Arizona doctor pursues autism breakthrough with inexpensive folate drug

In an Arizona clinic, pediatric neurologist Dr. Richard Frye is pursuing what he describes as a potential breakthrough in autism treatment: leucovorin, a cheap form of folate used for other conditions, given off label to autistic children to improve language and behavior.

Frye says dozens of previously nonverbal youngsters have begun to speak, with some forming complete sentences and expanding their vocabularies within months. One family told CBS News that their son Mason Conner, diagnosed with autism at age two and a half, spoke his first words just three days after starting daily leucovorin. Frye cautions that he is not claiming miracles, but rather applying a medication he believes can address a brain-level deficiency that may underlie some autism symptoms.

Leucovorin is a form of folate designed to cross the blood-brain barrier, unlike some standard folate supplements. Folate is essential for DNA synthesis and cellular growth, and researchers have suggested that a subset of autistic children may have inadequate folate reaching the brain due to autoantibodies that block the folate receptor alpha. In the early 2000s, scientists including Dr. Vincent Ramaekers in Belgium and Dr. Edward Quadros in New York studied folate transport in autistic brains and found normal blood folate but reduced cerebrospinal fluid folate, hinting at a brain-specific bottleneck. Building on that work, Frye and his team screen patients for the autoantibody and offer leucovorin to those who test positive, arguing that it can bypass the blocked transport and restore folate delivery to the brain.

Leucovorin is FDA-approved in the United States to protect healthy cells during chemotherapy, but not for autism. Doctors can prescribe it off label for other conditions if they deem it safe, and Frye says he has treated about one in five patients at his clinic with the drug, totaling roughly 2,000 users there. He stresses that many children still require traditional therapies—speech, occupational therapy, and behavioral interventions—alongside leucovorin. “They need that educational support to get their brain back to where it should be,” Frye has said.

The drug’s cost is a frequently cited hurdle in broader adoption. Leucovorin is sold in pills and bottles; one pill can cost around $2.50, and a typical 12-pill bottle runs about $30, though prices vary by supplier and insurance coverage. Frye notes the therapy can be far cheaper than some standard autism therapies, such as intensive applied behavior analysis (ABA), which can reach as high as $250,000 per year without insurance. He also cautions that leucovorin is not a stand-alone cure; many children will still need comprehensive educational and therapeutic supports.

In a recent trial, researchers reported that after four months on leucovorin, some autistic children showed significant improvements in language, including expressive and receptive skills. Frye’s team is now testing a liquid, tasteless form of L-leucovorin designed for children who may be sensitive to textures or tastes. He expects results from the latest trial by summer and said data thus far look promising, though the FDA has indicated that at least one more large, dose-finding trial is necessary before seeking formal approval. If approved, leucovorin could become more widely available for autism and potentially other conditions linked to folate deficiency.

The FDA’s current position is cautious: it would require additional large-scale studies to determine safe and effective dosing for autistic children before any formal approval could be pursued. In the meantime, Frye’s clinic has observed that a subset of patients responds well to leucovorin, but experts outside his practice voice measured optimism. Dr. Brandon Crawford, a developmental neurologist, said leucovorin shows promise for certain individuals with documented folate metabolism issues but emphasized that autism is multifactorial and typically requires a multimodal approach. Thomas Freeman, an analyst at ABA Technologies, urged tempered expectations, noting that while leucovorin could supplement therapy, it is not a replacement for evidence-based behavioral interventions.

The autism landscape in the United States has grown markedly in recent decades. Official estimates show diagnoses rising from about seven in 1,000 in the early 2000s to approximately one in 36 children in 2022, nearly two million people nationwide. Frye and his supporters point to the folate pathway as a potential lever to improve language and reduce certain core symptoms for a subset of children who are folate receptor alpha autoantibody positive. Critics, however, caution that more rigorous, independent research is needed to separate genuine benefit from optimism or placebo effects.

Beyond autism, Frye has suggested that leucovorin could help with other neurodevelopmental and psychiatric disorders in which folate transport to the brain may be impaired. He cited conditions such as Down syndrome, dementia, and schizophrenia as potential targets for future trials, pending a clearer understanding of who might benefit and how best to implement testing, dosing, and monitoring. He also envisions prenatal or preconception folate screening to identify those at risk, with the aim of preventing or mitigating autism’s onset in some cases. Critics urge patience and emphasize that any broad adoption should await robust evidence and regulatory approval.

If leucovorin ultimately gains FDA approval for autism, Frye and others hope it would become part of a broader, integrated treatment plan rather than a standalone solution. Dr. Frye has repeatedly stressed that the best outcomes likely arise when medication is paired with high-quality speech and educational therapies, as well as ongoing neurodevelopmental support. He said, in interviews and his clinic materials, that the field should remain hopeful but grounded in science: “It’s not going to be everyone, but even if a small percent benefit, that’s a real win.”