NAC (N-Acetylcysteine) and MTHFR

NAC (N-Acetylcysteine) and 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:

June 15, 2025

Table of Contents

    What is NAC and NACET?

    N-acetylcysteine (NAC) is a sulfhydryl-containing compound known for its potent antioxidant and anti-inflammatory effects in the human body. NAC has gained attention in recent years for its ability to help protect cells from damage caused by oxidative stress, which makes it effective in preventing or managing health conditions linked to cellular damage.1
    NAC is safe to use and easily absorbed.


    Studies have shown that NAC can be beneficial for various health conditions, including brain damage caused by temporary loss of blood flow (cerebral ischemia), managing pain and inflammation from infections, and restoring thyroid function.2


    NAC is also used by athletes to reduce inflammation and enhance health and performance.3


    More recent research suggests that NAC also may be useful for managing mental health conditions, including schizophrenia, bipolar disorder, and depression.4


    N-acetylcysteine ethyl ester (NACET) is a lipophilic and charge-free form of NAC that is absorbed more readily by the body than NAC. Studies show that NACET rapidly enters the cells where it is trapped, then converted into NAC and cysteine. Treatment with NACET can significantly increase glutathione content of bodily tissues, including the brain, and protects against oxidative stress.5

    How does NAC work in the body?

    NAC works in a few different ways, but its main mechanism is in protecting the body’s cells from damage caused by free radicals (unstable molecules).

    NAC helps make glutathione

    NAC is a modified form of the amino acid cysteine, a building block for glutathione (GSH), the body’s master antioxidant. Glutathione is essential for neutralizing harmful compounds caused by oxidative stress by donating electrons. It is also involved in detoxification, especially in the liver.6
    The human body often doesn’t produce enough glutathione on its own.


    NAC may be more effective in increasing glutathione levels inside cells than glutathione or cysteine supplements.

    NAC directly neutralizes harmful molecules

    NAC has a chemical group called a thiol that can directly interact with certain harmful molecules in the body, such as hydroxyl radicals and nitrogen dioxide. These are forms of reactive oxygen and nitrogen species that can damage DNA, proteins, and other parts of cells. NAC reacts with some of these directly to help neutralize them.


    NAC can also bind to certain metal ions, like copper, iron, mercury, or lead, forming compounds that the body can remove efficiently.7

    How does NAC interact with MTHFR?

    NAC has some important benefits for those with the MTHFR mutation.


    People with MTHFR are unable to fully convert folic acid to methylfolate, which is required for metabolizing homocysteine back to methionine. Homocysteine is a potentially harmful compound produced by the body as a result of methionine metabolism. Unmetabolized homocysteine accumulates in the blood, triggering inflammation and damage to endothelial cells and potentially increasing the risk of cardiovascular diseases, stroke, mood disorders, and cognitive impairment.8


    NAC supports an alternative route for homocysteine clearance via the transsulfuration pathway in the liver.9 This pathway does not require MTHFR and instead converts homocysteine into cysteine, which is then used to make glutathione.10 Glutathione is the body’s ‘master antioxidant’ which plays a key role in protecting cells from oxidative stress.


    Clinical studies show that NAC supplementation is highly effective in reducing homocysteine and oxidative stress, which is often high in those with MTHFR genetic mutations.11

    Benefits of NAC for MTHFR

    Reduces homocysteine

    NAC lowers homocysteine levels by providing cysteine, which allows homocysteine to be cleared from the body. NAC also displaces homocysteine from its protein-bound state, making it easier for the kidneys to remove it.12


    A ‘therapeutic cocktail’ including methylfolate methyl B12, betaine, and NAC has been shown to target multiple pathways at the same time, significantly decreasing homocysteine and its toxicity.13


    NAC supplementation over four weeks was shown to significantly decrease homocysteine levels, irrespective of hyperlipidemia or smoking status.14

    Protects brain function

    The brain is especially susceptible to oxidative stress because of its high energy demands and relatively low antioxidant enzymes.15 Glutathione deficiency has been shown to increase oxidative stress, mitochondrial dysfunction, and cell death. Neurodegenerative diseases such as Parkinson's and Alzheimer's disease are linked to glutathione depletion.16


    As well as increasing glutathione, NAC has been shown in human studies to cross the blood brain barrier and activate specific protective signaling pathways that reduce cell death and protect the brain against amyloid plaques (deposits found in the brains of people with Alzheimer's disease).17


    A prescription medical food that contains L‐methylfolate, methylB12, and NAC has been shown to significantly lower homocysteine and help protect against ischemic white matter atrophy in the brain, which may reduce the risk of neurodegenerative diseases.18

    Supports cardiovascular health

    Numerous animal studies have demonstrated that NAC significantly decreases the development and progression of atherosclerosis. NAC helps to lower other risks to cardiovascular health, including systolic blood pressure, thrombosis, and stroke volume.19 It also helps to reduce inflammation by attenuating production of inflammatory cytokines like tumor necrosis factor-alpha and interleukins.20


    NAC treatment also lowered systolic blood pressure, which is common in those with MTHFR.21 Researchers have recommended that L‐methylfolate, riboflavin, and NAC be included in alternative strategies for lowering homocysteine in people with high blood pressure.


    High homocysteine promotes excitotoxicity and neuronal DNA damage and apoptosis, which can then affect cognitive function including memory and learning.22


    NAC may help to ameliorate symptoms of several psychiatric disorders, including attention deficit hyperactivity disorder, anxiety, bipolar disorder, depression, posttraumatic stress disorder, and schizophrenia.23


    NAC modulates several key neurotransmitter systems including glutamate and dopamine by supplying cysteine to the brain’s cystine/glutamate antiporter. This helps to prevent excess glutamate (an excitatory neurotransmitter) from being released outside neurons, which can help to decrease feelings of anxiety.24

    NAC vs other MTHFR supplements

    NAC may be even more beneficial when taken alongside methylfolate, pyridoxal-5′-phosphate (active B6) and methylcobalamin. Research shows that this combination effectively reduces homocysteine levels, particularly in patients with MTHFR, MTR, and MTRR gene mutations.25 Methylfolate and methylcobalamin are critical for the metabolism of homocysteine via the remethylation pathway, and NAC works alongside these nutrients in countering oxidative stress.


    In addition, homocysteine is recycled to methionine through BHMT.
    Betaine supplementation has been shown to decrease homocysteine levels, improve memory and decrease tau hyperphosphorylation (a hallmark of neurodegenerative diseases such as Alzheimer's).26

    Other uses of NAC/other conditions that can be treated with NAC:

    Detoxification

    NAC has been shown to chelate toxic heavy metals including mercury, lead, cadmium, aluminum, arsenic, and gold. Although further research is pending, the use of NAC as a chelator of heavy metals appears to be a promising area of medical research.27


    NAC is an FDA-approved treatment for toxic overdoses of acetaminophen (a type of paracetamol).

    Mucolytic conditions

    NAC helps to break down mucus proteins and decrease mucus viscosity, allowing it to be cleared from the respiratory tract. NAC is used as a treatment in many conditions affected by lung mucosal secretions, such as chronic obstructive pulmonary disease [COPD], chronic bronchitis, pneumonia, and cystic fibrosis.28

    Male fertility

    The MTHFR C677T mutation has been associated with lower sperm counts and increased male infertility.29 NAC has positive effects on spermatogenesis and testicular function, and helps to reduce oxidative stress in the male reproductive system. Randomized clinical trials have shown that 600 mg/day of NAC for 3 months significantly improved sperm count, motility, and normal morphology.30

    Pregnancy and conception

    Oxidative stress can damage oocyte DNA (the female egg cell), potentially reducing fertility. NAC helps to reduce oxidative stress by increasing glutathione levels and scavenging reactive oxygen species. This has been shown to improve oocyte maturation and the subsequent development of embryos.31


    NAC combined with vitamins A and E plus essential fatty acids is also highly effective in reducing reactive oxygen species which has been shown to improve pregnancy rate.32

    Neuropathic pain

    NAC may help to reduce neuropathic pain by inhibiting specific enzymes involved in neural inflammation. This helps to reduce inflammatory chemicals and biomarkers associated with pain at both short and long-term stages of nerve injury.33

    NAC (N-Acetylcysteine) and MTHFR

    Key takeaways:

    • Icon People with the MTHFR mutation are at higher risk of elevated homocysteine and oxidative stress, both of which increase the risk of chronic illness.
    • Icon N-acetylcysteine (NAC) is a powerful antioxidant and a precursor to glutathione that can reduce homocysteine levels and protect against free radical damage and many disease processes.
    • Icon NAC can be used in combination with methylfolate and methylcobalamin.

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    Frequently Asked Questions about NAC

    Can you take NAC if you have MTHFR?

    Yes, clinicians recommend taking NAC if you have MTHFR as it helps your body to clear homocysteine. NAC also increases your body’s production of glutathione, which protects cells against oxidative stress and supports heavy metal detoxification.
    Taking NAC alongside methylfolate and methylcobalamin (active B12) has been shown to help reduce homocysteine levels and support healthy brain function.

    Does NAC help with methylation?

    While NAC doesn't add methyl groups, it helps reduce homocysteine levels via the transsulfuration pathway. It also increases production of glutathione, the body’s master antioxidant, which can support methylation pathways.

    Does NAC affect homocysteine?

    Studies suggest that NAC may help reduce homocysteine levels. It provides cysteine, a precursor to glutathione, which supports the breakdown of homocysteine. NAC may also help release homocysteine from proteins it is attached to, which makes it easier for the kidneys to remove it.

    Does NAC deplete serotonin?

    No, NAC may actually increase serotonin. An animal study involving rats found that treatment with propionic acid reduced serotonin levels by 33%. But when treated with NAC, this decline was only 14%34 Another study found that NAC improved the effects of serotonin-blocking medication in patients with obsessive-compulsive disorder.35

    References

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      https://pubmed.ncbi.nlm.nih.gov/37299425/

    4. Muhammed Ershad, Abdullah Naji, Preeti Patel, David Vearrier; "N-Acetylcysteine"; StatPearls [Internet]; 2024 Feb

      https://www.ncbi.nlm.nih.gov/books/NBK537183/

    5. Daniela Giustarini, Aldo Milzani, Isabella Dalle-Donne, Dimitrios Tsikas, Ranieri Rossi; "N-Acetylcysteine ethyl ester (NACET): A novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential"; Biochemical Pharmacology; 2012 Dec

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    9. Juan I Sbodio, Solomon H Snyder, Bindu D Paul; "Regulators of the transsulfuration pathway"; British journal of pharmacology; 2018 Aug

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      https://pmc.ncbi.nlm.nih.gov/articles/PMC2901774/

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      https://pubmed.ncbi.nlm.nih.gov/26447155/

    12. Shirinsadat Badri, Sahar Vahdat, Shiva Seirafian, Morteza Pourfarzam, Tahereh Gholipur-Shahraki, Sara Ataei; "Homocysteine-Lowering Interventions in Chronic Kidney Disease"; Journal of research in pharmacy practice; 2021 Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8809459/

    13. Michael Leon, Darrell Sawmiller, R Douglas Shytle, Jun Tan; "Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer’s Disease"; Cell medicine; 2018 Jan

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

    14. Wulf Hildebrandt, Roland Sauer, Gabriel Bonaterra, Klaus A Dugi, Lutz Edler, Ralf Kinscherf; "Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status"; The American journal of clinical nutrition; 2015 Nov

      https://pubmed.ncbi.nlm.nih.gov/26447155/

    15. Umesh Chandra Dash, Nitish Kumar Bhol, Sandeep Kumar Swain, Rashmi Rekha Samal, Prabhat Kumar Nayak, Vishakha Raina, Sandeep Kumar Panda, Rout George Kerry, Asim K. Duttaroy, Atala Bihari Jena; "Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications"; Acta Pharmaceutica Sinica B; 2025 Jan

      https://www.sciencedirect.com/science/article/pii/S2211383524004040

    16. Shoko Hashimoto, Yukio Matsuba, Mika Takahashi, Naoko Kamano, Naoto Watamura, Hiroki Sasaguri, Yuhei Takado, Yoshihiro Yoshihara, Takashi Saito, Takaomi C. Saido; "Neuronal glutathione loss leads to neurodegeneration involving gasdermin activation"; Scientific Reports; 2023 Jan

      http://nature.com/articles/s41598-023-27653-w

    17. Giuseppe Tardiolo, Placido Bramanti, Emanuela Mazzon; "Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases"; Molecules; 2018 Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6320789/

    18. William R Shankle, Junko Hara, Lori W Barrentine, Melanie V Curole; "CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease"; Journal of Alzheimer's disease; 2016 Oct

      https://pubmed.ncbi.nlm.nih.gov/27567825/

    19. Wulf Hildebrandt, Roland Sauer, Gabriel Bonaterra, Klaus A Dugi, Lutz Edler, Ralf Kinscherf; "Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status"; The American journal of clinical nutrition; 2015 Nov

      https://pubmed.ncbi.nlm.nih.gov/26447155/

    20. Yuqi Cui, Qiang Zhu, Hong Hao, Gregory C Flaker, Zhenguo Liu; "N-Acetylcysteine and Atherosclerosis: Promises and Challenges"; Antioxidants (Basel); 2023 Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10741030/

    21. Martina Rooney, Catherine F Hughes, J J Strain, Michelle Clements, Helene McNulty, Mary Ward; "Impact of the MTHFR C677T polymorphism on blood pressure and related central haemodynamic parameters in healthy adults"; Journal of human nutrition and dietetics; 2022 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9541256

    22. Michael Leon, Darrell Sawmiller, R Douglas Shytle, Jun Tan; "Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer’s Disease"; Cell medicine; 2018 Jan

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

    23. Irena Smaga, Małgorzata Frankowska, Małgorzata Filip; "N-acetylcysteine as a new prominent approach for treating psychiatric disorders"; British Journal of Pharmacology; 2021 Mar

      https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15456

    24. Irena Smaga, Małgorzata Frankowska, Małgorzata Filip; "N-acetylcysteine as a new prominent approach for treating psychiatric disorders"; British Journal of Pharmacology; 2021 Mar

      https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15456

    25. Evgeny Pokushalov, Andrey Ponomarenko, Sevda Bayramova, Claire Garcia, Inessa Pak, Evgenya Shrainer, Marina Ermolaeva, Dmitry Kudlay, Michael Johnson, Richard Miller; "Effect of Methylfolate, Pyridoxal-5′-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial;"; Nutrients; 2024

      https://www.mdpi.com/2072-6643/16/11/1550

    26. Gao-Shang Chai, Xia Jiang, Zhong-Fei Ni, Zhi-Wei Ma, Ao-Ji Xie, Xiang-Shu Cheng, Qun Wang, Jian-Zhi Wang, Gong-Ping Liu; "Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine"; Journal of neurochemistry; 2013 Feb

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    27. Daniel A. Rossignol; "The Use of N-Acetylcysteine as a Chelator for Metal Toxicity"; The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine; 2018 Sep

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    28. Muhammed Ershad, Abdullah Naji, Preeti Patel, David Vearrier; "N-Acetylcysteine"; StatPearls [Internet]; 2024 Feb

      https://www.ncbi.nlm.nih.gov/books/NBK537183/

    29. Wei Wu, Ouxi Shen, Yufeng Qin, Xiaobing Niu, Chuncheng Lu, Yankai Xia, Ling Song, Shoulin Wang, Xinru Wang; "Idiopathic Male Infertility Is Strongly Associated with Aberrant Promoter Methylation of Methylenetetrahydrofolate Reductase (MTHFR)"; PLoS One; 2010 Nov

      https://pmc.ncbi.nlm.nih.gov/articles/PMC2976703

    30. Rahil Jannatifar, Kazem Parivar, Nasim Hayati Roodbari, Mohammad Hossein Nasr-Esfahani; "Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men"; Reproductive biology and endocrinology; 2019 Feb

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    31. Yanfei Wang, Qingwei Wang, Quan Ji, Pengcheng An, Xiaodong Wang, Yonghong Ju, Ruiyang Li, Yong Ruan, Jiafu Zhao, Maosheng Cao, Xiang Chen; "Supplementation with N-Acetyl-L-cysteine during in vitro maturation improves goat oocyte developmental competence by regulating oxidative stress"; Theriogenology; 2025 Mar

      https://pubmed.ncbi.nlm.nih.gov/39855039

    32. Ashok Agarwal, Shyam S.R. Allamaneni; "Oxidants and antioxidants in human fertility"; Middle East Fertility Society; 2004 Dec

      https://utoronto.scholaris.ca/items/b888e838-c961-4936-a156-c420af763278

    33. Li, Jiajie; Xu, Lujie; Deng, Xueting; Jiang, Chunyi; Pan, Cailong; Chen, Lu; Han, Yuan; Dai, Wenling; Hu, Liang; Zhang, Guangqin; Cheng, Zhixiang; Liu, Wentaoa; "N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases"; PAIN; 2016 Aug

      https://journals.lww.com/pain/abstract/2016/08000/n_acetyl_cysteine_attenuates_neuropathic_pain_by.20.aspx

    34. Abeer M Aldbass, Ramesa Shafi Bhat, Afaf El-Ansary; "Protective and therapeutic potency of N-acetyl-cysteine on propionic acid-induced biochemical autistic features in rats"; Journal of Neuroinflammation; 2013

      https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-10-42

    35. Daniel L. Lafleur, Christopher Pittenger, Ben Kelmendi, Tom Gardner, Suzanne Wasylink, Robert T. Malison, Gerard Sanacora, John H. Krystal, Vladimir Coric; "N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder"; Psychopharmacology; 2005 Dec

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    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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