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Question
What does the medical literature state about the effectiveness of vitamin B12 for the treatment of fatigue in patients without vitamin B12 deficiency?

Response from Julie M. Sease, PharmD, BCPS, CDE Clinical Assistant Professor, Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, Columbia, South Carolina; Clinical Pharmacy Specialist, William Jennings Bryan Dorn VA Medical Center, Columbia, South Carolina

A Google search using the terms "fatigue" and "vitamin B12" (cyanocobalamin) generates about 439,000 results. Many of these are links to alternative or complementary medicine Web sites that suggest cyanocobalamin as a treatment for fatigue and tiredness. It is no wonder, then, that patients present to their doctors' offices or pharmacies requesting vitamin B12 and further information about the usefulness of this vitamin for fatigue.

Vitamin B12 is usually supplied as either hydroxycobalamin (preferred in parts of Europe) or cyanocobalamin (used most frequently in the United States).^[1] Cyanocobalamin maintenance therapy is often administered orally at 1000 mcg daily or intramuscularly (IM) at 1000 mcg monthly. There is evidence that patients have been prescribed vitamin B12 injections without documented B12 deficiency,^[2] and the likelihood of a physician treating a patient without assessing for B12 deficiency seems to increase with the patient's age. So, what is the clinical trial evidence to support the use of vitamin B12 for fatigue in the absence of vitamin B12 deficiency?

Claims that vitamin B12 supplementation improves well-being in patients who are not deficient in the vitamin can be found in the literature dating as far back as 1952.^[3] It was not until 1973, however, that a controlled trial evaluating this claim was published.^[4] In this small study, 29 subjects with a normal baseline vitamin B12 level were enrolled into a crossover within-subject study. Subjects were randomized to receive either hydroxycobalamin 5 mg by IM injection twice weekly or matching placebo for 2 consecutive weeks. After a 2-week washout period, each subject received the opposite treatment for the remaining 2 weeks of the 6-week trial. Response was determined using self-assessment cards with questions about appetite, general feeling of well-being, mood, fatigue, sleep, and the effect of injections. If the score was higher for an item while the patient was receiving hydroxycobalamin, it was determined that the patient preferred hydroxycobalamin. The converse was true for placebo.

Compared with patients who received placebo initially, patients who received hydroxycobalamin during the initial 2 weeks of the study had higher placebo preference scores or were less able to detect any difference during crossover to placebo. The authors speculated that treatment response to hydroxycobalamin lasted longer than the 2-week washout period. As a result, only data from the 14 subjects who received hydroxycobalamin first were analyzed further.

These subjects favored hydroxycobalamin over placebo (12 vs 2; P = .006) when rating general well-being. Subjects also favored hydroxycobalamin over placebo when rating happiness (9 vs 2; 3 subjects reported no difference; P = .032). No statistically significant differences were found in patient preferences between placebo and hydroxycobalamin for ratings of appetite, injection effect, or sleep. Likewise, no statistically significant differences were found in preferences for hydroxycobalamin or placebo when subjects were asked to rate their level of fatigue (P = .09).

One "n of 1" trial has been published evaluating the use of cyanocobalamin in the treatment of chronic fatigue syndrome.^[5] A 45-year-old woman received 3000 mcg vitamin B12 or matching placebo IM twice weekly over 1.5 weeks for 4 periods each. Crossover between drug and placebo occurred after each treatment period. Symptom scales ranging from 1-10 for energy, sleep, and "mental fog" were used to evaluate response. Cognitive impairment was also evaluated with the Mini-Mental State Examination (MMSE). No significant difference was found in the MMSE results or in the patient's report of energy level, sleep, or "mental fog" between treatment with vitamin B12 and treatment with placebo.

A double-blind, placebo-controlled, crossover trial evaluated a related medication, a liver extract-folic acid-cyanocobalamin combination, vs placebo for chronic fatigue syndrome.^[6] Fifteen patients who met the Centers for Disease Control criteria for chronic fatigue syndrome were enrolled. Vitamin B12 was provided to these patients in daily combined IM injections containing 20 mcg bovine liver extract, 0.8 mg folic acid, and 200 mcg cyanocobalamin. The placebo effect appeared to be strong in this particular study and no significant difference was found between the placebo and the study drug.

In conclusion, there is little available information about the use of vitamin B12 to treat fatigue in patients without vitamin B12 deficiency. Dosing regimens have been inconsistent among published studies. The results of the few and very small clinical trials evaluating vitamin B12 for fatigue do not support the claim that it will improve fatigue symptoms. Further investigation and proof of benefit are needed before we can recommend vitamin B12 for treatment of fatigue.