At a Sept. 22 press conference, the Trump administration unveiled what it says is an “exciting treatment” for autism: leucovorin, a decades-old drug that treats the toxic effects of chemotherapy. Early research suggests it may be useful for a select group of people with neurological conditions associated with autism, although some medical experts say it is not quite ready for as widespread use as the administration plans.
Here's what you need to know about leucovorin.
What is leucovorin?
Leucovorin is a form of folic acid, which is a synthetic form of folate (vitamin B9). Folic acid is important for helping the body make DNA and red blood cells, hair and nail cells, skin cells and other body cells. American College of Obstetricians and Gynecologists recommends All women who are pregnant or planning to become pregnant should take a daily folic acid supplement to help prevent neural tube and spinal defects in the developing fetus. Folic acid is also important in preventing certain types of anemia.
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Some cancers in children and adults are treated with methotrexate, a type of chemotherapy that can be toxic to the body, especially the kidneys, by interfering with the normal activity of folate in cells. Leucovorin, or folinic acid, can counteract these effects by replacing folate and allowing the body's folate processes to continue functioning in the presence of methotrexate.
What does leucovorin have to do with autism?
In recent years, scientists have reported that some children with autism have lower levels of folate in the brain, even if the rest of the body has normal folate levels. The deficiency could be explained by several factors, says Dr. Richard Fry, chief scientist at the Autism Discovery and Treatment Foundation and director of research at the Rossignol Medical Center, who has spent decades studying the link between folic acid and neurological disorders.
In some cases, people with lower brain folate levels may have antibodies that bind to folate receptors in the brain, blocking folate's ability to function in the brain. In 2005, researchers from the United States and Europe published a study. study linking these antibodies to cerebral folate deficiency (CFD), a rare condition in which people have low levels of folate in the brain, leading to certain neurological symptoms, including slow psychomotor and head growth, irritability, involuntary or repetitive movements and seizures. In this small study, folinic acid improved symptoms in children.
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Other people with low levels of folate in the brain have abnormal mitochondria, which regulate energy in cells, impairing the cells' ability to obtain folate. Some people also have genetic defects that produce defective folate receptors.
In 2013, Fry published a short study showing that leucovorin may benefit children with autism as well as children with CFD. In his study, up to 75% of children with autism showed folate deficiency in the brain, and that children with lower levels of folate receptor in particular improved their language, interpersonal, social and coping skills. Five years later, Fry confirmed these findings in his report. study This study compared children receiving leucovorin with a group receiving a placebo drug.
“I think [leucovorin] “This is an important step forward in treating many children and improving their ability to function,” he told TIME magazine. “This is especially innovative because many people don't think autism can be cured at its core. This treatment addresses underlying biological deficits and therefore can be disease modifying. It is not a cure, but it can significantly improve the functioning of many children.”
Dr. Marty Makary, commissioner of the US Food and Drug Administration (FDA), said during a press conference that the agency has begun the process of approving the drug, which is now a generic drug, to treat people with autism. However, the official statement from the FDA statement said the drug would be approved for people with CFD. Although CFD can lead to autism-like symptoms and developmental delays, it is different from autism. Many people with CFD have autism, but not all people with autism have CFD.
How can you tell if a person with autism has low levels of folate in the brain?
Doctors can test folate levels in the brain using a lumbar puncture (also known as a spinal tap) to determine the level of folate in the cerebrospinal fluid. They may also check for anti-folate antibodies in the blood using a folate receptor autoantibody test (FRAT), which is not part of a routine blood test.
Is leucovorin approved for the treatment of autism?
The drug is only approved to treat the effects of chemotherapy. But thanks to recent FDA action, doctors can prescribe it for CFD. “Autism may also be caused by an autoimmune reaction to the folate receptor in the brain, preventing this important vitamin from entering brain cells,” Makary said during the press conference. “We have a responsibility to let doctors and the public know that we are going to change the label to make it available. In my opinion, hundreds of thousands of children will benefit.”
A brand-name version of the drug made by GSK was originally released in the early 1980s, but the company stopped selling it in 1999 and the FDA withdrew its approval. Since then, generic versions have emerged, and some doctors have begun prescribing it off-label for autism patients. The FDA is currently working with GSK to re-introduce the drug in a new indication for the treatment of CFD.
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Fry believes that the current evidence supports the use of leucovorin for autism, especially since there are very few treatments. “Personally, I wouldn’t consider it experimental,” he says. “I would prescribe it as a treatment that has strong evidence of effectiveness.” He says the drug should not be a first-line treatment, but should be used after interventions such as speech and occupational therapy, and after addressing behavioral, sleep and bowel problems.
Frye says he is working to start a company to develop a version of leucovorin more suitable for children with autism—an oral form that is colorless, tasteless and odorless and can be given as a liquid because some children may have difficulty tolerating pills.
Is there really enough evidence that leucovorin helps with autism?
Not everyone in the field has the same confidence in data. Alicia Halladay, chief scientist at the Autism Research Foundation, says leucovorin is not yet ready to become a treatment for autism. “I think it's incredibly premature to say that leucovorin is anything more than a potential idea that hasn't had any real scientific data yet,” she says. “Most autism experts I know would not prescribe leucovorin or advise [families] take it.”
Halladay says there is not enough data on the drug's safety in children, much less in children with autism, who may have additional health problems, and some anecdotal reports suggest leucovorin may make some children with autism more hyperactive. “The reality is we don't have safety data yet. We need larger studies.” It remains to be seen how long children will have to take the drug because there have been no long-term studies. (Fry says that “for children who respond to treatment, it really does feel like long-term treatment.”)
Halladay also notes that the new focus on leucovorin could divert already limited resources, such as research funding and clinical trial support, from more thoroughly studied autism treatment strategies, such as behavioral interventions or other drug approaches, which may have stronger scientific support.
The American Academy of Pediatrics (AAP) has expressed similar concerns about the dangers of oversimplifying treatment. “When it comes to autism, we know that it is complex, highly variable and increasingly linked to genetics. There is no single root cause of autism, and there is no single cure that will give every autistic child or adult what they need,” AAP President Dr. Susan Kressley said in a statement. “Individualized plans, often incorporating a combination of developmental, behavioral, educational and social strategies, can help improve outcomes that matter to individuals and families.”
While Halladay welcomes the focus government announcements have placed on the need to better understand and treat autism, she cautions that not all attention is helpful. “Increasing awareness of autism and the needs of people with autism is very beneficial,” she says. “But using a platform to talk about things that don’t work, could be harmful, or potentially cause a lack of trust in science is not a good thing.”
