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Nitrous oxide misuse

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

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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)

Reference:

  • Hussain Z. Nitrous oxide: Doctors warn of "epidemic" of use by young people BMJ 2022; 378 :o2155.
  • 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.
  • 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

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