Vitamin B12 deficiency, cobalamin deficiency, affects an estimated 5–20% of the population and can manifest with a spectrum of hematological, neurological, and psychiatric manifestations. As a critical cofactor in DNA synthesis and nervous system function, B12 is indispensable for red blood cell production and neuronal integrity. Deficiency can lead to megaloblastic anemia, neuropathy, cognitive impairment, and psychiatric disturbances, significantly affecting quality of life [1]. Certain populations are at higher risk, including older adults with reduced absorption capacity, vegetarians and vegans, and individuals with food-cobalamin malabsorption or pernicious anemia (Biermer’s disease) [2]. Timely identification and appropriate management are essential to prevent irreversible neurological damage. Traditional supplementation methods, primarily intramuscular cyanocobalamin injections, have been the cornerstone of therapy. However, evolving strategies, including oral, sublingual, intranasal, transdermal, and intradermal routes, offer novel avenues to enhance patient adherence and clinical outcomes [3].

Vitamin B12 deficiency profoundly affects hematopoiesis due to its essential role in DNA synthesis and cell division [1]. The hallmark hematological manifestation is megaloblastic anemia, characterized by macrocytic red blood cells, increased mean corpuscular volume (MCV >100 fL), and hypersegmented neutrophils. Ineffective erythropoiesis leads to intramedullary hemolysis, resulting in elevated lactate dehydrogenase (LDH) and indirect bilirubin levels, decreased haptoglobin levels. Clinically, patients often present with fatigue, pallor, dyspnea on exertion, and tachycardia, reflecting reduced oxygen-carrying capacity [4]. Severe or prolonged deficiency can progress to pancytopenia, involving leukopenia and thrombocytopenia, which increase susceptibility to infections and bleeding tendencies. Pseudo-thrombotic micro-angiopathy is also reported in relation to cobalamin deficiency. Bone marrow examinations typically reveal megaloblastic changes with nuclear-cytoplasmic asynchrony in erythroid precursors. Additional laboratory features may include elevated homocysteine and methylmalonic acid levels, which serve as sensitive markers for B12 deficiency [4]. Prompt recognition and treatment are critical, as sustained deficiency can cause irreversible bone marrow suppression and hematological complications, whereas timely supplementation usually results in rapid hematologic recovery within weeks [4].

The three primary therapeutic forms of vitamin B12—cyanocobalamin, hydroxocobalamin, and methylcobalamin—each possess distinct pharmacokinetic and clinical profiles (Table 1) [1,3]. Cyanocobalamin, the most commonly used synthetic form, is favored for its stability, cost-effectiveness, and widespread availability, and can be administered intramuscularly, orally, or nasally; it is converted in vivo to active forms, methylcobalamin and adenosylcobalamin, although absorption may be suboptimal in patients with gastrointestinal disorders. Hydroxocobalamin, a naturally occurring form, is preferred in severe deficiencies or in individuals with poor oral absorption, providing higher bioavailability and prolonged retention, which allows for fewer injections; it is particularly useful in conditions such as pernicious anemia and Crohn’s disease. Methylcobalamin, the biologically active coenzyme form, bypasses conversion requirements and directly supports neurological repair and function, making it the preferred choice for managing neurological complications such as neuropathy and cognitive deficits, and it can be administered via injection or orally [3].

The choice of vitamin B12 administration route depends on deficiency severity, gastrointestinal absorption, patient preference, and adherence considerations (Table 2) [1,3]. Intramuscular (IM) injections remain the gold standard for severe deficiency or malabsorption, with initial daily doses of 1,000 µg for 1–2 weeks, then 1,000 µg/weekly for 4 weeks, followed by monthly maintenance, providing rapid and reliable restoration of B12 levels, particularly in patients with pernicious anemia. Intravenous (IV) administration is reserved for acute or severe deficiencies, especially when neurological involvement is present, allowing immediate systemic availability [1]. Oral supplementation, typically 1,000–2,000 µg daily, is effective and convenient for patients with intact gastrointestinal function and mild to moderate deficiency [1,3]. Sublingual administration bypasses the digestive tract, offering an effective alternative for malabsorption, with comparable efficacy to oral tablets and improved adherence. Intranasal delivery provides 500–1,000 µg per application once or twice weekly, serving as a non-invasive option for patients with absorption challenges or needle aversion [3]. Transdermal patches, an emerging modality, offer steady, sustained B12 delivery and are particularly promising for long-term supplementation in patients preferring non-invasive therapy. Intradermal injections, still under investigation, appear to offer comparable efficacy to IM injections with improved patient comfort. For patients unable to swallow, gastrostomy tube administration ensures reliable B12 delivery, addressing needs in cases of dysphagia or severe neurological impairment [3].

Treatment regimens vary according to severity (Table 3) [1]. Mild to moderate deficiency typically responds to oral supplementation (250–1,000 µg/day for ≥4 months), whereas severe deficiency requires high-dose IM or IV therapy (1,000 µg/day initially, potentially up to 2,000 µg for neurological symptoms). Long-term maintenance may involve monthly IM or IV injections or daily oral supplementation, depending on absorption capacity and patient preference [1,3].

Special populations require tailored approaches. The elderly may require higher or more frequent dosing due to impaired absorption. Pregnant women need adequate supplementation to support fetal neurodevelopment. Individuals with gastrointestinal disorders, including post-bariatric surgery patients, often require parenteral administration. Vegetarians and vegans typically respond well to oral supplementation but require dietary counseling and monitoring [4].

Allergic reactions to B12 formulations are rare. In cases of hypersensitivity to cyanocobalamin, hydroxocobalamin or methylcobalamin may be used, with alternative routes such as oral, sublingual, or intranasal forms considered to mitigate reaction risk. Pre-treatment with antihistamines or corticosteroids may be appropriate in mild cases under clinical supervision. Non-response or non-compliance should prompt reevaluation of administration routes, dosing schedules, and patient education. Switching to parenteral or alternative non-invasive routes may improve adherence and therapeutic outcomes [3].

Certain populations require tailored approaches to vitamin B12 supplementation. Elderly patients may need higher or more frequent dosing due to impaired absorption, while pregnant women require adequate supplementation to prevent maternal and fetal complications. Vegetarians and vegans generally respond well to oral supplementation, though education on diet and fortified foods is important to maintain sufficient B12 levels. Patients with gastrointestinal disorders, including those who have undergone bariatric surgery or have malabsorption syndromes, often require parenteral therapy to ensure effective correction of deficiency [4].

Vitamin B12 deficiency remains an underdiagnosed condition with significant clinical consequences, particularly in vulnerable populations such as the elderly, pregnant women, and patients with malabsorption syndromes. From a clinical perspective, early recognition of hematological and neurological manifestations is essential to prevent irreversible complications [1,3]. While IM cyanocobalamin remains the gold standard for severe deficiency, emerging routes of administration—including sublingual, intranasal, and transdermal formulations—offer effective, patient-centered alternatives that may improve adherence and quality of life. Oral cobalamin therapy may be discussed in relation to the high frequency of food-cobalamin malabsorption, especially in elderlies (gastric atrophy, Helicobacter pylori infection, proton pump inhibitors, and metformin long-term intake) [5]. Methylcobalamin, given its direct role in neurological repair, should be considered in cases with prominent neuropathic or cognitive deficits [3]. Treatment strategies must be individualized, accounting for absorption capacity, severity of deficiency, and patient preference, while long-term monitoring ensures sustained correction. Overall, integrating novel delivery methods with traditional approaches represents a paradigm shift in optimizing therapy for vitamin B12 deficiency, balancing efficacy, safety, and patient convenience.

Effective management of vitamin B12 deficiency requires an individualized approach considering severity, neurological involvement, and absorption capacity. While traditional IM or IV therapy remains essential for severe cases, emerging routes—sublingual, intranasal, and transdermal—offer promising alternatives that enhance adherence and patient convenience. Tailoring therapy to patient-specific factors, including special populations and comorbidities, ensures optimal clinical outcomes. Ongoing research into novel delivery systems will continue to refine management strategies, ultimately improving patient quality of life and global accessibility to effective B12 therapy.

The authors declare no conflicts of interest related to the content of this editorial.

The authors would like to sincerely thank the clinicians and researchers of the CARE B12 (CAREence en vitamine B12) group at the Hôpitaux Universitaires de Strasbourg (Strasbourg, France) for their invaluable contributions, insights, and support in advancing the understanding and management of vitamin B12 deficiency. Their expertise and dedication have been instrumental in guiding both clinical practice and research initiatives in this field.