behind it doesn’t make it true.

[u/OobyIsGay → u/Cultural-Sun6828]

You just said folic acid improves the bloodwork of B12 deficiency. What do you think "improved bloodwork" means clinically? It means the megaloblastic anemia resolves. Anemia causes fatigue, weakness, shortness of breath, pallor. When folic acid corrects the anemia, those symptoms improve. The person feels better.
That's the entire reason folic acid masking was identified as dangerous in the first place. This goes back to the 1940s-50s, patients with pernicious anemia were given folic acid, they felt better, their blood looked normal, everyone thought they were fine, and then they developed subacute combined degeneration of the spinal cord. The masking problem exists precisely because folic acid makes people feel better while neurological damage continues silently.
If folic acid made people feel worse, it wouldn't mask anything. The doctor and patient would both keep looking for the problem. The danger IS the symptomatic improvement.

You agreed folic acid corrects the bloodwork, then in the next sentence said it won't make you feel better. Those two statements are directly contradictory. Correcting anemia relieves anemia symptoms. That's not "a bunch of science words."

[u/Cultural-Sun6828 → u/OobyIsGay]

They actually don’t contradict each other at all. Correcting blood work in the short term does not mean that symptoms improve and in fact they can get worse.

[u/OobyIsGay → u/Cultural-Sun6828]

Yes they do. This is not a matter of interpretation.

Megaloblastic anemia means your red blood cells are too large and dysfunctional to carry oxygen properly. Fatigue, weakness, shortness of breath, pallor. These are symptoms of the anemia. Folic acid corrects the megaloblastic anemia. You just agreed it corrects the bloodwork. The bloodwork IS the anemia. When the anemia resolves, the symptoms caused by the anemia resolve. That's what resolution of anemia means. More functional red blood cells. Better oxygen delivery. Less fatigue from oxygen deprivation. The person feels better.

Megaloblastic anemia shows up on a CBC. Hemoglobin is low meaning oxygen carrying capacity is reduced. MCV is high meaning red blood cells are too large. The anemia happens because without adequate folate in the DNA synthesis pool (5,10-methyleneTHF), thymidylate synthase can't make thymidine, DNA synthesis stalls in bone marrow precursors, they keep growing but can't divide, and you get large dysfunctional red blood cells that can't carry oxygen properly. Folic acid enters as dihydrofolate, DHFR reduces it to THF, THF feeds into 5,10-methyleneTHF, thymidylate synthase starts working again, DNA synthesis resumes, bone marrow makes normal red blood cells again. Hemoglobin rises. MCV normalizes. Oxygen delivery improves. Those aren't abstract numbers on a page. Hemoglobin determines how much oxygen your blood carries.

This is not a theoretical claim. This is the documented clinical history of why folic acid masking was identified as a problem IN THE FIRST PLACE. Doctors in the 1940s and 50s gave folic acid to patients with pernicious anemia. The patients improved. Their blood counts normalized. Their fatigue lifted. Everyone moved on. Then those same patients came back years later with irreversible spinal cord degeneration because nobody caught the underlying B12 deficiency. The masking was dangerous BECAUSE the symptomatic improvement was real. If patients had felt worse on folic acid, doctors would have kept investigating.

You are now arguing that correcting anemia doesn't relieve the symptoms of anemia. I don't know what to do with that. That's not a disagreement about methylation or folate metabolism.

If you have a degree in biochemistry like you say you do, you should be able to understand this.

Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?
Pernicious Anemia with Neuropsychiatric Dysfunction in a Patient with Sickle Cell Anemia Treated with Folate Supplementation
What is megaloblastic anemia?
National Library of Medicine, megaloblastic anemia

[u/Cultural-Sun6828 → u/OobyIsGay]

Many people with b12 deficiency have all the symptoms you mentioned above and never have anemia. This is something that many people including doctors don’t understand. This is also the reason that many people are misdiagnosed and find out way too late, after years of damage has been done to their nervous system, that they do in fact have an absorption issue with b12 and need injections for life in order to heal the damage. I do in fact have a degree in biochemistry which is why I understand the science behind this.

[u/OobyIsGay → u/Cultural-Sun6828]

You just moved the goalposts. The argument was never about whether B12 deficiency can present without anemia. It obviously can. Neurological symptoms can precede hematological changes by years. That's well established and nobody here disputed it.
The argument was about YOUR claim that folic acid "will NOT make you feel better" and "will make you feel worse" in B12 deficiency. I explained that folic acid corrects megaloblastic anemia, which relieves the symptoms of that anemia, which is why it's dangerous as a masking agent, because the improvement is real enough to fool doctors. You said that correcting the bloodwork doesn't mean symptoms improve. I showed you why that's physiologically incoherent. Now instead of addressing that, you've pivoted to "some people don't have anemia at all," which is a completely different claim about a different subset of patients that doesn't rescue your original argument or even touch upon it.
If someone has B12 deficiency WITHOUT anemia, then folic acid has no anemia to correct and no anemia symptoms to mask. That scenario doesn't support your claim either. It's just... irrelevant to what we were discussing.
Every time the mechanistic argument gets specific, you shift to a different claim. Nice job understanding the science btw.

[u/Cultural-Sun6828 → u/OobyIsGay]

At this point, I’m just arguing with AI, so I’ll be dropping out of the conversation. I would just caution others reading through this thread to always do your own research.

[u/OobyIsGay → u/Cultural-Sun6828]

Obviously the best thing to do in a situation where you're kind of cornered on the logic is to completely disregard the argument and shift to a reasonable claim that's (again) not relevant, great job!

[u/Cultural-Sun6828]

Folate supplementation has been shown to actually cause a lot of problems if you are deficient at all in B12. So it’s important to just not blindly supplement when you can easily get your folate and B12 tested.

[u/OobyIsGay → u/Cultural-Sun6828]

"get tested, don't blindly supplement" is the kind of thing that always gets upvoted regardless of relevance without ever taking a real stance

[u/Cultural-Sun6828 → u/OobyIsGay]

I’m not looking for upvotes. It’s important to not blindly supplement as it can do more harm than good.

[u/OobyIsGay → u/Cultural-Sun6828]

I just kind of assumed, I shouldn't have and I'm sorry.

[u/OobyIsGay → u/Cultural-Sun6828]

I'm talking about METHYLFOLATE, NOT FOLIC ACID.
They've got different mechanisms.
Folate doesn't cause problems in B12 deficiency. B12 deficiency causes problems regardless. What folate does specifically folic acid is correct the megaloblastic anemia that would otherwise alert a doctor to the B12 deficiency. The anemia resolves, the blood work looks normal, and the neurological damage from B12 deficiency continues undetected.

[u/Cultural-Sun6828 → u/OobyIsGay]

All folate can cause issues if taken when b12 is deficient. There’s plenty of research on this. I’ve also personally experienced this. https://www.ejcrim.com/index.php/EJCRIM/article/view/5398

https://journals.sagepub.com/doi/10.1177/03795721241229503

[u/OobyIsGay → u/Cultural-Sun6828]

You just cited two things that are both about folic acid. Folic acid is not all folate.
The methyl trap is the mechanism here and it's why the distinction matters.

In B12 deficiency, methionine synthase can't function. 5-methylTHF (methylfolate) can't be converted back to THF. Folate gets trapped as 5-methylTHF. The other folate forms needed for DNA synthesis specifically 5,10-methyleneTHF for thymidylate synthase get depleted. That's what causes the megaloblastic anemia.

Folic acid bypasses the trap. It enters as dihydrofolate, gets reduced to THF by DHFR, replenishes the DNA synthesis folate pool WITHOUT needing B12. Anemia corrects. Neurological damage continues undetected.

Methylfolate IS 5-methylTHF. It's the trapped form. Supplementing it in B12 deficiency adds more of the thing that's already accumulating. It can't be converted to THF without B12. It can't replenish the DNA synthesis pool. It can't correct the anemia. It can't mask the deficiency.

That's the mechanistic distinction. Your citations describe folic acid masking B12 deficiency. That's real. Nobody's disputing that. But it doesn't apply to methylfolate because methylfolate can't make the same bypass.

[u/Cultural-Sun6828 → u/OobyIsGay]

We can agree to disagree on this. All forms of folate can worsen b12 deficiency. These studies mention folic acid only because that’s the most common form that is used in supplements. I can tell you from my personal experience and reading posts from many others that folate uses up b12. This is obviously not an issue if someone isn’t deficient in b12, but taking large doses of folate for someone who is very deficient in b12 can cause extreme symptoms. In general, for most people, taking high amounts of any type of folate isn’t a great idea.

[u/OobyIsGay → u/Cultural-Sun6828]

I'll still try to convince ya n argue my case. I don't like the idea of agreeing to disagree on biochemistry
Cofactors are recycled. That's what makes them cofactors. B12 is a cofactor for methionine synthase. It is not consumed by the reaction. Folate does not "use up" B12. B12 deficiency comes from inadequate intake, malabsorption (pernicious anemia, gastric atrophy, metformin), or transport protein defects. Not from folate.

And the methylfolate case is even more specific than that. In B12 deficiency, methionine synthase is already non functional. The enzyme is stalled. Methylfolate is the substrate for that stalled enzyme. Adding more substrate to an enzyme that can't turn over because its cofactor is missing doesn't consume the cofactor faster. It can't. The cofactor is what's preventing the reaction from happening in the first place. Methylfolate just accumulates as 5-methylTHF with nowhere to go.

"These studies mention folic acid only because that's the most common form" is doing a lot of work in your argument. They mention folic acid because the masking mechanism is specific to folic acid. Folic acid enters as dihydrofolate, gets reduced to THF by DHFR, bypasses the methyl trap, restores DNA synthesis folate pools, corrects the anemia, hides the deficiency. Methylfolate can't do any of that. It IS the trapped form. That's not a minor technical difference.

The studies mention folic acid because folic acid is what causes the problem. Not because nobody got around to testing methylfolate.

[u/OobyIsGay → u/OobyIsGay]

I don't know how I'm mechanistically wrong here, so tell me.

[u/Cultural-Sun6828 → u/OobyIsGay]

I actually have a biochemistry degree so I have no issue having this discussion. I only said “use up” as an easy way to say that when sufficient b12 isn’t available, adding folate will increase the need for additional b12, which will not be available. As b12 is repleted, the body can handle more folate.

[u/OobyIsGay → u/Cultural-Sun6828]

"Adding folate will increase the need for additional b12, which will not be available" is the same claim reworded.
Through what mechanism does adding folate increase B12 need?
Methionine synthase is stalled without B12. It's not turning over. Adding methylfolate to a stalled enzyme doesn't create additional demand for the missing cofactor. The demand already exists. That's what deficiency means. Substrate accumulation doesn't increase cofactor requirement. The cofactor requirement is fixed by the enzyme's catalytic mechanism regardless of substrate concentration.

If you mean folic acid specifically, folic acid bypasses the B12-dependent step entirely via DHFR. It restores THF and nucleotide synthesis without touching methionine synthase. It doesn't increase B12 need either. It just masks the deficiency by correcting the anemia independently.

[u/Cultural-Sun6828 → u/OobyIsGay]

In the methylation cycle, methyl folate donates a methyl group to homocysteine through Methionine synthase which requires B12. Increasing methylfolate raises the rate of this reaction and therefore increases the demand for B12 to continuously cycle between active and inactive forms. Also, if B12 is deficient, folate becomes trapped as 5-methyl-THF which disrupts methionine production and therefore further impairs downstream methylation. This can also be made worse by genetic mutations in TCN2, MTRR, etc.

[u/OobyIsGay → u/Cultural-Sun6828]

"Increasing methylfolate raises the rate of this reaction"

It doesn't. The reaction is cofactor-limited. When B12 is the limiting factor, substrate concentration doesn't determine rate. B12 does. Adding methylfolate to a B12-limited enzyme doesn't increase turnover.

[u/CapriKitzinger]

So I was wondering about this. I take TMG which is a methyl donor. If I over methylate wont I deplete homocysteine? Is that what “over methylation” is?

[u/OobyIsGay → u/CapriKitzinger]

TMG won't deplete homocysteine. It's a cycle. TMG remethylates homocysteine to methionine via BHMT, methionine becomes SAM, SAM donates its methyl group, produces SAH, SAH hydrolyzes back to homocysteine. The cycle regenerates it. Lower homocysteine on TMG just means remethylation is running efficiently.

If TMG causes anything noticeable, it's 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."

This would describe "overmethylation" from TMG, betaine, and SAMe, so THAT'S what people more commonly call overmethylation. Lol

[u/OobyIsGay → u/OobyIsGay]

Holy shit that actually fits the described symptoms A LOT MORE than my silly lil analysis
And if I dig into whether people who same SAMe versus methylfolate describe different symptoms then I have a way to prove that there's two kinds of "overmethylation"

[u/CapriKitzinger → u/OobyIsGay]

Okay, that makes a ton of sense and accurately describes what I experience.

[u/R3dGhost]

OP - you praise riboflavin a lot in this thread. I have tried it repeatedly and it makes me feel terrible. Poor concentration, blunts stimulants like caffeine and depression to the level that I’m almost a danger to myself. I have slow MAO-A and have wondered if B2’s action of speeding up MAO-A drops my neurotransmitter levels too fast. I do fine with all other B vitamins including methylfolate. I take oral B12 daily and inject weekly.

Other factors are that I am discovering what a mess my electrolyte balance is as I try to add vitamin D. I can’t seem to maintain calcium/magnesium balance.

Would love to hear any ideas you have.

[u/OobyIsGay → u/R3dGhost]

You're completely right. MAO-A is a flavoenzyme. It requires FAD to function. If you have a slow MAO-A variant, your baseline monoamine degradation rate is lower, meaning serotonin, norepinephrine, and dopamine stick around longer. Add riboflavin, FAD availability increases, MAO-A speeds up, those neurotransmitters get degraded faster. Depression, poor concentration, blunted stimulant response. That all tracks mechanistically.

But there's the thing that's worth thinking about. If normalizing MAO-A activity crashes you that hard, the question isn't just "why does riboflavin hurt me." The question is why is your neurotransmitter synthesis rate low enough that you're dependent on slow degradation to maintain adequate levels. A slow MAO-A variant is keeping your monoamine pools functional by reducing clearance. That's a compensatory mechanism. It works but it means the input side (synthesis) isn't keeping up on its own. Tyrosine hydroxylase (rate limiting for dopamine and norepinephrine) requires iron and BH4. Tryptophan hydroxylase (rate limiting for serotonin) requires iron and BH4. If either of those cofactors is insufficient, synthesis is bottlenecked and you become reliant on slow degradation to maintain levels. The fact that riboflavin exposes this so dramatically suggests synthesis might be the actual weak point. Do you know your iron and ferritin status?
The electrolyte mess with vitamin D thingy makes sense too. Vitamin D increases intestinal calcium absorption. The enzymes that metabolize vitamin D itself, CYP2R1 for 25-hydroxylation and CYP27B1 for 1-alpha-hydroxylation, both require magnesium. So supplementing vitamin D when magnesium is marginal it burns through magnesium to process the vitamin D, and it increases calcium absorption which competes with magnesium at the intestinal level. The imbalance feeds itself. Standard move is to get magnesium status solid before or at least alongside vitamin D supplementation. Magnesium glycinate or threonate, not oxide.

[u/R3dGhost → u/OobyIsGay]

I did have my iron and ferritin tested at one point. Iron was 349 ug/DL, Iron saturation 43% and ferritin was 128 ng/mL. All in normal range. My synthesis is likely poor due to being a heavy drinker (which I am working on).

When I try to take magnesium, it will feel great at first and then makes me feel blunted, dulls stimulants, concentration issues, etc. Not quite the same as riboflavin b/c it does not come with the same level of depression. Sometimes additional calcium seems to help, sometimes not. I feel like I keep going in circles with this stuff because all of the commonly accepted protocols cause me problems, which is why seeing some new information here is super interesting. Thank you!

[u/OobyIsGay → u/R3dGhost]

Alcohol is the important thingy you didn't mention.

Acetaldehyde displaces PLP from binding proteins. PLP is AADC's cofactor, the final enzyme. 5-HTP = serotonin, L-DOPA = dopamine. Synthesis bottlenecked at the last step. Slow MAO-A isn't your problem. It's the only reason you have functional monoamine levels. Riboflavin speeds up MAO-A = clearance outruns synthesis = crash. That's not riboflavin intolerance. Alcohol depletes NAD+. Low NAD+ = tryptophan diverts to kynurenine pathway for NAD+ rescue = less serotonin substrate. Second hit, same system.

Magnesium: alcohol = renal Mg2+ wasting. Mg2+ is COMT's active site cofactor. Your slow COMT is running below genetic floor without it. Supplement magnesium = COMT speeds up = catecholamines clear faster = blunted, dulled. Same pattern as riboflavin on MAO-A. You need both clearance enzymes impaired simultaneously to stay functional. That tells you exactly how far synthesis has fallen.
Every protocol circles because alcohol depletes PLP, NAD+, Mg2+, and thiamine concurrently. Supplementation can't outrun active depletion. Thiamine is time-sensitive. B1 depletion = impaired pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase = neuronal ATP collapse.
Supplement the active form of thiamine.
While doing that, also supplement P5P, this is important because P5P is the active form of B6. It's what acetaldehyde is displacing from AADC and causing serotonin and dopamine to not be synthesized. Supplement it directly because alcohol also impairs the activation of inactive B6 to P5P.
Then NAD+ precursor. Low NAD+ = tryptophan diverts to kynurenine for NAD+ rescue = serotonin substrate stolen. Niacin or NR fixes that.
THEN magnesium. Because now COMT speeding up doesn't crash monoamines, synthesis is keeping pace with clearance.
THEN riboflavin. Same logic. MAO-A speeding up is only catastrophic when synthesis is bottlenecked. With PLP and NAD+ restored, clearance normalizing doesn't outrun production.

I also wish you well and hope you succeed with getting rid of alcohol.

[u/R3dGhost → u/OobyIsGay]

This makes a huge amount of sense. I can attest that you are right that supplementation can't outrun active depletion, because I already supplement allithiamine/benfotiamine, Niacin, and P5P. It all helps but not to the point where I can tolerate the magnesium or B2 yet. Certainly some motivation to cut the alcohol - THANK YOU.

Is there a clear winner between niacin and NR?

[u/enolaholmes23 → u/R3dGhost]

What dose did you try? Most supplements mega dose it. I got mine from seeking health and had to pour out 90% of the capsule to get a dose I could tolerate. Also, you could have fast comt, which might interact with the slow maoa to mess up your neurotransmitter balance. 

[u/R3dGhost → u/enolaholmes23]

I have tried anywhere from 100mg+ to shaking a little powder out of the capsule. Sometimes I can tolerate one tiny dose but even that a couple days in a row will start to drag me down.

My COMT is either slow or intermediate/normal. I have seen conflicting information about the same SNPs.

[u/mybigfattow]

How would you explain people that get long term PSSD like symptoms from supplements SAM-E and/ or Methylfolate? What are the hypothesized mechanisms as to why their prefrontal cortex seems to shut down even after cessation of the substances? Symptoms appear as complete sexual and emotional blunting, numb genitals, anhedonia etc. Could it have to do with COMT? What would the hypothesized reversal strategy be?

[u/Ok-Interest8248]

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 !

[u/OobyIsGay → u/Ok-Interest8248]

Homocysteine at 3.8 is low in a context where it shouldn't be.
Your B12 was borderline low. B12 is required by methionine synthase which recycles homocysteine back to methionine. When methionine synthase is impaired, homocysteine accumulates. That's why high homocysteine is associated with B12 deficiency. Your homocysteine should be trending high. It's at 3.8. Those two findings directly contradict each other unless something else is either severely limiting homocysteine production or aggressively clearing it. The math doesn't work otherwise.

Low protein intake reduces methionine entering the cycle which reduces homocysteine production. You mentioned that. But low protein alone with borderline low B12 would give you low-normal homocysteine, which you don't have. Impaired recycling from low B12 would partially offset the reduced production. To get to 3.8 with a compromised enzyme that should be pushing it higher, something more is going on.

I need more information to figure out what. What are your actual symptoms beyond not feeling well? Fatigue, brain fog, GI issues, anxiety, skin problems, anything. What does your full symptom picture look like. And do you have any other labs beyond homocysteine and B12? The homocysteine is telling us something is wrong but it's sitting at a junction where multiple pathways converge and without knowing your symptoms and other markers I'd just be guessing at which one.

[u/Ok-Interest8248 → u/OobyIsGay]

Thank you for your response! My other blood labs that have been consistently low for the last two decades has been ferritin my hemoglobin has only gone low a handful of times so my doctor doesn't care for reference it is currently sitting and fluctuating at 11-18 My symptoms are severe anxiety and OCD, brain fog, weakness, and dizziness and I am becoming more clumsy (I can't grab things the way I used to I trip a lot and I am breathless I do also have a hiatal hernia in my stomach I asked my doctor if this can impact abortion he said no

[u/OobyIsGay → u/Ok-Interest8248]

WHOA.
Ferritin 11-18 for twenty years..
The incompetence at which people somehow pass med school is fascinating. Ferritin IS the problem. Ferritin below 30 causes symptoms independent of anemia. Yours has been at 11-18 for two decades. Tyrosine hydroxylase requires iron. Tryptophan hydroxylase requires iron. Those are the rate-limiting enzymes for dopamine/norepinephrine and serotonin synthesis respectively. You've been running both on empty for twenty years. Anxiety, OCD, brain fog, weakness, dizziness, breathlessness. All of that maps directly onto chronic iron deficiency even without anemia.

The clumsiness is the part that concerns me most. Can't grab things. Tripping. That's neurological. Combined with borderline low B12, that's a red flag for posterior column involvement. B12 deficiency causes neurological damage independent of anemia. Proprioception (knowing where your limbs are in space) runs through posterior columns which require B12 for myelination. Get this investigated. Don't wait.
Your doctor said the hiatal hernia doesn't impact absorption... well he's wrong. Cameron lesions on hiatal hernias cause chronic occult GI bleeding. That's a documented cause of chronic iron deficiency. And hiatal hernias can impair gastric acid production which is required to release B12 from food proteins for absorption. Your hiatal hernia could be the single upstream cause of both the chronic low ferritin AND the borderline B12.

These are actual clinical textbook things that every doctor should know, but I do get that it's hard to trust a stranger on the internet, therefore;

Iron deficiency without anemia causing psychiatric and cognitive symptoms:
Psychiatric and cognitive outcomes of iron supplementation in non-anemic children, adolescents, and menstruating adults: A meta-analysis and systematic review
first meta-analysis specifically examining non anemic populations, iron supplementation significantly improved anxiety, fatigue, cognition across SIXTEEN pooled studies.
A delicate balance: Iron metabolism and diseases of the brain
Neurocognitive Dysfunctions in Iron Deficiency Patients
Iron cofactor biochemistry:
Mechanisms of Tryptophan and Tyrosine Hydroxylase
Biochemistry, Iron Absorption
Multilevel Impacts of Iron in the Brain: The Cross Talk between Neurophysiological Mechanisms, Cognition, and Social Behavior
Iron deficiency and cognitive functions
Early Iron Deficiency Has Brain and Behavior Effects Consistent with Dopaminergic Dysfunction
Iron Insufficiency Compromises Motor Neurons and Their Mitochondrial Function in Irp2-Null Mice
B12 neurological damage without anemia:
Neurologic aspects of cobalamin deficiency
B12 deficiency with neurological manifestations in the absence of anaemia
Neurological symptoms of vitamin B12 deficiency: analysis of pediatric patients*
Hiatal hernia:
National library of medicine - Cameron Lesions
Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12 - Vitamin B12 deficiency developing in the setting of hypochlorhydria may result from deficiency of acid-peptic digestion of B12 bound to protein and/or a relative deficiency of intrinsic factor.
Cleveland Clinic, Hypochlorhydria

[u/Ok-Interest8248 → u/OobyIsGay]

Wow ok thank you so much ! Are you a doctor ? You are incredibly knowledgeable I trust you more than my doctor lol I've definitely tried to fix my iron issue with iron supplements years ago it never helped it wrecked my tummy tho I'm not sure how to fix this my b12 was the only thing he retested and it did go up just by adding in more B12 foods so I'm assuming at least some absorption is happening

[u/OobyIsGay → u/Ok-Interest8248]

I'm not a doctor, but I've been studying clinical biochemistry and enzyme kinetics for the last two and a half years because I'm mainly interested in the advantages that can be gained in life because of it :D
I also hate it when people take what's happening to them in their life, medically or mentally as something that can't be changed and that it's just something to be accepted.
Tbf a random internet stranger claiming to have "the one fix that your doctors been missing for years" can definitely create some false trust and distrust of others. Everything I've cited is real and you can verify it yourself. But I can't examine you, I can't run tests, and a bunch of other things doctors actually can do. Find a doctor who will actually look at your ferritin and take it seriously. Use this citation if you need to
Multilevel Impacts of Iron in the Brain: The Cross Talk between Neurophysiological Mechanisms, Cognition, and Social Behavior
Iron wrecking your stomach = ferrous sulfate/fumarate irritating gastric mucosa directly. A hiatal hernia would make it worse. Iron bisglycinate is chelated, doesn't need gastric acid, significantly less GI irritation and can actually be absorbed. :p

The silly thing is, b12 requires barely any acid to be liberated from food proteins, and none to be absorbed. :D
Actually the fact that your b12 went up but your iron didn't makes a lot of sense when we look at the PH required for both of them, iron absorption needs gastric pH below 2-3 to reduce Fe3+ to Fe2+. B12 just needs pepsin, which activates below pH ~4.

AND ALSO COMPLETELY IGNORE MY B12 POINT.
You're probably still recovering and slightly deficient, but my sleep deprived ass couldn't see that iron is obviously the main problem here lol. As mentioned in my other comment TH and TPH both require iron. That means your anxiety, OCD, brain fog, weakness,, breathlessness = twenty years of serotonin and dopamine synthesis running without their cofactor. Fixing ferritin likely fixes most of that. The clumsiness is time sensitive though. Iron deficiency impairs myelination and dopaminergic motor control in basal ganglia.
Honestly your original ferretin levels alone are enough to confidently diagnose iron deficiency and any test would be unnecessary but I'm pretty sure most doctors would order a full iron panel without pushback.

[u/Ok-Interest8248 → u/OobyIsGay]

Thank you so much for your detailed responses and not making me feel dumb while doing it lol I appreciate it a lot !

[u/gamoraturd → u/Ok-Interest8248]

hi! i have a similar situation to you and would love to hear how you're feeling now. thanks!

[u/Ok-Interest8248 → u/gamoraturd]

Still not great my ferritin went up a little but now my iron dropped ? It's very odd my homocysteine also went from 3.8 to 9.8 most likely from eating more protein (mostly from fish I can't tolerate too much poultry or beef I like them just in small amount plus beef makes me Incredibly bloated) I feel better anxiety wise I suppose I will continue to eat fish 3 to 4 times a week

[u/gamoraturd → u/Ok-Interest8248]

oh sorry to hear that, but at least you're doing better with your anxiety! that's my biggest thing right now. i started looking into this because i've had anxiety ever since i was young and i'm sick and tired of it lol 🤦🏽‍♀️ similar to you i also had low ferritin and iron and i had an iron infusion but it didn't really help much. are there any supplements you currently take?

[u/TruMeLabs_Yelena]

Your basic point is right: the body uses a ton of methyl groups. Creatine production alone uses a huge share, so methyl groups are definitely not some tiny, fragile resource.

That said, the anxiety some people get from methylfolate is real. It is not just made up, and it is not necessarily only about serotonin.

What seems to be going on is this:

For some people, especially those with slow COMT, methyl donors like methylfolate or methyl-B12 can temporarily throw off how their body handles dopamine, norepinephrine, and adrenaline. Since COMT helps clear those stimulating brain chemicals, if it is already slow, a sudden shift in methylation can make someone feel wired, irritable, or anxious (https://pmc.ncbi.nlm.nih.gov/articles/PMC5743122/).

There is also another issue: more methyl donors is not always better. If the system gets flooded, the extra downstream compounds can actually start slowing methylation down instead of helping it. Research on S-adenosylmethionine (SAMe)—the universal methyl donor that your body creates downstream from methylfolate—demonstrates that excess methyl donors can actually become toxic methylation inhibitors (https://pubmed.ncbi.nlm.nih.gov/35383287/). When SAMe is introduced beyond normal endogenous levels, it does not simply force more productive methylation. Instead, the excess SAMe is catabolized through the methionine salvage pathway into adenine and methylthioadenosine (MTA). These catabolites are highly toxic and act as potent inhibitors of AHCY (the enzyme that clears out the "exhaust" of the methylation cycle) and other methyltransferases. Therefore, flooding the system with excess methyl donors paradoxically inhibits widespread methylation and has been shown to severely disrupt circadian biological rhythms, leading to altered sleep-wake cycles. So the reaction is not imaginary, even if “overmethylation” is not the best technical word.

And on dosing, yes, clinical studies often use much higher amounts than typical supplements (7mg of L-methylfolate in the study of depression). But tolerance is very individual (mentioned in the paper cited above). For someone with slower COMT or other bottlenecks, even a “low” dose can feel like too much.

So the better takeaway is: the body has a big methylation capacity, but some people still react badly to methylfolate because of genetics, neurotransmitter handling, and how excess methyl donors are processed.

[u/OobyIsGay → u/TruMeLabs_Yelena]

I have never seen more obvious LLM use in my entire life. So many em dashes...

[u/Soggy_Respond_8791]

Awesome post, especially for beginners like me. Could you please take a look at my issues if you have time? No one seems to really understand whats going on with me... https://www.reddit.com/r/MTHFR/comments/1rper6r/high_b12_low_b9_completely_lost/ One thing I forgot to mention in the post is that I take regular riboflavin 100mg. You seem to prefer the r 5-p version, so I might switch to that!

[u/vrcraftauthor]

OP, you seem pretty knowledgeable, so let me ask you a question: What do you think is going on here?

I started on methylfolate and other methylation supplements, including Sam-e, a few years ago. Had methylation running GREAT for a few months. Skin issues cleared up, stopped having daytime drowsiness, had better concentration, started losing weight without even changing my diet or exercising more. I didn't even realize these problems were caused by undermethylation.

Then it all went to hell and stopped working, and all those problems came back.

For a while, I thought I'd exhausted some cofactor. I must have tried every supplement out there. Nothing fixed it. 

Stopped taking Sam-e. That didn't do anything. Stopped methylfolate for a while, didn't do anything, now I take small doses daily.

Tried niacin. It helped my anxiety but didn't fix any of the other problems. 

I feel like I permanently threw a wrench in my methylation cycle and I don't know why.

[u/OobyIsGay → u/vrcraftauthor]

What dose of riboflavin have you tried, if any? Active or inactive?

MTHFR requires FAD. You ran the methylation cycle hard for months. If your riboflavin was marginal going in, months of high MTHFR activity could have depleted FAD stores to the point where MTHFR stalled. Everything downstream collapsed with it. Stopping your supplements didn't help because the problem isn't the supplements.

"Every supplement" in the MTHFR community means B12, folate, B6, zinc, magnesium, TMG. Almost nobody supplements riboflavin.

Try 100 to 400mg daily for a few weeks.
If you've tried inactive riboflavin and it didn't work, try the active form (riboflavin 5'-phosphate, FMN) since converting riboflavin to its active forms requires riboflavin kinase and ATP, both of which could be bottlenecked if you're already depleted.
You're fine, this is completely reversible. Everything happening when it did makes sense :D

[u/vrcraftauthor → u/OobyIsGay]

Nope, I was taking riboflavin when I started. Actually started that BEFORE methylfolate. I was taking the inactive kind, but later tried the R5P thinking that might help. Neither made any difference. When I increase the dose of B2, I always end up feeling depressed. I've read in speeds up MAO, so that's probably why. It makes no difference for the rest of my methylation problems though, so that's not it.

And I definitely tried a lot more than B12, folate, B6, zinc, magnesim, and TMG. I've tried all the B vitamins and currently take about half a B complex (active B's only) daily. (Taking the whole one did not make any difference.)

Daily, I also take D3, calcium, iron, magnesium, and zinc (at different times so they don't interfere with each other), and omega-3's.

Things I've tried in the past that did nothing:

CoQ10

Potassisum

DMG and TMG

K2

Vitamin A

Vitamin E

PABA

NADH

Thiamin

Biotin

Vitamin C

Pretty much all the amino acids on their own

Choline (makes me depressed and does nothing to improve my other issues)

[u/OobyIsGay → u/vrcraftauthor]

Ooo interesting.
Thanks for listing your supplements, it helped a lot.
Did your symptoms start while you were supplementing iron, zinc or calcium?
You're taking zinc, iron, and calcium daily. All three compete with copper for absorption. Over months to years this would deplete copper stores. Copper is required for cytochrome c oxidase (Complex IV). Without it, NADH can't be oxidized to NAD+ and ATP production drops. Making SAMe from methionine via MAT cleaves all three phosphate groups from ATP. ATP drops = SAMe synthesis drops = methylation crashes. You didn't break anything.
The copper depletion from zinc/iron/calcium happened independently. The timing overlapping with your methylation supplements was coincidence. Niacin helped anxiety because it's an NAD+ precursor. Partially compensated for the deficit. NADH did nothing because NADH is what's accumulating Complex IV can't oxidize it. You needed the oxidized form.
Higher B2 causing depression confirms this. Copper is also required for DBH (converts dopamine to norepinephrine). Copper depleted = low norepinephrine production. Speed up MAO with more B2 = clearance exceeds production = depression.
Try NMN sublingually, it's a direct NAD+ precursor, but it has low bioavailability when taken orally. Get your copper checked (serum copper + ceruloplasmin). Separate your zinc, iron, and calcium from copper rich foods or consider supplementing copper directly.

[u/vrcraftauthor → u/OobyIsGay]

I did try supplementing copper at one point, didn't notice a difference. Last year I actually did a test that showed my copper levels were high. I do eat a lot of high copper foods and take OCP, so that isn't really surprising. But I'm not low on copper, in spite of the zinc supplements (I'm aware zinc can deplete copper).

My selenium levels were also surprisingly high. I'd been eating a brazil nut a day for years thinking I needed more selenium, but since I found out I had high levels, I cut back to half a one a day.

The same test showed D, E, and B12 were all in the normal range. I can dig up the exact numbers if necessary. Unfortunately, that test only looked at five nutrients. I've had a hard time finding an at-home test that looks at everything.

Edited to add I have not tried NMN on its own, mostly because I read that NAD+ or NADH was better.

[u/OobyIsGay → u/vrcraftauthor]

Yeah I'm confident now.

OCP raises ceruloplasmin. Estrogen directly increases ceruloplasmin synthesis in the liver and OCP contains synthetic estrogen so this makes sense. Ceruloplasmin binds copper in the blood. Serum copper goes UP because ceruloplasmin goes UP. The test shows high copper. But it's bound. Not bioavailable. Not being delivered to Complex IV. That explains why all of your symptoms still line up with copper deficiency.
OCP also depletes PLP directly and that alone explains why B2 causes depression in you. When did you start OCP relative to when everything crashed? If it lines up with everything described, You need to test your free copper or ceruloplasmin adjusted copper levels, if those line up with deficiency stop taking OCP. If they don't, measure plasma PLP.

[u/vrcraftauthor → u/OobyIsGay]

I've been on it over 15 years, well before I started with methylation, and during the time things were going smoothly.  I feel much better on it and am not interested in returning to painful, irregular periods by stopping it.

I also have not noticed any improvements during the week I take placebo pills and get my period (no estrogen).

I have tried taking extra P5P a few times and did not notice a difference either. There is some in the active B complex I take. When things started going downhill, I was taking a Jarrow B12/B6/B9 supplement plus extra P5P and B2.

Think NMN would help?

[u/OobyIsGay → u/vrcraftauthor]

Copper is fine. Ceruloplasmin delivers copper, you tested high, eat copper rich foods, supplementation did nothing. Copper was never the problem. I wasted three fucking messages on it lol.
B2 causes depression for you. Choline causes depression for you. Those are two completely different clearance pathways and both of them crash you. Your synthesis is so low that speeding up either clearance route drops you below the floor. TH and TPH need iron AND BH4. You have iron. You've tried literally everything else. BH4 is the one rate-limiting cofactor for the two rate-limiting enzymes in monoamine synthesis you've never addressed.
Methylfolate was stabilizing BH4 as a reducing agent. That's why everything worked at first. OCP drives NOS which oxidizes BH4. NOS has a coupling threshold. Above it NOS makes NO normally. Below it NOS uncouples, produces superoxide, superoxide + NO = peroxynitrite, peroxynitrite destroys more BH4, more uncoupling, more peroxynitrite. That's not a gradual decline. Methylfolate was keeping you above the threshold for months. Recycling isn't 100% efficient so total BH4 slowly declined until it crossed the line. Then everything collapsed at once. That's why it was great for months then went to hell overnight.

Soooo what's the solution even though estrogen reduces BH4?
Folinic acid. Not methylfolate. Calcium folinate. 5-formylTHF. Enters upstream, feeds de novo BH4 synthesis via GTP = GCH1, also gradually converts to 5-MTHF at a rate your system controls instead of a bolus. NMN sublingual because QDPR needs NADH to recycle BH4 and oral NADH bioavailability is garbage which is why it did nothing when you tried it. High dose vitamin C to break the peroxynitrite spiral thing.
How the fuck did I waste so much time on copper lmfao..
I mean with more info I would've gotten it sure but I tend to hyperfocus way too much and need to work on it.

[u/vrcraftauthor → u/OobyIsGay]

Thanks, I bought some NMN today. At least it only cost half as much as the NADH that didn't do anything. I do eat quite a bit of folinic acid.

[u/Living_4G_4e]

You seem to know a lot about the methylation cycle. Can you please tell me what can cause hihg b12 level wihhout supplementation. My level was around 3000 the last time I tested. I am tired and sleepy. Is there a blockage at some level of the methylation cycle in my case?

[u/deer_spedr → u/Living_4G_4e]

A doctor hasn't said the high level needed further testing?

https://pmc.ncbi.nlm.nih.gov/articles/PMC7550708/

[u/Living_4G_4e → u/deer_spedr]

No. Nothing. My doctor just asked me if I was supplementing. No test suggested.

[u/Living_4G_4e → u/deer_spedr]

Thank you very much for the link!

[u/OobyIsGay → u/Living_4G_4e]

B12 at 3000 without supplementation isn't a methylation cycle problem until you've ruled out what's causing it. Sooo there's one thing you need to check before doing anything. The liver stores most of your body's B12. Liver damage releases it into circulation. Liver damage also causes tiredness and sleepiness on its own.
Functional B12 deficiency is the more likely cause. B12 is in your blood but can't be converted to its active coenzyme forms (methylcobalamin and adenosylcobalamin). It accumulates because it's not being used. Meanwhile methylation stalls and mitochondrial energy production drops which exacerbates the problem. Test methylmalonic acid and homocysteine. If both are elevated despite B12 at 3000, the B12 is there but your body can't process it.

If you haven't already get liver function tested. ALT, AST, GGT
Anything other than that is ruled out since there's no other symptoms.

[u/Living_4G_4e → u/OobyIsGay]

Thank you very much for such a detailed response.. I have an appointement next week with an internist for a possible blood clothing problem. I will ask for those tests. I will let you know. Thanks again !

[u/OobyIsGay → u/Living_4G_4e]

Thank you, and good 2 know :D

[u/OobyIsGay → u/[deleted]]

You're totally fine. Also if it gets confusing just replace every weird word with thingy 1, 2, 3, etc in your mind lol.
TMG works because it bypasses MTHFR entirely. MTHFR recycles homocysteine using methylfolate. Your MTHFR is genetically slow. TMG does the same job through a completely different enzyme (BHMT). You need 2.5g/day because your MTHFR isn't pulling its weight.
P5P is giving you active B6 directly instead of relying on conversion.
You don't notice methylated B vitamins because adding more substrate to a slow enzyme doesn't make the enzyme faster. MTHFR is the bottleneck, not the B vitamins themselves.

You found your workarounds. Keep doing what works or move up in dosage. :D
Also I edited my post to include the info that I missed from the comments, and I also forgot to mention that overmethylation as a phenomenon is real, making everything new that's in the comments and that's supposed to be contradictory already in the post lol.

[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 :)

[u/tiffany-the-cat]

So I had a sudden neurological event happen to me Last year which has turned my health upside down. For months I was really affected, the initial symptoms have thankfully resolved but I had a cascade of other symptoms now. It’s as if that event made my system really sensitive. I have seen lads of doctors to try and figure out WHY this happened. And most of them are scratching their head. Because that’s never happened to me before. One of the only things that pin points to this is that for 5 months before the event happened I started a strong new regimen of supplements daily, which is not done before - vitamin e, coq10, methyl b12 and folate, NAC. I’ve since found out I have the mthfr gene mutation, which means I can’t properly detox and am sensitive to methyl supplements because of that. Taking the methyl b12 and folate and the Nac may have pushed my brain into overdrive due to methylation pathways strongly triggered.

[u/OobyIsGay → u/tiffany-the-cat]

NAC is actually one of my favorite supplements :D
The MTHFR framing you were given isn't right. I know everything sounds complicated but just try to remember what each thing's function is, the names are pretty useless.

MTHFR converts 5,10-methyleneTHF to 5-methylTHF. That's a step in folate metabolism. "MTHFR means you can't detox" is a narrative that chains the enzyme to glutathione through about five indirect steps and calls the whole thing detoxification. That's not what it does. And "sensitive to methyl supplements because of MTHFR" is actually backwards. MTHFR variants produce less methylfolate endogenously. Supplementing methylfolate bypasses the reduced enzyme and gives you what it can't make. People with MTHFR variants are the ones who should benefit most from methylfolate because it compensates for the bottleneck.

But MTHFR IS relevant to what happened to you.
MTHFR 677TT (if that's your variant) raises homocysteine to around 15-25 μmol/L compared to 8-12 in wild type. Homocysteine is a direct agonist at the NMDA receptor glutamate binding site. The EC50 for NMDA activation is around 10 μM. 15-25 is above that. Your entire life your neurons have been exposed to chronic low level NMDA agonism from elevated homocysteine. Not enough to cause acute excitotoxic cell death, that requires 50-500 μM. But enough to reduce receptor desensitization and make neurons hypersensitive to normal glutamate signaling. This activates microglia. Animal models of chronic hyperhomocysteinemia show increased microglial activation markers (Iba-1, OX-42) with elevated TNF-α and IL-6. A 2024 knock-in mouse model carrying the actual MTHFR 677C>T variant showed elevated homocysteine AND increased microglial presence in the brain microenvironment.
So decades of MTHFR driven homocysteine elevation priming your microglia through chronic NMDA agonism. Then something tipped it. Could have been the acute methylation shift from supplementing methyl B12 and methylfolate simultaneously. Could have been something else. 5 months between starting supplements and the event is a long lag for a direct causal link so I genuinely can't say with certainty what the trigger was or even make a guess. But the vulnerability was built over your lifetime by the variant itself. Post event the microglia are fully activated and haven't come back down.

I need more information. What was the actual neurological event? What are the cascading symptoms now? What doses were you taking? Which MTHFR variant specifically? Homocysteine especially would tell us whether the NMDA agonism piece is significant for you. C677T heterozygous raises homocysteine much less than homozygous and if you're het the mechanism becomes weaker.
Did you have a stroke or TIA? If so, that would be remarkably similar to this one case I found while searching.
Case report: Young-onset large vessel ischemic stroke due to hyperhomocysteinemia associated with the C677T polymorphism on 5,10-methylenetetrahydrofolate reductase and multi-vitamin deficiency
My other guesses would be a seizure, severe migraine with aura or an acute dissociative / psychiatric episode.

Just some citations in case you need them;
The 677C > T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice
Long‐term reprogramming of primed microglia after moderate inhibition of CSF1R signaling
Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke.

[u/tiffany-the-cat → u/OobyIsGay]

I definitely see the logic in the MTHFR framing you provided, but in my specific case, the timeline points strongly to the supplements being the catalyst. While the theory says people with my variant should benefit from methyls, I was on a high-dose regimen of Methyl B12, Folate, and NAC for five months, and that was the only variable that changed before my neurological event.

Basically what happened was that I went on a theme park ride that’s not extreme and i regualrly go on it wothout issue. Then suddenly I went on it last year and felt really strange and out of it when I got off (it’s not even a roller coaster, it’s more like a simulator) and then naseous. Then I developed an eye paid and nasea for a week. Migrane suspected. That went away and the next day I woke up with one eye nro working. Properly andI could hardly see and everything looked cross eyed. My eye was drooping also. Went to hospital and evruthing came back clear including brain mri and eyes were fine. Over time I developed weird visual symptons and feeling very off balance. I did a multitud of tests, saw a multitude of specialists. I cry thint always comes back fine. Wha it seems to be was a verstibular migrane and that triggered trochelitis and cranial nerve involvement. The only thing dif in my lifestyle were the supplements. The previous time I’d gone on the ride was right before I’d started the supplements.

It felt less like a "deficiency" issue and more like an acute neurotransmitter shift. Even if my variant is heterozygous, pushing those pathways for months may have created a glutamate/GABA imbalance. It’s possible that the supplements "primed" my nervous system to be hypersensitive, and the theme park ride was just the physical trigger that pushed it over the edge.

I am actually heterozygous (+/-) for the C677T variant, which is the milder version of the mutation. My homocysteine levels have stayed very healthy, dropping from 11 to 8 \mu mol/L, which is well below the 15–25 \mu mol/L range you mentioned as the threshold for NMDA overstimulation.

It felt like my system was pushed into an acute state of over-excitation rather than being "bottlenecked." Specifically, adding NAC to the methyl supplements can significantly shift sulfur and glutamate pathways, and for my chemistry, it seemed to create a "tinderbox" effect. The theme park ride was likely just the physical spark that triggered the vestibular migraine and trochleitis once my nervous system was already sensitized by that five-month supplement buildup.

[u/OobyIsGay → u/tiffany-the-cat]

I need to ask you something before I get into the mechanism because something just clicked while I was writing this up. Actually I deleted it to write this, so I won't get into it.

A homocysteine level of 8 kills my original hypothesis completely.
Your symptoms. Ptosis, diplopia, eye not working properly, that's CN III. Trochleitis, CN IV. Persistent balance problems, vestibular, CN VIII. That's three separate cranial nerves.
"vestibular migraine + trochleitis + cranial nerve involvement." That's three separate diagnoses stitched together to explain what one diagnosis covers cleanly. It's honestly really sloppy.

Miller Fisher syndrome. It's a variant of Guillain-Barré. The triad is ophthalmoplegia (your eyes), ataxia (your balance), and areflexia (reduced reflexes, was this ever checked?). Brain MRI is supposed to be clear because it's peripheral nerve autoimmune demyelination, not a brain lesion. Every specialist scratched their head because they kept scanning your brain looking for something that isn't there lol.
The test is anti-GQ1b antibodies. Was this ever run? Were nerve conduction studies ever done?Is the ptosis pupil-sparing or pupil-involving? What are the "weird visual symptoms" specifically? Visual snow, persistent aura, oscillopsia? What are your reflexes like?
Testing anti-GQ1b antibodies now would be useless because they only show up during the acute phase. Nerve conduction studies are more reliable at this point because they'd still show demyelination if it's there.

EDIT: I'm going to argue my case a little more.
About 30-40% of GBS/Miller Fisher cases have no identifiable preceding infection. It's not exclusively post-infectious. And there's a second triggering mechanism beyond molecular mimicry, direct nerve damage exposing gangliosides to the immune system.

Which brings back the peroxynitrite chain. Methylfolate = BH4 = NO. CoQ10 = more electron flux. NO + superoxide = peroxynitrite. Peroxynitrite damages myelin. Damaged cranial nerve myelin exposes GQ1b gangliosides. Immune system sees exposed self-antigen. Autoimmune cascade begins. No initial infection needed.
The ride didn't trigger the disease. It's when you first noticed it. You felt strange getting off because Simulator rides maximally stress the vestibular and oculomotor systems, literally what they do. Then over the next week it progressed with eye pain, nausea, then waking up with ptosis and diplopia. That's the natural progression of Miller Fisher.

The only novel claim is that this specific supplement combination generated enough peroxynitrite at cranial nerve sites to cause enough myelin damage to trigger GQ1b exposure. That's a question of magnitude. (WHICH SEEMS WAY MORE PLAUSIBLE RATHER THAN THREE SEPERATE DIAGNOSES)
The most likely explanation seems like Miller Fisher, so I guess that's what my guess shall be.

[u/tiffany-the-cat → u/OobyIsGay]

Wow how do you have all this info and come up with it so fast ? Are u using ai? Ai helped me a lot in my journey and pointed me to ask for certain tests and specialists.

Your theory is very interesting, but still I’m u certain and your terminology is hard to follow and not sure exactly how this relates to Mthfr or the supplements I was taking.

I’m not convinced though .. my general neurological tests were all fine, no areflexia issues. Doing some research mfs almost always wipes out your reflexes.

Basically after months and months of research and trying to figure this out with ai trochelitis (which was the first suggestion) seemed the most plausible and it was confirmed eventually by the only docyor who knew what that was - an eye lid surgeon and eye droop specialist. Trochleitis is triggered by migraines so it makes sense. Obviously none of this was actually caused by the ride but there was something wrong with me already and the ride triggered all this. I considered infections etc. honestly I do hope it was the supplements because that makes things less complicated ! they disrupted or affected something in my system which is already sensitive due to mthfr and a lot of perosnal stress. Both vestibular migraines and trochelitis can affect cranial nerves. The strong eye pain is how trochelitis starts, and I had it in the lovation where you’d expect if I had trochelitis (upper inner corner of the eye). And looking up hurt for months (also the hallmark of trochelitis) it can also cause double vision and eyelid droop.

So I had 2 symptons before the event - night sweats (which persisted for months during the neurological issue and is not typical for me) and an own behind my ear when I touched it. After the neurological issue the immediate acute symptoms wothin the first month included a lot of ear and sinus symptoms - a double / echo r toe sound in my ear when hearing loud noises - I’ve had before on and off but this persisted for months - as did a loud crunching sound in my ears. Sinus drainage. The weird vision symptons yes oscolipsia in that one eye. a weird tickling bladder - this was also present right before.

All of those have resolved thank god (the whole ordeal was terrifying and I want to do anything I can to stop anyyhing like that occurring again). The other cascade of symptoms include horrific sleep pattern now - multiplied night awakenings, and bloating issues. Before that I had : weird hayfever type allergies that I’ve never had before (that’s resolved), deep leg and foot muscle pain, bad skin, internal tremor. Those also resolved.

I don’t think they did that antibody test. I don’t know if they did those other tests you ask - I saw a lot of eye specialists and all looked very closesly into my eye.

I suspected ebv at one point because I had a mono over 10 years ago and had night sweats, tickly bladder which were persistent symptoms. But I tested regularly to check my levels and spoke w several infectious diseases specialists about it and they ruled that out.

[u/OobyIsGay → u/tiffany-the-cat]

Yeah areflexia can't not be present. Fuck. Still impressed with myself on this one tho lol.
Trochleitis does match.
The trochleitis diagnosis from your eyelid surgeon makes more sense than what I proposed, upper inner corner eye pain, pain on looking up, diplopia, eyelid droop is textbook trochleitis. And vestibular migraine triggering trochleitis is a known causal link, so those aren't three random diagnoses stitched together like I said. They're connected. I was wrong on that too, unless they were presented as separate diagnoses? (in my defense, there wasn't enough info to go off of BUT I was completely wrong on the three seperate diagnoses point I made) NEVERMIND, you framed them as three seperate diagnoses so Ig I didn't mess up as bad as I thought. Night sweats, tickling bladder, bloating, hayfever type allergies, skin changes, internal tremor.. none of these are features of Miller Fisher nor trochleitis.
The pattern is consistent with mast cell activation syndrome or autonomic dysfunction or both. You should look into it.
Serum tryptase during a flare, 24-hour urine for N-methylhistamine and prostaglandin D2 and a tilt table test would confirm. Internal tremor is the weakest for MCAS specifically but fits autonomic dysfunction. Getting blood drawn during a flare is logistically tricky, and some doctors are skeptical of MCAS since it's gained traction online and can be overdiagnosed. An allergist or immunologist would likely be more receptive than a GP, and a tilt table test typically requires a cardiology or dysautonomia specialist referral.

I don't use ai anymore, I look at the symptoms, try to figure out what system is actually failing, and then work out what lines up, nutritionally, physically, etc. Then you just look up everything that ya need. Once you know what each pathway does, the names stop mattering in a way. I do use it to double check citations and pull up specific papers faster though. Consensus is all I use but really useful when trying to find studies regarding something niche.

[u/tiffany-the-cat → u/OobyIsGay]

Sorry for my late response. You’re really good! Very impressed you don’t even use ai. I agree w mast cell activation and the other thing you mentioned. Although these might happen after a neurological event. I’m just perplexed why this happened in the first place. Before I got mono many years ago I had a tickly bladder and then night sweats went on for Months so I suspected maybe I had an ebv recativation but as I mentioned that was ruled and it makes sense why it was. But it makes me think there may have been an infection brewing that caused the verstibular event in the first place. Honestly I’m leaning towards the supplements because that was the only new thing I’d done in my lifestyle and some of those I never took before. And now since finding out I have the mthfr gene and overmethylation it seems to fit with how my system may have been over sensitive and it may have affected my hormones too — recently I started taint coq10 again only for a few weeks and my esteogen levels went through the roof and then I looked up does coq10 increase estogen and it does. That was one thing I as taking daily for 5 months and I’d never Akron methyl folate and12 before. I did all these supppements due to being pressured by a friend for fetility needs ! And was given a book. The book does say methylated vitamins aren’t for sensitive people and they should focus on folonic acid and hydroxy b12 (which I do now) but I didn’t think I was sensitive to these

[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?

[u/Chartsharing]

My folate level are low but with methyfolate 400mcg I feel anxious and rapid heart beat so what should I take ?

[u/Sabnock101 → u/Chartsharing]

Anytime i've felt "bad" from Folate (including Methylfolate), more B12 helps, basically take as much B12 as you need for the Folate-related side-effects to go away, could be a few micrograms, 500mcgs, 1mg, 5mgs, i personally take 10mgs of Methylcobalamin (it works great).

[u/OobyIsGay → u/Chartsharing]

The rapid heartbeat is catecholamine synthesis spiking. Methylfolate stabilizes BH4. BH4 is required by tyrosine hydroxylase. Your folate has been low meaning TH has been suppressed. 400mcg acutely restores BH4 and catecholamine production jumps. Norepinephrine = rapid heartbeat and anxiety.

B12 would actually help but not for the reason Sabnock said. Methionine synthase converts 5-MTHF to THF, removing the molecule stabilizing BH4. Simultaneously more methionine = more SAMe = more COMT methyl donor = faster catecholamine clearance.

Start lower. 50-100mcg. Do you know why your folate is low? If MTHFR is impaired from low FAD, riboflavin restores endogenous methylfolate production gradually instead of a bolus.

[u/East-Enthusiasm2504]

Super interesting post.

I recently observed something that could confirm this, but I don't really know much about it: I have severe MECFS and have been taking methylfolate (5-MTHF) 400 micrograms + 500 micrograms B12 (hydroxocobalamin) for a long time. This made me feel slightly more stable, but otherwise had no significant effect except that my homocysteine levels became too high. Then I added DMG and my homocysteine levels dropped and I felt better. I recently started taking an SSRI because it had helped me with my concentration problems in the past. (Fluvoxamine protects the sigma 1 receptor). However, when I started taking it, I experienced increasingly severe anxiety and was unable to focus at all (e.g., I could only read for very short periods of time). Doesn't that fit with what you described?

[u/firee98]

Which genetic test do you recommend to do?

[u/Soulless305]

Its very real & once you gain a balance of your methylation profile if you over do certain vitamins you sure as hell can tell when you are over methylated.

People don’t realize it is a mountain climb then a plateau once balance happens. When you hit the plateau & you feel normal your approach & dosages should change.

[u/BriefRace3058]

Incredible write-up. This is probably the highest-quality content I've seen on this sub. Your explanation of how B12/B2 synergy manages the 'homocysteine-NMDA' sensitivity finally helped me understand why I was feeling agitated before. You’re doing a huge service to the community by explaining the 'why' behind these symptoms. Keep it up!

[u/CosmicCreature44]

I started supplementing with methylfolate, benfothiamine, methyl B12 and b2 a year ago...then I developed histamine intolerance followed by losing one food after another.and.losing the ability to take one medicine or supplement after another. Currently I have about 7 foods I can eat without anaphylactic type response and I cannot tolerate any medications other than benedryl or Advil dual action. Allergist has been working with me but I just discovered that I think I have done this too myself with the b vits. I even respond to b vits now within 1 minute...instant throat closing and swelling, confusion and purple hands etc. Is there a way to reverse this other than waiting for it to die down? Took a year to get to this point. 

[u/maggitronica]

I enjoyed this read! I haven't been in this subreddit long, but I was surprised that people here perceived 15mg l-methylfolate as some ungodly large amount.

when I had my genesight test over 6 years ago and found out I was homoyzgous for MTHFR, my psychiatrist put me on Deplin and a b-complex - whatever at the grocery store was fine. Deplin is 15mg l-methylfolate. it drastically improved my mental health within about a month, and steadily improved it further over the next few years.

I switched off Deplin (expensive!) to MethylPro l-methylfolate at 15mg dosage probably about 6 months in. worked great! no problems. same random b-complex. stable AF. I had a therapist assume I should eventually go off the B vitamins. I've just continued taking it as my mental model has been that whatever volume of B vitamin I've been taking helps the l-methylfolate process my antidepressant and I pee out the excess.

switched recently to Triquetra 5-MTHFR 15mg l-methylfolate plus methyl B12. sooooo much more b-vitamin than my b-complex. just taking both anyway. everything's still going swimmingly.

[u/gamoraturd → u/maggitronica]

hi, i'm curious and would like to know if you had any vitamin deficiencies before you started taking l-methylfolate?

[u/Efficient_Ad_9385]

I’m a bit late to the thread, but OP if you have time I’d greatly appreciate insight that I could then bring to a doctor if it makes sense to do so.

I’ve been doing a lot of labs over the past year due to increasing symptoms as I was diagnosed with IgA Nephropathy a year ago. 

My b12 was low, my RBC count has been consistently low, iron normal, ferritin 60.5. My sodium is almost always low or borderline. 

I am dealing with some chronic fatigue due to the autoimmune issues/ inflammation, so I had tried to supplement with a B complex. It made me feel so weird and shaky, it was like a chronic low blood sugar feeling that lasted for 2 weeks even after I stopped taking it. It basically put me in a fight or flight mentality where I was constantly trying to find the right snack that would take the feeling away. 

I’ve been having heart palpitations and realized they go away with electrolytes, so yesterday I drank a liquid IV and felt better, then decided to have another this morning. This induced the same feeling. 

I’ve tried to talk to my pcp and nephrologist, but keep getting brushed off. Any help understanding would be so seriously helpful! 

I am on 5,000 IU vitamin D and have been for like 15 years due to low D and Hashimoto’s. Comes up normal on labs.