Research & Discovery

Q&A: What is leucovorin, now being hailed as an autism treatment?

The U.S. Food and Drug Administration is considering approval of the drug leucovorin to treat children with cerebral folate deficiency and symptoms of autism.

Kevin Pelphrey is the Harrison-Wood Jefferson Scholars Foundation Professor of Neurology at the University of Virginia School of Medicine. At UVA’s Child Health Research Center, he researches biological markers for autism and develops tools to better detect and treat those on the autism spectrum.

Dr. Beth Ellen Davis is a UVA Health developmental behavioral pediatrician specializing in autism. She works with families affected by the disorder.

Kevin Pelphrey in front of several diagrams of brain activity zones during different stimuli

Kevin Pelphrey researches tools to better detect and treat people with autism spectrum disorder. (Contributed photo)

Both spoke with UVA Today about leucovorin and what both patients and parents should know about the drug.

Q. What can you tell us about the drug, leucovorin, that has been making headlines?

Pelphrey: Leucovorin is a medication that was originally developed to be helpful in the administration of chemotherapy and all of the terrible side effects. It’s basically folinic acid, a member of the folate family commonly known as vitamin B9, a naturally occurring nutrient that you find in foods. One of the key elements of the medication known as leucovorin is that it gets into cells very easily, including into the brain.

Folate is really important for many aspects of brain function and if you have a deficiency in folate, you can have neurological and psychiatric symptoms, including fatigue, depression, anxiety and, in severe cases, seizures and abnormal brain development.

Neurologists discovered that some babies born with folate deficiency ended up having severe seizures that could be treated with folate replacement if started early. Those babies have folate receptor auto antibodies that can keep folate from getting into the brain, resulting in severe cerebral folate deficiencies.

Q. How has this news resonated with patients with autism, and parents of children with autism? Is this reason to be optimistic, or cautious?

Davis: Because there are so few developmental behavioral pediatricians in Virginia and the USA, we see thousands of children with autism and their families at UVA Health’s Neurodevelopmental and Behavioral Pediatrics from all over the state, every year. Caregivers have been asking us about the use of folinic acid for their child with an autism spectrum disorder for quite a few months. Parents are seeking medical guidance about the risks and benefits of using prescription dose folinic acid to improve autistic symptoms. Currently, there is no medication or supplements to cure autism, nor is it our clinical protocol to prescribe leucovorin for improvement or treatment of autism symptoms at this time.

Q. How does folinic acid, or a deficiency of it, relate to children with autism?

Pelphrey: It was discovered that about half of children with autism have more folate receptor auto antibodies than you see in children not on the autism spectrum, and we don’t yet know why. As a result, scientists thought to try leucovorin, because that drug gets folinic acid and folate into the cells of the brain because it bypasses those antibodies.

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There are a handful of trials that gave leucovorin to children with autism. Some of those trials measured how much of the antibodies these children produce against folate, and what they discovered was a modest, but very interesting, medium-to-large effect for decreasing symptoms, especially improving verbal communication in most of the kids. The improvement was better for kids who had high levels of these auto antibodies.

Q. What level of research or scrutiny has there been on leucovorin and any benefits to patients with autism spectrum disorder?

Davis: The scientific evidence for leucovorin is quite preliminary, modest and based on small studies without rigorous outcomes, to date. We are told there is a multi-site study underway with more patients and better outcome measurements that will help inform our conversation with families. Since we see children with autism every six to 12 months throughout childhood, we will continue to partner with families about the best care for their child with a neurodevelopmental condition, including autism.

Dr. Beth Ellen Davis emphasizes that there are no medicines or supplements that cure autism. (Contributed photo)

Q. What should people know about leucovorin?

Pelphrey: It’s a prescription-only drug, which should be prescribed by a doctor very familiar with their patient and that families trust. If the family feels like it’s something they want to try with their doctor’s advice in getting the medication, make sure it’s coming from a reputable pharmacy.

Several of the major drug companies make this medication, so Pfizer and several others, so there’s a good supply line. But I wouldn’t try to buy it somewhere else like Amazon, or bypass the prescription requirement, because it’s very difficult to then know what you’re actually getting.

The side effect profile for this medication includes stomach upset and headaches, but those are things that children with autism may find difficult to report to a parent. If you’re seeing an increase in tantrums or irritability, that’s what you might be seeing. There is a reaction to things like stomach upset and headache, but they can’t verbalize what they’re experiencing.

Q. Where else can folinic acid be found?

Pelphrey: Folinic acid or vitamin B9 occurs naturally in wide variety of foods, including leafy greens, spinach and eggs. Folate deficiencies during pregnancy can cause neural tube deficits or defects.

As a father of five kids, I know that telling Mom to eat more eggs and spinach is a good way to evoke morning sickness very quickly, because those aren’t the most appetizing things when you’re sick to your stomach.

The medical community has been recommending prenatal vitamins now for well over a decade that contain a lot of folate to help prevent neural tube defects. What’s different about this medication is that it’s taking that nutrient and making it what we call highly bioactive, so easily absorbed by the body. In the case of people making antibodies for folate, it’s a good way to get folate into the cells for people.