Should a child with autism spectrum disorder, particularly if they have folate‑receptor autoantibodies or low‑normal serum folate, be treated with leucovorin (folinic acid), and what dosing and safety monitoring are recommended?

Leucovorin Treatment in Autism Spectrum Disorder

Leucovorin (folinic acid) is not a standard treatment for autism spectrum disorder and should only be considered in children who test positive for folate receptor alpha autoantibodies (FRAAs) or soluble folate binding proteins (sFBPs), with dosing at 2 mg/kg/day (maximum 50 mg/day) under specialist supervision with monitoring for response and adverse effects. 1

Current Guideline Position

The American Academy of Child and Adolescent Psychiatry does not recommend leucovorin as standard treatment for ASD, classifying it among complementary/alternative medicine approaches with limited empirical support. 2, 1 However, clinicians should be prepared to discuss these treatments with parents, recognizing that most have little risk even when evidence of benefit is limited. 2

Evidence-based structured educational and behavioral interventions remain the foundation of ASD treatment and should never be replaced by leucovorin. 2, 1

When to Consider Leucovorin

Testing for Biomarkers

• Test for folate receptor alpha autoantibodies (FRAAs) in children with ASD, as 71-75% test positive. 3, 4, 5
• Test for soluble folate binding proteins (sFBPs), which identify a subset of medically complex ASD patients with severe symptoms. 6
• Higher binding FRAA titers correlate with lower cerebrospinal fluid 5-methyltetrahydrofolate concentrations and predict greater treatment response. 3, 4, 5

Rationale for Treatment

Leucovorin bypasses the blockage at folate receptor alpha by using the reduced folate carrier, an alternate pathway, allowing folate to enter the brain despite the presence of autoantibodies. 7, 5 This addresses cerebral folate deficiency, which has a pooled prevalence of 38% in ASD. 5

Dosing Protocol

Oral leucovorin calcium: 2 mg/kg/day (maximum 50 mg/day) given once daily. 4, 5

• This is the dose used in controlled trials showing efficacy. 4, 5
• Treatment duration in studies ranged from 4 months to longer-term use. 4, 5
• Do not confuse leucovorin (folinic acid) with folic acid—they are not interchangeable for this indication. 8

Expected Treatment Response

Core ASD Symptoms (based on controlled trials)

• Verbal communication improvements with medium-to-large effect sizes. 5
• Receptive and expressive language improvements. 4, 5
• Attention improvements with large effect sizes. 5
• Reduction in stereotypical behavior with large effect sizes. 5
• Approximately one-third of FRA-positive children demonstrate moderate to much improvement. 4

Associated Symptoms

• Irritability reduction (58% improvement rate). 5
• Overall ASD symptom improvement (67% improvement rate in those with cerebral folate deficiency). 5
• Higher binding FRAA titers associate with greater improvement in ABC irritability scores. 3

Timeline

Response is typically assessed over 4 months, though some improvements may be seen earlier. 4

Safety Monitoring

Adverse Effects Profile

The incidence of adverse effects is low, with most being mild. 4, 5 Common adverse effects include:

• Aggression (9.5% of patients). 5
• Excitement or agitation (11.7%). 5
• Insomnia (8.5%). 5
• Increased tantrums (6.2%). 5
• Headache (4.9%). 5

Monitoring Recommendations

• Consider complete blood count monitoring, particularly with higher doses, due to potential bone marrow suppression risk (though generally low when leucovorin is used alone). 1
• Monitor response using validated assessment tools such as the Social Responsiveness Scale (SRS) and Aberrant Behavior Checklist (ABC). 3, 4
• Reassess at regular intervals (e.g., every 3-4 months) to determine continued benefit. 3

Critical Pitfalls to Avoid

• Do not use folic acid instead of leucovorin—folic acid cannot bypass the folate receptor alpha blockage. 7, 5
• Do not delay or replace evidence-based behavioral and educational interventions with leucovorin treatment. 2, 1
• Do not assume all children with ASD will benefit—biomarker testing (FRAAs or sFBPs) helps identify those most likely to respond. 3, 4, 6
• Be aware that folic acid in doses above 0.1 mg daily may obscure pernicious anemia, though this is primarily a concern in adults. 8
• Recognize that leucovorin treatment may antagonize anticonvulsant effects of phenytoin if the child is on this medication. 8

Strength of Evidence

The evidence base includes four placebo-controlled trials, three prospective controlled studies, and multiple open-label studies showing consistent benefits. 5 The most recent and highest quality evidence from 2024 confirms that binding FRAA is a biomarker for leucovorin treatment response, with higher titers predicting greater improvement. 3 A 2021 systematic review and meta-analysis found that children with ASD were 19.03-fold more likely to be positive for FRAAs compared to typically developing children. 5