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Caroline Connor's concerns about her son Mason's development began around his first birthday, when she noticed he wasn't talking or using any words. Their pediatrician didn't seem worried, but the speech delay persisted. At 2 and a half, Mason was diagnosed with autism.

The Connors went on a mission, searching for anything that would help.

"We just started researching on our own. And that's when my husband Joe came across Dr. Frye in a research study he was doing," Caroline said.

Dr. Richard Frye, a pediatric neurologist, is one of many doctors searching for treatments that can help kids with autism. He's studying leucovorin, an inexpensive, generic drug derived from folic acid, also known as folate or vitamin B9. Leucovorin is currently prescribed to ease the side effects of cancer chemotherapy. Pregnant women are prescribed multivitamins with folic acid to prevent neural tube defects. The neural tube develops into the brain and spinal cord.

Leucovorin isn't a cure for autism, but "It could really have a substantial impact on a very good percentage of children with autism," Frye said

The theory behind the drug's use for autism postulates that some children have a blockage in the transport of folic acid into the brain that potentially contributes to some of the neurological problems associated with the disorder. Leucovorin bypasses that blockage and can help some autistic kids improve their ability to speak. Three randomized controlled trials of leucovorin to treat autism have shown positive effects on speech. However, few currently prescribe leucovorin for autism.

The science of cerebral folate deficiency[b]
Cerebral folate deficiency (CFD), or a deficiency of folate in the brain, was first described by Dr. Vincent Ramaekers. Ramaekers found that some kids with neurodevelopmental disorders had normal levels of folic acid in the blood, but low levels in their spinal fluid. He then teamed up with Dr. Edward Quadros, who had been studying how an autoimmune disorder might lead to a blockage of folic acid transport into the brain. Ramaekers and Quadros found that autoantibodies against the folate receptor alpha (FR⍺), which transports folic acid from the blood into the brain and the placenta, might cause abnormal fetal brain development and some autism spectrum disorders.

One study found that over 75% of children with autism spectrum disorder had FR⍺ autoantibodies, as compared to 10-15% of healthy kids. There is evidence that there's a familial or genetic predisposition for developing FR⍺ autoantibodies. While environmental and immune system dysregulation may also play a role, there's no evidence to suggest that vaccines cause the development of FR⍺ autoantibodies.

The brain has a backup system to the FR⍺ known as the reduced folate carrier, or RFC. The RFC isn't as efficient a transporter as the FR⍺, but it can transport leucovorin, also known as folinic acid, into the brain. Enzymes in the brain convert leucovorin into the active form of folate.

Treatment with leucovorin increases brain levels of folate in kids with CFD. In one study led by Frye, one-third of such kids experienced improvement in their speech and other behavior when treated with leucovorin. Two randomized trials conducted in France and India showed similar results. A folate receptor autoantibody test (FRAT) is available to help identify which children may most likely respond to leucovorin treatment.

Frye notes that there are many nuances to treating CFD with leucovorin, including the addition of adjunctive treatments to optimize mitochondrial function.

The side effects associated with leucovorin are mild. Some children experience hyperactivity during the first few weeks of treatment, but that typically subsides within a month or two. A similar pattern is seen with other B vitamins.

[b]Mason's "little bottle of hope”

Mason Connor's first words came just three days after he started taking leucovorin at the age of 3, his parents say.

Doctors can currently only prescribe the drug for autism off-label, which means repurposing a drug approved for one condition to treat another.

"We've done the science, and the next step is that we want to get more funding so we can actually get it FDA approved," Frye said.

But there's one big problem.

Leucovorin's an old drug and you can get it for a very low price. So nobody is going to make a lot of money on it. So there's no reason for them to invest," Frye said.

All of the studies on leucovorin to treat CFD and autism spectrum disorder have been relatively small. Although leucovorin is FDA-approved for other purposes, larger randomized, placebo-controlled clinical trials of leucovorin to treat autism spectrum disorders will be necessary to obtain specific FDA approval for that purpose.

An estimated 20-30% of all prescriptions in the U.S. are off-label, according to nonprofit Every Cure. This is often done as there are more than 14,000 known human diseases with no FDA-approved drugs to treat them. Drugs like leucovorin are frequently used off-label because doctors believe that the benefits outweigh the risks. However, there is often limited awareness about these treatments, so they may go unused.

Stunned families reveal how their children's autism symptoms were REVERSED by cheap 'life-changer' drug
READ MORE: Potential autism breakthrough as boy's symptoms are reversed
By EMILY JOSHU STERNE HEALTH REPORTER FOR DAILYMAIL.COM

Published: 20:18, 3 March 2025 | Updated: 21:45, 3 March 2025

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When Ryan Baldridge Jr was diagnosed with autism at age four, his family were told he may never speak coherently.

Then a year later, miraculously, he told his dad: 'I love you.'

Soon after, teachers in school were calling home, amazed by how rapidly Ryan began stringing together full sentences and asking everyone around him how their day was.

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Ryan, now eight, went from 'basically non-verbal' in kindergarten to now reciting his lines for the upcoming school play.

Speech therapy had yielded little progress until November 2023, when Ryan started taking leucovorin, a cheap medication derived from folic acid that works by unblocking pathways in the brain responsible for language.

Two weeks later, he was talking to his parents in full sentences.

Mr Baldridge, with tears in his eyes, told DailyMail.com: 'I had never experienced an unprompted "I love you" from my son in five years of his life.'

Ryan, from Missouri, now attends typical school with the help of an aide and dreams of being a pilot when he grows up.

Ryan Baldridge Jr (pictured here), an eight-year-old with autism, was almost completely non-verbal when he started taking leucovorin. Two weeks later, he told his father he loved him
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Ryan Baldridge Jr (pictured here), an eight-year-old with autism, was almost completely non-verbal when he started taking leucovorin. Two weeks later, he told his father he loved him

Dr Richard Frye, a pediatric neurologist at Rossignol Medical Center in Arizona, is one of 50 doctors in the US prescribing leucovorin to autistic children to improve their speech
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Dr Richard Frye, a pediatric neurologist at Rossignol Medical Center in Arizona, is one of 50 doctors in the US prescribing leucovorin to autistic children to improve their speech

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Ryan is one of the dozens of autistic patients whose symptoms have drastically improved after being prescribed a drug usually used to help cancer patients with chemotherapy side effects.

Dr Kathleen Schnier, whose 12-year-old son Nathaniel takes leucovorin, told this website 'you can't cure autism,' but likened the drug to the closest thing children like her son have to a cure.

Both families' children are patients of Dr Richard Frye, a pediatric neurologist at Rossignol Medical Center in Arizona who is working to understand how leucovorin can bypass chemical blockages in the brain and improve speech.


'That man is a life-changer for us,' Mr Baldridge said.

Leucovorin is a prescription medication derived from folic acid (also known as vitamin B9), a vital nutrient that helps synthesize DNA and replicates and repairs cells throughout the body.

Its naturally occurring form, folate, is found in foods such as leafy green vegetables, beans, and lentils.

Research suggests up to three in four autistic children don't get enough folate supply to their brain, causing delays in speech and behavioral issues.

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Dr Frye's team is now testing a new liquid form of leucovorin that could be FDA approved in three to five years for children with autism who have cerebral folate insufficiency, or a lack of folate in their brain.

Dozens of his patients have seen 'substantial improvements' since starting the drug, and most have experienced either mild or no side effects at all.

While the findings so far are promising, other experts have cautioned that the research on leucovorin and autism is still early.

Mr Baldridge told DailyMail.com he and his wife, Kim, came across Dr Frye's research after they 'refused to accept' Ryan would be non-verbal.

In January 2023, Ryan tested positive for cerebral folate insufficiency via a spinal tap, a test usually meant to look for neurological conditions like meningitis.

Dr Frye's research suggests the insufficiency is due to autoantibodies in children like Ryan's blood, which mistakenly target and attack the body.

In an estimated that in three in four autistic children, these autoantibodies block a protein called folate receptor alpha, which transports folic acid from the blood to the brain. Without folate, brain cells responsible for language can't function normally.

Ryan (pictured right with his younger brother Grayson), started speaking in full sentences and having conversations with his parents and teachers a few months after starting leucovorin. He has had no side effects
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Ryan (pictured right with his younger brother Grayson), started speaking in full sentences and having conversations with his parents and teachers a few months after starting leucovorin. He has had no side effects

Ryan, pictured here with his family, dreams of becoming a pilot for Southwest Airlines. His parents told DailyMail.com that starting next year, he should no longer need to have an aide in school
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Ryan, pictured here with his family, dreams of becoming a pilot for Southwest Airlines. His parents told DailyMail.com that starting next year, he should no longer need to have an aide in school

Ryan had what is known as echolalia, the ability only to repeat words his parents said back to them, rather than form sentences on his own.

Within days of starting twice-daily liquid dose of leucovorin, Ryan's echolalia had completely disappeared.

For the first time, he started speaking in full simple sentences unprompted and making eye contact with his parents and teachers.

It was just two weeks before he was telling his father he loved him.

Within six months, he was able to have back-and-forth conversations.

Teachers who were unaware Ryan was on leucovorin started calling home shocked about the progress, claiming he was 'blossoming' in the classroom.

Because he could now speak, he started playing with other kids at recess for the first time.

He now has a best friend and even a 'girlfriend,' he tells his parents.

Ryan even has a role in the school play this month and can recite his lines 'with enthusiasm.'

This school year, Ryan's parents were able to enroll him in a traditional school setting for the first time. He currently has an aide in his classroom to help keep him on task, but teachers believe if his progress continues, he won't need any assistance next year.

Mr Baldridge said: 'It was like an explosion of improvement all happening so quickly. Now you can't shut him up. He's doing unbelievable.'

Ten-year-old Meghan Dumesnil (pictured here) was diagnosed with autism as a preschooler after having 'very delayed speech.' She has had 'dramatic' improvements since starting leucovorin
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Ten-year-old Meghan Dumesnil (pictured here) was diagnosed with autism as a preschooler after having 'very delayed speech.' She has had 'dramatic' improvements since starting leucovorin

Meghan, pictured here with her older brother Alex, comes from a bilingual family, so her parents assumed at first that could have caused her speech delays. She now understands French but only speaks English
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Meghan, pictured here with her older brother Alex, comes from a bilingual family, so her parents assumed at first that could have caused her speech delays. She now understands French but only speaks English

When Meghan Dumesnil's speech started falling behind her peers', her parents assumed it may have been due to their bilingual household.

Sebastien and Marie Dumesnil had moved to Arizona from France several years prior and spoke both French and English at home to Meghan and her older brother Alex.

But by the time she was three years old, Meghan could only say a handful of words in either language. Like Ryan, she also had echolalia.

At age four and a half, she was diagnosed with autism and enrolled in speech therapy. Her family also started only speaking English to her at home.

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In 2020, when Meghan was six, Mrs Dumesnil came across Dr Frye's research on leucovorin in a parent Facebook group. 'It looked very legit,' she told DailyMail.com.

That November, Meghan was enrolled in one of Dr Frye's double-blind clinical trials, meaning neither the families nor the researchers knew which participants were on leucovorin and which were on a placebo.

Mrs Dumesnil said: 'We didn't know if she was either on leucovorin or the placebo, and we'll never know, but we started seeing changes within a few days.

'We're pretty certain she was on leucovorin because it was pretty dramatic.'

Meghan's speech therapists and teachers, who didn't know she was in the trial, told the Dumesnil's that for the first time, she was suddenly engaging in conversations and 'building sentences in a more proper way.'

'We noticed the interactions were a lot more constructive. She was actually answering questions and telling us and her therapists and anyone around her what she liked or disliked. She was expressing her needs,' Mr Dumesnil said.

'It just improved her quality of life just to have those useful conversations.'

After the clinical trial ended, Meghan started taking two leucovorin pills twice per day.

Since taking leucovorin, Meghan can now have conversations with her parents and teachers and play with other kids
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Since taking leucovorin, Meghan can now have conversations with her parents and teachers and play with other kids

The above is one of Meghan's recent drawings
One of Meghan's recent drawings is pictured above
The above images are examples of Meghan's recent artwork. Her parents told DailyMail.com she's a talented artist and that they hope she can make a career out of it one day

Now 10, she is enrolled in a private school targeted toward autistic children, and since taking leucovorin, her teachers have noted her reading, math, and language skills have all drastically improved, and she is now just one grade level behind her typically developing peers.

She also has started playing with other kids at recess, whereas before she preferred to isolated.

The Dumesnils said that while it's difficult to know which improvements are directly tied to leucovorin and which may be from Meghan's other therapies, she does seem 'more flexible' than many of her autistic peers.

While many autistic children struggle with aversions to certain foods and textures, Meghan 'is always happy to eat' and is not as picky.

She is also not as sensitive to loud noises as many of her peers and is able to participate in sports and go to the movies with noise-cancelling headphones.

Meghan's parents now hope she will continue fostering her love of drawing and animals, as they believe she now could have a career in one of those industries one day.

Mrs Dumesnil said: 'I think that's the most exciting part. Pretty much anything is possible.'

Nathaniel Schumann (pictured here), 12, would only speak two to three words at a time before starting leucovorin, and they would only be related to something he wanted
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Nathaniel Schumann (pictured here), 12, would only speak two to three words at a time before starting leucovorin, and they would only be related to something he wanted

Nathaniel, pictured here with his older sister Caroline, started talking back to his parents and teachers and holding conversations with them six weeks after starting leucovorin
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Nathaniel, pictured here with his older sister Caroline, started talking back to his parents and teachers and holding conversations with them six weeks after starting leucovorin

Like Meghan, Nathaniel also had limited language as a result of his autism, which he was diagnosed with at age three.

He could only speak two or three words at a time about something he wanted. This could mean 'hot dog' or 'tummy rumbling' if he was hungry.

When he was eight years old in 2021, Dr Schnier and her husband Paul Schumann took Nathaniel to see Dr Frye, who found he had cerebral folate insufficiency.

Dr Frye enrolled Nathaniel in one of his double-blind clinical trials. It's unclear if it was the same study Meghan was enrolled in.

Dr Schnier, who works as a provost at Colorado Technical University, told DailyMail.com: 'It was pretty quick when I realized he was actually on the drug itself.'

About six weeks after the trial started, Nathaniel suddenly started responding to people and being able to hold a conversation.

And for the first time, he could tell his parents and older sister, Caroline, if he didn't like something that had done, even going back years earlier.

Dr Schnier said: 'He would start telling us, "I didn't like when you wouldn't let me have that ice cream cone" or to my daughter, "I didn't like when you wouldn't let me play with your friends," but we didn't know if it was last week or five years ago.

'It was always in there but he was never able to let us know about it.'

Nathaniel also started getting 'very specific' about his food preferences, finally able to tell his parents 'I don't like that type of food.'

'His language exploded entirely with the leucovorin,' Dr Schnier said. 'By a year, he was a completely different conversationalist.'

When the family saw Dr Frye a year later and asked how he felt about his progress, Nathaniel told him, 'The TV in my brain I can say with my mouth now.'

Dr Schnier admits, however, that Nathaniel's improvements may not solely be due to leucovorin.

The now 12-year-old has been in speech therapy, horse therapy, and applied behavioral analysis (ABA) therapy - which uses positive reinforcement and repetition to autistic children's behavior - since he was diagnosed, which may have also helped his speech develop.

Dr Schnier said: 'It is a combination of therapies as well as leucovorin, but when leucovorin was added to the mix, that's when we noticed the change.'

Nathaniel is pictured here with his family. His mother told DailyMail.com that after starting leucovorin, he would suddenly tell his family if he didn't like something that happened weeks, months, or years prior
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Nathaniel is pictured here with his family. His mother told DailyMail.com that after starting leucovorin, he would suddenly tell his family if he didn't like something that happened weeks, months, or years prior

Nathaniel, pictured here, is now singing and participating in plays after his family was told he would never speak more than a handful of words at a time
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Nathaniel, pictured here, is now singing and participating in plays after his family was told he would never speak more than a handful of words at a time

Since the clinical trials ended, Nathaniel has taken four leucovorin pills daily, with the dosage gradually increasing as he gets older. He still does speech and ABA therapy as well.

Dr Schnier told this website that since Nathaniel started on leucovorin, he has gained a sense of 'independence and agency' and has had 'tremendous' improvements making friends.

'He is a very socially motivated child and he's very empathetic. If a kid is upset or sad, before he would cry. We just assumed he didn't like the loudness of it, but we later found out if was because he was upset for them,' she said.

'So now if he sees another child crying, he'll go to them and say, "Why are you upset? Do you want a hug? Are you going to be okay?"

'He doesn't have to cry about it because he's capable of empathy. He's capable of going up to them and talking to them about it.'

Not only is Nathaniel speaking, but he's also singing and participating in musicals alongside typically developing children.

Dr Schnier also believes her son now has a better chance of living on his own one day, holding down a job, or getting married now that his speech has improved.

She said: 'He's going to do amazing things because he has the ability to communicate. It's opened up all of his doors.

'I'm not saying he's going to win the race, but he's going to complete the race.'