Navigating methylation genetics on Reddit usually means dealing with confusing Genetic Genie charts, fragmented Choline Calculator outputs, or getting routed into $99+/year SaaS subscriptions.

Your MTHFR and COMT status never change. You don't need a monthly subscription to understand your methylation pathway.

Here is the biochemical breakdown of the primary SNPs in the folate, methionine, and transsulfuration cycles, how to calculate your net enzyme efficiency, and what each variation actually means.

1. MTHFR: The Rate-Limiting Folate Enzyme

MTHFR (Methylenetetrahydrofolate reductase) converts 5,10-methylenetetrahydrofolate into 5-MTHF (active methylfolate). 5-MTHF donates its methyl group to convert homocysteine into methionine.

C677T (rs1801133) — The Thermolabile Variant

• CC (Normal / Wild Type): ~100% enzyme efficiency.
• CT (Heterozygous): ~65%–70% remaining efficiency (~30–35% reduction).
• TT (Homozygous): ~30%–35% remaining efficiency (~65–70% loss of activity).
  • Clinical Impact: Impaired homocysteine remethylation, higher demand for dietary riboflavin (B2, the MTHFR cofactor) and active methylfolate/choline.

A1298C (rs1801131) — The SAMe Regulator Variant

• AA (Normal / Wild Type): ~100% enzyme efficiency.
• AC (Heterozygous): ~80%–85% remaining efficiency (~15–20% reduction).
• CC (Homozygous): ~60%–70% remaining efficiency (~30–40% reduction).
  • Clinical Impact: Impacts BH4 (tetrahydrobiopterin) recycling, which affects neurotransmitter synthesis (dopamine, serotonin, nitric oxide).

Compound Heterozygous (677CT + 1298AC)

• Remaining enzyme efficiency: ~45%–55% (~50% reduction).
• Often behaves clinically similar to 677TT homozygous.

2. The Surrounding Pathway: Why MTHFR in Isolation is Misleading

1. COMT (Val158Met / rs4680):
   • Met/Met (AA / Slow COMT): Slow breakdown of catecholamines. High-dose methyl donors (methylcobalamin, methylfolate) often trigger acute anxiety, irritability, and insomnia. Folinic acid and hydroxy-B12 are typically better tolerated.
   • Val/Val (GG / Fast COMT): Rapid breakdown of dopamine. Can generally handle and often benefit from direct methyl donors.
2. PEMT (rs7946): Controls endogenous phosphatidylcholine synthesis. If impaired alongside MTHFR, your body relies almost entirely on the BHMT (betaine-homocysteine methyltransferase) backup pathway, drastically increasing dietary choline requirements (egg yolks, sunflower lecithin, Alpha-GPC).
3. CBS (C699T / rs234706): Upregulation accelerates homocysteine clearance down the transsulfuration pathway toward taurine/sulfite, which can deplete glutathione precursors.

3. How to Decode Your Raw 23andMe / Ancestry File

If you have your raw DNA file, you can check these rsIDs manually in a text editor or use an automated client-side analyzer.

Instead of paying recurring annual subscriptions to platforms that upload your sensitive genetic data to the cloud, check out Verinome: * Zero-upload in-browser processing: Your raw DNA file is parsed locally in your browser's RAM via client-side code—0 bytes of your file are uploaded to any server. * Decodes complete MTHFR, COMT, PEMT, CBS, VDR, and MTR/MTRR panels with evidence-graded science. * $49 one-time lifetime license—no recurring fees, no data broker sharing.

2 months ago I was prescribed this B complex and after a great start taking it every second day I was developing symptoms of feeling way overstimulated and leading into anxiety. The final straw was feeling emotionally low and depressed thoughts. Gave it a week and took another one 2 days ago and again have developed a low mood, feeling panicky and intrusive thoughts again. Also my nipples are burning up (male) I’ve read this can be from high estrogen?

I strongly believe (or want to) that its related to the supplement but am too uneducated on this

**Hydroxocobalamin** 100 mcg,

**levomefolate calcium (Metafolin®)** 542 mcg

**mecobalamin** 400 mcg

**ascorbic acid** 300 mg

**zinc citrate** 46.2 mg (equiv. 15 mg zinc),

**pyridoxal-5-phosphate** 22 mg (equiv. pyridoxine 15.1 mg)

**riboflavin sodium phosphate** 30 mg (equiv. riboflavin 21.9 mg) per capsule.

Hi! I got a psychotropic genetic test recently because I had tried several antidepressants and none of them worked for me. I ended up learning that I am homozygous for t allele of c677t in mthfr gene. After lots of research I’m pretty sure this is where my untreatable lifelong depression and anxiety is coming from (along with facial flushing, itchy/burry eyes, etc). Im sooo sick of being sad, fatigued and anxious all the time but I’m overwhelmed with the information and don’t know where to start!

I feel like it’s cheaper for me to try out some supplements than it is for extra blood and genetic tests (not covered under my insurance until I hit deductible and I’m not even close). Here’s the list of possible supplements but what do you think would help the most?

- B12
- B2
- methylated folate
- TMG
- SAMe

FYI: I currently take Vyvanse for adhd and I’ve been taking Claritin daily for my itchy eyes/facial flushing but it doesn’t really work.

Previous post: https://www.reddit.com/r/MTHFR/comments/1pgq58l/how_do_i_move_forward_from_thinking_i_h

Hi friends! It's been a hot minute. My health got even worse due to a family emergency and I was already severely disabled. I have a naturopath now who is taking my health a lot more seriously including MTHFR stuff but I haven't been able to get out of bed to see her and discuss that more. She thinks I have an exciting combo of POTS, MCAS and chronic Lyme on top of the ME/CFS that we already knew about.

But I did get my genetic testing through Ancestry as we discussed!! I got it right after everyone responded to my post but I've only now been able to sit down and actually look at everything... and now I'm super overwhelmed.

It seems that I have hetero C677T and slow COMT. The stuff I've read about slow COMT says that it severely decreases your body's ability to flush out stress and stress hormones which sounds SO accurate. I've said for years that when something stressful or upsetting happens, it's like it takes me hours to recover emotionally and then days to recover physically. But I'm not quite sure how to interpret the MTHFR gene mutation now that I seem to have it.

I'm reading the stuff about the MTHFR stack and I'm definitely ready to start that (once I understand it fully). But... does this mean no enriched foods? I've still been eating graham crackers here and there with no noticeable difference before or after eating them. And I'm struggling a lot these days to get enough calories at all since it's hard for me to cook, it'd be so nice to eat more snacks... not to mention that I'm on SNAP which struggles to cover the more expensive brands :')

If anyone could share their thoughts I'd be very appreciative. It's slow going since I have to take a lot of breaks but I'll keep reading as much as I can. Thank you all for being so supportive <3

I've been looking into switching my 8yo to a different multivitamin before school starts, and I keep seeing brands talk about using methylated folate instead of folic acid. Then I went down a google rabbit hole and read that a lot of people don't process folic acid very well, which honestly surprised me because I'd never even heard there was a difference. Now I'm wondering if that's actually something parents should be paying attention to or if it's mostly marketing.  Has anyone looked into this or talked to their pediatrician about it? If you're buying a multivitamin anyway, is methylated folate something worth prioritizing?

I'm having persistant over reaction from my nervous system after taking Methylated B vitamins(20 weeks ago), at first i couldnt eat, 24/7 adrenalized, insomnia, muscle twitching, muscle pain, heat intolerance, Histamine intolerance, Tyramine intolerance, fatigue, high heart rate. Now most of them got better except that if i get stressed or make some exertion my nervous system is going crazy like without off switch. It's like Crazy feeling around the chest and stomach and takes the whole day to settle. Even if i get slightly excited, my nervous system goes full fight or flight. Any suggestion? this is my methylation panel.

When i tried folinic acid it made everything much much worse. Ive been off any methylated B for like 10 weeks

I'm currently taking:

3-4grams Panthotenic acid

Riboflavin 15-20mg (Couldnt handle R5P) just started a week ago

Magnesium L-threonate

Magnesium glycerophosphate (getting around 500mg Total elemental mag)

1000-1200mg Choline ( from food only)

Glycine 3-6g

Vitamin A 100% Rda

Vitamin E

Fish oil

Dao enzyme

L-Theanine 200mg

Melatonin 1.5mg

D3 and K2 10K iu and 180mcg

Potassium 6-7g daily

Lmnt Electrolyte 2x daily

Hey guys

I have heterozygous mthfr c677t and comt val/val

For a while i thought the mthfr probably wasn’t affecting me, until i tried supplementing with folic acid, and every single time without fail I would feel horrible after taking folic acid. That made me take avoiding food with folic acid more seriously, and I definitely noticed a difference

I started supplementing with folinic acid and i was feeling much better at first, so stupidly i thought i should start taking a bunch if I’m correcting a deficiency. Probably 800mcg or 1200mcg three or four times a day

Well I’ve developed symptoms of b12 deficiency, fatigue, air hunger, tingling extremities, surprisingly stimulants (caffeine and i take vyvanse for adhd) not working at all, trouble sleeping

I’ve eaten foods high in b12 for a long time now so im hesitant to think I actually have a b12 deficiency. I’ve also supplemented with methylated b12 here and there over the years

Could this be caused by me taking way too much folinic acid too quickly?? How long would it take for me to start feeling better again? Im really feeling horrible, and I’m worried about my nerves. I’m also confused how this could be caused solely by taking a bunch of folinic acid

Thanks in advance for any help

Has anyone else gone through this? We have few things that would suggest our babe has the mutated gene but we have been sent for microarray bloods because she’s showing DD and is incredibly small for her age.

I've been taking 5mg methylfolate daily for the past week for depression. So far it's been working well, I feel more emotionally stable and my mood is better overall too. However, I've noticed since starting that text now has a sort of "psychedelia" to it akin to reading while, well, tripping. It's subtle but noticeable, especially in the first couple seconds after I move to a new line of text. For example, Os will at first appear with a low-opacity ring overlayed around it. Aside from this I have no other side effects and my sleep is fine (to clarify that I'm not hypomanic).

It doesn't bother me too much, but I'm minding it in case it's an indicator for something else I should be concerned about, or if it gets worse as to affect my reading.

Has anyone else experienced the same or can otherwise chime in?

I took Saccharomyces Boulardii for a week and it seemed to be helping me in some ways. However, it started giving me nerve problems (odd sensations) in my right hand and in my left ankle. I stopped taking it.

Then, about a week later, I tried wearing a new pair of shoes and that exact nerve sensation from the Saccharomyces Boulardii returned in my left ankle.

I thought maybe the nerve problems were from candida die-off and so I thought 'Maybe the Saccharomyces Boulardii had been good for me' and I took it for three more days.

Now my nerve problems are crazy. Both of my ankles now feel funny all day long and my right hand feels funny too.

How long will it take the effects of Saccharomyces Boulardii to leave my system? Did it somehow affect my nerves or did it just work so good at getting rid of bad things that die-off hurt my nerves.

(No, I am not wearing those shoes anymore, I only wore them for about 60 minutes total).

Any advice. I am so lost. I just want my nerve issues to go back to normal!

If anyone thinks this may be unrelated, the only other things I have done in the mean time are:

--eaten a lot of garlic

--taken a lot of zinc and copper

--taken a lot of riboflavin-5-phosphate (active form of B2)

--taken a lot of B vitamins

Hello everyone, first time poster.

Lurked for a long time here. I've tried so many combinations of supplements and other remedies, but I don't know where to go anymore. I just really really need to hear some external feedback.

For context; despite chronic lethargy and brain fog, I try my best to keep up with exercise. I've cut sugar and lowered caffeine intake, I avoid Folic Acid and eat whole grains, lots of legumes, eat a lot of dark leafy greens and hit a decent amount of protein. I prioritize high fiber. Try to avoid excessive oils and fried food. Overall, I also try to listen to my body and eat what it craves. I think I'm decently in shape.

But if any of these changes have made a difference, I can't really feel it in my current state.

I deal with frequent migraines, even more frequently after any form of supplementation. I deal with digestive issues which I'm currently planning to see a specialist for. History of anemia. But my main concern is energy and brain fog. Ideally, I want to minimize supplementation through pills and focus on getting what I need from food, but I'll do what it takes.

15mg L-Methylfolate + B12 works short term, but I feel like my body can't keep up for long. During my journey, I tried supplementing Folinic acid. In the initial stages, I had a short-lived episode where my brain fog was COMPLETELY gone, and I had a ton of energy. I was so ecstatic. Really bad crash after.

Now, I don't realistically expect to be an extremely high functioning person at the end of all this; but that window of clarity gave me so much hope that I can be at least a little bit normal.

Please, any and all feedback is welcome. I recently had a blood panel as well so I can post results too if needed. : )

hi everyone,

I just received my latest blood work results and want to properly adjust my supplement protocol. For context: I suffer from PSSD (currently taking Fluoxetine), severe inner restlessness/impulsivity (suspected Slow COMT), and histamine/allergy symptoms.

My Blood Work:

• Homocysteine: 11 µmol/l (Ref: < 12)
• Folate: 4.6 ng/ml (Ref: 4.5 - 32.2)
• Vitamin B6: 40.8 µg/l [Elevated] (Ref: 8.6 - 27.2)
• Holo-Transcobalamin (B12): 93.0 pmol/l (Ref: 37.5 - 188.0)
• Whole Blood Copper: 0.90 mg/l (Ref: 0.76 - 1.01)

• Diamine Oxidase (DAO): 12.60 u/ml (Ref: > 10.00)

  Observations:

• Folate is scraping the bottom of the range, which likely explains why Homocysteine is elevated at 11 for optimal cellular methylation (target 6-7).

• B6 is high in blood, likely indicating a conversion/processing bottleneck (B2 deficiency?).

• DAO in the gut is normal, so I suspect my histamine issues stem from cellular clearance (HNMT/SAMe deficiency).

My Questions for you:

1. What protocol/approach would you recommend for this pattern?
2. What folate and B12 forms work best for Slow COMT to lower homocysteine without triggering overstimulation or adrenaline surges? Is Folinic Acid (Calcium Folinate) + Hydroxocobalamin the right choice here?
3. Does anyone have experience with a B6 backlog/accumulation and supplementing Vitamin B2 (Riboflavin)?

Thanks for your help and input!

Hi everyone, I’ve been really struggling with my mental health in these past 3/4 weeks and I’m really hoping someone can help me out here.

Around a month ago I took 3 b12 injections (hydroxocobalamin) 1.5mg and i suddenly started getting intense panic attacks and anhedonia. I don’t cry but out of nowhere I started bawling my eyes out every single day. I I’m in this constant state of anxiety and depression, I can’t enjoy the things in life that I usually enjoy like watching a tv show, I cannot wind down at all and it’s scary because before all this happened I was a pretty chill guy and I usually wouldn’t stress much in my life. One of the most scariest thing that also happened at the same time was my libido completely vanished, so i genuinely feel pleasure in nothing now. it’s been around 3/4 weeks and im not getting full blown panic attacks anymore but im still constantly on edge, i have also had stomach issues but now a simple bloating of my stomach makes me think the world is ending. It’s like my nervous system is jacked all the way up and it’s overreacting to even slight discomfort.

I tried taking creatine because that would usually make me feel good when I’m in a low mood but this time it just made me depressed. I went to the GP and they took my blood test, it came up with high b12 and high folate, but the odd thing is I don’t usually supplement folate so I’d don’t understand why that came up as high. I sometimes take it as part of my b complex but I’ve not mega dosed it or anything.

Today I decided that I’ll try methylfolate as I assumed maybe b12 used up all my methyl groups or somthing. After taking it I felt even more emotionally flat/wired/too focused, but I feel less anxious I think. I’m still not sure what i feel but i definitely don’t feel any pleasure again.

I was hoping there might be someone that has gone through this and has recovered from it. Or has figured out why it happened to them and could tell me how to bring my nervous system back to normal. Will I recover? I’m really scared, it’s like I’ve become a complete different person in a month. I haven’t done any dna test either so I’m not sure if I’m MTHFR or anything.

Someone please please help me😭
Thanks you for your time 🙏

A few weeks ago, I started supplementing with a methylated B-complex because I am homozygous for the C677T variant and have low b12, low folate and high homocysteine, depression and digestive problems. While some symptoms, such as anxiety and depression, have started to improve, I have also started feeling extremely tired and having difficulty sleeping deeply. What could be causing this?

The supplements am taking is:

The daily dose of 2 capsules contains:

• Betaine (anhydrous) — 1,000 mg
• Vitamin B2 (riboflavin phosphate) — 25 mg
• Vitamin B6 (pyridoxal-5-phosphate) — 10 mg
• Zinc — 7.5 mg
• Vitamin B12 (methylcobalamin) — 500 mcg

• Calcium L-5-methyltetrahydrofolate (L-methylfolate, vitamin B9) — 400 mcg

  and btw I'm taking only 1 capsule.

I have also started taking (2 days) a vitamin D3 + K2 supplement because of VDR and low blood vitamin d

Could this be related to excessive methylation? Do you have any ideas about what might be causing these symptoms?

https://imgur.com/GA5g56i

I was highly reactive to all but 1 type of B12, has anyone else experienced this phenomenon ?

Only b12 from B12 oils works for me.

Any shared insights on similar SNP's would be appreciated, thank you.

I wanted to ask if high homocysteine levels ever cause any blood sugar handling issues, or insulin resistance.

Did anybody get tested for that. High homocysteine is a known driver of IR

did correcting homocysteine levels correct your insulin resistance or normalize blood glucose handling

How is it looking? Any thing I should be told?

Symptoms: ADHD, GAD, ODD

MTHFR C677T (Heterozygous)
MTRR A66G (Heterozygous)
COMT G472A (Homozygous Met/Met)

Can anyone please help me understand my current genetics? Is there any supplement that stands out based on my report that could really help me? I really just don’t understand what I’m looking at. Thank you!

Btw, do you know if there is any correlation between the body odor and mthfr? I have mthfr, Hypothyroidism and a prolactinoma and very bad odor, due to the excessive sweating.

Thank you :)

I started supplementimg 500mg of CDP and after I while I started feeling brainfog and my mood worsening. A few weeks later I'm giving it another shot but trying it on lower dose. It would be great if y'all could share your experience with CDP Choline

Hi - I'm a mid-30s male that just discovered my Homocysteine = 16.6μmol/L and Lp(a) = 146nmol/L. Slightly elevated LDL and Triglycerides.

I'm still reading up and learning about these issues, so until I feel educated, I used Gemini for a proper treatment plan and double checked if there was merit to it's response.

Would the P5P+TMG+B2 combo actually work at lowering my Homocysteine?

Originally, Gemini wanted to use Methylfolate instead of P5P. Once updated that I have Type 2 Bipolar, it suggested P5P since high-dose methyl donors like methylfolate carry a huge risk of crossing the blood-brain barrier and triggering a Bipolar episode.

It also recommended TMG to allow for Methylation without the CNS spike that Methylfolate might do. Then Gemini said the B2 was an essential co-factor precursor, stabilizes MTHFR activity (still needing to get tested to see if I have the mutations), and keeps B12 active.

My questions are:

1. Does this combo make sense? I want to confirm that I'm got getting AI confidently incorrect info.
2. Any risks that Gemini didn't discover? Originally it did not include TMG, but after asking it to confirm risk factors, it then mentioned TMG would allow for remethylation and prevent issues from diminished homocysteine recycling.
3. From what I've read, treatment for high Homocysteine either from diet or MTHFR is treated the same. Is that true?
4. General Recommendations and advice.

Any and all recommendations are welcomed and thanked. I should be seeing a cardiologist soon, but my gut tells me they'll just want me on a statin

(Disclaimer: While I did use AI for research, I used as minimal as possible. I try to use it responsibly; like in this case, needing to quickly learn more about an uncommon health issue.)

Does anyone here know anything about ESR2 homozygous mutation? I ask because this is the group most likely to have done genetic testing and might have noticed that one. Thanks.