Does N-Acetylcysteine (NAC) Help with MTHFR?

Does N-Acetylcysteine (NAC) Help with MTHFR?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 23, 2025

Table of Contents

    Does N-Acetylcysteine (NAC) Help with MTHFR?

    People with MTHFR genetic mutations are often overwhelmed by the wide variety of supplement options. Methylfolate and vitamin B12 should be at the top of the list, but recent research suggests that N-Acetylcysteine (NAC) may also be beneficial.


    This article will explain NAC and how it may help those with MTHFR polymorphisms. We will weigh its benefits against other important MTHFR supplements such as methylfolate and methylcobalamin.

    What is NAC?

    N-acetylcysteine (NAC) is a drug used in clinical settings to treat poisoning, mainly acetaminophen (brand name Tylenol) toxicity. In the past few decades, its health benefits have made it popular as a dietary supplement and in the treatment of psychiatric disorders1.


    It is naturally present in plants of the Allium family, especially onions.


    NAC is the precursor to the amino acid L-cysteine, which is an essential precursor in glutathione synthesis. In this way, NAC can be used to replenish glutathione reserves. NAC increases glutathione levels2 in the brain and alleviates oxidative stress-associated damage.


    NAC is a potent antioxidant that binds to toxic metabolites and scavenges free radicals. It also increases oxygen delivery to tissues, boosts mitochondrial ATP (adenosine triphosphate) production, and alters the microvascular tone to increase blood and oxygen flow to the liver and other vital organs.


    In those with MTHFR, NAC is highly beneficial in managing elevated homocysteine3. NAC donates sulfhydryl groups and moves homocysteine away from its bond to plasmatic proteins, allowing it to be metabolized. In addition, NAC’s antioxidant power inhibits the production of reactive oxygen species (ROS) during methionine degradation. By balancing these metabolic pathways, NAC assists in maintaining healthy homocysteine levels.


    Homocysteine is either converted to methionine using folate as a cofactor or is directed to the transsulfuration pathway to produce glutathione. Glutathione is the body’s master antioxidant and detoxifier. It is especially crucial for managing oxidative stress in MTHFR.


    NAC’s antioxidant properties can help to reduce oxidative stress caused by elevated homocysteine, which may improve endothelial function4.


    NAC is also beneficial for those with depression by increasing NAC metabolite levels in the brain.

    Is NAC Safe?

    NAC is considered a safe substance5. Further clinical trials are being carried out to improve understanding of its potential uses.


    In any case, NAC has been used in medical settings since the 1960s, and the World Health Organization lists it as an antidote in poisonings. The use of NAC is projected to grow in the next five years.

    NAC Versus Other MTHFR Supplements?

    Other supplements recommended for people with MTHFR include methylfolate, methylcobalamin (B12), glutathione, betaine, and magnesium.

    The two most important of these supplements are methylfolate and methylcobalamin, which are often deficient in those with MTHFR but play crucial roles in one-carbon metabolism.

    • Magnesium is an essential mineral and a cofactor for the COMT (Catechol-O-methyltransferase) enzyme, which is required to transfer a methyl group from SAMe6 to metabolize dopamine, norepinephrine, and epinephrine. Essential for healthy mood, cardiovascular function, and nerve function.
    • Glutathione neutralizes free radicals, reduces inflammation, assists in heavy metal detoxification, and protects vitamin B-127 from reacting with toxins.
    • Betaine supplementation may directly enhance homocysteine remethylation8 in those with MTHFR, increasing methionine availability for protein synthesis and transmethylation.

    Methylfolate

    One-carbon metabolism is mediated by folate and facilitates numerous physiological processes9, including synthesizing neurotransmitters and antioxidants and maintaining amino acids (glycine, serine, and methionine).

     

    The methionine cycle and folate cycle occur within one-carbon metabolism and are dependent on serine and glycine bioavailability. It is from serine and glycine that other intermediates are produced to form cysteine.


    One-carbon metabolism is also how S-adenosylmethionine (SAM-e) is generated. SAM-e is the body’s most important biochemical methyl donor10 for processes such as DNA methylation and the synthesis of neurotransmitters, phospholipids, DNA, ribonucleic acid, and proteins.


    Deficiency in methylfolate impairs the production of these substances, which has a significant impact on the body and brain. 

    Methylcobalamin

    Methylcobalamin11 is essential for converting folic acid into tetrahydrofolate (THF), the active form of folate involved in DNA synthesis. Without methylcobalamin, folate cannot be used effectively in one-carbon metabolism.


    Methylcobalamin is required alongside methionine12 in the conversion of homocysteine to methionine. Methionine is essential for producing S-adenosylmethionine (SAM), which is required for the methylation of numerous biochemical reactions, including myelin sheath production and the synthesis of certain neurotransmitters, for maintaining brain and nervous system function.


    Without sufficient B12, the conversion of homocysteine to methionine and 5-methyltetrahydrofolate to tetrahydrofolate is compromised, leading to the buildup of homocysteine in the body.

    Methylated Multivitamins

    Methylated multivitamins are an excellent choice for patients with MTHFR mutations. Methylated vitamins are already in their active form, which means they need no further conversion13 in the body and will be absorbed and utilized at a much faster rate than unmethylated vitamins.


    Active B-vitamins such as methylfolate and methylcobalamin provide a large portion of methyl groups, which is crucial to those whose methylation processes are compromised due to an MTHFR mutation. Inactive vitamins such as folic acid and cyanocobalamin must undergo multi-step conversion processes before being used by the body.


    Methylated vitamins directly impact metabolic function, hormonal pathways, and the synthesis of vital nutrients in the body. Methylfolate and methylcobalamin are especially important for homocysteine metabolism and the synthesis of methionine and SAM-e.

    Takeaways

    MTHFR mutations can severely compromise the body’s ability to carry out vital methylation processes, which can subsequently impair numerous biochemical reactions. The most effective way to replenish the shortfall of essential nutrients is through supplementation for many people.


    Methylfolate and methylcobalamin are crucial coenzymes in methylation processes and are typically deficient in people with MTHFR mutations. Supplementing with these key nutrients should be the first priority for anyone affected by MTHFR as they will contribute to the production of other necessary substances, including glutathione.


    Methylated multivitamins provide a convenient source of these vitamins, along with other useful nutrients.


    Methyl-Life’s® Methylfolate, B-Methylated II, or Methylated Multivitamins are made with the internationally-patented Magnafolate® PRO. Magnafolate® PRO can bypass the MTHFR mutation and is clinically tested as the world’s purest and most bioavailable form of folate. B-Methylated II provides both methylfolate as Magnafolate® and highly bioavailable methylcobalamin, while the Methylated Multivitamin provides Magnafolate®, active B12, and a range of other vital nutrients.

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    References

    1. Minarini, A., Ferrari, S., Galletti, M., Giambalvo, N., Perrone, D., Rioli, G., & Galeazzi, G. M.; " N-acetylcysteine in the treatment of psychiatric disorders: Current status and future prospects​"; Expert Opinion on Drug Metabolism & Toxicology; 2017

      https://www.tandfonline.com/doi/abs/10.1080/17425255.2017.1251580?journalCode=iemt20

    2. Robillard, J. M., Gordon, G. R., Choi, H. B., Christie, B. R., MacVicar, B. A.​; "Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult"; PLoS ONE; 2011

      https://pubmed.ncbi.nlm.nih.gov/21655192/

    3. Dell'Edera D., Tinelli A., Milazzo G.N., Malvasi A., Domenico C., Pacella E., Pierluigi C., Tarantino G., Marcello G., Lomurno F., Epifania A.A.; "Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state"; Molecular Medicine Reports; 2013 Aug

      https://doi.org/10.3892/mmr.2013.1563

    4. Leon, M., Sawmiller, D., Shytle, R. D., Tan, J.; "Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer's Disease"; Cell Medicine; 2018

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172991/

    5. Špela Šalamon, Barbara Kramar, Tinkara Pirc Marolt, Borut Poljšak, Irina Milisav​; "Medical and Dietary Uses of N-Acetylcysteine"; Antioxidants; 2019 Apr

      http://mdpi.com/2076-3921/8/5/111

    6. Hoffbrand AV, Jackson BF; "Correction of the Methionine Synthase Defect in cblG Homocystinuria by Folinic Acid"; Journal of Inherited Metabolic Disease; 2014

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952716/

    7. William P. Watson, Tony Munter, Bernard T. Golding; "A new role for glutathione: protection of vitamin B12 from depletion by xenobiotic"; Chemical Research in Toxicology; 2004

      https://pubmed.ncbi.nlm.nih.gov/15606130/

    8. Bernd C. Schwahn, Maurice D. Laryea, Zhoutao Chen, Stepan Melnyk, Igor Pogribny, John W. Garrow, Teodoro Bottiglieri, Sharon J. Kirke, John M. Scott, John M. Murray, John F. Flynn, Ralph J. Martinez, Steven H. Zeisel, Rima Rozen; "Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency​"; Biochemical Journal​; 2004 Dec

      https://portlandpress.com/biochemj/article-abstract/382/3/831/43950/Betaine-rescue-of-an-animal-model-with?redirectedFrom=fulltext

    9. Gregory S. Ducker, Joshua D. Rabinowitz; "One-Carbon Metabolism in Health and Disease​"; Cell Metabolism; 2017 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353360/

    10. Karilyn E. Sant, Olivia S. Anderson; "B-vitamins & one-carbon metabolism: Impacts on the epigenome and implications for disease"; Nutritional Epigenomics, Vol. 14, pg. 319-336; 2019

      https://www.sciencedirect.com/science/article/pii/B9780128168431000199

    11. Chit Wai Wong; "Chapter 16 - Vitamin B12 Deficiency in the Elderly"; Nutrition and Functional Foods for Healthy Aging, pg. 159-166; 2017

      https://www.sciencedirect.com/science/article/pii/B9780128053768000162

    12. D. Sean Froese, Brian Fowler, Matthias R. Baumgartner; "Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation"; Journal of Inherited Metabolic Disease, Vol. 42, Iss. 4 p. 673-685; 2018 Dec

      https://onlinelibrary.wiley.com/doi/10.1002/jimd.12009

    13. 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

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/

    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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