How to lower homocysteine levels banner

How to lower homocysteine levels

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

January 26, 2025

Table of Contents

    How to lower homocysteine

    If you’re learning how to decrease homocysteine, the first step is to understand why your homocysteine is high. 

    Homocysteine is a naturally occurring amino acid that can cause serious harm to your cardiovascular system if too high. The most common cause is a deficiency in the B vitamins folate, B12, and/or B6. These nutrients are essential for the conversion of homocysteine to methionine, but if they are low, this process won’t happen as effectively as it should. 1


    For many people, a major cause of low folate levels is the MTHFR genetic mutation. One of the pathways used to convert homocysteine to methionine involves using methylfolate (vitamin B9), along with vitamin B6, and vitamin B12 (methylcobalamin). Studies show that people with an MTHFR genetic mutation are at increased risk of high homocysteine as they cannot process folate properly.2 If you have been diagnosed with high homocysteine, your health professional may suggest you get tested for MTHFR.


    The other pathway is the “transsulfuration pathway”, in which homocysteine is converted to another amino acid, cysteine. This pathway requires an enzyme called cystathionine beta-lyase, which is dependent on the availability of vitamin B6. 3

    How to lower homocysteine naturally

    Essentially, the regulation of homocysteine in the body depends on the availability of all three B vitamins: folate, vitamin B12, and vitamin B6. A deficiency in any of these nutrients can mean that homocysteine is not converted properly, resulting in elevated levels. It also means that SAMe is not created, which can have a significant impact on mental health.


    Diet

    Folate is essential for reducing homocysteine levels in the blood. It has been estimated that as little as 50% of naturally occurring folate is available from food, as different fruit and vegetables have different folate bioavailabilities. Citrus fruit and legumes are good sources of readily available folate. Depending on your genotype and whether you are able to process folate properly, it may help to include plenty of fresh fruits and vegetables in your diet, as well as legumes, nuts, and animal products such as dairy, eggs, and lean protein. These foods are rich in folate, B12, B6, and other important nutrients that support the methylation process. In a study comparing dietary strategies for lowering homocysteine, people who ate a range of folate-rich foods were able to increase their daily intake of folate to 600 μg a day. The main sources of dietary folate in the study were yeast and yeast products (around 250 μg/day), cereals, cereal products, beans and nuts (around 245 μg/d from haricot beans, chickpeas, peanuts, and bread and bakery products), vegetables, fruit, and fruit juices (around 185 μg/day from asparagus, spinach, broccoli, broad beans, peas, potatoes, oranges, and orange juice).

    However, it’s important to address whether your body is able to break down and absorb these foods properly. If your digestive health is poor (which is often the case), it is highly advisable to seek a consultation with a naturopath or health practitioner. And if you have MTHFR, your body may not be able to produce sufficient methylfolate for optimal homocysteine conversion. This is something to mention to your healthcare provider.


    A study from China found that fruits and vegetables helped to lower homocysteine in most MTHFR genotypes, while soy raised homocysteine in females with CC and CT genotypes. 

    Meat lowered homocysteine in men with TT genotype and women with CC/CT genotypes, while cereal/wheat raised homocysteine in men with CT genotype and women with TT genotype. Fried foods, sugar and salt were high-risk factors for homocysteine in all groups. 4


    Exercise

    Different forms of exercise have different effects on homocysteine. A meta-analysis found that acute exercise generally increases homocysteine levels, with higher volumes of exercise in a short space of time causing the most significant increase.  Resistance training was shown to help reduce homocysteine levels, while aerobic training did not show a significant effect. 5

    Another study found that practicing yoga for eight weeks was effective in lowering homocysteine levels, and possibly also helped in restoring endothelial function. 6

    How to lower homocysteine with supplements

    L-methylfolate

    L-methylfolate is the primary active form of folate that the body uses to convert homocysteine into methionine. Supplementing with L-methylfolate has been shown to significantly increase blood serum folate levels and reduce homocysteine levels. 7

    Methylfolate is superior to folic acid because it is already available for use in the body, which means it can begin methylating homocysteine immediately upon ingestion.
    Folic acid is a synthetic form of folate, and it can only be used in the body after it is converted to its active form. In people with an MTHFR mutation, this process is impaired, so they may not be able to use folic acid at all. 

    Folic acid is not the same as methylfolate as it is a synthetic form of folate. It does not directly lower homocysteine and unlike l-methylfolate, does not cross the blood-brain barrier. It may also cause renal toxicity.8 Research has shown that people with MTHFR mutations and MTRR mutations had the highest risk of failure when treated with folic acid for high homocysteine. 9

    Unlike folic acid, L‐methylfolate is unaffected by DHFR and MTHFR polymorphisms and has superior effectiveness for lowering homocysteine. L‐methylfolate is a natural food folate with no upper-limit safety concerns, unlike folic acid, with the dual benefit of lowering blood pressure. 10

    Vitamin B6 (P-5-P)

    The active form of vitamin B6 is known as pyridoxal-5-phosphate (P5P), and it’s required for the metabolism of homocysteine and tryptophan. Around 70-80% of vitamin B6 in plasma is in the form of P5P. 

    When vitamin B6 levels are low, the transsulfuration pathway will not be used. Instead, homocysteine will be mostly turned into S-adenosyl homocysteine (SAH), the biosynthetic precursor to homocysteine. The production of B12 will also be disrupted.  This can lead to a buildup of SAH, which blocks important methylation reactions. As a result, the production of key neurotransmitters like serotonin, dopamine, and epinephrine decreases. 11


    P5P is necessary for the function of two enzymes, cystathionine beta synthase (CBS) and cystathione γ-lyase (CSE) in the breakdown of homocysteine to cysteine.12 This is essential for reducing homocysteine levels and also in overall detoxification, as up to 50% of the cysteine produced through this pathway is used to create glutathione.13

    Taking P5P with methylfolate and methylcobalamin (active B12) has been shown to significantly reduce homocysteine levels within just three months.14

    Vitamin B12

    Vitamin B12 (methylcobalamin) is required for numerous functions within the nervous system and in the formation of red blood cells. Like methylfolate and B6, Vitamin B12 is a cofactor in the conversion of homocysteine to methionine. Deficiency in vitamin B12 can lead to hyperhomocysteinemia.15

    Vitamin B12 deficiency affects 5–20% of older adults, while up to 40% are low in B12.16 The prevalence of poor B12 increases with age, but it is also common in vegans, vegetarians, and people with malabsorption disorders. 

    TMG (Betaine)

    Trimethylglycine (TMG) also known as betaine, is a methyl donor that has two main mechanisms. The first is to either directly donate a methyl group to reduce homocysteine into L-methionine, and the second is to increase the body’s levels of S-Adenosylmethionine (SAMe). This allows SAMe and folate to go on and donate methyl groups to other parts of the body. This is why supplementation of betaine can indirectly support whole-body methylation, as well as directly reduce homocysteine. This has already been shown in moderate to high-dose supplementation. One study found that taking low-dose betaine for six weeks led to immediate and long-term lowering of homocysteine in men and women.17

    NAC

    N-acetylcysteine (NAC) is an amino acid and the precursor to glutathione, the body’s most important antioxidant. Taking NAC as a supplement has been shown to significantly lower homocysteine, oxidative stress, and inflammation.

    Cerefolin® NAC is a medical food that contains L‐methylfolate, methylB12, and NAC. It has been shown to significantly lower homocysteine as well as brain tissue loss due to reduced blood flow.18 However, NAC is a low lipophilic compound, so it has poor cell permeability. A newer compound, N-acetyl-L-cysteine ethyl ester (NACET) may be more effective as it can readily cross the blood-brain barrier and protect cells from oxidative stress.19

    How long does it take to lower homocysteine?

    Supplementing with specific B vitamins can speed up the process of reducing homocysteine. A 2024 study showed that taking methylfolate, P5P, and methylcobalamin supplements lowered homocysteine by 30% in MTHFR patients over six months.20

    A 2020 study showed that taking methylfolate supplements for three months was shown to significantly reduce homocysteine levels in patients with diabetes.21 When treated with a combination of L-methylfolate, methylcobalamin, and pyridoxal-5′-phosphate (Metanx) for 24 weeks, diabetic patients had significantly reduced homocysteine and consistent symptomatic relief.22

    Everyone is different, so the time it takes to lower your homocysteine will depend on your diet, lifestyle, and other health conditions.

    How to lower homocysteine levels

    Key Takeaways

    • Icon High homocysteine is associated with vascular conditions such as stroke, dementia, heart disease, and other chronic illnesses. Reducing your homocysteine levels should be a priority.
    • Icon L-methyfolate, B12, and B6 are the primary nutrients involved in metabolizing homocysteine in the body. Low levels of these nutrients (as in the case of MTHFR) can lead to high homocysteine.
    • Icon Lowering homocysteine involves eating a healthy diet and supplementing with methylfolate, B12, and B6.

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    Frequently Asked Questions about ways to lower homocysteine levels

    How can I lower my homocysteine levels naturally?

    Supplementing with methylfolate and B12 has been shown to lower homocysteine levels within just a few months, especially if you are already deficient in these nutrients.
    Eating a healthy diet with plenty of fresh fruits and vegetables and reducing intake of fried foods, sugar, and salt is also important. Yoga and resistance training have both been shown to help reduce homocysteine.
    A recent study found that eating naturally folate rich foods and supplementing with L-methylfolate helped patients reduce homocysteine concentrations. However, as a folate-rich diet isn’t possible for everyone, supplementation is often the best course of action - especially in the case of extremely high levels or in pregnancy.23

    What foods should I avoid if my homocysteine is high?

    Foods that raise homocysteine levels include meat, soy, sugar, salt, and fried foods. Refined cereals and wheat may also increase homocysteine. Foods that lower homocysteine levels include fruits, vegetables, eggs, fish, and milk. Population studies show that these foods are generally associated with reduced homocysteine levels. 24

    What is the best treatment for high homocysteine?

    Along with a healthy diet, the most effective way to reduce homocysteine is to supplement with the B vitamins methylfolate, B12, and B6.25 These nutrients are required for the process that converts homocysteine to methionine in the body, and low levels of these nutrients are one of the most common causes of high homocysteine.

    Which vitamins reduce homocysteine?

    The B vitamins methylfolate (B9), methylcobalamin (B12) and P5P (B6) are shown to be the most effective in reducing homocysteine. These vitamins work together in the one-carbon pathway to metabolize homocysteine to methionine.

    References

    1. Bruno Zappacosta, Pierpaolo Mastroiacovo, Silvia Persichilli, George Pounis, Stefania Ruggeri, Angelo Minucci, Emilia Carnovale, Generoso Andria, Roberta Ricci, Iris Scala, Orazio Genovese, Aida Turrini, Lorenza Mistura, Bruno Giardina, Licia Iacoviello; "Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia"; Nutrients; 2013 May

      https://pmc.ncbi.nlm.nih.gov/articles/PMC3708334/

    2. Laura Dean; "Methylenetetrahydrofolate Reductase Deficiency", Medical Genetics Summaries [Internet]; 2024 Nov

      https://www.ncbi.nlm.nih.gov/books/NBK66131

    3. Marc Yudkoff; "Disorders of Amino Acid Metabolism"; Basic Neurochemistry (Eighth Edition); 2012

      https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transsulfuration-pathway

    4. Qiang Zeng, Fan Li, Tianyuan Xiang, Weimin Wang, Cong Ma, Chao Yang, Haixu Chen, Hang Xiang; "Influence of food groups on plasma total homocysteine for specific MTHFR C677T genotypes in Chinese population"; Molecular Nutrition & Food Research; 2016 Oct

      https://pmc.ncbi.nlm.nih.gov/articles/PMC5297973/

    5. Rafael Deminice, Diogo Farias Ribeiro, Fernando Tadeu Trevisan Frajacomo; "The Effects of Acute Exercise and Exercise Training on Plasma Homocysteine: A Meta-Analysis", PLoS One; 2016 Mar

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4795785

    6. Li-Wei Chien, Hui-Chi Chang, Chi-Feng Liu; "Effect of yoga on serum homocysteine and nitric oxide levels in adolescent women with and without dysmenorrhea"; Journal Of Alternative And Complementary Medicine; 2013 Jan

      https://pubmed.ncbi.nlm.nih.gov/22963270/

    7. Doreen Schmidl, Kinga Howorka, Stephan Szegedi, Kristina Stjepanek, Stefan Puchner, Ahmed Bata, Ulrike Scheschy, Gerold Aschinger, René M Werkmeister, Leopold Schmetterer, Gerhard Garhofer; "A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes"; Molecular Vision; 2020 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190578/

    8. Klaus Pietrzik, Lynn Bailey, Barry Shane; "Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics"; Clinical pharmacokinetics; 2010 Aug

      https://pubmed.ncbi.nlm.nih.gov/20608755/

    9. Binghui Du, Huizi Tian, Dandan Tian, Chengda Zhang, Wenhua Wang, Lianke Wang, Mengying Ge, Quanliang Hou, Weidong Zhang; "Genetic polymorphisms of key enzymes in folate metabolism affect the efficacy of folate therapy in patients with hyperhomocysteinaemia"; The British Journal Of Nutrition; 2018 Apr

      https://pubmed.ncbi.nlm.nih.gov/29644956/

    10. Merrill F Elias, Craig J Brown; "Medical foods for lowering homocysteine in hypertensive patients"; Journal of Clinical Hypertension (Greenwich); 2022 Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9832224/

    11. Marcelina Parra, Seth Stahl, Hanjo Hellmann; "Vitamin B6 and Its Role in Cell Metabolism and Physiology"; Cells; 2018 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6071262/

    12. Jesse F Gregory, Barbara N DeRatt, Luisa Rios-Avila, Maria Ralat, Peter W Stacpoole; "Vitamin B6 Nutritional Status and Cellular Availability of Pyridoxal 5’-Phosphate Govern the Function of the Transsulfuration Pathway’s Canonical Reactions and Hydrogen Sulfide Production via Side Reactions"; Biochimie; 2016 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899128/

    13. Victor Vitvitsky, Mark Thomas, Anuja Ghorpade, Howard E. Gendelman, Ruma Banerjee; "A Functional Transsulfuration Pathway in the Brain Links to Glutathione Homeostasis"; Journal of Biological Chemistry Vol. 28 Iss. 47; 2006 Nov

      https://www.sciencedirect.com/science/article/pii/S0021925820681285

    14. Doreen Schmidl, Kinga Howorka, Stephan Szegedi, Kristina Stjepanek, Stefan Puchner, Ahmed Bata, Ulrike Scheschy, Gerold Aschinger, René M Werkmeister, Leopold Schmetterer, Gerhard Garhofer; "A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes", Molecular Vision; 2020 Apr

      https://pubmed.ncbi.nlm.nih.gov/32355442/

    15. Samanta Thomas-Valdés, Maria das Graças V. Tostes, Pamella C. Anunciação, Bárbara P. da Silva, Helena M. Pinheiro Sant'Ana; "Association between vitamin deficiency and metabolic disorders related to obesity"; Critical Reviews in Food Science and Nutrition Vol. 57 Iss. 15; 2017 May

      https://www.tandfonline.com/doi/full/10.1080/10408398.2015.1117413

    16. H W Baik, R M Russell; "Vitamin B12 deficiency in the elderly"; Annual Review Of Nutrition; 1999

      https://pubmed.ncbi.nlm.nih.gov/10448529/

    17. Olthof Margreet R, Verhoef Petra, van Vliet Trinette, Boelsma Esther; "Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women"; The Journal of Nutrition Vol. 133 Iss. 12; 2003 Dec

      https://www.sciencedirect.com/science/article/pii/S0022316622161778

    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. Gian Marco Tosi, Daniela Giustarini, Lorenzo Franci, Alberto Minetti, Francesco Imperatore, Elena Caldi, Paolo Fiorenzani, Anna Maria Aloisi, Anna Sparatore, Ranieri Rossi, Mario Chiariello, Maurizio Orlandini, Federico Galvagni; "Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage"; Internation Journal Of Molecular Sciences; 2021 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC7827200

    20. 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 May

      https://pmc.ncbi.nlm.nih.gov/articles/PMC11173557/

    21. Doreen Schmidl, Kinga Howorka, Stephan Szegedi, Kristina Stjepanek, Stefan Puchner, Ahmed Bata, Ulrike Scheschy, Gerold Aschinger, René M Werkmeister, Leopold Schmetterer, Gerhard Garhofer; "A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes", Molecular Vision; 2020 Apr

      https://pmc.ncbi.nlm.nih.gov/articles/PMC7190578/

    22. Vivian A. Fonseca, Lawrence A. Lavery, Tina K. Thethi, Yahya Daoud, Cyrus DeSouza, Fernando Ovalle, Douglas S. Denham, Teodoro Bottiglieri, Peter Sheehan, Julio Rosenstock; "Metanx in Type 2 Diabetes with Peripheral Neuropathy: A Randomized Trial"; The American Journal Of Medicine Vol. 126 Iss. 2; 2013 Feb

      https://www.sciencedirect.com/science/article/abs/pii/S0002934312005864

    23. Bruno Zappacosta, Pierpaolo Mastroiacovo, Silvia Persichilli, George Pounis, Stefania Ruggeri, Angelo Minucci, Emilia Carnovale, Generoso Andria, Roberta Ricci, Iris Scala, Orazio Genovese, Aida Turrini, Lorenza Mistura, Bruno Giardina, Licia Iacoviello; "Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia"; Nutrients; 2013 May

      https://pmc.ncbi.nlm.nih.gov/articles/PMC3708334/

    24. Qiang Zeng, Fan Li, Tianyuan Xiang, Weimin Wang, Cong Ma, Chao Yang, Haixu Chen, Hang Xiang; "Influence of food groups on plasma total homocysteine for specific MTHFR C677T genotypes in Chinese population"; Molecular Nutrition & Food Research; 2016 Oct

      https://pmc.ncbi.nlm.nih.gov/articles/PMC5297973/

    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 May

      https://pmc.ncbi.nlm.nih.gov/articles/PMC11173557/

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      https://www.freepik.com/

    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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