Calcium Folinate & Autism Spectrum Disorder

According to the CDC, about 1 in 36 children have been identified with autism spectrum disorder (ASD).[1] That statistic includes my son who has Asperger’s syndrome, an ASD. Although he is now a high functioning 24-year-old man who effectively manages his Asperger’s, it was a bit of a bumpy ride during his childhood school years. During that time, I had naturally researched nutraceuticals with potential for helping him to manage his Asperger’s, but options were far and few between. That’s why I’m particularly pleased to write this article about folinic acid and its relationship to ASD.?

What is folinic acid?

Folinic acid (aka, folinate) is a naturally occurring, reduced form of folic acid. Often, the terms folic acid and folinic acid are used interchangeably, but they are not the same. Folic acid is a synthetic, oxidized, and water-soluble form of folate that does not exist in nature, whereas folinic acid exists naturally and is biologically active[2]. Both compounds are classified under the general family of “folates” and are used in dietary supplements—although folinic acid is generally present as calcium folinate.

Cerebral folate deficiency

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Research[3] has shown that, in children with ASD, a high prevalence of FRAs was found at 75.3%. In some of these children, the concentration of FRA was correlated with below normal cerebrospinal fluid concentrations of the active form of folate (5-methyltetrahydrofolate). So, what happens when there is compensation for this folate deficiency?

Folinate and ASD study 1

Children with FRAs were supplemented with folinic acid as calcium folinate at a dose of 2 mg/kg of body weight per day. For example, if a child were 50 lbs (22.72 kg), that would translate to 45.45 mg. In any case the maximum dose given was 50 mg per day. Compared with controls, over about 4 months results showed significantly higher improvement ratings in treated children in verbal communication, receptive and expressive language, attention, and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from calcium folinate treatment.

Folinate and ASD study 2

A double-blind, placebo-controlled randomized trial[4] investigated the potential therapeutic effects of folinic acid (2 mg/kg up to 50 mg per day) or placebo as an adjuvant to risperidone (a medication used for treating irritability associated with ASD) on inappropriate speech and other behavioral symptoms of ASD in 55 ASD children. Results showed a significant effect on inappropriate speech (P = 0.044), stereotypic behavior (P = 0.036), and hyperactivity/noncompliance (P = 0.003) scores with folinate. These researchers concluded that the study provided evidence suggesting that folinic acid could be recommended as a beneficial complementary supplement for alleviating speech and behavioral symptoms in children with ASD.

Folinate and ASD study 3

Another 12-week, double-blind, placebo-controlled trial[5] was conducted with 48 ASD children to examine the effect of folinic acid (2 mg/kg up to 50 mg per day) or placebo on language impairment. Results were that improvement in verbal communication was significantly greater in participants receiving folinate as compared with those receiving placebo. FRA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups.

Folinate and ASD study 4

In previous cited studies, a relatively high dose of folinic acid was used. This randomized placebo-controlled trial[6] evaluated the efficacy of folinic acid (as calcium folinate) at a lower dose of 5 mg twice daily in ASD children. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety. Results were that the global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group. A greater change of ADOS global score was also observed in the folinic acid group, compared to the placebo group. No serious adverse events were observed.

Conclusion

As previously noted, for personal reasons, I’m excited about the potential for calcium folinate as part of a complete program for the care of ASD. Professionally, I believe there is also an opportunity for brand owners to capitalize on a novel dietary supplement for neurological care for children (and adults)—especially considering the high prevalence of FRAs, and the below normal levels of the active form of folate in the cerebrospinal fluid of these kids.

NutraFolate? Calcium Folinate

Nutraland USA offers clean, plant-based and sustainable branded ingredients supported by science. Our nutraceuticals are good for you, and good for the planet. For more information about how you can use NutraFolate? Calcium Folinate, in your dietary supplements, contact [email protected]; 949-988-7615.

Note: The information presented in this article is for educational purposes only. It does not constitute recommendations for structure/function claims.

References

[1] Data & Statistics on Autism Spectrum Disorder. National Center on Birth Defects and developmental Disabilities, Centers for Disease Control and Prevention. Last reviewed April 4, 2023. Retrieved October 13, 2023 from https://www.cdc.gov/ncbddd/autism/data.html.

[2] Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the samething. Xenobiotica. 2014 May;44(5):480-8.

[3] Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81.

[4] Batebi N, Moghaddam HS, Hasanzadeh A, Fakour Y, Mohammadi MR, Akhondzadeh S. Folinic Acid as Adjunctive Therapy in Treatment of Inappropriate Speech in Children with Autism: A Double-Blind and Placebo-Controlled Randomized Trial. Child Psychiatry Hum Dev. 2021 Oct;52(5):928-938.

[5] Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256.

[6] Renard E, Leheup B, Guéant-Rodriguez RM, Oussalah A, Quadros EV, Guéant JL. Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial. Biochimie. 2020 Jun;173:57-61.