Methylcobalamin

updated

Methylcobalamin is a form of vitamin B12 sold as the active form and as superior to cyanocobalamin. It raised serum B12 about as well as cyanocobalamin in three pediatric comparisons, and a PubMed search on 9 October 2026 found no randomized comparison for deficiency or clinical outcomes in adults.

Cobalamin (vitamin B12 form)

  • An openFDA query on 9 October 2026 for methylcobalamin or mecobalamin returned no application; the same database lists cyanocobalamin products, including NASCOBAL nasal spray (NDA 021642, 31 January 2005).
  • Cell and biochemical work shows the cell removes the methyl group and rebuilds both coenzymes from the same intermediate it makes from cyanocobalamin.
  • In three observational comparisons in Turkey (129, 158 and 312 children), sublingual methylcobalamin raised serum B12 about as well as cyanocobalamin by mouth or injection.
  • A PubMed search on 9 October 2026 found one randomized head-to-head comparison of the two forms: 20 healthy adults, sleep endpoints.
  • In a phase 3 trial in 130 patients with early ALS in Japan, injected methylcobalamin 50 mg twice weekly for 16 weeks slowed ALSFRS-R decline by 1.97 points.
  • A meta-analysis of 15 neuropathy trials (1707 patients, 11 at high risk of bias) found more patients with clinical efficacy on mecobalamin but no better pain or symptom scores.

What is methylcobalamin, and is it an approved drug?

Methylcobalamin is a form of vitamin B12 with a methyl group on the cobalamin core. An openFDA query on 9 October 2026 found no FDA-approved methylcobalamin drug, while the same database lists approved cyanocobalamin products.

Methylcobalamin (mecobalamin) is C63H91CoN13O14P (1344.4 g/mol, CAS 13422-55-4). PubChem holds several methylcobalamin records with the same formula and CAS that differ in stereo descriptors, so this page uses CID 10898559. Cyanocobalamin, the other common form of vitamin B12, is C63H88CoN14O14P (1355.4 g/mol, CAS 68-19-9). PubChem names both on the same cobalamin core, with a methyl ligand in one and a cyanide ligand in the other.

An openFDA Drugs@FDA query on 9 October 2026 for methylcobalamin or mecobalamin (brand, generic and active-ingredient fields) returned no application, so no FDA-approved methylcobalamin drug was located. The same database lists cyanocobalamin products, including NASCOBAL nasal spray (NDA 021642, original approval 31 January 2005) and a cyanocobalamin ANDA approved 26 April 1972. US supplement status for methylcobalamin is not established here.

Cyanocobalamin injection is FDA-labeled for vitamin B12 deficiency due to malabsorption, including pernicious anemia. The label calls cyanocobalamin the most widely used form of B12 and says hydroxocobalamin is equally effective.

PubChem: methylcobalamin and cyanocobalamin identity

Chemical identity record

National Library of Medicine. PubChem compound records CID 10898559 (methylcobalamin, mecobalamin) and CID 165339223 (cyanocobalamin, vitamin B12).

Methylcobalamin (mecobalamin): C63H91CoN13O14P, 1344.4 g/mol, CAS 13422-55-4. PubChem holds several other methylcobalamin records with the same formula and CAS that differ in stereo descriptors, so the CID used here is 10898559. Cyanocobalamin (vitamin B12): CID 165339223, C63H88CoN14O14P, 1355.4 g/mol, CAS 68-19-9. PubChem names both on the same cobalamin core, with a methyl (carbanide) ligand in one and a cyanide ligand in the other.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecules
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
openFDA query, 9 October 2026: no methylcobalamin application

Regulatory record

U.S. Food and Drug Administration. openFDA Drugs@FDA query for methylcobalamin or mecobalamin (brand, generic and active-ingredient fields), run on 9 October 2026.

The query returned no application, so no FDA-approved methylcobalamin drug was located. The same database lists cyanocobalamin products, including NASCOBAL nasal spray (NDA 021642, original approval 31 January 2005) and a cyanocobalamin ANDA approved 26 April 1972 (ANDA 080737).

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name query
Follow-up
Query run on 9 October 2026
Study design
Dated US approval-record query
Funding
not stated in the source

A negative query on one date is not proof about every product or jurisdiction. US supplement status for methylcobalamin is not established here.

Read the original source
Cyanocobalamin injection label, version effective 6 August 2026: indication, absorption, warnings

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Cyanocobalamin injection, for intramuscular or subcutaneous use, prescribing information, label version effective 6 August 2026. Set ID b1e35c97-2157-454e-967f-53a4300827de.

The label approves cyanocobalamin injection for vitamin B12 deficiency due to malabsorption, including pernicious anemia, gastrointestinal pathology or surgery, fish tapeworm, pancreatic or bowel malignancy, and folic acid deficiency. It calls cyanocobalamin the most widely used form of B12, with hematopoietic activity apparently identical to the antianemia factor in liver extract, and says hydroxocobalamin is equally effective. About 1% of an oral dose is absorbed by passive diffusion, adequate only with very large doses, and oral absorption is called too undependable to rely on in pernicious anemia. Warnings include severe and swift optic atrophy in patients with early Leber's disease treated with cyanocobalamin, hypokalemia and sudden death with intense treatment of severe megaloblastic anemia, and anaphylaxis after parenteral B12.

Participants / model
Patients with B12 deficiency from malabsorption
Treatment
Cyanocobalamin injection, intramuscular or subcutaneous
Follow-up
Label version effective 6 August 2026
Study design
FDA prescribing information
Funding
not stated in the source

This is a cyanocobalamin label. It does not cover methylcobalamin, and this page gives no regimen from it.

Read the original source

What did studies comparing methylcobalamin and cyanocobalamin find?

In three pediatric comparisons in Turkey, sublingual methylcobalamin raised serum B12 about as well as cyanocobalamin by mouth or injection. None was randomized. The one randomized head-to-head study was in 20 healthy adults with sleep endpoints.

Three comparisons in children with low B12 were retrospective or nonrandomized. In 129 children aged 5 to 18 (serum B12 200 pg/mL or less), intramuscular cyanocobalamin, sublingual cyanocobalamin and sublingual methylcobalamin all raised serum B12 significantly, and the authors concluded both sublingual forms were as effective as intramuscular cyanocobalamin for serum B12 and hematologic abnormalities. The abstract does not say which group was higher.

In 158 children aged 0 to 3 (serum B12 under 300 ng/L), oral cyanocobalamin, sublingual methylcobalamin and intramuscular cyanocobalamin each raised mean B12 above 300 ng/L, and the authors judged sublingual methylcobalamin as effective as both cyanocobalamin routes. In 312 children (serum B12 under 250 ng/L), median B12 went from 177 to 447 ng/L at 1.5 months and 321.5 ng/L at 3 months on intramuscular cyanocobalamin, versus 172 to 438 and 360 ng/L on sublingual methylcobalamin spray, with no significant between-group differences. Groups were assigned by treatment type, and 18% of the methylcobalamin group were under cancer treatment.

The one randomized head-to-head study gave 20 healthy adults (6 women, 14 men) 3 mg/day of cyanocobalamin or methylcobalamin for 14 days. B12 levels rose quickly in the first week on cyanocobalamin and linearly on methylcobalamin. Both forms lowered urinary melatonin-metabolite excretion and increased night-time activity, and sleep time fell only on methylcobalamin, which the authors read as an alerting effect. It was a preliminary study with sleep and circadian endpoints, not a deficiency trial.

Retrospective: 129 children aged 5 to 18 in Turkey, all three routes raised B12

Human study

Tuğba-Kartal A et al. Rev Invest Clin. 2020;72(6):380-385. PMID 33053572.

Intramuscular cyanocobalamin, sublingual cyanocobalamin and sublingual methylcobalamin all raised serum B12 significantly. The abstract reports a between-group difference without saying which group was higher. The authors concluded both sublingual forms were as effective as intramuscular cyanocobalamin for serum B12 and hematologic abnormalities.

Participants / model
129 children aged 5 to 18 with B12 deficiency (serum B12 200 pg/mL or less) in Turkey
Treatment
Intramuscular cyanocobalamin; sublingual cyanocobalamin; sublingual methylcobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized. The direction of the between-group difference is not stated in the abstract.

Read the original source
Retrospective: 158 children aged 0 to 3 in Turkey, methylcobalamin matched both cyanocobalamin routes

Human study

Orhan Kiliç B et al. Hematology. 2021;26(1):1013-1017. PMID 34871525.

Oral cyanocobalamin, sublingual methylcobalamin and intramuscular cyanocobalamin each raised mean B12 above 300 ng/L. The authors judged sublingual methylcobalamin as effective as both cyanocobalamin routes.

Participants / model
158 children aged 0 to 3 with serum B12 under 300 ng/L in Turkey
Treatment
Oral cyanocobalamin; sublingual methylcobalamin; intramuscular cyanocobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized.

Read the original source
Nonrandomized: 312 children in Turkey, no significant difference at 1.5 and 3 months

Human study

Aydin S et al. Children (Basel). 2025;12(4). PMID 40310078.

Median B12 went from 177 to 447 ng/L at 1.5 months and 321.5 ng/L at 3 months on cyanocobalamin, versus 172 to 438 and 360 ng/L on methylcobalamin, with no significant between-group differences. Groups were assigned by treatment type, not randomized, and 18% of the methylcobalamin group were under cancer treatment.

Participants / model
312 children aged 0.1 to 17 with serum B12 under 250 ng/L in Turkey (29 given intramuscular cyanocobalamin, 283 given sublingual methylcobalamin spray)
Treatment
Intramuscular cyanocobalamin versus sublingual methylcobalamin spray at age-based doses
Follow-up
1.5 and 3 months
Study design
Nonrandomized observational comparison
Funding
not stated in the source

Groups were assigned by treatment type, not randomized, and the methylcobalamin group included children under cancer treatment.

Read the original source
Only randomized head-to-head: 20 healthy adults, sleep and circadian endpoints

Randomized controlled trial

Mayer G et al. Neuropsychopharmacology. 1996;15(5):456-64. PMID 8914118.

B12 levels rose quickly in the first week on cyanocobalamin and linearly on methylcobalamin. Both forms lowered urinary melatonin-metabolite excretion and increased night-time activity. Sleep time fell only on methylcobalamin, which the authors read as an alerting effect.

Participants / model
20 healthy adults (6 women, 14 men)
Treatment
3 mg/day of cyanocobalamin or methylcobalamin; route not stated in the abstract
Follow-up
14 days
Study design
Randomized head-to-head study
Funding
not stated in the source

A preliminary study with sleep and circadian endpoints, not a deficiency trial.

Read the original source

Is methylcobalamin the superior form of B12?

The superiority claim is not supported. A PubMed search on 9 October 2026 found one randomized head-to-head study, in healthy adults with sleep endpoints, and no randomized comparison for deficiency or clinical outcomes in adults.

Sellers market methylcobalamin as the active form of vitamin B12 and claim it is superior to cyanocobalamin. A PubMed search on 9 October 2026 for methylcobalamin or mecobalamin with cyanocobalamin and randomized or trial terms returned 15 records. One was the randomized head-to-head comparison in healthy adults. The others were reviews, isotope-absorption studies using cyanocobalamin alone, and diet or single-arm studies.

A broader title and abstract search for comparison terms (53 records) added the pediatric observational comparisons and no other randomized comparison. No randomized trial in the records reviewed compared the two forms for correcting deficiency or for clinical outcomes in adults. A ClinicalTrials.gov query for the two names showed no head-to-head trial among the first 20 records.

A literature review favoring the natural forms has a mixed conclusion: it recommends them over cyanocobalamin, citing superior bioavailability and safety, while also saying that for most people all forms likely have similar bioavailability and effects. One of its authors is listed as chief medical officer of Designs for Health, Inc.

PubMed search, 9 October 2026: 15 records, one randomized head-to-head study

PubMed search record

PubMed search run on 9 October 2026: (methylcobalamin[tiab] OR mecobalamin[tiab]) AND cyanocobalamin[tiab] AND (randomized controlled trial[pt] OR randomized[tiab] OR randomised[tiab] OR trial[tiab]). 15 records returned. A broader title and abstract search for comparison terms returned 53 records.

The search returned 15 records. One was a randomized head-to-head comparison (20 healthy adults, sleep endpoints); the others were reviews, isotope-absorption studies using cyanocobalamin alone, and diet or single-arm studies. A broader title and abstract search for comparison terms (53 records) added the pediatric observational comparisons and no other randomized comparison. No randomized trial in the records reviewed compared the two forms for correcting deficiency or for clinical outcomes in adults. A ClinicalTrials.gov query for the two names showed no head-to-head trial among the first 20 records.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source
Retrospective: 129 children aged 5 to 18 in Turkey, all three routes raised B12

Human study

Tuğba-Kartal A et al. Rev Invest Clin. 2020;72(6):380-385. PMID 33053572.

Intramuscular cyanocobalamin, sublingual cyanocobalamin and sublingual methylcobalamin all raised serum B12 significantly. The abstract reports a between-group difference without saying which group was higher. The authors concluded both sublingual forms were as effective as intramuscular cyanocobalamin for serum B12 and hematologic abnormalities.

Participants / model
129 children aged 5 to 18 with B12 deficiency (serum B12 200 pg/mL or less) in Turkey
Treatment
Intramuscular cyanocobalamin; sublingual cyanocobalamin; sublingual methylcobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized. The direction of the between-group difference is not stated in the abstract.

Read the original source
Retrospective: 158 children aged 0 to 3 in Turkey, methylcobalamin matched both cyanocobalamin routes

Human study

Orhan Kiliç B et al. Hematology. 2021;26(1):1013-1017. PMID 34871525.

Oral cyanocobalamin, sublingual methylcobalamin and intramuscular cyanocobalamin each raised mean B12 above 300 ng/L. The authors judged sublingual methylcobalamin as effective as both cyanocobalamin routes.

Participants / model
158 children aged 0 to 3 with serum B12 under 300 ng/L in Turkey
Treatment
Oral cyanocobalamin; sublingual methylcobalamin; intramuscular cyanocobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized.

Read the original source
Nonrandomized: 312 children in Turkey, no significant difference at 1.5 and 3 months

Human study

Aydin S et al. Children (Basel). 2025;12(4). PMID 40310078.

Median B12 went from 177 to 447 ng/L at 1.5 months and 321.5 ng/L at 3 months on cyanocobalamin, versus 172 to 438 and 360 ng/L on methylcobalamin, with no significant between-group differences. Groups were assigned by treatment type, not randomized, and 18% of the methylcobalamin group were under cancer treatment.

Participants / model
312 children aged 0.1 to 17 with serum B12 under 250 ng/L in Turkey (29 given intramuscular cyanocobalamin, 283 given sublingual methylcobalamin spray)
Treatment
Intramuscular cyanocobalamin versus sublingual methylcobalamin spray at age-based doses
Follow-up
1.5 and 3 months
Study design
Nonrandomized observational comparison
Funding
not stated in the source

Groups were assigned by treatment type, not randomized, and the methylcobalamin group included children under cancer treatment.

Read the original source
Review favoring natural forms: mixed conclusion on bioavailability

Narrative review

Paul C et al. Integr Med (Encinitas). 2017;16(1):42-49. PMID 28223907.

The review states that all supplemental and food B12 forms are reduced to a core cobalamin that is converted to methylcobalamin and adenosylcobalamin in a ratio not influenced by the form ingested, and that the methyl and adenosyl groups of supplements are cleaved inside cells. Its conclusion is internally mixed: it recommends the natural forms over cyanocobalamin, citing superior bioavailability and safety, while also saying that for most people all forms likely have similar bioavailability and effects.

Participants / model
Not a clinical population
Treatment
Not applicable
Follow-up
Not applicable
Study design
Literature review
Funding
not stated in the source

One author is listed as chief medical officer of Designs for Health, Inc.

Read the original source

How does the body handle methylcobalamin?

Cells remove the methyl group and rebuild both B12 coenzymes from the same intermediate they make from cyanocobalamin. Biochemistry reviews conclude that supplementing methylcobalamin is unlikely to be advantageous.

A biochemistry review states that transport proteins bind and take up all the supplement forms. Inside the cell, the chaperone MMACHC decyanates cyanocobalamin and dealkylates methylcobalamin and adenosylcobalamin to a reduced cobalamin intermediate, from which both coenzymes are then made. The authors conclude methylcobalamin and adenosylcobalamin follow the same intracellular route as cyanocobalamin and that supplementing them is unlikely to be advantageous, while high parenteral hydroxocobalamin has advantages in inborn errors of cobalamin metabolism.

In cultured cells, adenosylcobalamin was converted to methylcobalamin, and labeled straight-chain alkylcobalamins served as substrates for making both coenzymes. Normal skin fibroblasts converted propylcobalamin to both coenzymes, while fibroblasts from 3 patients with MMACHC mutations showed little or no conversion. The authors conclude the cblC protein handles early processing of both cyanocobalamin (decyanation) and alkylcobalamins such as methylcobalamin (dealkylation).

On absorption, the cyanocobalamin injection label says about 1% of an oral dose is absorbed by passive diffusion, adequate only with very large doses, and calls oral absorption too undependable to rely on in pernicious anemia. That statement is about cyanocobalamin.

Biochemistry review: all supplement forms share one intracellular route

Narrative review

Obeid R et al. Mol Nutr Food Res. 2015;59(7):1364-72. PMID 25820384.

The review states that transport proteins bind and take up all the supplement forms, and that inside the cell the chaperone MMACHC decyanates cyanocobalamin and dealkylates methylcobalamin and adenosylcobalamin to a reduced cobalamin intermediate, from which both coenzymes are then made. The authors conclude methylcobalamin and adenosylcobalamin follow the same intracellular route as cyanocobalamin and that supplementing them is unlikely to be advantageous, while high parenteral hydroxocobalamin has advantages in inborn errors of cobalamin metabolism.

Participants / model
Not a clinical population
Treatment
Not applicable
Follow-up
Not applicable
Study design
Narrative review of cobalamin biochemistry
Funding
not stated in the source

A biochemistry review, not a clinical comparison.

Read the original source
Cell study: both coenzymes made from alkylcobalamins; cblC cells fail to convert

Cell study

Hannibal L et al. Mol Genet Metab. 2009;97(4):260-6. PMID 19447654.

In cultured cells, adenosylcobalamin was converted to methylcobalamin, and labeled straight-chain alkylcobalamins served as substrates for making both coenzymes. Normal skin fibroblasts converted propylcobalamin to both coenzymes, while fibroblasts from 3 patients with MMACHC mutations showed little or no conversion. The authors conclude the cblC protein handles early processing of both cyanocobalamin (decyanation) and alkylcobalamins such as methylcobalamin (dealkylation).

Participants / model
Cultured bovine aortic endothelial cells; human fibroblasts from healthy donors and 3 patients with cblC mutations
Treatment
In vitro 57Co-labeled cobalamins
Follow-up
not stated in the source
Study design
Cell study
Funding
not stated in the source

A cell study; it does not measure clinical outcomes.

Read the original source
Review favoring natural forms: mixed conclusion on bioavailability

Narrative review

Paul C et al. Integr Med (Encinitas). 2017;16(1):42-49. PMID 28223907.

The review states that all supplemental and food B12 forms are reduced to a core cobalamin that is converted to methylcobalamin and adenosylcobalamin in a ratio not influenced by the form ingested, and that the methyl and adenosyl groups of supplements are cleaved inside cells. Its conclusion is internally mixed: it recommends the natural forms over cyanocobalamin, citing superior bioavailability and safety, while also saying that for most people all forms likely have similar bioavailability and effects.

Participants / model
Not a clinical population
Treatment
Not applicable
Follow-up
Not applicable
Study design
Literature review
Funding
not stated in the source

One author is listed as chief medical officer of Designs for Health, Inc.

Read the original source
Cyanocobalamin injection label, version effective 6 August 2026: indication, absorption, warnings

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Cyanocobalamin injection, for intramuscular or subcutaneous use, prescribing information, label version effective 6 August 2026. Set ID b1e35c97-2157-454e-967f-53a4300827de.

The label approves cyanocobalamin injection for vitamin B12 deficiency due to malabsorption, including pernicious anemia, gastrointestinal pathology or surgery, fish tapeworm, pancreatic or bowel malignancy, and folic acid deficiency. It calls cyanocobalamin the most widely used form of B12, with hematopoietic activity apparently identical to the antianemia factor in liver extract, and says hydroxocobalamin is equally effective. About 1% of an oral dose is absorbed by passive diffusion, adequate only with very large doses, and oral absorption is called too undependable to rely on in pernicious anemia. Warnings include severe and swift optic atrophy in patients with early Leber's disease treated with cyanocobalamin, hypokalemia and sudden death with intense treatment of severe megaloblastic anemia, and anaphylaxis after parenteral B12.

Participants / model
Patients with B12 deficiency from malabsorption
Treatment
Cyanocobalamin injection, intramuscular or subcutaneous
Follow-up
Label version effective 6 August 2026
Study design
FDA prescribing information
Funding
not stated in the source

This is a cyanocobalamin label. It does not cover methylcobalamin, and this page gives no regimen from it.

Read the original source

Does mecobalamin help diabetic or herpetic neuropathy?

Mecobalamin improved the share of patients with clinical efficacy in a meta-analysis of 15 trials, but not pain or symptom scores, and most trials were at high risk of bias.

A meta-analysis of 15 randomized trials (1707 patients with diabetic or herpetic peripheral neuropathy; 11 of 15 trials at high risk of bias) found mecobalamin alone (RR 1.17, 95% CI 1.03 to 1.33) and in combination (RR 1.32, 95% CI 1.21 to 1.45) improved the share of patients with clinical therapeutic efficacy versus active controls. Neither improved pain or neuropathic symptom scores, and nerve conduction improved only with combinations.

The abstract does not name cyanocobalamin as a comparator, so the result does not show that methylcobalamin outperforms cyanocobalamin. No serious adverse events were reported.

Neuropathy meta-analysis: 15 trials, 1707 patients, efficacy rate up, pain and symptom scores not

Systematic review and meta-analysis

Sawangjit R et al. J Altern Complement Med. 2020;26(12):1117-1129. PMID 32716261.

Mecobalamin alone (RR 1.17, 95% CI 1.03 to 1.33) and in combination (RR 1.32, 95% CI 1.21 to 1.45) improved the share of patients with clinical therapeutic efficacy versus active controls, but neither improved pain or neuropathic symptom scores. Nerve conduction improved only with combinations. No serious adverse events were reported. The abstract does not name cyanocobalamin as a comparator.

Participants / model
1707 patients with diabetic or herpetic peripheral neuropathy across 15 randomized trials (11 of 15 at high risk of bias)
Treatment
Mecobalamin alone or combined, versus active control
Follow-up
Varied by included trial
Study design
Systematic review and meta-analysis of 15 randomized trials
Funding
not stated in the source

Most included trials were at high risk of bias, and cyanocobalamin was not named as a comparator.

Read the original source

What did the Japanese ALS trial find with injected methylcobalamin?

In 130 patients with early ALS, injected methylcobalamin slowed ALSFRS-R decline by 1.97 points over 16 weeks, with similar adverse events. It does not show that oral methylcobalamin beats cyanocobalamin.

In a phase 3 double-blind trial in Japan, 130 patients with ALS within 1 year of onset received intramuscular methylcobalamin 50 mg or placebo twice weekly for 16 weeks. ALSFRS-R decline was 1.97 points smaller on methylcobalamin (-2.66 versus -4.63; 95% CI 0.44 to 3.50), with similar adverse events.

This is a pharmacologic dose given by injection in a narrow ALS population. It is not evidence that oral methylcobalamin outperforms cyanocobalamin. Regulatory follow-up to the trial outside the United States is not covered here.

ALS phase 3: 130 patients, 16 weeks, injected methylcobalamin slowed decline

Randomized controlled trial

Oki R et al. JAMA Neurol. 2022;79(6):575-583. PMID 35532908.

ALSFRS-R decline was 1.97 points smaller on methylcobalamin (-2.66 versus -4.63; 95% CI 0.44 to 3.50), with similar adverse events.

Participants / model
130 patients with ALS within 1 year of onset in Japan
Treatment
Intramuscular methylcobalamin 50 mg or placebo, twice weekly
Follow-up
16 weeks
Study design
Phase 3 double-blind randomized trial
Funding
not stated in the source

A pharmacologic dose given by injection in a narrow ALS population; it is not evidence that oral methylcobalamin outperforms cyanocobalamin.

Read the original source

What warnings and side effects are reported?

The cyanocobalamin injection label warns of optic atrophy in early Leber's disease, hypokalemia and sudden death with intense treatment of severe megaloblastic anemia, and anaphylaxis. No serious adverse events were reported in the neuropathy meta-analysis.

No FDA label for methylcobalamin was located. The cyanocobalamin injection label warns of severe and swift optic atrophy in patients with early Leber's disease treated with cyanocobalamin, hypokalemia and sudden death with intense treatment of severe megaloblastic anemia, and anaphylaxis after parenteral B12.

No serious adverse events were reported in the neuropathy meta-analysis, and adverse events were similar between methylcobalamin and placebo in the phase 3 ALS trial. The other sources reviewed do not give adverse-event rates for methylcobalamin supplements, so those rates are not established here.

Cyanocobalamin injection label, version effective 6 August 2026: indication, absorption, warnings

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Cyanocobalamin injection, for intramuscular or subcutaneous use, prescribing information, label version effective 6 August 2026. Set ID b1e35c97-2157-454e-967f-53a4300827de.

The label approves cyanocobalamin injection for vitamin B12 deficiency due to malabsorption, including pernicious anemia, gastrointestinal pathology or surgery, fish tapeworm, pancreatic or bowel malignancy, and folic acid deficiency. It calls cyanocobalamin the most widely used form of B12, with hematopoietic activity apparently identical to the antianemia factor in liver extract, and says hydroxocobalamin is equally effective. About 1% of an oral dose is absorbed by passive diffusion, adequate only with very large doses, and oral absorption is called too undependable to rely on in pernicious anemia. Warnings include severe and swift optic atrophy in patients with early Leber's disease treated with cyanocobalamin, hypokalemia and sudden death with intense treatment of severe megaloblastic anemia, and anaphylaxis after parenteral B12.

Participants / model
Patients with B12 deficiency from malabsorption
Treatment
Cyanocobalamin injection, intramuscular or subcutaneous
Follow-up
Label version effective 6 August 2026
Study design
FDA prescribing information
Funding
not stated in the source

This is a cyanocobalamin label. It does not cover methylcobalamin, and this page gives no regimen from it.

Read the original source
Neuropathy meta-analysis: 15 trials, 1707 patients, efficacy rate up, pain and symptom scores not

Systematic review and meta-analysis

Sawangjit R et al. J Altern Complement Med. 2020;26(12):1117-1129. PMID 32716261.

Mecobalamin alone (RR 1.17, 95% CI 1.03 to 1.33) and in combination (RR 1.32, 95% CI 1.21 to 1.45) improved the share of patients with clinical therapeutic efficacy versus active controls, but neither improved pain or neuropathic symptom scores. Nerve conduction improved only with combinations. No serious adverse events were reported. The abstract does not name cyanocobalamin as a comparator.

Participants / model
1707 patients with diabetic or herpetic peripheral neuropathy across 15 randomized trials (11 of 15 at high risk of bias)
Treatment
Mecobalamin alone or combined, versus active control
Follow-up
Varied by included trial
Study design
Systematic review and meta-analysis of 15 randomized trials
Funding
not stated in the source

Most included trials were at high risk of bias, and cyanocobalamin was not named as a comparator.

Read the original source
ALS phase 3: 130 patients, 16 weeks, injected methylcobalamin slowed decline

Randomized controlled trial

Oki R et al. JAMA Neurol. 2022;79(6):575-583. PMID 35532908.

ALSFRS-R decline was 1.97 points smaller on methylcobalamin (-2.66 versus -4.63; 95% CI 0.44 to 3.50), with similar adverse events.

Participants / model
130 patients with ALS within 1 year of onset in Japan
Treatment
Intramuscular methylcobalamin 50 mg or placebo, twice weekly
Follow-up
16 weeks
Study design
Phase 3 double-blind randomized trial
Funding
not stated in the source

A pharmacologic dose given by injection in a narrow ALS population; it is not evidence that oral methylcobalamin outperforms cyanocobalamin.

Read the original source

Why does methylcobalamin sit in B tier?

Methylcobalamin works as a B12 source, and very high injected doses slowed decline in early ALS in one trial. It has no FDA approval and the superiority claim is not supported.

The B reflects the compound as a B12 source. In three pediatric comparisons it raised serum B12 about as well as oral or injected cyanocobalamin, and one phase 3 trial found that very high injected doses slowed functional decline in early ALS. It has no FDA approval, the neuropathy trials are mostly at high risk of bias, and the comparative evidence is observational and in children.

The supplier's active-form superiority claim is not supported. The records reviewed contain one small randomized head-to-head study, in healthy adults with sleep endpoints, and cell and biochemical work shows the cell removes the methyl group and rebuilds both coenzymes from the same intermediate it makes from cyanocobalamin.

Retrospective: 129 children aged 5 to 18 in Turkey, all three routes raised B12

Human study

Tuğba-Kartal A et al. Rev Invest Clin. 2020;72(6):380-385. PMID 33053572.

Intramuscular cyanocobalamin, sublingual cyanocobalamin and sublingual methylcobalamin all raised serum B12 significantly. The abstract reports a between-group difference without saying which group was higher. The authors concluded both sublingual forms were as effective as intramuscular cyanocobalamin for serum B12 and hematologic abnormalities.

Participants / model
129 children aged 5 to 18 with B12 deficiency (serum B12 200 pg/mL or less) in Turkey
Treatment
Intramuscular cyanocobalamin; sublingual cyanocobalamin; sublingual methylcobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized. The direction of the between-group difference is not stated in the abstract.

Read the original source
Retrospective: 158 children aged 0 to 3 in Turkey, methylcobalamin matched both cyanocobalamin routes

Human study

Orhan Kiliç B et al. Hematology. 2021;26(1):1013-1017. PMID 34871525.

Oral cyanocobalamin, sublingual methylcobalamin and intramuscular cyanocobalamin each raised mean B12 above 300 ng/L. The authors judged sublingual methylcobalamin as effective as both cyanocobalamin routes.

Participants / model
158 children aged 0 to 3 with serum B12 under 300 ng/L in Turkey
Treatment
Oral cyanocobalamin; sublingual methylcobalamin; intramuscular cyanocobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized.

Read the original source
Nonrandomized: 312 children in Turkey, no significant difference at 1.5 and 3 months

Human study

Aydin S et al. Children (Basel). 2025;12(4). PMID 40310078.

Median B12 went from 177 to 447 ng/L at 1.5 months and 321.5 ng/L at 3 months on cyanocobalamin, versus 172 to 438 and 360 ng/L on methylcobalamin, with no significant between-group differences. Groups were assigned by treatment type, not randomized, and 18% of the methylcobalamin group were under cancer treatment.

Participants / model
312 children aged 0.1 to 17 with serum B12 under 250 ng/L in Turkey (29 given intramuscular cyanocobalamin, 283 given sublingual methylcobalamin spray)
Treatment
Intramuscular cyanocobalamin versus sublingual methylcobalamin spray at age-based doses
Follow-up
1.5 and 3 months
Study design
Nonrandomized observational comparison
Funding
not stated in the source

Groups were assigned by treatment type, not randomized, and the methylcobalamin group included children under cancer treatment.

Read the original source
ALS phase 3: 130 patients, 16 weeks, injected methylcobalamin slowed decline

Randomized controlled trial

Oki R et al. JAMA Neurol. 2022;79(6):575-583. PMID 35532908.

ALSFRS-R decline was 1.97 points smaller on methylcobalamin (-2.66 versus -4.63; 95% CI 0.44 to 3.50), with similar adverse events.

Participants / model
130 patients with ALS within 1 year of onset in Japan
Treatment
Intramuscular methylcobalamin 50 mg or placebo, twice weekly
Follow-up
16 weeks
Study design
Phase 3 double-blind randomized trial
Funding
not stated in the source

A pharmacologic dose given by injection in a narrow ALS population; it is not evidence that oral methylcobalamin outperforms cyanocobalamin.

Read the original source
Neuropathy meta-analysis: 15 trials, 1707 patients, efficacy rate up, pain and symptom scores not

Systematic review and meta-analysis

Sawangjit R et al. J Altern Complement Med. 2020;26(12):1117-1129. PMID 32716261.

Mecobalamin alone (RR 1.17, 95% CI 1.03 to 1.33) and in combination (RR 1.32, 95% CI 1.21 to 1.45) improved the share of patients with clinical therapeutic efficacy versus active controls, but neither improved pain or neuropathic symptom scores. Nerve conduction improved only with combinations. No serious adverse events were reported. The abstract does not name cyanocobalamin as a comparator.

Participants / model
1707 patients with diabetic or herpetic peripheral neuropathy across 15 randomized trials (11 of 15 at high risk of bias)
Treatment
Mecobalamin alone or combined, versus active control
Follow-up
Varied by included trial
Study design
Systematic review and meta-analysis of 15 randomized trials
Funding
not stated in the source

Most included trials were at high risk of bias, and cyanocobalamin was not named as a comparator.

Read the original source
PubMed search, 9 October 2026: 15 records, one randomized head-to-head study

PubMed search record

PubMed search run on 9 October 2026: (methylcobalamin[tiab] OR mecobalamin[tiab]) AND cyanocobalamin[tiab] AND (randomized controlled trial[pt] OR randomized[tiab] OR randomised[tiab] OR trial[tiab]). 15 records returned. A broader title and abstract search for comparison terms returned 53 records.

The search returned 15 records. One was a randomized head-to-head comparison (20 healthy adults, sleep endpoints); the others were reviews, isotope-absorption studies using cyanocobalamin alone, and diet or single-arm studies. A broader title and abstract search for comparison terms (53 records) added the pediatric observational comparisons and no other randomized comparison. No randomized trial in the records reviewed compared the two forms for correcting deficiency or for clinical outcomes in adults. A ClinicalTrials.gov query for the two names showed no head-to-head trial among the first 20 records.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source
Biochemistry review: all supplement forms share one intracellular route

Narrative review

Obeid R et al. Mol Nutr Food Res. 2015;59(7):1364-72. PMID 25820384.

The review states that transport proteins bind and take up all the supplement forms, and that inside the cell the chaperone MMACHC decyanates cyanocobalamin and dealkylates methylcobalamin and adenosylcobalamin to a reduced cobalamin intermediate, from which both coenzymes are then made. The authors conclude methylcobalamin and adenosylcobalamin follow the same intracellular route as cyanocobalamin and that supplementing them is unlikely to be advantageous, while high parenteral hydroxocobalamin has advantages in inborn errors of cobalamin metabolism.

Participants / model
Not a clinical population
Treatment
Not applicable
Follow-up
Not applicable
Study design
Narrative review of cobalamin biochemistry
Funding
not stated in the source

A biochemistry review, not a clinical comparison.

Read the original source
openFDA query, 9 October 2026: no methylcobalamin application

Regulatory record

U.S. Food and Drug Administration. openFDA Drugs@FDA query for methylcobalamin or mecobalamin (brand, generic and active-ingredient fields), run on 9 October 2026.

The query returned no application, so no FDA-approved methylcobalamin drug was located. The same database lists cyanocobalamin products, including NASCOBAL nasal spray (NDA 021642, original approval 31 January 2005) and a cyanocobalamin ANDA approved 26 April 1972 (ANDA 080737).

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name query
Follow-up
Query run on 9 October 2026
Study design
Dated US approval-record query
Funding
not stated in the source

A negative query on one date is not proof about every product or jurisdiction. US supplement status for methylcobalamin is not established here.

Read the original source

Studies and sources

PubChem: methylcobalamin and cyanocobalamin identity

Chemical identity record

National Library of Medicine. PubChem compound records CID 10898559 (methylcobalamin, mecobalamin) and CID 165339223 (cyanocobalamin, vitamin B12).

Methylcobalamin (mecobalamin): C63H91CoN13O14P, 1344.4 g/mol, CAS 13422-55-4. PubChem holds several other methylcobalamin records with the same formula and CAS that differ in stereo descriptors, so the CID used here is 10898559. Cyanocobalamin (vitamin B12): CID 165339223, C63H88CoN14O14P, 1355.4 g/mol, CAS 68-19-9. PubChem names both on the same cobalamin core, with a methyl (carbanide) ligand in one and a cyanide ligand in the other.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecules
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
openFDA query, 9 October 2026: no methylcobalamin application

Regulatory record

U.S. Food and Drug Administration. openFDA Drugs@FDA query for methylcobalamin or mecobalamin (brand, generic and active-ingredient fields), run on 9 October 2026.

The query returned no application, so no FDA-approved methylcobalamin drug was located. The same database lists cyanocobalamin products, including NASCOBAL nasal spray (NDA 021642, original approval 31 January 2005) and a cyanocobalamin ANDA approved 26 April 1972 (ANDA 080737).

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name query
Follow-up
Query run on 9 October 2026
Study design
Dated US approval-record query
Funding
not stated in the source

A negative query on one date is not proof about every product or jurisdiction. US supplement status for methylcobalamin is not established here.

Read the original source
Cyanocobalamin injection label, version effective 6 August 2026: indication, absorption, warnings

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Cyanocobalamin injection, for intramuscular or subcutaneous use, prescribing information, label version effective 6 August 2026. Set ID b1e35c97-2157-454e-967f-53a4300827de.

The label approves cyanocobalamin injection for vitamin B12 deficiency due to malabsorption, including pernicious anemia, gastrointestinal pathology or surgery, fish tapeworm, pancreatic or bowel malignancy, and folic acid deficiency. It calls cyanocobalamin the most widely used form of B12, with hematopoietic activity apparently identical to the antianemia factor in liver extract, and says hydroxocobalamin is equally effective. About 1% of an oral dose is absorbed by passive diffusion, adequate only with very large doses, and oral absorption is called too undependable to rely on in pernicious anemia. Warnings include severe and swift optic atrophy in patients with early Leber's disease treated with cyanocobalamin, hypokalemia and sudden death with intense treatment of severe megaloblastic anemia, and anaphylaxis after parenteral B12.

Participants / model
Patients with B12 deficiency from malabsorption
Treatment
Cyanocobalamin injection, intramuscular or subcutaneous
Follow-up
Label version effective 6 August 2026
Study design
FDA prescribing information
Funding
not stated in the source

This is a cyanocobalamin label. It does not cover methylcobalamin, and this page gives no regimen from it.

Read the original source
Biochemistry review: all supplement forms share one intracellular route

Narrative review

Obeid R et al. Mol Nutr Food Res. 2015;59(7):1364-72. PMID 25820384.

The review states that transport proteins bind and take up all the supplement forms, and that inside the cell the chaperone MMACHC decyanates cyanocobalamin and dealkylates methylcobalamin and adenosylcobalamin to a reduced cobalamin intermediate, from which both coenzymes are then made. The authors conclude methylcobalamin and adenosylcobalamin follow the same intracellular route as cyanocobalamin and that supplementing them is unlikely to be advantageous, while high parenteral hydroxocobalamin has advantages in inborn errors of cobalamin metabolism.

Participants / model
Not a clinical population
Treatment
Not applicable
Follow-up
Not applicable
Study design
Narrative review of cobalamin biochemistry
Funding
not stated in the source

A biochemistry review, not a clinical comparison.

Read the original source
Cell study: both coenzymes made from alkylcobalamins; cblC cells fail to convert

Cell study

Hannibal L et al. Mol Genet Metab. 2009;97(4):260-6. PMID 19447654.

In cultured cells, adenosylcobalamin was converted to methylcobalamin, and labeled straight-chain alkylcobalamins served as substrates for making both coenzymes. Normal skin fibroblasts converted propylcobalamin to both coenzymes, while fibroblasts from 3 patients with MMACHC mutations showed little or no conversion. The authors conclude the cblC protein handles early processing of both cyanocobalamin (decyanation) and alkylcobalamins such as methylcobalamin (dealkylation).

Participants / model
Cultured bovine aortic endothelial cells; human fibroblasts from healthy donors and 3 patients with cblC mutations
Treatment
In vitro 57Co-labeled cobalamins
Follow-up
not stated in the source
Study design
Cell study
Funding
not stated in the source

A cell study; it does not measure clinical outcomes.

Read the original source
Review favoring natural forms: mixed conclusion on bioavailability

Narrative review

Paul C et al. Integr Med (Encinitas). 2017;16(1):42-49. PMID 28223907.

The review states that all supplemental and food B12 forms are reduced to a core cobalamin that is converted to methylcobalamin and adenosylcobalamin in a ratio not influenced by the form ingested, and that the methyl and adenosyl groups of supplements are cleaved inside cells. Its conclusion is internally mixed: it recommends the natural forms over cyanocobalamin, citing superior bioavailability and safety, while also saying that for most people all forms likely have similar bioavailability and effects.

Participants / model
Not a clinical population
Treatment
Not applicable
Follow-up
Not applicable
Study design
Literature review
Funding
not stated in the source

One author is listed as chief medical officer of Designs for Health, Inc.

Read the original source
Only randomized head-to-head: 20 healthy adults, sleep and circadian endpoints

Randomized controlled trial

Mayer G et al. Neuropsychopharmacology. 1996;15(5):456-64. PMID 8914118.

B12 levels rose quickly in the first week on cyanocobalamin and linearly on methylcobalamin. Both forms lowered urinary melatonin-metabolite excretion and increased night-time activity. Sleep time fell only on methylcobalamin, which the authors read as an alerting effect.

Participants / model
20 healthy adults (6 women, 14 men)
Treatment
3 mg/day of cyanocobalamin or methylcobalamin; route not stated in the abstract
Follow-up
14 days
Study design
Randomized head-to-head study
Funding
not stated in the source

A preliminary study with sleep and circadian endpoints, not a deficiency trial.

Read the original source
Retrospective: 129 children aged 5 to 18 in Turkey, all three routes raised B12

Human study

Tuğba-Kartal A et al. Rev Invest Clin. 2020;72(6):380-385. PMID 33053572.

Intramuscular cyanocobalamin, sublingual cyanocobalamin and sublingual methylcobalamin all raised serum B12 significantly. The abstract reports a between-group difference without saying which group was higher. The authors concluded both sublingual forms were as effective as intramuscular cyanocobalamin for serum B12 and hematologic abnormalities.

Participants / model
129 children aged 5 to 18 with B12 deficiency (serum B12 200 pg/mL or less) in Turkey
Treatment
Intramuscular cyanocobalamin; sublingual cyanocobalamin; sublingual methylcobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized. The direction of the between-group difference is not stated in the abstract.

Read the original source
Retrospective: 158 children aged 0 to 3 in Turkey, methylcobalamin matched both cyanocobalamin routes

Human study

Orhan Kiliç B et al. Hematology. 2021;26(1):1013-1017. PMID 34871525.

Oral cyanocobalamin, sublingual methylcobalamin and intramuscular cyanocobalamin each raised mean B12 above 300 ng/L. The authors judged sublingual methylcobalamin as effective as both cyanocobalamin routes.

Participants / model
158 children aged 0 to 3 with serum B12 under 300 ng/L in Turkey
Treatment
Oral cyanocobalamin; sublingual methylcobalamin; intramuscular cyanocobalamin
Follow-up
not stated in the source
Study design
Retrospective observational comparison
Funding
not stated in the source

Groups were not randomized.

Read the original source
Nonrandomized: 312 children in Turkey, no significant difference at 1.5 and 3 months

Human study

Aydin S et al. Children (Basel). 2025;12(4). PMID 40310078.

Median B12 went from 177 to 447 ng/L at 1.5 months and 321.5 ng/L at 3 months on cyanocobalamin, versus 172 to 438 and 360 ng/L on methylcobalamin, with no significant between-group differences. Groups were assigned by treatment type, not randomized, and 18% of the methylcobalamin group were under cancer treatment.

Participants / model
312 children aged 0.1 to 17 with serum B12 under 250 ng/L in Turkey (29 given intramuscular cyanocobalamin, 283 given sublingual methylcobalamin spray)
Treatment
Intramuscular cyanocobalamin versus sublingual methylcobalamin spray at age-based doses
Follow-up
1.5 and 3 months
Study design
Nonrandomized observational comparison
Funding
not stated in the source

Groups were assigned by treatment type, not randomized, and the methylcobalamin group included children under cancer treatment.

Read the original source
Neuropathy meta-analysis: 15 trials, 1707 patients, efficacy rate up, pain and symptom scores not

Systematic review and meta-analysis

Sawangjit R et al. J Altern Complement Med. 2020;26(12):1117-1129. PMID 32716261.

Mecobalamin alone (RR 1.17, 95% CI 1.03 to 1.33) and in combination (RR 1.32, 95% CI 1.21 to 1.45) improved the share of patients with clinical therapeutic efficacy versus active controls, but neither improved pain or neuropathic symptom scores. Nerve conduction improved only with combinations. No serious adverse events were reported. The abstract does not name cyanocobalamin as a comparator.

Participants / model
1707 patients with diabetic or herpetic peripheral neuropathy across 15 randomized trials (11 of 15 at high risk of bias)
Treatment
Mecobalamin alone or combined, versus active control
Follow-up
Varied by included trial
Study design
Systematic review and meta-analysis of 15 randomized trials
Funding
not stated in the source

Most included trials were at high risk of bias, and cyanocobalamin was not named as a comparator.

Read the original source
ALS phase 3: 130 patients, 16 weeks, injected methylcobalamin slowed decline

Randomized controlled trial

Oki R et al. JAMA Neurol. 2022;79(6):575-583. PMID 35532908.

ALSFRS-R decline was 1.97 points smaller on methylcobalamin (-2.66 versus -4.63; 95% CI 0.44 to 3.50), with similar adverse events.

Participants / model
130 patients with ALS within 1 year of onset in Japan
Treatment
Intramuscular methylcobalamin 50 mg or placebo, twice weekly
Follow-up
16 weeks
Study design
Phase 3 double-blind randomized trial
Funding
not stated in the source

A pharmacologic dose given by injection in a narrow ALS population; it is not evidence that oral methylcobalamin outperforms cyanocobalamin.

Read the original source

Why is Methylcobalamin in B tier?

B fits a compound that works as a source of vitamin B12 and has one positive injected-dose ALS trial, but has no FDA approval, mostly high-risk-of-bias neuropathy trials, and comparative evidence that is observational and in children. The grade reflects it as a B12 source, not the claim that it is superior.