Exclusive | Children with autism are showing ‘dramatic improvement’ with this cheap drug — and doctor behind its research says it may one day prevent the disorder

As scientists continue to investigate the roots of autism, a generic cancer drug might hold the key.

Leucovorin is prescribed to reduce the side effects of chemo. But in several studies conducted over the past 13 years, Dr. Richard Frye has compiled growing evidence that it can improve signs of autism, even leading nonverbal children to speak for the first time.

He told The Post that he believes these successes could be valuable in both treating autism and — down the line — potentially preventing the disorder altogether

“If you’re going to the doctor and looking for an autism pill, it doesn’t exist,” Frye, a pediatric neurologist from Arizona, told The Post. “But leucovorin has helped a lot of children.”

A growing need for solutions

Autism spectrum disorder encompasses a broad range of conditions that affect how people learn, behave, communicate and interact with others.

In recent years, the number of autism diagnoses in the US has skyrocketed, increasing by 175% between 2011 and 2022, largely driven by a spike in cases among young people. According to the CDC, around 1 in 36 children are on the spectrum in the US.

Researchers point to “increased advocacy and education” as one possible reason for the surge, with more people getting themselves or their children screened. Others suggest that the uptick could be attributed to shifts in screening practices, policy changes, environmental factors and evolving diagnosis definitions.

Leucovorin: A surprising autism treatment

Frye first turned to leucovorin as a potential treatment in the early 2000s after observing a striking pattern in children with autism. 

“I started to realize that the neurochemistry in the brain was off,” he said. 

Around the same time, new research emerged showing that many children with neurodevelopmental disorders had low levels of folate (vitamin B9) in their brains — a condition known as cerebral folate deficiency (CFD).

Notably, scientists also discovered that many of these children carried folate receptor alpha (FR⍺) autoantibodies, which block the proper transport of folate into the brain.

In fact, one study found that more than 75% of children with autism had FR⍺ autoantibodies, compared to just 10% to 15% of children without the disorder.

Intrigued by these findings, Frye began testing his own patients and found that many of them had FR⍺ autoantibodies.

He started treating some with leucovorin, a generic drug often used to alleviate the side effects of cancer treatments.

Frye chose leucovorin because it’s derived from folic acid, a form of folate, which is an essential B vitamin that helps the body repair and create new healthy cells. Research has shown that treating CFD patients with leucovorin can boost their folate levels by bypassing the blockage caused by FR⍺ autoantibodies.

Many of his patients saw “really dramatic improvement” soon after starting the drug.

“I had one kid who would just sit in the corner and have seizures,” he recalled. “We treated him, and he wasn’t normalized, but he was interacting with his family, playing with his brother and the seizures got better.”

Unlocking language and more

One of the most remarkable improvements Frye has observed is in nonverbal children with autism who suddenly began speaking.

In a 2012 clinical trial, Frye and his team tested leucovorin on 44 children with both autism and FR⍺ autoantibodies. One-third of those treated with the drug showed significant language improvement.

In another study published in 2018, Frye examined 48 children with autism and language impairments. Half were given leucovorin, while the other half received a placebo.

After 12 weeks, those who took the medication showed “improvement in measures of verbal communication” compared to the control group, particularly in those with FR⍺ autoantibodies.

In one recent, eye-popping case, a toddler with nonverbal autism — whose parents had been told their child would never speak — uttered his first words just three days after starting the drug. 

However, Frye noted that leucovorin on its own isn’t a cure-all. While his patients were taking the medication, they also continued other therapeutic interventions, such as applied behavior analysis and speech therapy.

“You have to treat a lot of things to make the body well,” Frye said. “What [leucovorin] does, we think, is accelerate the effectiveness of all these therapies.”

Frye’s team is now exploring whether leucovorin could help with other characteristics associated with autism, such as difficulty socializing.

In older children treated with the drug, he observed not only an increase in the number of words they could speak, but also improvements in their comprehension and a more sophisticated use of language.

“That’s really important for social interactions,” Frye said. “We’ve found that leucovorin also helps with attention, and it seems to help with repetitive behaviors too.”

Frye has seen positive outcomes in treating autistic adults with leucovorin as well. Other studies suggest the drug may benefit people with Down Syndrome, schizophrenia, certain seizure disorders and even dementia.

However, it’s still unclear whether long-term use is necessary to maintain these benefits. In one study, Frye found that about half of the autistic children who stopped taking the medication “regressed fairly quickly.”

Luckily, the drug’s side effects are generally mild. “The great thing about leucovorin is that it’s a B vitamin, which is water soluble,” Frye said. “So the worst thing you could do if you’re given leucovorin is make expensive pee.”

Exploring a potential genetic link

Frye said he “definitely” believes leucovorin’s success in treating children with autism offers valuable insights into the underlying factors potentially contributing to the disorder.

“We know that in about half of the kids with the folate autoantibody, their mothers have it too,” he said. “We are thinking that they have a double whammy of no folate before birth and then after they’re born.” 

Frye and his colleagues are now studying whether autism-like traits or risk factors can be passed down through generations, even if the ancestor did not have the disorder.

“If we identify it in parents, we’ll be able to treat them and maybe minimize or prevent autism from developing in the first place,” he said. “That’s one of our major goals.”

The road ahead

Leucovorin has been used for decades to alleviate the harmful effects of cancer treatments. While doctors can prescribe it off-label for other purposes, Frye noted that many are “very reluctant” to do so due to unfamiliarity with the drug.

Frye is currently testing a new form of leucovorin, hoping it will one day receive FDA approval specifically for treating autism.

In the meantime, he encourages parents to discuss the possibility of leucovorin with their child’s doctor or consult a specialist to explore whether it might be beneficial.

“What I’ve found is that the ability of the child to recover is correlated with the ability of the parent to advocate for them,” Frye said.