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A Dose-Finding Trial

Simone J. P. M. Eussen, MSc; Lisette C. P. G. M. de Groot, PhD; Robert Clarke, MD; Jörn Schneede, MD; Per M. Ueland, MD; Willibrord H. L. Hoefnagels, MD, PhD; Wija A. van Staveren, PhD

Arch Intern Med. 2005;165:1167-1172.

Background  Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B₁₂ deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain.

Methods  We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B₁₂ deficiency in older people with mild vitamin B₁₂ deficiency, defined as a serum vitamin B₁₂ level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 µmol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 µg of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B₁₂ deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration.

Results  Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 µg was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 µg of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration.

Conclusion  The lowest dose of oral cyanocobalamin required to normalize mild vitamin B₁₂ deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 µg daily.

Author Affiliations: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands (Ms Eussen and Drs de Groot and van Staveren); Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, England (Dr Clark); LOCUS of Homocysteine and Related Vitamins, University of Bergen, Bergen, Norway (Drs Schneede and Ueland); and Department of Geriatrics, Hospital St Radboud, Nijmegen, the Netherlands (Dr Hoefnagels).

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