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I see that cyanocobalamin is not naturally occurring, and is synthesized in vivo to methylcobalamin. As part of the synthetic pathway, cyanide is broken off. All opinions I can find are that this isn't a problem as cyanide is naturally occurring in many foods anyway, and is safely detoxified via the the Rhodenase pathway.

However, given its synthetic creation and vast prevalence as the primary B12 source in nearly all supplements, I was curious if any actual studies did exist to rule out potential (albeit minor) long term cyanide toxicity for this synthetic form of B12. I'm unable to find a single study where cyanide toxicity was directly tested for, only studies stating that RDA in excess of 1000 times the daily dosage isn't lethal.

I understand no evidence currently exists for cyanocobalamin toxicity, but this wouldn't be surprising if there aren't any studies done in the first place.

Would anyone be able to reference an actual study that directly measured levels of potential cyanide toxicity for cyanocobalamin in any animal or humans?

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    $\begingroup$ What is the reference to carcinogenicity? Cyanide is not carcinogenic. You can check here for doses of cyanide that are considered safe. $\endgroup$ – WYSIWYG Apr 27 '15 at 7:46
  • $\begingroup$ Mistake in the title sorry, corrected now. $\endgroup$ – user4779 Apr 27 '15 at 10:09
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The NIH RDA for vitamin B12 is 2-3µg/day. Cyanocobalamin has an $M_r$ of 1355, of which 26, or less than 2% ($CN^-$) is cyanide.

Since the Minimal Risk Level for cyanide is 50µg/kg/day, your studies are correct in that 1000x the RDA of vitamin B12 in the form of cyanocobalamin is not lethal, and furthermore is expected to not cause any negative effects even in the most sensitive of individuals.

This holds true even if 100% of the cyanide ligands dissociate from cyanocobalamin, which is unlikely to be the case in practice due to cyanide being a very strong binding ligand.

Cyanocobalamin contains too little cyanide, and is consumed in too low an amount, to cause cyanide toxicity. The dose makes the poison.

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  • $\begingroup$ A common mutation in the Methylenetetrahydrofolate Reductase gene (hetero & homozygous), implicated in a vast array of diseases, is prevalent in some populations as much as 38% Source* - and requires excess supplementation of B12 & folinic acid in order to complete the pathway for homocysteine -> methionine. A vast quantity of anecdotal reports show dosages up to 5mg B12 per day alleviate symptoms. Surely at this level the cyanide would start to matter if cyanocobalamin was supplemented, even if just 1% did break down? $\endgroup$ – user4779 Apr 28 '15 at 7:42
  • $\begingroup$ @user4779 It seems that there is no issue, even in your case of extreme overdosage of cyanocobalamin (100µg cyanide daily). Assuming 60kg body weight, one has to take 3mg cyanide daily to reach the MRL. $\endgroup$ – March Ho Apr 28 '15 at 7:52
  • $\begingroup$ I guess there's no arguing with the current numbers and evidence, given the studies of the MRL in rats. Thanks to you and WYSIWYF for providing the link to the cyanide toxicity. $\endgroup$ – user4779 Apr 28 '15 at 8:44
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Potassium cyanide is added to the cobalamins produced by bacteria to give rise to cyanocobalamin. CN is strongly bonded to Co and will not easily dissociate, thereby making this form of B12 inactive. Therefore, it has been argued that cyanocobalamin is not a good vitamin supplement and other variants such as hydroxycobalamin or methylcobalamin should be used. Displacement of CN from the complex would be energy expensive and even if the reaction is efficient the amount of cyanide released would not be in the toxic concentration. The CN-Co bond is so strong that hydroxycobalamin is used as an antidote for cyanide poisoning; it forms cyanocobalamin by displacing OH with CN.


Source: Wikipedia and the cross references.

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    $\begingroup$ Interesting, but for the molecules of B12 that are bioactive, I believe the cyano group dissociates as free cyanide. Just curious if any such effects have been studied, as free cyanide also breaks off in Amygdalin and that has been linked to cyanide toxicity in comparable dosages I believe. $\endgroup$ – user4779 Apr 28 '15 at 6:43
  • $\begingroup$ @user4779 Generally the bond between the Transition metal and cyanide is very strong. It would not easily dissociate. Even if it does, the minuscule concentration would not be toxic. For all practical purposes you can assume that CN- does not dissociate from the metal. Even potassium ferrocyanide K₄Fe(CN)₆ is non-toxic. $\endgroup$ – WYSIWYG Apr 28 '15 at 6:55
  • $\begingroup$ I believe CN- does in fact dissociate from cyanocobalamin, as otherwise it would not be bioavailable as vitamin B12. $\endgroup$ – March Ho Apr 28 '15 at 6:56
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    $\begingroup$ @MarchHo It should to a little extent but CN is much stronger ligand than others. And B12 bioavailability of cyanocobalamin is very low. $\endgroup$ – WYSIWYG Apr 28 '15 at 6:57
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    $\begingroup$ @user4779 In case of amygdalin the CN is not complexed with a metal. It is covalently bonded with carbon and is close to a hydrolyzable group. $\endgroup$ – WYSIWYG Apr 28 '15 at 7:04

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