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| Pronunciation | Leucovorin/ˌljuːkoʊˈvɔːrɪn/ |
| Other names | Leucovorin, citrovorum factor, 5-formyltetrahydrofolate |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608038 |
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| Routes of administration | By mouth,intramuscular,intravenous |
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| Pharmacokinetic data | |
| Bioavailability | Dose dependent |
| Protein binding | ~15% |
| Eliminationhalf-life | 6.2 hours |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.328 |
| Chemical and physical data | |
| Formula | C20H23N7O7 |
| Molar mass | 473.446 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 245 °C (473 °F) decomp |
| Solubility in water | ~0.3[4] mg/mL (20 °C) |
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Folinic acid, also known asleucovorin, is a medication used to decrease the toxic effects ofmethotrexate andpyrimethamine.[5][6] It is also used in combination with5-fluorouracil to treatcolorectal cancer andpancreatic cancer, and may be used to treatfolate deficiency,anemia, andmethanol poisoning.[6][7] It is taken by mouth,injection into a muscle, orinjection into a vein.[6]
Side effects may include trouble sleeping,allergic reactions, orfever.[5][6] Use inpregnancy orbreastfeeding is generally regarded as safe.[5] When used for anemia it is recommended thatpernicious anemia as a cause be ruled out first.[6] Folinic acid is a form offolic acid that does not require activation bydihydrofolate reductase to be useful to the body.[6]
Folinic acid was first made in 1945.[8] In 2025, the United StatesFood and Drug Administration approved leucovorin calcium tablets forcerebral folate deficiency, bypassing standard review and drawing expert criticism.[9][10] It is on theWorld Health Organization's List of Essential Medicines.[11]
Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).[12]
Folinic acid is administered aftermethotrexate as part of a comprehensive chemotherapy regimen to help preventbone marrow suppression and inflammation of the gastrointestinal mucosa. However, no apparent effect is seen on pre-existing methotrexate-inducednephrotoxicity.[13]
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 x 10−8 M.[14]
Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate inrheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.[15]
Folinic acid is also used in the treatment ofcerebral 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.[16]
As the use offolic acid cannot normalize cerebrospinal fluid levels of5-MTHF,[17] the USFood and Drug Administration (FDA) began the process of approving leucovorincalcium tablets for treating this syndrome.[9]
Folinic acid (or leucovorin) for the treatment ofautism spectrum disorder (ASD) is an experimental treatment which has shown positive outcomes in several small studies but has not been studied to the extent normally required for researchers, doctors, and regulators to endorse as a standard treatment.[18] 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.[19][20][18][21][22][9]
In January 2026, the largest trial of leucovorin in autistic children was retracted due to discovery of various errors.[23][24]
Folinic acid is a form of folate, an essential vitamin commonly known asvitamin B9. For most vitamins, the needed nutrients can be used by the body invarious chemical forms. In the case of folinic acid/leucovorin, this form is able to cross from theblood into the brain more easily than other forms.
In most humans, the body uses a group of proteins known as thefolate 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.[25][26] 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 calledcerebral 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."[27][28]
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.[27]
Earlier studies have examined the correlation between folate levels in early pregnancy and ASD diagnoses of children, with some finding strong correlation (30-70% lower likelihood of developing ASD) and others finding no significant correlation.[29]
Before any medical treatment gains widespread acceptance and adoption by medical practitioners, typically the treatment is studied in controlled, randomized, double-blind studies with large sample sizes (large numbers of patients).[30] 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.[31] Studies also used different doses, metrics, and methods of statistical analysis, which complicates their use as a basis from which to derive clinical suggestions.[32]
| Organization | Date | Statement |
|---|---|---|
| The American Academy of Pediatrics | October 2025 | "At this time, the American Academy of Pediatrics does not recommend the routine use of leucovorin (folinic acid) for autistic children."[19][20][18] |
| Autism Science Foundation | December 2025 | "This science is still in very early stages, and more studies are necessary before a definitive conclusion can be reached. While this drug poses no apparent health risks, there is not sufficient data to show that it improves autism symptoms."[21] |
| Society for Developmental & Behavioral Pediatrics | October 2025 | "Much more research is needed on folate receptor autoantibodies and leucovorin as possible treatments for autism. The research on leucovorin comes from a very limited number of studies of variable quality, each using different doses and measuring different outcomes, making it impossible to draw definitive conclusions."[18][33] |
| Autism Research Institute | September 2025 | "We are encouraged by the preliminary results suggesting that leucovorin supplementation may benefit certain subgroups of individuals with autism spectrum disorders. However, we emphasize that this research is still evolving, and larger, controlled studies are needed to fully validate these findings and establish optimal treatment protocols."[22] |
| US Food and Drug Administration (FDA) | September 2025 | "CFD has also been reported in a broader patient population with neuropsychiatric symptoms, including autistic features, and detectable serum autoantibodies to the folate receptor alpha; however, there are limitations on the available data for the use of leucovorin in this population and additional studies are needed to assess safety and efficacy."[9] |
Folinic acid is also used in combination with the chemotherapy agent5-fluorouracil in treatingcolon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibitingthymidylate synthase.
Folinic acid is also sometimes used to prevent toxic effects of high doses ofantimicrobialdihydrofolate reductase inhibitors such astrimethoprim andpyrimethamine, although its value for this indication has not been clearly established.[34] It may be prescribed in the treatment oftoxoplasmosisretinitis, in combination with the folic acid antagonistspyrimethamine andsulfadiazine.
Inpyridoxine-dependent epilepsy, folinic acid may be used as additional therapy if pyridoxine orpyridoxal phosphate fails to fully control the seizures.[35]
Folinic acid should not be administeredintrathecally. This may produce severe adverse effects or even death.[36] 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.[36]
In cancer patients, rarehypersensitivity reactions to folinic acid have been described.[37]
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Folinic acid is a 5-formyl derivative oftetrahydrofolic 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 ofdihydrofolate reductase for its conversion, its function as a vitamin is unaffected byinhibition of this enzyme by drugs such as methotrexate. This is the classical view of folinic acid rescue therapy. In 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists.[39]
Although the mechanism is not very clear, thepolyglutamylation 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.[40]
Folinic acid, therefore, allows for somepurine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normalDNA 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.[41] Levoleucovorin was approved by the FDA in 2008.[42]
Folinic acid was discovered as a needed growth factor for the bacteriumLeuconostoc citrovorum in 1948, by Sauberlich and Baumann.[43] This resulted in it being called "citrovorum factor", meaning citrovorum growth factor. It had an unknown structure, but was found to be a derivative of folate that had to be metabolized in the liver before it could support growth ofL. 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 resulted in increased citrovorum factor activity in the cell-free supernatants (producing, as now known, the 5-formyl derivative), and from this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced.[44]
In September 2025, the USFood and Drug Administration (FDA) initiated the process of approving leucovorin calcium tablets for the treatment ofcerebral folate deficiency, a condition associated with developmental delays, autistic features,seizures, and movement issues.[9] The approval bypassed the FDA's standard rigorous drug-review procedures, drawing criticism from experts and leading to increased sales of over-the-counter folinic acid supplements.[10][45]
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Folinic acid should be distinguished fromfolic acid (vitamin B9). However, folinic acid is avitamer for 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 thecalcium orsodium salt (calcium folinate [INN], sodium folinate, leucovorin calcium, leucovorin sodium).
