Is aggression and hyperactivity a common side effect of leucovorin in an 11-year-old non-verbal patient with Autism Spectrum Disorder (ASD), suspected Attention Deficit Hyperactivity Disorder (ADHD), anxiety, apraxia, and Sensory Processing Disorder (SPD)?

Aggression and Hyperactivity with Leucovorin in ASD

Aggression and hyperactivity are recognized adverse effects of leucovorin treatment in children with ASD, occurring in approximately 9.5% and 11.7% of cases respectively, and your child's response is consistent with documented side effects that warrant discontinuation or dose adjustment. 1

Understanding the Side Effect Profile

The behavioral changes you observed in your child are well-documented in the leucovorin literature for ASD:

• Aggression occurs in 9.5% of children with ASD treated with leucovorin 1
• Excitement or agitation (which manifests as hyperactivity) occurs in 11.7% of cases 1
• Increased tantrums are reported in 6.2% of treated children 1

These adverse effects are generally classified as mild but can be significant enough to warrant treatment discontinuation, as occurred in your child's case. 1

Why This Happens

Leucovorin (folinic acid) is a reduced form of folate that bypasses certain metabolic blocks to deliver folate to the brain. 2 While it has shown efficacy in improving core ASD symptoms in children with cerebral folate deficiency (CFD) or folate receptor alpha autoantibodies (FRAAs), the mechanism by which it causes behavioral activation in some children is not fully understood. 1

The behavioral side effects appear to be dose-related in some cases, though your child was on a relatively low dose of 5mg daily. 1

Clinical Context and Alternative Approaches

Before abandoning leucovorin entirely, consider these factors:

• Your child may have been started at too high a dose initially - some protocols use slower titration schedules to minimize behavioral side effects 1
• The timing of administration may matter - though this is not well-studied in the literature
• Combining leucovorin with behavioral interventions may improve tolerability, as combined approaches are recommended for managing behavioral symptoms in ASD 3

Managing Hyperactivity and Aggression in ASD

Since your child has suspected ADHD and demonstrated hyperactivity, you should address these symptoms directly with evidence-based treatments:

For Hyperactivity/Inattention:

• Methylphenidate is the first-line pharmacological treatment for hyperactivity in children with ASD, showing a 49% response rate (though lower than in typical ADHD) 3, 4
• Alpha-2 agonists (guanfacine or clonidine) are reasonable alternatives if stimulants are not tolerated 3, 4

For Aggression/Irritability:

• Risperidone is FDA-approved for irritability in ASD ages 5-17 years, with a 69% response rate for aggression, tantrums, and self-injurious behavior 3, 5
• Aripiprazole is also FDA-approved for the same indication ages 6-17 years, with a 56% response rate 3, 5

Common Pitfalls to Avoid

• Do not assume leucovorin will work for everyone with ASD - it is most effective in children with documented CFD or FRAAs (83% of CFD cases in ASD are attributed to FRAAs) 1
• Do not restart leucovorin at the same dose without medical supervision - if retrial is considered, a lower starting dose with slower titration may be better tolerated 1
• Do not ignore the primary behavioral symptoms - hyperactivity and aggression should be treated with evidence-based medications (stimulants or atypical antipsychotics) regardless of leucovorin status 3

Recommendation for Your Child

Given your child's presentation with suspected ADHD and the hyperactivity/aggression observed, prioritize treating these symptoms with methylphenidate as first-line therapy (if hyperactivity predominates) or risperidone (if aggression/irritability predominates), as these have the strongest evidence base in ASD. 3

If leucovorin is to be reconsidered in the future, it should only be attempted after:

1. Confirming the presence of FRAAs or CFD through laboratory testing 1
2. Stabilizing behavioral symptoms with appropriate psychotropic medication 3
3. Starting at a lower dose (potentially 2.5mg or less) with very slow titration 1
4. Close monitoring for behavioral activation with objective rating scales 3

The fact that leucovorin is tasteless does not outweigh the significant behavioral side effects your child experienced. Many liquid formulations of methylphenidate and risperidone are available that can be compounded to minimize taste if needed.