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.