Folinic acid

Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly). To reduce the effects of methotrexate Folinic acid is administered after methotrexate as part of a comprehensive chemotherapy regimen to help prevent bone marrow suppression and inflammation of the gastrointestinal mucosa. However, no apparent effect is seen on pre-existing methotrexate-induced nephrotoxicity. While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be redosed until the methotrexate level is less than 5 × 10−8 M. Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate in rheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores. Cerebral folate deficiency Folinic acid is also used in the treatment of cerebral folate deficiency (CFD), a syndrome of low levels of 5-methyltetrahydrofolate (5-MTHF), the active folate metabolite, within the cerebrospinal fluid (CSF). This disorder appears in the presence of normal folate metabolism outside the central nervous system and may be associated with decreased folate transport or increased folate turnover within the CSF. As the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF, the US Food and Drug Administration (FDA) began the process of approving leucovorin calcium tablets for treating this syndrome. All pediatric and ASD medical organizations which have issued statements have cautioned that more, better-quality studies are needed, and none have endorsed the treatment as of December 2025. Background Folinic acid is a form of folate, an essential vitamin commonly known as vitamin B9. For most vitamins, the needed nutrients can be used by the body in various chemical forms. In the case of folinic acid/leucovorin, this form can cross from the blood into the brain more easily than other forms. In most humans, the body uses a group of proteins known as the folate receptor alpha (FRα) transport system to carry common food sources of folate from the bloodstream into the brain. In an estimated 58–76% of children with ASD, folate receptor alpha autoantibodies (FRAAs) interfere with this normal route of folate transfer to the brain. In these cases, food- or supplement-based sources of folate might be plentiful in the bloodstream but unable to cross into the brain in needed amounts. This can cause a condition called cerebral folate deficiency (CFD). CFD has been associated with "seizures, delayed motor and cognitive development, autistic features, poor head growth, cerebellar ataxia, visual and hearing impairment, dyskinesia and spasticity." Folinic acid is a form of vitamin B9 that can circumvent these barriers and replenish the brain with folate, thus defeating the deficiency and treating CFD. Earlier studies have examined the correlation between folate levels in early pregnancy and ASD diagnoses of children, with some finding a strong correlation (30–70% lower likelihood of developing ASD) and others finding no significant correlation. Studies Before any medical treatment gains widespread acceptance and adoption by medical practitioners, typically, the treatment is studied in controlled, randomized, double-blind trials with large sample sizes (large numbers of patients). The scientific evidence for leucovorin use in ASD treatment is "quite preliminary, modest, and based on small studies without rigorous outcomes to date," according to Dr. Beth Ellen Davis, UVA developmental behavioral pediatrician. Studies also used different doses, metrics, and methods of statistical analysis, which complicates their use as a basis from which to derive clinical suggestions. Positions of medical organizations Other uses or indications Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase. Folinic acid is also sometimes used to prevent the toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine. Its value for this indication has not been clearly established. It may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine. In pyridoxine-dependent epilepsy, folinic acid may be used as additional therapy if pyridoxine or pyridoxal phosphate fails to control the seizures fully. == Side effects ==

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death. Severe neurotoxicity due to intrathecal folinic acid as treatment for intrathecally-administered methotrexate was first noted in an 11-year-old boy being treated for acute lymphocytic leukemia. == Drug interactions ==

• Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severe enterocolitis, diarrhea, and dehydration. • Sulfamethoxazole-trimethoprim: A potential drug interaction exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment of Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a common cause of pneumonia in AIDS patients. == Mechanism of action ==

Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., 5,10-methylenetetrahydrofolate, 5-methyltetrahydrofolate), thus has vitamin activity equivalent to that of folic acid. Since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate. This is the classical view of folinic acid rescue therapy. In the 1980s, however, folinic acid was found to reactivate dihydrofolate reductase itself even when methotrexate exists. Although the mechanism is not very clear, the polyglutamylation of methotrexate and dihydrofolate in malignant cells is considered to play an important role in the selective reactivation of dihydrofolate reductase by folinic acid in normal cells. Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normal DNA replication processes can proceed. Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability. Levoleucovorin was approved by the FDA in 2008. == History ==

Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This resulted in it being called "citrovorum factor", meaning citrovorum growth factor. It had an unknown structure, but was found to be a folate derivative that had to be metabolized in the liver before it could support the growth of L. citrovorum. The synthesis of citrovorum factor by liver cells in culture was eventually accomplished from pteroylglutamic acid in the presence of suitable concentrations of ascorbic acid. The simultaneous addition of sodium formate to such systems increased citrovorum factor activity in the cell-free supernatants (producing, as is now known, the 5-formyl derivative). From this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced. In September 2025, the US Food and Drug Administration (FDA) initiated the process of approving leucovorin calcium tablets for the treatment of cerebral folate deficiency, a condition associated with developmental delays, autistic features, seizures, and movement issues. On 10 March 2026, the FDA approved leucovorin tablets for FOLR1-related cerebral folate transport deficiency in children and adults. == Society and culture ==

Names Folinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer of folic acid and has the full vitamin activity of this vitamin. Levofolinic acid and its salts are the 2S-form of the molecule. They are the only forms of the molecule that are known to be biologically active. It is generally administered as the calcium or sodium salt (calcium folinate INN], sodium folinate, leucovorin calcium, leucovorin sodium). == References ==