Leucovorin and Autism
- Luciana Leo
- Sep 25
- 3 min read
Download the Printable Quick Guide:
What is Leucovorin?
Leucovorin, also known as folinic acid, is an active form of folate (vitamin B9). Unlike folic acid, leucovorin does not require multiple conversion steps to become usable in the body. This makes it an important option for children whose folate metabolism may be impaired.
Why is it being studied in Autism?
Over the last decade, researchers have explored the link between folate metabolism and autism spectrum disorder (ASD). Some children with autism show challenges in transporting folate into the brain, a condition known as Cerebral Folate Deficiency (CFD).
Clinical trials have found that leucovorin may improve:
Speech and language development
Social interaction
Behavior regulation
While not a cure, leucovorin may provide meaningful improvements for certain children.
Who may be a good candidate?
Children with ASD who show:
Language delay or regression
Irritability
Developmental regression
Research trials included children ages 3–14 years, with an average age around 6–7 years. Evidence is strongest in younger children, but older kids and teens may also benefit depending on individual factors.
What tests are helpful before starting?
Before considering leucovorin, some doctors recommend testing for:
Folate Receptor Alpha Autoantibodies (FRAT)
Serum or cerebrospinal fluid folate (when available)
MTHFR genetic variants
These tests help identify whether folate transport or metabolism may be affecting your child.
MTHFR vs. FRAA: What’s the difference?
MTHFR: A genetic variation that affects how folic acid is converted to active folate.
Folate Receptor Alpha Autoantibodies (FRAA): Immune proteins that block folate transport into the brain.
These are separate issues, and both can play a role. Testing for each gives a clearer picture.
Important Considerations
Even if a child tests positive for FRAA, the body has other folate transport systems that may still function.
The commonly cited statistic that 75% of kids with autism are FRAA-positive comes from a single study with only 96 participants. More research is needed.
A dairy-free diet is often recommended, as milk proteins can interfere with folate transport in FRAA-positive children.
Symptoms of Cerebral Folate Deficiency (CFD)
Some children with CFD may experience:
Regression of language or skills
Irritability
Seizures
Movement difficulties (ataxia)
Sleep disturbances
Because these symptoms overlap with autism, testing may be valuable when regression or unusual neurological symptoms appear.
Common Questions Parents Ask
Is leucovorin safe?Generally well tolerated. The most common side effect is hyperactivity or agitation, especially at the start.
How long before we see changes?Some children show improvements within weeks, others may take months.
Does a positive FRAA test guarantee leucovorin will work?Not necessarily. Response varies, and treatment should always be guided by a physician.
Key Takeaways for Parents
Leucovorin may benefit some children with autism, especially those with folate-related issues.
Testing (FRAT, folate levels, MTHFR) provides helpful guidance.
Diet, especially dairy-free, may enhance treatment success.
Always consult your physician before starting or changing treatments.
References
Frye RE, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry. 2018.
Ramaekers VT, Blau N. Cerebral folate deficiency. Developmental Medicine & Child Neurology. 2004.
Frye RE, et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry. 2013.
Ramaekers VT, et al. Folinic acid treatment for autism associated with cerebral folate deficiency. Molecular Psychiatry. 2007.
This blog provides families with evidence-based information, but every child is unique. Discuss testing and treatment options with your healthcare provider.
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