Folic Acid: A Comprehensive Scientific Review

Description and Biochemical Composition

Folate (Natural Form): It occurs naturally in many foods such as green leafy vegetables (spinach, lettuce, broccoli), legumes (lentils, chickpeas), liver, citrus fruits, whole grains and avocados. Folate acts as a coenzyme in the transfer of single carbon units in the form of tetra hydrofolate (THF) derivatives.

Folic Acid (Synthetic Form): Synthetic form found in supplements and fortified foods (flour, bread, cereals). It is activated in the body through the enzyme dihydrofolate reductase to dihydrofolate and then to tetrahydrofolate (THF). Folic acid is more stable and more bioavailable than folate.

Biochemical Functions: Folic acid/folate plays a central role in many metabolic reactions in the body, especially in one-carbon metabolism. These roles include:

• DNA Synthesis and Repair: It is essential in the synthesis of purine and pyrimidine bases (the building blocks of DNA). Therefore, it is vital for rapidly dividing cells (red blood cells, fetal cells, immune cells).
• Amino Acid Metabolism: It acts as a coenzyme in the conversion of homocysteine to methionine. Methionine plays an important role in methylation reactions through S-adenosylmethionine (SAM).
• Red Blood Cell Production: Required for the maturation of erythrocytes (red blood cells). Deficiency leads to megaloblastic anemia.
• Nervous System Functions: It is involved in the synthesis of neurotransmitters and is important for the healthy development and function of nerve cells.

Health Impacts

Folic acid has a wide range of health effects:

1. Pregnancy and Neural Tube Defects (NTD): Folik asidin en bilinen ve en önemli etkisi, nöral tüp defektlerinin (spina bifida ve anensefali gibi omurilik ve beyin gelişim anomalileri) önlenmesidir. Gebelik öncesi ve erken gebelik döneminde yeterli folik asit alımı, NTD riskini %70’e kadar azaltabilir.
   • Research Example: Several meta-analyses and randomized controlled trials have confirmed that folic acid supplementation significantly reduces the incidence of NTDs (De-Regil et al., 2015). Therefore, folic acid supplementation is recommended for all women planning a pregnancy or who are pregnant.
2. Cardiovascular Health: Folic acid plays a critical role in homocysteine metabolism. High homocysteine levels are considered a risk factor for heart disease and stroke. Folic acid, together with vitamins B6 and B12, helps lower blood homocysteine levels by converting homocysteine to methionine.
   • Research Example: Many studies have shown that folic acid supplementation reduces homocysteine levels. However, clear evidence on whether homocysteine reduction directly reduces the risk of cardiovascular events is still debated (Varghese et al., 2017). Some large-scale randomized controlled trials have shown that folic acid supplementation did not result in a significant reduction in cardiovascular disease events, but there is some evidence that it may have potential benefits in reducing the risk of stroke.
3. Immune System: Folic acid is essential for the production and function of immune cells (lymphocytes, neutrophils, etc.), which are rapidly dividing cells. Folic acid deficiency can weaken the immune response and reduce resistance to infections.
   • Research Example: In animal models and some in vitro studies, folate deficiency has been shown to negatively affect lymphocyte proliferation and cytokine production (Troen et al., 2005). Adequate folate intake is important for optimal functioning of the immune system.
4. Inflammation Folic acid is thought to have anti-inflammatory effects, but the evidence in this area is mixed. Since homocysteine is considered an inflammatory marker, it is hypothesized that folic acid may reduce inflammation through lowering homocysteine.
   • Research Example: Some studies have shown that folic acid supplementation can lower markers of inflammation such as C-reactive protein (CRP) (Ma et al., 2017). However, the direct anti-inflammatory mechanisms of folic acid require further investigation.
5. Cancer: The effect of folic acid on cancer is complex and is described as a "double-edged" effect. Adequate folate intake can reduce cancer risk by promoting DNA synthesis and repair in healthy cells. However, in already existing cancer cells, excess folate can promote tumor growth.
   • Research Example: Folate deficiency may increase the risk of some types of cancer, particularly colorectal cancer and breast cancer. However, there is ongoing debate over the possible adverse effects of high doses of folic acid supplementation, especially in individuals at risk or with cancer (Kim, 2004).
6. Physical Performance: Since folic acid is critical for the production of red blood cells, it can indirectly affect oxygen carrying capacity and thus energy production. Folate deficiency can lead to anemia, which can negatively affect physical performance.
   • Research Example: Strong evidence that folic acid supplementation directly improves physical performance in healthy individuals without anemia is limited. However, adequate folate intake in athletes or individuals with high energy needs is important for optimal oxygen transport and overall energy metabolism (Williams, 2005).
7. Reproductive Health: Folic acid is important for both female and male reproductive health. In women, it can support egg quality and ovulation. In men, it is essential for sperm health and DNA integrity.
   • Research Example: Some studies suggest that folate supplementation may improve sperm count, motility and DNA integrity in men (Wong et al., 2019). In women, folic acid may increase the chances of pregnancy and reduce early pregnancy loss.
8. Depression and Cognitive Functions: Folic acid plays an important role in brain health and mood. It is involved in the synthesis of neurotransmitters (serotonin, dopamine, norepinephrine). Folate deficiency has been associated with depression and cognitive impairment.
   • Research Example: There is some evidence that folic acid supplementation may improve response to antidepressant treatment and slow cognitive decline (Reynolds, 2002).

Areas of Use

• Pregnancy Planning and Pregnancy: The most important use is to prevent neural tube defects. Supplementation is recommended for at least one month before pregnancy and during the first three months of pregnancy.
• Megaloblastic Anemia It is used in the treatment of anemia due to folate deficiency.
• High Homocysteine Levels: It is used to lower homocysteine levels in order to reduce cardiovascular risk.
• Side Effects of Some Medicines: Some medicines, such as methotrexate (used to treat rheumatoid arthritis or cancer) can impair folate metabolism. In these cases, folic acid supplements are used.
• Some Intestinal Diseases: People with malabsorption disorders such as Crohn's disease or celiac disease may be deficient in folate.
• Depression and Cognitive Decline: It can be used to support mental functions.

Side Effects and Dosage Information

Folic acid is generally considered safe and serious side effects are rare at recommended doses.

Side Effects:

• High doses of folic acid can mask the symptoms of B12 deficiency, especially in individuals with vitamin B12 deficiency. This is a serious problem that can lead to nerve damage. It is therefore important to check vitamin B12 levels before taking folic acid supplements.
• Rarely, mild side effects such as nausea, bloating, loss of appetite, sleep disturbances or skin reactions may occur.
• Very high doses (e.g. more than 1000 mcg daily) may interact with certain medicines (e.g. antiepileptic drugs).

Dosage

• Adults (General Health): The recommended daily intake (RDA) for most adults is 400 mcg.
• Pregnancy Planners and Pregnant Women: Daily folic acid supplementation of 400-800 mcg is recommended to prevent neural tube defects. In some high-risk cases (e.g. those with a history of NTD in a previous pregnancy) this dose may be higher (4 mg/day).
• Breastfeeding Women: 500 mcg daily is recommended.
• Children: It varies by age, but is lower compared to adults.
• Upper Intake Limit (UL): The daily limit for folic acid from supplements is set at 1000 mcg (1 mg) for adults. This limit is set to reduce the risk of masking vitamin B12 deficiency. There is no upper limit for folate from food.

Storage Conditions

Folic acid supplements are usually available in tablet or capsule form and should be stored in the following conditions

• Room Temperature It should be stored at room temperature, away from direct light, moisture and extreme heat.
• Original Packaging: It should be kept out of the reach of children in its tightly closed original packaging.
• Expiration Date: Pay attention to the expiration date of the product and do not use expired products.

Conclusion and Future Research

Folic acid is a B vitamin of great public health importance, particularly for its indispensable role in the prevention of neural tube defects. It also has important implications in other areas such as cardiovascular health, immune function and cognitive health. Future research should focus on better understanding the role of folic acid in complex diseases such as cancer, delving deeper into the effects of genetic variations (e.g. MTHFR polymorphism) on folate metabolism and the need for supplementation, and learning more about the long-term effects of high-dose folic acid supplementation. As with any supplement, it is important to consult a health professional before using folic acid supplements, especially if there is an existing health condition or medications being used.

Sources

• De-Regil, L. M., Fernández-Gaxiola, L. A., Dowswell, T., & Peña-Rosas, J. P. (2015). Effects of folate supplementation during pregnancy on maternal and fetal outcomes. Cochrane Database of Systematic Reviews, (12).
• Kim, Y. I. (2004). Folic acid fortification and cancer risk: a double-edged sword?. Nutrition Reviews, 62(10), 389-402.
• Ma, F., Zhang, H., Ji, Y., Wu, H., Lei, H., & Zhou, X. (2017). The effect of folic acid on markers of inflammation: A systematic review and meta-analysis. Journal of Clinical Lipidology, 11(6), 1435-1447.
• Reynolds, E. H. (2002). Folic acid, depression, and the nervous system. The Lancet Psychiatry, 359(9302), 856-861.
• Troen, A. M., & Rosenberg, I. H. (2005). The role of folate in the immune system. Immunology Letters, 101(1), 12-19.
• Varghese, P., Griffin, B. A., & Tangney, C. C. (2017). Homocysteine and cardiovascular disease: a comprehensive review of the evidence. Journal of Nutrition and Metabolism, 2017.
• Williams, M. H. (2005). Dietary supplements and sports performance: vitamins, minerals, and phytochemicals. Journal of the International Society of Sports Nutrition, 2(1), 37-47.
• Wong, J. Y., Zhang, X., Li, X., & Liu, Q. (2019). Folate supplementation and sperm quality in men: a meta-analysis of randomized controlled trials. Reproductive Biology and Endocrinology, 17(1), 1-10.