Folate as Folinic Acid
Also known as: Folinic acid, Leucovorin, 5-Formyltetrahydrofolate, 5-Formyl Tetrahydrofolate, Folinic Acid
Overview
Folinic acid, also known as leucovorin or 5-formyltetrahydrofolate, is a biologically active form of folate (vitamin B9). It is naturally found in foods like leafy greens and liver. Unlike folic acid, folinic acid does not require enzymatic reduction by dihydrofolate reductase to be utilized by the body, making it more bioavailable, especially for individuals with impaired folate metabolism. It is used as a supplement to improve folate status, reduce homocysteine levels, and support DNA synthesis and repair. Clinically, it is used to mitigate the toxic effects of antifolate drugs like methotrexate. Research on folinic acid is extensive, with numerous randomized controlled trials and meta-analyses supporting its benefits.
Benefits
Folinic acid supplementation has been shown to significantly reduce serum homocysteine levels, a known cardiovascular risk factor. Meta-analyses indicate that folate supplementation, including folinic acid, can contribute to a 10% lower risk of stroke and a 4% lower risk of overall cardiovascular disease (CVD). Folinic acid also exhibits anti-inflammatory effects, demonstrated by a reduction in C-reactive protein (CRP) levels. These benefits are more pronounced in populations without mandatory folic acid grain fortification and those with elevated homocysteine levels. Longer durations of supplementation (≥3 years) are associated with greater cardiovascular benefits. Folinic acid is effective in primary prevention of stroke.
How it works
Folinic acid participates in one-carbon metabolism, a crucial process for DNA synthesis, repair, and methylation. It lowers homocysteine levels by providing methyl groups necessary for its remethylation to methionine. Folinic acid primarily affects the cardiovascular system by reducing homocysteine, which is linked to endothelial dysfunction and inflammation. It interacts with folate-dependent enzymes involved in nucleotide biosynthesis and methylation reactions. Unlike folic acid, folinic acid is absorbed efficiently and does not require enzymatic reduction, leading to higher bioavailability.
Side effects
Folinic acid is generally safe with a low incidence of adverse effects when used at recommended doses. Common side effects are rare, but mild gastrointestinal discomfort has been occasionally reported. Uncommon side effects include rare allergic reactions. Hypersensitivity reactions are very rare. Folinic acid can reduce the toxicity of antifolate chemotherapy drugs, so caution is advised in cancer patients. It is contraindicated in individuals with hypersensitivity to folate derivatives. Pregnant women benefit from folate supplementation, and folinic acid is preferred in certain metabolic disorders.
Dosage
For general supplementation, a typical effective dose of folinic acid ranges from 400 mcg to 1 mg daily. In clinical settings, dosages up to 5 mg daily may be used for homocysteine reduction or folate deficiency. There is no established upper limit, but doses up to 15 mg/day have been used safely under medical supervision. Daily dosing with meals may enhance absorption. Folinic acid is often preferred over folic acid in individuals with MTHFR polymorphisms or impaired folate metabolism. Vitamin B12 is an important cofactor for homocysteine metabolism alongside folate.
FAQs
Is folinic acid better than folic acid?
Yes, folinic acid is the active form and bypasses metabolic activation, making it more effective in certain populations, especially those with MTHFR polymorphisms.
Can folinic acid prevent stroke?
Evidence supports its role in primary stroke prevention through homocysteine reduction, a known risk factor for cardiovascular events.
Are there risks of overdose?
Overdose is rare; high doses should be supervised medically. Folinic acid is generally well-tolerated at recommended dosages.
How soon do benefits appear?
Homocysteine reduction can occur within weeks; cardiovascular benefits require longer-term use, often several years of consistent supplementation.
Research Sources
- https://pubmed.ncbi.nlm.nih.gov/39064642/ – This systematic review and meta-analysis, including 51 articles with 42,768 participants, evaluated folate-based B vitamin supplementation and confirmed significant cardiovascular benefits, particularly stroke risk reduction. The study addressed heterogeneity through subgroup analyses, accounting for variability in folate forms and dosages.
- https://pubmed.ncbi.nlm.nih.gov/34857394/ – A meta-analysis of 12 RCTs showed that folic acid supplementation significantly reduced CRP levels (WMD: −0.59 mg/L, p < 0.001) but had no significant effect on IL-6 or TNF-α, indicating selective anti-inflammatory effects. The study noted the need for larger, diverse populations to confirm these findings due to small sample sizes in some trials.
- https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1288417/full – This study provides insights into the role of folate in nutrition, highlighting its importance for various physiological processes. It underscores the significance of adequate folate intake for overall health and well-being.
- https://www.mdpi.com/2072-6643/13/7/2327 – This research explores the effects of folic acid supplementation on various health outcomes. It contributes to the understanding of folate's impact on human health and disease prevention.
- https://www.ahajournals.org/doi/10.1161/jaha.116.003768 – A 2016 meta-analysis of RCTs (n > 30,000) demonstrated a 10% reduction in stroke risk and 4% reduction in overall CVD risk with folic acid supplementation, with greater effects in populations without folic acid grain fortification and longer supplementation duration. The study acknowledged potential confounding by co-supplementation with B6/B12 and heterogeneity in baseline folate status.
