According to the Centers for Disease Control and Prevention (CDC), about one 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 26-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 nutraceuticals for ASD. Although these aren’t the only such nutraceuticals, this article will focus on research demonstrating the effectiveness of folinic acid, melatonin, vitamin K2 as MK-4 and a multivitamin supplement for ASD.
What Is Folinic Acid?
Folinic acid (aka folinate) is a naturally occurring form of folate. 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. Research3 has shown that, in children with ASD, a high prevalence of FRAs was found at 75.3 percent. 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 pounds (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 four 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 trial4 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 trial5 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 trial6 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.
Melatonin and ADD in Children
Melatonin is one of the supplements that I gave my son early on. It made a huge difference in his ability to get a good night’s sleep as an ASD kid.
A review in the journal Sleep Medicine7 examined the connection between insomnia and autism spectrum disorder (ASD) in children, focusing on the efficacy and safety of melatonin treatments. Various aspects of managing insomnia were considered, including the significance of comprehensively understanding the root causes of a child’s sleep difficulties for more effective, long-term management since insomnia greatly affects the lives of patients and caregivers. Results were that melatonin-based formulations were found to be effective and safe for treating ASD-related insomnia both short and long term. In particular, prolonged-release melatonin appeared to be the optimal choice for this patient population. This formulation is approved for the treatment of insomnia in children and adolescents aged 2 to 18 years suffering from ASD and/or Smith-Magenis syndrome, where sleep hygiene measures and behavioral treatments have not been sufficient. Emerging research in pediatric settings indicates long-term efficacy and safety, although further research efforts are still needed. Current guidelines recommend managing insomnia and sleep disturbances in ASD using a combination of behavioral and pharmacological methods, primarily melatonin.
This review also raised concerns about accidental melatonin ingestion and highlighted the need for high purity standards. For this reason, and due to concerns raised about potential adverse effects associated with a high intake of conventional synthetic melatonin, I prefer the use of natural phytomelatonin or plant-sources melatonin as a safer alternative8 (e.g., phytomelatonin from tomato extract or St. John’s wort extract).
A secondary analysis of results from a clinical trial in children with autism spectrum disorder demonstrated that supplementation with prolonged-release melatonin 2-5 mg nightly for 13 weeks improved externalizing behavior in 26 percent more patients when compared with those taking placebo.9 However, in another clinical trial immediate-release melatonin 1 mg or 4 mg before bedtime did not affect behavior when compared with placebo.10
MK-4 and ASD in Children
Although primarily known for its positive effects on bone health, the form of vitamin K2 known as menaquinone-4 (MK-4) also has potential for ASD. Researchers conducted a study11 to investigate the serum concentration of MK-4 and the correlations between it and developmental quotients in 731 children with autism spectrum disorder (ASD) who had been diagnosed for the first time. During the same period, 332 neurotypical children who underwent regular physical examinations were selected for comparative purposes. The general situation of children was investigated, including gender and age. Children in ASD group were assessed for autistic symptoms and development quotients, including Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), ADOS-2, and Griffiths Development Scales-Chinese Language Edition (GDS-C). Both groups of children were tested for serum MK-4 levels, and a correlation analysis was conducted between the level of MK-4 and the developmental quotient of children with ASD. Results were that the serum concentration of MK-4 in children with ASD is lower than that in children with typical development (t = -2.702, P = 0.007). The serum concentration of MK-4 is related to the developmental quotients of several subscales in ASD children, and this correlation is more obvious in males. In conclusion, MK-4 is present in lower concentrations in children with ASD, which may affect cognition and developmental quotients.
Multivitamin and ASD in Children
A randomized, double-blind, placebo-controlled three-month multivitamin treatment study was conducted with 141 children and adults with autism. Pre- and post-symptoms of autism were assessed. None of the participants had taken a vitamin/mineral supplement in the two months prior to the start of the study. For a subset of the participants (53 children ages 5-16) pre- and post-measurements of nutritional and metabolic status were also conducted. Results were that the multivitamin supplement (formulation in table below) was generally well-tolerated, and individually titrated to optimum benefit (i.e., adjusted based on baseline measured body weight up to a maximum of 100 pounds). Levels of many vitamins, minerals, and biomarkers improved/increased showing good compliance and absorption. Statistically significant improvements in metabolic status were many including: total sulfate (+17 percent, p = 0.001), S-adenosylmethionine (SAM; +6 percent, p = 0.003), reduced glutathione (+17 percent, p = 0.0008), ratio of oxidized glutathione to reduced glutathione (GSSG:GSH; -27 percent, p = 0.002), nitrotyrosine (-29 percent, p = 0.004), ATP (+25 percent, p = 0.000001), NADH (+28 percent, p = 0.0002) and NADPH (+30 percent, p = 0.001). Most of these metabolic biomarkers improved to normal or near-normal levels. Furthermore, the supplement group had significantly greater improvements than the placebo group on the Parental Global Impressions-Revised (PGI-R, Average Change, p = 0.008), and on the subscores for Hyperactivity (p = 0.003), Tantrumming (p = 0.009), Overall (p = 0.02), and Receptive Language (p = 0.03). The degree of improvement on the Average Change of the PGI-R was strongly associated with several biomarkers (p < 0.0005), with the initial levels of biotin and vitamin K being the most significant (p < 0.05) In conclusion, oral supplementation with this multivitamin is beneficial in improving the nutritional and metabolic status of children with autism, including improvements in methylation, glutathione, oxidative stress, sulfation, ATP, NADH and NADPH. The supplement group had significantly greater improvements than did the placebo group on the PGI-R Average Change. This suggests that a multivitamin supplement is a reasonable adjunct therapy to consider for most children and adults with autism.
Conclusion
Research has demonstrated that folinic acid, melatonin, vitamin K2 as MK-4, and a multivitamin supplement all offer potential as part of a complete program for the care of ASD. On a personal level, I have seen how the use of such supplements can be beneficial for ASD for my own son.VR 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 www.cdc.gov/ncbddd/autism/data.html.
2 Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. 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.
7 Bruni O, Biggio G, Malorgio E, Nobili L. Insomnia in children affected by autism spectrum disorder: The role of melatonin in treatment. Sleep Med. 2024;119:511-517. doi:10.1016/j.sleep.2024.05.046.
8 Arnao MB, Hernández-Ruiz J. Phytomelatonin versus synthetic melatonin in cancer treatments. Biomed Res Clin Prac. 2018; 3(3):1-6.
9 Schroder CM, Malow BA, Maras A, et al. Pediatric Prolonged-Release Melatonin for Sleep in Children with Autism Spectrum Disorder: Impact on Child Behavior and Caregiver’s Quality of Life. J Autism Dev Disord. 2019;49(8):3218-3230.
10 Hayashi M, Mishima K, Fukumizu M, et al. Melatonin treatment and adequate sleep hygiene interventions in children with autism spectrum disorder: A randomized controlled trial. J Autism Dev Disord 2021.
11 Dong H, Wang B, Feng J, Yue X, Jia F. Correlation Between Serum Concentrations of Menaquinone-4 and Developmental Quotients in Children With Autism Spectrum Disorder. Front Nutr. 2021 Sep 30;8:748513.
Gene Bruno, DBM, MHS, Professor Emeritus of Nutraceutical Science, is a writer, educator and a nutraceutical scientist with more than 45 years of experience educating natural product retailers and health care professionals and formulating natural products for dozens of dietary supplement companies. He has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. Bruno also hosts “The Vitamin Professor Podcast” brought to you by VRM Media. He can be reached at eugenejbruno@gmail.com.
