Efficacy of Folinic acid vs. L-Methylfolate supplementation in children with Autism Spectrum Disorders: a randomized trial

Autism Spectrum Disorders (ASD) are neuro-developmental disorders characterized by impairment in social interaction and communication, restricted interest and repetitive behaviors. It is a chronic, disabling condition posing numerous challenges for parents and patients themselves. There is a lack of effective pharmacological intervention that can cure the disorder. No pharmacological treatment is approved to manage the core symptoms of ASD. Currently available management strategies include supportive non-pharmacological treatments such as occupational therapy, behavior therapy, and special education.  Pharmacological treatment with oral Risperidone and Aripiprazole is often given to manage the associated symptoms of hyperactivity.

The etiology of ASD is hypothesized to be due to genetic and epigenetic abnormalities, among others. Emerging research from other countries has reported that children with ASD have cerebral folate deficiency owing to the presence of FRAA, which blocks the transport of folates to the brain by inhibiting the Folate receptor alpha. This deficiency of cerebral folate has been hypothesized to be the cause behind the communication and behavior problems of ASD. Also, studies from different countries have reported that FRAA may be found in approximately 70% cases of ASD. To manage this deficiency, folinic acid can be administered as it crosses the BBB using the reduced folate carrier (RFC), bypassing the Folate receptor alpha. Indeed, research from developed countries, including case series, single-arm trials, and some RCTs, has shown that the core symptoms of ASD improve significantly with oral folinic acid over 12 to 24 weeks. Some studies have shown improvement in symptoms of ASD on treatment with high doses of oral folinic acid (0.5 to 2mg/kg/ day, max up to 50mg/ day). Some studies have also found an association between FRAA and response to folinic acid. (Frye et al. 2020) No significant adverse effects have been reported in any previous studies with this treatment.

Research in this area from India is scarce, as only one Randomized controlled trial by Panda et al. (2024) has been conducted in the Indian context to date. They found that FRAA was present in high titres in 81% of their study population (N=80). They also reported that folinic acid at 2mg/kg/day was effective and safe in improving ASD symptoms over 12 and 24 weeks. The benefits were more in children with high FRAA titres.

Improvement in ASD symptoms has also been reported with low doses of folinic acid in France. Renard et al. (2020) conducted an RCT to evaluate the efficacy of folinic acid (5mg twice daily) in ASD, demonstrating significant improvement at 12 weeks.

A few studies have also found that ASD symptoms improve with the supplementation of 400-800mcg/day folic acid (Hohxa et al. 2021). Folic acid is converted to L-Methylfolate (the active form of folate) in the liver, which is then transported to the brain via RFC or other mechanisms. (Alam et al. 2020) Studies also suggest that conversion of folic acid to l-methylfolate may be limited in many individuals due to weak activity of the liver enzyme. (Menezo et al. 2022)

L-methylfolate may also be transported across the BBB via RFC and may address cerebral folate deficiency, similar to folinic acid. There is a paucity of studies demonstrating the efficacy of l-methylfolate in ASD.

Hence, the current study is planned to examine the efficacy of l-methylfolate and compare its effectiveness with low-dose folinic acid administration over 12 weeks. The study will also investigate the role of FRAA in predicting the response. The current research will utilize the strength of a 15mg tablet of folinic acid and 7.5mg tablet of l-methylfolate available in the Indian setting.