Folate is a vital nutrient for our body, playing key roles in DNA synthesis, cell division, and methylation processes. Many people take folic acid supplements without realizing that it may not be the best option for everyone, especially if you have certain genetic mutations. In this article, we will explore the differences between folic acid and methylated folate (5-MTHF), who benefits most from each, and why understanding your genetics is key to choosing the right form of supplementation.
The Difference Between Folic Acid and Methylated Folate
Before diving into the science, let's clarify the difference between folic acid and methylated folate:
- Folic Acid: This is the synthetic form of vitamin B9 found in many supplements and fortified foods. It requires multiple conversion steps before becoming the active form, 5-methyltetrahydrofolate (5-MTHF), that the body can use. This process heavily relies on the MTHFR enzyme, which can be inefficient in individuals with MTHFR gene mutations.
- Methylated Folate (5-MTHF): This is the bioactive form of folate that does not require conversion by the MTHFR enzyme. It is readily absorbed and can be utilized by the body immediately, making it a superior choice for those with reduced MTHFR function. It supports DNA synthesis, neurotransmitter production, and detoxification processes effectively, even when genetic variants impact folate metabolism.
Why the Right Form of Folate Matters: The Role of Genetics
Your body's ability to process and use folic acid depends on the activity of the MTHFR enzyme, encoded by the MTHFR gene. Variants in this gene, such as C677T and A1298C, can reduce the enzyme's efficiency by up to 70%, hindering the conversion of folic acid to its active form. This can result in unmetabolized folic acid building up in the blood, potentially leading to health issues like folate deficiency symptoms, impaired methylation, and elevated homocysteine levels.
Other related genetic mutations, such as those in the MTHFD1, SLC19A1, and MTRR genes, can also disrupt the folate cycle and homocysteine metabolism, affecting how well your body uses folate. These disruptions may cause:
- Impaired folate absorption and transport
- Reduced conversion to active 5-MTHF
- Elevated homocysteine levels, which are linked to cardiovascular and neurological diseases
Understanding the Folate-Homocysteine-Methionine Pathway
The folate-homocysteine-methionine pathway is crucial for overall health because it influences DNA synthesis, methylation (key for gene regulation), and detoxification processes.
Here’s a simplified breakdown:
- Folate Activation: Folate from our diet is converted into various active forms like 5-MTHF, which is crucial for methylation.
- Methylation Cycle: 5-MTHF donates a methyl group to homocysteine, converting it into methionine, an amino acid needed for protein synthesis and producing S-adenosylmethionine (SAMe), a universal methyl donor.
- Homocysteine Regulation: Proper function of this cycle helps keep homocysteine levels low. Elevated homocysteine can lead to cardiovascular diseases, neurodegeneration, and other health issues.
- Enzymes Involved: Key enzymes like MTHFR facilitate the conversion of folate into its active form. Polymorphisms in MTHFR can disrupt this conversion, leading to reduced methylation capacity and potential health complications.
Understanding this pathway helps highlight why folate supplementation (as folic acid or 5-MTHF) may have different effects depending on individual genetic factors.
Folate Deficiency and Its Impact on DNA Synthesis
Folate deficiency can disrupt normal cell division and DNA replication, particularly affecting the S-phase of the cell cycle. The S-phase is a critical period when the cell duplicates its DNA in preparation for division. When there isn’t enough folate, the synthesis of nucleotides (the building blocks of DNA) is impaired, leading to S-phase arrest. This means cells are unable to progress past the S-phase, effectively getting "stuck" because they cannot complete DNA replication. In one study, the percentage of cells arrested in the S-phase increased significantly from 11.7% to 21.1% due to folate deficiency. This disruption can impair tissue growth and repair, as well as affect rapidly dividing cells, such as those in the bone marrow, skin, and digestive tract. Supplementation with folic acid or 5-MTHF (methylated folate) can help resolve this issue, allowing the cell cycle to proceed normally.
Symptoms of Folate Deficiency
A deficiency in folate can present with a range of symptoms, which may often be subtle at first but can become severe over time. Common symptoms include:
- Fatigue and Weakness – Feeling persistently tired, lacking energy, and experiencing general weakness.
- Anemia (Megaloblastic Anemia) – Symptoms include paleness, shortness of breath, and lightheadedness due to a low red blood cell count.
- Cognitive Issues – Difficulty concentrating, forgetfulness, brain fog, and mental confusion.
- Digestive Problems – Diarrhea, bloating, or a swollen, red tongue (glossitis).
- Mouth Sores – Painful sores inside the mouth or a swollen tongue.
- Nerve Problems – Numbness or tingling in the hands and feet due to nervous system involvement.
- Mood Disorders – Depression, irritability, and mood swings are common in folate deficiency, as folate is crucial for neurotransmitter production.
- Growth Problems (in Children) – Slow growth and developmental delays, particularly in children.
- Elevated Homocysteine Levels – This can lead to cardiovascular issues, increasing the risk of heart disease and stroke.
- Poor Immune Function – Frequent infections and a reduced ability to heal wounds.
Recognizing these symptoms early and addressing folate deficiency through diet or supplementation can help prevent more severe complications, including anemia and increased risk of certain birth defects during pregnancy.
Folate Excess or methylation issues absorbing Folic Acid
Excess folate, particularly from unmetabolized folic acid (the synthetic form of vitamin B9), can lead to a range of symptoms and health issues. When the body struggles to process folic acid due to genetic mutations like MTHFR, it can accumulate unmetabolized folic acid (UMFA) in the blood, causing several problems. Here are the symptoms and concerns related to excess folate or unmetabolized folic acid:
Symptoms of Excess Folate/Folic Acid:
Neurological Symptoms:
- Numbness and tingling in hands and feet (peripheral neuropathy)
- Increased anxiety and restlessness
- Brain fog and confusion
- Irritability or mood changes
- Sleep disturbances and insomnia
Masked Vitamin B12 Deficiency:
- High levels of folic acid can mask the symptoms of vitamin B12 deficiency, leading to:
- Fatigue and weakness
- Short-term memory problems
- Difficulty concentrating
- Anemia-like symptoms (even when blood tests appear normal)
- Glossitis (swollen, smooth, and sore tongue)
Digestive and Gastrointestinal Issues:
- Bloating, gas, and nausea
- Loss of appetite
- Diarrhea or changes in bowel movements
- Indigestion and discomfort after eating fortified foods
Allergic or Immune Reactions:
- Rashes or skin irritation
- Flushing of the skin
- Hives (in rare cases)
- Increased susceptibility to infections, as excess folic acid may impair immune function
Increased Risk of Certain Cancers:
- Unmetabolized folic acid has been linked to increased cancer risk, especially colon, prostate, and breast cancer. It can potentially promote the growth of precancerous cells or tumors when intake is excessively high over long periods.
Aggravation of Pre-Existing Conditions:
- Worsening symptoms in individuals with:
- MTHFR mutations (reduced ability to convert folic acid to active methylated folate)
- Autism spectrum disorders, where excess folic acid has been linked to behavioral issues
- Bipolar disorder or schizophrenia, due to disrupted methylation and neurotransmitter imbalance
Elevated Homocysteine Levels:
- Although excess folic acid might seem beneficial, it can paradoxically lead to elevated homocysteine, especially if the folate is not being effectively converted to 5-MTHF. High homocysteine is a risk factor for:
- Heart disease
- Stroke
- Cognitive decline and dementia
Unmetabolized Folic Acid (UMFA) Syndrome:
- High levels of UMFA in the bloodstream can result in:
- Reduced natural killer (NK) cell activity, impairing immune response
- Increased oxidative stress, leading to inflammation and tissue damage
- Altered gene expression, impacting detoxification processes and methylation
Folate disruptions and Medications
Folate levels can also be influenced by medications that disrupt the folate-homocysteine-methionine cycle. Some drugs interfere with folate metabolism by inhibiting enzymes like DHFR and MTHFR, impairing folate and vitamin B12 absorption, affecting the elimination of folate, or inducing liver enzymes that alter its metabolism. Common examples of these medications include trimethoprim (Antibiotic to treat UTI’s - folic acid antagonist), methotrexate (IBD, RA), valproic acid (epilepsy and bipolar), sulfasalazine (RA), phenobarbital (epileptic fits • sedation) , phenytoin (epilepsy), and metformin (type 2). These medications may interfere with the body's ability to properly process and use folate.
Managing Excess Folic Acid or Folate Levels
If you suspect you have excess folic acid—often due to high intake of fortified foods, supplements, or an inability to process folic acid due to genetic mutations (like MTHFR)—the first step is to reduce or eliminate sources of synthetic folic acid. This means opting for whole foods naturally high in folate, such as leafy greens, legumes, and liver, rather than relying on fortified products. Switch to supplements containing methylated folate (5-MTHF), which your body can utilize more effectively. It’s also crucial to check your vitamin B12 levels, as excess folic acid can mask a deficiency in B12, leading to neurological symptoms. Consider incorporating lifestyle changes that support healthy folate metabolism, such as improving gut health and reducing oxidative stress.
Addressing Low Folate Levels
If you have reduced folate levels, increasing your intake of naturally folate-rich foods is a great place to start. Leafy greens like spinach and kale, lentils, chickpeas, avocado, and citrus fruits are excellent sources. If supplementation is necessary, opt for methylated folate (5-MTHF) instead of synthetic folic acid, especially if you have MTHFR gene mutations. Support your body’s ability to absorb and utilize folate by focusing on gut health—consider probiotics, digestive enzymes, and addressing any underlying gastrointestinal issues that may affect absorption. In addition, monitor your homocysteine and B12 levels, as they are closely linked with folate metabolism.
If you’re struggling with persistent low/high folate despite dietary changes, it may indicate an underlying issue that requires further testing. We can provide comprehensive genetic and nutrient testing to get to the root of the problem—schedule an appointment today to start your journey towards balanced folate levels and better health.
Testing for Folate Deficiency: What You Need to Know
The most effective way to assess folate status is by testing both plasma folate and red blood cell (RBC) folate levels. Plasma folate reflects recent intake, while RBC folate indicates long-term folate status. Elevated homocysteine can be a key marker of folate or vitamin B12 deficiency, especially in those with MTHFR polymorphisms.
In Australia, homocysteine testing is often overlooked, despite its valuable insights into methylation and cardiovascular health. High homocysteine levels can increase the risk of heart disease, stroke, and neurodegenerative conditions, while low levels may suggest nutrient absorption issues or chronic conditions affecting folate metabolism.
In Summary
Maintaining optimal folate levels is vital for cellular function and healthy development, particularly during pregnancy. Both deficiency and excessive intake of folate have been linked to health risks, highlighting the importance of understanding how folates are activated and the potential issues related to folate deficiency.
Folate, especially in its active form 5-MTHF, plays a key role in metabolic processes. Evidence shows that 5-MTHF more effectively supports cell metabolism compared to folic acid (FA), especially in individuals with MTHFR polymorphisms. Variants like 677C>T and 1298A>C are well-known for reducing MTHFR enzyme activity, making it difficult for the body to convert folic acid into its active form. For these individuals, supplementing with 5-MTHF bypasses the need for MTHFR enzyme activity, providing direct support for methylation and metabolic functions.
While higher doses of folic acid may help compensate for reduced MTHFR activity, the choice of folate form is crucial. Studies suggest that individuals with specific genetic variations benefit more from 5-MTHF supplementation. This is supported by research showing that cells supplemented with 5-MTHF achieve significantly higher levels of active folate, even when MTHFR activity is low, whereas folic acid supplementation tends to be less effective in such cases.
The International Federation of Obstetrics and Gynecology (FIGO) recommends increasing folic acid intake for individuals with polymorphisms in folate cycle genes. However, high doses of folic acid, although often beneficial during pregnancy, carry potential risks. These include masking vitamin B12 deficiency, contributing to insulin resistance, and increasing the risk of small-for-gestational-age infants, certain cancers, and cognitive impairments. Excessive folic acid can also interact with medications that inhibit dihydrofolate reductase (DHFR), making careful monitoring essential.
In conclusion, the form of folate supplementation matters, particularly for those with genetic variations affecting MTHFR activity. While folic acid may be sufficient for many, 5-MTHF offers a more direct and effective option for individuals with reduced MTHFR function, supporting better overall metabolic health and reducing the risk of complications.
Take Action for Your Health Today
If you are unsure about your folate needs or have concerns about symptoms like fatigue, brain fog, or elevated homocysteine, consider booking an appointment for a comprehensive genetic test. Understanding your genetic profile can help you make informed decisions about your supplementation, improve your health outcomes, and tailor a plan that meets your unique needs.
Don't leave your health to guesswork—schedule a consultation today to learn more about genetic testing and how we can help you optimize your folate intake and overall wellness.
Reference:
Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate - 2020 Sep 2;9(9):2836. doi: 10.3390/jcm9092836 https://pmc.ncbi.nlm.nih.gov/articles/PMC7564482/