Folinic acid

{{Short description|Derivative of folic acid used in cancer treatment}} {{Distinguish|Folic acid}} {{Use dmy dates|date=March 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | image = Folinic acid.svg | image_class = skin-invert-image | alt = Skeletal formula of folinic acid | width = 250 | image2 = Leucovorin molecule ball.png | image_class2 = bg-transparent | alt2 = Ball-and-stick model of the folinic acid molecule

| pronounce = Leucovorin {{IPAc-en|ˌ|lj|uː|k|oʊ|ˈ|v|ɔː|r|ɪ|n}} | Drugs.com = {{drugs.com|monograph|leucovorin-calcium}} | MedlinePlus = a608038 | DailyMedID = Leucovorin calcium | pregnancy_AU = A | routes_of_administration = By mouth, intramuscular, intravenous | ATC_prefix = V03 | ATC_suffix = AF03

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref>{{cite web | title=Leucovorin Calcium tablet | website=DailyMed | date=30 August 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=94669fc8-3c1c-4228-be27-09a1cd468c36 | access-date=9 February 2026}}</ref><ref>{{cite web | title=Leucovorin Calcium injection | website=DailyMed | date=14 October 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5d4f0fd-7520-43a9-9acc-f7e117e1f6ee | access-date=9 February 2026}}</ref><ref>{{cite web | title=Lederle Leucovorin- calcium folinate tablet | website=DailyMed | date=18 December 2025 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4734ce39-440d-4a8f-8613-2905408b42cd | access-date=9 February 2026}}</ref> | legal_UN =  | legal_UN_comment = | legal_status =

| IUPAC_name = (''2S'')-2-<nowiki/>{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8- tetrahydro-1''H''-pteridin-6-yl)methylamino] benzoyl]amino}pentanedioic acid | C = 20 | H = 23 | N = 7 | O = 7 | SMILES = O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O | StdInChI = 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 | StdInChIKey = VVIAGPKUTFNRDU-ABLWVSNPSA-N | density = | melting_point = 245 | melting_high = | melting_notes = decomp | solubility = ~0.3<ref>{{Cite web | title = Safety Data Sheet Folinic Acid (calcium salt) | url = https://www.caymanchem.com/msdss/20383m.pdf | access-date = 25 January 2018 }}</ref> }}

'''Folinic acid''', also known as '''leucovorin''', is a medication used to decrease the toxic effects of methotrexate and pyrimethamine.<ref name="BNF69">{{cite book | title = British national formulary: BNF 69 | pages = 576–577 | date = 2015 | publisher = British Medical Association | isbn = 978-0-85711-156-2 | edition = 69 }}</ref><ref name="AHFS2016">{{cite web | title = Leucovorin Calcium | url = https://www.drugs.com/monograph/leucovorin-calcium.html | publisher = The American Society of Health-System Pharmacists | access-date = 8 December 2016 | url-status = live | archive-url = https://web.archive.org/web/20170510115807/https://www.drugs.com/monograph/leucovorin-calcium.html | archive-date = 10 May 2017 }}</ref> 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.<ref name="AHFS2016" /><ref>{{cite book | vauthors = Munjal YP, Sharm SK | title = API Textbook of Medicine, Ninth Edition, Two Volume Set | page = 1945 | date = 2012 | publisher = JP Medical Ltd | isbn = 978-93-5025-074-7 | url = https://books.google.com/books?id=L7pW3yGjj7kC&pg=PA1945 | url-status = live | archive-url = https://web.archive.org/web/20170510215410/https://books.google.ca/books?id=L7pW3yGjj7kC&pg=PA1945 | archive-date = 10 May 2017 }}</ref> It is taken by mouth, injection into a muscle, or injection into a vein.<ref name="AHFS2016" />

Side effects may include trouble sleeping, allergic reactions, or fever.<ref name="BNF69" /><ref name="AHFS2016" /> Use in pregnancy or breastfeeding is generally regarded as safe.<ref name="BNF69" /> When used for anemia it is recommended that pernicious anemia as a cause be ruled out first.<ref name="AHFS2016" /> Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.<ref name="AHFS2016" />

Folinic acid was first made in 1945.<ref>{{cite book | vauthors = Sneader W | title = Drug Discovery: A History | page = 235 | date = 2005 | publisher = John Wiley & Sons | isbn = 978-0-471-89979-2 | url = https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA235 | url-status = live | archive-url = https://web.archive.org/web/20170510233831/https://books.google.ca/books?id=Cb6BOkj9fK4C&pg=PA235 | archive-date = 10 May 2017 }}</ref> In 2025, the United States Food and Drug Administration approved leucovorin calcium tablets for cerebral folate deficiency, bypassing standard review and drawing expert criticism.<ref name="FDA PR 20250922">{{cite press release | title = FDA Takes Action to Make a Treatment Available for Autism Symptoms | date = 2025-09-22 | url = https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms | access-date = 2025-09-24 | website = U.S. Food and Drug Administration (FDA) }}</ref><ref name="Jewett_2025" /> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO24th">{{cite book | title = The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list | year = 2025 | hdl = 10665/382243 | publisher = World Health Organization | location = Geneva | hdl-access = free | doi = 10.2471/B09474 | doi-access = free | id = License: CC BY-NC-SA 3.0 IGO }}</ref>

== Medical uses == class=skin-invert-image|thumb|Levofolinic acid Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).<ref>{{cite journal | vauthors = McGuire BW, Sia LL, Leese PT, Gutierrez ML, Stokstad EL | title = Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration | journal = Clinical Pharmacy | volume = 7 | issue = 1 | pages = 52–58 | date = January 1988 | pmid = 3257913 }}</ref>

=== 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.<ref>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|date=February 2015}}</ref>

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.<ref>{{cite web | title = Leucovorin | work = CCO Formulary | url = http://www.cancercare.on.ca/pdfdrugs/leucovo.pdf | access-date = 7 January 2014 | archive-url = https://web.archive.org/web/20081010050826/http://www.cancercare.on.ca/pdfdrugs/Leucovo.pdf | archive-date = 10 October 2008 }}</ref>

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.<ref>{{cite journal | vauthors = Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P | title = Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 5 | date = May 2013 | pmid = 23728635 | pmc = 7046011 | doi = 10.1002/14651858.CD000951.pub2 | article-number = CD000951 }}</ref>

=== 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.<ref>{{cite journal | vauthors = Ramaekers VT, Blau N | title = Cerebral folate deficiency | journal = Developmental Medicine and Child Neurology | volume = 46 | issue = 12 | pages = 843–851 | date = December 2004 | pmid = 15581159 | doi = 10.1111/j.1469-8749.2004.tb00451.x }}</ref>

As the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF,<ref name="Gordon_2009">{{cite journal | vauthors = Gordon N | title = Cerebral folate deficiency | journal = Developmental Medicine and Child Neurology | volume = 51 | issue = 3 | pages = 180–182 | date = March 2009 | pmid = 19260931 | doi = 10.1111/j.1469-8749.2008.03185.x | s2cid = 7373721 }}</ref> the US Food and Drug Administration (FDA) began the process of approving leucovorin calcium tablets for treating this syndrome.<ref name="FDA PR 20250922" />

=== 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.<ref name="Cha_2025">{{cite news | vauthors = Cha AE | title = A Trump-touted drug for autism is now in demand, but doctors see a dilemma | date = 2025-12-14 | newspaper = The Washington Post | url = https://www.washingtonpost.com/health/2025/12/13/trump-leucovorin-autism-treatment/ | access-date = 2025-12-15 }}</ref> 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.<ref name="Pant_2025">{{cite journal | vauthors = Pant S | title = AAP: Leucovorin Not Recommended for Autism | journal = JAMA | volume = 334 | issue = 23 | page = 2061 | date = December 2025 | pmid = 41236735 | doi = 10.1001/jama.2025.19739 | publisher = American Medical Association (AMA) }}</ref><ref name="j433">{{cite web | title = Interim Guidance from the American Academy of Pediatrics: Use of Leucovorin in Autistic Pediatric Patients | date = 2025-10-31 | website = AAP | url = https://www.aap.org/en/patient-care/autism/use-of-leucovorin-in-autistic-pediatric-patients/ | access-date = 2025-12-15 }}</ref><ref name="Cha_2025">{{cite news | vauthors = Cha AE | title = A Trump-touted drug for autism is now in demand, but doctors see a dilemma | date = 2025-12-14 | newspaper = The Washington Post | url = https://www.washingtonpost.com/health/2025/12/13/trump-leucovorin-autism-treatment/ | access-date = 2025-12-15 }}</ref><ref name="g389">{{cite web | title = Leucovorin | date = 2025-09-09 | website = Autism Science Foundation – Supporting and sharing autism research to improve the real lives of real people | url = https://autismsciencefoundation.org/leucovorin/ | access-date = 2025-12-15 }}</ref><ref name="z307">{{cite web | title = ARI Statement on Acetaminophen, Leucovorin and Autism | date = 2025-09-22 | website = Autism Research Institute | url = https://autism.org/acetaminophen-leucovorin/ | access-date = 2025-12-15 }}</ref><ref name="FDA PR 20250922" />

In January 2026, the largest trial of leucovorin in autistic children was retracted due to discovery of various errors.<ref name="largest">{{cite news | vauthors = López Lloreda C |title=Largest leucovorin-autism trial retracted |url=https://www.thetransmitter.org/spectrum/largest-leucovorin-autism-trial-retracted/ |access-date=4 February 2026 |work=The Transmitter: Neuroscience News and Perspectives |date=3 February 2026}}</ref><ref name="panda-retraction">{{cite journal | vauthors = Panda PK, Sharawat IK, Saha S, Gupta D, Palayullakandi A, Meena K | title = Retraction Note: Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial | journal = European Journal of Pediatrics | volume = 185 | issue = 2 | page = 109 | date = January 2026 | pmid = 41606385 | doi = 10.1007/s00431-026-06769-x }}</ref>

==== 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.<ref name="y479">{{cite web | title = Mental Health: Leucovorin and Autism: What Pediatricians Should Know | date = 2025-10-31 | website = Children's Mercy | url = https://www.childrensmercy.org/health-care-providers/refer-or-manage-a-patient/connect-with-childrens-mercy/newsletter-the-link/the-link-2025/the-link---october-2025/mental-health-leucovorin-and-autism-what-pediatricians-should-know/ | access-date = 2025-12-15 }}</ref><ref name="Hyland_2010">{{cite journal | vauthors = Hyland K, Shoffner J, Heales SJ | title = Cerebral folate deficiency | journal = Journal of Inherited Metabolic Disease | volume = 33 | issue = 5 | pages = 563–570 | date = October 2010 | pmid = 20668945 | doi = 10.1007/s10545-010-9159-6 }}</ref> 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."<ref name="PerezDuenas_2011">{{cite journal | vauthors = Pérez-Dueñas B, Ormazábal A, Toma C, Torrico B, Cormand B, Serrano M, Sierra C, De Grandis E, Marfa MP, García-Cazorla A, Campistol J, Pascual JM, Artuch R | title = Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects | journal = Archives of Neurology | volume = 68 | issue = 5 | pages = 615–621 | date = May 2011 | pmid = 21555636 | doi = 10.1001/archneurol.2011.80 }}</ref><ref name="McFarland_2012">{{cite journal | vauthors = McFarland R | title = Cerebral folate deficiency--mishaps and misdirection | journal = Brain | volume = 135 | issue = Pt 7 | pages = 2002–2003 | date = July 2012 | pmid = 22734130 | doi = 10.1093/brain/aws166 }}</ref>

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.<ref name="PerezDuenas_2011">{{cite journal | vauthors = Pérez-Dueñas B, Ormazábal A, Toma C, Torrico B, Cormand B, Serrano M, Sierra C, De Grandis E, Marfa MP, García-Cazorla A, Campistol J, Pascual JM, Artuch R | title = Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects | journal = Archives of Neurology | volume = 68 | issue = 5 | pages = 615–621 | date = May 2011 | pmid = 21555636 | doi = 10.1001/archneurol.2011.80 }}</ref>

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.<ref name="j340">{{cite web | title = What we know about rising autism rates and Trump's unproven Tylenol link | date = 2025-09-23 | website = BBC Home | url = https://www.bbc.com/news/articles/cpq51dry7wgo | access-date = 2025-12-15 }}</ref>

==== 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).<ref name="Parker_2023">{{cite journal | vauthors = Parker RA, Cook JA | title = The importance of clinical importance when determining the target difference in sample size calculations | journal = Trials | volume = 24 | issue = 1 | date = August 2023 | pmid = 37542276 | pmc = 10401796 | doi = 10.1186/s13063-023-07532-5 | doi-access = free | article-number = 495 }}</ref> 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.<ref name="Mohammed_2025">{{cite web | vauthors = Mohammed Z | title = Q&A: What is leucovorin, now being hailed as an autism treatment? | date = 2025-09-24 | website = UVA Today | url = https://news.virginia.edu/content/qa-what-leucovorin-now-being-hailed-autism-treatment | access-date = 2025-12-15 }}</ref> Studies also used different doses, metrics, and methods of statistical analysis, which complicates their use as a basis from which to derive clinical suggestions.<ref name="Perrone_2025">{{cite web | vauthors = Perrone M | title = Trump's touting of an unproven autism drug surprised many, including the doctor who proposed it | date = 2025-09-24 | website = AP News | url = https://apnews.com/article/autism-drug-leucovorin-trump-kennedy-d2b36faef3c4fc1f85e9fa9f958ad6c6 | access-date = 2025-12-15 }}</ref>

==== Positions of medical organizations ====

{| class="wikitable" |- ! 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."<ref name="Pant_2025" /><ref name="j433">{{cite web | title = Interim Guidance from the American Academy of Pediatrics: Use of Leucovorin in Autistic Pediatric Patients | date = 2025-10-31 | website = AAP | url = https://www.aap.org/en/patient-care/autism/use-of-leucovorin-in-autistic-pediatric-patients/ | access-date = 2025-12-15 }}</ref><ref name="Cha_2025">{{cite news | vauthors = Cha AE | title = A Trump-touted drug for autism is now in demand, but doctors see a dilemma | date = 2025-12-14 | newspaper = The Washington Post | url = https://www.washingtonpost.com/health/2025/12/13/trump-leucovorin-autism-treatment/ | access-date = 2025-12-15 }}</ref> |- | 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."<ref name="g389">{{cite web | title = Leucovorin | date = 2025-09-09 | website = Autism Science Foundation – Supporting and sharing autism research to improve the real lives of real people | url = https://autismsciencefoundation.org/leucovorin/ | access-date = 2025-12-15 }}</ref> |- | 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."<ref name="Cha_2025">{{cite news | vauthors = Cha AE | title = A Trump-touted drug for autism is now in demand, but doctors see a dilemma | date = 2025-12-14 | newspaper = The Washington Post | url = https://www.washingtonpost.com/health/2025/12/13/trump-leucovorin-autism-treatment/ | access-date = 2025-12-15 }}</ref><ref name="t740">{{cite web | title = A Statement from the Society for Developmental and Behavioral Pediatrics On Recent Autism Claims | work = The Society for Developmental and Behavioral Pediatrics (SDBP) | url = https://www.stanfordchildrens.org/content/dam/sch/content-public/services/pdf/SDBP-autism-statement.pdf | access-date = 2025-12-15 }}</ref> |- | 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 validate these findings fully and establish optimal treatment protocols."<ref name="z307">{{cite web | title = ARI Statement on Acetaminophen, Leucovorin and Autism | date = 2025-09-22 | website = Autism Research Institute | url = https://autism.org/acetaminophen-leucovorin/ | access-date = 2025-12-15 }}</ref> |- | 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."<ref name="FDA PR 20250922" /> |- |}

=== 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.<ref>{{cite book | vauthors = Trubiano JA, Grayson ML | veditors = Grayson ML, Cosgrove S, Crowe S, Hope W, McCarthy J, Mills J, Mouton JW, Paterson D | chapter = Trimethoprim and Trimethoprim–Sulfamethoxazole (Cotrimoxazole) | title = Kucers' the Use of Antibiotics | page = 1652 | year = 2017 | doi = 10.1201/9781498747967 | edition = 7th | url = https://www.taylorfrancis.com/books/edit/10.1201/9781498747967/kucers-use-antibiotics-lindsay-grayson-sara-cosgrove-suzanne-crowe-lindsay-grayson-william-hope-james-mccarthy-john-mills-johan-mouton-david-paterson | isbn = 978-1-4987-4796-7 | chapter-url = https://www.taylorfrancis.com/chapters/edit/10.1201/9781498747967-92/trimethoprim-trimethoprim%E2%80%93sulfamethoxazole-cotrimoxazole-jason-trubiano-lindsay-grayson | publisher = CRC Press }}</ref> 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.<ref name="Kaminiow_2021">{{cite journal | vauthors = Kaminiów K, Pająk M, Pająk R, Paprocka J | title = Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures | journal = Brain Sciences | volume = 12 | issue = 1 | page = 65 | date = December 2021 | pmid = 35053812 | pmc = 8773593 | doi = 10.3390/brainsci12010065 | doi-access = free }}</ref>

== Side effects == Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.<ref name="Jardine_1996">{{cite journal | vauthors = Jardine LF, Ingram LC, Bleyer WA | title = Intrathecal leucovorin after intrathecal methotrexate overdose | journal = Journal of Pediatric Hematology/Oncology | volume = 18 | issue = 3 | pages = 302–304 | date = August 1996 | pmid = 8689347 | doi = 10.1097/00043426-199608000-00014 | s2cid = 43280375 }}</ref> 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.<ref name="Jardine_1996" />

In cancer patients, rare hypersensitivity reactions to folinic acid have been described.<ref name="FloritSureda_2016">{{cite journal | vauthors = Florit-Sureda M, Conde-Estévez D, Vidal J, Montagut C | title = Hypersensitivity reaction caused by folinic acid administration: a case report and literature review | journal = Journal of Chemotherapy | volume = 28 | issue = 6 | pages = 500–505 | date = December 2016 | pmid = 26042586 | doi = 10.1179/1973947815Y.0000000048 | hdl-access = free | s2cid = 25420102 | hdl = 10230/27696 }}</ref>

== 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.{{Citation needed|date=September 2025}} *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.<ref>{{cite journal | vauthors = Razavi B, Lund B, Allen BL, Schlesinger L | title = Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use | journal = Infection | volume = 30 | issue = 1 | pages = 41–42 | date = January 2002 | pmid = 11876516 | doi = 10.1007/s15010-001-1172-0 | s2cid = 35513636 }}</ref>

== Mechanism of action == {{More citations needed|section=Section name|date=September 2025}} 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.<ref>{{cite book | vauthors = Gristan YD, Patel P, Moosavi L | chapter = Folinic Acid | title = StatPearls | date = 2025 | pmid = 31424816 | url = http://www.ncbi.nlm.nih.gov/books/NBK545232/ | access-date = 2025-12-08 | place = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref>

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.<ref name="Goldman_1987">{{cite journal | vauthors = Goldman ID, Matherly LH | title = 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 | journal = NCI Monographs | issue = 5 | pages = 17–26 | year = 1987 | pmid = 2448654 }}</ref>

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.<ref>{{cite journal | vauthors = Kovoor PA, Karim SM, Marshall JL | title = Is levoleucovorin an alternative to racemic leucovorin? A literature review | journal = Clinical Colorectal Cancer | volume = 8 | issue = 4 | pages = 200–206 | date = October 2009 | pmid = 19822510 | doi = 10.3816/CCC.2009.n.034 }}</ref> Levoleucovorin was approved by the FDA in 2008.<ref>{{cite web | title = FDA Approves Levoleucovorin | date = 7 May 2008 | url = https://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html | work = Drugs.com | access-date = 7 June 2009 | url-status = live | archive-url = https://web.archive.org/web/20090702033819/http://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html | archive-date = 2 July 2009 }}</ref>

== History == Folinic acid was discovered as a needed growth factor for the bacterium ''Leuconostoc citrovorum'' in 1948, by Sauberlich and Baumann.<ref>{{cite journal | title = NEW form of folic acid, the Leuconostoc citrovorum factor | journal = Nutrition Reviews | volume = 8 | issue = 9 | pages = 282–284 | date = September 1950 | pmid = 14775946 | doi = 10.1111/j.1753-4887.1950.tb02478.x }}</ref> 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.<ref>{{cite journal | vauthors = Rabinowitz JC, Pricer Jr WE | title = Formimino-tetrahydrofolic acid and methenyltetrahydrofolic acid as intermediates in the formation of N10-formyltetrahydrofolic acid. | journal = Journal of the American Chemical Society | volume = 78 | issue = 21 | pages = 5702–5704 | date = 1956 | doi = 10.1021/ja01602a073 | bibcode = 1956JAChS..78.5702R }}</ref>

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.<ref name="FDA PR 20250922" /> 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.<ref name="Jewett_2025">{{Cite news | vauthors = Jewett C, Mueller B | title = F.D.A.'s Approval of a Drug for Autism Upends Review Process | date = 2025-09-23 | url = https://www.nytimes.com/2025/09/23/health/fda-autism-treatment-leucovorin.html | access-date = 2025-09-24 | work = The New York Times }}</ref><ref name="Stobbe_2024">{{cite web | vauthors = Stobbe M, Seitz A, Johnson C, Perrone M, Hunzinger E | title = Meet the medical contrarians picked to lead health agencies under Trump and Kennedy | date = 27 November 2024 | url = https://apnews.com/article/trump-health-nih-bhattacharya-kennedy-covid-vaccines-a7396d40ec7f770b4699af9b68794073 | website = AP News | access-date = 26 September 2025 }}</ref>

On 10 March 2026, the FDA approved leucovorin tablets for ''FOLR1''-related cerebral folate transport deficiency in children and adults.<ref>{{Cite web |last= |first= |date=2026-03-10 |title=FDA Approves First Treatment for Patients with Cerebral Folate Transport Deficiency |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency |access-date=2026-03-10 |website=FDA |language=en|archive-url=https://web.archive.org/web/20260310213312/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency|archive-date=10 March 2026}}</ref>

== Society and culture == === Names === {{Unreferenced section|date=September 2025}} 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 [<nowiki/>INN], sodium folinate, leucovorin calcium, leucovorin sodium).

== References == {{reflist}}

== External links == * {{cite web | title = Leucovorin | website = MedlinePlus | url = https://medlineplus.gov/druginfo/meds/a682336.html }}

Category:Chemotherapeutic adjuvants Category:Folates Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate