Bad B-12 Side Effects - Try Methylfol... - Pernicious Anaemi...

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Bad B-12 Side Effects - Try Methylfolate?


Hi Everyone,

I am newly diagnosed and put out a couple of recent posts - thanks to all for the feedback! Now I am stuck in a total rut because I have tried all three cobalamins (Cyano, Hydroxo and Methyl) and have difficulty tolerating each one. Cyano is the worst but the other two are pretty bad as well just in different ways.

I'm doing sub-q injections but have also tried sublingual Methyl tablets. I am unable to handle the side effects at any dose higher than 250 mcg no matter what the form.

I just ordered the kit from 23andme and hope to get more info to help me figure this all out. But given the long time frame before I get results back I'm feeling desperate to try something that might help me tolerate the B-12 right now. I am becoming more incapacitated and have been home bound for 3 months. I need to get back to work :(

I'm thinking of trying some Methylfolate but when I was first tested (before supplementing with B-12) my Folate Serum was 20.0 ng/mL which was good given a reference range of >3.0 (I'm in the U.S.). I have not been tested since injecting B-12 over the last 2 months.


-Should I only take Methylfolate if my Folate level is low or do some people just try the Methylfolate anyway to see if it helps them tolerate the B-12 and feel better overall?

-If I have my GP re-test the Folate to see if it has gone down are there any other tests I should do also like:

*Homocysteine and Ferritin (which have never been checked)

*MMA (which was originally high at 469 with reference range of 0-378)

*B-12 (which was originally 181 and went up to 1999 after one month of loading)

Any feedback would be much appreciated!! Thanks in advance!!

27 Replies

Should I only take Methylfolate if my Folate level is low or do some people just try the Methylfolate anyway to see if it helps them tolerate the B-12 and feel better overall?

I minority of the population do have problems with the final step of the conversion process folic acid -> tetrahydromethylfolate (aka methylfolate). This final step is facilitated by the enzyme Methylenetetrahydrofolate Reductase (MTHFR).

Less than 10% of the population have a mutation in the gene for this enzyme that causes it to be less stable than the normal enzyme. The human body has ways of getting around that decrease in stability (making for enzyme, for example). But a few will benefit from taking the end product of that reaction - methylfolate - as a supplement.

The blood test for folate actually measures several different molecules - folic acid, dihydrofolate, tetrahydrofolate and methylenetetrahydrofolate - that are earlier steps in the production of methylfolate. So you can score high on the blood test even though you have little methylfolate in the body.

I would ask for a check on ferritin (if you have PA then you might easily have problems with iron absorption) and I would ask for a test of your anti-IF (Intrinsic Factor) antibodies, to see if you have PA (although that test gives a false negative in half of all people with PA).

Apart from that I wouldn't bother with any more blood tests as they won't show you anything more than you already know (high MMA means a possibility of low B12 and/or folate; low B12 means low B12; high folate could still mean a deficiency of methylfolate).

When you get your 23andMe results try loading the raw data into Promethease - - then use it's excellent user interface to look for the gene MTHFR and the SNP Rs1801133. The normal base pair at that location is C,C - the bad mutation is T,T. Some people have C,T which means their MTHFR enzyme is just a bit less stable but not enough to cause problems (despite the rubbish you might read elsewhere).

Of course, the SNPs (Single Nucleotide Polymorphisms) that 23andMe test for are just the ones known to science. It's perfectly possible for any person to have a mutation in that gene that is not known to science (there are a couple of thousand base pairs in the coding part of the gene and Promethease lists just 15 of them!).

Taking methylfolate at a reasonable dose - 400 ug a day - will do no harm. You may as well give it a go as the only downside is the cost.

RAAnn in reply to fbirder

Thank you SO much fbirder!

I was tested for the anti-IF antibody and it came back positive so I definitely have PA. I will follow your advice on what to do with my 23andMe results and hopefully that will provide some more guidance.

As for the Methylfolate brands, I noticed on Amazon that they are not sublingual.

-Does it need to bypass the stomach?

-Is it the same as B-12 in that everyone tolerates/needs a different dosage?

-Any brand that it is best?


fbirder in reply to RAAnn

No need to have sublingual folate. It's a small enough molecule as to not need any help across the gut wall, unlike B12 which is a fairly big molecule.

400 to 800 ug a day should easily be enough. Sometimes people are prescribed up to 5000 ug for a short while.

I tend to buy the cheapest methylfolate. I've got the double-dose of the C677>T MTHFR mutation, which I ignored for quite a while. Then I decided to try methylfolate and found that I felt much better on 400ug a day.

RAAnn in reply to fbirder

After a really hard weekend it's made my day to get such quick and helpful responses. Thanks again!!

fbirder in reply to RAAnn

My pleasure. It took me months and months to fight my way through some of the shullbit surrounding this topic - and I'm a scientist. Anything I can do to help others avoid such a journey is the least I can do.

beatrix2010 in reply to fbirder

What kind of a scientist are you?

fbirder in reply to beatrix2010

A mass spectroscopist specialising in xenobiotic metabolism.

When you say you can't tolerate it, what are your symptoms? Headache, hyperactivity?

RAAnn in reply to pvanderaa

Hi pvanderaa! Thanks for responding. My symptoms are nausea, headache, racing heart mixed with exhaustion, strange light-headed feeling and stomach upset.

The Methylcobalamin seems to cause a higher degree of the nausea, and the Hydroxocobalamin causes more of the headache. I have to keep the doses at 250 mcg and even then it takes me 2-3 days to recover and get back to my "normal sick".

I am trying to get in 1,000 mcg. of B-12 per month (following the US guideline) which I know means nothing really but it's a place to start. That means (1) 250 mcg. injection per week which is tough because of my recovery time. I know people say to figure out dosage based on symptom improvement but I can't use that guideline because I'm just trying to tolerate the B-12.

Kind of a mess right now :)

pvanderaa in reply to RAAnn

The nausea is probably coming from the repair of the vagus nerve. It lasts 2-3 days because it takes that long for the brain to recalibrate.

B12 is working and you are very deficient. To me, this would be an indication that you need more B12.

If you can convince your brain (mind) that this symptom is a "good" indication and the stronger signal is only an illusion, you might get through it faster.

Worry increases stress and stress makes these symptoms appear to be worse than they really are. Pain is another counterintuitive symptom that arises from nerve repair.

By knowing that these symptoms appear after the B12 injections, you can stop worrying and eliminate the stress that makes them seem worse.

It really is a mind game sometimes.

Have you started a logbook?

RAAnn in reply to pvanderaa

Hi again! Yes, I just started a logbook 2 days ago so I haven't benefitted from the info yet but am hoping to soon. I did dawn on me just this morning though that I seem to sleep straight through the night for several days after an injection vs. getting up between and 2 and 4 am with insomnia. It's nice to think I am getting at least one clear improvement from treatment amongst all the other difficulty :)

As for your input on the vagus nerve and an indication that I actually need more B-12 - I'm open to trying but am not sure what to do. Right now I am doing 250 mcg. 1x per week. Does increasing it to 2x per week sound like a reasonable way to go? It's so crazy that we are all going through this without adequate medical care - it feels like a game of darts right now!

I also have not figured out whether the methyl or hydroxo is best, so I will have to rotate those for another week or so to figure it out.

Many thanks again...

pvanderaa in reply to RAAnn

Hydroxocobalamin is an analog form that needs to get converted in the body to either methylcobalamin or adenosylcobalamin which are the two active forms used within the cells.

Cyanocobalamin is a similar analog that also needs to get converted to be used by the cells.

With IM injections The two analogs sit in the muscle until activity releases them into the blood stream.

With methyl, it can be actively use by the cells but harder to convert into the adenosyl form. So you end up deficient for this form.

Taking more frequent and smaller injections seems a reasonable compromise as you are spreading out that peak high that is probably causing you the largest symptoms.

Are you taking folic acid to support the B12? Start with 800 mcg a couple of times a day. Build up to 5 mg max per day. Take what you can tolerate that balances the amount of B12 you are taking.

I currrently inject cyano 2x weekly 500 mcg to spread the peak high out. I'm at 4.8 mg of folic acid that I take as 1.6 mg three times a day.

I use methyl sublinguals throughout the day to supplement are keep a clear head.

I also take TMG - trimethylglycine which provides a parallel path from B12 to convert homocysteine into methionine.

Google methionine loop to get a picture of the metabolic process. It picture is of two circles side by side with B12 at the intersection of the two circles. The circle on the left is the folate loop and the circle on the right is the methionine loop.

Are you also taking a multivitamin to support all the other B vitamins that B12 needs to do its job?

fbirder in reply to pvanderaa

With methyl, it can be actively use by the cells but harder to convert into the adenosyl form. So you end up deficient for this form.

This is a common misunderstanding, started by somebody who posted an erroneous entry on Wikipedia (now fixed).

The latest thinking - - is that all forms of B12 have their top ligand (cyano, hydroxo, methyl, adenosyl) removed as soon as they enter the cell. The remaining molecule then gets passed on to the various bits of the cell where it's needed and the required ligand (methyl or adenosyl) is stuck on.

RAAnn in reply to fbirder

Thanks for this clarification! What a learning curve... :)

pvanderaa in reply to fbirder

Good to know. Thanks

RAAnn in reply to pvanderaa

Thanks so much for all this info!! I didn't know about the TMG so that's really helpful. I haven't been taking other B vitamins yet. My system is so sensitive that I need to only take one new thing at a time so if I have a negative reaction I can track what is causing it. As soon as I am more clear on which cobalamin to use and how I am reacting to the Methylfolate I'll move on to a multivitamin.

I had no idea what a rabbit hole I was going to fall into when I got the PA diagnosis. I think I have a ways to go before I get my protocol down like you do. Thanks for the help and support in getting there!

fbirder in reply to RAAnn

Thanks so much for all this info!! I didn't know about the TMG so that's really helpful.

No real point in wasting money of betaine (TMG) unless your homocysteine levels are too high. And the normal cause of that if a deficiency in B12 and/or folate. So correct supplementation with those vitamins should mean normal levels of hCys.

RAAnn in reply to fbirder

Thanks again :)

I was originally put on high dose sublingual methylcobalamin and methylfolate. It was absolutely intolerable to me.

I do better on smaller dose injections.

What happens if you stay on the smaller dose and give it time?

I found magnesium, potassium, iron, and vitamin c to be somewhat helpful.

You may feel well on methylfolate, as some people do, and that would be great. However it is possible to have side effects from that as well, so be aware.

What sort of side effects do you have?

RAAnn in reply to Allyson1

Hi Allyson1! Thanks so much for your input. You can read my response to pvanderaa about basic doses I've been doing and the specific side effects.

I've been doing B-12 injections for over 2 months now and it's not getting any easier. I will try the other supplements you suggested to see if they help. I also have a bladder condition called Interstitial Cystitis that affects my bladder lining, so certain supplements and foods can burn and cause problems. It can be a bit of a rubix cube to manage so I try new things in small doses and just cross my fingers.

I will definitely be very cautious with the Methylfolate. I know it may not work for me but it's worth a shot in case it helps. Hopefully my genetic testing will make this feel a little bit less like the wild wild west of medical treatment :)

Thanks again for responding!

pvanderaa in reply to RAAnn

How much orange juice do you drink? I used to get a UTI every couple of months and went through the whole gamut of testing including cystoscopy for inconclusive results.

The consultant finally said "orange juice is your friend" as the acidity cleans out all the plumbing where bugs can live and cause the infections.

Being low on B12 also triggers a random UTI for me. And getting the next injection and drinking orange juice clears it up. Now I rarely need an antibiotic to get rid of a UTI.

RAAnn in reply to pvanderaa

Hi again Pvanderaa! Interstitial Cystitis develops when there is no actual infection in the bladder (though it feel like there is) but the immune system thinks there is so it attacks the bladder lining to get at it. This results in a breakdown of the GAG layer (cracks and fissures in the lining), which leads to a "leaky bladder" ie: toxins re-entering the body rather than being eliminated. Or at least this is one theory...

With this autoimmune response patient's are then more vulnerable to other autoimmune conditions. It's interesting that with PA my body is now essentially attacking a protein in my stomach that compromises that lining as well.

So... anything acidic that I eat/drink causes a great deal of burning and pain to my bladder lining which counts orange juice off my list (as well as many other foods with certain enzymes in them). I know the orange juice can be beneficial with UTI's though so I'm glad it works for you because they are very painful!

Thanks for thinking of me though. Everyone here goes above and beyond in considering each individual's situation and trying to lighten their load. I'm so grateful!

Your B12 was extremely low RAAnn and, although it's very common when first receiving parental B12 for symptoms to feel much worse before they improve (as though the nerves are coming back to life), looking at your past posts with history of IBS, fibromyalgia and and interstitial cystitis as well as this abstract, had me wondering about the connections, as researchers now believe 'leaky gut' is the root cause of autoimmune disease :

'Some people with IC/BPS have been diagnosed with other conditions such as irritable bowel syndrome (IBS), fibromyalgia, chronic fatigue syndrome, allergies, Sjogren's syndrome, which raises the possibility that interstitial cystitis may be caused by mechanisms that cause these other conditions.[11] There is also some evidence of an association between urologic pain syndromes, such as IC/BPS and CP/CPPS, with non-celiac gluten sensitivity in some patients.[12][13][14] "

As you are in the US, I was wondering if you'd considered a doctor, who practises functional medicine and might be more open to 'thinking outside the box', to get to the bottom of why you are unable to absorb or tolerate higher doses of B12. It seems more than likely that PA and IBS could be affecting absorption of not only B12 but many other vital nutrients.

There is also the chance that any other medications you might be taking could be affecting uptake of B12 in whatever form?

This is what the BCSH guidelines have to say about PA and autoimmune disease in general:

"Pernicious anaemia is one of a number of autoimmune diseases, including Hashimito disease, type 1 diabetes, vitiligo and hypoadrenalism, which may coexist together."

" During investigation of pernicious anaemia, other autoimmune disorders may be found to co-exist, particularly thyroid disease and type 1 diabetes, and it has been suggested that investigation for these should be considered".


The above BMJ research document has important information on testing under 'How is Response Assessed' - bottom of page 4 :

"Cobalamin and holotranscobalamin levels are not helpful because they increase with vitamin B12 influx regardless of the effectiveness of treatment, and retesting is not usually required."

I hope you are able to find answers soon, as adequate B12 treatment is so important to a speedy recovery.

RAAnn in reply to Polaris

Wow - thanks for all your time with this response! It has been a very long health journey for me and this new diagnosis of PA only confirms the absorption issues that I have been working to understand/resolve for some time now. I have seen all forms of practitioners who think outside the box and currently work with someone who specializes in functional medicine/nutrition and autoimmune disease. She was the doctor who flagged a possible PA diagnosis when she saw my initial lab results and thinks that B-12 could be a key in my health improving. Unfortunately though she cannot help when it comes to the nuts and bolts of figuring out treatment.

I am not on any medications so at least I can rule that out as possibly affecting my uptake of B-12, and I've gotten some great feedback on this forum to help me keep moving forward.

Thanks again for your "above and beyond" response!

Polaris in reply to RAAnn

You're welcome RAAnn.

Like you, I've found it not just a vitamin deficiency but a long and complex journey.

Having had IBS, as well as other long standing digestive issues over the years, I found these all resolved after following a gluten free diet and taking daily spoonfuls of organic sauerkraut (better than any other probiotic I'd ever tried and, hopefully, helping to heal the microvilli in my digestive system).

I'd recommend Dr Datis Kharrazian's book, "Why isn't my Brain Working?". He lectures postgraduates and his teachings on Autoimmune Disease are respected and followed by many all over the world.

RAAnn in reply to Polaris

I too am gluten free and it helps. I'm also working on building up my tolerance for raw organic sauerkraut.

I will look into your book recommendation. I'm glad to hear that you have found improvements with your health and really appreciate the community of people who understand and support each other through all of this.

Thanks again!

Polaris in reply to RAAnn


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