Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry

Author(s): Mark A. Gillman*.

Journal Name: Current Drug Research Reviews

Volume 11 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Joseph Priestley’s discovery of nitrous oxide (N2O) was recorded in 1772. In the late 1790’s, Humphry Davy experimented with the psychotropic properties of N2O, describing his observations in a book, published in 1800. A dentist, Horace Wells discovered anaesthesia with N2O in 1844. Over a century after Davy, its potential usefulness in psychiatry was first recognised. The seminal researches in neuropsychiatry, between 1920 and 1950, mainly used anaesthetic concentrations of the gas. The psychotropic actions of N2O, at non-anaesthetic doses, were first used by dentists, mainly for its anxiolytic action. In modern dentistry, N2O is always mixed with at least 30% oxygen and titrated to doses rarely exceeding 40% of N2O. At these lower concentrations, untoward effects are almost always avoided, including over-sedation and/or anaesthesia. In the early 1980’s, the low-dose dental titration technique was first used to investigate and treat psychiatric conditions, including substance abuse. Until then, most physicians regarded the gas only as an anaesthetic agent. An exception was obstetricians who used a fixed 50% concentration of N2O diluted with oxygen for analgesia during parturition. In 1994, to clearly distinguish between anaesthetic and non-anaesthetic concentrations (as used in dentistry), the term Psychotropic Analgesic Nitrous oxide (PAN) was introduced.

Objective: This paper will give a brief history of the use of the N2O in psychiatry since the psychotropic actions were first recognised in the 18th century until the present.

Conclusion: The role of other non- opioid systems, and the extent to which they contribute to the psychotropic properties of N2O, still remains to be established.

Keywords: Psychotropic analgesic nitrous oxide, N2O, dental titration, neuropsychiatry, substance abuse, psychiatry, neurology.

Gillman MA, Lichtigfeld FJ. Clinical role and mechanisms of action of analgesic nitrous oxide. Int J Neurosci 1998; 93(1-2): 55-62.
Frost EAM. A history of nitrous oxide Nitrous oxide/N2ONew York. Elsevier 1985; pp. 1-22.
Smith RA, Beirne OR. The use of nitrous oxide by dentistsNitrous oxide/N2ONew York. Elsevier 1985; pp. 281-304.
Gillman MA. Words of caution on using fixed 50% concentrations of nitrous oxide in psychiatry. J Clin Psychopharmacol in press
Nagele P, Duma A, Kopec M, et al. Nitrous oxide for treatment-resistant major depression: A proof-of-concept trial. Biol Psychiatry 2015; 78(1): 10-8.
Griffin GC, Campbell VD, Jones R. Nitrous oxide--oxygen sedation for minor surgery. Experience in a pediatric setting. JAMA 1981; 245(23): 2411-3.
Davy H. Researches, chemical and philosophical; chiefly concerning nitrous oxide: Or dephlosgisticated nitrous air, and its respirationLondon. Butterworth 1977.
Cohen PJ. History and theories of general anesthesiaThe pharmacological basis of therapeuticsNew York. MacMillan 1975; pp. 53-65.
Zador J. Der Lachgas (N2O) - Rausch in seiner Bedeutung für Psychiatie und Neurologie. Archiv f Psychiat 1928; 84: 1-72.
Richards W, Parbrook GD, Wilson J. Stanislav Klikovich (1853-1910). Pioneer of nitrous oxide and oxygen analgesia. Anaesthesia 1976; 31(7): 933-40.
Gillman MA, Lichtigfeld FJ. Therapeutic use of nitrous oxide (an opioid agonist) in psychiatry (abstract VII World Congress of Psychiatry. July 11-16; 1983.
Lichtigfeld FJ, Gillman MA. The therapeutic uses of opioid substances in psychiatry, with special references to analgesic concentrations of nitrous oxide Update of psychiatric management, South Africa. Durban: Society of Psychiatrists of SA 1985; pp. 76-9.
Gillman MA, Matussek N, Lichtigfeld FJ. Effect of nitrous oxide on depressive patients and volunteers Biological Psychiatry, Higher Nervous Activity. Boston: Springer 1985.
Gillman MA, Lichtigfeld FJ. Opioid properties of psychotropic analgesic nitrous oxide (laughing gas). Perspect Biol Med 1994; 38(1): 125-38.
Gillman MA, Lichtigfeld FJ. Analgesic nitrous oxide in neuropsychiatry: past, present and future. Int J Neurosci 1989; 49(1-2): 75-81.
Fogel EJ, Gray LP. Nitrous oxide anoxia in the treatment of schizophrenia. Am J Psychiatry 1940; 97: 677-85.
Rogerson CH. Narco-analysis with nitrous oxide. BMJ 1944; 1(4354): 811-2.
Lehmann H, Bos C. The advantages of nitrous oxide inhalation in psychiatric treatment. Am J Psychiatry 1947; 104(3): 164-70.
Daras C, Cantrill RC, Gillman MA. (3H) Naloxone displacement: evidence for nitrous oxide as opioid receptor agonist Eur J Pharmacol 1983; l 89: 177-8.
Gillman MA. Analgesic nitrous oxide should join the opioid family after almost two centuries. S Afr J Sci 1993; 89: 25-7.
Jevtović-Todorović V, Todorović SM, Mennerick S, et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 1998; 4(4): 460-3.
Hoffman M. A new role for gases: Neurotransmission. Science 1991; 252(5014): 1788.
Gillman MA. The role of gases in neurotransmission. S Afr J Sci 1991; 87: 573.
Gillman MA. Nitrous oxide as neurotransmitter. Lancet 1992; 339(8788): 307.
Brill NQ, Crumpton E, Eiduson S, Grayson HM, Hellman LI, Richards RA. AMA Arch Neur Psych 1959; 81: 627-35.
Langa H. Relative analgesia in dental practice: Inhalation analgesia with nitrous oxide. Philadelphia: WB Saunders 1968.
Marx GF, Bassel GM. Nitrous oxide/N2O. New York: Elsevier 1985; pp. 185-201.
Malamed SF. Sedation: A guide to patient management. 2nd ed. St Louis: Mosby 1989.
Becker DE, Rosenberg M. Nitrous oxide and the inhalation anesthetics. Anesth Prog 2008; 55(4): 124-30.
Henrie JR, Parkhouse J, Bickford RG. Alteration of human consciousness by nitrous oxide as assessed by nitrous oxide as assessed by electroencephalography and psychological tests. Anesthesiology 1961; 22: 247-59.
MacDonald IJ. Entonox as a psychotherapeutic aid. BMJ 1970; 1(5707): 483.
Kripke BJ, Hechtman HB. Nitrous oxide for pentazocine addiction and for intractable pain: Report of case. Anesth Analg 1972; 51(4): 520-7.
Lichtigfeld FJ, Gillman MA. The treatment of alcoholic withdrawal states with oxygen and nitrous oxide. S Afr Med J 1982; 61(10): 349-51.
Daynes G. The initial management of alcoholism using oxygen and nitrous oxide: A transcultural study. Int J Neurosci 1989; 49(1-2): 83-6.
Ojutkangas R, Gillman MA. Psychotropic analgesic nitrous oxide for treating alcohol withdrawal in an outpatient setting. Int J Neurosci 1994; 76(1-2): 35-9.
Gillman MA, Lichtigfeld FJ. Minimal sedation required with nitrous oxide-oxygen treatment of the alcohol withdrawal state. Br J Psychiatry 1986; 148: 604-6.
Gillman MA, Lichtigfeld FJ. Enlarged double-blind randomised trial of benzodiazepines against psychotropic analgesic nitrous oxide for alcohol withdrawal. Addict Behav 2004; 29(6): 1183-7.
Diaper AM, Law FD, Melichar JK. Pharmacological strategies for detoxification. Br J Clin Pharmacol 2014; 77(2): 302-14.
Cooper E, Vernon J. The effectiveness of pharmacological approaches in the treatment of alcohol withdrawal syndrome (AWS): a literature review. J Psychiatr Ment Health Nurs 2013; 20(7): 601-12.
Daynes G, Gillman MA. Psychotropic analgesic nitrous oxide prevents craving after withdrawal for alcohol, cannabis and tobacco. Int J Neurosci 1994; 76(1-2): 13-6.
Gillman MA, Harker N, Lichtigfeld FJ. Combined cannabis/methaqualone withdrawal treated with psychotropic analgesic nitrous oxide. Int J Neurosci 2006; 116(7): 859-69.
Gillman MA, Shevel J. Analgesic nitrous oxide and oxygen for acute withdrawal from cigarette smoking. Proceedings of Drug and Alcohol Forum 1988; 66-74.
Bayrakdarian C. Effectiveness of nitrous Oxide [N2O] in reducing cigarette smoking in subjects with nicotine dependence. American Psychiatric Association Meeting May 2000; 2h.
Gillman MA. Nitrous oxide and neurotransmissionNew York. Novo Science 2012.
Gillman MA, Lichtigfeld FJ. Opioid effects of analgesic (subanesthetic) nitrous oxide on the alcohol withdrawal state. Ann N Y Acad Sci 1991; 625: 784-5.
Gillman MA, Lichtigfeld FJ, Young T. Psychotropic analgesic nitrous oxide for alcoholic withdrawal states. (Review) Cochrane Library, Syst Rev 2008; (2)
Lichtigfeld FJ, Gillman MA. The effect of placebo in the alcohol withdrawal state. Alcohol Alcohol 1989; 24(2): 109-12.
Lichtigfeld FJ, Gillman MA. Analgesic nitrous oxide for alcohol withdrawal is better than placebo. Int J Neurosci 1989; 49(1-2): 71-4.
Berkowitz BA, Ngai SH, Finck AD. Nitrous oxide “analgesia”: resemblance to opiate action. Science 1976; 194(4268): 967-8.
Yang JC, Clark WC, Ngai SH. Antagonism of nitrous oxide analgesia by naloxone in man. Anesthesiology 1980; 52(5): 414-7.
Gillman MA, Kok L, Lichtigfeld FJ. Paradoxical effect of naloxone on nitrous oxide analgesia in man. Eur J Pharmacol 1980; 61(2): 175-7.
Gillman MA, Lichtigfeld FJ. A comparison of the effects of morphine sulphate and nitrous oxide analgesia on chronic pain states in man. J Neurol Sci 1981; 49(1): 41-5.
Gillman MA. Psychotropic analgesic nitrous oxide as an investigative diagnostic and therapeutic tool. Int J Neurosci 1994; 76(1-2): 1-3.
Gillman MA, Lichtigfeld FJ. The effect of nitrous oxide and naloxone on orgasm in human females. A Preliminary report. J Sex Res 1983; 19: 49-57.
Malamed SF, Serxner K, Weidenfeld AM. The incidence of sexual phenomena in females receiving nitrous oxide and oxygen sedation. J Am Analg Soc 1988; 22: 9-10.
Murphy MR, Checkley SA, Seckl JR, Lightman SL. Naloxone inhibits oxytocin release at orgasm in man. J Clin Endocrinol Metab 1990; 71(4): 1056-8.
Leknes S, Tracey I. A common neurobiology for pain and pleasure. Nat Rev Neurosci 2008; 9(4): 314-20.
Carter CS. Oxytocin and sexual behavior. Neurosci Biobehav Rev 1992; 16(2): 131-44.
Berridge KC, Kringelbach ML. Building a neuroscience of pleasure and well-being. Psychol Well Being 2011; 1(1): 1-3.
Pfaus JG, Kippin TE, Coria-Avila GA, et al. Who, what, where, when (and maybe even why)? How the experience of sexual reward connects sexual desire, preference, and performance. Arch Sex Behav 2012; 41(1): 31-62.
Manninen S, Tuominen L, Dunbar RI, et al. Social laughter triggers endogenous opioid release in humans. J Neurosci 2017; 37(25): 6125-31.
Gillman MA, Sandyk R, Lichtigfeld FJ. Evidence for underactivity of the opioid system in neuroleptic-induced akathisia. Psychiatry Res 1984; 13(2): 187.
Ori C, Ford-Rice F, London ED. Effects of nitrous oxide and halothane on mu and kappa opioid receptors in guinea-pig brain. Anesthesiology 1989; 70(3): 541-4.
Jaffe JH, Martin WR. Opioid analgesics and antagonists Goodman and Gilman’s the pharmacological basis of therapeutics. New York: Pergamon 1990; pp. 485-521.
Carlson ET, Simpson MM. Opium as a tranquilizer. Am J Psychiatry 1963; 120: 112-7.
Comfort A. Morphine as an antipsychotic. Relevance of a 19th-century therapeutic fashion. Lancet 1977; 2(8035): 448-9.
Walters A, Hening W, Chokroverty S, Fahn S. Opioid responsiveness in patients with neuroleptic-induced akathisia. Mov Disord 1986; 1(2): 119-27.
Gillman MA, Sandyk R. Tourette syndrome: Effect of analgesic concentrations of nitrous oxide and naloxone. Br Med J (Clin Res Ed) 1984; 288: 114.
Chappell PB, Leckman JF, Scahill LD, Hardin MT, Anderson G, Cohen DJ. Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette’s syndrome: A pilot study. Psychiatry Res 1993; 47(3): 267-80.
Van Wattum PJ, Chappell PB, Zelterman D, Scahill LD, Leckman JF. Patterns of response to acute naloxone infusion in Tourette’s syndrome. Mov Disord 2000; 15(6): 1252-4.
Gillman MA, Sandyk R. Nitrous oxide ameliorates spasmodic torticollis. Eur Neurol 1985; 24(5): 292-3.
McAllister JM, Hall ES, Hertenstein GER, Merhar SL, Uebel PL, Wexelblatt SL. Torticollis in infants with a history of neonatal abstinence syndrome. J Pediatr 2018; 196: 305-8.
Desborough JP. The stress response to trauma and surgery. Br J Anaesth 2000; 85(1): 109-17.
Singh M. Stress response and anaesthesia. Indian J Anaesth 2003; 47: 427-34.
Walker E, Elliot C. Nitrous oxide: A potential unconditioned positive stimulus in cognitive therapy for depression. Behav Ther 1987; 4: 90-2.
de Wet J, Lichtigfeld FJ, Gillman MA. Psychotropic analgesic nitrous oxide (PAN) for hyperactivity. Aust N Z J Psychiatry 2001; 35(4): 543-4.
Lichtigfeld FJ, Gillman MA. Another marker for different types of depression. Int J Neuropsychopharmacol 2003; 6(1): 91-2.
Gillman MA. Nitrous oxide as an opioid agonist: Some experimental and clinical observations. DSC Thesis, Potchefstroom University, South Africa, 1984
Weber MM. Die ‘Opiumkur’ in der Psychiatrie. Ein Beitrag zur Geschichte der Psychophatmakotherapie (The‘opium cure’ in psychiatry. A contribution to the history of psychopharmacotherapy). Sudhoff’s Archiv 1987; 71: 31-61.
Gross-Isseroff R, Dillon KA, Israeli M, Biegon A. Regionally selective increases in mu opioid receptor density in the brains of suicide victims. Brain Res 1990; 530(2): 312-6.
Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol 1995; 15(1): 49-57.
Hegadoren KM, O’Donnell T, Lanius R, Coupland NJ, Lacaze-Masmonteil N. The role of β-endorphin in the pathophysiology of major depression. Neuropeptides 2009; 43(5): 341-53.
Nagele P, Zorumski CF, Conway C. Exploring nitrous oxide as treatment of mood disorders. J Clin Psychopharmacol 2018; 38(2): 144-8.
Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG. Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology 1999; 90(1): 174-82.
Sarton E, Teppema LJ, Olievier C, et al. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Anesth Analg 2001; 93(6): 1495-500.
Johnson JW, Kotermanski SE. Mechanism of action of memantine. Curr Opin Pharmacol 2006; 6(1): 61-7.
Conway C, Nagele P. Recent trial data from nitrous oxide effects in treatment-resistant depression. Biol Psychiatry 2017; 81: S140-276.
Gillman MA. Minireview: Analgesic [sub anaesthetic] nitrous oxide interacts with the endogenous opioid system: A review of the evidence. Life Sci 1986; 39: l209-2l.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [12 - 20]
Pages: 9
DOI: 10.2174/1874473711666181008163107

Article Metrics

PDF: 40