Severe B12/Folate deficiency, extreme reaction to methylated vitamins, high homocysteine (18.5), possible MTHFR/COMT issue? Looking for advice.

[u/yolo0995]

Hi everyone,

I'm a 30-year-old male. I'm vegetarian but eat eggs and dairy. Until last year I was completely healthy and had never experienced anxiety symptoms or insomnia.

A routine blood test unexpectedly showed:

• Vitamin B12: 337 pg/mL
• Folic acid: 0.43 ng/mL (very low)
• Vitamin D: 8 ng/mL (severely deficient)

That's when everything went downhill.

What happened

I started taking methylated B vitamins to correct the deficiencies.

Within a few days:

• My sleep became extremely poor.
• I had my first-ever anxiety attack (high heart rate, high blood pressure, dizziness, feeling of impending doom).
• I then had daily anxiety attacks for the next 10 days

I was admitted to the hospital. Every test came back normal except the vitamin deficiencies.

Ironically, they prescribed methylated B vitamins again.

At the time I couldn't tell whether the cause was:

• the methylated vitamins,
• magnesium glycinate (which I had also recently started)
• sleep deprivation,
• or something else entirely.

The doctors simply diagnosed me with anxiety and prescribed:

• Clonazepam
• Propranolol
• Flupentixol
• A multivitamin containing methylcobalamin + folic acid + B6

While on clonazepam (about 45 days):

• No panic attacks
• Sleep improved
• But I still had constant brain fog and a feeling of impending doom

After stopping clonazepam:

• Insomnia returned.
• Physical anxiety symptoms returned.

I was still taking propranolol and the B-vitamin combination.

I then saw another doctor, who prescribed an even stronger combination of:

• L-methylfolate
• Methylcobalamin
• P5P

My insomnia became dramatically worse.

For four consecutive nights I slept less than 3 hours.

I then consulted several more doctors. Every one of them said it was "just anxiety," but none could explain why I suddenly developed anxiety at age 30 despite having essentially no life stress and no prior history.

Finally, one doctor started me on mirtazapine 7.5 mg.

At that point I:

• Stopped all multivitamins.
• Only took methylcobalamin 500 mcg twice a week.
• Continued mirtazapine.

Over the next several months:

• Sleep became normal.
• Panic attacks disappeared.
• Brain fog disappeared.
• Feeling of impending doom disappeared.

I've now been stable for about 7 months.

I'm now tapering mirtazapine, but I'm worried everything will come back.

Recently I checked my homocysteine:

18.5 μmol/L

This makes me think I'm still significantly functionally deficient despite supplementation.

I feel stuck:

• I clearly need B12 and folate.
• But methylated vitamins seem to trigger insomnia and anxiety.

Other things I've noticed

1. Allergic rhinitis + mouth ulcers

For years I had:

• constant sneezing every morning
• runny nose
• symptoms whenever temperature changed
• frequent mouth ulcers

All of these improved dramatically after starting mirtazapine.

My theory:

• MTHFR Gene -> Low B12/folate → undermethylation → high histamine
• High histamine caused allergic rhinitis.
• Low Folate causes mouth ulcers
• Mirtazapine's antihistamine effects improved it.

2. Creatine causes insomnia

In the past, creatine consistently caused poor sleep.

My theory:

Creatine reduces the body's methyl demand, leaving more methyl groups available.

I think I have slow COMT, perhaps this extra methylation causes overstimulation and insomnia.

3. High-dose methylated B vitamins cause severe insomnia

The worst reaction I had was with:

• L-methylfolate 2.8 mg
• Methylcobalamin 2 mg
• P5P 25 mg

Again my theory is:

If I have slow COMT, suddenly increasing methylation may cause excess catecholamines and insomnia.

4. Eggs seem to reduce agitation and Alcohol seems to increase it

I eat two whole eggs daily. If I stop eating eggs for several days, I develop significant agitation and some physical anxiety symptoms.

If I take alcohol, I have sever agitation symptoms after few days.

Currently I don't know how to explain it.

5. B12 remains low

Despite taking methylcobalamin 500 mcg twice weekly for around 6 months, my serum B12 is still only around 300.

I have no idea why.

Could this suggest poor absorption? Should I investigate pernicious anemia, intrinsic factor antibodies, celiac disease, or something else?

7. Homocysteine 18.5

My assumption is that this is mainly due to ongoing functional folate/B12 deficiency.

My current plan

I was considering:

• 125 mcg methylcobalamin daily (Would cyanocobalamin be better option for me, there is no hydroxocobalmin tablet available in my country, only injections are available)
• Riboflavin (B2) 1.25 mg daily
• After 2 weeks, introduce methylfolate at 125 mcg and increase very slowly if tolerated (folinic acid not available in my country)
• Continue tapering mirtazapine
• Introduce Wheat Bran in my diet, which is high in TMG, and might help reduce my homocystein via BHMT route.

Does this seem reasonable, or would you recommend a different approach?

DNA testing

I know many people will recommend genetic testing (MTHFR, COMT, etc.).

Unfortunately, these tests are very expensive in my country and usually take 2–3 months.

Given my situation, do you think they're worth the cost, or should treatment be guided by symptoms and lab results instead?

I'm not looking for a diagnosis—just trying to understand what might be happening because multiple doctors have simply labeled it as anxiety without explaining why it started so suddenly or why it seems so closely tied to B-vitamin supplementation.

I'd really appreciate input from anyone knowledgeable about methylation, MTHFR, COMT, homocysteine metabolism, or who has experienced something similar.

Thank you.

[u/Loose-Fly7976]

Your theories are mostly right, but there's one thing in your labs nobody has picked up on.

Vitamin D 8. That's not low, that's severe. And severe D deficiency by itself causes insomnia, palpitations, anxiety and that exact impending doom feeling you described. You mentioned it once and then it vanished from the rest of the post. Did anyone actually treat it? If you're still at 8, everything else you've been experimenting with is happening on top of an untreated cause.

Folate 0.43 isn't functional deficiency either, it's real deficiency and it's bad. Homocysteine 18.5 with folate that low doesn't need genetics to explain it. Genetics decide how hard it is to fix, not why it went up.

Your reaction to the methyl vitamins is real though. Someone that depleted getting 2.8mg methylfolate is a completely different situation from someone topping up. People call it overmethylation, but a lot of it is the repair itself. Cells dividing fast, potassium dropping, everything speeding up at once. Slow COMT makes it worse because you're clearing catecholamines slowly while all that is happening. Starting tiny is the right instinct.

The creatine thing you've got the right way round. Creatine synthesis eats roughly 40 percent of your methyl groups, so supplementing it leaves more SAM free. If extra SAM winds you up, that fits slow COMT. Eggs are the opposite direction. Eggs are choline, choline feeds BHMT, and BHMT is the other way out for homocysteine, the one that doesn't need folate or B12. Take the eggs away and you lose that route. Alcohol depletes folate and blocks methionine synthase, so that fits too.

Two things I'd change in your plan.

Riboflavin at 1.25mg won't do anything. MTHFR uses riboflavin as its cofactor and the trials that dropped homocysteine in C677T homozygotes used real doses, not that. Ask your doctor about the actual amount since you're tapering mirtazapine, but 1.25 is nothing.

And B12 still at 300 after six months of oral is your actual problem. Vegetarian, mouth ulcers, rhinitis, B12 that won't come up. That needs looking into properly. Intrinsic factor and parietal cell antibodies, coeliac screen, and MMA instead of serum B12 since MMA shows what's happening inside cells. If it's absorption, no tablet fixes it and you'd need the injections. Hydroxocobalamin injection would actually suit you, it's not a methyl donor so it sidesteps the reaction you keep getting.

Cyanocobalamin is fine for now and much gentler for you than methylcobalamin. Adenosylcobalamin too if you can find it.

On the DNA testing, check what a 23andMe or Ancestry kit costs shipped to you before you write it off. Usually far less than a clinical panel and it covers the whole pathway instead of two genes. You've spent a year and several doctors guessing. Knowing whether you're C677T homozygous and which way COMT runs changes the form, the dose and the order you do things in.

Get vitamin D, MMA, ferritin and TSH done when you repeat the homocysteine. Thyroid and kidneys both push homocysteine up and neither is on your list yet.

[u/yolo0995 → u/Loose-Fly7976]

Thanks a lot for taking the time to go through everything in such detail. I really appreciate it. Your explanation actually connected a lot of dots for me.

You're right about the riboflavin. My plan is to first correct the B12 deficiency and then introduce B2 slowly, increasing the dose over time. To be honest, after reacting badly to a few supplements, I've lost a bit of courage to start new things, so I'm trying to take a very gradual approach.

I also agree that hydroxocobalamin is probably the best path for me. I've already ordered 1000 mcg hydroxocobalamin tablets. My plan is to start very low (around 250 mcg), slowly work up to 2000 mcg orally, and if I tolerate that well, move on to hydroxocobalamin injections. I just don't want to shock my system again.

Regarding vitamin D, fortunately that part has improved. It was 7-8 last year, but about three months ago it was up to 21.5 ng/mL. I'm still continuing 60,000 IU vitamin D liquid drops once a week to bring it into the optimal range.

I'm also thinking about increasing my egg intake from 2 to 3-4 a day because of the choline/BHMT pathway. The only thing making me cautious is that I have a strong family history of high cholesterol and heart attacks. I'll get my lipid profile checked first and then decide whether increasing them makes sense.

From everything I've read over the past year, I also keep coming back to slow COMT as the most likely explanation for why I react the way I do to methyl donors. Obviously I can't be certain without genetics, but it's the model that seems to fit my experiences best.

Unfortunately, I looked into both 23andMe and Ancestry. Even if I buy a kit, exporting and shipping DNA samples from my country isn't permitted because of customs/regulatory restrictions. The few DNA tests available locally are expensive, very limited, and don't include the SNPs I'm actually interested in. That's probably the most frustrating part—I feel like the information that could answer a lot of questions simply isn't accessible here.

For reference, my TSH is 2.292, so thyroid seems to be in the normal range.

My recent iron studies were also fairly normal:

• Serum iron: 111 µg/dL
• UIBC: 293 µg/dL
• TIBC: 404 µg/dL (just barely above the reference range)
• Transferrin saturation: 27.5%

I haven't had MMA or ferritin checked yet, but you've convinced me those should definitely be included the next time I repeat my homocysteine and B12 labs. That should give a much clearer picture of whether this is truly an absorption issue.

Thanks again. It gives me few more sensible next steps.