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Recent media have highlighted treating autism with Leucovorin (Folinic Acid)
What is Leucovorin?
Leucovorin is a medication used in the treatment of methotrexate toxicity and chemotherapy regimens.1 It is a folate analog.1 Leucovorin is a 5-formyl derivative of folic acid.
Traditional use of Leucovorin1
Decrease the toxic effects of methotrexate
Occasionally used in the treatment of megaloblastic anemia
May be used in palliative treatment of colon cancer in combination with 5-fluorouracil
Off-label uses include1
Neoadjuvant treatment of bladder cancer
Cofactor in methanol toxicity
Prevention of hematological toxicity of pyrimethamine in patients with AIDs
Ectopic pregnancy treatment + methotrexate
Treatment of advanced
Esophageal cancer
Gastric cancer
Pancreatic cancer
How is Cerebral Folate Deficiency (CFD) related to Autism?
According to Stefanyshyn and colleagues, autism spectrum disorders may be associated with cerebral folate deficiency. Folate receptor alpha autoantibodies (FRAA) and variants of the SLC19A1 gene are discussed as possible contributing factors. The authors aimed to investigate a specific gene variant (rs1051266 variant of the SLC19A1 gene) in patients with ASD and CFD and determine the relationship. The study included 227 children with ASD. Of these 227 children, 156 had ASD.
The authors found significant correlations between homocysteine levels and vitamins B9, B12, and B6 and between verbal impairments and vitamin B12. In ASD and CFD patients, vitamin B12 levels were elevated. In the ASD group, correlations were found between homocysteine levels and demyelination.
The findings of the above study highlight that there are many different and highly variable differences in patients who have ASD and CFD. The variant of the gene and then the specific folate abnormality are important to consider when developing a personalized plan.
Testing for CFD
Systemic deficiencies of CFD are not diagnostic because a person with CFD may have normal folate levels. CFD refers to cerebral folate deficiency, not systemic folate deficiency. The correct test would involve measuring 5-methyltetrahydrofolate in the cerebrospinal fluid obtained via a lumbar puncture.
Since this test is invasive (lumbar puncture), it is best ordered and interpreted by specialists (neurologist and geneticist).
APANP recommendations
If caregivers request leucovorin
Consider referring the child to a metabolic geneticist for genotyping and evaluation, and a neurologist for further evaluation.
Consider advising the family that there is not a single cause of autism, over 100 genes have been implicated3 as causes for autism, and there are different timelines for pathology (prenatally and postnatally).4 Therefore, it is unlikely that leucovorin is a cure-all for autism. Leucovorin has possible side effects, including seizures, syncope, hives, nausea and vomiting, abdominal toxicity, and anaphylaxis. Therefore, after appropriate genotyping, evaluation by specialists, Leucovorin may be considered an option by the specialists; however, the medication is not without risk.
Prescribing Leucovorin to all patients with ASD without first evaluating for an accurate diagnosis of cerebral folate deficiency is not appropriate. This diagnosis requires a lumbar puncture. The procedure has risks and is painful and invasive, and is best ordered by a neurologist or geneticist after careful weighing of risks and benefits.
Respectfully,
APANP
References:
Hegde VS, Nagalli S. Leucovorin. In: StatPearls Treasure Island (FL): StatPearls Publishing; 2025 Web site. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553114/
Stefanyshyn V, Stetsyuk R, Hrebeniuk O, et al. Analysis of the association between the SLC19A1 genetic variant (rs1051266) and autism spectrum disorders, cerebral folate deficiency, and clinical and laboratory parameters. J Mol Neurosci. 2025 Mar 29;75(2):42. doi: 10.1007/s12031-025-02338-3.
Forrest MP, Penzes P. Autism genetics: over 100 risk genes and counting. Pediatr Neurol Briefs. 2020 Dec 4;34:13. doi: 10.15844/pedneurbriefs-34-13.
Litman A, Sauerwald N, Green Snyder L, et al. Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs. Nat Genet. 2025, 57(7):1611-1619. doi: 10.1038/s41588-025-02224-z.
