Nitrous oxide (N2O), commonly referred to as laughing gas, is a colourless, non-flammable, inorganic volatile with psychedelic effects. It has assorted uses among diverse fields: in medicine and dentistry, N2O provides a source of dissociative anaesthesia and analgesia; in the food and automobile industries, N2O serves as a propellant in whipped cream canisters and as an engine booster, respectively.
N2O is inexpensive and readily available at supermarkets as gas cylinders and dispensers for soda streams and whipped cream. It is among the top five most common inhalants abused by adolescents in the United States of America.Reference Celine, Gunter and Kurt 1 A questionnaire-based study completed in New Zealand noted that 12% of first-year students at the University of Auckland inhaled N2O recreationally, and 3% used it at least monthly.Reference Ng, O'Grady, Pettit and Frith 2 Even though most people have an unremarkable, or even unpleasant, experience with N2O intoxication, some find the dissociative encounter euphoric, with associated sensations of “floating”, body tingling, warmth and numbness.
Various cases of N2O abuse have surfaced in the literature, although isolated psychiatric presentations are uncommon. As cessation from N2O exposure and treatment with vitamin B12 usually lead to complete resolution of psychiatric symptoms, it is important to consider such a precipitant when a patient presents with neuropsychiatric manifestations of an uncertain etiology, especially when N2O use is obtained on history.
Case Report
A man in his 30s presented with new-onset psychotic symptoms and personality changes a few days after inhaling N2O for several (<10) hours. He described having demons in his head, and expressed concerns over his family’s safety for no apparent reason. Those around him noted that he was perseverating, repeating words and short phrases. He had also become rude and verbally aggressive.
The patient’s past medical and psychiatric history were unremarkable. There were no psychiatric disorders on family history. No other causes or precipitants for physical or mental illnesses could be identified. He denied use of any medications or supplements, illicit drug abuse, or exposure to toxins. There was a history of intermittent N2O use for several years, including three episodes within two weeks.
On evaluation, the patient was alert and appeared his stated age. Vital signs were stable. He was emotionally labile, easily angered, and smiled inappropriately throughout the interview. Commands were followed inconsistently. He was easily distractible and paranoid about his safety. Cranial nerve examination was normal. Paratonia was present and he was strong in all four extremities. Sensory and gait examinations were initially deferred due to poor cooperation, but were found to be normal the following day.
Laboratory investigations were mostly unremarkable with regard to hematological cell counts and morphology, except for slight neutrophilia. Extended electrolytes, liver, renal and thyroid functions were normal. Toxicology screen was negative. Immunometric vitamin B12 level was 148 pmol/L (normal 156-672 pmol/L), and holotranscobalamin concentration was 36 pmol/L (normal 32-125 pmol/L). Functional measures of cobalamin activity were markedly abnormal, with elevations of both homocysteine and methylmalonic acid at 48.0 µmol/L (normal <15.5 µmol/L) and 1.7 µmol/L (normal 0.05-0.27 µmol/L), respectively. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain did not reveal any significant findings.
On the night of admission, the patient was started on intravenous thiamine, oral folic acid, intramuscular cobalamin 1000 µg daily, and an anti-psychotic medication. Three days later, his mental status was back to baseline and he was discharged with a prescription for parenteral, followed by oral, vitamin B12. No further psychiatric manifestations had developed or recurred in a follow-up appointment several months later.
Discussion
Vitamin B12, or cobalamin, is a collection of chemical compounds characterized by a central cobalt ion surrounded by a corrin ring. Cobalamin plays a key role in two essential metabolic pathways (Figure): in the mitochondria, adenosylcobalamin serves as a co-factor for methylmalonyl-coenzyme A mutase in the synthesis of succinyl-coenzyme A from methylmalonyl-coenzyme A. In the cytosol, methylcobalamin is a co-factor for methionine synthase in the reduction of homocysteine (HC) to methionine. Methionine synthase is involved in the generation of methyl groups for DNA and RNA synthesis. In cobalamin deficiency, both methylmalonic acid (MMA) and HC concentrations are elevated due to reduced metabolism.
Figure Metabolic pathways involving cobalamin as a co-factor.
N2O abuse is a rare, but known, cause of functional cobalamin deficiency. N2O inactivates vitamin B12 via an irreversible oxidation of the cobalt core from the monovalent to the trivalent state.Reference Sethi, Mullin, Torgovnick and Capasso 3 Inhibition of the methylmalonyl-coenzyme A mutase enzyme leads to an accumulation of methylmalonate and propionate; these compounds appear to provide an atypical source of substrate for fatty acid synthesis, leading to the integration of aberrant fatty acids into the myelin sheath. In the second pathway, impediment of methionine and ultimately S-adenosyl methionine synthesis precludes the methylation of myelin sheath phospholipids, thereby diminishing myelin formation.Reference Pema, Horak and Wyatt 4
The precise pathophysiology behind the development of psychiatric abnormalities in N2O users remains unknown. Tym and AlexanderReference Tym and Alexander 5 have hypothesized about an increased production of nitric oxide via activation of the pre-synaptic nitric oxide synthase enzyme. Nitric oxide, in turn, reacts with superoxide free radicals and forms peroxynitrite, a potent oxidant and neurotoxin. N2O’s ability to act as a non-competitive N-methyl-D-aspartate (NMDA) antagonist may further contribute to its psychogenic properties.Reference Celine, Gunter and Kurt 1
When individuals with a borderline vitamin B12 reserve abuse N2O acutely or chronically, cobalamin deficiency may be precipitated.Reference Sethi, Mullin, Torgovnick and Capasso 3 Some people may remain completely asymptomatic, but others may present with the more well-known neurological and/or hematological manifestations. These findings are listed in the Table, and are beyond the scope of this report. Less commonly documented are the psychiatric sequelae, with only a handful of cases described in the medical literature.Reference Celine, Gunter and Kurt 1 , Reference Sethi, Mullin, Torgovnick and Capasso 3 , Reference Tym and Alexander 5 , Reference Brodsky and Zuniga 6 These may occur in the absence of hematological and/or neurological abnormalities. Personality changes, mood disorders (depression, hypomania), paranoid psychosis with visual and auditory hallucinations (“megaloblastic madness”), and violent behavior have all been depicted.Reference Celine, Gunter and Kurt 1 , Reference Sethi, Mullin, Torgovnick and Capasso 3 , Reference Tym and Alexander 5 , Reference Brodsky and Zuniga 6
Table Clinical presentations and findings associated with nitrous oxide (N2O) use and intoxication
Total serum vitamin B12 level is one of the standard laboratory investigations ordered to assess for cobalamin deficiency. Holotranscobalamin is a more sensitive test for vitamin B12 deficiency that is now commercially available. However, both tests measure whether cobalamin is present, rather than whether it is functionally active. With N2O abuse, the vitamin B12 result may return decreased or within reference limits, given that N2O causes a functional deficiency. Therefore, surrogate functional markers – namely, MMA and HC – may be more helpful and, if both return elevated, can support the diagnosis of N2O-associated cobalamin deficiency.
Management of N2O-induced psychosis comprises of a two-pronged approach: abstinence from N2O inhalation, and short-term (e.g. 1 week) supplementation with intramuscular or oral cobalamin (typically 1000 μg daily). An antipsychotic is often prescribed in the interim until psychiatric symptoms resolve. The prognosis is generally favorable, with complete resolution of most, if not all, psychiatric abnormalities. Mild neurological sequelae, if present, may persist.
Conclusion
Nitrous oxide is a readily available and commonly abused inhalant which is often overlooked on clinical history. Acute and chronic users may present with neuropsychiatric and/or hematological manifestations, and are especially at risk when their vitamin B12 reserve is marginal. Ordering serum total cobalamin, MMA and HC levels can assist in the diagnosis. Given the safety and simplicity of therapy, clinicians should have a high index of suspicion and readily recognize the diverse symptoms and signs of N2O abuse, thereby allowing prompt initiation of cobalamin supplementation and removal from further N2O exposure.
