Few topics in my clinic have generated as many questions from families over the past year as folinic acid – also known by its pharmaceutical name, leucovorin. Since a viral CBS News segment in February 2025 described a child who reportedly spoke his first word within days of starting the medication, and especially after a September 2025 White House announcement promoting it as a treatment for autism, the requests have been relentless.[1] Parents arrive with printouts, social media posts, and hope.
That hope deserves a thoughtful, honest response. This post is my attempt to lay out what the science actually says – the promising parts, the limitations, and what families should know before making decisions.
What Is Folinic Acid, and Why Are People Talking About It?
Folinic acid (d,l-leucovorin calcium) is a reduced, biologically active form of folate – a B vitamin essential for brain development. It is not the same as the folic acid found in prenatal vitamins or fortified foods. Folinic acid has been used safely in medicine for decades, primarily to rescue patients from methotrexate toxicity in cancer treatment.[2]
The interest in autism stems from a specific biological hypothesis: that a subset of children with autism may have cerebral folate deficiency – meaning their brains are not getting enough folate even when blood levels are normal.[3] The proposed culprit? Folate receptor alpha autoantibodies (FRAAs) – immune proteins that block the primary gateway folate uses to cross the blood-brain barrier.[3][4]
The logic is straightforward: if autoantibodies are blocking the front door, folinic acid can slip in through the back door an alternate transport system called the reduced folate carrier.[4][5] Once inside the brain, it can support the critical metabolic processes that folate normally fuels: DNA methylation, neurotransmitter synthesis (including serotonin and dopamine), and antioxidant defense via glutathione.[4][6]
It is a biologically elegant hypothesis. But biological plausibility is not the same as clinical proof.
The Clinical Trial Evidence: Promising but Preliminary
The entire evidence base for folinic acid in autism rests on three small, short-term randomized controlled trials with a combined enrollment of approximately 122 children.[7][8][9]
Here is what each found:
The Frye 2018 Trial: The Landmark Study
This double-blind, placebo-controlled trial randomized 48 children with autism and language impairment to receive high-dose folinic acid (2 mg/kg/day maximum 50 mg/day) or placebo for 12 weeks.[7] The results were encouraging: children receiving folinic acid showed a 5.7-point improvement in verbal communication compared to placebo, with a medium-to-large effect size (Cohen’s d=0.70).[7] Among children who tested positive for FRAAs, the effect was even larger a 7.3-point improvement with a large effect size (d=0.91)[7] Improvements were also seen on the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, and other secondary measures.[7] Adverse effects did not differ between groups.[7]
The EFFET Trial (Renard et al. 2020)
This French pilot trial enrolled only 19 children and used a lower fixed dose (5 mg twice daily).[8] The folinic acid group showed a 2.78-point improvement on the ADOS (a gold-standard clinician-administered autism assessment), compared to a 0.4-point change in the placebo group.[8] No serious adverse events occurred.[8] However, with only 19 participants, the study was severely underpowered to draw firm conclusions.
The Batebi 2021 Trial
This Iranian trial tested folinic acid as an add-on to risperidone in 55 children over 10 weeks.[9] Significant improvements were found in inappropriate speech, stereotypic behavior, and hyperactivity.[9] However, there was no significant effect on social withdrawal or irritability two of the most disabling features of autism.[9]
What a Network Meta-Analysis Concluded
A 2022 network meta-analysis in Molecular Autism that analyzed 125 RCTs across 41 drugs and 17 supplements for autism found that the evidence for folinic acid was “imprecise and not robust” with very low to low confidence in the estimates.[10] The authors concluded that routine prescription of medications for core autism symptoms could not be recommended based on available evidence.[10]
The Autoantibody Question: Should Every Child Be Tested?
Folate receptor alpha autoantibodies have been detected in 58-76% of children with autism across multiple studies, compared to much lower rates in typically developing controls.[3][4][5] Children with autism are approximately 19-fold more likely to be FRAA-positive.[12] In the Frye 2018 trial, FRAA-positive children showed a stronger treatment response.[7]
This sounds like a clear biomarker story test for the antibody, treat if positive. But there are important caveats:
- FRAAs are also found in 75% of unaffected siblings and 59-69% of parents of children with autism, meaning the antibodies alone are clearly not sufficient to cause autism.[3]
- FRAA titers fluctuate over time, complicating interpretation of a single test result.[5][8]
- Prevalence estimates vary widely (33.7%-77.5%) depending on the assay used, the population studied, and the cutoff thresholds applied.[4][12]
- The FRAA testing used in research is not widely available through standard commercial laboratories, and the clinical validity of the test as a treatment-selection biomarker has not been prospectively validated in a large trial.
What Do the Guidelines Say?
The American Academy of Pediatrics (AAP) currently does not recommend leucovorin for children with autism.[2] No other major medical organization – including the American Academy of Neurology or the American Academy of Child and Adolescent Psychiatry – has issued a guideline endorsing its use for this indication.
The FDA approved leucovorin in March 2026 – but not for autism. The approval was specifically for cerebral folate transport deficiency in patients with a confirmed FOLR1 gene variant (FOLR1-CFTD), an extremely rare genetic condition.[2] The FDA did not approve leucovorin for autism spectrum disorder.[1][2]
A 2025 systematic review of experimental psychopharmacology for autism placed folinic acid among a small group of compounds that “may already be considered, with due caution, for clinical use, because there is promising evidence of efficacy and a high safety profile” but this was explicitly framed as a cautious, expert-opinion statement, not a guideline recommendation.[1]
Safety: Generally Favorable, but Gaps Remain
In the clinical trials conducted to date, folinic acid has shown a favorable short-term safety profile.[7][8][9] No significant differences in adverse effects were found between folinic acid and placebo in the Frye 2018 trial.[7] Across open-label studies, the most commonly reported side effects include increased aggression (9.5%), excitement or agitation (11.7%), insomnia (8.5%), and increased tantrums (6.2%).[12]
However, there are important safety considerations:
- No long-term safety data exist from controlled trials. All studies were 12 weeks or shorter.[7][8][9]
- Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone, potentially increasing seizure frequency. This is particularly relevant given that epilepsy co-occurs in approximately 20-30% of individuals with autism.[2]
- Known adverse reactions to leucovorin per the FDA label include allergic sensitization (including anaphylactoid reactions), rash, and dyspnea.[2]
The Prescribing Surge: Evidence vs. Enthusiasm
A May 2026 study in JAMA Network Open documented a sharp rise in leucovorin prescriptions for children with autism.[1] Using the Epic Cosmos database (representing over 300 million patient records), the researchers found that prescribing rates had been stable for two years before beginning a steady increase in February 2025 coinciding with the CBS News segment and then surging further after the September 2025 White House announcement.[1]
This gap between prescribing practice and evidence is exactly the kind of situation that should give clinicians pause. We have seen this pattern before in developmental pediatrics – a biologically plausible intervention, early positive signals from small trials, media amplification, and widespread adoption before the confirmatory studies are done.
What I Tell Families in My Clinic
When parents ask about folinic acid, here is how the conversation typically goes:
“Is there any evidence it works?” Yes – small, early-stage trials have shown improvements in verbal communication and some behavioral measures, particularly in children who test positive for folate receptor autoantibodies.[7][8][9] The biological rationale is scientifically coherent.[4][5] This is not snake oil. But the studies are very small (the largest had 55 children), very short (10-12 weeks), and have not been independently replicated at scale.[10][11]
“Is it safe?” In the short term, it appears to be well-tolerated in most children.[7][8][9] But we do not have long-term safety data, and there are specific concerns for children on anti-seizure medications.[2] This is a prescription medication, not a supplement – it should be prescribed and monitored by a physician.
“Should we get the antibody test?” The FRAA test is not widely available through standard labs, and its role as a clinical decision-making tool has not been validated in a large prospective trial. If a family is strongly considering a trial of folinic acid, testing may help inform the decision, but a negative result does not definitively rule out potential benefit, and a positive result does not guarantee response.[3][7]
“What would you recommend?” The evidence is not yet strong enough for a blanket recommendation. What is strongly recommended and supported by decades of robust evidence is early intensive behavioral intervention, speech-language therapy, and occupational therapy.[2] These remain the cornerstone of autism treatment. If a family wishes to pursue a trial of folinic acid after a thorough discussion of the evidence and its limitations, this should be done under medical supervision with clear outcome measures and a defined timeline to assess response.
What We Still Need
The single most important thing that could move this field forward is a large, multi-center, adequately powered randomized controlled trial – ideally with FRAA-stratified enrollment, standardized outcome measures, and a duration long enough to assess meaningful developmental change (not just 12 weeks).[10][11][1] Until that trial is done, we are making clinical decisions based on a total of ~122 children studied in controlled settings.
We also need:
- Prospective validation of FRAA as a predictive biomarker for treatment response
- Long-term safety surveillance in the pediatric autism population
- Standardized, commercially available FRAA testing with established clinical cutoffs
- Head-to-head comparisons with established interventions
The Bottom Line
Folinic acid for autism is a scientifically grounded hypothesis supported by preliminary but insufficient evidence. The biological rationale involving folate receptor autoantibodies and cerebral folate deficiency is compelling.[3][4][5] Three small RCTs have shown encouraging signals, particularly for verbal communication.[7][8][9] The short-term safety profile appears favorable.[7][8][9]
But the evidence base is too small, too short-term, and too concentrated among a few research groups to support routine clinical use.[10][11] The AAP does not recommend it.[2] The FDA did not approve it for autism.[1][2] And a relevant trial was recently retracted.[11]
As developmental pediatricians, our job is to be honest brokers of evidence to validate families’ desire to help their children while protecting those children from interventions that have not been adequately proven. Folinic acid may ultimately prove to be a meaningful treatment for a subgroup of children with autism. But we are not there yet, and prescribing ahead of the evidence carries risks we cannot fully quantify.
The families in our clinics deserve both our compassion and our scientific rigor. Right now, the most responsible path is to acknowledge the promise, name the uncertainty, and advocate loudly for the large-scale trials that could give us real answers.
The information in this post reflects the evidence available as of May 2026 and is intended for educational purposes. Clinical decisions should be made in partnership with a child’s medical team.
If you are a parent wondering whether folinic acid might be right for your child, I am here to help you navigate that decision. Every child is different, and this conversation is best had one-on-one where we can review your child’s specific history, discuss the current evidence in detail, weigh the potential benefits and risks together, and make a plan that puts your child’s well-being first. Call today to schedule a consultation. You don’t have to sort through the headlines alone let’s talk about what the science means for your child.
References
- Clinical Concerns and Considerations for Leucovorin Use in Autism Spectrum Disorder. Howard C, Mekhail J, Ravikoff LM, Milanaik R. Current Opinion in Pediatrics. 2026;38(2):207-211. doi:10.1097/MOP.0000000000001547.
- Folinic Acid Improves Verbal Communication in Children With Autism and Language Impairment: A Randomized Double-Blind Placebo-Controlled Trial. Frye RE, Slattery J, Delhey L, et al. Molecular Psychiatry. 2018;23(2):247-256. doi:10.1038/mp.2016.168.
- Folinic Acid Improves the Score of Autism in the EFFET Placebo-Controlled Randomized Trial. Renard E, Leheup B, Guéant-Rodriguez RM, et al. Biochimie. 2020;173:57-61. doi:10.1016/j.biochi.2020.04.019.
- Cerebral Folate Receptor Autoantibodies in Autism Spectrum Disorder. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Molecular Psychiatry. 2013;18(3):369-81. doi:10.1038/mp.2011.175.
- Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder. Frye RE, Rossignol DA, Scahill L, et al. Seminars in Pediatric Neurology. 2020;35:100835. doi:10.1016/j.spen.2020.100835.
- Emerging Discussions on Folinic Acid and Acetaminophen in Autism. Balkanas M, Durcan G, Doğangün B. Journal of Autism and Developmental Disorders. 2026;56(5):2084-2086. doi:10.1007/s10803-026-07307-2.
- Folinic Acid as Adjunctive Therapy in Treatment of Inappropriate Speech in Children With Autism: A Double-Blind and Placebo-Controlled Randomized Trial. Batebi N, Moghaddam HS, Hasanzadeh A, et al. Child Psychiatry and Human Development. 2021;52(5):928-938. doi:10.1007/s10578-020-01072-8.
- Targeted Biomedical Treatment for Autism Spectrum Disorders. Pacheva I, Ivanov I. Current Pharmaceutical Design. 2019;25(41):4430-4453. doi:10.2174/1381612825666191205091312.
- Efficacy of Methylcobalamin and Folinic Acid Treatment on Glutathione Redox Status in Children With Autism. James SJ, Melnyk S, Fuchs G, et al. The American Journal of Clinical Nutrition. 2009;89(1):425-30. doi:10.3945/ajcn.2008.26615.
- Rates of Leucovorin Prescriptions for Children With Autism. Rothman JM, Kwan B, Longhurst CA, Jena AB. JAMA Network Open. 2026;9(5):e2613286. doi:10.1001/jamanetworkopen.2026.13286.
- Comparative Analysis of Treatment With Folate Forms in Clinical Practice. Skavinska O, Rossokha Z, Stefanyshyn V, et al. Nutrition Reviews. 2025;:nuaf216. doi:10.1093/nutrit/nuaf216.
- The Pediatric Psychopharmacology of Autism Spectrum Disorder: A Systematic Review – Part II: The Future. Persico AM, Asta L, Chehbani F, et al. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2025;136:111176. doi:10.1016/j.pnpbp.2024.111176.
