What is leucovorin and is it a treatment for autism?

The US FDA has recently announced controversial guidance on the prevention and treatment of autism in children. While the nonsensical recommendation discouraging pregnant women from taking paracetamol to prevent autism received all the media attention, the recommendations also include using the drug leucovorin to treat speech-related difficulties that children with autism sometimes experience.

So, what is leucovorin and what does the science say about its ability to treat autism?

What is Leucovorin?

According to the Mayo Clinic, Leucovorin is used as an antidote to the harmful effects of methotrexate (a form of chemotherapy) that is given in high doses. It is used also to prevent or treat certain kinds of anemia. Leucovorin acts the same way in the body as folic acid, which may be low in these patients.

Leucovorin is also known as folinic acid. Unlike regular folic acid, folinic acid can cross into the brain even when folate transport is impaired.  Some studies suggest that folate transport is blocked in some children with autism, resulting in low brain levels of folate, but these findings have been inconsistent.  This science is still in very early stages, and more studies are necessary before a definitive conclusion can be reached. While this drug poses no apparent health risks, there is not sufficient data to show that it improves autism symptoms.

Why is it getting attention now?

Like with many niche treatments, the purported benefits of leucovorin began spreading in the autism community via word of mouth. For decades, some parents have sworn that folinic acid, a dietary supplement, improved their autistic children’s ability to speak and communicate, and some doctors would prescribe leucovorin, a drug with the same key ingredient.

Leucovorin came onto the FDA’s radar when the US National Institute of Health met with experts and autistic people to create a list of about a dozen drugs that some doctors prescribe off-label for autism traits, says George Tidmarsh, director for the Center for Drug Evaluation and Research at the FDA. “Leucovorin was near the top of the list,” Tidmarsh told The Transmitter in an interview.

When Tidmarsh and his colleagues examined the literature, they identified 23 studies that suggest leucovorin treatment benefits a distinct group of people: those with cerebral folate deficiency (CFD), a rare neurological condition characterized by developmental delays, autism-like traits and seizures.

Cerebral folate deficiency can be caused by rogue antibodies that attack the body’s own proteins – in this case, proteins that ensure import of folate into the brain. The treatment normalizes levels of folate in their cerebrospinal fluid, decreases the number of seizures and boosts their ability to communicate and interact socially.

Some studies have found the two conditions do overlap, including one report suggesting that 38% of people with autism have cerebral folate deficiency.

According to The Transmitter, the push to address autism itself with leucovorin may stem from a yet-unproven hypothesis that some cases of CFD and autism could be caused by autoantibodies against folate receptors that lead to folate deficiency. (Some of this research on the autoantibodies has been led by Richard Frye, a child neurologist and advocate for the use of leucovorin).

Frye published his findings in two studies, both from 2012, Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis and his clinical trial, Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism.

 

Is the hype real?

According to The American Journal of Managed Care, even though the FDA cites Frye's clinical trial, it had a very small sample size. The agency acknowledged this, and noted that further research is still needed to determine the safety and efficacy of leucovorin to treat CFD.

The placebo-controlled, double-blind randomized trial consisted of 80 children aged 2 to 10 years with ASD, evenly split between the folic acid and placebo groups. The study, conducted between January 2022 and January 2024, used the Childhood Autism Rating Scale to assess child participants before and after 24 weeks of treatment. The severity of autism observed in children improved significantly in the folic acid group when compared with the placebo group. Behavioral problems measured by the Child Behavior Checklist also improved more in the folic acid group when compared with the placebo group.

None of the participants in either group developed any adverse events in relation to the study medication. By contrast, previous studies have shown increases in agitation, aggression, insomnia, tantrums, headaches, and gastroesophageal reflux, suggesting that some of the adverse events observed may not be related to folic acid.

Four randomized controlled trials, performed in the US, France, India, and China, demonstrated improvement in different domains including verbal communication, social reciprocity, and other behaviors (daily living skills, irritability, stereotyped behavior and hyperactivity), within the leucovorin treatment group, particularly in individuals who tested positive for the folate receptor autoantibodies:

1. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial
2. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial
3. Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial
4. Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms

 

Not a magic bullet

Scientific American says that the FDA’s proposed approval, which has not yet been finalized, would apply only to people with low levels of folate in the fluid surrounding the brain and spinal cord. That represents about 7% - 30% of autistic people, depending on how folate levels are measured, says Alycia Halladay, chief science officer of the Autism Science Foundation in New York City. 

The lack of data from large trials means that doctors will have little to go on when determining what dose to prescribe, or how long children should take leucovorin before deciding if it is or is not working, says Halladay. “We hope there’s eventually going to be guidance,” she says. 

According to Robert Hendren, a retired autism researcher at the University of California, San Francisco, who conducted one of the studies into leucovorin, parents should not expect too much "My experience and what I can read in the literature is, even if they have cerebral folate deficiency, their response to leucovorin or folinic acid is going to be modest. It’s not gonna be great. It’s not gonna cure autism." he says.

"It’s not gonna make them speak or fully be able to communicate, but it’ll make things a little bit better. I think that’s where the field is increasingly going and needing to go: Autism is a really complex disorder that has a number of genes that are involved and they’re not the same ones for every person with autism, but there are environmental interactions that occur at particular points — inflammation or oxidative stress or whatever."

 

FAQ's: Folinic Acid (Leucovorin) and Autism

(From the Children's hospital of Orange County)

Did the FDA approve folinic acid for autism? 
No. The FDA has not approved folinic acid (also called leucovorin) for autism. The FDA recently updated the label of an older medicine to include a condition called cerebral folate deficiency (CFD). CFD can sometimes look like autism in some children, but this is not the same as approval for autism.

So, can folinic acid treat autism? 
We do not know.  Studies are still ongoing. Some children with autism may also have folate problems, like CFD or certain antibodies, and may respond better to folinic acid. But to be clear:  folinic acid is not approved as an autism treatment for all children.

What is folinic acid?
Is it the same as folic acid? Folinic acid is a special form of folate (a type of vitamin B). It is different from folic acid (the common vitamin in foods and supplements) and from L-methylfolate. Folinic acid canreach the brain even when usual folate pathways are blocked.

Who might benefit?
Children who have CFD or certain antibodies (called folate receptor antibodies) may beneft from folinic acid. Some very early research in a few small studies shows these children may see small improvements in language and some autism-related behaviors. At this time, it is too early to know who might benefit.

What does research show?
A few small studies found some children improved in language, social interaction and behavior when taking folinic acid. Some studies have found that treatment with folinic acid, a form of folate that bypasses the blocked receptors, can improve symptoms in children with autism who test positive for people who make antibodies against their own folate receptors, preventing the brain from absorbing folate which is needed for brain function and health.Results are hopeful but not conclusive. Larger studies are needed before any broad recommendations can be made.

Is folinic acid safe?
In short-term use, it is usually well tolerated. Long-term safety is not known.  Side effects can include upset stomach, diarrhea, nausea and vomiting, fatigue, trouble sleeping, loss of appetite, irritability, hair loss, and skin inflammation. As with any drug or food, fatal allergic reactions can occur. Always talk to your doctor before starting any medicine.

Do we need special tests first?
Sometimes. Spinal fluid tests or checking for folate receptor autoantibodies in the fluid that surrounds the brain can help decide if a child has CFD and might response to folinic acid.  Most insurance will not pay for tests to check for blood antibodies against the folate receptor. Your doctor will guide you.

Can my child try folinic acid now?
Possibly. Doctors can prescribe it “off label” (not officially for autism). 

 

Medical Disclaimer

The information provided in this post is for educational and informational purposes only and is not intended as medical advice. We do not provide medical diagnosis, treatment recommendations, or individualized healthcare guidance. Any mention of specific tests, treatments, or research studies is for informational purposes and does not constitute an endorsement. The use of medications for conditions not originally approved (off-label use) should be carefully evaluated by a licensed physician.