What science says about leucovorin, the drug Trump touted for autism

By Brenda Goodman, CNN

(CNN) — Six months ago, 4-year-old Jose Morales-Ortiz was struggling to say two-word sentences. Jose has severe autism, and he couldn’t have a conversation and wouldn’t answer to his name most of the time — all things that kids his age are supposed to be able to do.

By the end of June, though, it was clear something had changed.

Keith Joyce, his guardian, said Jose was able to tell him about the other kids at school and answer follow-up questions.

“The first time I realized I’d had a conversation with him, I cried,” said Joyce, 60, of St. Paul, Minnesota, who has been raising Jose since he was a baby and calls him “my guy.”

Joyce credits these milestones to leucovorin, a drug currently approved by the US Food and Drug Administration to ease the side effects of certain kinds of chemotherapy.

On Monday, FDA Commissioner Dr. Marty Makary said the agency would speed a label change for leucovorin to help kids with folate deficiency in their brains — something he said could cause developmental delays and features of autism, including difficulties with communication, sensory processing and repetitive behaviors. With the label change, state Medicaid programs will be able to cover it, and the administration has pledged to conduct more research on it as a therapy.

“This gives hope to the many parents with autistic children that it may be possible to improve their lives,” President Donald Trump said at Monday’s news conference. “That’s one of the things that I’m very, very happy about.”

At the same briefing, Trump also made unsupported claims about the painkiller Tylenol as a cause of autism and cautioned parents about getting too many vaccines for their kids.

Trump’s comments sparked widespread concern and criticism from many in the autism community. But there’s some curiosity about a new use for the old drug, too.

“A much higher standard of science would be needed to determine if leucovorin is an effective and safe treatment for autism,” the Autism Science Foundation said of the FDA’s announcement. The group said it doesn’t currently recommend the drug as a treatment for autism based on existing evidence, but “we welcome additional investigation into leucovorin.”

Low folate levels in the brain

The theory behind leucovorin is that it treats a condition called cerebral folate deficiency, or low folate levels in the brain. Folate is a B vitamin that’s critical for neural development.

Pregnant women take the synthetic form, folic acid, in prenatal vitamins. Folic acid is also used to fortify flour and grain products, to help prevent neural tube defects like spina bifida in the womb.

In 2005, a pediatric neurologist in Germany discovered that some children with symptoms of autism had normal folate levels in their blood but low folate levels in their brains. These children also made antibodies – specialized Y-shaped proteins – that blocked the receptors, or gateways, that carry folate into the brain.

In a subsequent study, 25 of 28 children with cerebral folate deficiency made these antibodies, while none of 28 typically developing children had them. The study was published in the New England Journal of Medicine.

The German doctor worked with a cell biologist at SUNY-Downstate named Edward Quadros who had developed a blood test called FRAT, for Folate Receptor Autoantibody Test. That test has since been licensed to a private lab, and doctors can order it for about $300.

Dr. Richard Frye, a pediatric neurologist in private practice in Phoenix, Arizona, was intrigued by the research and began testing kids who came through his clinic.

“We showed that about 75% of the kids with autism have this folate receptor alpha that blocks the ability of folate to get into the nervous system,” Frye said. “And we treated them with leucovorin and showed that their language improved, their verbal communication improved.”

In a clinical trial published in 2013, Frye found that one-third of treated children saw moderate to much improvement compared with a control group of children who were on a waiting list for this therapy, “mostly in communication, verbal communication, expressive speech, receptive language and such,” he said.

Frye was able to repeat those findings in another study published a few years later. His results have been confirmed in small clinical trials in France, India, Singapore, China and Iran.

Frye is still cautious, though.

“There’s no autism pill,” he said. “And there’s no one-size-fits-all. The one thing we know about autism is that it’s very complicated, and kids need to be taken individually.”

Joyce, Jose’s guardian, first read about leucovorin in December, but there wasn’t much to go on — just a handful of small studies.

He said he’s constantly on the lookout for new science or medicine that can help Jose, who is in school and specialized therapy for 65 hours a week, but he was wary. It took three months before he even asked Jose’s doctor about the drug.

“I completely believe in the whole scientific method,” Joyce said, and there simply wasn’t enough science to support its use for children with autism.

But it’s also a very safe medicine. It’s a high dose form of vitamin B9, so the body flushes out what it doesn’t use.

Joyce eventually thought it might be worth a trial but couldn’t get an off-label prescription for Jose until a specialized developmental pediatrician who Jose sees, who had just been to a conference where it was discussed, agreed it had promise.

Because the medication is pretty safe, they decided to forgo the antibody test – which wasn’t covered by their insurance – and just give the drug a try.

Jose had a baseline speech assessment in April so they would be able to measure whether the medication was helping. Within a couple months, though, the changes were so noticeable, nobody felt like the follow-up test was necessary.

“We went in for a follow-up four months later, and the changes were so dramatic,” Joyce said. The doctor was blown away. “She was just like, ‘Wow!’”

A drug with little evidence and some risks

There have been no large placebo-controlled trials of leucovorin for autism, as would typically be required by the FDA before it approves a drug. In some cases, the effects – which were measured over a few weeks or months – seem modest, said Dr. David Mandell, who directs the Penn Center for Mental Health at the University of Pennsylvania Perelman School of Medicine.

Mandell says the most rigorous study, from China, “finds a one-point change, on average, in on a 60-point scale in favor of leucovorin. So like a tiny, really not clinically significant change.”

Still, Mandell agrees that the medication is pretty safe. The most common side effects in kids are stomach issues like nausea, vomiting, diarrhea and loss of appetite. Children with autism may already be prone to these kinds of issues, so he says that needs to be watched.

More seriously, he said, kids with autism who also take certain medications for seizures may see an increase in those seizures if they take leucovorin. The use of this medication needs to be monitored by a doctor.

Frye also said leucovorin can also intensify hyperactivity and behavioral issues.

That happened to a degree with Jose, Joyce said. “He’s definitely more hyper and more active than he was, but it’s within tolerable limits.”

For a while, it also made daily life overwhelming.

At soccer practice, for example, Jose would go out onto the field but come off five minutes later and not be able to re-engage.

“Our theory is that his world grew so big, so fast, he was having a problem digesting it,” Joyce said, adding that it doesn’t happen so much anymore.

In a news release Monday, the FDA said it had conducted its own review of scientific evidence for leucovorin and concluded it was enough to change the label of the drug to indicate that it could help children with low levels of folate in their brains.

“Children are suffering and deserve access to potential treatments that have shown promise. We are using gold standard science and common sense to deliver for the American people,” Makary said in a statement.

The agency has not made its scientific review available to the public, however.

“The FDA will release its review of the data and will publish a manuscript in the near future,” said Andrew Nixon, director of communications for the US Department of Health and Human Services, in a statement to CNN.

He said the FDA also intends to issue updated prescribing information for the drug that will include “the essential scientific information needed for the safe and effective use of these drug products for the treatment of cerebral folate deficiency in adults and pediatric patients.”

A rush to find folinic acid

From his own review, Mandell at the University of Pennsylvania said that the evidence behind leucovorin for autism doesn’t rise to the level of “gold-standard science” and that the approval for autism is dangerous on a couple of levels: First, because it sets a dangerous precedent for drug approvals, and second, because it could be giving false hope to desperate families.

If the FDA grants a new indication for leucovorin, as it has said that it intends to do, it would be the first time that’s happened for a drug with such a small amount of evidence behind it, said a former FDA official who declined to be named because they feared retaliation from the Trump administration.

“The hypocrisy of what’s going on here, of saying that you want to use gold-standard science and then using the lowest standard of junk science, I mean, this is a really low standard to make a major sweeping change. It should not be lost on people,” the official said.

The announcement of the drug approval in a high-profile White House news conference may also push people to experiment on their own, without guidance from a doctor or the FDA.

In May, Joyce started a Facebook group called “Leucovorin for Autism” to share his research into leucovorin and answer questions in case other parents wanted their children to try it. Since the White House announcement, it has gained more than 10,000 members.

He has noticed a worrying trend: people rushing to buy over-the-counter folinic acid supplements, which are different from the prescription version and contain only micrograms of its active ingredient.

In clinical trials, children were dosed leucovorin based on their weight but could take up to 50 milligrams per day.

Some of the supplements “have as little as 800 micrograms (0.8 milligrams) of folinic acid, leading to having to take a lot to get a therapeutic dose,” Joyce said.

The supplements may also have additives or extra ingredients that kids are getting in big doses, which could cause problems, he added.

The group has a rule, Joyce said: no talking about the causes of autism. He said he spent part of the day on Tuesday deleting posts and mean comments about the painkiller Tylenol.

“I’m trying to ignore the source and thankful for the attention,” he said.

He’s also hopeful for Jose, who has had improvements in communication and in learning since starting the drug.

Before, when Joyce would take Jose to a Minnesota Loons soccer game, the child would hyperfocus on the field, rarely looking up to notice the crowd around him.

But this summer, Jose began to pay attention to the fans’ chants during the game and watched when people waved their scarves.

“I was just like, ‘Wow, he knows the world’s here,’ ” Joyce said.

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