Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression

Abstract

Vitamin B12 is often used to improve cognitive function, depressive symptoms, and fatigue. In most cases, such complaints are not associated with overt vitamin B12 deficiency or advanced neurological disorders and the effectiveness of vitamin B12 supplementation in such cases is uncertain. The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) is to assess the effects of vitamin B12 alone (B12 alone), in addition to vitamin B12 and folic acid with or without vitamin B6 (B complex) on cognitive function, depressive symptoms, and idiopathic fatigue in patients without advanced neurological disorders or overt vitamin B12 deficiency. Medline, Embase, PsycInfo, Cochrane Library, and Scopus were searched. A total of 16 RCTs with 6276 participants were included. Regarding cognitive function outcomes, we found no evidence for an effect of B12 alone or B complex supplementation on any subdomain of cognitive function outcomes. Further, meta-regression showed no significant associations of treatment effects with any of the potential predictors. We also found no overall effect of vitamin supplementation on measures of depression. Further, only one study reported effects on idiopathic fatigue, and therefore, no analysis was possible. Vitamin B12 supplementation is likely ineffective for improving cognitive function and depressive symptoms in patients without advanced neurological disorders.

Keywords: RCT; cognitive function; depressive symptoms; fatigue; meta-analysis; vitamin B12.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. * ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), EU Clinical Trial Register, and ISRCTN registry.

Figure 2

Forest plot for effects on cognitive executive function. CDT: Clock Drawing Test; CFT: Category Fluency Test; COWAT: Controlled Oral Word Association Test; SCWT: Stroop Color–Word Test; SCWT-A: Stroop Color–Word Test Abridged; VFT: Verbal Fluency Test; WAIS: Similarities Wechsler Adult Intelligence Scale.

Figure 3

Forest plot for effects on cognitive memory function. AVLT: Auditory Verbal Learning Test; CPAL: Continuous Paired Associates Learning; CVLT: California Verbal Learning Test; DCT: Digit Cancellation Test; ISLT: International Shopping List Test; RAVLT: Rey Auditory Verbal Learning Test; TICS-M: Telephone Interview for Cognitive Status Modified.

Figure 4

Forest plot for effects on depressive symptoms. † with antidepressant; †† without antidepressant. BDI: Beck Depression Inventory; HDRS: Hamilton Depression Rating Scale; K10: Kessler Psychological Distress Scale; MDI: Major Depression Inventory; MCS: PHQ-9: Patient Health Questionnaire 9.