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Disturbances in Biological Parameters in Patients Exposed to Nitrous Oxide Abuse Experience of the Rene Dubos Hospital Centre in Pontoise

Received: 9 July 2024     Accepted: 8 August 2024     Published: 20 August 2024
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Abstract

Nitrous oxide abuse is increasingly common among young people. It's a gas consumed at parties, where access is easy and less expensive. It can cause vitamin deficiencies, leading to neurological and non-neurological clinical manifestations. The aim of this study was to establish the blood biology profile of patients hospitalized for neurological disorders in the context of nitrous oxide abuse. Methodology, we conducted a retrospective and prospective descriptive study from January 2021 to April 2023. We studied frequency of consumption, inhaled dose and time of exposure to nitrous oxide. Blood levels of vitamin B12 and B9 were measured. Methylmalonic acid and homocysteine were also measured in the blood. Results include 15 patients recruited during the study period. 7 of the 15 patients used nitrous oxide daily. One patient consumed 9600 grams per week. Ten patients had a delay in toxicity beyond one year. Vitamin B12 blood levels were normal in 8 of 15 patients. On average, vitamin B12 levels were normal at 207.57 pmol/l. Vitamin B9 was not routinely measured in 9 patients. Blood homocysteine levels were elevated in 12 of 13 patients, with a high mean of 83.36 µmol/l. In conclusion, blood homocysteine levels are a more reliable marker than vitamin B12 for demonstrating biological disturbances associated with laughing gas abuse.

Published in Advances in Biochemistry (Volume 12, Issue 3)
DOI 10.11648/j.ab.20241203.12
Page(s) 99-104
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Homocysteine, Neurology, Nitrous Oxide, Vitamin B12

1. Introduction
Nitrous oxide is a gas legally used in various fields, notably medicine . According to a study conducted by NSDUH (National Survey of Drug Use and Health), nearly 21% of teenagers worldwide use drugs, starting with nitrous oxide . Nitrous oxide (N2O), or laughing gas, abused at parties is a growing problem . Vitamin B12 as a cofactor of several metabolic pathways becomes dysfunctional due to its oxidation linked to chronic N2O consumption . Indeed, nitrous oxide inhibits the methionine synthetase enzyme in the liver This inhibition leads to inactivation of vitamin B12, resulting in methionine deficiency and capture of the tetrahydrofolate molecule . This leads not only to vitamin B12 deficiency, but also to a drop in intracellular folate concentration, with a consequent reduction in nucleotide synthesis. This enzymatic action is due to the fact that nitrous oxide inactivates methylcobalamin by oxidation of the cobalt ion it contains. Methylcobalamin no longer acts as a cofactor for methionine synthetase . This blocks the various synthesis cascades of major cellular elements. Vitamin B12 deficiency can lead to myelopathy and/or encephalopathy, but mainly peripheral neuropathy . Blood tests for vitamin B12, homocysteine, vitamin B9 and methyl melanonic acid should be carried out systematically.
Given the extent of nitrous oxide abuse during parties, the aim of our study was to measure biological parameters in patients to detect abnormalities in order to assess the severity of impairment and the effectiveness of management.
2. Materials and Methods
2.1. Setting of the Study
Neurology Department of the Centre Hospitalier René Dubois, Pontoise.
2.2. Type of Study
We conducted a retrospective and prospective descriptive study covering the period from January 2021 to April 2023
2.3. Study Population
The study population consisted mainly of patients with neurological disorders related to nitrous oxide abuse. These patients were admitted to neurological hospitals. Most of them came from the emergency department, the neurological consultation pool or general medicine. Patients hospitalized for peripheral and spinal neurological disorders without nitrous oxide consumption were not included in our study. Data were collected from patients' hospitalization records, using a standardized questionnaire.
2.4. Variables Studied and Data Collection
*Characteristics of nitrous oxide consumption: frequency of exposure (day, week or month), approximate quantity inhaled (in grams) for each patient. Time to toxicity in number of months
*Biological parameters blood levels of vitamin B9, B12, homocysteine and methylmalonic acid. average blood rate of vitamine B12, B9, Homocysteine and methylmalonic.
.Qualitative data is expressed as a percentage. Quantitative data were expressed as mean +/- standard deviation. Data entry and results analysis were performed using Excel software. The confidentiality of the data collected was guaranteed by the anonymous nature of the data collection, based essentially on file numbers.
3. Results
3.1. Characteristics of Nitrous Oxide Consumption
We enrolled 15 patients during the study period. Data on nitrous oxide consumption are summarized in Table 1.
3.2. Biological Parameters
Vitamin B12 was not measured in 1 patient. Vitamin B9 dosage was only performed in 8 patients. Vitamin B12 deficiency was noted in 6 out of 11 patients; vitamin B9 deficiency in 2 out of 8 patients. On average, blood levels of vitamin B12 and B9 were normal (Table 2). Data on homocysteine and methylmalonic acid levels are summarized in Table 3.
Table 1. Characteristics of nitrous oxide consumption.

Patients

Consumption frequency

Average consumption (grams/week)

Toxicity time

1

3-6 times a week

Not specified

6 months

2

1 time a week

80

Less than 1 month

3

2times a week

160

More than 12 months

4

Daily

Not specified

More than12 months

5

Daily

1600

More than 6 months

6

Daily

3200

More than12 months

7

Daily

1600

More than12 months

8

Daily

4000

More than12 months

9

Daily

2400

More than12 months

10

Daily

3200

More than12 months

11

2 times a week

3200

6 months

12

4 times a week

6400

2 months

13

4 times a week

9600

More than12 months

14

3 times a week

4800

More than12months

15

3 times a week

Not specified

More than12 months

Seven patients had been taking nitrous oxide daily for more than six to twelve months.
Table 2. Vitamin B12 and B9 blood test results.

Patients

Vitamin B12 assay (pmol/l)

Vitamin B9 assay (nmol/l)

1

213 (normal)

11 (limit of normal)

2

231 (normal)

11.7 (limit of normal)

3

254 (normal)

10.1 (deficiency)

4

<109 (deficiency)

11.3 (limit of normal)

5

289 (normal)

13.4 (normal)

6

124 (deficiency)

15.8 (normal)

7

172 (deficiency)

Not realized

8

278 (normal)

Not realized

9

186 (limit of normal)

Not realized

10

<109 (deficiency)

17.9 (normal)

11

342 (normal)

Not realized

12

363 (normal)

Not realized

13

123 (deficiency)

Not realized

14

Not realized

Not realized

15

113 (deficiency)

8.6 (deficiency)

Average

207.57 (normal)

12.47 (normal)

Eight out of fourteen patients had normal vitamin B12 levels. On average, vitamin B12 levels were normal. Vitamin B9 dosage was not routinely performed
Table 3. Blood results for homocysteine and methylmalonic acid.

Patients

Homocysteine assay (µmol/l)

Determination of methylmalonic acid (µmol/l))

1

120.67 (increased)

Not realized

2

17(increased slightly)

29.1 (normal)

3

110.91 (increased)

840 (increased)

4

2 (normal)

17 (normal)

5

56.4 (increased)

134.5 (normal)

6

61.39 (increased)

Not realized

7

152.14 (increased)

Not realized

8

146.85 (increased)

Not realized

9

101.37 (increased)

Not realized

10

21.23 (increased)

Not realized

11

46.24 (increased)

132.1 (normal)

12

126.31(increased)

Not realized

13

121.23(increased)

Not realized

14

Not realized

Not realized

15

Not realized

Not realized

Average

83.36 (increased)

230.5 (normal)

On average, homocysteine levels were normal.
4. Discussion
4.1. Characteristics of Nitrous Oxide Consumption
It was difficult to specify exactly how much was inhaled. However, based on the fact that a cartridge for a whipped cream siphon contained 8 grams of nitrous oxide, we were able to accumulate the dose consumed per week. The dose varied from 80 grams to 9600 grams per week, with the majority of patients consuming every day. Accordind to Agarwal and al, the use of nitrous oxide is still legal and beyond the reach of the Drug Enforcement Administration . This exposure took place at parties. 10 out of 15 patients had a toxicity delay of over a year. This shows the addictive nature of this drug. According to Van and al Recreational N2O users, however, voluntarily and repeatedly expose themselves to (very) high doses of N2O .
4.2. Biological Parameters
Overuse of inhaled nitrous oxide is becoming increasingly common. It leads to altered concentrations of vitamin B12, a cofactor for methionine synthase and methylmalonyl-CoA mutase activity. Consequently, the measurement of biomarkers of cobalamin metabolism, including vitamin B12, homocysteine and methylmalonic acid, could help in the management of patients with complex clinical presentations or those who deny nitrous oxide consumption . We observed vitamin B12 deficiency in 6 of 14 patients. Mean vitamin B12 levels were normal at 207.57 pmol/l. On the other hand, Mondesert et al reported a vitamin B12 deficiency in their study, with a mean blood level estimated at 134.6 pmol/L . It was difficult to assess vitamin B9 levels, as these are not routinely measured. Homocysteine levels were elevated in 13 patients, with a mean level of 83.36 µmol/l.
Methylmalonic acid levels were increased in 1 of the 5 patients who benefited from this assay.
Methylmalonic acid levels were increased in 1 of the 5 patients who benefited from this assay. As homocysteine is a reliable biomarker of N2O toxicity, it should be routinely measured. In their cohort, Swart and al noted vitamin B12 deficiency in 10 out of 20 patients . They reported profiles of nitrous oxide abusers with neurological signs but normal blood levels of vitamin B12. Vitamin B12 levels did not correlate significantly with cumulative nitrous oxide use. Also in their study, Swart et al reported elevated homocysteine in virtually all patients, which may be a more sensitive marker than vitamin B12 levels . In the same vein, Grzych et al report that there is no specific marker of nitrous oxide abuse according to the level of consumption, and the total decrease in vitamin B12 can be used neither as a marker of consumption nor as a marker of severity. Nevertheless, homocysteine is systematically increased and could be used as a marker of recent N2O consumption. On the other hand, they reported that methyl malonic acid could be used as a marker of clinical severity A recent neurodiagnostic study identified greater motor axonal dysfunction in patients with N2O abuse than in those with vitamin B12 deficiency (who had greater sensory axonal dysfunction) . This suggests a unique pathophysiology, not solely dependent on vitamin B12 function .
5. Conclusion
Recreational nitrous oxide abuse is a real public health problem. Classified as a drug, it is responsible for biological disturbances in chronic users. To confirm the diagnosis outside the clinic, biological parameters such as vitamin B12, B9, homocysteine and methylmalonic acid need to be measured. Homocysteine is a reliable marker for the impact of nitrous oxide abuse, while vitamin B12 may be normal. Moreover, there is no cumulative correlation between inhaled dose and vitamin B12 deficiency. In addition to homocysteine, methylmalonic acid should also be systematically measured, to reinforce the biological diagnosis and clarify the severity of the clinical picture, as well as for proper follow-up after treatment.
Abbreviations

N2O

Nitrous Oxide

Acknowledgments
To the staff of the neurology department of the Pontoise hospital.
Doctor Pottier Corinne
To the head of the neurology department at Pontoise hospital: Doctor Philippe Niclot.
Author Contributions
Yannick Thibaut Koffi: Conceptualization, Data curation
Corrine Pottier: Supervision, Validation
Samuel Nawa Yeo: Data curation
Philippe Niclot: Resources
Data Availability Statement
The data is available from the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare no Conflicts of Interest.
References
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[2] Yu, M., Qiao, Y., Li, W., Fang, X., Gao, H., Zheng, D., Ma Y. Analysis of clinical characteristics and prognostic factors in 110 patients with nitrous oxide abuse. Brain Behav. 2022 Apr; 12(4): e2533.
[3] Ménétrier, T., Denimal, D. Vitamin B12 Status in Recreational Users of Nitrous Oxide: A Systematic Review Focusing on the Prevalence of Laboratory Abnormalities. Antioxidants (Bsel).2023May31; 12(6): 1191.
[4] Vollhardt, R., Mazoyer, J., Bernardaud, L., Haddad, A., Jaubert, P., Coman, I., Manceau P., Mongin, M., Degos, B. Neurological consequences of recreational nitrous oxide abuse during SARSCoV-2 pandemic. J Neurol. 2022 Apr; 269(4): 1921-1926.
[5] Thayabaran, D., Burrage, D. Nitrous oxide-induced neurotoxicity: A case report and literature review. Br J Clin Pharmacol. 2021 Sep; 87(9): 3622-3626.
[6] Adrien J. Usage et mésusage du protoxyde d’azote. Thèse N° 57, UFR Phamarcie, Université de Bordeaux. Mai 2022.
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[8] Agarwal, P., Khor, SY., Do, S., Charles, L., Tikaria, R. Recreational Nitrous Oxide-Induced Subacute Combined Degeneration of the Spinal Cord. Cureus. 2021 Nov 8; 13(11): e19377.
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[10] Crisp, RS. Cracking the Whippet: The Inconsistent Treatment of Myeloneuropathy Secondary to Chronic Nitrous Oxide Misuse. Cureus. 2024 Jan 26; 16(1): e52978.
[11] Oussalah, A., Julien, M., Levy, J., Hajjar, O., Franczak, C., Stephan, C., Laugel, E., Wandzel, M., Filhine-Tresarrieu, P., Green, R., Guéant, JL. Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis. J Clin Med. 2019 Apr 23; 8(4): 551.
[12] Mondesert, E., Eiden, C., Peyriere, H., Formoso, A., Corti, L., Cristol, JP., Badiou, S. Functional vitamin B12 deficiency is a consistent feature in hospital admissions for neurological disorders due to the use of nitrous oxide. Clin Toxicol (Phila). 2023Sep; 61(9): 674-679.
[13] Swart, G., Blair, C., Lu, Z., Yogendran, S., Offord, J., Sutherland, E., Barnes, S., Palavra, N., Cremer, P., Bolitho, S., Michael, H. Nitrous oxide-induced myeloneuropathy. Eur J Neurol. 2021 Dec; 28(12): 3938-3944
[14] Grzych G., Deheul, S., Gernez, E., Davion, JB., Dobbelaere, D., Carton, L., Kim, I., Guichard, JC., Girot, M., Humbert, L., Bennis, A., Joncquel, M., Chieux, V., Joly, A., Nasserdine P, Trillot N, Douillard C, Pigny P, Tard C. Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study. J Neurol. 2023 Apr; 270(4): 2237-2245.
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Cite This Article
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    Koffi, Y. T., Yeo, S. N., Pottier, C., Niclot, P. (2024). Disturbances in Biological Parameters in Patients Exposed to Nitrous Oxide Abuse Experience of the Rene Dubos Hospital Centre in Pontoise. Advances in Biochemistry, 12(3), 99-104. https://doi.org/10.11648/j.ab.20241203.12

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    ACS Style

    Koffi, Y. T.; Yeo, S. N.; Pottier, C.; Niclot, P. Disturbances in Biological Parameters in Patients Exposed to Nitrous Oxide Abuse Experience of the Rene Dubos Hospital Centre in Pontoise. Adv. Biochem. 2024, 12(3), 99-104. doi: 10.11648/j.ab.20241203.12

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    AMA Style

    Koffi YT, Yeo SN, Pottier C, Niclot P. Disturbances in Biological Parameters in Patients Exposed to Nitrous Oxide Abuse Experience of the Rene Dubos Hospital Centre in Pontoise. Adv Biochem. 2024;12(3):99-104. doi: 10.11648/j.ab.20241203.12

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  • @article{10.11648/j.ab.20241203.12,
      author = {Yannick Thibaut Koffi and Samuel Nawa Yeo and Corinne Pottier and Philippe Niclot},
      title = {Disturbances in Biological Parameters in Patients Exposed to Nitrous Oxide Abuse Experience of the Rene Dubos Hospital Centre in Pontoise
    },
      journal = {Advances in Biochemistry},
      volume = {12},
      number = {3},
      pages = {99-104},
      doi = {10.11648/j.ab.20241203.12},
      url = {https://doi.org/10.11648/j.ab.20241203.12},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ab.20241203.12},
      abstract = {Nitrous oxide abuse is increasingly common among young people. It's a gas consumed at parties, where access is easy and less expensive. It can cause vitamin deficiencies, leading to neurological and non-neurological clinical manifestations. The aim of this study was to establish the blood biology profile of patients hospitalized for neurological disorders in the context of nitrous oxide abuse. Methodology, we conducted a retrospective and prospective descriptive study from January 2021 to April 2023. We studied frequency of consumption, inhaled dose and time of exposure to nitrous oxide. Blood levels of vitamin B12 and B9 were measured. Methylmalonic acid and homocysteine were also measured in the blood. Results include 15 patients recruited during the study period. 7 of the 15 patients used nitrous oxide daily. One patient consumed 9600 grams per week. Ten patients had a delay in toxicity beyond one year. Vitamin B12 blood levels were normal in 8 of 15 patients. On average, vitamin B12 levels were normal at 207.57 pmol/l. Vitamin B9 was not routinely measured in 9 patients. Blood homocysteine levels were elevated in 12 of 13 patients, with a high mean of 83.36 µmol/l. In conclusion, blood homocysteine levels are a more reliable marker than vitamin B12 for demonstrating biological disturbances associated with laughing gas abuse.
    },
     year = {2024}
    }
    

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  • TY  - JOUR
    T1  - Disturbances in Biological Parameters in Patients Exposed to Nitrous Oxide Abuse Experience of the Rene Dubos Hospital Centre in Pontoise
    
    AU  - Yannick Thibaut Koffi
    AU  - Samuel Nawa Yeo
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    Y1  - 2024/08/20
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    N1  - https://doi.org/10.11648/j.ab.20241203.12
    DO  - 10.11648/j.ab.20241203.12
    T2  - Advances in Biochemistry
    JF  - Advances in Biochemistry
    JO  - Advances in Biochemistry
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    EP  - 104
    PB  - Science Publishing Group
    SN  - 2329-0862
    UR  - https://doi.org/10.11648/j.ab.20241203.12
    AB  - Nitrous oxide abuse is increasingly common among young people. It's a gas consumed at parties, where access is easy and less expensive. It can cause vitamin deficiencies, leading to neurological and non-neurological clinical manifestations. The aim of this study was to establish the blood biology profile of patients hospitalized for neurological disorders in the context of nitrous oxide abuse. Methodology, we conducted a retrospective and prospective descriptive study from January 2021 to April 2023. We studied frequency of consumption, inhaled dose and time of exposure to nitrous oxide. Blood levels of vitamin B12 and B9 were measured. Methylmalonic acid and homocysteine were also measured in the blood. Results include 15 patients recruited during the study period. 7 of the 15 patients used nitrous oxide daily. One patient consumed 9600 grams per week. Ten patients had a delay in toxicity beyond one year. Vitamin B12 blood levels were normal in 8 of 15 patients. On average, vitamin B12 levels were normal at 207.57 pmol/l. Vitamin B9 was not routinely measured in 9 patients. Blood homocysteine levels were elevated in 12 of 13 patients, with a high mean of 83.36 µmol/l. In conclusion, blood homocysteine levels are a more reliable marker than vitamin B12 for demonstrating biological disturbances associated with laughing gas abuse.
    
    VL  - 12
    IS  - 3
    ER  - 

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Author Information
  • Neurology Department, Bouake University Hospital Centre, Bouake, Ivory Coast

  • Neurology Department, Bouake University Hospital Centre, Bouake, Ivory Coast

  • Neurology Department, Rene Dubos Hospital, Pontoise, France

  • Neurology Department, Rene Dubos Hospital, Pontoise, France