Folic acid side effects
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Folic Acid Side Effects: A Comprehensive Overview
Introduction to Folic Acid and Its Uses
Folic acid, a synthetic form of folate, is widely used in dietary supplements and food fortification to prevent neural tube defects (NTDs) in newborns and to support overall health. However, its use is not without potential side effects, which can vary depending on the context of its application.
Gastrointestinal and Hepatic Side Effects in Methotrexate Therapy
Gastrointestinal Side Effects
Folic acid is often used to mitigate the side effects of methotrexate (MTX) therapy in patients with rheumatoid arthritis (RA). Studies have shown that folic acid supplementation can significantly reduce gastrointestinal (GI) side effects such as nausea, vomiting, and abdominal pain. A systematic review found a 26% relative risk reduction in GI side effects for patients receiving folic acid alongside MTX therapy1. Another meta-analysis reported a 79% reduction in mucosal and GI side effects with folic acid supplementation2 6.
Hepatic Side Effects
Folic acid also appears to protect against hepatic dysfunction caused by MTX. Patients supplemented with folic acid showed a 76.9% relative risk reduction in abnormal serum transaminase levels, indicating reduced liver toxicity1. This protective effect is crucial for patients undergoing long-term MTX therapy.
Hematologic Side Effects
While the evidence is less robust, some studies suggest that folic acid may help reduce hematologic side effects associated with MTX therapy. However, the data are not as conclusive, and further research is needed to confirm these findings1 6.
Cognitive Function and Neurocognitive Disorders
Folic acid has been studied for its potential benefits in improving cognitive function and managing neurocognitive disorders. It may help by decreasing homocysteine levels, improving vascular health, reducing inflammation, and providing antioxidant benefits. However, the effectiveness of folic acid in this context is still under investigation, and more research is needed to establish its role in cognitive health3.
Potential Adverse Effects of Excess Folic Acid
Unmetabolized Folic Acid and Cancer Risk
One of the concerns with high folic acid intake is the presence of unmetabolized folic acid (UMFA) in the bloodstream, which may be linked to an increased risk of cancer. Some studies suggest that high levels of folic acid could exacerbate the progression of pre-existing neoplastic cells, although the evidence is not conclusive4 5 8.
Masking Vitamin B-12 Deficiency
Excessive folic acid intake can mask the symptoms of vitamin B-12 deficiency, potentially leading to neurological damage if left untreated. This is particularly concerning for the elderly, who are more susceptible to vitamin B-12 deficiency4 7.
Other Health Risks
High folic acid intake has also been associated with decreased natural killer cell activity, which could impair the immune response. Additionally, in pregnant women, high folate levels combined with low vitamin B-12 status may increase the risk of insulin resistance and obesity in their children8.
Conclusion
While folic acid supplementation offers significant benefits, particularly in reducing the side effects of methotrexate therapy and preventing neural tube defects, it is not without potential risks. High intake levels may lead to adverse effects such as increased cancer risk, masking of vitamin B-12 deficiency, and other health issues. Therefore, it is essential to balance the benefits and risks of folic acid supplementation and to conduct further research to fully understand its impact on health.
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Most relevant research papers on this topic
Folic Acid and Folinic Acid for Reducing Side Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis
Folic acid and folinic acid supplementation significantly reduces gastrointestinal side effects and abnormal serum transaminase elevation in patients with rheumatoid arthritis receiving methotrexate therapy.
Highly CitedThe efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials.
Folate supplementation significantly reduces oral and gastrointestinal side effects of low dose methotrexate in rheumatoid arthritis patients.
Meta-AnalysisHighly CitedThe effects and potential mechanisms of folic acid on cognitive function: a comprehensive review
Folic acid supplementation may improve cognitive function in the elderly by decreasing homocysteine levels, vascular care, attenuating inflammation, modifying cerebral folic acid deficiency, and promoting antioxidant responses.
Systematic ReviewIntended and Unintended Benefits of Folic Acid Fortification—A Narrative Review
Mandatory folic acid fortification in processed cereals and cereal products reduces neural tube defects in newborns, but may also reduce anemia, blood serum homocysteine, and cardiovascular disease risk.
Systematic ReviewKnowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.
Excess folic acid intake and elevated folate status may have adverse effects on health, but current evidence is inconclusive and more research is needed to clarify these issues and bridge knowledge gaps.
Very Rigorous JournalHighly CitedFolic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.
Folic acid supplementation significantly reduces mucosal and gastrointestinal side effects in patients receiving low-dose methotrexate for rheumatoid arthritis, but does not alter methotrexate efficacy.
Meta-AnalysisSafety of folic acid
Current mandatory folic acid fortification programs in many countries do not pose risks for adverse consequences, supporting public health and adhering to the precautionary principle.
Rigorous JournalHighly CitedIs folic acid good for everyone?
High folic acid intake may be harmful for some people, and nations considering fortification should carefully research its effects before implementing it.
Very Rigorous JournalHighly CitedEffects and safety of periconceptional folate supplementation for preventing birth defects.
Folic acid supplementation before and during pregnancy effectively prevents neural tube defects but has no clear effect on other birth defects.
Systematic ReviewVery Rigorous JournalHighly CitedFolic Acid Supplement Intake in Early Pregnancy Increases Risk of Gestational Diabetes Mellitus: Evidence From a Prospective Cohort Study
Early prenatal folic acid supplementation increases the risk of gestational diabetes mellitus, but the potential adverse effects of high maternal folate levels remain unclear.
Observational StudyVery Rigorous Journal