Vitamin B12

Methylcobalamin, C₆₃H₉₁CoN₁₃O₁₄P

Evidence: Strong

Methylcobalamin, a metabolically active form of Vitamin B12, is essential for neurological function and cellular metabolism. While not directly involved in digestion, its role in nerve signal transmission is critical for proper gut motility and coordination, indirectly supporting digestive regularity and efficiency.

There are 38,487 peer-reviewed scientific studies on this ingredient.

Selected Resource 1/2:

NIH, Vitamin B12
Fact Sheet for Health Professionals: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

Resource Summary:

Vitamin B12 (cobalamin) is a water-soluble vitamin essential for central-nervous-system development, red-blood-cell formation, and DNA synthesis; it serves as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. Active forms are methyl- and 5-deoxyadenosyl-cobalamin. Protein-bound B12 in food is freed by gastric acid, binds intrinsic factor, and is absorbed in the ileum; B12 in fortified foods and supplements is already free and more readily absorbed. The adult RDA is 2.4 µg (2.6 µg in pregnancy, 2.8 µg in lactation). Animal foods—meat, fish, dairy, eggs—are natural sources; many breakfast cereals and nutritional yeasts are fortified. Supplements (typically 50–1,000 µg cyanocobalamin) and prescription injections or nasal gels are used therapeutically.

Most adults consume adequate amounts, yet ~3–4 % have clinical deficiency and about 12 % have marginal status; serum B12 < 200 pg/mL or elevated methylmalonic acid confirms deficiency. Risk factors include advanced age, pernicious anemia, atrophic gastritis, gastrointestinal surgery or disorders, vegetarian/vegan diets, prolonged use of proton-pump inhibitors or metformin, and exclusive breastfeeding by B12-deficient mothers. Deficiency can cause megaloblastic anemia, neuropathy, glossitis, fatigue, and infertility; high-dose oral B12 (1–2 mg/day) is usually as effective as intramuscular therapy.

No tolerable upper intake level is set because toxicity is negligible. Evidence shows B12 supplementation does not reduce cardiovascular disease, improve cognition, boost energy, or enhance athletic performance in people with adequate status, and research on cancer risk is inconclusive. Meeting needs through a balanced diet, fortified foods, or supplements for at-risk groups is recommended, and clinicians should monitor status when risk factors or interacting medications are present. 

Selected Study 2/2:

Zarembska, E., Ślusarczyk, K., & Wrzosek, M. (2023). The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases. International Journal of Molecular Sciences, 25(1), 193. https://doi.org/10.3390/ijms25010193

Study Summary:

Study type (and why it matters):
A 2024 narrative review in International Journal of Molecular Sciences collates >300 basic, observational and clinical papers on the common MTHFR C677T variant and allied polymorphisms; it does not enroll new participants but weighs the totality of existing evidence. For context, the “T” version is carried by ≈10 %–15 % of Europeans and as many as one-quarter of East-Asian adults, so its public-health footprint is large.

Observed benefits / risks:
The review shows that, rather than conferring benefit, the 677 T allele consistently raises fasting homocysteine and is linked to higher risks of hypertension, stroke, cardiovascular disease, pregnancy complications, diabetes and obesity, especially when dietary folate and B-vitamin intake are low. Several meta-analyses cited in the paper note that good folate status can blunt or even nullify these associations in fortified populations.

Mechanisms of action:
MTHFR is the enzyme that folds folate into its “active” form, a bit like converting raw flour into usable dough. The C→T swap makes the enzyme wobbly and 50-70 % less efficient, so less methyl-folate is produced. Without enough methyl-folate the body struggles to recycle homocysteine back to methionine; homocysteine then rises, irritating blood-vessel walls and upsetting DNA-methylation patterns that guide growth and metabolism.

Why methylated B-12 can help:
That recycling step also needs vitamin B12 in its methylated form (methylcobalamin) as a co-factor. Giving pre-methylated B12 provides the “methyl hand-off” instantly, bypassing one more conversion that can be slow in people with MTHFR variants or low stomach acid. Clinical and dialysis-patient studies show that combining methylcobalamin with folate can lower homocysteine by 20-30 %. Although some head-to-head work finds cyanocobalamin maintains B12 status just as well in vegans, the pre-activated form is favored by many clinicians for people who genetically or medically have sluggish one-carbon metabolism.

Side effects:
Because the review analyses a genetic trait, it reports no supplement-related adverse events. High-dose folate or methyl-B12 are generally safe, but the authors and public-health agencies remind readers that megadoses can mask B12 deficiency or interfere with anticoagulant therapy.

Strength of evidence:
The review weaves a biologically coherent story supported by several dozen meta-analyses and large cohort studies, giving moderate overall certainty that C677T is a modifiable risk marker. However, many intervention trials are small or focus on blood markers rather than hard clinical outcomes, so more long-term randomized work is needed to confirm whether targeted methyl-folate/B-12 supplementation translates into fewer heart attacks, strokes or pregnancy complications in carriers.