Last winter, Brian Noonan read online that some doctors prescribe the ambiguous drugs that are usually given to cancer patients because of autism. Curious, he looked into his son Benjamin, who had just been diagnosed with autism in October.
“We jumped on it,” Noonan said. “It feels right and makes sense.”
The drug therapy was leucovorin, also known as folinic acid. This is the synthetic form of vitamin B9 or folic acid that the body needs to produce healthy blood cells. During pregnancy, folic acid is important to reduce the risk of birth defects.
Last Monday, the drug was entered the national spotlight by President Donald Trump for a rambling press conference on autism that focused primarily on President Robert F. Kennedy and the Health Secretary, saying that taking acetaminophen while pregnant could cause autism. Trump simply said that “previous drugs” (referring to leucovorin) could help certain symptoms of autism.
For those in the autism community, leukovorin is nothing new. Dr. Richard Fry, a behavioral child neurologist in Phoenix, has been studying leucovorin and autism for 20 years. He revealed that it is not a treatment for autism and requires more research. But he prescribes it to some people with autism.
Benjamin, the son of Noonan, 4 years old, is one of Fry’s patients.
“He’s working,” Noonan said. “He’s verbally, but he really struggled to put together his sentences.” Since starting the drug, his family believes Benjamin’s speech has improved, but he still has hyperactivity and impulsive difficulties.
Still, Noonan added, he has no impression that the drug is a miraculous pill. Benjamin is also taking part in an action program that prepares him for kindergarten, Noonan said, and he plans to enroll him in language and occupational therapy. “We really understand that we are still taking experimental medications,” he said.
Other families say the drug has provided greater benefits.
Ben Bromglen of Minneapolis said her 11-year-old son, Josh, was prescribed a leucovorin off-label in February after risking being kicked out of school even if she tried to correct her behavior.
“He’s pretty tough,” Bromglen said. “He had no language skills. He was not trained in the toilet.”
After starting medication, Bromgren said Josh’s sleep improved and he was fully toilet trained and stopped running away from him.
“It wasn’t overnight, but there were significant improvements,” he said.
Yomarie Miranda of Florida said her 7-year-old son Ethan saw improvements after starting medications that included class instructions.
Ethan was prescribed medication off-label earlier this month, she said.
“When I talk to him, he’s looking at me now. He’s speaking more in full writing than before,” she said.
Very unusual movement
The Food and Drug Administration first approved leucovorin in the 1980s to reduce the toxic side effects of certain chemotherapeutic drugs.
Since then, researchers have also been studying whether it may treat brain folate deficiency (CFD), a neurological condition that makes it difficult for the lobes to reach the brain. Some children with autism also have brain folate deficiency, which neurologists say can affect speech, mood and behavior. Last Monday, the FDA said it plans to update its drug labels to include its use.
But experts say the agency’s decisions depend on just a handful of small studies. And despite Trump’s support, GSK, the maker of the brand name edition, has yet to file an application with its agency to change its label. In a statement, GSK said it would not mention autism in the statement, but would submit a request to expand its approval to include brain folate deficiency. (Leucovorin is already an FDA approved drug, so doctors were able to prescribe “unlabeled” for other uses, but insurance doesn’t cover that.)
This is a very unusual move for the FDA. It is to push drugs as treatment for autism without formal submission and limited evidence for chemotherapy side effects.
“It’s incredibly irresponsible,” said Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School. “For over 60 years, we have relied on the FDA to help patients distinguish between functional and non-functional products. Here we have announced that the FDA has relied on an unclear data overview and has already decided to approve it.”
Alycia Halladay, chief science officer of the nonprofit Autism Science Foundation, was unhappy with the meaning that this was a breakthrough in autism research.
“It’s not like scientists who haven’t seen autism treatment have been staring at the belly button for 20 years,” Halladay said in an interview earlier this week. “They have, but the standard is very high to approve (treatment).”
In a statement, Andrew Nixon, a spokesman for the Department of Health and Human Services, who oversees the FDA, said: Nixon’s statement did not mention autism and did not respond to follow-up questions.
David Mandel, a professor of psychiatry at the University of Pennsylvania, said he argued that HHS’s claim that 85% of patients experienced benefits was a “very conceptual leap” because he assumes that people with brain folate deficiency also have autism.
Cerebrofolate deficiency is “a very rare event, accompanied by symptoms of epilepsy, very severe neurodevelopmental problems, and some of those symptoms can look like autism, but not,” he said.
“We have not thought of one FDA approval in the last 20 years that has such weak evidence,” Mandel added.
Fry, a Phoenix neurologist, estimates that up to a quarter of children with autism have antibodies associated with brain folate deficiency based on his research. Other estimates are much lower. Alycia Halladay, chief science officer of the Nonprofit Autism Science Foundation, has moved the fees from about 10% to 30%.
The research on Rocovorin is small but looks interesting, said former FDA commissioner Dr. Scott Gottlieb.
“It certainly deserves follow-up,” Gottlieb said.
One study found a placebo-controlled trial of over 40 children with antibodies published in Molecular Psychiatry in 2018: about two-thirds of children who got the drug through oral communication 12 weeks later. Others didn’t see the changes. All children had speech disorders and a common type of autism that was not associated with other neurological disorders.
However, Mandel said the results should not be considered evidence.
“They claim they are already finding these very large effects in a specific subgroup of children in a small sample,” he says, adding that there is a need for large-scale trials that establish clear results in advance to verify the results.
Kesselheim said it is important that patients have access to medications that could benefit them, especially when there are unmet medical needs. However, he said there are still many unanswered questions.
“There is no exact test on this,” he said. “What are the low folic acid levels? What is the normal folic acid levels? All of that needs to be resolved.”
Fry said he is currently using two methods to assess whether a child has folate deficiency: inserting the hip into the waist to insert a needle from the spinal cord into the waist, and a developed folate receptor antibody test for pregnant women who are not approved by the FDA to diagnose folate failure in children.
Edward Quadros, a research professor at SUNY Downstate Health Sciences University, is working with Frye, who is studying Leucovorin for autism, saying her parents are already unregulated and are trying drugs that contain dangerous supplement versions.
“We’re giving the FDA at least a quality dosing by getting the FDA to approve it and approving a reputable pharmaceutical company that makes it and sells it,” Quadros said.
