Vitamin B12 Deficiency in Neuropsychiatry: Neurobiological Mechanisms, Clinical Manifestations, Diagnostic Challenges, and Therapeutic Implications
Valmin Ramos-Silva
*
Hospital Padre Humberto (MEPES), Anchieta, Espirito Santo, State University of Minas Gerais (UEMG), Divinopolis, Minas Gerais, Brazil.
Inocencia Peralta
Faculty of Medicine, Universidad Central del Paraguay, Ciudad del Este, Paraguay.
Greice Kelly Alves Reis
Postgraduate Program in Pharmaceutical Sciences, Federal University of Sao Joao del-Rei (UFSJ), Sao Joao del-Rei, Brazil.
Thiago Correa Sa Ricardo
Undergraduate Medical Program, Federal University of Sao Joao del-Rei (UFSJ), Sao Joao del-Rei, Brazil.
Mateus Henrique Oliveira Souza
Undergraduate Medical Program, Federal University of Sao Joao del-Rei (UFSJ), Sao Joao del-Rei, Brazil.
Ariselma Magalhaes Peçanha
Hospital Padre Humberto (MEPES), Anchieta, Espirito Santo, Brazil.
Joel Alves Lamounier
Postgraduate Program in Public Health, Federal University of Sao Joao del-Rei (UFSJ), Sao Joao del-Rei, Brazil.
Wendell Costa Bila
Graduate Program in Biosciences and Human Health, State University of Minas Gerais (UEMG), Divinopolis, Minas Gerais, Brazil.
Janine Pereira-Silva
Faculdade de Medicina FAESA, Vitoria, Espirito Santo, Brazil.
*Author to whom correspondence should be addressed.
Abstract
Background: Vitamin B12 (cobalamin) deficiency can affect neurological, cognitive, and psychiatric function, yet interpretation is complicated by variation in biomarkers, clinical phenotypes, and the distinction between biochemical and functional deficiency.
Aims: The review aims to critically synthesise current evidence on the relationship between vitamin B12 deficiency or impaired cobalamin status and neuropsychiatric manifestations, with an emphasis on mechanisms, clinical phenotypes, diagnostic biomarkers, and therapeutic implications.
Study Design: Critical integrative review with a structured literature search and narrative synthesis.
Methodology: Evidence published from 2 January 2021 to 24 July 2026 was considered. Observational studies, clinical trials, systematic reviews, meta-analyses, and selected case reports or case series were included when relevant to the review objectives. Evidence was interpreted according to study design, population, definition of vitamin B12 status, biomarkers, neuropsychiatric outcomes, and baseline deficiency before treatment.
Results: Vitamin B12 deficiency is an established cause of neurological dysfunction and may present with cognitive, affective, behavioural, or psychotic manifestations, sometimes without anaemia or macrocytosis. Observational studies report associations between lower vitamin B12 status and depression, anxiety, psychotic-spectrum disorders, cognitive impairment, and selected neurodevelopmental outcomes; however, causality remains uncertain. Serum vitamin B12 alone may not identify functional deficiency, particularly after nitrous oxide exposure, for which methylmalonic acid and homocysteine may be informative. Replacement of documented deficiency is clinically indicated and may reverse selected manifestations, whereas randomised evidence does not support routine vitamin B12 supplementation for common neuropsychiatric disorders in individuals without established deficiency.
Conclusion: Vitamin B12 should be considered a potentially reversible contributor or modifier in selected neuropsychiatric presentations. Targeted assessment based on clinical phenotype and risk factors is more defensible than indiscriminate screening or supplementation.
Keywords: Vitamin B12, cobalamin deficiency, neuropsychiatry, depression, anxiety, psychosis, cognitive impairment, functional deficiency, methylmalonic acid, nitrous oxide