Original Reference: Eur J Pediatr. 2024 Nov;183(11):4827-4835
Retraction Notice: Eur J Pediatr. 2026 Jan 29;185(2):109
Practice Point: The evidence for the use of leucovorin for autism remains weak and at best suggests leucovorin might be helpful only in a specific subset of patients.
EBM Pearl: Garbage in, garbage out: if the data are unreliable, the conclusion will be too.
Leucovorin (also called folinic acid) has rapidly become one of the most requested off-label medications for children with autism spectrum disorder (ASD). Leucovorin is primarily used to mitigate the side effects of chemotherapy and to treat certain types of anemia, but it has also been used effectively to treat cerebral folate deficiency, a rare genetic condition characterized by developmental delays in cognition and speech. The yet-unproven hypothesis is that ASD and cerebral folate deficiency could share a similar underlying mechanism, in which case the drug might also improve ASD symptoms.
Despite a lack of strong supporting evidence, the FDA began the process to fast-track approval for leucovorin for ASD in September 2025. Although this might have sounded like good news to parents with a child with ASD, the FDA’s decision alarmed researchers and clinicians alike, as the evidence base underpinning this approval is shaky at best. But now, as of January 2026, the largest randomized trial (which included only 80 children, which says something in itself) was retracted, representing a substantial crack in the foundation of evidence supporting the value of leucovorin for ASD. If we take a look at the study in question from an EBM perspective, it’s easy to see why it was retracted.
The study, originally published in the European Journal of Pediatrics in June 2024, enrolled 80 children aged 2-10 years with ASD and randomly assigned them to receive either oral leucovorin or placebo for 24 weeks. Both groups also received standard behavioral interventions based on individual patient needs. The reported results showed that children who took leucovorin had significantly greater improvements on several commonly used neuropsychological assessments, such as the Child Autism Rating Scale (CARS, which measures overall symptom severity) and Child Behavior Checklist (CBCL, which measures behavioral problems). No medication-related adverse effects were reported. The researchers concluded that "oral folinic acid supplementation is safe and efficacious in improving the severity of symptoms in children with ASD."
But looking closely at the data, it’s clear that something is amiss. In one of the data tables, it is reported that the placebo group had a reduction in CBCL score of 12.6 points (compared to 19.7 points in the folinic acid group, resulting in a significant difference between groups favoring folinic acid). However, in another data table, the change in CBCL score in the placebo group was reported to be 22.6 points. If the statistics were to be recalculated using the second set of numbers, the result would be nonsignificant. There is also a similar inconsistency between these two tables in the reported data for a CBCL subscale. As one might expect, a postpublication statistical review was unable to replicate the significant results reported in the study, which resulted in the retraction.
Aside from the stated reasons for retraction, there are also other concerns that make the conclusions sound dubious, even if we assume the data reporting error was a typo and accept the statistically significant result. First, over 80% of the children in the study had high serum levels of folate receptor autoantibodies (FRAA), suggesting a folate deficiency. Since leucovorin is known to treat cerebral folate deficiency, this aspect of the patient population may have been the largest driving factor for any significant effects in this study. However, it’s unclear how common this deficiency is in the overall population of people with ASD.
There were other issues too: the actual magnitude of the effect of leucovorin was tiny, with only a 3.6-point change in CARS score from baseline, which is lower than the published minimal clinically important difference for the assessment (4 points). The sample was also 94% boys, and while there is a gender imbalance in autism prevalence, it’s not nearly that wide. So, at the very best, if we take the data at face value, this study suggested that leucovorin could have a very small and clinically unimportant difference in boys with ASD who specifically have high serum FRAA. Not exactly a universal autism cure. This might sound promising for this specific patient population, but extrapolating to ASD as a whole is a leap that just isn’t supported by the data.
Taken together, the current evidence for leucovorin in ASD remains far too weak, and now demonstrably unreliable, to support routine clinical use without additional rigorous studies. New therapies must earn their way into practice through reproducible, clinically meaningful, and methodologically sound research, not through parental hopefulness or unfounded hype. At this point, leucovorin has not cleared that bar.
For more information, see the topic Autism Spectrum Disorder (ASD) in Children and Adolescents in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed. Edited by Katharine DeGeorge, MD, MS, Executive Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Senior Clinical Writer at DynaMed; Michael Butler, PhD, Medical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.