Vitamin B12 (Cyanocobalamin/Methylcobalamin)

1. Introduction

Vitamin B12, also known as cobalamin, is a water-soluble vitamin that plays a critical role in numerous physiological processes. It is unique among vitamins as it contains the mineral cobalt, and compounds exhibiting Vitamin B12 activity are collectively termed cobalamins [1].

The two primary metabolically active forms of Vitamin B12 in the human body are methylcobalamin and 5-deoxyadenosylcobalamin [1]. The supplemental forms, cyanocobalamin (a synthetic form often used in supplements and fortified foods) and hydroxycobalamin (another natural form), must be converted into these active forms to be utilized by the body [1, 2].

Mechanism of Action

Vitamin B12 functions as a cofactor for only two enzymes in the human body, both of which are essential for life [1, 3]:

1. Methionine Synthase: Methylcobalamin is the required cofactor for this enzyme, which catalyzes the conversion of homocysteine to the essential amino acid methionine. Methionine is, in turn, necessary for the formation of S-adenosylmethionine (SAM), a universal methyl donor involved in nearly 100 different methylation reactions, including those for DNA, RNA, proteins, and lipids [1, 4].
2. L-methylmalonyl-CoA Mutase: 5-deoxyadenosylcobalamin is the required cofactor for this enzyme, which converts L-methylmalonyl-CoA to succinyl-CoA, a key step in the metabolism of propionate, a short-chain fatty acid [1].

This mechanism underpins B12’s essential roles in the development, myelination, and function of the central nervous system, as well as in the synthesis of DNA and the formation of healthy red blood cells [1, 4].

2. Chemical Composition/Key Bioactive Roles

Cobalamins are characterized by a corrin ring structure surrounding a central cobalt atom. The different forms of Vitamin B12 are distinguished by the group attached to the cobalt atom.

Form of Vitamin B12	Chemical Structure/Source	Key Bioactive Role
Methylcobalamin	Natural, active coenzyme form	Cofactor for methionine synthase (Homocysteine metabolism) [1]
5-Deoxyadenosylcobalamin	Natural, active coenzyme form	Cofactor for L-methylmalonyl-CoA mutase (Energy metabolism) [1]
Cyanocobalamin	Synthetic (most common supplemental form)	Converted to active forms in the body [2]
Hydroxycobalamin	Natural (found in food, injectable form)	Converted to active forms in the body [2]

3. Health Benefits

Vitamin B12 is essential for maintaining health, and its supplementation is primarily focused on preventing and treating deficiency, which can have severe consequences [3].

Central Nervous System and Cognitive Function

Vitamin B12 is crucial for the health of the nervous system, particularly for the synthesis of myelin, the protective sheath around nerve fibers [1]. Deficiency can lead to a range of neurological symptoms, including peripheral neuropathy, paresthesia, and cognitive impairment [3]. While observational studies have linked low B12 levels to poor cognitive function, randomized controlled trials have generally not shown that B12 supplementation improves cognitive function in individuals without a pre-existing deficiency [1].

Hematopoiesis (Red Blood Cell Formation)

A primary consequence of B12 deficiency is megaloblastic anemia, a condition characterized by large, immature, and dysfunctional red blood cells [3]. This occurs because B12 is required for DNA synthesis, and its deficiency impairs the maturation and division of red blood cell precursors in the bone marrow [1]. Supplementation effectively reverses this condition [3].

Cardiovascular Health (Homocysteine Reduction)

Vitamin B12, along with folate and Vitamin B6, is involved in the metabolism of homocysteine, an amino acid. High levels of homocysteine are an independent risk factor for cardiovascular disease (CVD) [5]. B12 supplementation, by facilitating the conversion of homocysteine to methionine, can effectively lower circulating homocysteine levels [5]. However, large-scale clinical trials have generally not found that B12 supplementation, even when it successfully lowers homocysteine, leads to a reduction in the risk of cardiovascular events [1, 5].

4. Dosage and Usage

Recommended Dietary Allowance (RDA)

The Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine has established the following RDAs for Vitamin B12 [1]:

Life Stage	RDA (micrograms/day, mcg/day)
Infants (0–6 months)	0.4 (Adequate Intake)
Children (1–3 years)	0.9
Children (4–8 years)	1.2
Adolescents (9–13 years)	1.8
Adults (14+ years)	2.4
Pregnant women	2.6
Lactating women	2.8

Dosage for Deficiency Treatment

For treating Vitamin B12 deficiency, especially in cases of malabsorption (such as pernicious anemia), much higher dosages are used.

• Oral Supplementation: High-dose oral therapy, often 1,000 mcg (1 mg) to 2,000 mcg (2 mg) per day of cyanocobalamin, has been shown to be effective for many patients, including those with pernicious anemia, due to passive diffusion across the intestinal wall [3, 6].
• Intramuscular Injection: The traditional treatment for pernicious anemia involves intramuscular injections of 100 mcg to 1,000 mcg of cyanocobalamin or hydroxocobalamin, administered daily, weekly, or monthly depending on the severity and maintenance phase [3].

Food Sources

Vitamin B12 is naturally present only in foods of animal origin. It is not naturally found in plant foods [1].

• High Sources: Clams, beef liver, trout, salmon, tuna, and beef.
• Other Sources: Milk, yogurt, cheese, and eggs.
• Fortified Foods: Many breakfast cereals, nutritional yeasts, and plant-based milk alternatives are fortified with cyanocobalamin, making them important sources for vegetarians and vegans [1].

5. Safety and Precautions

Safety

Vitamin B12 is generally considered extremely safe. It is a water-soluble vitamin, and the body does not store excessive amounts [1].

• Tolerable Upper Intake Level (UL): The FNB has not established a UL for Vitamin B12 because there is no known toxicity associated with high intakes from food or supplements in healthy individuals [1]. Even at high doses (e.g., 1,000 mcg/day), it is well-tolerated.

Side Effects

Side effects are rare. In some cases, high doses of B12, particularly via injection, have been anecdotally linked to mild side effects such as acne or rosacea, but this is not consistently supported by clinical evidence.

Contraindications and Warnings

• Leber’s Disease: Vitamin B12 supplementation is contraindicated in patients with Leber’s hereditary optic atrophy as it can severely worsen the condition [7].
• Pernicious Anemia: While B12 treats the anemia, the underlying cause (lack of intrinsic factor) is not cured. Treatment must be lifelong. Furthermore, B12 supplementation can mask a folate deficiency, and high-dose folate can mask a B12 deficiency, allowing neurological damage to progress [1].
• Cancer Risk: Some observational studies have suggested a potential link between very high B12 status and an increased risk of certain cancers, but the evidence is inconsistent and more research is needed to clarify this association [1].

Drug Interactions

Vitamin B12 supplements may interact with certain medications [1]:

• Gastric Acid Inhibitors (e.g., Proton Pump Inhibitors and H2-receptor antagonists): These medications reduce stomach acid secretion, which is necessary to release food-bound B12 for absorption, potentially leading to deficiency with long-term use.
• Metformin: This common diabetes medication can reduce the absorption of Vitamin B12 from the digestive tract, and monitoring B12 levels is recommended for patients on long-term metformin therapy.
• Chloramphenicol (Chloromycetin): This antibiotic can interfere with the formation of new blood cells in people with B12 deficiency.

6. References

[1] Office of Dietary Supplements (ODS), National Institutes of Health (NIH). Vitamin B12 – Health Professional Fact Sheet. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

[2] Paul C, Brady DM. Comparative bioavailability and utilization of particular forms of B(12) Supplements with potential to mitigate B(12)-related genetic polymorphisms. Integr Med (Encinitas). 2017;16(1):42-49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/

[3] Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014;349:g5226. https://www.bmj.com/content/349/bmj.g5226

[4] O’Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010;2(3):299-316. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257642/

[5] Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006612.pub5/full

[6] Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. Oral vitamin B(12) versus intramuscular vitamin B(12) for vitamin B(12) deficiency. Cochrane Database Syst Rev. 2018;3(3):CD004655. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004655.pub3/full

[7] Mayo Clinic. Vitamin B-12 (Oral Route, Parenteral Route). https://www.mayoclinic.org/drugs-supplements/vitamin-b12-oral-route-parenteral-route/precautions/drg-20062403