Each review contains information about the ingredient’s clinical applications, formulations, dosing & administration, adverse effects, and pharmacokinetics. Learn more about our critical appraisal research or contact us for initial guidance and more information.

Vitamin B12

Vitamin B12 is an essential water-soluble nutrient that can be converted to the active coenzymes, methylcobalamin and adenosylcobalamin. It is also a cofactor for methionine synthase and l-methylmalonyl-CoA mutase, which synthesize methionine from homocysteine, and convert methylmalonyl coenzyme A to succinyl coenzyme A, respectively. It is crucial for the formation of DNA and red blood cells, and proper neurological function. (16)(18)(34)

Main uses

Anemias
Autoimmune conditions (Celiac’s disease)
B12 deficiency prevention
Homocysteine management
Neurological conditions
Neuropathy and pain-related conditions

Formulations

Form	Bioavailability
Intranasal	2-5% bioavailability (1,000 μg hydroxocobalamin) compared to intramuscular administration but retention is 50% higher (29)(31) 10-20x higher plasma B12 with nasal hydroxocobalamin (750-1,500 μg) than oral administration (31)
Oral	2% bioavailability, 5% bioavailability (5,000 μg cyanocobalamin) in formulation with the addition of SNAC at compared to intravenous administration (6) Equivalent retention between forms of varying doses of cyanocobalamin, methylcobalamin, & hydroxocobalamin (1, 5, & 25 μg) (1)
Parenteral	B12 increased more in hydroxocobalamin (500-1,000 μg) than cyanocobalamin via 33-44% higher relative retention (12)
Sublingual	Equal increase in serum cobalamin to the oral group (500 μg cyanocobalamin) (25)

Dosing & administration

Autism spectrum disorder
General outcomes from A-level evidence	No data currently available.
Dosing & administration	75 μg/kg subcutaneous injection every 3 days (methylcobalamin) for 8 weeks
Outcomes	↓ Clinical Global Impressions-Improvement score and was positively correlated with increased plasma methionine, SAM:SAH ratio, & decreased SAH (14)
Class of evidence	B
Dosing & administration	64.5 μg/kg subcutaneous injection every 3 days (methylcobalamin) for 6 weeks
Outcomes	↓ Clinical Global Impression score in 30% of Px ↑ plasma GSH & GSH:GSSG ratio only in responsive subgroup (4)
Class of evidence	C

B12 deficiency
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1000 μg per day
Outcomes	↑ serum and total B12 ↓ methylmalonic acid (MMA) and total homocysteine (15)
Class of evidence	A

B12 deficiency: gastric bypass/bariatric surgery-related
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1,000 μg per day after Roux-en-Y Gastric Bypass
Outcomes	↑ B12 levels (20)
Class of evidence	A
Dosing & administration	350 μg perioperatively in bariatric surgery
Outcomes	↑ B12 levels (27)
Class of evidence	A

B12 deficiency: GI disorder-related
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1000 μg per day for 1 month, then 125-1000 μg ongoing to normalization
Outcomes	↑ serum B12 in deficiencies from food malabsorption (atrophic gastritis, chronic carriage of H. pylori, bacterial overgrowth, long-term antacid use, chronic alcoholism, gastric surgeries, chronic pancreatitis, or Crohn’s disease), vegan/vegetarianism deficiencies (2)
Class of evidence	A

B12 deficiency: pediatric
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1000 μg per day, 4 months
Outcomes	↑ B12 levels in children, but decreases with increased body weight (3)
Class of evidence	A

Celiac’s disease
General outcomes from A-level evidence	No data currently available.
Dosing & administration	0.5 mg (cyanocobalamin) with 0.8 mg folic acid and 3 mg pyridoxine per day for 6 months
Outcomes	↑ well being, anxiety, mood ↓ total homocysteine (13)
Class of evidence	B

Chronic obstructive pulmonary disease
General outcomes from A-level evidence	No data currently available.
Dosing & administration	500 mg per day, 8 weeks
Outcomes	↑ serum B12 and exercise tolerance alone and with exercise compared with exercise and placebo groups (24)
Class of evidence	C

Cognition
General outcomes from A-level evidence	No data currently available.
Dosing & administration	15 μg per day for 5 weeks
Outcomes	↑ memory performance (5)
Class of evidence	B

Diabetic neuropathy
General outcomes from A-level evidence	No data currently available.
Dosing & administration	500 mg three times per day (methylcobalamin) for 4 months
Outcomes	↓ somatic symptoms, autonomic symptoms, & peripheral neuropathy signs score (35)
Class of evidence	B
Dosing & administration	1500 μg per day (methylcobalamin) for 3 months
Outcomes	↑ 2-point discrimination ability, median nerve max motor conduction velocity & scalp somatosensory response ↓ pain & cramps (9)
Class of evidence	C

Fatigue
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg (hydroxocobalamin injections) twice weekly for 2 weeks
Outcomes	↑ appetite, mood, energy, sleep & well-being (11)
Class of evidence	C

Growth
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1.8 μg per day for infants aged 6-11 months; 3.6 μg for older than 12 months for 6 months
Outcomes	↑ weight for age ↑ weight for age & height for age in wasted, underweight, stunted children (28)
Class of evidence	B

Hyperhomocysteinemia
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2-10 μg per day (cyanocobalamin), for 4-12 months
Outcomes	↓ total homocysteine (8)
Class of evidence	B
Dosing & administration	1000 μg every other day (methylcobalamin) for 16 weeks, vegetarians
Outcomes	↓ total plasma homocysteine (22)
Class of evidence	C

Multiple sclerosis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1000 μg per week (intramuscular) for 24 weeks
Outcomes	↓ Guy’s Neurological Disability Scale (33)
Class of evidence	B

Pernicious anemia
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1000 μg per day, ongoing
Outcomes	↓ B12 levels (2)(7)
Class of evidence	A

Recurrent aphthous stomatitis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1000 μg per day, 6 months
Outcomes	↓ duration, number and pain of canker sores (32)
Class of evidence	B

Adverse effects

Adverse effects from B12 intake and supplementation are atypical. (16) Intravenous administration may produce reddening of the skin, pustular/papular rash, headaches, erythema at the injection site, decrease in lymphocyte percentage, nausea, pruritus, chest discomfort, dysphagia, and increased blood pressure in some volunteers. (30)

Pharmacokinetics

Absorption

Oral absorption is low. Total B12 absorption increases with increasing doses, but relative absorption decreases (eg. absorption of 50% of 1 μg, 20% of 5 μg, 5% of 25 μg, and 1% 500 μg). Small amounts absorbed are often sufficient to meet the recommended daily allowance.
B12 bound to proteins in food are uncoupled by stomach acid and pepsin to allow for binding to R proteins. B12 supplements are not bound to proteins and thus more available for R protein binding for gastric transport.
Upon contact with pancreatic proteases, B12 is released from R proteins, and small amounts of free B12 in high concentrations can be absorbed through passive diffusion in the small intestine. In low concentrations, the majority of B12 binds to intrinsic factor allowing active transport in the mucosa of the ileum. (23)

Distribution

B12 circulates through the blood after binding to transcobalamin I, II, or III.
Most is bound to transcobalamin I but transcobalamin II is primarily responsible for deposition in most peripheral tissues.
The liver stores 50% of circulating B12 and may hold 2-3 mg. (16)

Metabolism

Upon transport into peripheral tissue cells, lysosomes disassociate B12 from transcobalamin II.
All B12 forms are then reduced in cytosol to the core form, cobalamin.
Cobalamin is either methylated to the active cofactor, methylcobalamin, using 5-MTHF or SAMe, or it can enter the mitochondria to combine with adenosyl from ATP molecules to form the active cofactor, adenosylcobalamin. (23)
Methylcobalamin and vitamin B6 are used to reduce homocysteine and produce methionine, tetrahydrofolate, and subsequently, purines and pyrimidines used in RNA and DNA synthesis. (17)(19)(26)
Adenosylcobalamin is used by methylmalonyl CoA mutase to convert methylmalonyl CoA to Succinyl CoA, which enters the Krebs cycle. (23)

Excretion

B12 is primarily excreted in stool, but can be excreted in urine if blood is saturated. (16)
Between 1.4-5.1 μg are lost each day in healthy and elderly individuals. (10)