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Folinic Acid (Leucovorin)

Summary: Folinic acid (tradename Leucovorin) is a form of folic acid that has long been given to protect people against harmful side effects of cancer treatment medications such as methotrexate. Newer research suggests that folinic acid is associated with improvements in core and associated symptoms of ASD. It appears to be safe and well-tolerated.
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What is Folate, Folic Acid, Methylfolate and Folinic Acid? 

Folate is an essential B vitamin required for normal brain development; it is the natural form of vitamin B9 found in foods such as dark green leafy vegetables.

Folic acid is a synthetic form of folate often placed into supplements and fortified foods.

After ingesting folate or folic acid, an enzyme produced by the MTHFR gene converts folate or folic acid into folinic acid, a form that the brain can use.

  • A problem at this step is that people may have trouble with the enzyme that converts 5-MTHF into folinic acid.

Folinic acid is then converted into the active form methylfolate.

Cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain.

  • A problem at this step is that some people have folate receptor alpha autoantibodies (FRAAS), which keeps 5-MTHF from getting into the brain.

Unfortunately, many problems can lead to low brain folate, aka cerebral folate deficiency (CFD), which is associated with:

  • Autism spectrum disorders (ASD). People with ASD have FRAAS much more frequently than other people.
  • Physical abnormalities.

When people have low folate in the brain (cerebral folate deficiency), about 44% have ASD (Rossignol, 2021).

When people have ASD, their chance of having FRAA is 19X more likely than typically developing children without an ASD sibling (Rossignol, 2021).

The Folate Pathway

Folate or folic acid

Converted by MTHFR enzyme

Folinic acid (leucovorin)

Methylfolate, aka 5-methyltetrahydrofolate (5-MTHF)

Transported into the brain

What is Folinic Acid?

Folinic acid is a treatment for low folate and has been used for years to help protect against low folate in people who receive cancer treatments such as methotrexate. Newer studies show that perhaps it can help people with autism spectrum disorder (ASD).

What Can Folinic Acid Help With?

As of Jun 2022, twenty-one studies (including four placebo-controlled and three prospective controlled) have treated individuals with ASD using folinic acid (Rossignol, 2021).

For individuals with ASD and cerebral folate deficiency (CFD), a meta-analysis found improvements with folinic acid in

  • Overall ASD symptoms (67%),
  • Irritability (58%),
  • Ataxia (88%),
  • Pyramidal signs (76%),
  • Movement disorders (47%),
  • Epilepsy (75%).

For individuals with ASD in general, leucovorin improves

  • Communication (significant improvement with medium-to-large effect sizes)
  • Core ASD symptoms
  • Attention (with large effect sizes)
  • Stereotypy (i.e. unusual movements) (with large effect sizes).

How to Find Folinic Acid Treatment?

Are you in Canada?

  • See a physician, as folinic acid is available by prescription only.

Can I Use Folate, Folic Acid or Methylfolate?

Folate, folic acid and methylfolate are available as over-the-counter medications in pharmacies and online retailers. There is promising research on folate, folic acid and methylfolate for various conditions.

For ASD however, folinic acid (leucovorin) appears to have the most convincing positive research to date.

For more information about folate and mental health in general,

https://www.ementalhealth.ca/index.php?m=article&ID=83462

Dosage of Folinic Acid (Leucovorin)

Typical dosage of folinic acid (leucovorin)

  • Available as 5 mg tablets.
  • 0.5-2 mg/kg/day divided twice a day (Ramaekers, 2019)
  • Maximum dose 50mg / day.

Dosage for specific weights

  • For 20 kg child
    • Start 10 mg twice daily x 1-week, then 15 mg twice daily x 1-week, then go up to 20 mg twice daily.
  • For 40 kg child
    • Start 20 mg twice daily, and go up to 25 mg twice daily.
  • For 60 kg child/teen
    • Start 25 mg twice daily.

Duration of treatment

  • 4-months (Frye, 2012).

Side Effects of Folinic Acid

Most people do not have significant side effects from folinic acid. However most common are

  • Aggression (9.5%), excitement or
  • Excitement or agitation (11.7%),
  • Headache (4.9%),
  • Insomnia (8.5%), and increased tantrums (6.2%).

References

Frye, R.; Sequeira, J.M.; Quadros, E.V.; James, S.J.; Rossignol, D. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol. Psychiatry 2012, 18, 369–381.

https://www.nature.com/articles/mp2011175

Ramaekers, V.T.; Sequeira, J.M.; Di Duca, M.; Vrancken, G.; Thomas, A.; Philippe, C.; Peters, M.; Jadot, A.; Quadros, E.V. Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial. Autism Res. Treat. 2019, 2019, 1–12.

https://www.hindawi.com/journals/aurt/2019/7486431/

Rossignol DA, Frye RE. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. Journal of Personalized Medicine. 2021; 11(11):1141. https://doi.org/10.3390/jpm11111141

References regarding folate, folic acid, methylfolate

Kim YI. Folic acid fortification and supplementation–good for some but not so good for others. Nutr Rev 2007;65(11):504-511.

https://doi.org/10.1111/j.1753-4887.2007.tb00275.x

Scaglione F, et al. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014 May;44(5):480-8

https://www.ncbi.nlm.nih.gov/pubmed/24494987

R Prinz-Langenohl, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009 Dec; 158(8): 2014–2021

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807663/

Authors

Written by the health professionals at CHEO and the Department of Psychiatry, at Ottawa. Thanks to Mary Velez, Nursing Student, Class of 2024, for the French version.

Disclaimer

Information in this pamphlet is offered ‘as is' and is meant only to provide general information that supplements but do not replace your health provider's information. Always contact a qualified health professional for further information in your specific situation or circumstance.

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Date Posted: Jun 22, 2022
Date of Last Revision: Jun 22, 2022

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