# A High-dose Folinic Acid Treatment for Core and Associated Symptoms of Autism

> **NIH NIH R01** · PHOENIX CHILDREN'S HOSPITAL · 2020 · $546,663

## Abstract

Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder that affects 1-2% of individuals
in the United States. However, no effective medical treatment has been developed to address core
(communication, social function, stereotyped behavior) or associated (attention, hyperactivity, irritability) ASD
symptoms and/or underlying pathophysiological abnormalities associated with ASD. The goal of this work is to
develop a safe, well-tolerated medical treatment with efficacy for improving core and associated ASD
symptoms and pathophysiological abnormalities associated with ASD. Such an innovative treatment would
have the potential to be disease-modifying and could augment on-going standard-of-care educational and
behavioral therapies. Studies have demonstrated the importance of folate metabolism in children with ASD.
Several folate-dependent metabolic systems, including methylation and glutathione redox metabolism,
demonstrate abnormalities in individuals with ASD. Several detrimental polymorphisms in folate and folate-
related pathway genes have been associated with ASD. Autoantibodies to the folate receptor alpha have a
high prevalence in children with ASD and can interfere with folate transport into the brain. Most importantly, we
have demonstrated that a reduced form of folate, known as folinic acid, may have efficacy in improving both
core and associated symptoms of ASD and physiological abnormalities associated with ASD. Most notable, in
a small double-blind placebo-controlled study, we have demonstrated that folinic acid significantly improves
language in children with ASD with a medium-to-large effect size, confirming findings from our earlier open-
label studies. This effect appears to be particularly strong in children with ASD who manifest folate receptor
alpha autoantibodies with a large effect sizes and number needed to treat of about 2. Hyperactivity, lethargy
and irritability were also found to significantly improve. We propose to conduct a large (N=162) multicenter
double-blind placebo-controlled study to confirm the efficacy of high-dose folinic acid on core and associated
symptoms of ASD using centers and infrastructure developed as part of the Research Units on Pediatric
Psychopharmacology (RUPP) Autism Network which has conducted many of the major ASD drug trials,
including Emory and Harvard University sites in addition to Arkansas Children's Hospital. This study will also
examine whether immune (folate receptor alpha autoantibodies) and genetic (polymorphism in folate-related
metabolic pathways) biomarkers can predict response to treatment in order to better identify the individuals
that will benefit from this treatment. This project is innovative as it investigates a treatment that addresses both
ASD symptoms and underlying pathophysiological abnormalities associated with ASD, and aims to define
biomarkers that identify subgroups of children with ASD who will response to the treatment. Given that
physiological ab...

## Key facts

- **NIH application ID:** 9970228
- **Project number:** 5R01HD088528-04
- **Recipient organization:** PHOENIX CHILDREN'S HOSPITAL
- **Principal Investigator:** RICHARD Eugene FRYE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $546,663
- **Award type:** 5
- **Project period:** 2017-09-13 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970228

## Citation

> US National Institutes of Health, RePORTER application 9970228, A High-dose Folinic Acid Treatment for Core and Associated Symptoms of Autism (5R01HD088528-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970228. Licensed CC0.

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