Drug-Induced Vitamin B12 Deficiency: Current Evidence, Diagnostic Challenges, and Therapeutic Strategies

Background/Objectives: Drug-associated vitamin B12 deficiency has emerged as a significant concern in clinical nutrition, as long-term use of metformin and proton pump inhibitors (PPIs) is common and may compromise cobalamin status through different physiological mechanisms. This narrative review summarizes mechanisms, risk profiles, diagnostic pitfalls, monitoring strategies and treatment options for vitamin B12 deficiency associated with chronic medication use. Methods: A narrative literature review was conducted by searching major biomedical databases and screening reference lists to identify relevant clinical studies, meta-analyses, narrative and systematic reviews, and clinical practice guidelines on vitamin B12 physiology, drug–nutrient interactions, biomarkers of cobalamin status, and supplementation strategies. Results: Metformin is consistently associated with lower serum vitamin B12 concentrations, particularly with high doses and prolonged exposure; PPIs may reduce the release of food-bound cobalamin through gastric acid suppression. Combined use may increase risk in older adults and in patients with restrictive diets, malabsorption or neurological symptoms. Serum vitamin B12 alone has limited diagnostic accuracy in borderline ranges; methylmalonic acid and homocysteine may help identify functional deficiency. High-dose oral vitamin B12 is effective in most clinical scenarios and may reduce healthcare burden compared with intramuscular therapy. Conclusions: A proactive, risk-based approach to monitoring and treatment may prevent hematological and neurological complications while preserving essential therapies such as metformin.