Folinic acid

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, and may be used to treat folate deficiency, anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.
Side effects may include trouble sleeping, allergic reactions, or fever. Use in pregnancy or breastfeeding is generally regarded as safe. When used for anemia it is recommended that pernicious anemia as a cause be ruled out first. Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.
Folinic acid was first made in 1945. In 2025, the United States Food and Drug Administration began approving leucovorin calcium tablets for cerebral folate deficiency, bypassing standard review and drawing expert criticism. It is on the World Health Organization's List of Essential Medicines.

Medical uses

Folinic acid can be taken as a pill or injected into a vein or muscle.

To reduce 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 x 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, a syndrome of low levels of 5-methyltetrahydrofolate, the active folate metabolite, within the cerebrospinal fluid. 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 began the process of approving leucovorin calcium tablets for treating this syndrome.

Autism spectrum disorder

Folinic acid for the treatment of autism spectrum disorder 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. 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 is able to 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 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 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 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 strong correlation 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 studies with large sample sizes. 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

Organization	Date	Statement
The American Academy of Pediatrics	October 31, 2025	"At this time, the American Academy of Pediatrics does not recommend the routine use of leucovorin for autistic children."
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."
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."
Autism Research Institute	September 22, 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."
Food and Drug Administration	September 22, 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."

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 toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine, although 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 fully control the seizures.

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.
In cancer patients, rare hypersensitivity reactions to folinic acid have been described.

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, 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, 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 1980s, however, folinic acid was found to reactivate the 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 and racemic folinic acid have similar efficacy and tolerability. Levoleucovorin was approved by the FDA in 2008.