Does Nitrous Oxide Cause Adverse Reactions for People with MTHFR?

Does Nitrous Oxide Cause Adverse Reactions for People with MTHFR?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

April 16, 2025

Table of Contents

    Does Nitrous Oxide Cause Adverse Reactions for People with MTHFR?

    Those with an MTHFR mutation may already be aware that they have a higher risk of certain health conditions like nutritional deficiencies, elevated homocysteine, depression, and more.


    However, many may not be aware of the potential dangers of the common anesthesia, nitrous oxide.


    Nitrous oxide (NO) is a colorless gas used as an anxiolytic and anesthetic during medical procedures, usually in dentistry. Studies show that patients with the common MTHFR mutations C677T or A1298C may develop higher plasma homocysteine concentrations after nitrous oxide1 anesthesia than those without the mutation. In serious cases, the combination of elevated homocysteine and nitrous oxide has been fatal.


    This article will explain the use of nitrous oxide and how it affects people with MTHFR mutations. We will also discuss other forms of anesthesia and their impact on MTHFR, and whether any safe alternatives exist.

    How is Nitrous Oxide Used?

    Also known as laughing gas, nitrous oxide-oxygen2 is a form of inhalation sedation commonly used by dentists and medical professionals. It has been used in the medical industry for over 150 years and continues to be the most popular of all gaseous anesthetics in the world. When administered with the correct equipment, it is said to have “an extremely high success rate3 and a low rate of adverse effects and complications”.


    When inhaled, nitrous oxide gas produces feelings of euphoria and calm. This makes it useful for providing sedation and pain relief for patients undergoing minor medical procedures. It also helps to reduce fear and anxiety.


    In dentistry, nitrous oxide inhalation sedation usually involves a combination of low-dose N2O and high-dose oxygen4. This combination induces relaxation and prevents the psychological tension experienced by patients who have "dental phobia". The high-dose oxygen also helps to prevent fainting caused by the pain.


    Although still used recreationally in some countries, access to NO is now mostly limited to dentists and hospitals.


    Other anesthetics have since been introduced, but nitrous oxide is still a major form of anesthesia. It may also be used in patients undergoing withdrawal symptoms from drugs and alcohol, as a propellant in processed food products such as whipped cream, and in cars to improve engine performance.

    How Does Nitrous Oxide Affect People with MTHFR?

    Although highly effective as a relaxant during a medical procedure, nitrous oxide (NO) may have serious negative effects for those with the MTHFR mutation.


    The inhibition of enzymes in the vitamin B12 pathway is most serious in patients with MTHFR mutations.


    NO causes irreversible oxidation of the cobalt atom of vitamin B125 (cobalamin), effectively destroying it. Methionine synthase is dependent on vitamin B12. By inhibiting this enzyme, homocysteine cannot be broken down, resulting in homocysteine elevation. For this reason, nitrous oxide is known to cause hyperhomocysteinemia6 in MTHFR patients.


    A large proportion of methionine is converted to S‐adenosylmethionine (SAMe), which donates methyl groups required for the synthesis of DNA and RNA, as well as many hormones, neurotransmitters, proteins, and lipids. SAMe is also crucial for the conversion of 5-methyl-tetrahydrofolate into tetrahydrofolate.


    NO also means vitamin B12 is not available to function as a cofactor for the methylmalonyl CoA mutase pathway, which is necessary for producing succinyl CoA, a crucial mitochondrial enzyme7 involved in ATP production. Succinyl CoA also plays a key role in the citric acid cycle, ketone metabolism, and the making of red blood cells.


    MTHFR patients who have received anesthesia with nitrous oxide generally end up with lower serum vitamin B12 compared to their preoperative levels.


    One study showed that nitrous oxide in MTHFR patients caused an acute increase in plasma homocysteine8 that lasted several days. Another study found that homocysteine was three times higher in homozygous MTHFR patients9 after nitrous oxide compared with those without the mutation.


    Elevated homocysteine levels have been found to be an independent risk factor for cardiovascular events including stroke and heart attacks, especially during surgery.


    When a patient with hyperhomocysteinemia is exposed to nitrous oxide, they may suffer severe neurological damage. Common neurologic manifestations include subacute combined degeneration of the spinal cord10, resulting in loss of coordination, balance, and speech (ataxia), burning or prickling sensation in the hands, arms, legs, or feet (paresthesia), and general loss of vibratory and position sensation.

    Is Using Nitrous Oxide Dangerous for MTHFR?

    Nitrous oxide interferes with the body’s ability to metabolize vitamin B12, which is essential for the production of DNA and red blood cells and for the normal function of the brain and the nervous system.


    Those with MTHFR mutations already have lower enzyme activity, higher homocysteine levels, and lower folate levels than those without the mutation.


    Using nitrous oxide poses a serious risk of increasing homocysteine further, which can lead to inflammation of endothelial cells11 and a higher risk of thrombosis, atherosclerosis, myocardial infarction, and cerebrovascular events.


    People who have a homozygous MTHFR polymorphism are three to six times more at risk12 of arterial or venous thrombosis compared with the rest of the population.


    Adequate nutrients must be provided before nitrous oxide to restore the cobalamin back to its active and effective state.

    Are Other forms of Anesthesia Dangerous with MTHFR?

    For MTHFR patients, avoiding nitrous oxide is key. However, it should be noted that nitrous oxide is primarily used as a weak general anesthetic. This is why it is usually used as a carrier gas combined with oxygen, and administered alongside more powerful general anesthetic drugs such as sevoflurane or desflurane.


    In terms of anesthetics, halogenated and intravenous anesthetics are generally considered safe for those with MTHFR mutations. The intravenous hypnotic propofol and volatile anesthetic sevoflurane13are found to have no effect on homocysteine levels in child patients with MTHFR deficiency. Coadministration of propofol and sevoflurane is also shown to provide faster awakening14 and extubation with a low incidence of emergence coughing and agitation compared to sevoflurane maintenance.

    What Alternatives Can You Request at the Dentist?

    Alternatives offered by some dental surgeries include calming agents such as NuCalm or CBD oil. Some clinics may also offer various anti-anxiety techniques such as meditation or tapping, meditation videos prior to the procedure, or headphones to wear during the treatment.


    These are safe alternatives to nitrous oxide that provide anxiolytic benefits and have no effects on B12 or homocysteine levels. 

    What if You Can’t Avoid Nitrous?

    For patients who cannot avoid being treated with nitrous oxide, there may be some benefit in taking Vitamin B12 beforehand.


    One study found that the administration of B-vitamins before nitrous oxide anesthesia helped to blunt the increase in homocysteine levels15, but did not decrease the rate and magnitude of risk factors for cardiac events. However, the researchers concluded that practitioners who felt their MTHFR patients would benefit from nitrous oxide need not refrain from providing it.


    Another study found that vitamin B12 infusion before administering nitrous oxide significantly decreased homocysteine16 levels, but not when infused afterward. However, it is important to note this study used only IV infusion of B12, and not oral supplementation.


    Increasing intake of vitamin B12 and liposomal glutathione before your dental appointment is highly recommended. Vitamin B12 is essential for the breakdown of homocysteine, while glutathione has also been shown to help reduce homocysteine levels17.


    Taking a methylated B12 vitamin alongside methylfolate can help support the body’s methylation process.


    Methyl-Life’s® B-Methylated-II contains methylfolate, which is essential for maintaining healthy homocysteine levels, and methylcobalamin (B12), which works closely alongside folate in converting homocysteine to methionine.


    Folate and B12 are also both required to produce S-adenosylmethionine (SAMe)18, the compound involved in methyl donation in neurotransmitter synthesis, free radical scavenging, stimulating glutathione production, reducing inflammation, and providing neuroprotective effects. 

    Methylcobalamin is the active form of B1219 and the most efficient means of supplying the nutrient as it is bioidentical to the B12 forms occurring in human physiology.


    Treatment with nitrous oxide should be preceded and followed by a low-homocysteine diet and supplementation with methylfolate, methylcobalamin, and other nutrients shown to help lower homocysteine: glutathione, NAC, vitamin B6, TMG or DMG, and taurine.

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    References

    1. N H Badner, W S Beattie, D Freeman, J D Spence; "Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy"; Anesthesia and Analgesia; 2000 Nov

      https://pubmed.ncbi.nlm.nih.gov/11049886/

    2. Stanley F Malamed, Moris S Clark; "Nitrous oxide-oxygen: a new look at a very old technique"; Journal of the California Dental Association; 2003 May

      https://pubmed.ncbi.nlm.nih.gov/12839232/

    3. Stanley F Malamed, Moris S Clark; "Nitrous oxide-oxygen: a new look at a very old technique"; Journal of the California Dental Association; 2003 May

      https://pubmed.ncbi.nlm.nih.gov/12839232/

    4. Yojiro Ogawa, Toru Misaki; "[The advantage and harmful effects of nitrous oxide in dental management]"; Masui. The Japanese journal of anesthesiology; 2011 Mar

      https://pubmed.ncbi.nlm.nih.gov/21485102/

    5. Ehizogie Edigin, Oyintayo Ajiboye, Avantika Nathani; "Nitrous Oxide-induced B12 Deficiency Presenting With Myeloneuropathy"; Curēus; 2019 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777927/

    6. American Association of Nurse Anesthesiology

      https://www.aana.com/docs/default-source/aana-journal-web-documents-1/hale-ra48cc95468c14ee289cfd09d81c4d946.pdf?sfvrsn=e4b32e5a_4

    7. Darci Phillips, Angel M Aponte, Stephanie A French, David J Chess, Robert S Balaban; "Succinyl-CoA Synthetase is a Phosphate Target for the Activation of Mitochondrial Metabolism"; Biochemistry; 2010 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766921/

    8. Peter Nagele, Frank Brown, Amber Francis, Mitchell G Scott, Brian F Gage, J Philip Miller, for the VINO study team; "Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR gene polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial"; Anesthesiology; 2014 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC3919550/

    9. American Society of Anesthesiologists

      https://pubs.asahq.org/anesthesiology/article/109/1/36/9027/Influence-of-Methylenetetrahydrofolate-Reductase

    10. Ehizogie Edigin, Oyintayo Ajiboye, Avantika Nathani; "Nitrous Oxide-induced B12 Deficiency Presenting With Myeloneuropathy"; Curēus; 2019 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777927/

    11. D Tousoulis, G Davies, C Stefanadis, P Toutouzas, J A Ambrose; "Inflammatory and thrombotic mechanisms in coronary atherosclerosis"; Heart; 2003 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767836/

    12. Hamilton Shay, Robert J Frumento, Alexandra Bastien; "General anesthesia and methylenetetrahydrofolate reductase deficiency"; Journal of anesthesia; 2007

      https://pubmed.ncbi.nlm.nih.gov/18008117/

    13. Zeynep Nur Orhon, Emine Nursen Koltka, Sevil Tüfekçi, Çiğdem Buldağ, Alperen Kısa, Çiğdem Ulukaya Durakbaşa, Melek Çelik; "Methylene Tetrahydrofolate Reductase Deficiency: the Hidden Risk in Paediatric Anaesthesia"; Turkish journal of anaesthesiology and reanimation; 2017 Oct

      https://pubmed.ncbi.nlm.nih.gov/29114412/

    14. Chao Liang, Ming Ding, Fang Du, Jing Cang, Zhanggang Xue; "Sevoflurane/propofol coadministration provides better recovery than sevoflurane in combined general/epidural anesthesia: a randomized clinical trial"; Journal of anesthesia; 2014 Oct

      https://pubmed.ncbi.nlm.nih.gov/24557087/

    15. Peter Nagele, Frank Brown, Amber Francis, Mitchell G Scott, Brian F Gage, J Philip Miller, for the VINO study team; "Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR gene polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial"; Anesthesiology; 2014 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919550/

    16. Alieh Zamani Kiasari, Abolfazl Firouzian, Afshin Gholipour Baradari, Hamid Sharif Nia, Seyed Hosein Moosavi Kiasari; "The Effect of Vitamin B12 Infusion on Prevention of Nitrous Oxide-induced Homocysteine Increase: A Double-blind Randomized Controlled Trial"; Oman medical journal; 2014 May

      https://pubmed.ncbi.nlm.nih.gov/24936269/

    17. Kjell K. Øvrebø, Asbjørn Svarda; "The Effect of Glutathione Modulation on the Concentration of Homocysteine in Plasma of Rats"; Pharmacology & Toxicology; 2000

      https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-0773.2000.pto870301.x

    18. David Mischoulon, Jonathan E Alpert, Erland Arning, Teodoro Bottiglieri, Maurizio Fava, George I Papakostas; "Bioavailability of S-Adenosyl Methionine and Impact on Response in a Randomized Controlled Trial in Major Depressive Disorder"; The Journal of clinical psychiatry; 2014 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156851/

    19. Cristiana Paul, David M Brady; "Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms"; Integrative medicine; 2017 Feb

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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