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“Best” depends on what problem you’re solving, how often you want to inject, and what your pharmacy/insurer will actually supply.

Below is a head-to-head snapshot followed by practical guidance.

FeatureHydroxocobalaminCyanocobalaminMethylcobalamin
Regulatory status (U S.)FDA-approved RxFDA-approved RxNot FDA-approved (503A/503B compounded)
Typical concentration1 mg/mL (10 mL vial or single ampule)1 mg/mL (30 mL MDV)5-25 mg/mL (compounded)
Biological retentionStays bound to transcobalamin longer → injections as far apart as every 8–12 weeks (Oral vitamin B12 versus intramuscular vitamin ... - PubMed Central, Retention of Injected Hydroxocobalamin Versus Cyanocobalamin ...)Cleared faster → maintenance every 4 weeksSimilar to cyano for blood-level curves, but doses are usually higher (5-10 mg)
Evidence baseLong-term deficiency data; 1st-line in U.K. & EUExtensive U.S. data; insurer defaultLimited RCTs; modest benefit for peripheral neuropathy when combined with other agents (Efficacy and Safety of Mecobalamin on Peripheral Neuropathy, Safety and efficacy of intravenous ultra-high dose methylcobalamin ..., Methylcobalamin as a candidate for chronic peripheral neuropathic ...)
Cost / coverageHigher cash cost; many U.S. insurers stock only 1 mg vial packsCheapest; universally covered$$; rarely covered; patient-pay
ExtrasAntidote for cyanide poisoningStable, shelf-friendly“Active” co-enzyme; widely marketed for nerve support
DrawbacksHarder to source in the U.S.More frequent shotsRegulatory gray zone; purity & sterility depend on compounder

How to decide

If you……then best practical choiceWhy
Need conventional B-12 replacement, want insurance to pay, don’t mind monthly shotsCyanocobalamin (1 mg IM/SC monthly)Readily stocked; CPT J3420 billing; lowest cost.
Want the fewest injections and can obtain product (or live in EU/UK)Hydroxocobalamin (1 mg IM every 8–12 weeks once replete)Superior tissue retention; accepted first-line abroad.
Are targeting peripheral neuropathy or high-dose “neuroprotection” and self-pay is OKMethylcobalamin (5–10 mg SC two-three times weekly)Small trials show symptom and nerve-conduction benefits at supraphysiologic doses; patients often tolerate large SC doses well (Safety and efficacy of intravenous ultra-high dose methylcobalamin ..., Methylcobalamin as a candidate for chronic peripheral neuropathic ...).
Treating cyanide poisoning or severe nitroprusside toxicityHydroxocobalamin 5 g IVOnly formulation FDA-approved for this indication.
Have chronic kidney disease and worry about added cyanide moietyEither hydroxo- or methyl-…They lack the cyanide ligand present in cyano; no large trials show harm, but many nephrologists prefer cyanide-free forms.

Practical take-aways for U.S. clinicians

  1. Stock & coverage drive the default: most retail and mail-order pharmacies only carry cyanocobalamin MDVs, so it remains the path of least resistance (Cyanocobalamin - StatPearls - NCBI Bookshelf).
  2. Hydroxocobalamin is superior for persistence, but you may need to special-order (McKesson, Cardinal) or use a compounding-outsourcing facility.
  3. Methylcobalamin is perfectly safe when compounded to USP <797> standards, but quality varies—stick with PCAB-accredited 503A pharmacies (e.g., Empower, Belmar).
  4. Dosing flexibility matters more than molecule choice: after deficiency is corrected, titrate injection spacing so that trough serum B-12 stays >400 pg/mL and methylmalonic acid normalizes—regardless of formulation.
  5. Document the ICD-10 code and why you’re choosing a non-standard product to satisfy audits or prior authorizations.

Bottom line:

  • Most insured U.S. patients: cyanocobalamin monthly gets the job done.
  • Patients seeking convenience or with adherence issues: hydroxocobalamin every 2–3 months is worth the extra cost/effort.
  • Neuropathy or “biohacker” goals: compounded high-dose methylcobalamin is reasonable when evidence-based therapies are maximized and the patient is informed about regulatory status.

Need sample prescriptions, supplier contacts, or European (INFARMED, EMA) sourcing notes


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