Is leucovorin (folinic acid) effective in treating autism?

Leucovorin (Folinic Acid) for Autism Spectrum Disorder

Leucovorin (folinic acid) may be effective for treating specific subgroups of children with autism spectrum disorder who have folate metabolism abnormalities, particularly those with folate receptor alpha autoantibodies, but is not recommended as a general treatment for all autism cases.

Mechanism and Rationale

Leucovorin (folinic acid) is a reduced form of folate that can bypass blockages in the primary folate transport mechanism in the brain. The scientific rationale for its use in autism includes:

• Folate is essential for normal neurodevelopment 1
• Cerebral folate deficiency (CFD) has been identified in some children with ASD 2
• Folate receptor alpha autoantibodies (FRAAs) that block folate transport into the brain have been found in 58-76% of children with ASD 1
• Blood titers of these autoantibodies correlate with reduced folate levels in cerebrospinal fluid 3

Evidence for Effectiveness

The most recent and highest quality evidence suggests:

• A high prevalence (71%) of folate receptor alpha autoantibodies has been consistently found in children with ASD 2
• Children with ASD are 19 times more likely to be positive for FRAAs compared to typically developing children 2
• In a retrospective analysis of 110 ASD patients, those treated with leucovorin showed improvements in:
  • Social Responsiveness Scale (SRS) scores (measuring core ASD symptoms)
  • Aberrant Behavior Checklist (ABC) irritability scores 4
• Higher binding FRAA titers were associated with greater treatment response 4

Patient Selection

Leucovorin appears most effective for specific subgroups:

• Children who test positive for folate receptor alpha autoantibodies (FRAAs) 4, 2
• Children who test positive for soluble folate binding proteins (sFBPs) 5
• Children with documented cerebral folate deficiency 2

Dosing

Based on available research:

• Typical dose: 2 mg/kg/day (maximum 50 mg per day) 3
• Treatment duration: Studies have shown benefits over treatment periods of 4 months or longer 3

Safety Profile

Leucovorin treatment for ASD appears generally well-tolerated:

• Most adverse effects are mild 2
• Common side effects include:
  • Aggression (9.5%)
  • Excitement or agitation (11.7%)
  • Headache (4.9%)
  • Insomnia (8.5%)
  • Increased tantrums (6.2%) 2

Limitations and Considerations

• Not currently recommended in major autism treatment guidelines 6, 7
• Testing for folate receptor autoantibodies should precede treatment
• Response rates vary, with approximately one-third of treated FRAA-positive children showing moderate to significant improvement 3
• More controlled clinical trials are needed to confirm efficacy

Clinical Approach

1. Consider testing for folate receptor alpha autoantibodies in children with ASD
2. If positive for FRAAs or sFBPs, a trial of leucovorin may be warranted
3. Monitor response using standardized assessments (SRS, ABC)
4. Continue treatment if positive response is observed
5. Monitor for adverse effects

While leucovorin shows promise for a specific subgroup of children with ASD, it should be considered as part of a comprehensive treatment approach rather than as a standalone therapy for all autism cases.