Methylcobalamin & Adenosylcobalamin
- Methylcobalamin Trial in Vegans
- Anecdotal Report from a Vegan
Cyanocobalamin is a well-studied, reliable, inexpensive form of vitamin B12. Nonetheless, many alternative health practitioners and supplement companies promote the co-enzyme forms of B12, methylcobalamin and adenosylcobalamin. Requirements for these forms have not been fully elucidated and common recommendations are for 1,000 µg/day.
There are four forms of vitamin B12, differentiated by the side group attached to the cobalamin molecule:
- Adenosylcobalamin - AdoCbl
- Cyanocobalamin - CNCbl
- Hydroxocobalamin - HOCbl
- Methylcobalamin - MeCbl
MeCbl and AdoCbl are the two forms of vitamin B12 that are co-enzymes: the body requires each of them for different reactions.
CNCbl is the form most commonly found in supplements and fortified foods. It is the most stable because the side group, cyanide, has the strongest attraction to the cobalamin molecule.
HOCbl is the form usually contained in B12 shots and the hydroxyl side group has the least attraction to the cobalamin molecule.
AdoCbl is technically 5'-deoxy-5′-adenosylcobalamin, and also known as dibencozide, cobamamide, and cobinamide.
The co-enzyme form of B12 supplements, AdoCbl and MeCbl, are sometimes promoted as being superior to CNCbl for two reasons:
- CNCbl contains a molecule of cyanide.
- The body must convert CNCbl into AdoCbl and MeCbl before using it.
Others suggest that CNCbl is the best choice for most people because it is the most stable form, it has been well studied and proven to increase vitamin B12 status, it is the most common, and least expensive.
Let's examine the claims in favor of the co-enzyme forms.
The safety of CNCbl has raised concerns due to the fact that cyanide is a component of CNCbl, and the cyanide molecule is removed from CNCbl when used by the body's cells. Cyanide is also found in many fruits and vegetables and so humans are always ingesting small amounts of cyanide, and like in most fruits and vegetables, the amount of cyanide in CNCbl is considered to be physiologically insignificant.
For an analysis of the amount of cyanide in vitamin B12 supplements, see the table in Side Effects of B12 Supplements.
A 2015 paper by Obeid et al. suggests that people do not benefit more from the co-enzyme forms because all forms, except injected HOCbl, must have their side groups stripped by the target cell before the necessary side group is added for the co-enzyme form needed. People with genetic defects of vitamin B12 metabolism may benefit from HOCbl injections.
Currently, we do not have sufficient evidence to suggest that the benefits of using MeCbl or AdoCbl override that of using CNCbl or HOCbl in terms of bioavailability, biochemical effects, or clinical efficacy. There is uncertainty regarding the claimed superior role of [B12] coenzyme forms for prevention and treatment of [B12] deficiency. However, HOCbl may be an advantageous precursor of the cofactors, particularly in the inherited disorders of metabolic Cbl processing. CNCbl is a more stable and inexpensive form that appears to be best suited for oral supplementation and parenteral [intravenous] treatment as well.
Some researchers question whether the co-enzyme supplements are stable in their oral form and usually recommend much higher doses of MeCBl–typically 1,000 µg/day.
A 1971 study found that at doses of 1 µg, 5 µg, and 25 µg, CNCbl, HOCbl, MeCbl, and AdoCbl were all absorbed at about the same rate (6). However, the researchers suggested, based on other research, that at higher doses, CNCbl is better absorbed. They theorized that this could be because absorption of MeCbl by way of intrinsic factor is efficient while CNCbl is better absorbed through passive diffusion.
Here's a table of the absorption rates:
A 1973 study suggests that once absorbed, MeCbl may be retained in the body better than CNCbl (1).
A 2011 clinical trial from Korea found that 1,500 µg/day of MeCbl was effective at raising vitamin B12 levels, reducing or eliminating neurological symptoms of B12 deficiency, and lowering homocysteine levels (5). This trial was done on people who had a gastrectomy and, therefore, had vitamin B12 malabsorption, indicating that for most people 1,500 µg/day would be more than enough. There was no comparison group receiving CNCbl.
I am unaware of any clinical trials testing the various forms of vitamin B12 against each other among the general population and most people seem to do well using CNCbl.
Some people with chronic fatigue report getting more relief from AdoCbl than either MeCbl or CNCbl (more info), while other people report feeling better only when taking both AdoCbl and MeCbl. It's possible this could be a real effect, but could also be due to a placebo effect or taking more B12 and inadvertently counteracting malabsorption.
Donaldson (2) (2000, USA) studied 3 vegans with elevated urinary MMA levels who were treated with 1/2 to 1 sublingual MeCbl tablet, 2 times/day for 3 weeks. Correspondence with the author (March 21, 2002) verified that these tablets contained 1,000 µg MeCbl each.
Two of the subjects' urinary MMA normalized while the remaining subject's stayed slightly elevated at 4.1 µg/mg creatinine (normal is < 4.0 µg/mg creatinine). Thus, at a rate of 1,000-2,000 µg/day, MeCbl appears to be absorbed at a high enough rate to improve B12 status in some vegans. Additionally, this indicates that the MeCbl was converted to AdoCbl for use in the MMA pathway.
In 2011, a reader sent in this report:
I'd been taking 500 µg of methylcobalamin for years, not knowing that the B12 dosages so often cited (daily 25 - 100 µg) are just for CNCbl. So, about a week ago I started taking 1000-2000 µg of methylcobalamin instead of just 500 µg, and I feel a difference!
It should be noted that this person might suffer from B12 malabsorption of any form of B12, and might have had the same experience with CNCbl.
HOCbl is the form of B12 typically found in food. There are not many oral forms for people to take; it is normally injected. One study suggests that after injections, HOCbl is retained in the body better than CNCbl (4).
2. Donaldson MS. Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000;44(5-6):229-34. The subjects receiving methylcobalamin was only a small part of this paper, mentioned on p. 232.
3. Obeid R, Fedosov SN, Nexo E. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res. 2015 Jul;59(7):1364-72. | link
4. Tudhope GR, Swan HT, Spray GH. Patient variation in pernicious anaemia, as shown in a clinical trial of cyanocobalamin, hydroxocobalamin and cyanocobalamin-zinc tannate. Br J Haematol. 1967 Mar;13(2):216-28.
5. Kim HI, Hyung WJ, Song KJ, Choi SH, Kim CB, Noh SH. Oral vitamin B12 replacement: an effective treatment for vitamin B12 deficiency after total gastrectomy in gastric cancer patients. Ann Surg Oncol. 2011 Dec;18(13):3711-7. | link
6. Adams JF, Ross SK, Mervyn L, Boddy K, King P. Absorption of cyanocobalamin, coenzyme B 12 , methylcobalamin, and hydroxocobalamin at different dose levels. Scand J Gastroenterol. 1971;6(3):249-52. | link
Kelly G. The co-enzyme forms of vitamin B12: Toward an understanding of their therapeutic potential. Alt Med Rev. 1997;2(6):459-471.