Abstract: Three RCTs met our inclusion criteria. The trials randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to IM vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 38.6 to 72 years. The treatment frequency and daily dose of vitamin B12 in the oral and IM groups varied among trials. Only one trial had low or unclear risk of bias across all domains and outcome measures. Two trials reported data for serum vitamin B12 levels. The overall quality of evidence for this outcome was low due to serious imprecision (low number of trials and participants). In two trials employing 1000 μg/day oral vitamin B12, there was no clinically relevant difference in vitamin B12 levels when compared with IM vitamin B12. One trial used 2000 μg/day vitamin B12 and demonstrated a mean difference of 680 pg/mL (95% confidence interval 392.7 to 967.3) in favour of oral vitamin B12. Two trials reported data on adverse events (very low-quality evidence due to risk of performance bias, detection bias, and serious imprecision). One trial stated that no treatment-related adverse events were seen in both the oral and IM vitamin B12 groups. One trial reported that 2 of 30 participants (6.7%) in the oral vitamin B12 group left the trial early due to adverse events. Orally taken vitamin B12 showed lower treatment-associated costs than IM vitamin B12 in one trial (low-quality evidence due to serious imprecision). No trial reported on clinical signs and symptoms of vitamin B12 deficiency, health-related quality of life, or acceptability of the treatment scheme. Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less. We found very low-quality evidence that oral vitamin B12 appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12 deficiency, health related-quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting.

Plain-language summary: We found three randomised controlled studies (clinical studies where people are randomly put into one of two or more treatment groups). The studies randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to intramuscular vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 39 to 72 years. Two studies used 1000 μg/day oral vitamin B12 and showed no relevant difference to intramuscularly applied vitamin B12 with regard to vitamin B12 blood levels. One trial used 2000 μg/day vitamin B12 and showed higher vitamin B12 blood levels in favour of oral vitamin B12. Two studies reported side effects. One study stated that no treatment-related side effects were seen in both the oral and intramuscular vitamin B12 groups. One study reported that 2 of 30 participants in the oral vitamin B12 group left the trial early due to side effects. Orally taken vitamin B12 showed lower treatment-associated costs than intramuscular vitamin B12 in one trial. No study reported on clinical signs and symptoms of vitamin B12 deficiency (e.g. fatigue, depression, neurological complications), health-related quality of life, or acceptability of the treatment scheme. The overall quality of the evidence was low or very low, mainly due to the small number of included studies and the low numbers of participants in these studies.