Effect of two different sublingual dosages of vitamin B12 on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: A randomized controlled trial

Clin Nutr. 2019 Apr;38(2):575-583. doi: 10.1016/j.clnu.2018.02.008. Epub 2018 Feb 15.


Background & aims: Vegetarians and vegans are more vulnerable to vitamin B12 deficiency with severe risks of megaloblastic anemia, cognitive decline, neuropathy, and depression. An easy and simple method of supplementation consists of taking one weekly dosage of 2000 μg. However, single large oral doses of vitamin B12 are poorly absorbed. The present research evaluates the ability of two different sublingual dosages of vitamin B12 (350 μg/week vs 2000 μg/week) in improving cyanocobalamin (vitamin B12) nutritional status in vegans and vegetarians with a marginal deficiency.

Methods: A 12-week randomized, double-blind, controlled, parallel intervention trial was performed. Forty subjects with marginal vitamin B12 deficiency were enrolled and randomly divided into two groups: test group Ld (low dose, 350 μg/week) and control group Hd (high dose, 2000 μg/week) vitamin B12 supplementation. Blood samples were collected at baseline and after 15, 30, 60, and 90 days from the intervention for the determination of vitamin B12, related metabolic markers, and blood cell counts.

Results: Two-way analysis of variance showed a significant effect of time (P < 0.0001) and of time × treatment interaction (P = 0.012) on serum concentration of vitamin B12 that increased after 90-day supplementation (Ld and Hd) compared to baseline. Both the supplements increased (P < 0.0001, time effect) the levels of holotranscobalamin, succinic acid, methionine and wellness parameter, while decreased (P < 0.0001, time effect) the levels of methylmalonic acid, homocysteine and folate compared to baseline. No difference was observed between groups (Ld vs Hd). No effect was detected for vitamin B6 and blood cell count.

Conclusions: In our experimental conditions, both supplements were able to restore adequate serum concentrations of vitamin B12 and to improve the levels of related metabolic blood markers in subjects with a marginal deficiency. The results support the use of a sublingual dosage of 50 μg/day (350 μg/week) of cobalamin, instead of 2000 μg/week (provided as a single dose), to reach a state of nutritional adequacy of vitamin B12 in this target population. This study was registered at www.isrctn.org as ISRCTN75099618.

Keywords: Metabolites; Sublingual supplements; Vegans; Vegetarians; Vitamin B(12).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Sublingual
  • Adult
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Nutritional Status*
  • Treatment Outcome
  • Vegans / statistics & numerical data
  • Vegetarians / statistics & numerical data*
  • Vitamin B 12 / administration & dosage*
  • Vitamin B 12 / blood*
  • Vitamin B 12 / therapeutic use
  • Vitamin B 12 Deficiency / blood*
  • Vitamin B 12 Deficiency / drug therapy*
  • Vitamins / administration & dosage
  • Vitamins / blood
  • Vitamins / therapeutic use


  • Vitamins
  • Vitamin B 12

Associated data

  • ISRCTN/ISRCTN75099618