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Vitamin B12 (cyanocobalamin and derivates)

Classification: A

Drug products: Behepan®, Betolvex®, Betolvidon®, Novavita, Vitamin B12, VITAMIN B12 ROTEXMEDICA

ATC code: B03BA01


Multivitamin supplementation containing vitamin B12 increases the blood levels of vitamin B12 in both men and women. Studies on sex differences regarding adverse effects and pharmacokinetics of vitamin B12 are lacking.

Additional information

The main indications for vitamin B12 (cyanocobalamin) are treatment of pernicious anemia, long term use of medications such as L-DOPA which decreases B12-absorption, or neurologic deficits due to low B12-levels [1-4].

Vitamin B12 insufficiency leads to macrocytosis. A retrospective study (872 men, 1474 women) assessed the incidence of macrocytosis in men and women using a threshold of B12 of 0.16 nmol/L (160 pmol/L) in men and 0.11 nmol/L (110 pmol/L) in women respectively. Macrocytosis defined as a MCV > 100 fL was detected in 24 % of the men and 31% of the women [5].

Pharmacokinetics and dosing

No studies with a clinically relevant sex analysis regarding the pharmacokinetics of vitamin B12 have been found. There is no difference in recommended intake of vitamin B12 between men and women.


Data from two randomized, double-blind, placebo-controlled trials in healthy individuals (19 men, 28 women) aged 55-65 years, 16 weeks with a daily multivitamin supplementation containing 120 µg vitamin B12 for men and 115 µg B12 for women resulted in an increase of vitamin B12 levels from 300 to 435 pmol/L in women and from 265 to 342 pmol/L in men. No effects of cognitive function were observed in men or women [6].

Both men and women have been included in randomized clinical trials comparing intramuscular and oral administration of B12 [7, 8]. The intramuscular route seems to lead to more rapid increase of the B12-levels, but after three months similar levels were detected in both treatment groups. However, no analysis of sex differences has been found and sex-divided data is lacking.

A randomized placebo-controlled trial of asymptomatic, nonanemic older people with moderate vitamin B12 deficiency (94 men, 107 women) did not detect any benefits of daily vitamin B12 supplementation over 1 year on neurologic or cognitive function. Adjustment for age and sex did not alter the findings [9].

Adverse effects

No studies with a clinically relevant sex analysis regarding adverse effects of vitamin B12 have been found.

Reproductive healt issues

Low maternal levels of vitamin B12 have been linked to an increased risk of preterm birth [10]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan). 

Other information

Several reports indicate higher vitamin B12 levels in women as compared to men. These studies include healthy individuals [6, 11], adolescents [12], patients with or without depression [13] and elderly [8, 14-16].

Healthy individuals

In a European population-based study (2889 men, 2557 women), women had 324 pmol/L (95% CI 174-589) and men 297 pmol/L (95% CI 161-523) [11].


B12 levels in adolescents (499 boys, 552 girls) are reported to be 334 pmol/L in girls vs 302 pmol/L in boys [12].

Patients with or without depression

A Finnish study (1328 men, 1478 women) investigating the relationship between B12 and depression reported higher levels pf B12 in women (343 ± 168 pmol/L) than in men (312 ± 171 pmol/L) [13]. It was also noted that individuals with melancholic depression had the lowest B12 levels (292±112 pmol/L), however, no analysis of sex differences were reported. Adjustment for age, sex, use of antidepressants, and chronic diseases were performed.


Lower B12 levels in men are reported in a population-based US study (845 men, 925 women; >60 years), with serum B12 of 494 pg/mL (364 pmol/L) in men and 573 pg/mL (423 pmol/L) in women [8]. B12 deficiency defined as values <200 µg/ml was noted in 3.6% of the men and in 2.7% of the women [8].

In a Swedish study (94 men, 130 women; >70 years), lower B12 levels in men were observed (252.6 pmol/L vs 315,6 pmol/L in women) [14]. Also in a Finnish study (423 men, 598 women; >65 years), lower B12 levels were noted in men (281 pmol/L vs 293 pmol/L in women). The odds ratio for B12 deficiency for men compared to women was 1.9 (95% CI 1.2-2.9) [15]. A similar pattern was also noted in a Dutch study of fragile elderly people (51 men, 143 women), B12 mean was 288 pmol/L in women and 238 pmol/L in men [16].

Updated: 2018-12-18

Date of litterature search: 2017-12-01


  1. Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood. 2017;129(19):2603-2611. PubMed
  2. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014;349(1):g5226. PubMed
  3. Stabler SP. Clinical practice Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149-60. PubMed
  4. Kumar N. Neurologic aspects of cobalamin (B12) deficiency. Handb Clin Neurol. 2014;120(1):915-26. PubMed
  5. vant Sant P, Küsters PF, Harthoorn-Lasthuizen EJ. Dependency of MCV and haemoglobin concentration on plasma vitamin B12 levels in relation to sex and age. Clin Lab Haematol. 1997;19(1):27-31. PubMed
  6. Harris E, Macpherson H, Pipingas A. Improved blood biomarkers but no cognitive effects from 16 weeks of multivitamin supplementation in healthy older adults. Nutrients. 2015;7(5):3796-812. PubMed
  7. Castelli MC, Friedman K, Sherry J, Brazzillo K, Genoble L, Bhargava P et al. Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. Clin Ther. 2011;33(3):358-371e2. PubMed
  8. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther. 2003;25(12):3124-34. PubMed
  9. Dangour AD, Allen E, Clarke R, Elbourne D, Fletcher AE, Letley L et al. Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial. Am J Clin Nutr. 2015;102(3):639-47. PubMed
  10. Rogne T, Tielemans MJ, Chong MF, Yajnik CS, Krishnaveni GV, Poston L et al. Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data. Am J Epidemiol. 2017;185(3):212-223. PubMed
  11. Eussen SJ, Nilsen RM, Midttun Ø, Hustad S, IJssennagger N, Meyer K et al. North-south gradients in plasma concentrations of B-vitamins and other components of one-carbon metabolism in Western Europe: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. Br J Nutr. 2013;110(2):363-74. PubMed
  12. González-Gross M, Benser J, Breidenassel C, Albers U, Huybrechts I, Valtueña J et al. Gender and age influence blood folate, vitamin B12, vitamin B6, and homocysteine levels in European adolescents: the Helena Study. Nutr Res. 2012;32(11):817-26. PubMed
  13. Seppälä J, Koponen H, Kautiainen H, Eriksson JG, Kampman O, Leiviskä J et al. Association between vitamin b12 levels and melancholic depressive symptoms: a Finnish population-based study. BMC Psychiatry. 2013;13(1):145. PubMed
  14. Björkegren K, Svärdsudd K. Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes--a population-based study. J Intern Med. 2001;249(5):423-32. PubMed
  15. Loikas S, Koskinen P, Irjala K, Löppönen M, Isoaho R, Kivelä SL et al. Vitamin B12 deficiency in the aged: a population-based study. Age Ageing. 2007;36(2):177-83. PubMed
  16. Dhonukshe-Rutten RA, Lips M, de Jong N, Chin A Paw MJ, Hiddink GJ, van Dusseldorp M et al. Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr. 2003;133(3):801-7. PubMed
  17. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-12-06.] länk

Authors: Carl-Olav Stiller, Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson