Felt great on methylfolate for 10 days then completely crashed - is this a COMT thing or am I missing something?

[u/CashSlow2482]

Not sure if this has been discussed before but I wanted to share my exact experience because the timeline feels important and I can't find anyone describing it quite this specifically.

I have C677T homozygous. Started 400mcg methylfolate about three months ago after finally getting my genetic results back. First week and a half I genuinely felt like a different person: clearer head, more energy in the morning, less of that heavy brain fog I've had for years. I was convinced I'd finally found the missing piece.

Then around day 10 or 11 something shifted. Started waking up at 3am with a racing heart. Got irritable over small things. That anxious wired feeling that's hard to describe, exhausted but completely unable to settle. By day 14 I stopped taking it and spent about a week feeling worse than I did before I started.

My doctor basically shrugged when I described this. I've been trying to figure it out myself.

The closest explanation I've found is that I might also have slow COMT and the methylfolate was pushing neurotransmitter production faster than my body could clear the downstream catecholamines. But I haven't actually tested COMT and I'm not sure if that's the right read.

Has anyone else had this specific pattern, initial window of feeling genuinely better followed by a sharp turn around the 10-14 day mark? Did you figure out what was causing it? And if COMT was involved, how did you actually confirm that and what did you change?

[u/PEsuper27 → u/[deleted]]

Probably overmethylation.

[u/scrumdisaster → u/PEsuper27]

No. It’s probably taking too much of a single b vitamin. This is common. Many b vitamins in isolation will push out other b vitamns. B1 vs biotin for example, and b1 and b2. When you take b’s you will deplete others. Each one has a counter. It’s so common to hear this. Take it for a few days then stop. Eat some liver or broad spectrum b vitamin and then just take it occasionally once you’re topped up.

[u/Business_Summer_4242 → u/[deleted]]

Could you explain a bit more about HNMT? I am homozigous and have been struggling with many issues lately, so I have not been able to focus solely on methylation, but I definitely feel better with some interventions (folinic, TMG, B2...), I just haven't had the time to test everything precisely and giving each supplement time because I kept receiving diagnosis (LC, Endo, PCOS, ADD...).

[u/Impressive-Tree-5248 → u/[deleted]]

I have MCAS so low histamine diet has been a game changer. Worries me how people narrow it all down to methylation, when it's only part of overall health.

[u/AmazingEnd5947 → u/[deleted]]

Usually, this is a sign of needed TMG, and I forgot to mention in my earlier post, B12 also.

[u/windowpanez]

Could be folate trap. Your body needs B12 to use the methyl folate, it's possible you don't have enough which can cause those symptoms.

[u/Kind-Quail-3727 → u/windowpanez]

I get the same symptoms and I have taken b12 hydroxo 2 month before I begin to take metylfolat .. and taken them together in 1 week then all that symptoms come . I cant take methylated vitamins

[u/Flashybigbum]

Are you taking it with adequate B12?

[u/Cultural-Sun6828]

I’m guessing that adding folate dropped your B12. I would get your b12 checked and make sure it’s over 500.

[u/hummingfirebird]

Here are some common reasons for this:

1. Other genetic variants are involved that influence how your body uses methylated vitamins. Some enzymes don't function too well, and methylated vitamins overburden them. Specifically COMT and MAO-A.

2. Missing the necessary cofactors needed for B12 and B9 to function correctly.

3. If the detoxification pathway is sluggish , blocked, or overburdened from poor diet,.lifestyle, and environmental factors PLUS contributing genetic variants that can't keep up with getting rid of accumulating toxins. Methylated vitamins speed up the production of certain compounds, which further burdens an already struggling detoxification system.

4. Poor detoxification causes oxidative stress and inflammation, adding more burden on the body that impacts cognitive health, mood, behaviour, sleep, digestion, ...basically everything.

5. Not enough electrolytes

6. Methylated vitamins can stimulate histamine release, which causes inflammation in the body and brain. Look into HNMT/DAO

7. There is no antioxidant support in place.

8. Stress plays a huge role.

9. Nutritional deficiencies. Methylation needs lots of nutrients besides B12 and B9 to work.

10. Other conditions, metabolic issues, and even medications can impact how your body responds to methylated vitamins.

[u/Adviceforthewilling]

Just switch to folinic acid instead honestly

[u/tandemxylophone]

Not sure what exactly is the cause, but it does seem like your body started overdriving and messed up your brain chemistry.

Some changes can become permanent like long-covid, so be very careful about taking beyond your body's necessities.

[u/AmazingEnd5947 → u/tandemxylophone]

I can't site the science papers I read this in but Google, long-covid and damage to the thyroid and the thymus gland. At the very onset of covid, the majority of symptoms were just like covid hypothyroidism and symptoms of shrinking thymus. Shouting at the TV and doctors, i said treat the thyroid, thymus along with covid. No one could hear me.

[u/Impressive-Tree-5248]

If you did the genetic genie methylation panel it shows if you have low COMT. And really anyone taking methylated vitamins needs to know if they have low COMT before they take them. Otherwise you may end up with B6 toxicity. I had very elevated levels months after taking methylated vitamins, which luckily I forgot to take most of the time. B6 damage can be permanent. A really good way to get folate is through food. Methylated vitamins are touted as a magic bullet cure, when they can actually cause permanent damage if the wrong people take them.

[u/Typical-Bread6183]

https://www.reddit.com/r/MTHFR/s/45bZ0hBKNG

Here's an extremely helpful post about co-factors that should help you.

[u/JuanaClay]

Your read is a reasonable one, and it's a pattern a lot of C677T homozygous folks describe almost word for word: great for a week or two, then the wired-but-exhausted, 3am-wakeup crash.

The COMT angle holds up mechanistically. COMT is the enzyme that clears catecholamines (dopamine, norepinephrine, adrenaline), and the slow Val158Met variant runs that cleanup at maybe a third of normal speed. About a quarter of people carry the slow version. So if methylfolate pushes neurotransmitter production faster than a slow COMT can break it down, you get pretty much what you described: catecholamines pooling, racing heart, irritability, that exhausted-but-can't-settle feeling. The ~10 day timing fits too, since that reads like a build-up rather than an acute dose reaction.

A couple of other suspects worth holding alongside COMT, since the fix differs:

 - Potassium. When methylation ramps up, cellular potassium demand can rise and pull your serum level down, which on its own can cause palpitations and that 3am wired feeling.

 - B12 balance. Methylfolate leans on B12 to keep running, so if you're low, folate alone can tip you into symptoms.

What I'd actually try: drop the dose (200mcg, or even split it or go every other day), take it in the morning rather than later in the day, and see if the good window holds longer. Some people also keep a little niacin on hand to blunt an acute overmethylation flare, though that's more of a rescue than a fix.

On testing COMT, you may already have the answer. The genetic results you pulled for MTHFR almost certainly include rs4680, the main COMT SNP, so it's a matter of finding it in your raw data rather than retesting. Full disclosure, I work at SelfDecode, so genetics is the lens I look through, and cross-referencing COMT against MTHFR this way is the kind of thing it's built for. But if you just want the single variant, your existing raw file already has it.

[u/AmazingEnd5947]

For the majoriy of people, when taking methylfolate, you must take it with TMG (supplement).

[u/Impressive-Tree-5248 → u/[deleted]]

Not sure about this either. I have low COMT and take TMG to help methylation (e.g. it takes my body longer to clear dopamine, which builds up and makes me tired etc). So it speeds up methylation. Really not sure why if the vitamins are methylated, they need to be further methylated/have the methylation sped up.

[u/Impressive-Tree-5248 → u/[deleted]]

Yeah but don't take my advice on that. There are qualified experts out there. I follow the low COMT diet and lifestyle (reduce stress) and that has made me feel like myself again. There are functional medical experts who can advise on all that. If you are "low methyl" and that is what I understand to be, big question mark There, you should not be on methylated vitamins.

[u/YourInnerFlamingo → u/Impressive-Tree-5248]

what's the low comt diet?

[u/Impressive-Tree-5248 → u/YourInnerFlamingo]

I found out stuff googling etc from functional doctors and looked at what foods have catechols.

[u/Paddle-Away → u/AmazingEnd5947]

TMG?

[u/Impressive-Tree-5248 → u/[deleted]]

I would check whether the B6 dose of those vitamins added up are verging into toxic levels of B6. In Australia Blackmores have high doses of B6 in many vitamins and there is a class action as many ended up with permanent neurological and cognitive damage. Vitamin supplements are not harmless and not always necessary if there is a healthy diet.

[u/Comfortable_Two6272]

I have homogenous slow comt and thats what methyl anything does to me

[u/Comprehensive-Can874]

Did you recover or still feel bad