Efficacy of Sublingual and Oral Vitamin B12 Versus Intramuscular Administration: Insights from a Systematic Review and Meta-Analysis

Marta Mazur^1,2Artnora Ndokaj^1*Claudia Salerno^3,4Jessica Vallone¹Roman Ardan⁵Sabina Bietolini⁶Florence Carrouel⁷Aleksandra Wilk⁸Rachel Sarig⁹Livia Ottolenghi¹Denis Bourgeois⁷

• ¹Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, 00161 Rome, Italy, Rome, Italy
• ²Department of Interdisciplinary Dentistry, Pomeranian Medical University, 70-111 Szczecin, Poland, Szczecin, Poland
• ³Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20112 Milan, Italy, Milan, Italy
• ⁴Department of Restorative, Preventive and Pediatric Dentistry, School of Dental Medicine, University of Bern, 3012 Bern, Switzerland, Bern, Switzerland
• ⁵Department of Economic Sciences, Koszalin University of Technology, 75-343 Koszalin, Poland, Koszalin, Poland
• ⁶Niccolò Cusano University (UNICUSANO), Rome, Italy, Rome, Italy
• ⁷Health Systemic Process Laboratory (P2S), UR4129, University Claude Bernard Lyon 1, University of Lyon, Lyon, France, Lyon, Rhône-Alpes, France
• ⁸Department of Histology and Embryology, Pomeranian Medical University, 70-111 Szczecin, Poland, Szczecin, Poland
• ⁹Department of Oral Biology, Tel Aviv University, 6997801, Tel Aviv, Israel, Tel Aviv, Israel

Background: Vitamin B12 deficiency is a widespread condition, particularly among elderly individuals, patients with malabsorption syndromes, and those following plant-based diets. This systematic review and meta-analysis aimed to evaluate and compare the effectiveness of sublingual and oral vitamin B12 administration in comparison with intramuscular (IM) injections for improving serum cobalamin and reducing homocysteine levels. Methods: A comprehensive search was conducted across PubMed, Scopus, and Embase up to July 2024. Eligible studies included randomized controlled trials, cohort, and case-control studies assessing B12 supplementation efficacy via oral, sublingual, or IM administration. Meta-analyses were performed using random-effects models. Subgroup analyses evaluated four key factors: administration route efficacy, daily dosage, age group and clinical conditions affecting vitamin B12 metabolism. Sixteen studies were included in the quantitative synthesis, comprising 6,098 participants. Results: Vitamin B12 supplementation was associated with a significant increase in serum cobalamin levels across all routes of administration (pooled mean difference = +402.6 pg/mL; 95% CI: 293.6 to 511.5; p < 0.001). Homocysteine levels were also significantly reduced (pooled mean difference = −4.83 µmol/L; 95% CI: −6.55 to −3.11; p < 0.001). No statistically significant differences were observed between oral, sublingual, and intramuscular routes (p = 0.270 for cobalamin and p = 0.485 for homocysteine), nor between randomized controlled trials and observational studies (p = 0.268 for cobalamin). No dose-response effect was found (p = 0.485), suggesting that absorption efficiency rather than dosage may be the determining factor. Subgroup analyses by age and clinical conditions revealed comparable efficacy across populations. However, heterogeneity was substantial (I² > 80% in most comparisons), and Egger's test indicated potential publication bias. Further studies are needed to confirm these results. Conclusion: Sublingual and oral B12 supplementation appear to be as effective as intramuscular injections in improving cobalamin status and reducing homocysteine levels. Given their non-invasive nature, accessibility, and cost-effectiveness, they may represent a promising approach for long-term B12 management, particularly in patients with impaired absorption or in resource-limited settings. Further high-quality RCTs are warranted to refine dosing strategies and confirm long-term outcomes.