The Toxic Legacy of Recreational Nitrous Oxide Use: A Systematic Review and Meta-Analysis of Multisystem Complications From Functional Vitamin B12 Deficiency

Background and Purpose: Recreational nitrous oxide (N 2 O) use has increased globally and is increasingly associated with functional vitamin B12 deficiency leading to neurological, hematologic, and systemic complications. This review aimed to synthesize published evidence to characterize the spectrum of clinical and biochemical findings and clarify diagnostic limitations in N 2 O-related B12 dysfunction. Experimental Approach: A systematic review and meta-analysis were conducted of PubMed and Embase databases using the terms “nitrous oxide” and “B12.” Eligible studies included human case reports and series describing N 2 O-associated vitamin B12 deficiency. Data on demographics, exposure duration, clinical features, laboratory values, imaging, and electrophysiology were extracted and analyzed for frequency and pattern of abnormalities. Key Results: A total of 1,809 patients were identified from 257 studies. Neurological symptoms, particularly paresthesias and gait disturbances, were most frequent. Elevated methylmalonic acid (MMA) and homocysteine were observed in 68–85% of patients, often despite normal serum B12 or hematologic indices. MRI and nerve conduction studies commonly revealed abnormalities even when hemoglobin and MCV were normal, highlighting under-recognition of functional deficiency. Conclusion and Implications: Nitrous oxide–induced B12 deficiency predominantly manifests as a functional disorder detectable by MMA and homocysteine rather than serum B12 alone. Clinicians should maintain high suspicion in patients with neurological symptoms, regardless of hematologic results. These findings underscore the need for early recognition and testing to prevent irreversible neurotoxicity amid rising recreational N 2 O use.