Folic Acid
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Folic acid Supplements - what you should know!

Folic acid is crucial for the early development of the unborn child, it preserves mental capacity throughout life, and can provide protection against cardiovascular disease, migraine and cancer, amongst others.

Folic acid belongs to the family of water-soluble B vitamins, and is also known as vitamin B9. Members of the vitamin B complex are closely interacting: Folic acid and vitamin B12 have a special biochemical relationship and rely on each other.

Folic acid is a fundamental element for cellular function throughout the body and brain. It promotes the degradation of homocysteine in the blood, which contributes to cardiovascular disease.

Folic acid is consumed as folate in the diet. Rich sources of folate include offal, green leafy vegetables, nuts and eggs. As folic acid deficiency during pregnancy can lead to neural tube defects of the embryo, adequate intake of folic acid during this time is paramount.[1]

What are the functions of folic acid?

Folic acid is part of the One-Carbon-Metabolism that greatly contributes to cell division and repair. Via its modification of plasma homocysteine levels, folic acid also controls DNA regulation.[2] [3] These cellular processes represent the basis for the different functions of folic acid throughout the body:

  • Folic acid protects mother and baby: Increased intake of folic acid during the pregnancy supports the enormous speed of cell division during this time and decreases the risk of severe birth defects such as spina bifida.[1]

  • Folic acid reduces the risk of cardiovascular disease: Folic acid deficiency increases the level of homocysteine in the blood. Homocysteine in turn obstructs the blood vessels and contributes to cardiovascular disease and stroke.[2]

  • Folic acid relieves migraine: Homocysteine appears to also be negatively associated with the occurrence of headaches and migraine. Folic acid can reduce the frequency of migraine episodes.[4]

  • Folic acid preserves your mental fitness: Folic acid deficiency contributes to the age-mediated decline of mental flexibility and memory, as well as to the development of Alzheimer’s disease. Folic acid preserves the cognitive capacity and can reduce the risk of Alzheimer’s disease.[5]

  • Folic acid contributes to the protection against cancer: Folic acid deficiency increases the chances of developing various types of cancer. Adequate levels of folic acid are therefore able to support the body in preventing cancer.[2]

Folic acid deficiency – what causes it and what are the symptoms?

Folic acid deficiency is considered the most widespread deficiency amongst Western industrial countries. However, first signs of folic acid deficiency are often not apparent until the body’s folic acid storage units have been depleted, typically after 3 to 6 months.[2]

Causes of folic acid deficiency include insufficient uptake with the diet, or inability to process ingested folic acid. The latter may have underlying genetic reasons, such as mutations in the enzyme for folic acid conversion, or may be caused by disease, such as irritable bowel syndrome or celiac disease.

Persons affected by an enzymatic defect should not take folic acid supplements, but supply the body with the active form of folate, 5-methyltetrahydrofolate (5-MTHF), bypassing the enzymatic conversion step of folic acid.

Folic acid deficiency is typically not an insulated symptom here, but may present with other micronutrient deficiencies. Upon suspected folic acid deficiency, evaluation of the concentration of other vitamins and trace elements is recommended, particularly of other B vitamins.

Possible symptoms of folic acid deficiency include:[6]

  • Fatigue, exhaustion
  • Headaches, migraine
  • Attention deficits
  • Irritability
  • Dyspnoea (breathlessness)
  • Tachycardia (rapid heart beat)
  • Sore ulcers in mouth and larynx
  • Changes in the pigmentation of skin, hair and nails

Folic acid dosage recommendations

The recommended daily intake of folic acid is measured in folate equivalents. These define the sum of ingested folate and its derivatives.

Recommended daily intake of folate equivalents in µg (micrograms):[7]
  • New-borns up to 4 months: 60 µg/day
  • Babies from 5 to 12 months: 80 µg/day
  • Children from 1 to 3 years: 120 µg/day
  • Children from 4 to 7 years: 140 µg/day
  • Children from 8 to 10 years: 180 µg/day
  • Children from 11 to 12 years: 240 µg/day
  • Children from 13 years, adolescents and adults: 300 µg/day
  • Pregnancy: 550 µg/day*
  • Lactation: 450 µg/day

* Pregnant women and those trying to conceive should supplement their daily dietary intake of folic acid with at least 400 µg of folic acid or folate per day.

Who needs folic acid?

The body requires daily amounts of folic acid to be taken in with the diet. Special care to ensure adequate intake of folic acid should be taking in preparation for or during a pregnancy and the lactation period.

Additional intake of folic acid is also important if the body is unable to optimally process folic acid, eg due to genetic or disease-mediated factors.[2] [6]

Folic acid and fertility

Folic acid is especially required by those cells that divide rapidly, such as hematopoietic stem cells, responsible for the continuous renewal of blood cells. This is also reflected in the major role of folic acid during pregnancy, when an enormous number of new cells have to be produced in a short period of time.

Providing the body with insufficient amounts of folic acid can lead to severe birth defects including neural tube defects and spina bifida. The risk is further elevated if the mother has reduced ability to process folic acid, eg due to a polymorphism causing reduced enzyme activity (methylenetetrahydrofolate reductase).[1] [8]

Folic acid and fertility

Folic acid may help increase fertility in women. In 2006, the American Society for Reproductive Medicine reported findings of a study involving 18,500 women hoping to get pregnant over an eight-year period.

The study found that women taking a daily multivitamin containing folic acid for six or more days a week were forty percent less likely to experience ovulatory failure than women who did not supplement their diets with folic acid.

On the other hand, a 2014 study published in Reproductive Biomedicine Online found that folic acid use in women with unexplained fertility issues was not correlated with successful in vitro fertilization (IVF) outcomes.

Thus, though more research is needed, these studies may suggest that folic acid supplementation can increase fertility in women trying to conceive through non-IVF methods.

Folic acid reduces the risk of cardiovascular disease

Insufficient uptake of folic acid increases the concentration of homocysteine circulating in the blood stream. Increased homocysteine levels are associated with a higher risk of developing cardiovascular disease or stroke.[1]

The direct link between folic acid and homocysteine levels however is complex, as a deficiency in vitamin B12 also leads to higher homocysteine concentrations. Supplementing folic acid alone is therefore probably not sufficient to reduce the risk of cardiovascular disease, but may be effective as part of a restoration of a balanced micronutrient household.

Taking a vitamin B complex that contains folic acid significantly reduces the levels of blood homocysteine. Folic acid and other B vitamins also reduce the risk of stroke.[9] Scientist discovered recently that folic acid directly acts on the inner lining of the blood vessels, the epithelium, protecting it from oxidative damage, a common reason for heart attacks.[10]

Folic acid and stroke

Folic acid benefits may include protection against a possible heart attack or stroke.

In a recent study published in the Journal of the American Medical Association, researchers studied more than 20,000 adults in China with high blood pressure.

  • In China, unlike the United States, food is not fortified with folic acid. Participants were assigned into two groups: one group took a pill that contained both folic acid and a high blood pressure medication, while another group took a pill containing only a high blood pressure medication.
  • The median length of treatment for the participants was 4.5 years. The study found that 2.7 percent of participants experienced a first stroke when taking both folic acid and high blood pressure medication, while first strokes occurred in 3.4 percent of participants taking only the medication.

Thus, the study suggests that supplementation with folic acid, when used in conjunction with high blood pressure medication, can help decrease the risk of a stroke.

Folic acid relieves migraine

Elevated homocysteine levels are associated with the frequency of recurrent migraine episodes. Scientists revealed that people with a less active form of the enzyme methylenetetrahydrofolate reductase are more like to suffer from migraine. Underlying reason is a folic acid deficiency caused by the low enzymatic activity and subsequent increased homocysteine levels.

A study conducted by Australian researchers demonstrated that within this patient population, lower migraine frequency correlated with higher the folic acid levels.[4]

Folic acid preserves your mental fitness

The critical role of folic acid during the development of neuronal cells and the brain is apparent by the direct link of folic acid deficiency with neuronal birth defects. The positive impact of folic acid on the preservation of neuronal cells is maintained through all stages of life though.

Folic acid deficiency correlates with poor cognitive abilities in older people. Supplementation with folic acid in turn improves mental and memory capacities in persons with mild cognitive impairment. In addition, biomarkers associated with the development of Alzheimer’s disease can be reduced by the intake of folic acid.[5]

Folic acid contributes to the protection against cancer

Folic acid donates a methyl group during the methylation of DNA. This is an important step in the regulation of DNA, as well as for repair after DNA damage has occurred. If available amounts of folic acid are insufficient, DNA methylation is impaired. Strikingly, inadequately methylated DNA is a hallmark of tumour cells, together with low repair activity. The thus derived cellular instability contributes to the flexibility and aggressiveness of cancer.

Cellular methylation levels can be improved by folic acid, reducing the cancer risk, as shown in a study on smokers with lung carcinoma. Low folic acid levels were also associated with the development of colon, cervical, esophageal, pancreatic, and breast cancer. Scientist are therefore calling for an increase in global folic acid intake, eg via fortified food.[2] [6]

Why take a Folic acid supplement?

Folic supplements should be taken by individual, who want to
  • maintain healthy levels of folic acid
  • reduce blood levels of homocysteine
  • decrease risk of stroke
  • prevent neural tube defects in growing baby
  • ensure successful pregnancy

Folic acid in food

Spinach, liver, yeast, asparagus and brussel sprouts represent the best providers of folic acid.[6] Folic acid is also contained in a variety of other foods. These include green leafy vegetables, fruit, fruit juice, nuts, peas and beans, dairy products, eggs, meat and offal, seafood, and cereal.

Folic acid side effects

The question whether too much folic acid can be detrimental to your health is still controversial. Scientists are concerned that increased folic acid levels could mask a vitamin B12 deficiency, as concentrations of both vitamins are determined by blood homocysteine levels.

Due to its methylation activity, excess folic acid is suspected to negatively impact on genome stability, thereby contributing to the development of cancer. Based on these assumptions, an upper limit of 1000 µg (1 mg) of folic acid intake per day is recommended.[6]

Folic acid interactions

Several medications can influence the uptake and the effect of folic acid:

Methotrexate is a chemotherapy agent used to treat cancer as well as autoimmune diseases including psoriasis and rheumatoid arthritis. Methotrexate works as a folate agonist, thereby reducing the amount of available folic acid, which appears to increase drug toxicity of the agent.

Additional supplementation with folic acid during treatment with methotrexate can reduce drug toxicity and the severity of the side effects. Special care is recommended though, as excessive intake of folic acid can reduce the effectiveness of methotrexate.[6] [11]

Anti-epileptics are used to treat epilepsy. The use of several anti-epileptics can reduce the concentration of available folic acid in the body, leading to folic acid deficiency. Supplementation with folic acid in turn can reduce the effectiveness of the epilepsy treatment.[6]

Sulfasalazine is primarily used to treat ulcerative colitis. This drug can block the uptake of folic acid via the intestinal epithelium, thereby contributing to folic acid deficiency.[6]

During use of medication that alters the uptake or bioavailability of folic acid, folic acid levels should be monitored and increased under medical supervision if indicated.

Folic Acid Studies and references

  1. Northrup H, Volcik KA. Spina bifida and other neural tube defects. Curr Probl Pediatr. 2000 Nov-Dec;30(10):313-32.
  2. Stanger O. Physiology of Folic Acid in Health and Disease. Curr Drug Metab. 2002 Apr;3(2):211-23.
  3. Fenech M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res. 2012 May 1;733(1-2):21-33.
  4. Menon S, Lea RA, Ingle S. Effects of dietary folate intake on migraine disability and frequency. Headache. 2015 Feb;55(2):301-9.
  5. Ma F, Li Q, Zhou X. Effects of folic acid supplementation on cognitive function and Aβ-related biomarkers in mild cognitive impairment: a randomized controlled trail. Eur J Nutr. 2017 Dec 18.
  6. National Institutes of health Folate - Dietary Supplement Fact Sheet
  7. Deutsche Gesellschaft für Ernährung e.V. Folat - Empfohlene Zufuhr
  8. Chitayat D, Matsui D, Amitai Y. Folic acid supplementation for pregnant women and those planning pregnancy: 2015 update. J Clin Pharmacol. 2016 Feb;56(2):170-5.
  9. Martí-Carvajal AJ, Solà I, Lathyris D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017 Aug 17;8:CD006612.
  10. Gao L, Chalupsky K, Stefani E. Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity. J Mol Cell Cardiol. 2009 Dec;47(6):752-60.
  11. Baran W, Batycka-Baran A, Zychowska M. Folate supplementation reduces the side effects of methotrexate therapy for psoriasis. Expert Opin Drug Saf. 2014 Aug;13(8):1015-21.