Mental Health: Leucovorin and Autism: What Pediatricians Should Know

In recent months, headlines about leucovorin (“folinic acid”) as a potential treatment for autism spectrum disorder (ASD) have generated significant misinformation and oversimplified political rhetoric. As a result, pediatricians are increasingly fielding questions from families while trying to sift through conflicting reports to understand what the evidence shows. While early research is promising, particularly for a subset of children with cerebral folate deficiency, this is not a universal therapy and careful, evidence-based guidance is essential.

This article summarizes current findings and offers evidence-based information and prescribing recommendations for pediatricians who may be approached by families about leucovorin.

Background:

Leucovorin is a reduced, active form of folate that bypasses the folate receptor alpha (FRα) transport system. In some children with ASD, the presence of folate receptor alpha autoantibodies (FRAAs) interferes with folate transport into the brain, leading to a state of cerebral folate deficiency. FRAAs have been shown to be relatively common, detected in roughly 58%-76% of children with ASD.^1-5 Several studies, including a 2024 randomized controlled trial in the European Journal of Pediatrics,¹ have shown that children who test positive for these antibodies are more likely to experience improvements in verbal communication and social interaction when treated with leucovorin.

That being said, the overall strength of the evidence remains moderate at best. Most trials are small, short in duration, and rely heavily on parent-reported outcomes. While some children show meaningful gains, others experience no observable improvement. It’s crucial to counsel families that this is not a proven or universally effective treatment, and to set realistic expectations early. Overly high hopes can lead to disappointment or frustration if changes are subtle or absent.

Testing:

Clinicians should consider checking a complete blood count and B12 level prior to initiating treatment with leucovorin, as folinic acid can mask megaloblastic anemia and B12 deficiency, allowing neurologic complications to progress.

While FRAA testing can help identify children most likely to benefit, within the providers of our division at Children’s Mercy, we are NOT recommending pre-treatment FRAA testing (e.g., FRAT®) for the following reasons:

• The test is not widely available, can be costly, and has uncertain predictive value.
• Randomized controlled trials and systematic reviews have shown positive outcomes regardless of FRAA status, and no studies require FRAA testing before initiation.
• Given the high prevalence of FRAAs and leucovorin’s strong safety profile, empirical treatment is supported in both research and clinical practice.

Dosing and Administration:

• Start:5 mg/kg/day divided twice daily (morning and evening).
• Titrate: Gradually increase to 2 mg/kg/day (maximum 50 mg/day), as tolerated.
• Formulations: 5 mg, 10 mg, 15 mg, 25 mg tablets—may be split or crushed.
• Duration: Evaluate progress at 12-24 weeks; maximal gains often appear after four to six months of continuous use.

Safety and Monitoring:

• Leucovorin is well tolerated in most children.
• Common adverse effects: transient excitement or agitation (11.7%), aggression (9.5%), insomnia (8.5%), increased tantrums (6.2%), headache (4.9%), and mild gastrointestinal discomfort.⁶
• Key precaution: Rule out vitamin B12 deficiency and anemia prior to treatment for reasons described above.
• Drug interactions: may lower serum levels of phenytoin, phenobarbital and trimethoprim.

Clinical Pearls for Pediatricians:

• Set expectations early: Leucovorin is not a cure but may improve communication, social reciprocity, and adaptive behavior in some children.
• Empirical use is appropriate: Leucovorin is generally safe and well tolerated. It may be appropriate for many families to try, though the likelihood of benefit is still unclear at this time.
• Trial period: Continue for four to six months before judging response.
• Collaborate: Partner with families. Use in conjunction with, not in lieu of, standard therapies (e.g., risperidone and aripiprazole for aggression and self-injurious behaviors, behavioral, speech, and educational interventions).

References:

1. Panda PK, Sharawat IK, Saha S, et al. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024;183(11):4827-4835. PMID: 39243316. doi:10.1007/s00431-024-05762-6
2. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013;18(3):369-81. PMID: 22230883. doi:10.1038/mp.2011.175
3. Frye RE, Rossignol DA, Scahill L, et al. Treatment of folate metabolism abnormalities in autism spectrum disorder. Semin Pediatr Neurol. 2020;35:100835. PMID: 32892962. doi:10.1016/j.spen.2020.100835
4. Frye RE, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018;23(2):247-256. PMID: 27752075. doi:10.1038/mp.2016.168
5. Desai A, Sequeira JM, Quadros EV. Prevention of behavioral deficits in rats exposed to folate receptor antibodies: implication in autism. Mol Psychiatry. 2017;22(9):1291-1297. PMID: 27646260. doi:10.1038/mp.2016.153
6. Rossignol DA, Frye RE. Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: a systematic review and meta-analysis. J Pers Med. 2021;11(11):1141. doi:10.3390/jpm11111141
7. Hegde VS, Nagalli S. In: StatPearls [Internet]. StatPearls Publishing. Updated July 3, 2023. https://www.ncbi.nlm.nih.gov/books/NBK553114/
8. Leucovorin (oral route). Mayo Clinic. Accessed August 2025. https://www.mayoclinic.org/drugs-supplements/leucovorin-oral-route-intravenous-route-injection-route/description/drg-20064503