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The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis

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Abstract

Background

Nitrous oxide (N2O) has been initially confirmed by clinical trials to benefit to patients with major depressive disorder (MDD). However, there needs to be a meta-analysis to compare the efficacy and tolerability of N2O in MDD.

Methods

PubMed, EMBASE, and Cochrane Library were searched for relevant studies up to Jan 1st, 2023. The meta-analysis mainly compared the outcome of the change in depression severity scores, response, remission, and adverse events in patients with MDD receiving 50% N2O and placebo.

Results

Four studies with 133 patients were eventually identified. We found that the N2O group and control group showed an overall significant difference in the change in depression severity score for patients at 2 h, 24 h, and 2 weeks or more (2 h, SMD =  − 0.64, 95% CI − 0.01 to − 0.28, p < 0.0001) (24 h, SMD =  − 0.65, 95% CI − 1.01 to − 0.29, p < 0.0001) (2 weeks, SMD =  − 0.76, 95% CI − 1.16 to − 0.36, p < 0.0001). For the response and remission rate, the long-term effect of N2O was also statistically significant (for the response, RR = 2.33, 95% CI 1.23 to 4.44, p = 0.01) (for the remission, RR = 4.68, 95% CI 1.49 to 14.68, p = 0.008). For safety outcomes, patients treated with N2O had higher odds of nausea or vomiting (RR = 10.15, 95% CI 1.96 to 52.59, p = 0.009).

Conclusion

Our study suggested that N2O has a rapid and long-lasting antidepressant effect in patients with MDD. However, the efficacy of lower or titrated concentration of N2O should be further investigated.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  • Agarwal P, Khor SY, Do S, Charles L, Tikaria R (2021) Recreational nitrous oxide-induced subacute combined degeneration of the spinal cord. Cureus 13(11):e19377

    PubMed  PubMed Central  Google Scholar 

  • Cole J, Sohn MN, Harris AD, Bray SL, Patten SB, McGirr A (2022) Efficacy of adjunctive D-cycloserine to intermittent theta-burst stimulation for major depressive disorder: a randomized clinical trial. JAMA Psychiat 79(12):1153–1161

    Article  Google Scholar 

  • Collaborators GDAH (2017) Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390(10100):1260–1344

    Article  Google Scholar 

  • Comfort A (1977) Morphine as an antipsychotic. Relevance of a 19th-century therapeutic fashion. Lancet 2(8035):448–449

    Article  CAS  PubMed  Google Scholar 

  • Conway CR, George MS, Sackeim HA (2017) Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiat 74(1):9–10

    Article  Google Scholar 

  • Daras C, Cantrill RC, Gillman MA (1983) [3H]naloxone displacement: evidence for nitrous oxide as opioid receptor agonist. Eur J Pharmacol 89(1–2):177–178

    Article  CAS  PubMed  Google Scholar 

  • de Aguiar Neto FS, Rosa JLG (2019) Depression biomarkers using non-invasive EEG: a review. Neurosci Biobehav Rev 105:83–93

    Article  PubMed  Google Scholar 

  • Fang X, Yu M, Zheng D, Gao H, Li W, Ma Y (2023) Electrophysiologic characteristics of nitrous-oxide-associated peripheral neuropathy: a retrospective study of 76 patients. J Clin Neurol 19(1):44–51

    Article  PubMed  PubMed Central  Google Scholar 

  • Gillman MA (1986) Analgesic (sub anesthetic) nitrous oxide interacts with the endogenous opioid system: a review of the evidence. Life Sci 39(14):1209–1221

    Article  CAS  PubMed  Google Scholar 

  • Gillman MA (2019) Mini-review: a brief history of nitrous oxide (N2O) use in neuropsychiatry. Curr Drug Res Rev 11(1):12–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillman MA (2021) Opioid properties of nitrous oxide and ketamine contribute to their antidepressant actions. Int J Neuropsychopharmacol 24(11):892–893

    Article  PubMed  PubMed Central  Google Scholar 

  • Gillman MA (2022) What is better for psychiatry: titrated or fixed concentrations of nitrous oxide? Front Psychiatry 13:773190

    Article  PubMed  PubMed Central  Google Scholar 

  • Gross-Isseroff R, Dillon KA, Israeli M, Biegon A (1990) Regionally selective increases in mu opioid receptor density in the brains of suicide victims. Brain Res 530(2):312–316

    Article  CAS  PubMed  Google Scholar 

  • Guimarães MC, Guimarães TM, Hallak JE, Abrão J, Machado-de-Sousa JP (2021) Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial. Braz J Psychiatry 43(5):484–493

    Article  PubMed  PubMed Central  Google Scholar 

  • Herden U, Sterneck M, Buchholz BM, Achilles EG, Ott A, Fischer L (2021) A single-center, open-label, randomized cross-over study to evaluate the pharmacokinetics and bioavailability of once-daily prolonged-release formulations of tacrolimus in de novo liver transplant recipients. Immun Inflamm Dis 9(4):1771–1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong HY, Karadaghy O, Kallogjeri D, Brown FT, Yee B, Piccirillo JF, Nagele P (2018) Effect of nitrous oxide as a treatment for subjective, idiopathic, nonpulsatile bothersome tinnitus: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg 144(9):781–787

    Article  PubMed  Google Scholar 

  • Jastak JT (1989) Nitrous oxide in dental practice. Int Anesthesiol Clin 27(2):92–97

    Article  CAS  PubMed  Google Scholar 

  • Jelen LA, Stone JM, Young AH, Mehta MA (2022) The opioid system in depression. Neurosci Biobehav Rev 140:104800

    Article  CAS  PubMed  Google Scholar 

  • Jevtović-Todorović V, Todorović SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW (1998) Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 4(4):460–463

    Article  PubMed  Google Scholar 

  • Kaar SJ, Ferris J, Waldron J, Devaney M, Ramsey J, Winstock AR (2016) Up: the rise of nitrous oxide abuse. an international survey of contemporary nitrous oxide use. J Psychopharmacol 30(4):395–401

    Article  CAS  PubMed  Google Scholar 

  • Kalmoe MC, Janski AM, Zorumski CF, Nagele P, Palanca BJ, Conway CR (2020) Ketamine and nitrous oxide: the evolution of NMDA receptor antagonists as antidepressant agents. J Neurol Sci 412:116778

    Article  CAS  PubMed  Google Scholar 

  • Keddie S, Adams A, Kelso ARC, Turner B, Schmierer K, Gnanapavan S, Malaspina A, Giovannoni G, Basnett I, Noyce AJ (2018) No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation. J Neurol 265(5):1089–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim WSH, Dimick MK, Omrin D, Mitchell RHB, Riegert D, Levitt A, Schaffer A, Belo S, Iazzetta J, Detzler G, Choi M, Choi S, Herrmann N, McIntyre RS, MacIntosh BJ, Orser BA, Goldstein BI (2023) Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement. Bipolar Disord 25:221–232

    Article  CAS  PubMed  Google Scholar 

  • Klein ME, Chandra J, Sheriff S, Malinow R (2020) “Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents.” Proc Natl Acad Sci U S A 117(5):2656-2662

  • Kupfer DJ, Frank E, Phillips ML (2012) Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 379(9820):1045–1055

    Article  PubMed  Google Scholar 

  • Lam RW, McIntosh D, Wang J, Enns MW, Kolivakis T, Michalak EE, Sareen J, Song WY, Kennedy SH, MacQueen GM, Milev RV, Parikh SV, Ravindran AV (2016) Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 1. Disease burden and principles of care. Can J Psychiatry 61(9):510–523

    Article  PubMed  PubMed Central  Google Scholar 

  • Layzer RB, Fishman RA, Schafer JA (1978) Neuropathy following abuse of nitrous oxide. Neurology 28(5):504–506

    Article  CAS  PubMed  Google Scholar 

  • Lichtigfeld FJ, Gillman MA (1982) The treatment of alcoholic withdrawal states with oxygen and nitrous oxide. S Afr Med J 61(10):349–351

    CAS  PubMed  Google Scholar 

  • Ma K, Zhang H, Baloch Z (2016) Pathogenetic and therapeutic applications of tumor necrosis factor-α (TNF-α) in major depressive disorder: a systematic review. Int J Mol Sci 17

  • Matussek N (2003) Opioid system in depression. Int J Neuropsychopharmacol 6(4):443

    Article  PubMed  Google Scholar 

  • Maze M, Fujinaga M (2000) Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia 55(4):311–314

    Article  CAS  PubMed  Google Scholar 

  • Nagashima K, Zorumski CF, Izumi Y (2005) Nitrous oxide (laughing gas) facilitates excitability in rat hippocampal slices through gamma-aminobutyric acid A receptor-mediated disinhibition. Anesthesiology 102(1):230–234

    Article  PubMed  Google Scholar 

  • Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, Janski A, Panagopoulos VN, Cristancho P, Miller JP, Zorumski CF, Conway CR (2015) Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biol Psychiatry 78(1):10–18

    Article  CAS  PubMed  Google Scholar 

  • Nagele P, Palanca BJ, Gott B, Brown F, Barnes L, Nguyen T, Xiong W, Salloum NC, Espejo GD, Lessov-Schlaggar CN, Jain N, Cheng WWL, Komen H, Yee B, Bolzenius JD, Janski A, Gibbons R, Zorumski CF, Conway CR (2021) A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Sci Transl Med 13

  • Nagele P, Zorumski CF, Conway C (2018) Exploring nitrous oxide as treatment of mood disorders: basic concepts. J Clin Psychopharmacol 38(2):144–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niciu MJ, Ionescu DF, Richards EM, Zarate CA Jr (2014) Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm (Vienna) 121(8):907–924

    Article  CAS  PubMed  Google Scholar 

  • Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71

    Article  PubMed  PubMed Central  Google Scholar 

  • Patel KK, Mejia Munne JC, Gunness VRN, Hersey D, Alshafai N, Sciubba D, Nasser R, Gimbel D, Cheng J, Nouri A (2018) Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: a systematic review of cases. Clin Neurol Neurosurg 173:163–168

    Article  PubMed  Google Scholar 

  • Petersen JK (1994) Nitrous oxide analgesia in dental practice. Acta Anaesthesiol Scand 38(8):773–774

    Article  CAS  PubMed  Google Scholar 

  • Peyton PJ, Wu CY (2014) Nitrous oxide-related postoperative nausea and vomiting depends on duration of exposure. Anesthesiology 120(5):1137–1145

    Article  CAS  PubMed  Google Scholar 

  • Qaseem A, Barry MJ, Kansagara D (2016) Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: a clinical practice guideline from the American college of physicians. Ann Intern Med 164(5):350–359

    Article  PubMed  Google Scholar 

  • Siddaway AP, Wood AM, Hedges LV (2019) How to do a systematic review: a best practice guide for conducting and reporting narrative reviews, meta-analyses, and meta-syntheses. Annu Rev Psychol 70:747–770

    Article  PubMed  Google Scholar 

  • Stotz G, Woggon B, Angst J (1999) Psychostimulants in the therapy of treatment-resistant depression review of the literature and findings from a retrospective study in 65 depressed patients. Dialogues Clin Neurosci 1(3):165–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV (2022) Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry 179(7):490–499

    Article  PubMed  Google Scholar 

  • Thornicroft G, Chatterji S, Evans-Lacko S, Gruber M, Sampson N, Aguilar-Gaxiola S, Al-Hamzawi A, Alonso J, Andrade L, Borges G, Bruffaerts R, Bunting B, de Almeida JM, Florescu S, de Girolamo G, Gureje O, Haro JM, He Y, Hinkov H, Karam E, Kawakami N, Lee S, Navarro-Mateu F, Piazza M, Posada-Villa J, de Galvis YT, Kessler RC (2017) Undertreatment of people with major depressive disorder in 21 countries. Br J Psychiatry 210(2):119–124

    Article  PubMed  PubMed Central  Google Scholar 

  • Tsunoka T, Kishi T, Ikeda M, Kitajima T, Yamanouchi Y, Kinoshita Y, Kawashima K, Okochi T, Okumura T, Inada T, Ozaki N, Iwata N (2009) Association analysis of group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population. Prog Neuropsychopharmacol Biol Psychiatry 33(5):875–879

    Article  CAS  PubMed  Google Scholar 

  • van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, Salyakina D, Lamberts SW, Holsboer F (2006) Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 59(8):681–688

    Article  PubMed  Google Scholar 

  • Vyklicky V, Korinek M, Smejkalova T, Balik A, Krausova B, Kaniakova M, Lichnerova K, Cerny J, Krusek J, Dittert I, Horak M, Vyklicky L (2014) Structure, function, and pharmacology of NMDA receptor channels. Physiol Res 63(Suppl 1):S191-203

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Duan X, Dong M, Sun S, Zhang P, Liu F, Wang L, Wang R (2022) Clinical feature and sural biopsy study in nitrous oxide-induced peripheral neuropathy. PLoS One 17(9):e0274765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winstock AR, Ferris JA (2020) Nitrous oxide causes peripheral neuropathy in a dose dependent manner among recreational users. J Psychopharmacol 34(2):229–236

    Article  PubMed  Google Scholar 

  • Yan D, Liu B, Wei X, Ou W, Liao M, Ji S, Peng Y, Liu J, Wu S, Wang M, Ju Y, Zhang L, Li Z, Li L, Zhang Y (2022) Efficacy and safety of nitrous oxide for patients with treatment-resistant depression, a randomized controlled trial. Psychiatry Res 317:114867

    Article  CAS  PubMed  Google Scholar 

  • Zacny JP, Cho AM, Toledano AY, Galinkin J, Coalson DW, Klock PA, Klafta JM, Young CJ (1997) Effects of information on the reinforcing, subjective, and psychomotor effects of nitrous oxide in healthy volunteers. Drug Alcohol Depend 48(2):85–95

    Article  CAS  PubMed  Google Scholar 

  • Zorumski CF, Nagele P, Mennerick S, Conway CR (2015) Treatment-resistant major depression: rationale for NMDA receptors as targets and nitrous oxide as therapy. Front Psychiatry 6:172

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Suzhou Health Talents Training Project (Grants No GSWS2019002).

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Author notes

  1. Youjia Qiu and Longyuan Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, China

    Youjia Qiu, Longyuan Li, Aojie Duan, Minjia Xie, Zhouqing Chen & Zhong Wang

  2. Suzhou Medical College of Soochow USniversity, Suzhou, 215002, Jiangsu Province, China

    Menghan Wang

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  1. Youjia Qiu
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Contributions

The principal investigators: YJQ and LYL; data design: ZW and ZQC; data analysis: AJD and MHW; drafting of the manuscript: LYL, MJX, and ZQC; approval of the final version for publication: all the authors.

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Correspondence to Zhouqing Chen or Zhong Wang.

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Qiu, Y., Li, L., Duan, A. et al. The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis. Psychopharmacology 240, 2033–2043 (2023). https://doi.org/10.1007/s00213-023-06449-w

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