Nitrous oxide misuse

Nitrous oxide misuse

• used to induce laughter and hallucinations, the gas is not illegal to possess and can be purchased online in the small silver canisters known as "whippits" (1)
  • is concern after seeing more users presenting neurological complications after inhaling often from large canisters of the gas, usually 80 times the size of whippits
  • prolonged use of nitrous oxide can have disabling neurological sequelae due to functional inactivation of vitamin B12 (2)
• nitrous oxide misuse
  • 2019-20 Crime Survey for England and Wales found that almost 9% of 16-24 year olds said that they had taken nitrous oxide in the previous year, up from 6.1% in 2012-13
  • toxic effects are mediated by inactivation of vitamin B12, typically producing a myelopathy, though there have been cases of an isolated lower motor neurone syndrome (2)
  • by inactivating vitamin B12, nitrous oxide can lead to a paraparesis via myelopathy due to B12 affecting the posterior columns of the spinal cord
  • can also cause neuropathy again via B12 deficiency
    • toxic effects of nitric oxide are mediated through oxidation of cobalt ions in vitamin B12 and hence cause its inactivation
      • leads to reduced recycling of homocysteine to methionine
      • prevents methylation of myelin proteins, thus causing demyelination within the central and peripheral nervous systems
      • demyelination may not be the only pathophysiological mechanism:
        • a case report has noted no pathological evidence of demyelination but of an ischaemic neuropathy (2)
    • in most cases reported in the literature, the neurological presentation associated with nitrous oxide misuse is that of a myelopathy particularly affecting the dorsal columns-subacute combined degeneration of the spinal cord (2)
  • B12 can be normal, depending on the assay - methylmalonic acid is markedly raised
    
    
• a review notes (3):
  • serum B12 is often normal in nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD)
    • functional B12 testing with methylmalonic acid or homocysteine can help to establish the diagnosis
      • active vitamin B12 is essential for the enzymatic conversion of homocysteine to methionine and of methylmalonic co-enzyme A to succinyl co-enzyme A
        • therefore, vitamin B12 deficiency or B12 inactivation tends to increase plasma homocysteine and methylmalonic acid (MMA). Tests for assessing B12 status include serum B12, homocysteine, MMA and holotranscobalamin
    • investigations in suspected N2O-SACD may support the clinical diagnosis, but there should be no delay in starting treatment promptly (with intramuscular B12 injections) while undertaking results
      
      
  • intramuscular B12 injection is a low-risk, high-impact treatment and should be given as promptly as possible once N2O-SACD is suspected
    
    
  • B12 injections should continue until improvement reaches a plateau; abstinence from N2O is crucial to recovery and allows B12 injections to work
    • serum folate should be checked and replaced if low
    • methionine or folic acid may be possible treatment adjuncts however, there is no clinical evidence to support their routine use (3)

Nitrous oxide misuse and mental health in UK adolescents

• a survey of 13-14 year olds (n=6672) found 5.1% and 4.9% reported using nitrous oxide and volatile solvents. Users of either were found more likely to report probable depressive and conduct disorders with volatile solvents also associated with anxiety and auditory hallucinations (4)

Reference:

1. Hussain Z. Nitrous oxide: Doctors warn of "epidemic" of use by young people BMJ 2022; 378 :o2155.
2. Thompson AG, Leite MI, Lunn MP, Bennett DL. Whippits, nitrous oxide and the dangers of legal highs. Pract Neurol. 2015 Jun;15(3):207-9.
3. Paris A, Lake L, Joseph A, et al. Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment.Practical Neurology Published Online First: 22 February 2023. doi: 10.1136/pn-2022-003631
4. Hawkins J, Hines LA, Bonell C, et al. Association of volatile substance, nitrous oxide and alkyl nitrate use with mental health in UK adolescents. The British Journal of Psychiatry. Published online 2024:1-6.