Leucovorin
Many clinicians have little experience with leucovorin because until recently, it has been a rarely used medication, typically reserved for oncologists managing the side effects of chemotherapy. Leucovorin, or folinic acid, is a modified version of vitamin B9. Vitamin B9, or folate, is found naturally in foods like beans, leafy greens, eggs, beets and citrus.
Why is leucovorin gaining popularity?
In September 2025, the Food and Drug Administration (FDA) said it is considering approving leucovorin tablets for patients with cerebral folate deficiency. This decision was made after reviewing some studies that suggest that this medication can improve certain symptoms, particularly language skills, in people who may have antibodies that interfere with folate transport within the body, which is more common in people with autism spectrum disorder (ASD).
What do we know about leucovorin?
In a 2024 study in India, some children with autism had an improvement in ASD symptoms when given oral folinic acid supplementation. The benefits of folinic acid supplementation are more pronounced when a child has high titers of folate receptor autoantibodies. Cerebral folate deficiency is a rare condition and requires a comprehensive medical work-up. Not all children with ASD have cerebral folate deficiency.
What are some concerns about using leucovorin?
While the studies that the FDA reviewed are promising, the sample size is small, and it is too soon to say whether leucovorin will work for all patients with ASD. Given that leucovorin is derived from a vitamin, one might assume the side effects to be minimal, but one study did see side effects including aggression, agitation, headache, insomnia and tantrums.
Leucovorin is a prescription medication. Although it is derived from Vitamin B9, it is a more active form that can cross the blood-brain barrier. Therefore, over-the-counter supplements like folate are not a substitute for leucovorin, and families should not try to use over-the-counter supplements as an alternative to a prescription. The cost of leucovorin depends on the formulation (tablet versus compounded liquid) and insurance coverage. The recent FDA comments specify that leucovorin can be used in patients who have a cerebral folate deficiency – not broadly for all patients with ASD. This is important because this medication is not widely available, and increased demand could hinder access for those who need it.
What are we still learning?
Larger, multi-site studies would help us better understand the possible benefits of using leucovorin in children with ASD. According to the Society for Developmental and Behavioral Pediatrics, the poor quality of the research to date makes it “impossible to draw definitive conclusions.” Furthermore, the current folate receptor autoantibody testing (FRAT) is unreliable. Therefore, we need more rigorous studies before we can recommend leucovorin treatment for ASD.
The most important thing to remember is that a large body of research over many years has shown that ASD has complex causes that combine genetic factors with environmental influences during critical periods of brain development. Children's Hospital of Philadelphia doctors are eagerly following as new research is published and will offer advanced testing and intervention whenever there is convincing evidence to support it.
Leucovorin
Many clinicians have little experience with leucovorin because until recently, it has been a rarely used medication, typically reserved for oncologists managing the side effects of chemotherapy. Leucovorin, or folinic acid, is a modified version of vitamin B9. Vitamin B9, or folate, is found naturally in foods like beans, leafy greens, eggs, beets and citrus.
Why is leucovorin gaining popularity?
In September 2025, the Food and Drug Administration (FDA) said it is considering approving leucovorin tablets for patients with cerebral folate deficiency. This decision was made after reviewing some studies that suggest that this medication can improve certain symptoms, particularly language skills, in people who may have antibodies that interfere with folate transport within the body, which is more common in people with autism spectrum disorder (ASD).
What do we know about leucovorin?
In a 2024 study in India, some children with autism had an improvement in ASD symptoms when given oral folinic acid supplementation. The benefits of folinic acid supplementation are more pronounced when a child has high titers of folate receptor autoantibodies. Cerebral folate deficiency is a rare condition and requires a comprehensive medical work-up. Not all children with ASD have cerebral folate deficiency.
What are some concerns about using leucovorin?
While the studies that the FDA reviewed are promising, the sample size is small, and it is too soon to say whether leucovorin will work for all patients with ASD. Given that leucovorin is derived from a vitamin, one might assume the side effects to be minimal, but one study did see side effects including aggression, agitation, headache, insomnia and tantrums.
Leucovorin is a prescription medication. Although it is derived from Vitamin B9, it is a more active form that can cross the blood-brain barrier. Therefore, over-the-counter supplements like folate are not a substitute for leucovorin, and families should not try to use over-the-counter supplements as an alternative to a prescription. The cost of leucovorin depends on the formulation (tablet versus compounded liquid) and insurance coverage. The recent FDA comments specify that leucovorin can be used in patients who have a cerebral folate deficiency – not broadly for all patients with ASD. This is important because this medication is not widely available, and increased demand could hinder access for those who need it.
What are we still learning?
Larger, multi-site studies would help us better understand the possible benefits of using leucovorin in children with ASD. According to the Society for Developmental and Behavioral Pediatrics, the poor quality of the research to date makes it “impossible to draw definitive conclusions.” Furthermore, the current folate receptor autoantibody testing (FRAT) is unreliable. Therefore, we need more rigorous studies before we can recommend leucovorin treatment for ASD.
The most important thing to remember is that a large body of research over many years has shown that ASD has complex causes that combine genetic factors with environmental influences during critical periods of brain development. Children's Hospital of Philadelphia doctors are eagerly following as new research is published and will offer advanced testing and intervention whenever there is convincing evidence to support it.
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