Addiction Medicine Assistant Program Director Larkin Community Hospital, Florida
Background & Introduction: Non-medical use of nitrous oxide (N₂O) is an emerging substance use disorder driven by legal availability and the perception of low risk. Chronic exposure oxidizes the cobalt ion of vitamin B12, resulting in functional inactivation that can cause hematologic abnormalities, cognitive impairment, ataxia, and potentially irreversible myeloneuropathy. While neurologic complications are well described, early psychiatric and cognitive presentations are frequently underrecognized, and patients often present to psychiatric settings without identification of inhalant exposure. This diagnostic gap is clinically significant, as delayed recognition may result in permanent neurologic injury, whereas early diagnosis can allow for meaningful recovery with cessation and vitamin B12 repletion. The objective of this case is to highlight nitrous oxide use disorder presenting primarily as severe depression with cognitive slowing and ataxia, and to demonstrate that timely recognition can result in rapid and clinically significant neurologic improvement.
Case Description: A 60-year-old male with hypertension, hyperlipidemia, and prior aortic dissection repair presented voluntarily for worsening depression and inability to cope with psychosocial stressors. Urine drug screen was positive only for benzodiazepines, consistent with prescribed alprazolam. He denied alcohol, opioid, stimulant, cannabis, or hallucinogen use.
On further evaluation, the patient disclosed that one month prior he began inhaling nitrous oxide to manage sadness and anxiety. Use rapidly escalated to daily inhalation for up to six hours per day. He described the behavior as compulsive and difficult to control, with only brief relief followed by worsening distress. He reported escalating his use to larger volume commercial tanks containing 2 grams nitrous oxide obtained through non-medical channels, reflecting increasing severity of use and loss of control.
Psychiatric evaluation revealed severe depressive symptoms including anhedonia, hopelessness, guilt, low energy, poor concentration, and psychomotor slowing. Although he denied active suicidal intent, he reported feeling unsafe outside the hospital and was admitted for stabilization.
During the first several days of hospitalization, the patient demonstrated slowed cognitive processing and mild ataxia on examination. Laboratory evaluation revealed borderline low vitamin B12 (214 pg/mL), macrocytosis (mean corpuscular volume 96.4 fL), and mild anemia (red blood cell count 3.87 M/uL), raising concern for nitrous oxide–induced functional B12 deficiency.
Addiction Medicine was consulted and diagnosed inhalant use disorder. The patient received education regarding medical risks, motivational interviewing for cessation, and was started on naltrexone off-label for craving modulation. Intramuscular vitamin B12 replacement was initiated.
Within several days of nitrous oxide cessation and daily B12 injections, the patient demonstrated marked improvement in cognitive processing and resolution of ataxia, supporting a diagnosis of reversible nitrous oxide–associated neurotoxicity. He remained hospitalized for continued psychiatric stabilization and discharge planning.
Conclusion & Discussion: This case illustrates a clinically important and frequently missed presentation of nitrous oxide toxicity, in which depressive symptoms accompanied by cognitive slowing and ataxia reflected functional vitamin B12 deficiency rather than a primary psychiatric disorder alone. Importantly, the patient’s neurologic findings improved rapidly following cessation and vitamin B12 repletion, emphasizing the potential reversibility of symptoms with timely recognition.
Clinicians in psychiatric, emergency, and primary care settings may not routinely screen for inhalant use, contributing to delayed diagnosis. Mood symptoms accompanied by gait disturbance, cognitive slowing, or macrocytosis should prompt targeted assessment for nitrous oxide exposure to prevent progression to irreversible neurologic injury.
A limitation of this case is the absence of confirmatory methylmalonic acid or homocysteine testing to further characterize functional B12 deficiency.
This case underscores the need for increased clinician awareness of inhalant-related neuropsychiatric presentations and highlights the value of Addiction Medicine consultation in complex psychiatric settings.
References: Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review. Am J Addict. 2016;25(5):358–369.
Thompson AG, Leite MI, Lunn MP, Bennett DL. Whippits, nitrous oxide and the dangers of legal highs. Pract Neurol. 2015;15(3):207–209.
Keddie S, Adams A, Kelso ARC, et al. No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation. J Neurol. 2018;265:1089–1095.
Oussalah A, Julien M, Levy J, et al. Global burden related to nitrous oxide exposure in medical and recreational settings: A systematic review. J Clin Med. 2019;8(4):551.
Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet. 1978;2(8085):1227–1230.
Disclosure(s):
Sarina Rouholfada, MD: No financial relationships to disclose
Bledar Haxhiu, MD: No financial relationships to disclose
Learning Objectives:
Recognize psychiatric and neurologic presentations of nitrous oxide–induced functional vitamin B12 deficiency.
Identify clinical and laboratory findings that should prompt evaluation for inhalant exposure.
Understand the potential for neurologic recovery with early cessation and vitamin B12 repletion.
