Non-Synthetic Forms of Vitamin B12
The non-synthetic forms of vitamin B12 are methylcobalamin, adenosylcobalamin, and hydroxocobalamin—these are the bioidentical forms that naturally occur in human physiology and animal foods, unlike cyanocobalamin which is a synthetic compound. 1, 2
Natural vs Synthetic B12 Forms
The three naturally occurring forms of vitamin B12 available commercially are:
Methylcobalamin (MeCbl): A bioidentical form that occurs naturally in human tissues and animal foods, primarily involved in hematopoiesis and brain development 3, 2
Adenosylcobalamin (AdCbl): Another bioidentical form essential for carbohydrate, fat, and amino acid metabolism, and critical for myelin formation 3, 2
Hydroxocobalamin (OHCbl): A natural form that serves as a precursor to both active coenzyme forms in the body 3, 2
In contrast, cyanocobalamin (CNCbl) is a synthetic compound used for food fortification and supplements that occurs only in trace amounts in human tissues as a result of cyanide intake from smoking or other sources 2. This synthetic form is not naturally present in the human body or in food sources 2.
Clinical Superiority of Natural Forms
Current guidelines recommend using methylcobalamin or hydroxocobalamin instead of cyanocobalamin, particularly in patients with renal dysfunction or cardiovascular disease, due to superior bioavailability and safety. 4, 5
The American Heart Association specifically advises against cyanocobalamin in certain populations:
In patients with cardiovascular disease or stroke history, methylcobalamin or hydroxocobalamin should be used instead of cyanocobalamin due to increased risk of cardiovascular events associated with the synthetic form, especially in renal dysfunction 4
B vitamins including B12 reduced ischemic stroke by 43% in meta-analyses, but this benefit requires using the appropriate form 4
Metabolic Processing
All forms of B12—whether natural or synthetic—undergo intracellular processing:
All supplemental or food-derived B12 forms are reduced to a core cobalamin molecule inside cells, which then converts to the two intracellular active forms: methylcobalamin and adenosylcobalamin 2, 6
The MMACHC protein (CblC) processes dietary B12 by removing the upper-axial ligand, yielding cob(II)alamin, which is then trafficked to the two B12-dependent enzymes 6
The methyl and adenosyl components of supplemental methylcobalamin and adenosylcobalamin are cleaved inside cells and are not directly used in synthesis of intracellular active forms—the body regenerates them through its own metabolic pathways 2
Practical Recommendations
For supplementation purposes:
Supplementing with any of the naturally bioidentical forms (methylcobalamin, hydroxocobalamin, and/or adenosylcobalamin) is preferred over cyanocobalamin due to superior bioavailability and safety 2
For the general population without specific risk factors, all natural B12 forms likely have similar bioavailabilities, making methylcobalamin a cost-effective choice 2
A combination of all three naturally occurring forms may be beneficial for individuals with genetic polymorphisms affecting B12 metabolism, though this requires either trial-and-error or using a multi-form supplement 2
In patients with methylmalonic acidemia due to specific genetic defects (cblA, cblB, cblD variant 2), hydroxocobalamin or methylcobalamin should be used rather than cyanocobalamin, with dramatically higher doses required (milligram doses daily) 5