Folinic Acid Supplementation Improves Symptoms of Autism

Written by Chrystal Moulton, Science Writer. After 12 weeks, researchers observed a significant change in social reciprocity among participants in the intervention group (P = 0.01).

young boyAutism spectrum disorder is a developmental disease affecting 1 in 54 children worldwide1-3. Currently, there’s no approved drug to treat the symptoms or underlying abnormalities associated with autism4. One of the abnormalities associated with autism spectrum disorder is folic acid metabolism and targeting this pathway could improve symptoms4. Clinical studies have shown that high dose folinic could improve specific traits of autism, namely, social interaction, communication, and linguistic expression5-7. Other considerations required in autism treatment include gene polymorphisms which could affect the body’s ability to process folic acid in the folate metabolism pathway. MTHFR (methylenetetrahydrofolate reductase) is one of the most studied gene polymorphisms associated with autism. One study showed that decreased MTHFR activity could significantly decrease the pool of bioavailable folate in the body8. Supplementation with folic acid you could overcome any reduction in MTHFR activity9,10. Understanding the interaction between gene polymorphisms specific to fully metabolism segmentation is important to identifying possible therapies for autism. In the current trial, researchers investigated the safety and efficacy of high dose folinic acid in children with autism spectrum disorder11.

This study was designed as a 12-week randomized control trial. Healthy Children between the age of 3 and 6 years old, who were diagnosed with autism spectrum disorder were included in this study. Children with mental, genetic, metabolic, mitochondrial, or neurological conditions were excluded from this trial. Participants were randomly assigned to receive 2mg/kg per day or placebo. Supplementation was provided in 6–8-hour intervals twice daily. Researchers used the 3rd edition of the Psychoeducational Profile (PEP-3) to assess the effect of folinic acid supplementation on behavioral changes in children. Low scores indicated higher level of autistic traits. Blood samples were collected from volunteers at baseline to conduct genotyping. Researchers used t-tests to evaluate the efficacy of folinic acid supplementation and linear regression was used to determine association between genotypes and the efficacy of folinic acid supplementation.

A total of 76 participants completed this trial (intervention = 49, control = 27). No significant differences were observed between groups accept in birth weight (P = 0.041) and maternal education (P= 0.027). No significant adverse reactions were observed in the high dose of folinic acid supplementation group. After 12 weeks, researchers observed a significant change in social reciprocity among participants in the intervention group (P = 0.01). No other significant differences were observed between groups based on the PEP-3 assessment. Evaluation of gene polymorphisms across groups showed no significant differences in the distribution of polymorphisms between biological sex. Multivariate adjusted regression models showed that children supplementing with folinic acid who possessed the MTHFR A1298C polymorphism was significantly associated with improvements in social reciprocity (P= 0.004), visual- motor imitation (P = 0.03), communication (P = 0.037), motor functioning (P = 0.003). Also, the MTRR A66G gene polymorphism was significantly associated with improvement in expressive language (P = 0.006) and cognitive verbal/ preverbal factors (P = 0.038).

Overall, 12-week supplementation with high dose folinic acid was well tolerated and associated with improvement in social reciprocity among children with autism. Linear regression analysis showed that children with the MTHFR A1298C gene polymorphism were more likely to experience improvement in several areas compared to wild type. Additional studies will be needed to verify these findings.

Source: Zhang, Caiyun, Yanlin Chen, Fang Hou, Yanzhi Li, Wanxin Wang, Lan Guo, Caixia Zhang, Li Li, and Ciyong Lu. “Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms.” Nutrients 17, no. 9 (2025): 1602.

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/
licenses/by/4.0/).

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Posted July 2, 2025.

Chrystal Moulton BA, PMP, is a 2008 graduate of the University of Illinois at Chicago. She graduated with a bachelor’s in psychology with a focus on premedical studies and is a licensed project manager. She currently resides in Indianapolis, IN.

References:

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