Evidence-Based Nutrient Recommendations

Coenzyme Supplements: Methylcobalamin and Adenosylcobalamin

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Contents

Summary

Cyanocobalamin is a well-studied, reliable, inexpensive form of vitamin B12, though it does contain a molecule of cyanide, which, in normal amounts, should be physiologically inconsequential for most people. Many alternative health practitioners and supplement companies promote the coenzyme forms of B12, methylcobalamin and adenosylcobalamin. Requirements for these alternative forms have not been fully elucidated and common recommendations are for 1,000 µg/day.

Introduction

There are four forms of vitamin B12, differentiated by the side group attached to the cobalamin molecule:

  • Adenosylcobalamin
  • Cyanocobalamin
  • Hydroxocobalamin
  • Methylcobalamin

Methylcobalamin and adenosylcobalamin are the two forms of vitamin B12 that are coenzymes: the body requires each of them for different reactions.

Cyanocobalamin 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.

Hydroxocobalamin is the form usually contained in B12 shots and the hydroxyl side group has the least attraction to the cobalamin molecule.

Adenosylcobalamin is technically 5′-deoxy-5′-adenosylcobalamin, and also known as dibencozide, cobamamide, and cobinamide.

The coenzyme form of B12 supplements, adenosylcobalamin and methylcobalamin, are sometimes promoted as being superior to cyanocobalamin for two reasons:

  1. Cyanocobalamin contains a molecule of cyanide.
  2. The body must convert cyanocobalamin into adenosylcobalamin and methylcobalamin before using it.

Others suggest that cyanocobalamin 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 coenzyme forms.

Cyanide

The safety of cyanocobalamin has raised concerns due to the fact that cyanide is a component of cyanocobalamin. The amount of cyanide in a cyanocobalamin supplement is a fraction of the amount of cyanide most people ingest on a daily basis and is considered to be physiologically insignificant.

For more information, see our detailed analysis in Vitamin B12 and Cyanide.

Effectiveness

Obeid et al. (2015) suggest that people do not benefit more from the coenzyme forms because all forms, except injected hydroxocobalamin, must have their side groups stripped by the target cell before the necessary side group is added for the coenzyme form needed. In other words, any form of cobalamin supplement can be turned into both of the coenzyme forms (methylcobalamin and adenosylcobalamin). They state:

Currently, we do not have sufficient evidence to suggest that the benefits of using [methylcobalamin] or [adenosylcobalamin] override that of using [cyanocobalamin] or [hydroxocobalamin] 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, [hydroxocobalamin] may be an advantageous precursor of the cofactors, particularly in the inherited disorders of metabolic [cobalamin] processing. [Cyanocobalamin] is a more stable and inexpensive form that appears to be best suited for oral supplementation and parenteral [intravenous] treatment as well.

People with genetic defects of vitamin B12 metabolism may benefit from hydroxocobalamin injections; Obeid et al. describe these genetic defects in more detail in their paper.

Absorption

Some researchers question whether the coenzyme supplements are stable in their oral form and usually recommend much higher doses of methylcobalamin—typically 1,000 µg/day.

A 1971 study found that at doses of 1 µg, 5 µg, and 25 µg, cyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin were all absorbed at about the same rate (Adams, 1971). However, the researchers suggested, based on other research, that at higher doses, cyanocobalamin is better absorbed. They theorized that this could be because the absorption of methylcobalamin by way of intrinsic factor is efficient while cyanocobalamin is better absorbed through passive diffusion.

Here’s a table of the absorption rates:

A 1973 study suggests that once absorbed, methylcobalamin may be retained in the body better than cyanocobalamin (Okuda, 1973).

A clinical trial from Korea found that 3 months of 1,500 µg/day of methylcobalamin raised B12 levels, reduced or eliminated neurological symptoms of B12 deficiency, and lowered homocysteine levels (Kim, 2011). 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 cyanocobalamin.

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 cyanocobalamin.

Some people with chronic fatigue report getting more relief from adenosylcobalamin than either methylcobalamin or cyanocobalamin (more info), while other people report feeling better only when taking both adenosylcobalamin and methylcobalamin. 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.

Methylcobalamin Trial in Vegans

Donaldson (2000, USA) studied 3 vegans with elevated urinary MMA levels who were treated with 1/2 to 1 sublingual methylcobalamin tablet, 2 times/day for 3 weeks. Correspondence with the author (March 21, 2002) verified that these tablets contained 1,000 µg methylcobalamin 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, methylcobalamin appears to be absorbed at a high enough rate to improve B12 status in some vegans. Additionally, this indicates that the methylcobalamin was converted to adenosylcobalamin for use in the MMA pathway.

Cross-sectional Data from Romania

A cross-sectional study from Romania found that vegans supplementing with cyanocobalamin had higher levels of holotranscobalamin than those supplementing with methylcobalamin (150 pmol/l and 78.5 pmol/l, respectively; p-value=0.030; Zugrav et al, 2021). However, those taking methylcobalamin supplemented less and the amounts varied.

A holotranscobalamin level of 78.5 pmol/l is well above the minimum healthy range indicating that the methylcobalamin regimen was adequate. The average dose for those supplementing with cyanocobalamin and methylcobalamin was 582 µg and 988 µg, respectively. The frequency of methylcobalamin intake was 21% daily, 36% twice per week, and 43% once a week. Without assessing MMA levels and more precisely correlating values with intake amounts and frequency it’s not possible to determine a reliable regimen.

Anecdotal Report from a Vegan

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 cyanocobalamin. 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 cyanocobalamin.

Hydroxocobalamin

Hydroxocobalamin 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, hydroxocobalamin is retained in the body better than cyanocobalamin (Tudhope, 1967).

Bibliography

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.

Chalmers JN, Shinton NK. Comparison of hydroxocobalamin and cyanocobalamin in the treatment of pernicious anaemia. Lancet. 1965 Dec 25;2(7426):1305-8. B12 administered by injection. Not cited.

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.

Kelly G. The co-enzyme forms of vitamin B12: Toward an understanding of their therapeutic potential. Alt Med Rev. 1997;2(6):459-471. Not cited.

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.

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.

Okuda K, Yashima K, Kitazaki T, Takara I. Intestinal absorption and concurrent chemical changes of methylcobalamin. J Lab Clin Med. 1973 Apr;81(4):557-67.

Paul C, Brady DM. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms. Integr Med (Encinitas). 2017 Feb;16(1):42-49. Not cited.

Sawangjit R, Thongphui S, Chaichompu W, Phumart P. Efficacy and Safety of Mecobalamin on Peripheral Neuropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Altern Complement Med. 2020 Dec;26(12):1117-1129. Concluded that mecobalamin (aka methylcobalamin) taken orally (1500 mg/day), intramuscularly, or intravenously (500 mg/day) may be effective for the treatment of diabetic neuropathy. Not cited.

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.

Zugravu CA, Macri A, Belc N, Bohiltea R. Efficacy of supplementation with methylcobalamin and cyancobalamin in maintaining the level of serum holotranscobalamin in a group of plant-based diet (vegan) adults. Exp Ther Med. 2021 Sep;22(3):993.

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