Trump Derangement Syndrome comes for heralded off-label autism treatment after president endorses

The medical establishment and mainstream media are uniting against the Trump administration's re-purposing of an inexpensive drug to treat an epidemic, calling it "unproven," not "backed by science," "not a cure" and "shocking" to endorse, with The New York Times emphasizing no profit-driven drug company suggested it.

In President Trump's first term, it was ivermectin and hydroxychloroquine to treat COVID-19. In his second, it's prescription leucovorin to treat autism spectrum disorder.

Long used to treat chemotherapy side effects, leucovorin calcium tablets got approved last week by the Food and Drug Administration to treat "cerebral folate deficiency" (CFD), whose clinical symptoms include "global developmental delays with autistic features," following its own "systematic analysis of literature" from 2009 through last year.

"Published case reports provided patient-level data on over 40 patients," adult and child, with most of those given leucovorin treatment showing "substantial improvement of symptoms of CFD that would not be expected when compared to the natural history of CFD due to FOLR1 gene variants," the Federal Register notice says.

Health and Human Services Secretary Robert F. Kennedy Jr. touted leucovorin to treat autism Monday with Trump and Centers for Medicare and Medicaid Services Administrator Mehmet Oz, but it was quickly overshadowed by the other autism-related recommendation that pregnant women limit their use of Tylenol, which prompted a new TikTok challenge.

Tylenol maker Kenvue surreptitiously reversed its own eight-year-old recommendation that pregnant women not take Tylenol at all, reaffirmed two years later, in response to the federal recommendation, now claiming it's "safe when used as directed" by pregnant women.

Officials went on Trump's favorite medium to direct attention back to leucovorin, also known as folinic acid — not to be confused with the synthetic form of folate known as folic acid — but cited varying uncredited estimates of its effectiveness against autism.

Oz told Fox News on Tuesday that he consulted both major academic centers and other practitioners on treating autism with leucovorin, and found the latter more receptive. All but one clinician, a self-identified "purist," told Oz they would use it for autism in their own kids.

"The clinical trials will probably take five years" so he's telling parents of young children that leucovorin "has a good theoretical argument in favor of it and has already been studied in a couple hundred kids," claiming half "seem to have some benefit." 

The FDA label change will make the drug available via Medicaid and the Children's Health Insurance Program, Oz said. Multiple agencies plan to gather data from parents every three months on "whether your child is speaking better or behaving differently."

Leucovorin's approval was the "most exciting part of the announcement that got left out of a lot of the coverage," Makary told C-SPAN, predicting it "may help 50-60% of kids with autism" by letting folate bypass antibody-blocked receptors on the blood-brain barrier. He also cited unnamed studies that show two in three kids will "see improvements."

Published in smaller journals because autism research 'outside Overton window'

Robert Malone, mRNA vaccine pioneer-turned-critic, exhaustively described leucovorin and its mechanism in a Thursday essay and pointed to peer-reviewed research on the treatment and role of "folate receptor autoantibodies" in autism going back to 2008, in The American Journal of Clinical Nutrition, Molecular Psychiatry twice and Nutrients.

"Notice anything about these publications and journals?" Malone wrote. "These findings are not being published in ‘big' journals," showing that "this basic and clinical research area has been treated as if any research or findings relating to ASD diagnosis and treatment are outside the Overton window of allowable medical and scientific discourse."

Precigenetic CEO Parmita Mishra, who calls herself "neurodivergent" and "a brain methylation researcher," provided lengthy background on the research ahead of Kennedy's announcement. "There is no approved drug for autism’s core biology" but "in a subset of cases, folinic acid helped with communication and cognition," she said.

Advocacy group Autism Speaks agreed "leucovorin shows promise in improving speech in minimally verbal children" while calling for "larger, well-controlled clinical trials" to confirm its efficacy and safety, saying it's "encouraged by the recent, increased focus on autism" and the increased investment in research.

The University of Virginia health system's Neurodevelopmental and Behavioral Pediatrics is not "at this time" prescribing leucovorin for autism treatment, despite caregivers for children asking about it "for quite a few months," UVA Health developmental behavioral pediatrician Beth Ellen Davis told the Public Ivy's in-house publication.

CBS News medical contributor and doctor Celine Gounder wrote a hopeful feature in February on leucovorin as an off-label autism treatment with only "mild" side effects, profiling a boy diagnosed with autism at two-and-a-half years old whose parents claim he spoke his first words three days after starting leucovorin at age 3. 

She touted the research for leucovorin to treat autism, including three randomized controlled trials in India, France and the U.S., in which pediatric neurologist Richard Frye has studied it for more than a decade.

Drug makers have no incentive to get leucovorin approved by the FDA to treat autism because it's "an old drug, and you can get it for a very low price," Frye told Gounder.

Frye's 2012 study in Molecular Psychiatry found about a third of treated children with CFD, given the same leucorovin calcium tablets the FDA approved this week, "demonstrated moderate to much improvement" in "verbal communication, receptive and expressive language, attention and stereotypical behavior." 

He confirmed the results four years later in a randomized double-blind placebo-controlled trial, published a month before Trump's 2016 election victory. 

Gounder added or replaced several paragraphs in her seven-month-old story after the Trump administration touted the treatment (see text comparison below). The tone became much more skeptical, with Gounder implying the FDA was reckless by approving the treatment without phase-three trials despite previously touting its off-label benefits versus its low risks. 

She added several new quotes from Frye pouring cold water on the approval, saying the FDA "may have been a little premature" and some leucovorin formulations aren't tolerated well in kids. Frye is miffed that his group didn't get funding from the feds' Autism Data Science Initiative and that "he was not consulted on the design of upcoming leucovorin trials."

The Times also emphasized the procedural oddity, extensively quoted critics of the approval and noted Oz was a former "pitchman" for folinic-acid maker iHerb while conceding he stepped down from the company and divested his stock months earlier.

CNN's report features a 4-year-old boy whose guardian said he struggled to say "two-word sentences" or answer to his name before going on leucovorin, without first taking an antibody test, and within "a couple months" the boy could tell the guardian "about the other kids at school and answer follow-up questions."

The boy experienced one of the known side effects, increased hyperactivity, "but it’s within tolerable limits" and has largely subsided, the guardian told CNN. “Our theory is that his world grew so big, so fast, he was having a problem digesting it."