Is leucovorin used to treat autism and behavioral issues in children?

Leucovorin for Autism Spectrum Disorder in Children

Leucovorin is not included in standard autism treatment guidelines, but emerging research evidence suggests it may improve core and associated symptoms in children with ASD who have folate pathway abnormalities, particularly those positive for folate receptor alpha autoantibodies (FRAAs). 1, 2

Guideline Position

The American Academy of Child and Adolescent Psychiatry's practice parameters for autism spectrum disorder do not include leucovorin as a recommended pharmacological intervention for core autism symptoms. 1 The guidelines emphasize that most alternative or complementary treatment approaches have very limited empirical support for use in children with ASD, though they are commonly pursued by families. 3

Emerging Research Evidence

Despite the absence of guideline recommendations, recent research provides compelling evidence for leucovorin use in specific ASD subpopulations:

Prevalence of Folate Pathway Abnormalities

• FRAAs are highly prevalent in ASD, with 71-75.3% of children with ASD testing positive for these autoantibodies compared to typically developing children. 4, 5
• Children with ASD are 19.03-fold more likely to be positive for FRAAs compared to typically developing children without an ASD sibling. 5
• The pooled prevalence of cerebral folate deficiency (CFD) in ASD is 38%, with FRAAs accounting for 83% of CFD cases. 5

Mechanism and Biomarkers

• FRAAs interfere with folate transport across the blood-brain barrier via the folate receptor alpha, causing CFD. 6, 4
• Higher FRAA serum titers significantly correlate with lower cerebrospinal fluid 5-methyltetrahydrofolate concentrations. 4, 5
• Soluble folate binding proteins (sFBPs) have been identified in some ASD patients and may serve as additional biomarkers for treatment response. 7
• Children positive for sFBPs had more severe ASD symptoms at baseline. 8

Treatment Efficacy

Meta-analysis and controlled studies demonstrate significant improvements with leucovorin treatment:

• Overall ASD symptoms improved in 67% of individuals with ASD and CFD. 5
• Communication improved with medium-to-large effect sizes in controlled studies. 5
• Specific improvements included: verbal communication, receptive and expressive language, attention, and stereotypical behavior. 4
• Approximately one-third of FRA-positive children demonstrated moderate to much improvement over 4 months. 4
• Higher binding FRAA titers were associated with greater treatment response. 8
• ABC irritability scores improved with leucovorin treatment. 8

Dosing

• Standard dosing is 2 mg/kg/day of oral leucovorin calcium (maximum 50 mg per day). 4

Safety Profile

• Leucovorin generally has a favorable safety profile when used alone. 1
• Adverse effects are generally mild, with the most common being: aggression (9.5%), excitement or agitation (11.7%), insomnia (8.5%), headache (4.9%), and increased tantrums (6.2%). 5
• The incidence of adverse effects was low in treatment studies. 4

Clinical Approach

For children with ASD and behavioral concerns, consider the following algorithm:

1. Testing for folate pathway abnormalities is not routinely performed in standard autism care 1, but given the high prevalence of FRAAs (71-75%) and the potential for treatment response, testing for FRAAs and sFBPs may be reasonable in children with ASD, particularly those with more severe symptoms or treatment-resistant behaviors. 8, 4, 5

2. If FRAAs or sFBPs are positive, empirical treatment with leucovorin calcium (2 mg/kg/day, maximum 50 mg/day) may be a reasonable and non-invasive approach. 4

3. Monitor treatment response over 4 months using standardized assessments focusing on communication, language, attention, and stereotypical behaviors. 4

4. Behavioral interventions remain the first-line approach and should be implemented alongside any pharmacological treatment. 1, 2

Important Caveats

• The strongest evidence comes from blinded, placebo-controlled studies, but these are limited in number. 5
• This treatment targets an underlying pathophysiological abnormality rather than core autism features directly. 6
• Further controlled studies are needed to confirm and expand on these findings. 5
• Clinicians should discuss this emerging treatment option with families, recognizing their motivation to seek all possible treatments while providing evidence-based guidance. 3