Folinic acid

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Folinic acid
Folinic acid.svg
Leucovorin molecule ball.png
Clinical data
PronunciationLeucovorin /ˌljuːkoʊˈvɔːrɪn/
Other namesLeucovorin, citrovorum factor, 5-formyltetrahydrofolate
AHFS/Drugs.com Monograph
MedlinePlus a608038
License data
Pregnancy
category
  • AU:A
Routes of
administration 		By mouth, intramuscular, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Dose dependent
Protein binding ~15%
Elimination half-life 6.2 hours
Excretion Kidney
Identifiers
  • (2S)-2-{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-
    tetrahydro-1H-pteridin-6-yl)methylamino]
    benzoyl]amino}pentanedioic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.328 OOjs UI icon edit-ltr-progressive.svg
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 [1]  mg/mL (20 °C)
  • O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O
  • InChI=1S/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12?,13-/m0/s1 Yes check.svgY
  • Key:VVIAGPKUTFNRDU-ABLWVSNPSA-N Yes check.svgY

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. [2] [3] 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. [3] [4] It is taken by mouth, injection into a muscle, or injection into a vein. [3]

Contents

Side effects may include trouble sleeping, allergic reactions, or fever. [2] [3] Use in pregnancy or breastfeeding is generally regarded as safe. [2] When used for anemia it is recommended that pernicious anemia as a cause be ruled out first. [3] Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body. [3]

Folinic acid was first made in 1945. [5] 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. [6] [7] Folinic acid garnered international attention following a wide-ranging September 22, 2025 press conference in the White House with US president Donald Trump, Health and Human Services secretary Robert F. Kennedy Jr., and CMS Administrator Dr. Mehmet Oz. [8] [9] It is on the World Health Organization's List of Essential Medicines. [10]

Medical uses

Levofolinic acid Levofolinic acid.svg
Levofolinic acid

Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly). [11]

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. [12]

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. [13]

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. [14]

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. [15]

As the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF, [16] the US Food and Drug Administration (FDA) began the process of approving leucovorin calcium tablets for treating this syndrome. [17]

Autism spectrum disorder

Folinic acid (or leucovorin) for the treatment of autism 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] [23]

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 (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. [24] [25] 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." [26] [27]

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. [26]

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. [28]

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 (large numbers of patients). [29] 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. [30] Studies also used different doses, metrics, and methods of statistical analysis, which complicates their use as a basis from which to derive clinical suggestions. [31]

Positions of medical organizations

OrganizationDateStatement
The American Academy of PediatricsOctober 31, 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 FoundationDecember 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 PediatricsOctober 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] [32]
Autism Research InstituteSeptember 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." [22]
Food and Drug Administration (FDA)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." [23]

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. [33] 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. [34]

Side effects

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death. [35] 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. [35]

In cancer patients, rare hypersensitivity reactions to folinic acid have been described. [36]

Drug interactions

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 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists. [38]

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. [39]

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. [40] Levoleucovorin was approved by the FDA in 2008. [41]

History

Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. [42] 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 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 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. [43]

On 22 September 2025, the US Food and Drug Administration (FDA) under medical contrarian and US secretary of health and human services Robert F. Kennedy Jr. 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, based on literature allegedly showing potential benefit, while noting further research is needed for broader neuropsychiatric populations. [17] 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. [7] [44]

Names

Folinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer 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 the calcium or sodium salt (calcium folinate [ INN], sodium folinate, leucovorin calcium, leucovorin sodium).

References

  1. ↑ "Safety Data Sheet Folinic Acid (calcium salt)" (PDF). Retrieved 25 January 2018.
  2. 1 2 3 British national formulary: BNF 69 (69 ed.). British Medical Association. 2015. pp. 576–577. ISBN   978-0-85711-156-2.
  3. 1 2 3 4 5 6 "Leucovorin Calcium". The American Society of Health-System Pharmacists. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
  4. ↑ Munjal YP, Sharm SK (2012). API Textbook of Medicine, Ninth Edition, Two Volume Set. JP Medical Ltd. p. 1945. ISBN   978-93-5025-074-7. Archived from the original on 10 May 2017.
  5. ↑ Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 235. ISBN   978-0-471-89979-2. Archived from the original on 10 May 2017.
  6. ↑ Office of the Commissioner (22 September 2025). "FDA Takes Action to Make a Treatment Available for Autism Symptoms". FDA. Retrieved 24 September 2025.
  7. 1 2 Jewett C, Mueller B (23 September 2025). "F.D.A.'s Approval of a Drug for Autism Upends Review Process". The New York Times. Retrieved 24 September 2025.
  8. ↑ Press A (24 September 2025). "What to know about leucovorin, unproven autism drug touted by Trump". PBS News. Retrieved 15 December 2025.
  9. ↑ "President Trump, Secretary Kennedy Announce Bold Actions to Tackle Autism Epidemic". HHS.gov. 22 September 2025. Retrieved 15 December 2025.
  10. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ↑ McGuire BW, Sia LL, Leese PT, Gutierrez ML, Stokstad EL (January 1988). "Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration". Clinical Pharmacy. 7 (1): 52–58. PMID   3257913.
  12. ↑ Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.[ page needed ]
  13. ↑ "Leucovorin" (PDF). CCO Formulary. Archived from the original (PDF) on 10 October 2008. Retrieved 7 January 2014.
  14. ↑ Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. (May 2013). "Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis". The Cochrane Database of Systematic Reviews. 2013 (5) CD000951. doi:10.1002/14651858.CD000951.pub2. PMC   7046011 . PMID   23728635.
  15. ↑ Ramaekers VT, Blau N (December 2004). "Cerebral folate deficiency". Developmental Medicine and Child Neurology. 46 (12): 843–851. doi:10.1111/j.1469-8749.2004.tb00451.x. PMID   15581159.
  16. ↑ Gordon N (March 2009). "Cerebral folate deficiency". Developmental Medicine and Child Neurology. 51 (3): 180–182. doi:10.1111/j.1469-8749.2008.03185.x. PMID   19260931. S2CID   7373721.
  17. 1 2 Office of the Commissioner (22 September 2025). "FDA Takes Action to Make a Treatment Available for Autism Symptoms". FDA. Retrieved 24 September 2025.
  18. 1 2 3 4 Cha AE (14 December 2025). "A Trump-touted drug for autism is now in demand, but doctors see a dilemma". The Washington Post. Retrieved 15 December 2025.
  19. 1 2 Pant S (December 2025). "AAP: Leucovorin Not Recommended for Autism". JAMA. 334 (23). American Medical Association (AMA): 2061. doi:10.1001/jama.2025.19739. PMID   41236735.
  20. 1 2 "Interim Guidance from the American Academy of Pediatrics: Use of Leucovorin in Autistic Pediatric Patients". AAP. 31 October 2025. Retrieved 15 December 2025.
  21. 1 2 "Leucovorin". Autism Science Foundation - Supporting and sharing autism research to improve the real lives of real people. 9 September 2025. Retrieved 15 December 2025.
  22. 1 2 "ARI Statement on Acetaminophen, Leucovorin and Autism". Autism Research Institute. 22 September 2025. Retrieved 15 December 2025.
  23. 1 2 "FDA Takes Action to Make a Treatment Available for Autism Symptoms". U.S. Food and Drug Administration. 22 September 2025. Retrieved 15 December 2025.
  24. ↑ "Mental Health: Leucovorin and Autism: What Pediatricians Should Know". Children's Mercy. 31 October 2025. Retrieved 15 December 2025.
  25. ↑ Hyland K, Shoffner J, Heales SJ (October 2010). "Cerebral folate deficiency". Journal of Inherited Metabolic Disease. 33 (5): 563–570. doi:10.1007/s10545-010-9159-6. PMID   20668945.
  26. 1 2 Pérez-Dueñas B, Ormazábal A, Toma C, Torrico B, Cormand B, Serrano M, et al. (May 2011). "Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects". Archives of Neurology. 68 (5): 615–621. doi:10.1001/archneurol.2011.80. PMID   21555636.
  27. ↑ McFarland R (July 2012). "Cerebral folate deficiency--mishaps and misdirection". Brain. 135 (Pt 7): 2002–2003. doi:10.1093/brain/aws166. PMID   22734130.
  28. ↑ "What we know about rising autism rates and Trump's unproven Tylenol link". BBC Home. 23 September 2025. Retrieved 15 December 2025.
  29. ↑ Parker RA, Cook JA (August 2023). "The importance of clinical importance when determining the target difference in sample size calculations". Trials. 24 (1) 495. doi: 10.1186/s13063-023-07532-5 . PMC   10401796 . PMID   37542276.
  30. ↑ Mohammed Z (24 September 2025). "Q&A: What is leucovorin, now being hailed as an autism treatment?". UVA Today. Retrieved 15 December 2025.
  31. ↑ Perrone M (24 September 2025). "Trump's touting of an unproven autism drug surprised many, including the doctor who proposed it". AP News. Retrieved 15 December 2025.
  32. ↑ "A Statement from the Society for Developmental and Behavioral Pediatrics On Recent Autism Claims" (PDF). The Society for Developmental and Behavioral Pediatrics (SDBP). Retrieved 15 December 2025.
  33. ↑ Trubiano JA, Grayson ML (2017). "Trimethoprim and Trimethoprim–Sulfamethoxazole (Cotrimoxazole)". In Grayson ML, Cosgrove S, Crowe S, Hope W, McCarthy J, Mills J, Mouton JW, Paterson D (eds.). Kucers' the Use of Antibiotics (7th ed.). CRC Press. p. 1652. doi:10.1201/9781498747967. ISBN   978-1-4987-4796-7.
  34. ↑ Kaminiów K, Pająk M, Pająk R, Paprocka J (December 2021). "Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures". Brain Sciences. 12 (1): 65. doi: 10.3390/brainsci12010065 . PMC   8773593 . PMID   35053812.
  35. 1 2 Jardine LF, Ingram LC, Bleyer WA (August 1996). "Intrathecal leucovorin after intrathecal methotrexate overdose". Journal of Pediatric Hematology/Oncology. 18 (3): 302–304. doi:10.1097/00043426-199608000-00014. PMID   8689347. S2CID   43280375.
  36. ↑ Florit-Sureda M, Conde-Estévez D, Vidal J, Montagut C (December 2016). "Hypersensitivity reaction caused by folinic acid administration: a case report and literature review". Journal of Chemotherapy. 28 (6): 500–505. doi:10.1179/1973947815Y.0000000048. hdl: 10230/27696 . PMID   26042586. S2CID   25420102.
  37. ↑ Razavi B, Lund B, Allen BL, Schlesinger L (January 2002). "Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use". Infection. 30 (1): 41–42. doi:10.1007/s15010-001-1172-0. PMID   11876516. S2CID   35513636.
  38. ↑ Gristan YD, Patel P, Moosavi L (2025). "Folinic Acid". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   31424816 . Retrieved 8 December 2025.
  39. ↑ Goldman ID, Matherly LH (1987). "Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates". NCI Monographs (5): 17–26. PMID   2448654.
  40. ↑ Kovoor PA, Karim SM, Marshall JL (October 2009). "Is levoleucovorin an alternative to racemic leucovorin? A literature review". Clinical Colorectal Cancer. 8 (4): 200–206. doi:10.3816/CCC.2009.n.034. PMID   19822510.
  41. ↑ "FDA Approves Levoleucovorin". Drugs.com. 7 May 2008. Archived from the original on 2 July 2009. Retrieved 7 June 2009.
  42. ↑ "NEW form of folic acid, the Leuconostoc citrovorum factor". Nutrition Reviews. 8 (9): 282–284. September 1950. doi:10.1111/j.1753-4887.1950.tb02478.x. PMID   14775946.
  43. ↑ Rabinowitz JC, Pricer Jr WE (1956). "Formimino-tetrahydrofolic acid and methenyltetrahydrofolic acid as intermediates in the formation of N10-formyltetrahydrofolic acid". Journal of the American Chemical Society. 78 (21): 5702–5704. Bibcode:1956JAChS..78.5702R. doi:10.1021/ja01602a073.
  44. ↑ Stobbe M, Seitz A, Johnson C, Perrone M, Hunzinger E (27 November 2024). "Meet the medical contrarians picked to lead health agencies under Trump and Kennedy". AP News. Retrieved 26 September 2025.
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