Leucovorin Spike

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger

A release from the University of Michigan:

Leucovorin prescriptions for children spiked after federal officials claimed the drug was an effective treatment for autism during a September 2025 press conference, according to a new Michigan Medicine-led study published in The New England Journal of Medicine.

During the highly publicized event, the United States Department of Health and Human Services announced a plan to update leucovorin’s label to include cerebral folate deficiency, a rare genetic condition that can sometimes include symptoms of autism.

At the same time, federal officials also touted leucovorin’s effectiveness for autism, despite limited evidence supporting that claim.

After the press conference, the number of children aged 0-17 with a filled leucovorin prescription increased 46%, from 4.6 children per 100,000 in the week before the conference to 6.7 per 100,000 during the week of the conference, according to the new research.

"Our findings suggest the press conference may have increased off-label prescribing of leucovorin to children with autism,” said lead author Kao-Ping Chua, M.D., Ph.D., a pediatrician and researcher at University of Michigan Health C.S. Mott Children's Hospital and director of the Susan B. Meister Child Health Evaluation and Research Center.

"This increase is concerning because the effectiveness and long-term safety of leucovorin for children with autism is uncertain."

The authors analyzed a database representing nearly all prescriptions filled in U.S. retail pharmacies.

During 2025, the database included 150,026 leucovorin prescriptions dispensed to 47,394 children.

The weekly number of children with filled leucovorin prescriptions rose from 734 to 5,858 children between the beginning and end of 2025 – a 700% jump.

Much of this increase was driven by the spike in leucovorin dispensing after the press conference, and the largest increases were seen among children ages 6 to 11 and in the southern United States.

By comparison, leucovorin dispensing to adults did not spike after the press conference.

Leucovorin, a decades-old version of Vitamin B9, has mainly been used to counter side effects from methotrexate, a drug used in treating cancer and autoimmune conditions.

A handful of small studies have suggested that leucovorin can help improve some autism symptoms in children, but large randomized clinical trials have not been conducted.

By using a comprehensive national database, the new study builds on earlier research that used smaller databases to assess changes in leucovorin prescribing to children after the press conference.

Concerns about increased off-label use

The new research also showed that there was an increase in leucovorin dispensing to children even before the press conference.

The trend may have been driven by national news coverage featuring compelling patient stories that may have increased interest among some families.

Chua says the rise in leucovorin use among children raises several concerns, including the potential to create false hope for families, displace evidence-based therapies and expose young children to a treatment whose effectiveness and long term safety have not been established.

Other researchers have speculated that increased off-label prescribing of leucovorin may have contributed to ongoing drug shortages that have reduced access for cancer patients who depend on the medication.

"Our findings demonstrate the power of the federal government to influence medical practice," Chua said.

"Given this power, it is important that the government’s messaging about medications is based on rigorous evidence.”

Additional authors: Sijia He, M.S. and Rena M. Conti, Ph.D.

Study Cited: "Leucovorin Dispensing to U.S. Children in 2025,” NEJM.

The Leucovorin Surge

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger.

Rothman JM, Kwan B, Longhurst CA, Jena AB. Rates of Leucovorin Prescriptions for Children With Autism. JAMA Netw Open. 2026;9(5):e2613286. doi:10.1001/jamanetworkopen.2026.13286

Our data suggest that leucovorin prescription rates rose sharply following the September 2025 announcement by White House leaders but began a steadier increase in February 2025, after being stable for 2 years. A recent analysis4 reported increased leucovorin prescriptions in children following the White House announcement. Our study extends these findings by examining a longer observation period and restricting the cohort to children with a prior ASD diagnosis, which reveals that the upward trend in prescribing began months before the announcement and was specific to the population of greatest clinical interest.

A February 17, 2025, CBS Evening News segment titled “Parents say off-label drug helped son with autism speak”6 described a family whose child was diagnosed with autism when aged 2.5 years and was prescribed off-label leucovorin when aged 3 years. According to his mother, he spoke his first word within days of starting the medication, and by age 5 years, he had enrolled in a mainstream kindergarten program. Following the CBS segment, the story received substantial media attention, and Autism Speaks, the largest autism nonprofit organization in the US, highlighted the news on their website on February 25, 2025.7

Our findings suggest that mainstream media information about leucovorin’s potential use in ASD and the 2025 announcement by White House leaders may be associated with substantial increases in leucovorin use in children with ASD. Although no large randomized clinical trials have been initiated to assess the safety and efficacy of leucovorin for ASD, an increasing number of patients are being prescribed the medication. Notably, on March 10, 2026, the FDA approved leucovorin for the treatment of cerebral folate transport deficiency due to confirmed FOLR1 gene variants.8 However, the FDA did not approve leucovorin for ASD. This regulatory decision warrants ongoing surveillance of leucovorin prescribing for children with ASD. This study has limitations, including reliance on prescription-level data without confirmation of medical indication, inability to assess patient-level clinical outcomes, and lack of adjustment for site-level variation in Epic Cosmos participation. The rapid increase in leucovorin use for ASD, the timing of which is associated with otherwise exogenous events, may offer a novel natural experiment to better understand the potential behavioral effects of leucovorin in ASD.

 

RFK Jr. and Leucovorin

 A number of posts discussed Trump's support for discredited notions about autism A September news conference was a firehose of lies.

Dr. Paul Offit:

Supporters of leucovorin point to a study that showed that the drug was effective and safe. On January 28, 2026, the journal that published that study retracted it because of “errors in results and concerns with the statistical analyses.” On March 10, 2026, the FDA backed away from its broad claims of efficacy of leucovorin stating that it would only work in that rare child who had a defect in the FOLR1 gene. For that reason, groups like the American Academy of Pediatrics (AAP), the American Psychiatric Association, the Society for Developmental and Behavioral Pediatrics, the Autism Science Foundation, and several major pediatric healthcare centers don’t recommend leucovorin as a treatment for autism. “The reason the AAP is not broadly recommending leucovorin is because we know that autistic children deserve the same level of evidence to support interventions as anyone else,” said Dr. Kristin Sohl. Once again, RFK Jr. was wrong. And, once again, he failed to apologize for misleading parents.

For many parents, autism can be financially burdensome and emotionally draining. Nonetheless, physicians who are still willing to prescribe leucovorin charge as much as $1,500 for an initial visit. There is nothing more sinister than people who offer false hope to those desperate to do something, anything to help their children. Robert F. Kennedy Jr. continues to use children with autism as a prop to further his anti-vaccine agenda. For that, this opportunist and interloper should be roundly condemned.

Leucovorin Walkback

 A number of posts discussed Trump's support for discredited notions about autism A September news conference was a firehose of lies.

Ariana Eunjung Cha and Rachel Roubein at WP:

Nearly six months ago, federal health officials gathered at the White House with President Donald Trump and vowed to “go bold” on autism. They sketched out plans for what they described as an “exciting treatment” for children with the condition — a decades-old drug, leucovorin, newly recast as a potential breakthrough.

“Hundreds of thousands of kids, in my opinion, will benefit,” Food and Drug Administration Commissioner Marty Makary said at the time.


But the administration is scaling back that vision. FDA announced Tuesday that it will expand approval for leucovorin, but only for a separate condition that some people with autism also have — not for autism itself.

...
“When we first started considering the ability to expand an indication for leucovorin, we did consider broadly whether there was data to support its use in a broader autism spectrum disorder population,” said a senior agency official.


But a systematic review of the literature led the agency to focus elsewhere. The “strongest data,” officials said, were concentrated among patients with the genetic form of cerebral folate deficiency, a condition they estimate affects “less than one in a million” people.
...


The initial press conference in September where Trump and his aides touted the prospect of expanding the drug’s use triggered immediate pushback. The president separately blamed Tylenol for causing autism — a claim without a proven link — and many in the medical establishment questioned the idea of prescribing leucovorin for a much broader population. Professional societies and individual physicians alike warned that the evidence base was thin.

A decades-old drug typically used alongside chemotherapy, leucovorin has been tested for autism-related symptoms in only a handful of small clinical trials in the United States and abroad. Some studies suggested modest gains in speech and behavior. But the data fell far short of the rigorous, large-scale evidence the FDA generally requires before granting approval for a new use.

The largest of the leucovorin-autism studies was retracted by the European Journal of Pediatrics on Jan. 29; after the authors acknowledged some errors, the editors wrote that the publication “no longer has confidence in the validity of the results and conclusions reported in this article.”

Leucovorin Study Retracted

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger.

Trump and RFK, Jr. recently touted leucovorin.

Claudia López Lloreda at The Transmitter:

The largest study to date of leucovorin’s effectiveness for treating autism traits has been retracted because of data inconsistencies and statistical issues, according to a notice posted last week by the European Journal of Pediatrics.

The study included 77 autistic children and is one of only five randomized clinical trials that have tested leucovorin, also known as folinic acid, in autistic people.

“The retraction of this paper removes a significant portion of the already weak evidence supporting the value of folinic acid as a treatment for autism,” Thomas Challman, a pediatrician at Geisinger College of Health Sciences who specializes in neurodevelopmental conditions, wrote in an email to The Transmitter. “Until we have acceptable evidence of safety and effectiveness, folinic acid use as a treatment for autism is not appropriate outside of a well-designed clinical trial.”

Panda, P.K., Sharawat, I.K., Saha, S. et al. Retraction Note: Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr 185, 109 (2026). https://doi.org/10.1007/s00431-026-06769-x

This article has been retracted by the Editor. Following publication, a number of concerns were raised about the data reported in this study directly to the publisher and via PubPeer, in particular that there appear to be errors in the results reported in tables 2 and 3 and concerns with the statistical analyses performed. The authors provided a response to these concerns and identified a number of errors in the reported results. Post publication statistical review confirmed several of the concerns raised with the data and statistical analysis and was unable to replicate the results reported in the article from the dataset provided. The Editor therefore no longer has confidence in the validity of the results and conclusions reported in this article. The authors have been offered the opportunity to submit a revised version of their article to the journal addressing all the concerns raised, which would undergo full peer review.

Curb Your Enthusiasm About Leucovorin

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger.

Trump and RFK, Jr. recently touted leucovorin.

 Jon Hamilton at NPR:

All of this is part of a familiar cycle for Dr. Paul Offit, who 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 yet the next magic medicine to treat autism, in a long line of magic medicines to treat autism that haven't worked," Offit says.

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

"First it was secretin, an intestinal hormone," he says. "Then it was Lupron, chemical castration, antibiotics, megavitamins, nicotine patches, and my personal favorite, which is raw camel's milk."

Leucovorin is likely to find a place on that cautionary list, Offit says, adding that the FDA has failed to protect the public from an autism remedy that "clearly hasn't been well tested to be effective."

...

Decades ago, the drug became a popular treatment for children with Fragile X syndrome, an inherited condition that affects a region of the X chromosome and is a leading cause of autism.

Until genetic tests for Fragile X arrived in the 1990s, scientists used a microscope to look for "fragile" or "broken" regions on the X chromosome. And they found that those abnormalities were easier to see in brain cells grown in a medium low in folic acid (a synthetic form of folate).

"So the very first, and most obvious theory was that Fragile X must have something to do with folic acid metabolism," says Dr. Michael Tranfaglia, medical director of the FRAXA Research Foundation and parent of an adult child who has the disorder and severe autism.

Parents started giving folic acid to their children with Fragile X. When that didn't work, they moved on to folinic acid — leucovorin.

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

Now, Tranfaglia says, leucovorin is back.

"It's not terribly surprising," he says, "because for every supplement and every vitamin you can possibly imagine, someone has proposed some kind of link to autism."

Usually, though, that someone is not running the FDA — the agency that determines whether a drug is safe and effective.

Demand for Leucovorin

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger.

Trump and RFK, Jr. recently touted leucovorin.

Tom Bartlett at The Atlantic:

The theory behind treating autism with leucovorin is that the drug gives autistic kids something they’re missing. Children with autism seem to be more likely than other children to produce an antibody that prevents folate, also known as vitamin B9, from reaching their brain. Because folate plays a role in brain development, some researchers—most notable among them Richard Frye, a doctor who has been prescribing and promoting leucovorin for nearly two decades, and who told me he spoke with leaders in the Health and Human Services Department before the press conference—think these antibodies might hamper the growth of a child’s language abilities. Leucovorin is essentially a massive dose of folate, delivered in a form that can bypass those antibodies.

...

But that theory, which has long been debated in autism subreddits and Facebook groups, hasn’t gained traction among mainstream autism scientists. They point to a 2018 study that found that autistic children and their non-autistic siblings were equally likely to have these antibodies. The clinical evidence for leucovorin’s effectiveness for autistic kids is limited to a handful of small studies that don’t measure the same outcomes. No large, randomized, placebo-controlled trial has ever been conducted. If you want to get the drug for autism, it has to be prescribed off-label, which many doctors refuse to do.

...

Several researchers I spoke with compared the excitement about leucovorin to the enthusiasm for secretin, another drug that was popular as an autism treatment in the 1990s after early promising results. More rigorous clinical trials later showed that it wasn’t effective. [AFH chief science officer Alycia] Halladay said she’s heard from multiple doctors, including her child’s pediatrician, that they’ve been besieged with calls from parents hoping to get a prescription. One doctor in Chicago told me he had received dozens of inquiries.

...

Offline, parents have been calling Frye, the longtime leucovorin doctor, who believes that as many as 1 million kids could benefit from the drug. He mostly treats children with significant language delays, though he says that the drug can sometimes help higher-functioning kids too. Frye was the lead author of a small 2016 study that found that children with autism who received leucovorin showed improvements in verbal communication, compared with those given a placebo; he also recently published a book called The Folate Fix. Ever since the press conference, his office has been inundated with calls and emails from parents who want the drug for their children.

For years, Frye has had a backlog of patients wanting to see him, but the White House announcement, he told me, made an “impossible situation worse.” He already has about 1,000 patients who are taking leucovorin, and he isn’t planning to accept any new ones until 2028. According to Frye, the FDA has asked him to submit an application to conduct clinical trials on leucovorin as an autism treatment, but last week, he told me that “not much is going on at this time.” He guesses those trials will take about two years. In the meantime, parents will be left to experiment with leucovorin on their own.

Leucovorin Update

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger.

Ariana Eunjung Cha at WP:

Pediatrician Kristin Sohl has lost count of how many times parents of children with autism have asked her for a prescription for leucovorin — the drug thrust into the spotlight after President Donald Trump touted it at a White House event this fall.

Since September, despite the rising queries, Sohl has typically told her patients no.

Early clinical trials of the drug showed hints of promise in boosting communication and cognition for some children with autism. But the studies have been small, often just a few dozen participants. Normally, approval by the Food and Drug Administration comes only after years of large-scale testing. But Trump’s pledge to fast-track the drug in September, bypassing that process, has left many doctors on the front lines divided.

“It leaves me as a practicing physician with a lot of unanswered questions,” said Sohl, a professor of pediatrics at the University of Missouri School of Medicine, who has been working in the field of autism for over 20 years.

As interest in the drug surges, Facebook groups devoted to it are swelling in membership, message boards are inundated with questions and Google searches are climbing. Physicians, who typically rely on evidence-based guidelines and clear treatment algorithms, are finding that with leucovorin they must — lacking robust scientific data — improvise. Some are cautiously moving forward with prescribing the drug, but many are still holding off.

At Children’s National Hospital in Washington, D.C., neurodevelopmental pediatrician Sinan Turnacioglu said the hospital convened a meeting of various departments — including those specializing in autism, developmental pediatrics, genetics and psychiatry, as well as primary care doctors — to come up with a systemwide policy. Their conclusion: that they would like to see more robust research before prescribing it.

Leucovorin

A number of posts discussed Trump's support for dubious notions about autism.

The history of autism "cures" is a history of dashed hopes and frequent danger.

Julie Steenhuysen at  The Independent:

A drug endorsed by the Donald Trump administration which allegedly treats against a rare disorder that causes autism-like symptoms has triggered a surge in demand from parents, despite a lack of data supporting its use.

More parents in the U.S. are asking for leucovorin, believing it could unlock speech and social connection in their autistic children.

Pediatricians and specialists caution the science on leucovorin in autistic people as the data is limited and does not support widespread use.

...

“My Facebook feed is flooded with parents swearing that leucovorin works,” said Dr. David Mandell, a professor of psychiatry and autism researcher at the University of Pennsylvania.

...

Mandell and other scientists and doctors say Trump’s endorsement, without requiring large, randomized clinical trials, leaves practitioners facing emotional pleas from families while lacking data, guidance or confidence to prescribe the drug responsibly.

Leucovorin is approved to treat chemotherapy side effects but can be prescribed off-label for autism symptoms.

"It puts physicians in a very tough position because they're being asked to prescribe something that is not evidence-based," said Dr. Shafali Jeste, an autism expert and head of pediatrics at UCLA, who does not prescribe leucovorin despite repeated requests.

From the American  Academy of Pediatrics:

Autistic children, adolescents, and young adults are valued members of our communities, and they deserve access to evidence-based care supported by high-quality research. Autism is a complex neurodevelopmental condition with diverse presentations and no single known cause. Current research points to a combination of genetic and environmental influences. For decades, autistic individuals have been subjected to treatments based on unproven theories—some of which caused harm with little to no benefit. As such, any new intervention must be carefully evaluated for both its potential benefits and risks before being widely adopted.

At this time, the American Academy of Pediatrics (AAP) does not recommend the routine use of leucovorin (folinic acid) for autistic children.

Early, small-scale studies have explored its use—particularly among children with documented cerebral folate deficiency—and some findings suggest potential benefit in carefully selected cases. These preliminary results are promising and have laid the groundwork for further investigation.

However, the current evidence base remains too limited to support specific clinical recommendations. Key questions about who may benefit, what dosing and monitoring are appropriate, and what the long-term safety profile looks like have not yet been adequately answered. Larger, well-controlled clinical trials are needed to determine whether leucovorin is a safe and effective option for the broader autistic pediatric population.

The AAP supports research and innovation that improve the quality of life for autistic children and their families. We also recognize the need for any emerging guidance to be grounded in both scientific rigor and respect for neurodiversity.

Pediatricians and prescribing pediatric care providers, including other physicians, physician assistants, and nurse practitioners, are encouraged to engage in shared decision-making with families who inquire about or request leucovorin, providing clear information about current evidence and potential risks. Autistic children, adolescents, and young adults benefit from access to robust supports and services based on their individual needs. Pediatricians and other pediatric care providers should work with families to optimize recommended services and emphasize continuation of well-established supports and therapies that are beneficial to the well-being of the child. The AAP does not have prescribing guidelines for leucovorin for the indication of autism. If a pediatrician or other physician, physician assistant, or nurse practitioner prescribes leucovorin for a pediatric patient, they should prioritize harm mitigation, closely monitor for adverse effects, and support families in navigating complex therapeutic decisions grounded in compassion, transparency, and scientific integrity.

As the evidence base continues to evolve, the AAP remains committed to reviewing new data and updating this guidance accordingly. The AAP supports continued research into all promising therapies that may improve health and developmental outcomes for autistic children, adolescents, and young adults.

 

Blast Radius from the Trump News Conference

A number of posts discussed Trump's support for discredited notions about autism The Monday White House news conference was a firehose of lies.

Liz Essley Whyte at WSJ:

Health Secretary Robert F. Kennedy Jr.’s team had decided by the beginning of September to tell Americans that acetaminophen, the active ingredient in Tylenol, was a possible cause of autism. But officials were divided over how much emphasis to put on the painkiller and were planning to discuss it as one of many possible causes, people familiar with the matter said.

Doctors that Kennedy had selected to lead key agencies under him—Jay Bhattacharya, Mehmet Oz and Marty Makary—suggested the big story should be leucovorin, a little-known generic drug in which they saw promise for alleviating autism symptoms.


But a meeting with Tylenol’s maker convinced Kennedy to put the emphasis on acetaminophen.

...

The result was the explosive White House news conference Monday, when the president laid out in no uncertain terms that pregnant women should avoid Tylenol (“Don’t take it”), despite the mixed evidence linking the painkiller to autism. The event stunned many of the nation’s doctors and public health experts, some of whom called Trump’s actions dangerous.

In the end, Trump and Kennedy went with their own messaging instincts, and leucovorin became more of an afterthought. Trump didn’t mention it by name at the press conference, giving only a passing mention to a new label for “an existing drug” that may help alleviate autism symptoms. “That’s one of the things that I’m very, very happy about,” he said.

The elderly Trump struggled to pronounce "acetaminophen" and probably did not want to try "leucovorin."

“Ah-ced-uv — well, let’s see how we say that.”

— Trump butchers pronunciation of acetaminophen while announcing his admin is falsely linking it to autism pic.twitter.com/5rwUnDYMCC

— The Recount (@therecount) September 22, 2025

Heidi Ledford at Nature:

According to Martin Makary, head of the US Food and Drug Administration (FDA), the drug leucovorin will help “hundreds of thousands of kids” with autism. But a day after Makary praised leucovorin’s powers at a White House event, some specialists are warning that the science to warrant Makary’s enthusiasm is far from solid.

Those researchers say that the drug’s efficacy has not been established, that scientists don’t know how much of the drug to give or how people should take it, and that safety data in children are lacking. According to the FDA’s current plans, leucovorin will be available to only a minority of autistic people.

All of this has led to widespread confusion, say clinicians, who also worry about the expectations created by Makary and other officials in the administration of US president Donald Trump.

“I’ve heard from a lot of families,” says psychologist Catherine Lord at the University of California, Los Angeles. “The major thing they say is, ‘What is this? What do we do?’”

“I don’t want to get everyone’s hopes up that this is a magic cure,” says Rebecca Schmidt, a molecular epidemiologist at the University of California, Davis. “It’s not for everybody.”

 Jon Hamilton Yuki Noguchi at NPR:

"It's a bit tough to get really, really excited about what they would call a 'miracle drug,'" says Shelby Smith, a Dallas mother of a 6-year-old autistic son who is considered non-verbal. Parents, she says, are accustomed to being peddled vitamins, supplements, and even fake therapies. "It's always something being pushed," Smith says, which can at times then make symptoms worse.

...

Given the lack of conclusive evidence, many doctors and researchers think it's too soon to be suggesting leucovorin as a treatment.

"They are jumping the gun a little bit," says Alycia Halladay, a biopsychologist and chief science officer of the Autism Science Foundation.

The Coalition of Autism Scientists issued a statement saying, "It is premature to claim that leucovorin is an effective treatment for autism."

Medical and scientific groups say they'd like to see the same sort of research on leucovorin that the FDA requires of other drugs: two large, rigorous clinical trials showing that the product lives up to its label.