Is methylfolate safe for kids? What do naturopathic doctors use folate for?

What is folate? What is the difference between folic acid and folate?

Folate is a water-soluble B vitamin found in many plant and animal foods. It may also be referred to as vitamin B9 or folic acid. However, the term “folic acid” is often used inappropriately and synonymously with folate. Folic acid is not found in nature or food sources, rather it is the synthetic form found in fortified food products. The term folate refers to the type found in nature and in food sources. The activated form of folate is called methyl tetrahydrofolate (MTHF) or methylfolate. It becomes activated in the body and is not found in nature. That may be hard to keep straight, so here’s a recap:

●  Folate = the type found in food

●  Folic acid = the type found in supplements or fortified foods; not found in natural foods

●  Methylfolate or methyl tetrahydrofolate = the activated form of folate in the body and not found in natural foods

What does folate do?

Folate’s primary role is in transferring single carbon units to acceptor molecules.¹ In doing so, it becomes essential for the production of healthy red blood cells, acts as a methyl donor in the reaction that converts homocysteine to methionine, is critical in the synthesis of DNA and RNA, cell division, and growth and development.¹

Food sources of folate

Folate is considered an essential nutrient because we cannot synthesize it on our own. Rich food sources of folate include lentils, legumes, egg yolks, avocado, liver, beets, and dark green vegetables like spinach, brussel sprouts, and broccoli.

What is The folate cycle?

Homocysteine is an amino acid that is converted to methionine or cysteine. Methionine is an essential amino acid that acts as an antioxidant and is required for synthesizing certain proteins. Cysteine is a nonessential amino acid that has anti-inflammatory roles, especially for the immune system and liver.¹ The conversion of homocysteine to methionine requires an enzyme that needs folate and vitamin B12 to function. Without adequate folate and vitamin B12, homocysteine cannot convert to methionine and it begins to accumulate in the body. Too much homocysteine can damage the lining of the arteries, leading to blood clots and artery damage that increases the risk of heart attack and cardiovascular disease.

The conversion of homocysteine to methionine produces S-adenosylmethionine, or SAMe for short. SAMe is known as the universal methyl donor because it readily gives away its methyl group to various substances in the body. Methylation is super important and has a hand in regulating activities of the cardiovascular, neurological, reproductive, and detoxification systems.³ It impacts everything from eye health, to estrogen metabolism, DNA and neurotransmitter production, liver health, and so much more.³ Think of methylation as the mechanism that keeps the body’s gears turning in the right direction. Without it, processes get stuck and it can be seriously detrimental to your health.

In short, homocysteine is converted to methionine and later to SAMe with the help of folate and vitamin B12. SAMe is essential for methylation which impacts many body systems and our overall health. Without enough folate or vitamin B12 this cycle breaks down, leading to elevations of homocysteine and impaired methylation.

Recommended Dietary Allowance (RDA) of folate

Folate is measured in micrograms (mcg) of dietary folate equivalents (DFE).² Men and women over the age of 19 years old should obtain 400 mcg DFE daily, while pregnant and lactating women should obtain 600 mcg DFE and 500 mcg DFE respectively. Women of childbearing age are encouraged to supplement with at least 400 mcg DFE daily since a folate deficiency can cause neural tube defects in the offspring. There is no risk of toxicity from whole foods sources of folate, but the Tolerable Upper Intake Level from fortified foods or supplements is set at 1,000 mcg.²

The RDA for children is as follows:

●  Birth to 3 years old– 25-100 mcg per day

●  Children 4 to 6 years old– 75-400 mcg per day

●  Children 7-10 years old– 100-400 mcg per day

Signs of folate deficiency

A folate deficiency is usually precipitated by inadequate intake, absorption, or utilization OR by increased demands or increased losses. Folate deficiencies are rare in the United States, but the risk is increased in alcoholics or people with impaired absorptive capacities like those with Crohn’s disease, ulcerative colitis, or short bowel syndrome.¹

Certain pharmaceutical drugs such as methotrexate, oral contraceptives, PPIs and acid blockers can inhibit folate absorption and lead to a deficiency. Pregnancy increases the demand for folate and a deficiency can occur without intentional supplementation. Since folate is required for healthy red blood cell production, a deficiency can lead to megaloblastic anemia. This means that the red blood cells are too large in size and too few in number. Signs of a folate deficiency stem from this anemia and the subsequent diminishing oxygen carrying capacity. Symptoms include weakness, fatigue, irregular heartbeat, shortness of breath, difficulty concentrating, hair loss, pale skin, and mouth sores.² A folate deficiency may also result in elevated blood homocysteine levels.¹ By the time symptoms present, a folate deficiency has likely been occurring for months.

Signs of folate toxicity

It’s nearly impossible to reach toxic levels of folate through food sources and symptoms associated with toxicity are rare. However, over supplementation can be problematic because it may mask a vitamin B12 deficiency. This can be dangerous because a vitamin B12 deficiency can lead to irreversible neurological symptoms. Supplementation of folic acid should not exceed 400 mcg a day unless the individual is pregnant or breastfeeding, since much of the food supply in the United States is fortified with additional folic acid.

Folic acid, folinic acid and methylfolate supplementation

There are a few types of supplemental folate available. As a refresher, folinic acid is another term used for folate and is the type found in whole foods like leafy greens, avocado, and legumes. Folic acid is the type used in supplements and fortified foods, but isn’t found in natural whole food items. Methylfolate is the activated form of folate that is often recommended for people with a genetic mutation called MTHFR. Research suggests that up to 60% of people may have at least one genetic mutation in their MTHFR gene, while 10-25% have two genetic mutations.⁵ This is important because MTHFR is the gene that makes the enzyme needed to convert folic acid to its active form, methylfolate. Without methylfolate, methylation pathways are inhibited, leading to a variety of downstream effects including fertility challenges and neural tube defects during pregnancy. A methylfolate supplement essentially bypasses the need for the enzyme that converts folic acid to methylfolate.

Another benefit of methylfolate supplements is that they don’t mask a vitamin B12 deficiency like high doses of folic acid might. Methylfolate supplements may be listed as L-methylfolate, L-5-MTHF, 5 MTHF, or metafolin on a supplement or multivitamin labels. Deplin is the prescription form of methylfolate, used to treat folate deficiencies or conditions related to a deficiency. Deplin is very potent and usually prescribed in rather large doses. Although some people, especially those with MTHFR mutations, require methylfolate for adequate methylation, many people don’t need as much as they’re prescribed.

The most common occurrence related to overconsuming methylfolate is overmethylation.⁶ This can lead to fatigue, muscle or joint aches, depression, anxiety, and migraines, all of which are also indicators of undermethylation. Other side effects include digestive symptoms and abdominal pain or allergic symptoms like skin rashes and histamine intolerance. Think of it as the goldilocks principle in that we need enough methylfolate to keep methylation going, but too much can impair methylation and lead to similar symptoms. Some people who don’t have a MTHFR gene mutation may still experience overmethylation and it’s important to remember that there is high variability in the individual response to folate supplementation.

An option for people without a MTHFR gene variant is to supplement with folic acid. Folic acid is the primary supplemental form of folate and it’s what’s used in the mandatory fortification of grain products. It requires four conversions to get to the active form, and thus it’s highly dependent on individual genetics and several other nutrients for maximum conversion.⁵ Another option for people without the gene variant is to obtain adequate folate by eating plenty of dark leafy greens, avocado, legumes, liver, and cruciferous vegetables.

Genetic testing to detect the presence of a MTHFR gene mutation is useful in determining which supplemental folate to select. Working with a qualified medical or nutrition professional can help narrow down the type that’s appropriate for your unique genetic code and disposition.

Lab testing for folate deficiency

Assessing folate can be a little tricky and looking at numerous markers as pieces of the puzzle is best practice for determining a patient’s true folate status. Serum folate is the most common assessment used because it’s cheap and fast. However, this only gives us a snapshot of what’s available and doesn’t indicate how the body’s actually using the folate it has on board. Often organic acid testing is a much more reliable way of testing folate and folate utilization. Organic acid testing helps us see the way a nutrient is being used versus the amount of that nutrient in circulation. In terms of folate, formiminoglutamate (FIGLU) and homocysteine are the gold standards of assessment.

FIGLU is a byproduct of the conversion of histidine to glutamate. It requires folate for proper conversion and without it, the conversion gets stuck and leads to an accumulation of FIGLU. Therefore, elevated FIGLU indicates a folate need. The folate cycle discussed above went into detail regarding the conversion of homocysteine to methionine and SAMe with the help of folate. When there is inadequate folate, this cycle breaks down and homocysteine begins to build up. Assessing homocysteine can give us an indication of folate needs. The caveat with homocysteine is that a vitamin B12 deficiency can result in elevated homocysteine since it’s also required for its conversion to methionine. The organic acid test for methylmalonate (MMA) is the best way to assess vitamin B12. An elevation of MMA is one of the most widely recognized functional biomarkers of vitamin B12 and can help us distinguish between a folate and B12 deficiency.

How do naturopathic doctors use folate?

Prevention of neural tube defects

Since folate is required for the synthesis of DNA and RNA, it gets used rapidly during pregnancy when fetal growth and development are taking place. Neural tube defects (NTDs) include a variety of malformations such as brain or spine lesions and are characterized by a failure of embryonic neural tube closure sometime between the 21st and 27th day after conception.² Many people may not even know they’re pregnant at this point.

Although the exact mechanism by which folate impacts neural tube development remains unknown, there was a marked decrease in the prevalence of NTDs in the United States after the mandatory fortification of folic acid in enriched grain products.² Some studies show a 60-100% reduction in NTD cases in women who consume folic acid supplements one month before and after conception. Since NTDs develop before many people even know they’re pregnant, women who could become pregnant are encouraged by conventional medicine to take 400 ug of folic acid a day.

The connection between enriching grain products with folic acid and a reduction in NTDs is well documented. Some controversy exists around the potential risks associated with widespread and mandatory folic acid fortification. The first and most common argument is that too much folic acid can mask a vitamin B12 deficiency and allow a progression to cognitive and neurological impairments.⁴ Other concerns are potential increased risks of certain types of cancer, effects on diabetes and thyroid disorders, unknown effects of unmetabolized folic acid, and effects on offspring.⁴ This is one reason most naturopathic doctors recommend potentially pregnant women to take methylfolate or folinic acid instead of folic acid.

The evidence surrounding folate and cancer suggests that it may have both protective and detrimental health effects depending on the dose and the timing of the intake in relation to cancer stage.⁴ Although folate is essential for healthy cell production, too much may accelerate the growth of pre-existing tumors, especially in colorectal and prostate cancers. However, the evidence is rather inconsistent and a causal connection is difficult to make. There are weak associations with high blood folate, colon, and prostate cancer, and a decreased risk in breast and total cancer risk.⁴

There is no evidence that high folate status negatively impacts type 1 or type 2 diabetes, nor does it impair glucose and insulin metabolism in adults. There is some concern of an increased risk of hypersensitivity symptoms such as asthma, eczema, and allergies in children born to a mother who took supplemental folic acid during pregnancy. However, there is “no conclusive evidence that maternal supplementation increases the risk of atopy, asthma, wheezing, eczema, atopic dermatitis, susceptibility to respiratory infection, childhood cancer, or autism spectrum disorders.”⁴

There is a limit to one’s ability to metabolize large amounts of folic acid, and leftover amounts remain in the circulation as unmetabolized folic acid (UMFA)4. There is some concern around the impact UMFA may have, especially in people with low vitamin B12. However, the evidence is too inconsistent and insufficient to outweigh the benefits of protecting against NTDs.

Mood Disorders, including pediatric depression

Supplemental folate is well documented as a tool for managing depressive symptoms in adults. In one study on adult patients with depression, researchers found that Deplin (prescription folate), taken for 12 weeks resulted in significant improvements in depressive symptoms in 70% of patients, and remission in 46% of patients.⁷

Although an estimated 15-20% of children struggle with pediatric depression, clinical trials on folate as a management tool for depression are limited. However, researchers have found that folate is closely related to depression and may impact the symptoms and development of depression in children. Diets high in B vitamins, especially folate, are associated with a reduction in the prevalence and severity of depression in childhood.⁸ In fact, patients with depression have an average of 25% less blood folate than healthy controls. Additional studies suggest that low levels of folate are associated with poor outcomes of antidepressant therapy, while supplementing with 500 mcg of folic acid can enhance the effectiveness of antidepressant medication.⁷

A retrospective analysis of methylfolate supplementation in a pediatric population looked at the effect of prescribed methylfolate on a variety of neuropsychiatric conditions, including depression, anxiety disorders, and mood disorders.⁸ There were few adverse outcomes associated with methylfolate, although impaired sleep and increased anxiety were the most common occurrences.⁸ 22.5% of the children taking methylfolate showed improvements in symptoms associated with their neuropsychiatric conditions.⁸ Another case series included ten adolescents with treatment-resistant depression who were prescribed methylfolate. Methylfolate was well tolerated and 80% of patients showed improvements in depression, anxiety, and irritability.⁹

Although the specific dose of folate supplementation should be determined by a child’s physician, increasing their intake of folate rich foods like leafy greens, lentils and legumes, avocados, and citrus can help boost their folate levels without risk of toxicity. If children are averse to these foods, try blending leafy greens into a smoothie or wilting them into dishes they enjoy like mac and cheese or scrambled eggs. Mash avocado and use it as a dip or spread on sandwiches or wraps, or add lentils and legumes to soups or turn them into yummy bean dips.

For more information about treating depression in children naturally, see our article: Nutritional interventions for depression and anxiety in children

Gingivitis

Studies suggest that folic acid intake may be important for the prevention of gingival inflammation, although the exact mechanisms of action remain unclear10. Pediatric specific clinical trials are limited, but there is an interesting connection between drug induced gingival hyperplasia and folic acid.¹¹ Phenytoin is a medication used to control seizure disorders in children. One of the common side effects of this medication is gingival hyperplasia. A daily oral dose of 0.5 mg of folic acid was found to significantly reduce the risk of gingival overgrowth in children taking phenytoin.

Other studies show that folate has a positive effect on several oral conditions such as recurrent aphthous stomatitis, gingival hyperplasia, and childhood caries and periodontal diseases.¹² Adequate folate intake reduces gum bleeding and aids in preventing early childhood dental caries by preserving the integrity of the periodontal tissues.¹²

Vitiligo

Vitiligo is an autoimmune and genetic condition in which the skin loses its natural color due to a lack of pigmentation. Although there is no cure for this condition, some researchers suggest a role of folic acid and vitamin B12 as a strategy to regain natural skin color^.13 In one study, folic acid, vitamin B12 and sun exposure enhanced repigmentation in 38% of patients and stopped its spread in 64% of patients after three to six months of treatment.

In children, 1-2 mg of folic acid a day, in conjunction with 100-400 IU of vitamin E, a multivitamin, and antioxidant cosmetics improved the appearance of facial vitiligo.¹⁴ It’s difficult to determine how much of the effect can be attributed to folic acid and how much is a combination of all components. However, the risks are relatively small and the benefits are difficult to deny.

Chronic Fatigue Syndrome and Fibromyalgia

Folate and vitamin B12 may be beneficial for people struggling with chronic fatigue syndrome or fibromyalgia.¹⁵ Studies show that people with fibromyalgia often have several B vitamin deficiencies and these same patients report positive effects of B12 and folic acid supplementation.¹⁵ Due to folate’s roles in red blood cell synthesis and thus oxygen transport and energy production, it’s easy to see how insufficient intake may contribute to fatigue and dysregulated mood. Supplementing with folate in patients who have unexplained fatigue may be beneficial, although the principle of ‘test don’t guess’ applies here in order to prevent triggering overmethylation symptoms or masking a B12 deficiency.

Safety:

Whole food sources of folate are generally recognized as safe. Choosing the appropriate supplement should be considered on a case by case basis, and women of childbearing age should certainly consider a supplement under the guidance of their primary care provider. Folate supplements during pregnancy are not only safe, but highly recommended for preventing neural tube defects in the child.

Summary:

Folate is a water-soluble B vitamin that plays important roles in cell production and numerous body systems as a methyl donor. Adequate intake through regular consumption of dark leafy greens, legumes, and avocados can prevent a deficiency. Some people with the MTHFR gene mutation may require supplementation with activated folate, methylfolate. Women who could become pregnant are encouraged to supplement with at least 400 ug/day to prevent neural tube defects in their offspring. Although some of the clinical trials are limited, there is some evidence suggesting a positive effect of folate in depression, anxiety, gingivitis, vitiligo, and unexplained fatigue in children. Since over supplementing with folate can mask a vitamin B12 deficiency, it’s important to assess for both vitamins before introducing a new supplement.

Resources

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