The Toxic Legacy of Recreational Nitrous Oxide Use: A Systematic Review and Meta-Analysis of Multisystem...

Recreational nitrous oxide (N₂O) use has increased in recent years and is an increasingly recognized cause of functional vitamin B₁₂ deficiency with associated neurological and systemic complications. This systematic review and meta-analysis summarizes published case reports and case series describing the clinical, biochemical, and neurodiagnostic features of N₂O-induced B₁₂ deficiency. A comprehensive literature search of PubMed and Embase using the terms "nitrous oxide" and "B12" identified 458 publications. After exclusion of non-English and inaccessible articles, 257 studies were included, comprising 462 individual case reports and 1,291 patients from aggregated case series. Data extracted included demographics, duration of N₂O exposure, clinical presentation, laboratory values (hemoglobin, mean corpuscular volume (MCV), serum B₁₂, methylmalonic acid (MMA), and homocysteine), and findings from MRI and nerve conduction studies. A total of 1,809 patients were analyzed, including 1,753 with neuropathy and 56 with other presentations such as thrombosis, psychosis, or skin changes. Neurological symptoms were the most common manifestation, with paresthesia reported most frequently. In individual case reports, abnormal results were found in homocysteine (83.0%), MMA (68.4%), MCV (63.0%), serum B₁₂ (55.8%), and hemoglobin (42.3%). Case series showed similar trends, with abnormalities most commonly observed in homocysteine (84.9%) and MMA (83.7%), followed by serum B₁₂ (47.2%), hemoglobin (25.3%), and MCV (20.8%). MMA and homocysteine testing were performed in approximately 40% and 60% of patients, respectively. MRI and nerve conduction studies frequently demonstrated abnormalities even when hemoglobin, MCV, or serum B₁₂ levels were normal. Significant differences in hemoglobin abnormalities and paresthesia presentation were observed between individual case reports and case series (p < 0.001). These findings indicate that N₂O-induced functional B₁₂ deficiency often presents with neurological symptoms without accompanying hematologic abnormalities and that MMA and homocysteine are more sensitive markers than serum B₁₂ alone. Clinicians should consider N₂O exposure and pursue appropriate metabolic testing in symptomatic patients, even in the presence of normal serum B₁₂ or hemoglobin levels.