Cases That Test Your Skills

‘Self-anesthetizing’ to cope with grief

Current Psychiatry. 2017 November;16(11):48-53

References

1. Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol. 2005;19(2):187-194.
2. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988;318(26)1720-1728.
3. Herres J, Chudnofsky CR, Manur R, et al. The use of inhaled nitrous oxide for analgesia in adult ED patients: a pilot study. Am J Emerg Med. 2016;34(2):269-273.
4. Aboumarzouk OM, Agarwal T, Syed Nong Chek SA, et al. Nitrous oxide for colonoscopy. Cochrane Database Syst Rev. 2011;(8):CD008506.
5. National Institute on Drug Abuse. Drug facts: inhalants. http://www.drugabuse.gov/publications/drugfacts/inhalants. Updated February 2017. Accessed September 30, 2017.
6. SAMHSA, Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health 2012 and 2013: Table 1.88C. https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs2013.pdf. Published September 4, 2017. Accessed September 30, 2017.
7. Brouette T, Anton R. Clinical review of inhalants. Am J Addict. 2001;10(1):79-94.
8. Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007;54(1):9-18.
9. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Am J Addict. 2016;25(5):358-369.
10. Hathout L, El-Saden S. Nitrous oxide-induced B₁₂ deficiency myelopathy: perspectives on the clinical biochemistry of vitamin B₁₂. J Neurol Sci. 2011;301(1-2):1-8.
11. van Tonder SV, Ruck A, van der Westhuyzen J, et al. Dissociation of methionine synthetase (EC 2.1.1.13) activity and impairment of DNA synthesis in fruit bats (Rousettus aegyptiacus) with nitrous oxide-induced vitamin B12 deficiency. Br J Nutr. 1986;55(1):187-192.
12. Schrier SL, Mentzer WC, Tirnauer JS. Diagnosis and treatment of vitamin B12 and folate deficiency. UpToDate. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency. Updated September 30, 2011. Accessed September 8, 2015.
13. Sethi NK, Mullin P, Torgovnick J, et al. Nitrous oxide “whippit” abuse presenting with cobalamin responsive psychosis. J Med Toxicol. 2006;2(2):71-74.
14. Cousaert C, Heylens G, Audenaert K. Laughing gas abuse is no joke. An overview of the implications for psychiatric practice. Clin Neurol Neurosurg. 2013;115(7):859-862.
15. Brodsky L, Zuniga J. Nitrous oxide: a psychotogenic agent. Compr Psychiatry. 1975;16(2):185-188.
16. Wong SL, Harrison R, Mattman A, et al. Nitrous oxide (N₂O)-induced acute psychosis. Can J Neurol Sci. 2014;41(5):672-674.
17. Smith AD. Megaloblastic madness. Br Med J. 1960;2(5216):1840-1845.
18. Masalha R, Chudakov B, Muhamad M, et al. Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency. Isr Med Associ J. 2001;3(9):701-703.
19. Kuo SC, Yeh SB, Yeh YW, et al. Schizophrenia-like psychotic episode precipitated by cobalamin deficiency. Gen Hosp Psychiatry. 2009;31(6):586-588.
20. Raveendranathan D, Shiva L, Venkatasubramanian G, et al. Vitamin B₁₂deficiency masquerading as clozapine-resistant psychotic symptoms in schizophrenia. J Neuropsychiatry Clin Neurosci. 2013;25(2):E34-E35.
21. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513.
22. Moore THM, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319-328.
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The authors’ observations

N₂O, also known as “laughing gas,” is routinely used by dentists and pediatric anesthesiologists, and has other medical uses. Some studies have examined an adjunctive use of N₂O for pain control in the ED and during colonoscopies.^3,4

In the 2013 U.S. National Survey on Drug Use and Health, 16% of respondents reported lifetime illicit use of N₂O.^5,6 It is readily available in tanks used in medicine and industry and in small dispensers called “whippits” that can be legally purchased. Acute effects of N₂O include euphoric mood, numbness, feeling of warmth, dizziness, and auditory hallucinations.⁷ The anesthetic effects of N₂O are linked to endogenous release of opiates, and recent research links its anxiolytic activity to the facilitation of GABAergic inhibitory and N-methyl-d-aspartic acid (NMDA)-mediated transmission.⁸ Abuse of N₂O has been the presumptive cause of death in 29 cases.⁹

N₂O may cause neurologic and psychiatric dysfunction by 2 main routes: direct toxic CNS effects and inactivating vitamin B₁₂. Putative mechanisms of action of vitamin B₁₂ deficiency–induced neuronal dysfunction include dysregulation of cytokine and growth factor levels in the CSF.¹⁰ By irreversible oxidation of its cobalt ion, N₂O inactivates vitamin B₁₂ and causes functional deficiency.¹¹ Vitamin B₁₂ deficiency can cause various signs and symptoms, including macrocytosis, depression, and hallucinations (Table 2).^2,12 Several case reports have linked abuse of N₂O with vitamin B₁₂ deficiency and reported psychotic symptoms as the sole presenting abnormalities, with an absence of other signs and symptoms.^13-16

Beginning with a 1960 report of a series of patients with “megaloblastic madness,”¹⁷ there have been calls for increased awareness of the potential for vitamin B₁₂ deficiency–induced psychiatric disorders, even in the absence of other hematologic or neurologic sequelae that would alert clinicians of the deficiency. In a case series of 141 patients with a broad array of neurologic and psychiatric symptoms associated with vitamin B₁₂ deficiency, 40 (28%) patients had no anemia or macrocytosis.²

Vitamin B₁₂-responsive psychosis has been reported as the sole manifestation of illness, without associated neurologic or hematologic symptoms, in only a few case reports. Vitamin B₁₂ levels in these cases ranged from 75 to 236 pg/mL (reference range, 160 to 950 pg/mL).^18-20 In all of these cases, the vitamin B₁₂ deficiency was traced to dietary causes. The clinical evaluation of suspected vitamin B₁₂ deficiency is outlined in the Figure.²¹Mr. M had used Cannabis recreationally for a long time, and his Cannabis use acutely escalated with use of N₂O. Long-term use of Cannabis alone is a risk factor for psychotic illness.²² Combined abuse of Cannabis and N₂O has been reported to provoke psychotic illness. In a case report of a 22-year-old male who was treated for paranoid delusions, using Cannabis and 100 cartridges of N₂O daily was associated with low vitamin B₁₂ and elevated homocysteine and methylmalonic acid levels.²³

Cannabis use may have played a role in Mr. M’s escalating N₂O use. In a study comparing 9 active Cannabis users with 9 non-using controls, users rated the subjective effects of N₂O as more intense than non-users.²⁴ In our patient’s case, Cannabis may have played a role in both sustaining his escalating N₂O abuse and potentiating its psychotomimetic effects.

It also is possible that Mr. M may have been “self-medicating” his grief with N₂O. In a recent placebo-controlled crossover trial of 20 patients with treatment-resistant depression, Nagele et al²⁵ found a significant rapid and week-long antidepressant effect of subanesthetic N₂O use. A model involving NMDA receptor activation has been proposed.^25,26 Zorumski et al²⁶ further reviewed possible antidepressant mechanisms of N₂O. They compared N₂O with ketamine as an NMDA receptor antagonist, but also noted its distinct effects on glutaminergic and GABAergic neurotransmitter systems as well as other receptors and channels.²⁶ However, illicit use of N₂O poses toxicity dangers and has no current indication for psychiatric treatment.

References

Fentanyl analogues an increasing factor in opioid deaths

‘Self-anesthetizing’ to cope with grief

References

The authors’ observations

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