Injectable Methylcobalamin for Vitamin B12 Deficiency
Injectable methylcobalamin can be used to treat adult vitamin B12 deficiency, but hydroxocobalamin is the guideline-recommended first-line injectable form with established dosing protocols and superior tissue retention. 1
Guideline-Recommended Injectable Forms
Hydroxocobalamin is preferred over methylcobalamin because all major medical societies (British Medical Journal, NICE, Clinical Nutrition) provide specific, evidence-based dosing regimens for hydroxocobalamin but not for methylcobalamin. 1 The standard maintenance protocol is hydroxocobalamin 1000 mcg (1 mg) intramuscularly every 2-3 months for life after initial loading. 1, 2
When Methylcobalamin Is Specifically Indicated
In patients with renal dysfunction (eGFR < 50 mL/min), methylcobalamin or hydroxocobalamin should be used instead of cyanocobalamin because cyanocobalamin generates cyanide metabolites requiring renal clearance and is associated with doubled cardiovascular risk (hazard ratio 2.0) in diabetic nephropathy patients. 1, 2
Standard Dosing Protocols
For Neurological Involvement
- Hydroxocobalamin 1 mg intramuscularly on alternate days until neurological improvement plateaus, then switch to 1 mg every 2 months for lifelong maintenance 1, 2
- Neurological symptoms include paresthesias, numbness, gait disturbances, cognitive difficulties, memory problems, and glossitis 1
Without Neurological Symptoms
- Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, followed by 1 mg every 2-3 months for life 1, 2
Post-Bariatric Surgery
- Prophylactic hydroxocobalamin 1 mg intramuscularly every 3 months indefinitely, regardless of documented deficiency 1, 2
Methylcobalamin-Specific Evidence
While methylcobalamin can be effective, the evidence base is limited:
A 2018 study found that methylcobalamin 500 mcg three times weekly produced significantly higher serum cobalamin levels (1892 pg/mL) compared to 1500 mcg once weekly (1438 pg/mL) in peripheral neuropathy patients. 3
A 2002 Japanese study demonstrated that oral methylcobalamin 1500 mcg daily for 7 days every 1-3 months maintained normal B12 levels, with individual variation requiring monthly dosing in some patients. 4
Critical Dosing Considerations
If using methylcobalamin instead of hydroxocobalamin, follow the same dosing schedule established for hydroxocobalamin (1 mg every 2-3 months maintenance), as no specific methylcobalamin protocols exist in current guidelines. 1
Monthly dosing (1000 mcg IM monthly) is an acceptable alternative to every 2-3 months and may better meet metabolic requirements in patients with persistent symptoms, post-bariatric surgery, or extensive ileal disease. 1, 2, 5
Practical Algorithm for Injectable B12 Selection
Check renal function first 1
- eGFR ≥ 50 mL/min: Hydroxocobalamin preferred (cyanocobalamin acceptable)
- eGFR < 50 mL/min: Hydroxocobalamin or methylcobalamin only (avoid cyanocobalamin)
Assess for neurological involvement 1
- Present: Alternate-day dosing until improvement
- Absent: Three times weekly for 2 weeks
Transition to maintenance 1, 2
- Standard: 1 mg every 2-3 months
- Consider monthly if symptoms persist
Critical Pitfalls to Avoid
Never administer folic acid before correcting B12 deficiency, as folic acid can mask megaloblastic anemia while allowing irreversible subacute combined degeneration of the spinal cord to progress. 1, 2
Do not "titrate" injection frequency based on serum B12 or methylmalonic acid levels—up to 50% of patients require individualized regimens with more frequent dosing (ranging from twice weekly to every 2-4 weeks) to remain symptom-free, based on clinical response rather than laboratory values. 6
Do not assume oral/sublingual supplementation can replace injections in malabsorption—there is currently no evidence supporting this substitution in patients with pernicious anemia, ileal resection >20 cm, or post-bariatric surgery. 6
Monitoring Strategy
- Recheck B12 levels at 3,6, and 12 months in the first year, then annually 1
- Target homocysteine < 10 μmol/L for optimal cardiovascular outcomes 1, 2
- Monitor for neurological symptom improvement (paresthesias, gait, cognition) rather than relying solely on laboratory values 1, 6
- Measure methylmalonic acid (MMA) if symptoms persist despite normal B12, targeting MMA < 271 nmol/L 7, 1