A new scientific review weighs natural and synthetic forms of vitamin B12, revealing where methylcobalamin may outperform standard supplements and why deficiency remains a clinical blind spot.
Study: Vitamin B12: A Comprehensive Review of Natural vs Synthetic Forms of Consumption and Supplementation. Image Credit: Fida Olga / Shutterstock
Vitamin B12 refers to any of three forms of cobalamin: cyanocobalamin, methylcobalamin, and adenosylcobalamin. It is an essential human vitamin, obtained mostly from animal-based foods.
Vitamin B12 deficiency may cause megaloblastic anemia, neuropathy, and complications of pregnancy. While supplementation raises its levels similar to dietary intake in healthy people, overt deficiency disease requires supplementation in addition to dietary intake. A recent review in the journal Cureus compares the natural forms of B12 found in the diet with synthetic B12 (cyanocobalamin) in terms of absorption and clinical-physiological effects.
Physiology of Dietary B12 Absorption
Vitamin B12 is a polar molecule found in protein-bound form in food. Proteolytic digestion frees B12 from the food protein. It is then protectively bound to haptocorrin, a glycoprotein that preserves it from denaturation by stomach acid.
Haptocorrin is degraded by pancreatic proteases in the duodenum. Free B12 forms a complex with intrinsic factor (IF), a glycoprotein produced by the stomach’s parietal cells. Following absorption in the distal ileum via receptors, it leaves the enterocytes to enter the portal blood, where it binds to the transport protein transcobalamin II and is carried to the bone marrow and other tissues.
Core Metabolic Functions of Cobalamin
In humans, the central role of B12 is as a cofactor for methionine synthesis from homocysteine while regenerating the methyl donor tetrahydrofolate. The latter is essential for DNA synthesis, including during red cell formation, and multiple other cellular pathways, including energy metabolism.
B12 is also a cofactor for methylmalonyl-coenzyme A (MMCoA) mutase, which is key to protein and fat metabolism, including myelination.
Clinical and Neurological Consequences of Deficiency
B12 deficiency interrupts DNA synthesis, resulting in ineffective red cell formation. The nucleus cannot mature normally, causing large, immature red cells (macrocytes) to appear, with overall reductions in red cell count and hemoglobin concentration, resulting in macrocytic anemia.
Other clinical features include neuropathy and cognitive disorders. Initial symptoms may include a sore mouth or tongue, a yellow skin tinge, weight loss, numbness or tingling of the extremities, and visual problems. Pregnancy complicated by B12 deficiency can lead to spina bifida and other neural tube defects.
Some cases of depression respond to B12 supplementation, with delayed onset of symptoms and enhanced antidepressant efficacy. While observational and mechanistic studies suggest that disturbed one-carbon metabolism, elevated homocysteine, and mitochondrial dysfunction may contribute to neurodegenerative pathways, current evidence does not establish a direct causal link between B12 deficiency and Alzheimer’s disease.
Deranged MMCoA function in B12 deficiency can cause demyelination of the lateral and posterior spinal columns, leading to subacute combined degeneration. Its role in immunoregulation is under investigation, including potential antiviral effects. B12 increases lymphocyte count and activity and counters systemic inflammation, though clinical relevance remains uncertain. Emerging research has explored potential roles for B12 in coronavirus disease 2019 (COVID-19), but findings are mixed, and benefits remain unproven.
B12 reduces homocysteine levels. Because homocysteine predisposes to lipid peroxidation by reactive oxygen species, inducing endothelial damage, adequate B12 status may lower the risk of thromboembolic complications, although evidence remains associative. B12 also contributes to muscle and gut health; deficiency may reduce vagal tone, disrupt the muscle-gut-brain axis, and contribute to neurobehavioral disorders. Severe deficiency may result in peripheral neuropathy, loss of bowel control, paralysis, erectile dysfunction, depression, and paranoia. Pernicious anemia is sometimes followed by stomach cancer.
Dietary Intake, Risk Factors, and Requirements
Older people, vegans, and vegetarians are at increased risk of B12 deficiency. It may also arise due to gastritis, pernicious anemia, Crohn’s disease, celiac disease, gut surgery, alcoholism, and Sjögren’s syndrome. Overuse of medications such as metformin, proton pump inhibitors, histamine H2 blockers, and oral contraceptive pills can reduce B12 levels.
Most people have normal B12 levels. About 3% of people aged 20 to 39 are deficient, increasing to 6% among those aged 60 and older. Given the wide range of manifestations and blood levels, testing is essential to confirm deficiency, defined as <150 pg/mL. In most cases, dietary intake is not the problem; rather, malabsorption or impaired utilization is responsible.
The best dietary sources of B12 include beef liver, fortified yeast, salmon, Greek yogurt, eggs, and clams. Beef liver may contain ~71 μg per serving versus 0.5 μg per serving of egg. The recommended intake for adults is 2.4 μg/day, increasing to 2.6 μg in pregnancy and 2.8 μg during lactation.
Comparing Natural and Synthetic Cobalamin Forms
Cobalamin from food or supplements is activated through its conversion to methylcobalamin and adenosylcobalamin. Both are chemically identical to natural vitamin B12.
In contrast, cyanocobalamin, the synthetic form commonly used in supplements, must first be converted to cobalamin by detaching the cyanide group before activation. Mutations in B12 metabolic pathways may impair this conversion in a subset of individuals.
Cyanocobalamin storage in the liver is lower than that of natural vitamin B12. Some studies also indicate greater urinary losses of cyanocobalamin compared with methylcobalamin. The liver may not convert adequate cyanocobalamin to its biologically active form, potentially affecting neuronal health.
The methyl group in methylcobalamin may enhance serotonin production, protecting the brain from excitatory toxins. Current evidence suggests, but does not conclusively prove, that overall findings favor methylcobalamin supplementation over cyanocobalamin. It may also be preferable in megaloblastic anemia due to higher bioavailability and potential conversion to S-adenosylmethionine, which promotes metabolic health. Nonetheless, both cyanocobalamin and methylcobalamin effectively raise serum B12 levels, and comparative outcome data remain limited.
Clinical Implications and Future Directions
The review suggests screening for B12 deficiency in the older adults, vegetarians and vegans, and those with certain gastrointestinal disorders. Early detection and treatment may help prevent long-term neurological and hematologic complications.
Both methylcobalamin and cyanocobalamin can be used as supplements, and both increase blood B12 levels. However, methylcobalamin appears more consistently effective and bioavailable, and may be preferable for individuals with impaired absorption or methylation pathways. Future research should clarify long-term outcomes and preventive benefits in high-risk groups.
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