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No active regulatory warnings
Sources: FDA MedWatch, EMA EudraVigilance, WHO VigiBase, WADA Prohibited List · 2026-05-29
1 Identity
Cobalamin
Cyanocobalamin / Methylcobalamin
Generally SafeEvidence: StrongWater-Soluble VitaminsCobalamin (vitamin B12) is a water-soluble cobalt-containing vitamin essential for two enzymatic reactions in humans: methionine synthase (which regenerates methionine from homocysteine and releases tetrahydrofolate) and methylmalonyl-CoA mutase (which metabolizes propionate and odd-chain fatty acids) [1]. It is unique among vitamins in being synthesized exclusively by microorganisms — no plant or animal can produce it de novo [2]. Hepatic stores of B12 are large (2–5 mg), and clinical deficiency typically takes 3–5 years to develop after complete cessation of intake [3]. Pernicious anemia (autoimmune destruction of gastric parietal cells) is the classic cause of B12 deficiency in developed countries [4].
2 Risk self-assessment
Vegan diet without supplementation (no plant B12 sources) [2]
Pernicious anemia (autoimmune anti-IF/anti-parietal cell antibodies) [4]
Age >60 years (atrophic gastritis, reduced acid/pepsin) [9]
Long-term metformin therapy [7]
Chronic PPI or H2 blocker use [9]
Gastrectomy or ileal resection [3]
Crohn disease affecting the terminal ileum [2]
Chronic alcoholism [2]
Select factors above to see your risk level
4 Dietary sources
Animal products are the only significant natural dietary sources [5]. Vegans MUST supplement or consume B12-fortified foods (nutritional yeast, plant milks, cereals) [2]. Tempeh, nori, and spirulina are NOT reliable B12 sources — they contain predominantly inactive analogues [2]. Cooking losses are moderate (10–30%) [1].
5 Lab interpreter
Serum cobalamin (B12)
Your level:
Enter a value above
⚕ For healthcare professionals. Does not replace clinical judgment.
6 Quick facts
CategoryWater-Soluble Vitamins
Safety levelGenerally Safe
EvidenceStrong
RDA2.4 mcg
Upper limit (UL)No UL
Scientific nameCyanocobalamin / Methylcobalamin
Chemical classWater-soluble corrinoid (cobalt-centered tetrapyrrole) [1]
Active formsMethylcobalamin (cytoplasmic) and adenosylcobalamin (mitochondrial) [1]
Primary biomarkerSerum cobalamin (B12) [2]
Functional markersMethylmalonic acid (MMA), homocysteine [2]
DeficiencySerum B12 <148 pmol/L (200 pg/mL) [2]
Borderline148–221 pmol/L (200–300 pg/mL) — check MMA [2]
Body stores2–5 mg in liver; sufficient for 3–5 years [3]
RDA2.4 µg/day (adults) [1]
7 Dosage by population
Adults Moderate
See product label
Elderly Moderate
See product label
Consider reduced renal/hepatic clearance. Start at lower end of range.
Pregnancy Moderate
Infant deficiency from maternal deficit causes permanent neurological damage [8].
Pediatric Moderate
See guidance
Infants 0–6 months: 0.4 µg/day AI; children 1–3 years: 0.9 µg/day; 4–8 years: 1.2 µg/day [1]. Infants of B12-deficient mothers (especially vegans) can develop severe deficiency within months, presenting with failure to thrive, developmental regression, megaloblastic anemia, and irreversible…
Athletes Limited
Standard dose
Obesity Limited
Standard dose
Fat-soluble compounds may require dose adjustment in obesity.
Renal Limited
Consult specialist
Dose adjustment may be needed in renal impairment.
Vegan Moderate
Non-negotiable. No reliable plant sources exist [2].
Absorption of B12 is limited by intrinsic factor (IF) capacity: approximately 1.5–2 µg per meal via IF-mediated transport. At doses exceeding 200 µg, approximately 1% is absorbed via passive diffusion, which is clinically relevant for oral treatment of pernicious anemia [4].
8 Form comparison
| Form | Bioavailability | Vegan | Cost/day |
|---|---|---|---|
| ['Cyanocobalamin', 'common', 'Synthetic form most commonly used in supplements and fortification. Must be converted to active forms (methyl- and adenosylcobalamin). Stable and inexpensive. Contains a cyanide moiety released upon conversion (trace amounts, clinically insignificant) [1].'] | Standard | Check label | |
| ['Methylcobalamin', 'preferred', 'Bioactive form — the coenzyme for methionine synthase. Does not require conversion. Commonly marketed for neurological conditions. Less stable than cyanocobalamin (light-sensitive) [2].'] | Standard | Check label | |
| ['Hydroxocobalamin', '', 'Used for intramuscular injection. Longer retention time than cyanocobalamin. Also used as cyanide antidote (Cyanokit). Preferred IM form in many countries [4].'] | Standard | Check label | |
| ['Adenosylcobalamin', '', 'Mitochondrial coenzyme form for methylmalonyl-CoA mutase. Available in some supplements. Less commonly used than methylcobalamin [1].'] | Standard | Check label |
9 Clinical evidence
Strong evidence
Treatment and prevention of megaloblastic (pernicious) anemia [4]. Prevention and treatment of subacute combined degeneration of the spinal cord (posterior and lateral column demyelination) [3]. Reduction of elevated homocysteine and methylmalonic acid [2]. Essential supplementation for vegans — no plant-based food contains bioavailable B12 [2]. HIGH
Moderate evidence
Cognitive function in deficient elderly: B12 supplementation improves cognitive scores in individuals with documented deficiency and elevated MMA [6]. Peripheral neuropathy improvement: early treatment of B12-deficient neuropathy can reverse symptoms if initiated before irreversible axonal damage [3]. Diabetic neuropathy: metformin-induced B12 depletion contributes to neuropathy; supplementation may improve symptoms [7]. MODERATE
Insufficient evidence
Cancer prevention: no consistent evidence [2]. Cardiovascular disease prevention through homocysteine lowering: B12 + folate reduces homocysteine but major trials (HOPE-2, VITATOPS) showed mixed cardiovascular results [2]. Enhancement of energy or athletic performance in B12-replete individuals: no evidence of benefit [1]. LOW
10 Safety
🚩 Red flags — when to stop and refer
● Gait ataxia + posterior column signs (vibration/position sense loss) — subacute combined degeneration. Treat urgently with B12 [3]
● Vegan infant with failure to thrive and developmental regression — check B12 status immediately [8]
● Megaloblastic anemia treated with folic acid alone showing neurological deterioration — B12 deficiency was masked [1]
● Metformin user with unexplained peripheral neuropathy — check serum B12 and MMA [7]
● Post-nitrous oxide exposure with acute paresthesias or confusion — acute B12 inactivation [3]
Pregnancy
RDA during pregnancy: 2.6 µg/day; during lactation: 2.8 µg/day [1]. Maternal B12 deficiency, particularly in vegan mothers, can cause severe developmental delay, failure to thrive, and permanent neurological damage in exclusively breastfed infants [8]. B12 supplementation is mandatory for vegan pregnant and lactating women. Nitrous oxide exposure during labor can acutely inactivate B12 — relevant in borderline-deficient individuals [3].
Pediatric
Infants 0–6 months: 0.4 µg/day AI; children 1–3 years: 0.9 µg/day; 4–8 years: 1.2 µg/day [1]. Infants of B12-deficient mothers (especially vegans) can develop severe deficiency within months, presenting with failure to thrive, developmental regression, megaloblastic anemia, and irreversible neurological damage [8]. Early recognition and treatment are essential.
11 Toxicity and overdose
12 Drug interactions
Metformin Major
Mechanism: Metformin alters calcium-dependent ileal membrane uptake of the IF-B12 complex, reducing absorption by 10–30%. [7]
Effect: Serum B12 decline over years; 5–30% develop biochemical deficiency. May contribute to neuropathy mistakenly attributed to diabetes. [7]
Action: Monitor serum B12 annually in all metformin users. Supplement if deficient. Calcium supplementation may partially reverse the effect [7].
Proton pump inhibitors (chronic >2 years) Moderate
Mechanism: PPIs suppress gastric acid, preventing acid-pepsin release of protein-bound B12 from food. Crystalline B12 (supplements) is not affected. [9]
Effect: Food-bound B12 malabsorption. Serum B12 declines over years of use. [9]
Action: Monitor B12 periodically in chronic PPI users, especially elderly. Crystalline B12 supplements bypass this interaction [9].
Nitrous oxide (N2O) Major
Mechanism: N2O irreversibly oxidizes the cobalt atom of B12, permanently inactivating methionine synthase. [3]
Effect: Acute precipitation of subacute combined degeneration in borderline-deficient patients. Can occur after a single prolonged exposure. [3]
Action: Check B12 status before elective surgery if risk factors present. Absolute contraindication to recreational N2O use in deficient patients [3].
13 Supplement interactions
Best combined with
Folate · 400–800 µg DFE/day
B12 is required to release active tetrahydrofolate from the 5-MTHF methyl trap. Without B12, folate cycle stalls. Co-supplementation ensures both pathways function [2].
B12 is required to release active tetrahydrofolate from the 5-MTHF methyl trap. Without B12, folate cycle stalls. Co-supplementation ensures both pathways function [2].
Iron · As per deficiency protocol
B12 deficiency causes megaloblastic ineffective erythropoiesis. Iron may be needed concurrently if iron-deficient or if recovering from pancytopenia [2].
B12 deficiency causes megaloblastic ineffective erythropoiesis. Iron may be needed concurrently if iron-deficient or if recovering from pancytopenia [2].
Vitamin D · 600–2,000 IU/day
Both deficiencies are common in elderly and vegan populations. Co-supplementation addresses the two most common nutrient gaps in these groups [2].
Both deficiencies are common in elderly and vegan populations. Co-supplementation addresses the two most common nutrient gaps in these groups [2].
14 Laboratory monitoring
Serum cobalamin (B12) Primary
Target: >221 pmol/L (300 pg/mL) preferred; <148 pmol/L (200 pg/mL) = deficient · At baseline if risk factors or symptoms; repeat 2–3 months after starting treatment [2].
Can be normal despite tissue deficiency (false normal in liver disease, myeloproliferative disorders). If borderline, check MMA [2].
Methylmalonic acid (MMA) Secondary
Target: <370 nmol/L · If serum B12 is borderline (148–221 pmol/L) or clinical suspicion despite normal B12 [2].
Plasma homocysteine Secondary
Target: <15 µmol/L · Adjunct marker. Not B12-specific [2].
Complete blood count (CBC) Secondary
Target: MCV 80–100 fL; no hypersegmented neutrophils · If anemia suspected or monitoring treatment [2].
Anti-intrinsic factor antibodies Secondary
Target: Negative · If pernicious anemia suspected [4].
15 Deficiency and prevalence
Risk factors
• Vegan diet without supplementation (no plant B12 sources) [2]
• Pernicious anemia (autoimmune anti-IF/anti-parietal cell antibodies) [4]
• Age >60 years (atrophic gastritis, reduced acid/pepsin) [9]
• Long-term metformin therapy [7]
• Chronic PPI or H2 blocker use [9]
• Gastrectomy or ileal resection [3]
• Crohn disease affecting the terminal ileum [2]
• Chronic alcoholism [2]
• Nitrous oxide abuse or repeated exposure [3]
16 Frequently asked questions
Can vegans get B12 from any plant sources? ▼
How is pernicious anemia diagnosed? ▼
Pernicious anemia is diagnosed by: low serum B12, elevated MMA, megaloblastic anemia, and positive anti-intrinsic factor antibodies (highly specific, ~50% sensitive) or anti-parietal cell antibodies (less specific, ~80% sensitive) [4]. The Schilling test is no longer routinely available. Patients require lifelong B12 replacement (IM or high-dose oral) [4].
Can oral B12 work for pernicious anemia? ▼
Yes — at high doses (1,000–2,000 µg/day), approximately 1% of oral B12 is absorbed by passive diffusion, bypassing intrinsic factor [4]. Multiple studies show equivalence between high-dose oral and intramuscular B12 for maintaining serum levels. However, adherence may be better with monthly IM injections [4].
Does metformin cause B12 deficiency? ▼
Long-term metformin use reduces B12 absorption by 10–30%, likely by altering calcium-dependent ileal membrane uptake [7]. The ADA recommends periodic B12 monitoring in patients on metformin, particularly those with anemia or peripheral neuropathy. Supplementation is straightforward and effective [7].
17 Regulatory status
United States (FDA): Classified as a dietary supplement. No mandatory fortification but voluntarily added to many products. Injectable B12 (cyanocobalamin, hydroxocobalamin) is prescription in some jurisdictions. No UL established (low toxicity) [1].
European Union (EFSA): Authorized health claims for energy metabolism, nervous system function, homocysteine metabolism, psychological function, red blood cell formation, immune function, and reduction of fatigue [10]. No UL established.
Japan (MHLW): Eligible for Foods with Function Claims. Recommended intake: 2.4 µg/day. Methylcobalamin widely available as OTC pharmaceutical for neuropathy.
South Korea (MFDS): Registered health functional food ingredient. Approved claims: energy metabolism and blood cell formation.
18 References
[1]Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998. doi:10.17226/6015 REVIEW
[2]National Institutes of Health, Office of Dietary Supplements. Vitamin B12 — Fact sheet for health professionals. Updated 2024. ods.od.nih.gov REVIEW
[3]Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149-160. doi:10.1056/NEJMcp1113996 REVIEW
[4]Green R, et al. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017;3:17040. doi:10.1038/nrdp.2017.40 REVIEW
[5]U.S. Department of Agriculture. FoodData Central. fdc.nal.usda.gov GOVERNMENT
[6]Moore E, et al. Cognitive impairment and vitamin B12: a review. Int Psychogeriatr. 2012;24(4):541-556. doi:10.1017/S1041610211002511 REVIEW
[7]Aroda VR, et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-1761. doi:10.1210/jc.2015-3754 REVIEW
[8]Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008;66(5):250-255. doi:10.1111/j.1753-4887.2008.00031.x REVIEW
[9]Lam JR, et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442. doi:10.1001/jama.2013.280490 REVIEW
[10]EFSA Panel on Dietetic Products, Nutrition and Allergies. Scientific opinion on the substantiation of health claims related to cobalamin (vitamin B12). EFSA J. 2009;7(9):1223. doi:10.2903/j.efsa.2009.1223 GOVERNMENT
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20 Cite this page
Vancouver
Pkhakadze G. Cobalamin — safety profile [Internet]. Tbilisi: Public Health Institute of Georgia; 2026 [cited 2026 May 30]. Available from: https://supplement.ge/ingredients/cobalamin/
APA 7th
Pkhakadze, G. (2026). Cobalamin — Safety profile. Public Health Institute of Georgia. https://supplement.ge/ingredients/cobalamin/
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Reviewed by Prof. G. Pkhakadze, MD, MPH, PhD
Editor-in-Chief, Georgian Medical Journal · Chair, PHIG
Last reviewed: May 2026 · Next: November 2026
This entry is provided for educational and public health purposes under CC BY 4.0. Consult your healthcare provider before starting any supplement. For corrections: info@accreditation.ge.
Publisher: PHIG · Editor-in-Chief: Prof. Giorgi Pkhakadze, MD, MPH, PhD
Publisher: PHIG · Editor-in-Chief: Prof. Giorgi Pkhakadze, MD, MPH, PhD