Dr Richard Frye has spent the better part of 20 years trying to understand how a cheap drug could ease certain behaviors of autism.

Across the US, there are about 50 doctors who prescribe the drug leucovorin, costing $2.50 per pill, to autistic children. This medication is derived from folic acid, a key nutrient given to pregnant women to promote proper brain development in fetuses.

Leucovorin is traditionally used to aid cancer patients in protecting their cells from the harmful effects of chemotherapy. However, it can also be prescribed off-label to children diagnosed with autism.

The drug has been shown to enhance language pathways in the brain, enabling many previously non-verbal children to speak for the first time when used daily.

Recently, the FDA announced they have begun the approval process for leucovorin to be used in individuals with cerebral folate deficiency (CFD), a condition where the brain struggles to absorb folate, which is a natural form of folic acid found in foods such as leafy greens.

Current studies indicate that around 75% of autistic individuals may have CFD, which could be responsible for some of the speech and behavioral issues observed in autism.

Dr. Frye, a pediatric neurologist at Rossignol Medical Center in Arizona, reports significant improvements in autistic children taking leucovorin, with some non-verbal children starting to speak in full sentences within weeks, and showing reductions in aggression and anxiety.

He told the Daily Mail he is in talks with the FDA about developing a liquid form of leucovorin just for children and adults with autism, and was ‘surprised’ by the agency’s announcement about initiating approval for a pill form. 

Dr Richard Frye, pictured here, is one of 50 doctors in the US prescribing leucovorin to autistic children to improve their speech and behavioral issues like irritability

FDA commissioner Dr Marty Makary (pictured above with President Trump and Robert F Kennedy Jr) announced Monday the FDA would initiate approval for leucovorin

He told this website while he is excited health agencies are devoting attention to leucovorin, he cautioned that it’s ‘not an autism pill,’ and that autistic people would likely need to pair it with other standard measures like speech, occupational and applied behavioral therapy. 

The FDA said last month it will initiate approval, which means it is in the process of being reviewed and is not fully available to the public for autism. This process can take several months to years. 

It is expected to be covered by government-subsidized insurance programs like Medicaid, and administrator for the Center for Medicare & Medicaid Services Dr Mehmet Oz said Monday that private insurance companies ‘are likely to follow.’ 

Dr Frye said: ‘I think it’s really terrific that the administration has recognized that there is a potential treatment for autism. We’ve gone 20 years without research really concentrating in any way on treatments, just mostly genetics and behavioral issues.

‘[Leucovorin] is potentially a life-changing treatment for kids with autism. I’ve been researching it for 20 years, and I think we have some good evidence that it’s a very promising treatment.’

Dr Frye also cautioned against President Donald Trump’s recent advice for pregnant women to avoid taking acetaminophen during pregnancy due to an increased risk of autism, slamming the statement as ‘absolutely ridiculous’ and urging women to talk to their doctors. 

Leucovorin is 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.

Folic acid is an essential part of prenatal vitamins as it helps with healthy brain and neural tube development.  

Research on leucovorin dates back to the early 2000s, during which scientists Dr Vincent Ramaekers of University of Liege in Belgium and Dr Edward Quadros of SUNY Downstate University of New York, took blood and spinal fluid samples from autistic children and found that while they had normal folic acid levels in their blood, there was much less in their cerebrospinal fluid, which protects the brain and spinal cord.

Leucovorin is typically given to cancer patients to help protect their red blood cells from chemotherapy. However, research suggests it may clear chemical blockages in autistic children’s brains, improving their language skills

This suggested that something was blocking folate’s absorption by the brain.

The researchers also found 75 percent of autistic children had autoantibodies in their blood, a type of antibody that mistakenly targets and attacks the body’s tissues and organs.

These autoantibodies are known to block a protein called folate receptor alpha, a protein that transports folic acid from the blood into the brain and placenta.

Folic acid is a precursor to DNA and RNA, which are needed to help replicate a cell’s genome, a set of instructions that help cells function properly. This is why most prenatal vitamins contain folic acid.

Research suggests that leucovorin may clear chemical blockages in the brains of autistic children, and this contributes to improving their language skills

But unlike other forms of folate, such as those in vitamin supplements, leucovorin is able to cross the blood-brain barrier, a semi-permeable layer lining the inner surface of blood vessels in the brain that protects it from potentially damaging substances in the blood.

This means it can directly penetrate the brain and have a direct effect, which Dr Frye notes is why it’s been found to be so effective.  

In a recent trial, researchers found that after four months on leucovorin, autistic children on the medication ‘had significant improvements in language, particularly verbal communication, expressive language, and receptive language.’

President Trump is pictured Monday during his announcement alongside Robert F Kennedy Jr

Dr Frye noted there have been five double-blind studies on leucovorin, meaning both participants and researchers did not know if a person received the drug or a placebo. They have included about 250 children total. 

‘That is the equivalent to the number of patients that were used to approve the currently approved drugs for autism,’ he said, which are the antipsychotic medications called risperidone and aripiprazole.

He estimates leucovorin has helped around 70 percent of the autistic patients who have taken it.

Dr Frye said: ‘The effect is robust. Depending on how you slice autism and how you use the drug, it seems to work. However, I have my concerns.’ 

The FDA also said in its announcement that it has initiated approval for leucovorin calcium tablets, which could pose issues with autistic patients, many of whom have trouble swallowing pills and coping with the texture.

Some parents are able to crush a pill up and mix it into a drink for their child, but for kids only drinking water, they may still notice the drug and refuse to take it. 

‘[Pills] are kind of a no-go for a lot of kiddos,’ Dr Frye told this website. ‘The product we’re working on, its indistinguishable from water, so we’ve already had experience where we’ve found that we can give it to those kids that won’t drink anything else.’ 

FDA’s approval could still take several years, as the pill’s manufacturer may request additional safety trials. It’s also still unclear what the optimal dose is and who exactly may qualify for the treatment. 

Additionally, a formal diagnosis of CFD can only be confirmed with a lumbar puncture to measure the amount of folate in the cerebral spinal fluid. Though the procedure is generally safe, in rare cases, it can lead to bleeding in the spinal canal or infections.

Nathaniel Schumann (left), 12, would only speak two to three words at a time before starting leucovorin. Now, he can speak in full sentences. And 10-year-old Meghan Dumesnil (right) has seen ‘dramatic’ speech improvements since starting the drug

And while leucovorin may improve speech and other behaviors in some autistic people without additional therapies, it is not a cure for the condition. It often also needs to be used alongside other therapies and medications like risperidone and aripiprazole.

Dr Frye said: ‘It’s not the autism pill. There is no autism pill, and it has to be used in conjunction with other treatments and has to be used at the right time.’

He also noted many autistic children have other conditions that need to be addressed as well, such as sleep disorders, epilepsy, ADHD, anxiety, depression and gastrointestinal issues like acid reflux. 

These may occur due neuron damage that affects brain function, disruption of their sleep cycle and alterations in their gut microbiome. 

Dr Frye encouraged parents with autistic children or autistic adults who are curious about leucovorin to contact their doctor or ask for a referral to physicians who are familiar with the treatment. 

There are only about 50 doctors nationwide prescribing it off label for autism, including Dr Frye, but he noted he is working on webinars and other resources to educate more doctors. 

Dr Frye also noted that while more research is needed on acetaminophen’s, sold under the brand name Tylenol, impact on autism risk, Trumps suggestion that ‘there’s one thing causing autism is absolutely ridiculous’ (stock image) 

In his announcement last month, Trump also declared pregnant women should avoid taking acetaminophen, sold under the brand name Tylenol, over links to autism in children.

Like much of the scientific community, Dr Frye is skeptical. 

He told this website: ‘The data is weak, but it looks like there’s a bit of a smoking run there. 

‘I don’t think it’s hard to think maybe there’s too much of a good thing. A little is good, but a lot may not be that good. 

‘But the idea that there’s one thing causing autism is absolutely ridiculous. This is something where I think they’ve just gone too far, too fast. 

‘The idea that it’s the only thing or that we have to stop taking Tylenol, I think that’s just very premature and short-sighted without really being measured.’

He also noted that while more investigation is likely needed to determine how much pregnant women should take, it’s not ‘helpful to just tell women to stop taking it.’  

‘I think that for the most part, Tylenol is fine. Maybe there’s some other issues if you take an overdose of it without knowing it, but for the most part, I don’t think it’s helpful to just tell women to stop taking it.’