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Pernicious Anaemia Society
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Methylcobalamin vs hydroxocobalmin

Hi can anyone tell me which is the better out of the two ? I’ve been taking SI hydroxo but I don’t know that it really makes much difference to me. Still have the brain fog and pins and needles etc. I SI approx every 2 weeks and I have read that your body still needs to convert this to methylcobalamin so I wondered if I am converting effectively enough. Thanks

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Hydroxocobalamin is just as effective as methylcobalamin - ncbi.nlm.nih.gov/pubmed/258...

In addition it is cheaper, easier to obtain, more stable and less likely to produce an adverse reaction.

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"Better" is a relative term. There are three types of B12:

1. Cyanocobalamin is the most shelf-stable (meaning it doesn't need refrigeration), but it is thought that it doesn't last as long in the body as:

2. Hydroxocobalamin is the form used to treat cyanide poisoning. It is not as shelf-stable as cyanocobalamin, but is thought to take longer to wear off than cyanocobalamin.

3. Methylcobalamin is the most recently developed form of B12. Although the idea is that it is identical to form the body needs, and would therefore be absorbed more easily, it actually has to go through all of the same conversion steps as the other forms of B12 to reach your cells. It is also the least shelf-stable and most expensive form available.

Having said all of that, those of us who have trialled the different forms often find that we respond better to one form or another. It is highly individual. At this time there is no known scientific reason for a person to respond better to any of the three forms (lack of research on the subject).

It is a case of trying different forms and seeing how you repond to each to determine which is best for you.

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Although all the different forms are equivalent once they enter the cell, differences in behaviour before they get into the cell wouldn’t be surprising. In particular, crossing the blood-brain barrier might be quite different.

I know that injecting methylcobalamin causes horrible side-effects for me. I’d heard about how much better methylcobalamin was, so I decided to test it myself. Never again.

Oh, and hydroxocobalamin doesn’t need refrigeration either. Store in the dark below 25° C.

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actually there are 4 forms of B12 that are commercially available - cyano, hydroxo, methyl and ADENOSYL. There are two forms of B12 that are used at the cell level - methyl and adenosyl. They are listed in order of stability - with adenosyl being the least stable - and as a result it is practically impossible to get it in a injectable form.

As fbirder says - the form that you take in isn't the form that ends up in your cells because it needs to be converted to holotranscobalamin (TC2) in order to get into your cells and then is recombined with either the methyl or the adenosyl element depending on what process your cell needs it for. There is no way of knowing which form suits you best other than to try - personally I use all 4 forms - injecting either cyano or hydroxo depending on which I have purchased - and using hydroxo and methyl nasal spray and adenosyl sublinguals as additional supplements because I find that methyl and adenosyl work on different symptoms - but that is what works for me - what works for someone else is likely to be very different.

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All forms of B12 can bind to the TC2 transporter protein to form holotranscobalamin (also known as ‘Active B12’). The holotranscobalamin can be actively transported into the cell, during which the TC2 protein is removed.

Straight away, the MMACHC enzyme removes the top ligand (the methyl, hydroxo, cyano, adenosyl, or other group) to form cobal(II)amin. So all the different B12 types become the same molecule as soon as they enter the cell. Any difference in their effects must be manifested before they get into individusl cells.

The cobal(II)amin gets transported to the area of the cell where it is needed, where it is converted to methylcobalamin or adenosylcobalamin.

When you take methylcobalamin it is converted to cobal(II)amin as soon as it enters the cell.

When you take hydroxocobalamin it is converted to cobal(II)amin as soon as it enters the cell.

When you take cyanocobalamin it is converted to cobal(II)amin as soon as it enters the cell.

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thanks for clarifying

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Great explanation, fbirder. Based on this, inter-individual differences in the efficacy of various B12 forms should depend on either 1) binding to TC2, 2) TC2 removal, or 3) MMACHC activation? Is there any research showing what factors (genetics, cofactors, etc.) underlie the differences in these B12 processing steps?

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I’ve not seen anything about differences in TC binding except papers that say that all forms bind equally. I’ve seen a paper that looks at the efficacy of MMACHC at removing various ligands and it seems there’s very little difference, even with unusual ligands like ethyl.

There’s some speculation that problems with methylcobalamin may be due to mutations in some genes like COMT (catechecol O-methyl transferase) that are involved with neurotransmitter synthesis.

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thanks for this, but im confused why there is an issue then why some say that whilst they have high levels of b12 due to injecting etc their bodies are not using the b12 at a cellular level ? what im not sure of is if this is the case for me which is why i wondered whether methylcobalmin may be better if its direct to the cell ?

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What you describe (high levels in the blood, low activity in the cell) is functional B12 deficiency. If you have this then an MMA or homocysteine test will show high levels, despite the large amounts of B12 in the blood.

Both methylcobalamin and hydroxocobalamin should be equally able to enter the cell. There’s no reason why methylcobalamin would find it easier.

And once they get into the cell both forms are transformed into cobal(II)amin.

The speculated causes of functional B12 deficiency are many. Some people have a mutation in the gene that makes the TC protein (TCN2). But a homozygous mutation makes itself obvious in infancy while a heterozygous mutation (like what I’ve got) doesn’t seem to do anything.

Then there are the transporter proteins that carry the TC-B12 from he blood into the cell. I don’t think anybody’s taken a good look at those. Nor do I think that potential mutations to MMACHC have been investigated.

And I believe that B12 is involved in other biochemical processes apart from the two common ones. That would explain why I have high levels of B12, low levels of MMA and hCys, yet feel terrible if I don’t inject twice a week.

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Thanks again.. still struggling to get my head around it all! I have PA was diagnosed when my blood levels were just 50 but I still don’t know if some of the things I suffer from are part and parcel of getting older (I’m 51) or even in my head some of the time. I am pretty fit although I’m wiped out today after doing a 23 mile hilly bike ride.. but before it would not have affected me this much 😫 I accept I can’t do what I used to do but worry more about the impact on mental health

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fbirder You wrote: "When you take methylcobalamin it is converted to cobal(II)amin as soon as it enters the cell."

I wonder when you take methylcobalamin, doesn't it get used first (by giving up its methyl group to the methioinine cycle) and then later gets converted to cobal(II)amin? It's just a guess on my part.

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No. Methylcobalamin will always get converted to cobal(II)amin as soon as it gets into the cell.

At the site of activity of the methionine synthase enzyme the cobal(II)amin is bound to the enzyme. Then a methyl group is transferred from methyltetrahydrofolate to the enzyme-bound cobal(II)amin to form methylcobalamin. That methyl group is then transferred, by the enzyme, to a homocysteine molecule to form methionine.

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fbirder I can't quite understand what's happening with B12 trafficking even when I look at this diagram. I am looking at the wrong diagram? Please kindly advise.

upload.wikimedia.org/wikipe...

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That diagram is very complex, showing all of the minor processes, including some (like the MMADHC enzyme) that aren’t fully understood yet.

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I have tried both , and have to say that I found no difference in effect. But we all know that everyone is different , as we see here on our forum. Some benefit from sub-linguals , sprays and patches . I do not . . Also P.A. Is not a well-researched condition unfortunately . So we have to experiment ourselves . Luckily there is no danger involved in using any of the different forms of B12 .

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The guidelines in the ampoules packaging say to inject every other day or daily, while the NICE and British Heamatology guidelines say every other day, until neurological symptoms resolve.

I, and many others need to inject at least daily.

Maybe you just need more jabs?

For the extra B12 to work properly you need a wide range of extra vitamins and minerals so many people can benefit from a broad spectrum multivitamin and mineral supplement plus extra folate, potassium, magnesium and maybe iron. There are different forms of these available and some people need a specific type to be effective.

If you have tried all this and still have symptoms then it is worth investing other things, particularly other auto immune conditions as they frequently go together.

Good luck!

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thanks Deniseinmilden i have tried other supplements alongside the injections. If im honest my symptoms dont seem nearly as bad as some people on this site, but i just want to make sure i am doing the right thing and taking the best possible form of b12

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Below is Dr Wilhelmina Rietsema's explanation in BMJ 'Rapid Responses' to BMJ research article on B12:

"There are two active forms of the B12 enzyme in the human cell. First, Methylcobalamin acts as a co-enzyme for the conversion of homocysteine to methionine. Methionine then acts as a methyl-donor to a great number of reactions that need a methyl group, including the synthesis of myelin, serotonin, dopamine, noradrenalin, DNA and phospholipids.

Second, Adenosylcobalamin is a co-enzyme for the conversion of L-methylmalonyl-CoA into succinyl-CoA which feeds into the citric acid cycle.

Is it important which form is used in treatment? In most people, it does not matter. They can convert cyano- and hydroxo-cobalamin into the active forms needed. However, I have recently reported a case in which it did matter. The severe vitamin B12 deficiency, including dementia and psychosis, responded to treatment with high dose oral methylcobalamin, but not to equally high dose oral hydroxocobalamin. [1]"

1. Rietsema WJ. Unexpected Recovery of Moderate Cognitive Impairment on Treatment with Oral Methylcobalamin. Journal of the American Geriatrics Society 2014;62(8):1611-12 doi: 10.1111/jgs.12966[published Online First: Epub Date]|.

........................

What comes through clearly on the forum is that we are all individuals with different responses to various forms of cobalamin, oral and parental:

ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/pmc/articl...

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thanks thats really interesting. Maybe i should try oral methylcobalamin alongside the HC injections

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Thank you Polaris - really clear explanation. I think it's brilliant how we all work together to find things that help understand this.

I live in hope that one day someone will pull everything together for medical training!

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Sally Pacholok, "Could it be B12?", recommends both 🙂

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I have read that if you have a MTHFR mutation then you don't methylate properly and the cyanocobalamin form can give you toxic effects. There are two common MTHFR mutations & can even effect you if you are just heterozygous for one of the mutations (as I am). But being heterozygous for both mutations or homozygous for one of them effects you even more. For me in the US, I started with the oral cyanocobalamin & got fevers & worse symptoms of B12 deficiency, then I tried a few shots of the cyanocobalamin & had very weird fever chills on & off and was very lethargic, etc. I've switched to the oral of the other forms, but they aren't enough. Just ordered my first hydroxycobalamin ampoules, so I'm hoping they go better then the cyanocobalamin shots!

Thanks for all the biochemistry detailed posts about the differences!

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Here is a lot of nonsense on he interwebs about MTHFR.

No. MTHFR mutations cannot make cyanocobalamin give you toxic effects.

There are dozens of common MTHFR mutations. Almost everybody carries at least one.

There is only one mutation that has been shown by repeatable, reputable, scientific studies to have any significant effects. That is being homozygous (two copies) of the C677T mutation. This decreases the activity of the MTHFR enzyme to about 25% of normal. For many people this isn’t a problem, the body just makes more of the enzyme.

People who are heterozygous for C677T have an enzyme working at about 75% efficiency. That is easily compensated by the body.

If you are one of the 9% that is homozygous for C677T then it is easily fixed by supplementing with methylfolate, 400 mcg a day. There is no requirement to take methylcobalamin. I have this mutation (and a couple of others on the MTHFR gene). Swapping from folic acid to methylfolate I noticed no difference except for a decrease in my joint pain with methylfolate.

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HI I;M FROM INDIA . AN AMERICAN DOCTOR GAVE ME PYCNOGENOL 5 YEARS BACK FOR PELVIC PAIN . IT'S A NITRIC OXIDE BOOSTER AND I DEVELOPPED SEVERE MIGRAINES/ WHICH I DID'NT HAVE BEFORE . MY GP PUT ME ON METHYLCOBALAMIN SHOTS =6 SHOTS , , after which migraines reduced BY 60 PERCENT .MY B 12 LEVELS WERE LESS THAN 200 AND AFTER SEVEREAL B 12= I TOOK MORE THAN 6 LEVELS ARE OVER 3000 .AFTER THE 6 TH INJECTION ,METHYLCOBALAMIN IS INEFFECTIVE IN REDUCING MIGRAINES . I WANT TO TAKE HYDROXOCOBALAMIN AS IT CAN QUENCH NITRIC OXIDE BETTER . THE PROBLEM WITH ME IS ONLY 30 PERCENT OF B 12 IS BOUND TO PROTEINS REST IS CIRCULATING IN BLOOD . I WANT TO KNOW FROM YOU IF I TAKE HYTDROXOCOBALAMIN, WILL IT ENTER THE CELLS AS I READ ONLY 30 PERCENT IS BOUND TO PROTEINS .WILL HYDROIXOCOBALAMIN BE EFFECTIVE SINCE METHYLCOBALAMIN IS NOT EFFECTIVE AT ALL AFTER THE SIXTH SHOT-PLS REPLY

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Hi PInkypop I think you will need to post this on the forum as opposed to in this chain. Sorry I can’t help. I’m not sure how you know only 30% of b12 attaches to protein?

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I found at different times one worked better than the other. I think is has to do with the methylation cycle of your body.

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I think the question at the end of the day is going to boil down to how much you are willing to pay to get methylcobalamin over hydroxocobalamin? Looking to the Australian b12 supplier methyl comes in at £3.25 per ampoule delivered and only sold in packs of 10 with no further discount I could see for bulk buying. Hydroxo from an average amazon.de supplier was 60p delivered when bought in a 100 pack.

I'm sure there are other retailers selling methyl ampoules online but I havent delved into that as it's still comparitively rare compared to hydroxo.

That's a big price difference so; do you think you would get sufficient benefit over hydroxo by going with methyl instead?

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I think it’s more down to which works better and obtaining it ! Right now can’t seem to get hydroxo either ! All saying out of stock on line 😫

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Amazon.de worked for me. I have 100 ampoules coming today; I ordered them a few days ago. amazon.de/Vitamin-Depot-Rot...

You get a number of sellers (pharmacies) selling for that listing so: Several of them should always have stock at least.

You can click the globe icon below the search button on their site to switch it to English if needed.

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