Can the prescription drug leucovorin treat autism? History says, probably not : NPR

Interest in leucovorin is growing among some parents of autistic children. But researchers like Dr. Paul Offit say the drug’s popularity is far ahead of the science.

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At a press conference in late 2025, federal officials made some statements big complaints about leucovorin, a prescription drug usually reserved for people undergoing cancer chemotherapy.

“We are going to change the label to make it available [to children with autism spectrum disorder]” said Dr. Marty Makary, commissioner of the Food and Drug Administration. “Hundreds of thousands of children, in my opinion, will benefit. “

The FDA still has not made this label change.

Since Makary’s remarks, more than 25,000 people have joined a Facebook group called Leucovorin for Autism. Most members appear to be parents seeking this medication for their autistic children.

Also since the press conference, some doctors have started writing off-label prescriptions for autistic children, against advice medical groups, including the American Academy of Pediatrics.

The buzz around leucovorin has led to a shortage of the drug. In response, the FDA is temporarily authorize imports of tablets manufactured in Spain and sold in Canada, but not approved in the United States

It’s all part of a familiar cycle for Dr Paul Offitwho directs the Vaccine Education Center at Children’s Hospital of Philadelphia. Offit says he realized years ago that leucovorin’s popularity was far ahead of the science.

“I saw it for what it was, which was the next magic drug to treat autism, in a long line of magic drugs to treat autism that didn’t work,” Offit says.

Offit has chronicled the rise and fall of many of these products in his books and blog posts.

“First it was secretin, a gut hormone,” he says. “Then there was Lupron, chemical castration, antibiotics, megavitamins, nicotine patches and my favorite, which is raw camel milk.”

Leucovorin will likely find a place on that warning list, Offit says, adding that the FDA has failed to protect the public from an autism cure whose “clearly hasn’t been well tested for effectiveness.”

A deficiency discovered

The rationale for leucovorin’s use in autism is based on its link to a form of vitamin B called folate – and to a disease called brain folate deficiency.

Folate is a dietary nutrient essential for brain development. Children whose brains don’t get enough of it are prone to seizures, muscle weakness, cognitive impairment and, in some cases, autism.

People with brain folate deficiency have normal levels of folate in the blood, but low levels in the brain.

One of the causes of brain folate deficiency is a group of rare genetic mutations discovered starting in the 1990s. These mutations disable the proteins needed to extract folate from the blood and transport it into the cerebrospinal fluid – the fluid that surrounds the spinal cord and brain.

In the early 2000s, scientists began to find evidence that brain folate deficiency could also be caused by the body’s immune system.

Animal studies have shown that immune cells sometimes produce antibodies that act like these rare genetic mutations to block folate in the blood from reaching the brain.

A link with autism?

A 2005 study In The New England Journal of Medicine suggested a link between brain folate deficiency and autism.

The study involved 28 children treated by a doctor in Germany for a range of developmental disorders, including autism. All children had low levels of folate in their spinal fluid.

At first, the German doctor didn’t know why folate levels were low, he explains. Édouard Quadrosstudy co-author and research professor at SUNY Downstate Health Sciences University in Brooklyn.

“So he contacted us and asked, ‘Could this be an autoimmune disease?’ ” Quadros said. In other words: Did these children’s immune systems produce an antibody that could block folate in the blood from reaching the brain?

The Quadros laboratory was ready to answer this question. She had developed a test that could detect folate-blocking antibodies in the blood.

Samples taken from the 28 children showed that 25 of them carried these antibodies.

“So we had an explanation why, even though they had normal circulation of folate, the brain wasn’t getting folate,” Quadros says.

They also thought they could correct the deficiency with leucovorin, a form of folate that can take “an alternative route to the brain,” Quadros says.

When children in the study received leucovorin, folate levels in their brains increased, and in some, their symptoms seemed to decrease.

Studies with reservations

The results obtained with leucovorin, although very preliminary, have been prevalent in the autism community for over a decade.

Then in 2018, another small study increased interest in the drug.

The study involved 48 autistic children with language disorders. It was found that those who received leucovorin during the 12-week study period showed greater improvement in their communication skills.

The first author of the study was Dr. Richard Fryecontroversial figure in the medical community and prominent advocate of leucovorin treatment for autistic children.

But even Frye says the drug is far from a cure.

“It’s not a panacea, it’s not the pill for autism,” he says. “Some kids react dramatically, but that’s not the norm.”

Most improve slowly over several years, he says, and require a range of therapies in addition to leucovorin.

Frye studied the drug during appointments at the University of Arkansas and then at Children’s Hospital in Phoenix. He left both institutions after his research was called into question and now practices in a private clinic.

Frye believes that a brain folate deficiency is present in many autistic children. But confirming the deficiency requires a lumbar puncture, which can be painful.

As a result, Frye says, he and other researchers generally use a less reliable measure: the presence of folate-blocking antibodies in a child’s blood.

“So we can’t say they have brain folate deficiency,” he says, “but we can say, okay, there’s some sort of blockage that would put them at risk.”

Another caveat is that leucovorin appears to help many children who do not have folate-blocking antibodies.

To Frye, this simply suggests that leucovorin works in another way.

“There is strong data that this is a very promising treatment,” Frye says. “Is that enough to change the label? That depends on the FDA.”

Frye is working on a randomized, controlled trial that uses a purified form of leucovorin to treat children with autism. This should provide clearer results, he says.

Been there, done that

In the meantime, the FDA is relying on very flawed studies, says Dr Shafali Jestechair of pediatrics at the University of California, Los Angeles.

“These trials were conducted without the rigor necessary to determine whether something should be approved by the FDA for autism,” she says.

Jeste therefore does not prescribe leucovorin. And when her parents ask her questions, she has a standard answer:

“If I had a pill that I could give to your child to help them speak or to completely reverse the core symptoms of autism, I would be the first to prescribe it,” she says. “We don’t have any.”

At least one segment of the autism community has already tried leucovorin – and found it lacking.

Decades ago, this medication became a popular treatment for children with Fragile X syndromean inherited disorder that affects a region of the X chromosome and is one of the main causes of autism.

Until the advent of genetic testing for fragile X in the 1990s, scientists used a microscope to look for “fragile” or “broken” regions on the

“The very first and most obvious theory was that fragile X must have something to do with folic acid metabolism,” explains Dr Michael Tranfagliamedical director of the FRAXA Research Foundation and parent of an adult child suffering from this disorder and severe autism.

Parents started giving folic acid to their children with Fragile X. When that didn’t work, they switched to folinic acid, leucovorin.

“There was a lot of excitement about it, until people started doing actual clinical trials,” Tranfaglia says. Then it became clear that the drug was no better than a placebo.

Now, Tranfaglia says, leucovorin is back.

“It’s not really surprising,” he says, “because for every supplement and every vitamin you can imagine, someone has proposed some sort of link to autism.”

Usually, though, it’s not someone who runs the FDA — the agency that determines whether a drug is safe and effective.