What Experts Want Parents To Know About Leucovorin and Autism

The Food and Drug Administration (FDA) recently announced that it’s in the process of approving a tablet version of leucovorin for patients with cerebral folate deficiency (CFD), a neurological condition that some kids with autism also have.

Leucovorin treatments for autism raise many questions from parents. Meanwhile, experts who treat autism are split on whether or not this drug, which is commonly used in cancer patients alongside chemotherapy, is a good option for kids. Many suggest that additional research is needed before doctors can be sure its effective and safe and that, no matter what, it may only be effective for a specific set of kids with autism.

We break down what parents need to know.

What Is Leucovorin?

Leucovorin, or folinic acid, is a biologically active derivative of folic acid, essential for DNA synthesis, repair, and cell division, explains Sam Zand, MD, a psychiatrist and the founder of Anywhere Clinic.

“Our bodies normally have to convert folic acid into its active form before the brain can use it, but leucovorin is already active, so it gets right to work,” says Dr. Zand.”

Leucovorin has been a mainstay in cancer care for decades, especially in chemotherapy regimens.

“Doctors typically give leucovorin after high-dose methotrexate chemotherapy to protect healthy cells from toxicity without reducing the anti-cancer effects against malignant cells,” says Dr. Zand. “It’s also used alongside certain chemotherapy drugs, where it can enhance the effectiveness of certain cancer treatments.”

Leucovorin’s Connection to Autism

Leucovorin’s relevance to autism comes from its role in CFD, which Ryan Sultan, MD, a double board-certified psychiatrist, explains is “a rare metabolic condition.”

“Researchers discovered that some autistic children have autoantibodies or other issues that block folate transport into the brain,” explains Dr. Sultan, the research and medical director at Integrative Psych. “In those cases, leucovorin can bypass the blockage by directly supplying folinic acid that can get into the brain.”

Over the past 15 to 20 years, adds Dr. Zand, health care providers observed that some children with autism, particularly those with underlying folate metabolism or transport issues, experienced improvements in language and social interaction when treated with leucovorin. 

“This led to small clinical trials and, subsequently, off-label use of the drug by families and specialists when specific testing confirmed problems with folate transport,” says Dr. Zand. “Multiple randomized clinical trials across the U.S., France, and India have since reported statistically significant, though not universal, improvements in language abilities and autism symptom severity among treated children.”

These early findings drove further research. “They helped pave the way toward official acknowledgment and more rigorous study of leucovorin as a targeted intervention in autism spectrum disorders,” adds Dr. Zand.

What Leucovorin Isn’t

Findings like these need to be approached with two non-negotiables, says Ryann Sutera, MS, CCC-SLP, a licensed speech-language pathologist and founder of Support The Spectrum. First, autism is a neurotype, not a problem that needs to be fixed, and second, no single intervention is right for everyone, says Sutera.

“Some children with CFD or folate receptor autoantibodies (FRAAs) may benefit, but current samples are small,” says Sutera. “Also, this is not a cure.”

The latter is a point Zishan Khan, MD, a board-certified child and adolescent psychiatrist with Mindpath Health, stresses as leucovorin is sometimes billed this way.

Its use to treat autism grew after studies suggested that some autistic children have trouble transporting folate into the brain, explains Sutera. A 2016 randomized controlled trial found that high-dose folinic acid improved verbal communication in children with autism and language impairment, with the strongest results in those with folate receptor autoantibodies.

But not every child responds, and the side effects, such as irritability or changes in sleep patterns, can occur, says Sutera.

“Research is promising but still relatively limited, and testing for folate pathway issues is not yet routine,” says Sutera. “Families should keep expectations realistic and view leucovorin as one possible tool to support development, ideally alongside therapies like speech and occupational therapy.”

Are There Benefits of Leucovorin for Autism?

According to Dr. Sultan, when the FDA made leucovorin an approved treatment option for autism symptoms in CFD, this was an unusual, fast-tracking step. For this reason, he says parents need to understand the potential benefits and limitations.

On the plus side, this is not another heavy-duty psychiatric drug, says Dr. Sultan.

“Up until now, the only FDA-approved medicines for autism were two antipsychotics (risperidone and aripiprazole) used to manage severe irritability, and both are associated with serious side effects,” shares Dr. Sultan. “Leucovorin is different. It’s basically a targeted vitamin therapy, so it tends to be much gentler on the body.”

Another advantage is that the side effects of leucovorin are generally mild too, he says. For example, a few kids experience increased hyperactivity or irritability in the first couple of weeks, but that typically subsides within a month.

Symptoms may also improve for some. “Some children, especially those with confirmed folate pathway issues, may see meaningful gains in language and social interaction with this treatment,” says Dr. Sultan.

Downsides of Leucovorin for Autism

Even though leucovorin may offer language or social improvement primarily in children with documented folate transport problems, Dr. Zhan stresses that this drug is not a universal autism treatment.

“Most autistic children will not have CFD,” says Dr. Khan. “Therefore, giving leucovorin broadly without testing risks false hope and unnecessary medication exposure.”

He notes that evidence of its benefits is also limited, and the drug’s trials were relatively small, used different doses, and had variable inclusion criteria. Larger, confirmatory trials are needed, he says.

Dr. Sultan agrees, sharing, “The research is still preliminary and more data are needed. It seems to benefit a subset of children, so identifying the right candidates is important.” 

Also, Dr. Khan says children may experience irritability, hyperactivity, or gastrointestinal (GI) symptoms when taking this medication.

“In rare cases, behavior can actually worsen due to their inability to communicate their discomfort as a result of taking the leucovorin,” says Dr. Khan. “Any medication should be started and monitored by a clinician.”

He points out the key tests for cerebrospinal fluid folate or folate-receptor antibody testing are highly specialized and sometimes not widely available. There is also the risk that they are not covered by insurance.

Bottom line: if you are considering this drug, discuss this option with your child’s health care provider or psychiatrist. They can assess whether folinic acid makes sense—and potentially check folate levels or antibodies and monitor its use, says Dr. Khan.