Safety of Cyanide in Cyanocobalamin

Due to some articles going around the Internet, many people have written me asking whether vitamin B12 supplements in the form of cyanocobalamin are safe due to the cyanide content. Because so many people have asked, I have updated the page Side Effects of B12 Supplements of Vitamin B12: Are You Getting It? with the following information:

The safety of cyanocobalamin has raised concerns due to the fact that cyanide is a component of cyanocobalamin, and the cyanide molecule is removed from cyanocobalamin 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 cyanocobalamin is considered to be physiologically insignificant.

According to the European Food Safety Authority, “Data of from a Norwegian dietary survey show that the average and high (97.5th percentile) daily intake of [cyanide] among consumers amounts to respectively 95 and 372 micrograms/person or 1.4 and 5.4 micrograms/kg bw/day (7).” The amount of cyanide in a 1,000 microgram cyanocobalamin is 20 micrograms.

Table 1 contains some additional numbers regarding cyanide amounts in cyanocobalamin for comparison purposes.

Table 1. Cyanide Content of Cyanocobalamin
molecular weight of vitamin B12 1,355 g/mol
molecular weight of cyanide 27 g/mol
Percentage of cyanide in vitamin B12 by weight 2.0%
Amount of cyanide in 1,000 micrograms of cyanocobalamin 20 micrograms
Minimal Risk Level for oral cyanide4, a 0.05 mg/kg of body weight per day
Minimal Risk Level for oral cyanide for 140 lb person 3,175 micrograms/day
Percentage of Minimal Risk Level in 1,000 micrograms of cyanocobalamin 0.6%
Lethal dose of cyanide5 0.5 to 3.0 mg/kg of body weight
Lower end of lethal dose of cyanide for 140 lb person 31,750 micrograms
Percentage of lethal dose in 1,000 micrograms of cyanocobalamin 0.06%
aMinimal Risk Level do not assess cancer risk (6).

In summary, the amount of cyanide in 1,000 micrograms of cyanocobalamin is about .6% of the amount that is thought to be the lower level that causes harm.

References

See Side Effects of B12 Supplements.

Thank you, Ginny, for sending some of the research!

91 Responses to “Safety of Cyanide in Cyanocobalamin”

  1. TheVeganScientist Says:

    Oh, I am revising my calculations because I forgot the 500µL dilution factor. I was on the train texting the original, sorry.

    10µM/500µL = 20000pM.Still this is 45x plasma levels directly injected into a homogenized liver tissue, bypassing normal metabolism, cellular membranes, disrupting cellular processes, working directly with the enzymes themselves at dosages impossible to achieve in natural free living conditions.

    The end result of this kind of research is find some upstream enzyme, cofactor, etc… that causes the etiology of some disease and find a molecule to block it, or find a target that will upregulate/downregulate a process that will have an beneficial effect, then find a molecule that can induce that preferred state.

    Nothing can be concluded about supplementation from this research. In introduction/background, the researchers explain some of the cellular processes they are investigating. They do not say or imply anything about their work being anyway related to vitamin supplementation or that their work can be extrapolated toward therapeutic use in any animal by any route of administration.

  2. Karl Baba Says:

    Thanks
    The Fact remains that Cyanocobalamin requires cofactors to be converted to active Methylcobalamin. Are we so sure that those cofactors are always present in the required amounts or could that be part of the mechanism of deficiency?

  3. Jack Norris RD Says:

    Karl,

    > The Fact remains that Cyanocobalamin requires cofactors to be converted to active Methylcobalamin.

    I’m not sure of that as I don’t know the biochemical pathways, though I imagine TheVeganScientist does. But isn’t “co-factor” just another way of saying “vitamins and/or minerals”? And if so, if there isn’t enough in the body to allow for the conversion of cyano- to methyl-, then you’d have a deficiency of that other vitamin or mineral, not, technically, a deficiency of B12. So the focus should be on solving the other deficiency.

  4. Karl Baba Says:

    The conversion and cycle take ATP, glutathione, and Sam-e as far as I can tell and probably the properly functioning enzymes to make the conversions.
    One deficiency may cause another but when you can supply a needed nutrient that doesn’t need conversion, it can kick start the cycle of creating the others or at least fulfill it’s role, which is what a consider to be a merit of going straight to Methylcobalamin, you know it’s not going to be held up by a deficiency you might not know or be aware of. After all, testing glutathione and Sam-e levels is fairly rare

  5. Jack Norris RD Says:

    Karl,

    Many years ago, I put together a chart of the Methionine-Homocysteine-Folate-B12 Cycle here: http://veganhealth.org/b12/cycle. It hadn’t occurred to me that the way the body converts cyanocobalamin to methylcobalamin is by entering the cycle in the position of “cobalamin” in the chart. I had assumed it must come from outside of that cycle, though right now it’s not making sense to me why that would be, nor is it making sense why the body would ever need an exogenous source of B12 for this pathway since that methylcobalamin –> cobalamin –> methylcobalamin looks like a continual loop as long as there is S-adenosylmethionine or folate. Perhaps that’s why folate can mask a B12 deficiency and the need for vitamin B12 for this pathway is only conditional on not having plenty of folate (or S-adenosylmethionine), while the need for vitamin B12 in the S-adenosylcobalamin co-enzyme function is the only function for which B12 is absolutely essential.

  6. Karl Baba Says:

    I like your chart. While it looks like theoretically there are these continual loops in biochemical cycles, inefficiencies found everywhere in nature result in losses in conversions resulting in the need to replenish these nutrients through foods and in some cases supplements (which is the subject of this particular blog post we are commenting on)

    Those inefficiencies are exacerbated by genetic polymorphisms that affect the enzymes that enable these cyclic conversions. For instance, those with the MTHFR C677T +/+ mutation have about a 30% MTHfR enzyme effectiveness, greatly reducing their ability to convert folic acid from the diet to the 5-MTHF in your chart and interfering with the methylation cycle and interacting with the B-12 cycle you illustrated. Folic acid can actually be problematic for the ones with the worst genetics who will need to take the active form of folate to feed their methylation cycle and reduce building homocysteine.

    The conversions in those cycles are controlled by enzymes at each point and variants of the genes that make those enzymes are sometimes common, sometimes rare. It is estimated that over 40% (maybe more) of Americans have some MTHFR variant +/+ or +/- as well is the A1298C MTHFR variant.

    It’s because of the hangups in these enzymatic conversions that I advocate taking the active (don’t need conversion) forms of B-12 and Folate because the people who are deficient (outside of Vegans) are often the ones with troubles converting

  7. Karl Baba Says:

    Thank you by the way, for your time in engaging on this subject. Wishing you and all your readers the best

  8. TheVeganScientist Says:

    Exogenous Cobalamin has cobalt in the Co(III) state, irrespective of the vitamer. In order for it to be useful, it has to be reduced to the Co(I) state. This is performed by Cobalamin Reductase in the cytoplasm, (though there is some evidence it also happens in liver mitochondria) In the process the ligand is removed.

    Cobal(I)min is extremely reactive and unstable, called a “supernucleophile” it will react with just about anything it can donate electrons to. If you were to prepare a MethylCobal(I)amin exogenously and inject, eat or snort it, it would end up in the MethylCobal(III)amin state before it reached the cell and would have to be re-reduced.

    I have never come across in literature any Cobalamin reductase isoform that will not convert Cyanocobal(III)amin to cobalamin(I) but will reduce other vitamers.

    All these other ideas that Cyanocobalmin requires ATP, glutathione, etc… are not really relevant, since ATP is the general energy currency and there is only one enzyme that converts all the cobalamins. The conversion just needs NADPH to fuel it. You would have a real problem if you were NADPH deficient, because your cells would be dying rapidly.

    Handwaving arguments aside, the biomolecular , clinical intervention and epidemiological evidence all aligns with Cyanocobalamin being equally effective as other administered bioactive-vitamers of cobalamin in providing sufficient biological activity. The only possible caveat would be in heavy smokers and megadose (5mg) of cyanocobalamin, but that has to do with cyanide, not B12.

    People can take whatever form. It’s just cyanocobalamin is inexpensive and equally effective. There’s just no evidence one vitamer is better than the other. If someone finds some, they should try to publish it.

  9. Jack Norris RD Says:

    TheVeganScientist,

    Some researchers believe that only active vitamin B12 can attach to transcobalamin II. Is that your view? And do you know if there are any forms of cobalamin that are inactive for humans? My understanding was that only 4 forms have been shown to be active for humans–methyl, adenosyl, hydroxo, and cyano, but there are others.

    Thank you for any help in this matter.

  10. TheVeganScientist Says:

    Oh. Here’s a link to a paper that outlines the adsorption, transport and conversion of Cobalmin extracellularly and connects it to the cellular activity.

    The conversion of Cobal(III) to Cobal(I)amin is also illustrated.

    Also, note the publication date and subject matter. As of 4 years ago there was no data suggesting methylcobalamin could alleviate inborn errors where cyanocobalamin cannot.

    “Inborn errors of cobalamin absorption and metabolism”
    http://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.30288/abstract. You’ll need access to the journal to see the full paper. I can send it, if requested.

  11. TheVeganScientist Says:

    Oh, for completeness, I just remembered seeing a case study where hydroxocobalamin (injected intramuscularly) did lower MMA and Homocysteine levels in a couple of patients that had methylmalonic acidemia but their levels were seriously 100x normal and the cyanoB12 dropped it down to 10x normal where the hydroxo dropped it down to normal.

    For those two people the hydroxoform seemed to work better. It doesn’t necessarily mean it works better in all cases. That’s why they are called “case studies. ” They are interesting and can lead to follow up research, but you really can’t extrapolate someone with a severe genetic disorder to everyone because therapeutics (and micronutrients) do no follow a linear curve.

  12. Karl Baba Says:

    Thanks for the time on the additional replies.

    You’ve inspired me to do a very unscientific experiment. When I take 5mg MethylB-12 or 1mg HydroxB-12 sublingually, I can strongly feel the effects immediately in extra energy, a pretty rare reaction for me from any nutrient. I’m interested if I’ll feel that with cyanocobalamin. I think my Mom has some of it lying around.

    I know it will have limited meaning in general regardless of the results but It will be significant for me. I’ll look forward to clearer studies on the effects of genetics on B-12. As it is, there’s tons of research on specific diseases and forms of B-12 but hard to parse much out of it without an unreasonable amount of time spent for somebody who has a million other things to learn

  13. theveganscientist Says:

    That’s the spirit!

    I do these types of personal experiments regularly, but usually use objective test results as an indicator of efficacy. For example, my family has a history of Low HDL (mine is typically ~30mg/dL without intervention.) I figured we might have a higher turnover rate in the liver, so I started experimenting with Nicotinic acid. Over the counter stuff (500mg delayed release) which inverted my cholesterol number so my HDL was 55mg/dL and my LDL was 42mg/dL (total was decreased by about 8%). I decreased the dose until a mere 50mg/day was enough to keep my HDL ~50mg/dL and my LDL ~62mg/dL with my total staying around 118-125mg/dL (4 years stable now). This probably doesn’t work for everyone given typical clinical dosages are 1000-2000mg/day.

    I don’t know if low HDL is a risk factor for vegans. There’s no real data to suggest one way or another, but given my family’s terrible history of heart disease I try to control the variables I have control over.

    Btw, I used to work for a health food/supplement company an we normally had to “taste test” our 1000uG Cyanocobalamin B12 lozenges. When I got my B12 levels tested, my plasma levels were 1219pg/mL, homocysteine was ~4.8uM.

  14. surinder Says:

    very good.list of Cyanocobalamin producing bacteria?can you produce b12 at home?

  15. Jack Norris RD Says:

    surinder,

    > very good.list of Cyanocobalamin producing bacteria?can you produce b12 at home?

    This info is somewhat old but here are the bacteria I found to produce B12:

    http://veganhealth.org/b12/vegansources

    See the 3rd paragraph.
    There is no reliable way to produce B12 at home.

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