What is the MTHFR gene?

The MTHFR gene impacts health in multiple ways; including mental health, heart disease, diabetes, and cancer. Knowing how your body functions can help you make better choices and live a healthier life. For example, knowing your genetics may help your physician better determine which medications may work best for you.

Methyltetrahydrofolate reductase, an enzyme, is encoded by the MTHFR gene. An enzyme is a type of protein that interacts with another molecule in the body by either adding something to it or taking something away.  Methyltetrahydrofolate reductase removes a methyl group (CH3) from the chemical compound in the body called 5,10-methyltetrahydrofolate, which makes 5-methyltetrahydrofolate (5-MTHF), another name for the active form of folate that our bodies use. Folate is a necessary vitamin our body produces and is also naturally available in many vegetables.

Why is this gene important?


The activation and inactivation of genes in our bodies is called epigenetics. DNA methylation and epigenetics play a key role in atherosclerosis, cancers, diabetes, and more. The methyl group removed is used in the nucleus of the cell to help regulate gene expression. Adding or removing methyl groups to a gene is our body’s way of controlling whether genes are active or not. The added group physically blocks the gene making it unavailable for use. Our body maintains many genes in an inactive state to help us remain healthy. Our diet and environment have a huge impact on whether genes are active or not.


People capable of giving birth who wish to become pregnant are recommended to take extra folic acid leading up to and during pregnancy. This reduces the incidence of neural tube defects such as the major brain defect, anencephaly (loss of parts of the structures of the brain or scull), and Spina Bifida (a failure of the neural tube to close completely). Folic acid is the synthetic form of folate and must be changed to the active form to be used by the body.


Active folate, 5-methyltetrahydrofolate (5-MTHF), is a precursor to the manufacture of the neurotransmitters dopamine, norepinephrine, and serotonin.

Dopamine is involved with our pleasure and reward systems. This neurotransmitter also helps to regulate behavior, voluntary movement, motivation, sleep, mood, attention, and more. In certain cells, dopamine is changed to norepinephrine.

Norepinephrine leads to increased heart rate and blood pressure. Glucose, the body’s most important energy source, is also increased throughout the body from norepinephrine. Norepinephrine increases alertness, arousal, and attention. The body’s response to this neurotransmitter helps us to react quickly and function well under stress. As part of our fight-or-flight response to danger, norepinephrine may also be changed to epinephrine when needed under extreme stress.

Serotonin, also a neurotransmitter and byproduct of 5-MTHF, is widely known for its psychological properties.  Serotonin affects mood, perception, appetite, memory, and more. However, serotonin is expressed more outside of the central nervous system than inside. Most serotonin in the body is located in the gut and is involved with all parts of the digestive system. As part of maintaining proper blood flow and platelet function, serotonin also affects the rate of clotting.

How does this gene potentially affect medication?

When the MTHFR enzyme has reduced function, the body can become low in active folate. Less active folate can lead to many problems.

A reduction in the production of neurotransmitters can lead to an imbalance. Depression, schizophrenia, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) are all affected.

Some genes are automatically silenced by our bodies. However, if our cells are unable to properly regulate gene expression then potentially dangerous genes can be reactivated. For example, a cell that is supposed to die may become immortal due to the genes that increase the rate of cell division becoming active in the wrong cell. Many cancers turn on genes that cause the body to grow new blood vessels for the cancer, allowing the cancer to continue to grow and potentially spread. Epigenetics, through the donation of the methyl groups removed from the MTHFR enzyme, helps protect our cells and can reduce the chance of a cancerous cell forming.

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Why include MTHFR in pharmacogenetic testing?


Replacing folate in the body through good nutrition or supplementation in people who have reduced function of the MTHFR gene may lead to the reduction of numerous diseases. These specific patients may obtain better control of their symptoms with the addition of 5-MTHF, the active folate, rather than folic acid. Diet and environment impact health greatly. Diets rich in dark green leafy vegetables can especially impact patients whose MTHFR function is diminished.

Mental Health

Patients who suffer from depression experience improved symptoms and better control over their condition when given 5-MTHF with their other antidepressant therapy. In addition, 5-MTHF alone may also greatly improve symptoms.  Almost three-quarters of patients with psychological problems have a reduced function MTHFR gene. Supplementing solely with folic acid may not be enough since the folic acid must be changed to the active form in the body before use.

Cancer or Other Medications

The inability to manufacture enough active folate in the body can also lead to increased side effects from multiple medications. Many cancer agents specifically affect the folate cycle, leading to an increased need for folate in the body. Methotrexate, cyclophosphamide, 5-fluorouracil, and raltitrexed require folate replacement to reduce toxicity. Phenytoin, primidone, barbiturates, nitrofurantoin, alcohol, and others also reduce folate. A patient with difficulty replacing folate, either due to a poorly functioning gene or poor nutrition, may experience extreme unexpected toxicities.

Why test for MTHFR?

Pharmacogenetic testing helps the prescriber and patient understand which medications may better benefit the patient. Multiple medications affect folate. Knowing ahead of time that a patient is at increased risk of side effects encourages the physician to choose a different medication; or, in the case of reduced active folate, may lead the physician to insist on proper folate supplementation during therapy if the folate-reducing medication is required for improved outcome. Supplementing appropriately may significantly reduce the risk of potential toxicities.

Prior knowledge that a mental health patient has a reduced functioning MTHFR gene, allows the prescriber to improve patient care. The prescriber may choose to encourage greater dietary changes or insist on the addition of a 5-MTHF supplement prior to prescribing antidepressant or antipsychotic medications. Adding the extra-active folate may be the only medicine the patient needs to improve symptoms, especially in less severe mental health cases.

In summary, the MTHFR gene is necessary to produce active folate. Active folate is necessary for the manufacturing of neurotransmitters. The extra methyl groups formed when activating the folate are required to help with epigenetic control of the genes. With the reduced function of this gene, mental health disorders, heart issues, diabetes, and cancer can all be negatively impacted. The negative consequences of poor nutrition are compounded in these individuals. Knowing your status can help you and your doctor make better-educated decisions regarding your health.

ClarityX offers a pharmacogenetics test called the Mindwell that tests for several genes including MTHFR. Our Mindwell test includes over 130 mental health medications including depression, anxiety, ADHD, and many more!

Resources accessed:

Wan, L., Li, Y., Zhang, Z. et al. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry 8, 242 (2018). https://doi.org/10.1038/s41398-018-0276-6

Marsh S, McLeod HL. Cancer pharmacogenetics. Br J Cancer. 2004 Jan 12;90(1):8-11. doi: 10.1038/sj.bjc.6601487. PMID: 14710198; PMCID: PMC2395337.

Eszlari, N., Kovacs, D., Petschner, P. et al. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry 6, e745 (2016). https://doi.org/10.1038/tp.2016.19

Lee HT, Oh S, Ro DH, Yoo H, Kwon YW. The key role of DNA methylation and histone acetylation in epigenetics of atherosclerosis. J Lipid Atheroscler. 2020;9(3):419–434. doi: 10.12997/jla.2020.9.3.419. - DOI - PMC - PubMed

DOI: 10.1200/JCO.2004.07.151 Journal of Clinical Oncology 22, no. 22 (November 15, 2004) 4632-4642.



https://www.nature.com/articles/s41398-018-0276-6 - 1 and 2