Adenosylcobalamin

[alicec]

Also, I'm grateful you mentioned a research paper by Quadros in another thread. I downloaded that paper and, although much of it is beyond my comprehension, the parts I half-understand are excellent such as Quadros's chart of pathways in Fig.1.

I'm happy to help if there is anything in the paper or elsewhere that you would like to understand better.

 

[Banana94]

Thanks for your post.

I'm still wondering why people are going to extra effort to find AB12, when MB12 is easier to find.

Because i want to try every supplement for itself. If I have multivitamins i cant find out whats helps me or what does harm..
Other point: Freddd reported a hugh improvment by taking AdenoB12 with LCF.

 

[Creachur]

I'm happy to help if there is anything in the paper or elsewhere that you would like to understand better.

@alicec
Hi Alice. There is something I am trying to understand. I think I may have asked this question elsewhere but don't have a clear understanding.... Can I take adenosylcobalamin at the same time as methylcobalamin?

I think I need to take adenosylcobalamin 2 or 3 times a day because it's effect seems to fade. It could be due to some untypical location in the pathways my genetic illness is occurring, so I must confirm this with more tests. Maybe my adenosylcobalamin stores have become depleted over the years and my recent supplementation has not filled them up yet. I also want to take methylcobalamin although perhaps not every single day.

Could I take adenosylcobalamin at the same time as methylcobalamin? I take them subligually to avoid the very restricted B12 absorption from the gut. I am taking doses of approx 1,000 to 2,000 mcg of each.

Do these compete for transport or interfere with one another in any way?

Quadros ("Advances in the understanding of cobalamin assimilation and metabolism") has a section on absorption but I can't make sense of it. I did see you once post about haptocorrin and transcobalamin which are compounds, as far as I can tell, that seem to be involved in absorption but I really can't understand much about it.

Thanks for any info.
Regards, C


PS: I saw an old posting by Freddd saying in his personal experiments with adeno- and methyl- cobalamin he felt he needed to take at least 20% of the lower amount. However I don't know if that was just an early observation and anyway he says his metabolism is untypical. So this didn't really give me much information.

 

[alicec]

Can I take adenosylcobalamin at the same time as methylcobalamin?

Theoretically yes - ie taking the two different forms at the same time shouldn't matter though the amount of the total dose might. There is very limited capacity to absorb B12 via the oral or sublingual route (it appears that sublingual is actually oral. It appears to be more efficient because the lozenge dissolves slowly and the amount entering the gut for absorption is kept low, so more ends up being absorbed compared with the full dose going into the stomach at the same time.).

Having said that, the fact that you respond more favourably to the adenosyl form suggests that the normal B12 processing steps maybe don't apply to you and we enter the murky territory of poorly understood alternative pathways.

@Freddd has reported that for him at least, the two forms appear to compete and he takes them separately. As for the proportions of each that he finds helpful, I am sure that is an individual thing. You would need to determine your own response to each form.

In your case taking the two forms separately might be a wise precaution. In any case it is a good idea regardless of form to spread out doses.

You might want to consider alternative application routes, eg injection or topical. I'm not sure if the adenosyl form is available via injection - I seem to recall Freddd saying it is. You would need to check, certainly the methyl form is.

This is undoubtedly the best way to build up high levels and achieve the flooding of the CNS that Freddd talks about.

Alternatively there is the topical route. These products have been tried by a number of people on PR, including myself. Some swear by them, others who needed high doses have returned to injections. I alternate between the methyl oil and a homemade version (see more below) plus a little adenosyl in sublingual form.

The scientist who runs the company is very helpful about answering questions. He says in experiments done to develop the product, he found about 80% absorption of these oils. Absorption from sublingual is at best around 10%. Absorption from injections close to 100%.

If you try the oils I would suggest you at least start with separate adenosyl and methyl forms.

The homemade version just uses liquid methylcobalamin (not sure if a liquid adensoyl is available anywhere) mixed with a little body lotion in the palm of the hand and rubbed into the soft skin of the underarms, abdomen or buttocks.

Quadros ("Advances in the understanding of cobalamin assimilation and metabolism") has a section on absorption but I can't make sense of it. I did see you once post about haptocorrin and transcobalamin which are compounds, as far as I can tell, that seem to be involved in absorption but I really can't understand much about it.

Haptocorrin (HC) and transcobalamin 2 (TCN2) are carrier proteins which transport cobalamin in the blood. HC is also present in saliva.

Cobalamin is a very reactive molecule and the cobalt atom at its centre is very susceptible to oxidation. Consequently the molecule is not left naked in the body, it is always accompanied by some sort of protein which acts in a protective role.

Cobalamin in food is usually protein bound already but just in case, there is HC around in saliva. Once in the stomach the acid environment helps to separate cobalamin from protein and it then is bound to intrinsic factor (IF).

The IF-cobalamin is absorbed in the small intestine via a specific receptor for the complex, called cubilin. In the absence of IF, little absorption occurs. This is the case for pernicious anaemia.

Before it reaches the peripheral circulation, cobalamin is transferred from IF to HC and TCN2. About 80% of cobalamin in the blood is bound to HC, the rest to TCN2. It is only the later form that is taken up into cells in the body, again via a specific receptor for the complex. I have described what happens to the cobalamin-TCN2-receptor complex inside the cell in an earlier post.

I honestly don't know if TCN2 has a preference for one form of cobalamin over another. Undoubtedly I could find out by reading detailed studies about the carrier protein, but I haven't the energy for it. Normally, the predominant form in the blood is methylcobalamin. In the case where large amounts of other forms are supplemented (particular via injection where high concentrations could be reached), presumably those forms would be more abundant than methyl.

As far as I know they should all be bound to TCN2 and taken into the cell.

Also as far as I know naked cobalamin is not taken into the cell, it must be bound to a serum factor. In the alternative route of passive diffusion of cobalamin into the cell (ie not via the usual receptor mediated mechanism) which is usually referred to in studies but not further defined, I don't know if the protein is TCN2, nor have I seen any studies of what happens to cobalamin taken up via this route.

Freddd appears to have adult onset cblC disease. The genetic defect here lies in the processing which occurs after cobalamin has been separated from TCN2 inside the cell. Normally, the upper axial ligand (ie the methyl, adensoyl etc group) is then removed by the protein product of the gene MMACHC.

Cobalamin is then routed to either the methionine synthase enzyme where it is methylated and used by that enzyme, or to the mitochondrion where it is adenylated and used by methylmalonyl CoA mutase.

When MMACHC is defective, both B12 dependant enzymes receive insufficient cofactor and so both are unable to function properly. Consequently people with this defect show both elevated homocysteine and MMA.

In your case I am assuming that the defect may lie only in the mitochondrial pathway, but that is only an assumption. Have you had homocysteine measured?

 

[Galixie]

There is very limited capacity to absorb B12 via the oral or sublingual route (it appears that sublingual is actually oral. It appears to be more efficient because the lozenge dissolves slowly and the amount entering the gut for absorption is kept low, so more ends up being absorbed compared with the full dose going into the stomach at the same time.).

Do you have any links to that research or can you point me in the direction of finding it somehow? I would very much like to read it.

I wonder how liquid sublinguals compare to lozenges? But mostly I just would love to see whatever research into the subject that has been done.

Many insurers are pushing tablets instead of injections for B12 deficiency and they base it on research that shows oral B12 raises serum level. I've noticed that none of the research they cite gives any mention of neurological improvement and the anecdotal stories I've heard indicate that the tablets don't correct the symptoms of deficiency as effectively as injections. If there's any research about why the serum level rises but symptoms don't improve on oral B12, I would be very interested in reading that too.

 

[alicec]

Many insurers are pushing tablets instead of injections for B12 deficiency and they base it on research that shows oral B12 raises serum level. I've noticed that none of the research they cite gives any mention of neurological improvement and the anecdotal stories I've heard indicate that the tablets don't correct the symptoms of deficiency as effectively as injections. If there's any research about why the serum level rises but symptoms don't improve on oral B12, I would be very interested in reading that too.

Sorry I haven't bother to book mark any of the detail about this subject. I think the main point is that just increasing serum B12 levels doesn't necessarily mean that symptoms are reduced.

If you look at a site like this, clinicians say that in practice, injections are much better at controlling symptoms, particularly severe neurological ones in many patients.

If you look at reference 2, they indicate several studies which document this. They just list a series of authors. If you search for each group of authors on google or google scholar, I'm sure you would find the original papers.

There may be other useful info on this or other sites like it.

Sorry I can't be more helpful.

 

[Learner1]

Regarding TCN2 - this from the OMIM database:

A pro259-to-arg (P259R) mutation (613441.0002) is the most common polymorphism of the TCN2 gene in white populations. Miller et al. (2002), among others, examined the influence of TCN2 genotype on indices of B12 status; specifically, they studied total serum B12, the amount of B12 bound to TC II, methylmalonic acid, and homocysteine in 128 healthy older adults (ages 40 to 88 years). Mean total B12 and homocysteine concentrations were not significantly different among the 3 genotypes. Mean concentration of bound B12 was significantly higher in those subjects homozygous for the proline form of TC II compared with those homozygous for the arginine form and heterozygotes (p = 0.006). In addition, mean methylmalonic acid concentrations were significantly lower in the proline homozygous and heterozygous groups compared with the arginine homozygous group (p less than or equal to 0.02). The proline homozygous genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCN2 genotype may thus influence susceptibility to B12 deficiency

 

[Galixie]

@alicec Thank you! I am excited to dig into the reference material they list.

 

[pattismith]

Hydroxo is difficult to find orally and in injectible in the US. I called 25 compounding pharmacies across the US and only 2 could fill a prescription for injectible hydroxo.

Most doctors think cyanocobalamin is the standard version and don't realize that some of us don't use it well, especially if high doses are needed.

It's a reality here in France, no HydroxoB available here, no methylB and no AdenosylB either...

 

[pattismith]

Regarding TCN2 - this from the OMIM database:

I have two heterozygous missense mutation on TCN2 (unfrequent ones), it may be interesting to dig in, thank you!

 

[Marc_NL]

Alternatively there is the topical route. These products have been tried by a number of people on PR, including myself. Some swear by them, others who needed high doses have returned to injections. I alternate between the methyl oil and a homemade version (see more below) plus a little adenosyl in sublingual form.

The scientist who runs the company is very helpful about answering questions. He says in experiments done to develop the product, he found about 80% absorption of these oils. Absorption from sublingual is at best around 10%. Absorption from injections close to 100%.

Do you have reason to believe the 80% figure is right, I know experiments were done but nothing was published AFAIK.

BTW, I am currently also using these oils

 

[Creachur]

I wonder how liquid sublinguals compare to lozenges? But mostly I just would love to see whatever research into the subject that has been done.

Many insurers are pushing tablets instead of injections for B12 deficiency and they base it on research that shows oral B12 raises serum level. I've noticed that none of the research they cite gives any mention of neurological improvement and the anecdotal stories I've heard indicate that the tablets don't correct the symptoms of deficiency as effectively as injections. If there's any research about why the serum level rises but symptoms don't improve on oral B12, I would be very interested in reading that too.

@Galixie I'm too new to all this to give much considered information but in my readings to catch up I spotted the following in a book which may be of interest. It deals with some of the variations in the ways B12 is administered. It doesn't mention subligual and maybe that's because, as AliceC mentioned, sublingual could be the same as slow oral.

The two quotations come from:
Vitamins in Foods - Analysis, Bioavailability and Stability by George Ball (2006) page 282ff
Google Books link = https://books.google.co.uk/books?id=vXnLBQAAQBAJ&pg=PA282

The intrinsic factor-mediated system is capable of handling between 1.5
and 3.0 mcg of vitamin B12. The limited capacity of the ileum to absorb B12
can be explained by the limited number of receptor sites, there being only
about one receptor per microvillus. Saturation of the system at one meal
does not preclude absorption of normal amounts of the vitamin some
hours later. The entire absorptive process, from ingestion of the vitamin
to its appearance in the portal vein, takes 8–12 h.

Absorption can also occur by simple diffusion across the entire
small intestine. This process probably accounts for the absorption of
only 1–3% of the vitamin consumed in ordinary diets, but can provide
a physiologically significant source of the vitamin when it is administered
as free cobalamin in pharmacological doses of 30 mcg or more.

14.5 Bioavailability
14.5.1 Efficiency of Absorption

The percentage of ingested vitamin B12 that is absorbed decreases as the
actual amount in the diet increases. At intakes of 0.5 mcg or less, ca. 70%
of the available vitamin B12 is absorbed. At an intake of 5.0 mcg, a mean
of 28% is absorbed (range, 2–50%) while at a 10-mcg intake the mean
absorption is 16% (range, 0–34%). When 100 mcg or more of crystalline
vitamin B12 is taken, the absorption efficiency drops to 1%, and the excess
vitamin is excreted in the urine.

 

[Creachur]

@alicec You make many interesting points although the biochemistry you give is still rather too detailed for my level of understanding! Thank you very much for your effort to help me understand matters. I appreciate it.

Freddd appears to have adult onset cblC disease. The genetic defect here lies in the processing which occurs after cobalamin has been separated from TCN2 inside the cell. Normally, the upper axial ligand (ie the methyl, adensoyl etc group) is then removed by the protein product of the gene MMACHC.

In your case I am assuming that the defect may lie only in the mitochondrial pathway, but that is only an assumption. Have you had homocysteine measured?

That's very interesting about Freddd's condition. I appear to have a similar adult-onset problem myself. Mine started in my 40s but wasn't recognised for what it really was for many years and the lethargy was seen as some form of depression. Only two years ago I managed see that my symptoms were likely to be metabolic and after that read up whenever I was well enough to comprehend things.

Somewhere in my readings and mis-readings, I got the feeling I had some problem with "mutase" on account of the way I responded to adenosylcobalamin. I am not really clear about this but hopefully it will make sense at some point. The strange thing I observe is that 3mg adenosylcobalamin taken subligually the morning does not last until the evening; surely the morning's adenosylcobalamin would get stored?

In my case, when my condition is affecting me the symptoms are very severe (like a stroke, epileptic attack or diabetic hypo) and there seems to be a lot of different toxicities going on in me, in addition to energy depletion in my brain & nerves leading to delirium. There were some oversights in diagnosis by the neurologists who investigated me, so I am going back to get re-tested more carefully.

I am now so full of supplements (such as B12, carnitine, and arginine) to stave off the worse symptoms each day that it can affect the results of testing. However if I stop taking supplements I am far too ill to make the journey to the testing centre. I'm working on this! This means I haven't had my homocysteine tested.

Alternatively there is the topical route. These products have been tried by a number of people on PR, including myself. Some swear by them, others who needed high doses have returned to injections. I alternate between the methyl oil and a homemade version (see more below) plus a little adenosyl in sublingual form.

The scientist who runs the company is very helpful about answering questions. He says in experiments done to develop the product, he found about 80% absorption of these oils. Absorption from sublingual is at best around 10%. Absorption from injections close to 100%.

I am miffed that my huge 3,000 mcg Country Life tablet is mostly going into the gut (despite being taken sublingually) where it effectively overloads the gut's aborption pathways. I wonder what the rationale is for such a large dose in a single tablet. Even breaking the tablet four ways still overload the gut's tranporters.

I am tempted by the idea of a homemade B12 oil or lotion although my interest is for adenosylcobalamin rather than methylcobalamin. As B12 is water soluble then is it possible to dissolve in water the B12 from a crushed tablet of my Country Life Dibencozide to provide a adenosylcobalamin solution. (I guess it would have to be done away from light.) After that I am not sure how to incorporate this solution into an oil because the B12 won't truly mix with oil. Would I just add B12 solution to body lotion as you described?

 

[alicec]

Do you have reason to believe the 80% figure is right, I know experiments were done but nothing was published AFAIK.

BTW, I am currently also using these oils

Yes I'm not aware that anything has been published either though I believe the transdermal process is patented so it might be possible to find the patent. This is what Greg Russel Jones, the scientist behind B12 oils, has said. He is a reputable scientist who has published in the B12 field and has expertise in oral and topical uptake of various substances, so I have no reason to doubt him.

He is also director of a consulting group which advises on things like oral and topical uptake - there might be some useful info on the website.

Greg also maintains a B12 website that might have useful info to answer some of the questions people have been raising. Here it is. Forgot about this yesterday.

 

[alicec]

@alicec Thank you! I am excited to dig into the reference material they list.

You might find some more helpful info in the B12 website I just linked.

 

[alicec]

I got the feeling I had some problem with "mutase" on account of the way I responded to adenosylcobalamin.

That was my assumption.

The strange thing I observe is that 3mg adenosylcobalamin taken subligually the morning does not last until the evening; surely the morning's adenosylcobalamin would get stored?

Well in a normal person even 1% of 3 mg (which might be a realistic figure for how much of the sublingual is absorbed) would be a vast excess and some would get stored, but your B12 metabolism does not appear to be normal.

Speaking generally, when an enzyme is defective, sometimes a vast excess of a cofactor or substrate can stimulate it sufficiently to achieve some function. It depends on the actual defect. Most of the dose is actually wasted but the initial high concentration is needed to drive the reaction.

The high concentration is needed at the actual enzyme. So to achieve that, given that we appear to be dealing with a minor undefined uptake pathway which is taking entire adenosylB12 into the cell, you would need an absolutely vast amount to start with. A vast amount will be wasted also.

If the benefits are running out by evening then you just need to take further doses during the day.

so I am going back to get re-tested more carefully.

Does that include genetic testing for the B12 pathway? This could be definitive.

I am miffed that my huge 3,000 mcg Country Life tablet is mostly going into the gut (despite being taken sublingually) where it effectively overloads the gut's aborption pathways. I wonder what the rationale is for such a large dose in a single tablet. Even breaking the tablet four ways still overload the gut's tranporters.

Most of a sublingual or oral dose will always be wasted. By starting with a relatively high dose, maximum possible absorption is ensured, though of course more will be wasted.

You could slow things down by placing the lozenge between gum and upper lip rather than under the tongue.

I am tempted by the idea of a homemade B12 oil or lotion although my interest is for adenosylcobalamin rather than methylcobalamin. As B12 is water soluble then is it possible to dissolve in water the B12 from a crushed tablet of my Country Life Dibencozide to provide a adenosylcobalamin solution. (I guess it would have to be done away from light.) After that I am not sure how to incorporate this solution into an oil because the B12 won't truly mix with oil. Would I just add B12 solution to body lotion as you described?

You could try dissolving the lozenge - definitely exclude light (so a bit difficult unless you have a dark room with red light). You would have all the carrier gunk in the lozenge which probably wouldn't be soluble but you could try just mixing this slurry with some body lotion and rubbing into skin. Any gunk left on the skin could just be wiped off.

Alternatively I googled liquid adenosylB12 and found this and this. There are probably others.

 

[CCC]

Coming in late here, so I'm responding to a few points ...

B12 oils - home made
@ahmo had a lot of success with homemade oils. It didn't work for our 15 year old patient - too messy. If she comes in here, she can maybe tell you how she did it

We need two forms of B12, and we can feel the difference

We need both adenosyl and methyl B12. We started with sublinguals until we reached about 15mg of mB12 a day, then switched to the B12 oils @alicec was talking about.

We needed huge amounts to begin with: 2 slurps of the ab12/mb12 combination plus another 2 slurps of the straight mb12 oil (four slurps in total, all in the morning). And then there was methylfolate, B2 etc on top of all that.

After two years, we're just about down to one slurp of each, applied to the back in the morning.

Hope this helps.

 

[ahmo]

Hi @CCC I was just on another thread where you mentioned me, re AdB12. I'm taking them weekly only, and no folate or MB12 that day. Seems to be working fine. Also 3 LCF/day, Doctor's Best. I early AM, 12 midday, away from foods. Can't tell by symptoms, but self-testing, body says this is good for me.

I crushed B12 tablets onto a piece of fabric, put some oil or lotion on top, and use a small size tube sock w/ ends cut off, so it makes a cuff, to fasten to my leg. I'm not doing this for B12 now, using nasal spray instead. But I still use this method for B2, twice a day.

 

[benxwz]

Hello,

does anyone know where to find Adenosylcobalamin injection? In powder or bulb?

Thank you in advance

Benjamin

 

[Eastman]

@benxwz

I can't help with injections but in case you don't get any response on your question, maybe you can consider transdermal B12? It is said to have good absorption and provide smoother delivery into the bloodstream. In case you haven't seen them, the relevant threads are: Anybody else using DIY transdermal B12? and Transdermal B12 oils. There was also some discussion on it in this thread.