{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:00:13Z","timestamp":1790190013519,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T00:00:00Z","timestamp":1555977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["INSERM UMR_S 1256"],"award-info":[{"award-number":["INSERM UMR_S 1256"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The risk of adverse effects of nitrous oxide (N2O) exposure is insufficiently recognized despite its widespread use. These effects are mainly reported through case reports. We conducted an individual patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with N2O exposure in medical and recreational settings. We calculated the pooled estimates for the studied outcomes and assessed the potential bias related to population stratification using principal component analysis. Eighty-five publications met the inclusion criteria and reported on 100 patients with a median age of 27 years and 57% of recreational users. The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%). A T2 signal hyperintensity in the spinal cord was reported in 68% (57.2\u201378.8%) of patients. The most frequent clinical manifestations included paresthesia (80%; 72.0\u201388.0%), unsteady gait (58%; 48.2\u201367.8%), and weakness (43%; 33.1\u201352.9%). At least one hematological abnormality was retrieved in 71.7% (59.9\u201383.4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 &lt;150 pmol\/L (70.7%; 60.7\u201380.8%), homocysteine &gt;15 \u00b5mol\/L (90.3%; 79.3\u2013100%), and methylmalonic acid &gt;0.4 \u00b5mol\/L (93.8%; 80.4\u2013100%). Consistently, 85% of patients exhibited a possibly or probably deficient vitamin B12 status according to the cB12 scoring system. N2O can produce severe outcomes, with neurological or hematological disorders in almost all published cases. More than half of them are reported in the setting of recreational use. The N2O-related burden is dominated by vitamin B12 deficiency. This highlights the need to evaluate whether correcting B12 deficiency would prevent N2O-related toxicity, particularly in countries with a high prevalence of B12 deficiency.<\/jats:p>","DOI":"10.3390\/jcm8040551","type":"journal-article","created":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T03:14:28Z","timestamp":1556075668000},"page":"551","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":133,"title":["Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9731-4529","authenticated-orcid":false,"given":"Abderrahim","family":"Oussalah","sequence":"first","affiliation":[{"name":"University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France"},{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"},{"name":"Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lissa","family":"Julien","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Hajjar","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Franczak","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Stephan","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Laugel","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Wandzel","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Filhine-Tresarrieu","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5067-042X","authenticated-orcid":false,"given":"Jean-Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[{"name":"University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France"},{"name":"Department of Molecular Medicine and Personalized Therapeutics, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000 Nancy, France"},{"name":"Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"key":"ref_1","first-page":"421","article-title":"The discoverer of anaesthesia: Dr. Horace wells of hartford","volume":"5","author":"Erving","year":"1933","journal-title":"Yale J. Biol. Med."},{"key":"ref_2","first-page":"1","article-title":"Lessons from history: Horace wells and the moral features of clinical contexts","volume":"42","author":"Finder","year":"1995","journal-title":"Anesth. Prog."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/bja\/aev297","article-title":"The increasing recreational use of nitrous oxide: History revisited","volume":"116","author":"Randhawa","year":"2016","journal-title":"Br. J. Anaesth."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/ajad.12372","article-title":"Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature","volume":"25","author":"Garakani","year":"2016","journal-title":"Am. J. Addict."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0140-6736(56)90593-1","article-title":"Treatment of tetanus; severe bone-marrow depression after prolonged nitrous-oxide anaesthesia","volume":"270","author":"Lassen","year":"1956","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S0140-6736(78)92941-0","article-title":"Megaloblastic haemopoiesis in patients receiving nitrous oxide","volume":"2","author":"Amess","year":"1978","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_7","unstructured":"Reuters, T. (2013). Endnote x7, Thomson Reuters."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of observational studies in epidemiology (moose) group","volume":"283","author":"Stroup","year":"2000","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1515\/cclm-2014-0818","article-title":"Combined indicator of vitamin b12 status: Modification for missing biomarkers and folate status and recommendations for revised cut-points","volume":"53","author":"Fedosov","year":"2015","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Efron, B., and Tibshirani, R.J. (1994). An inTroduction to the Bootstrap, Taylor & Francis.","DOI":"10.1201\/9780429246593"},{"key":"ref_12","unstructured":"Organization of Word Health (2018, September 27). Iron Deficiency Anaemia Assessment, Prevention, and Control a Guide for Programme Managers. Available online: http:\/\/www.who.int\/nutrition\/publications\/en\/ida_assessment_prevention_control.pdf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/ajmg.a.20234","article-title":"Methionine synthase (mtr) 2756 (a -->g) polymorphism, double heterozygosity methionine synthase 2756 ag\/methionine synthase reductase (mtrr) 66 ag, and elevated homocysteinemia are three risk factors for having a child with down syndrome","volume":"121","author":"Bosco","year":"2003","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1159\/000075307","article-title":"Vitamin b12 is a strong determinant of low methionine synthase activity and DNA hypomethylation in gastrectomized rats","volume":"68","author":"Brunaud","year":"2003","journal-title":"Digestion"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1159\/000080350","article-title":"Homocysteine increases methionine synthase mrna level in caco-2 cells","volume":"14","author":"Ortiou","year":"2004","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1160\/TH06-02-0082","article-title":"Association of homocysteine (but not of mthfr 677 c > t, mtr 2756 a > g, mtrr 66 a > g and tcn2 776 c>g) with ischaemic cerebrovascular disease in sicily","volume":"96","author":"Bosco","year":"2006","journal-title":"Thromb. Haemost."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.ymgme.2007.05.002","article-title":"Mice deficient in cystathionine beta synthase display altered homocysteine remethylation pathway","volume":"91","author":"Alberto","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1002\/ajmg.a.32199","article-title":"Nutritional and genetic determinants of vitamin b and homocysteine metabolisms in neural tube defects: A multicenter case-control study","volume":"146","author":"Candito","year":"2008","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4591","DOI":"10.1093\/hmg\/ddt308","article-title":"Interaction between methionine synthase isoforms and mmachc: Characterization in cblg-variant, cblg and cblc inherited causes of megaloblastic anaemia","volume":"22","author":"Mrabet","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e553","DOI":"10.1038\/cddis.2013.69","article-title":"Decreased vitamin b12 availability induces er stress through impaired sirt1-deacetylation of hsf1","volume":"4","author":"Ghemrawi","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.bbadis.2016.10.016","article-title":"Methionine synthase and methionine synthase reductase interact with mmachc and with mmadhc","volume":"1863","author":"Bassila","year":"2017","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17040","DOI":"10.1038\/nrdp.2017.40","article-title":"Vitamin b12 deficiency","volume":"3","author":"Green","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1182\/blood-2016-10-569186","article-title":"Vitamin b12 deficiency from the perspective of a practicing hematologist","volume":"129","author":"Green","year":"2017","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jns.2010.10.033","article-title":"Nitrous oxide-induced b(1)(2) deficiency myelopathy: Perspectives on the clinical biochemistry of vitamin b(1)(2)","volume":"301","author":"Hathout","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/S0140-6736(78)92314-0","article-title":"Animal model for subacute combined degeneration","volume":"2","author":"Dinn","year":"1978","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1016\/0024-3205(82)90039-X","article-title":"Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: Protection by methionine and aggravation by folates","volume":"31","author":"Metz","year":"1982","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1146\/annurev.nu.12.070192.000423","article-title":"Cobalamin deficiency and the pathogenesis of nervous system disease","volume":"12","author":"Metz","year":"1992","journal-title":"Annu. Rev. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/0305-0491(83)90407-8","article-title":"Protein profile of the myelin membrane of the fruit bat rousettus aegyptiacus","volume":"76","author":"Cantrill","year":"1983","journal-title":"Comp. Biochem. Physiol. B"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0022-510X(86)90040-7","article-title":"Vitamin b12 neuropathy is not due to failure to methylate myelin basic protein","volume":"72","author":"Deacon","year":"1986","journal-title":"J. Neurol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jneuroim.2006.04.002","article-title":"Increased levels of the cd40:Cd40 ligand dyad in the cerebrospinal fluid of rats with vitamin b12(cobalamin)-deficient central neuropathy","volume":"176","author":"Veber","year":"2006","journal-title":"J. Neuroimmunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1096\/fasebj.13.14.2083","article-title":"Epidermal growth factor as a local mediator of the neurotrophic action of vitamin b(12) (cobalamin) in the rat central nervous system","volume":"13","author":"Scalabrino","year":"1999","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1093\/jnen\/59.9.808","article-title":"Further evidence for the involvement of epidermal growth factor in the signaling pathway of vitamin b12 (cobalamin) in the rat central nervous system","volume":"59","author":"Scalabrino","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.neulet.2005.11.029","article-title":"Increased spinal cord ngf levels in rats with cobalamin (vitamin b12) deficiency","volume":"396","author":"Scalabrino","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/ana.20325","article-title":"High tumor necrosis factor-alpha [corrected] levels in cerebrospinal fluid of cobalamin-deficient patients","volume":"56","author":"Scalabrino","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1172\/JCI110155","article-title":"Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats","volume":"67","author":"Kondo","year":"1981","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1093\/bja\/aen085","article-title":"Effect of nitrous oxide on plasma homocysteine and folate in patients undergoing major surgery","volume":"100","author":"Myles","year":"2008","journal-title":"Br. J. Anaesth."},{"key":"ref_37","unstructured":"Home Office (2018, July 28). Drug Misuse: Findings from the 2016\/17 Crime Survey for England and Wales, Available online: https:\/\/assets.Publishing.Service.Gov.Uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/642738\/drug-misuse-2017-hosb1117.Pdf."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1177\/0269881116632375","article-title":"Up: The rise of nitrous oxide abuse. An international survey of contemporary nitrous oxide use","volume":"30","author":"Kaar","year":"2016","journal-title":"J. Psychopharmacol."},{"key":"ref_39","unstructured":"Survey, G.D. (2018, July 28). Key Findings from the Global Drug Survey 2016 (data collected nov 15 January 16). Available online: https:\/\/www.Globaldrugsurvey.Com\/past-findings\/the-global-drug-survey-2016-findings\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1093\/bja\/aet416","article-title":"Does anaesthesia with nitrous oxide affect mortality or cardiovascular morbidity? A systematic review with meta-analysis and trial sequential analysis","volume":"112","author":"Imberger","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1093\/ajcn\/79.4.619","article-title":"High prevalence of hyperhomocysteinemia related to folate deficiency and the 677c-->t mutation of the gene encoding methylenetetrahydrofolate reductase in coastal west africa","volume":"79","author":"Amouzou","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1161\/01.STR.0000204061.73332.aa","article-title":"Heterogeneity of association between mthfr and stroke among european regions: Additional population studies are needed in italy","volume":"37","author":"Bosco","year":"2006","journal-title":"Stroke"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1111\/j.1538-7836.2007.02535.x","article-title":"Left ventricular systolic dysfunction is an independent predictor of homocysteine in angiographically documented patients with or without coronary artery lesions","volume":"5","author":"Juilliere","year":"2007","journal-title":"J. Thromb. Haemost. Jth"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1111\/j.1572-0241.2007.01170.x","article-title":"Vascular and cellular stress in inflammatory bowel disease: Revisiting the role of homocysteine","volume":"102","author":"Chamaillard","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1515\/CCLM.2007.065","article-title":"Association of vitamin b12, folate and homocysteine with functional and pathological characteristics of the elderly in a mountainous village in sicily","volume":"45","author":"Spada","year":"2007","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.atherosclerosis.2010.11.031","article-title":"Homocysteine is a determinant of apoa-i and both are associated with ankle brachial index, in an ambulatory elderly population","volume":"214","author":"Spada","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1056\/NEJM199603213341203","article-title":"Hyperhomocysteinemia as a risk factor for deep-vein thrombosis","volume":"334","author":"Koster","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1093\/ije\/31.1.115","article-title":"Direction and impact of language bias in meta-analyses of controlled trials: Empirical study","volume":"31","author":"Juni","year":"2002","journal-title":"Int. J. Epidemiol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/4\/551\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:46:38Z","timestamp":1760186798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/4\/551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,23]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["jcm8040551"],"URL":"https:\/\/doi.org\/10.3390\/jcm8040551","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,23]]}}}