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Vitamin B12: which routes of administration and which forms are best?

Vitamin B12 is a group of cobalt-containing compounds that are collectively called cobalamins. The biologically active coenzyme forms of vitamin B12 that play a role in human metabolism are methylcobalamin and 5-deoxyadenosylcobalamin (commonly known as adenosylcobalamin). Vitamin B12 is involved in DNA synthesis, red blood cell formation, homocysteine metabolism, and synthesis of S-adenosylmethionine, and is essential for the normal functioning of the nervous system and immune system.

The main use for vitamin B12 is to prevent and treat vitamin B12 deficiency. However, this vitamin has also been used for a wide range of other conditions, including bursitis, hepatitis, idiopathic facial paralysis (Bell's palsy), vitiligo, herpes zoster, hyperhomocysteinemia, sciatica, trigeminal neuralgia, depression, dementia, chronic fatigue, neurodermatitis, diabetic neuropathy, hyperthyroidism, asthma, infertility, tobacco amblyopia, and cyanide poisoning.

Routes of Administration

Vitamin B12 preparations are available for oral, sublingual, intranasal, and parenteral (intramuscular, subcutaneous, or intravenous) administration. Oral supplements are generally effective for preventing and treating vitamin B12 deficiency. Even patients with vitamin B12 malabsorption secondary to pernicious anemia can be effectively treated with oral supplements, provided that a sufficient dosage is used (500-1000 [micro]g per day) and the patient adheres to the recommended treatment regimen. However, since failure to correct vitamin B12 deficiency can lead to permanent neurological damage, periodic intramuscular injections may be preferable to oral supplementation when compliance with oral treatment is uncertain. Sublingual vitamin B12 does not appear to be absorbed more efficiently than oral vitamin B12. (1)

Vitamin B12 given intranasally produced higher peak plasma vitamin B12 concentrations than those achieved with oral administration, but lower concentrations than those obtained with intramuscular injections. (2) However, the long-term safety of intranasal vitamin B12 has not been demonstrated, and it is possible that it could damage the nasal mucosa. Administration of vitamin B12 by inhalation resulted in a rapid increase in serum vitamin B12 levels, indicating that the vitamin was absorbed through pulmonary alveoli. However, pulmonary damage could result from this route of administration, since pulmonary fibrosis has occurred in dogs exposed to prolonged inhalation of cobalt. (3) Because of the lack of long-term safety data, I have avoided the use of intranasal and inhaled vitamin B12 preparations.

For most of the conditions that respond to vitamin B12, the vitamin probably does not work by correcting a deficiency. Rather, it may exert a pharmacological effect or compensate for impaired uptake of vitamin B12 into specific body tissues. In patients who are not vitamin B12 deficient, treatment efficacy usually seems to depend on the attainment of supraphysiological serum concentrations, concentrations that can be achieved only by parenteral administration. For that reason, patients who improve with intramuscular injections often do not respond to oral, sublingual, or intranasal therapy. Subcutaneous injections have not been widely used in clinical trials, but they are said to cause less local burning than intramuscular injections. (4) Intravenous vitamin B12 may be less effective than intramuscular injections, presumably because the transiently high serum levels that follow intravenous administration may cause more of the vitamin to be lost in the urine.

Forms of Vitamin B12

Cyanocobalamin is the most widely used form of vitamin B12, because of its stability and low cost, and because it can be converted in vivo to the biologically active forms of vitamin B12. However, only traces of cyanocobalamin occur naturally in the human body, which contains primarily hydroxocobalamin, adenosylcobalamin, and methylcobalamin. In addition, treatment with cyanocobalamin leads to the release of small amounts of cyanide, which may be atherogenic or otherwise harmful to patients who are unable to excrete cyanide efficiently because of impaired renal function. It has been suggested that the failure of some homocysteine-lowering studies to produce clinical benefit was due to the use of cyanocobalamin in patients with mild renal impairment.

Hydroxocobalamin does occur naturally in the human body. It is a stable form of vitamin B12 that can be converted to the active coenzyme forms. Hydroxocobalamin does not contain a cyanide molecule, and is therefore safer than cyanocobalamin for patients who are sensitive to the deleterious effects of small doses of cyanide. In addition, unlike cyanocobalamin, hydroxocobalamin is a powerful cyanide antagonist, and therefore is of value in the treatment of tobacco amblyopia and cyanide poisoning. Furthermore, as compared with cyanocobalamin, hydroxocobalamin treatment produces higher and more sustained serum vitamin B12 levels. (5,6) For these reasons, hydroxocobalamin is highly preferable to cyanocobalamin, and some investigators have recommended that cyanocobalamin be withdrawn from the market.

Methylcobalamin, one of the coenzyme forms of vitamin B12, has been shown to be beneficial in the treatment of several medical conditions. In recent years, some investigators and supplement companies have argued that methylcobalamin is the preferred form of vitamin B12 for supplementation because it biologically active. However, no comparison studies have been done, and there is no clear evidence that methylcobalamin is preferable to hydroxocobalamin. Likewise, there is no clear evidence that adenosylcobalamin (the other coenzyme form of vitamin B12) is preferable to hydroxocobalamin, except in the treatment of a rare inborn error of adenosylcobalamin biosynthesis. (7)

A potential disadvantage of methylcobalamin is that it cannot apparently be converted to adenosylcobalamin. (8) Each of these coenzyme forms of vitamin B12 has distinct biochemical functions, and they serve as cofactors for different enzymes. Whereas treatment with hydroxocobalamin or cyanocobalamin would increase the concentration of both biologically active forms of vitamin B12, treatment with methylcobalamin may not increase the concentration of adenosylcobalamin. That fact may be particularly important when treating vitamin B12 deficiency.

Based on the limited evidence available, hydroxocobalamin appears to be the preferred form of vitamin B12 for therapeutic use. Additional research is needed to determine in what situations, if any, methylcobalamin has an advantage over hydroxocobalamin. If methylcobalamin is used to treat vitamin B12 deficiency, it may be prudent to administer it in combination with other forms of vitamin B12.

Alan R. Gaby, MD


(1.) Sharabi A et al. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br I Clin Pharmacol. 2003;56:635-638.

(2.) Van der Kuy PHM et al. Pharmacokinetics of intranasal and oral hydroxocobalamin in healthy subjects. Br I Clin Pharmacol. 2001 ;51:505P.

(3.) Shinton NK, Singh AK. Vitamin B12 absorption by inhalation. Br J Haematol. 1967; 13:75-79.

(4.) Managing patients with evidence of a vitamin B12 deficiency [online article]. Centers for Disease Control and Prevention, patients.html. Accessed February 7, 2015.

(5.) Glass GBJ et al. Hydroxocobalamin. I. Blood levels and urinary excretion of vitamin B12 in man after a single parenteral dose of aqueous hydroxocobalamin, aqueous cyanocobalamin and cyanocobalamin zinctannate complex. Blood. 1961;18:511-521.

(6.) Glass GBJ et al. Prolonged maintenance of high vitamin B12 blood levels following a short course of hydroxocobalamin injections. Blood. 1966;27:234241.

(7.) Bhatt HR et al. Treatment of hydroxocobalamin resistant methylmalonic acidaemia with adenosylcobalamin. Lancet. 1986;2:465.

(8.) Thakkar K, Billa G. Treatment of vitamin B12 deficiency--methylcobalamine? cyancobalamine? hydroxocobalamin?--clearing the confusion. Eur J Clin Nutr. 2015;69:1-2.
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Author:Gaby, Alan R.
Publication:Townsend Letter
Article Type:Editorial
Geographic Code:1USA
Date:May 1, 2015
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