APC: Autism Spectrum Disorder and Methylation and Methylcobalamin

April 26, 2023

Autism Spectrum Disorder and Methylation and Methylcobalamin

Compounding pharmacists can be a valuable resource for patients with autism. Many treatment options for autism are not available commercially and must be compounded by a reputable pharmacy. While the molecular basis for autism spectrum disorder (ASD) remains unclear, research is underway which may reveal a better understanding of the disorders root cause.

The outward signs of ASD include poor communication skills, repetitive behaviors or movements, delayed language and movement skills. Other symptoms prevalent in ASD patients include gastrointestinal irregularities, unusual sleeping habits, stress and anxiety, and sensitivity to food, flavors or textures.1 Although these are recognized signs and symptoms, the root cause of ASD still remains a mystery—a mystery that, if solved, could lead to a cure.

As technology advances, so does our knowledge. Discoveries in biotechnology have allowed scientists to detect evidence of DNA methylation abnormalities in patients with ASD.

Methylation occurs when a molecule donates its methyl-group (CH3) to another molecule. Many important biological functions depend on methylation and epigenetic changes are just one aspect. Patients with ASD have different methylation patterns across their entire genome, resulting in increased inflammation, altered metabolism and altered gene expression.2

DNA methylation can cause changes in gene expression without altering the DNA sequence. This type of epigenetic change can alter brain development.3 We also know that a mother’s intake of methyl-donors (chemicals that donate a methyl group to another substance) in food or by supplementation during the period just prior to and during conception can change the epigenetics of an unborn child.4

Many have wondered if these methyl-group donors could also produce positive changes in patients affected by ASD. Research seems to indicate that they do.

Considering the ever-growing body of research, methylcobalamin has been utilized as a methyl-donor in patients with ASD at dosages ranging from 64.5 to 75 micrograms/kg/doses administered as subcutaneous and oral dosage forms. Clinical results revealed improvements in methylation capacity, with glutathione redox resulting in clinical improvements as well. Sleep, gastrointestinal symptoms, eye contact, bed wetting, expressive communication, daily living skills, as well as inter-personal and coping skills were markedly improved after methylcobalamin utilization. Adverse effects are generally mild and do not cause discontinuation of treatment. Hyperactivity is the most common adverse effect.5,6

Methylcobalamin is a naturally occurring form of B12 that provides better tissue retention compared to its commercially available counterpart—cyanocobalamin—and does not increase the risk of cyanide accumulation.7 Your compounding pharmacist is able to work with your prescriber to offer treatment options for methylcobalamin that are not commercially available.

Recently, the compounding community was at risk of losing access to this critical treatment option. The FDA’s Pharmacy Compounding Advisory Committee (PCAC) placed methylcobalamin under review because it is not a graded chemical, nor is it available in a commercial drug product. After much preparation, A.J. Day, PharmD, Richard Frye, MD, and James Neubrander, MD, defended methylcobalamin’s usefulness to the PCAC committee and secured a vote in favor of maintaining access to methylcobalamin. FDA has yet to propose a rule to keep or remove methylcobalamin on their final list, and for now it is included on FDA’s Interim Policy Category 1 Bulk Drug Substances list, meaning it is currently available for prescribers and compounders to help patients, including those with ASD.8

Your compounding pharmacist can work with your prescriber in order to offer customized treatment options—including methylcobalamin—that are not commercially available.

By Tricia Heitman, PharmD, PCCA Clinical Services



  1. CDC. (Last reviewed March 28, 2022). Signs and Symptoms of Autism Spectrum Disorder. Accessed March 2023 at https://www.cdc.gov/ncbddd/autism/signs.html

  2. Wong C.C.Y., Smith R.G, Hannon E., et al. (**2019 Jul) Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue. Hum Mol Genet. 1;28(13):2201-2211. PMID: 31220268; PMCID: PMC6602383. DOI: 10.1093/hmg/ddz052

  3. Tremblay M.W., Jiang Y.H. (Jan 2019). DNA Methylation and Susceptibility to Autism Spectrum Disorder. Annu Rev Med. 27;70:151-166. PMID: 30691368; PMCID: PMC6597259. DOI**: 10.1146/annurev-med-120417-091431 .

  4. Pauwels, S., Ghosh, M., Duca, R.C. et al. (2017). Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants. Clin Epigenet 9, 16**. Accessed March 2023 at https://doi.org/10.1186/s13148-017-0321-y

  5. Frye R.E,. Melnyk S., Fuchs G., et al. (**2013 Oct). Effectiveness of methylcobalamin and folinic acid treatment on adaptive behavior in children with autistic disorder is related to glutathione redox status. Autism Res Treat. 2013;2013:609705. PMID: 24224089; PMCID: PMC3810468. DOI: 10.1155/2013/609705. Epub

  6. Rossignol D.A., Frye R.E. (**2021 Aug) The Effectiveness of Cobalamin (B12) Treatment for Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. J Pers Med. 11;11(8):784. PMID: 34442428; PMCID: PMC8400809. DOI: 10.3390/jpm11080784

  7. Paul C., Brady D.M. (**2017 Feb) Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms. Integr Med (Encinitas). 16(1):42-49. PMID: 28223907; PMCID: PMC5312744.

  8. FDA. (Content current as of 2020 Feb) Bulk Drug Substances Used in Compounding Under Section 503B of the FD&C Act. Accessed March 2023 at https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503b-fdc-act