Leucovorin: Uses, Benefits, and Its Emerging Role in Autism and Cerebral Folate Deficiency

Leucovorin is used to counteract the negative effects of high doses of the cancer medication methotrexate. Additionally, it is used to treat or prevent some types of anemia. Folic acid, which may be deficient in these individuals, functions similarly in the body to leucovorin. Leucovorin is also used to treat colon (bowel) cancer in conjunction with the cancer medication fluorouracil. Leucovorin can only be obtained with a prescription. As with many specialized therapies, leucovorin's alleged advantages began circulating among the autistic community by word of mouth. Several doctors would administer leucovorin, a medication that contains the same essential element, while many parents have long asserted that folinic acid, a dietary supplement, helped their autistic children speak and converse better.

However, President Trump's recent statement that the federal government will update the label of leucovorin and authorize leucovorin calcium tablets to make the medication publicly available formally ends the drug's cult status.

Why is this drug, Leucovorin, prescribed?

When methotrexate (Rheumatrex, Trexall; a cancer chemotherapy medication) is used to treat specific cancers, leucovorin is utilized to prevent negative side effects. Additionally, leucovorin is used to treat patients who have inadvertently taken too much methotrexate or a similar drug. Leucovorin belongs to a group of drugs known as folic acid analogs. It functions by allowing methotrexate to penetrate and destroy cancer cells while shielding healthy cells from the effects of the drug or similar medications.

How is this medication to be taken?

Leucovorin is available as an oral tablet. It is typically taken every six hours until laboratory tests indicate it is no longer required. Depending on the reason it is prescribed, leucovorin may be taken on a varied schedule. It should be taken daily at approximately the same time or times. Pay close attention to the instructions on your prescription label, and ask your pharmacist or doctor to clarify any parts you don't understand. Take leucovorin exactly as prescribed. Never take more or less than directed, or take it more frequently than your doctor recommends.

Common Side Effects of the Medication

A medication may have certain unintended side effects in addition to its intended ones. Even though not all of these adverse effects occur, they may require medical attention if they arise.

Consult your physician immediately if any of the following adverse effects occur:

• Very rarely: itching, hives, skin rash, or wheezing

Consult your physician immediately if you experience any of the following rare adverse effects:

• Shivering (convulsions)

Some patients may also experience other unlisted adverse effects. Consult your healthcare provider if you notice any additional side effects. For medical advice regarding side effects, contact your doctor. The FDA’s number for reporting side effects is 1-800-FDA-1088.

The Essential Function of Folate

Folic acid is essential for the synthesis of DNA and other genetic materials, which cells require for healthy growth and repair. This is especially important during pregnancy. Inadequate folate intake is associated with spina bifida, a condition in which a baby’s spine does not form properly. Folic acid supplements are therefore frequently recommended for women both prior to conception and during the first few months of pregnancy. Furthermore, folate is essential for maintaining the synthesis of red blood cells and for overall brain function. The Certification Course in Healthy Child provides thorough insights for medical professionals who wish to expand their knowledge of child development and health.

The FDA Acts to Provide a Therapy for Autism Symptoms

Leucovorin calcium tablets were approved by the U.S. Food and Drug Administration today for use in treating individuals with cerebral folate deficiency (CFD), a neurological disorder that impairs the brain's ability to absorb folate, a nutrient vital for brain function. Cerebral folate deficiency has been linked to seizures, movement and coordination issues, and developmental delays with autism characteristics (such as difficulties with social communication, sensory processing, and repetitive behaviors).

After a thorough review of the literature from 2009 to 2024, including published case reports with patient-level details and mechanistic data, the FDA concluded that the evidence supports the idea that leucovorin calcium can benefit people with CFD.

Over the past 20 years, autism has tragically increased fourfold, according to FDA Commissioner Marty Makary, M.D., M.P.H. “Children should have access to promising treatments because they are suffering. To provide for the American people, we are utilizing common sense and the highest caliber of science.”

To incorporate the crucial scientific data required for the safe and efficient use of these medications for adults and pediatric patients with CFD, the FDA is collaborating with GSK, the company that developed Wellcovorin (leucovorin calcium). GSK has tentatively agreed to collaborate with the FDA on this relabeling endeavor as the holder of the New Drug Application (NDA) for this medication.

The Value of Addressing Verbal Communication and Language in Autism Spectrum Disorder

Leucovorin significantly impacted verbal communication in children with ASD, according to our open-label clinical study. Targeting verbal communication is crucial for several reasons. First, improved social communication can be fostered through verbal communication development. Second, more severe symptoms of ASD are linked to deficiencies in language processing. Therefore, enhancing language skills may lessen the intensity of ASD symptoms, lead to better long-term outcomes, and improve the family's quality of life. Lastly, improving delayed language may benefit brain development as well. To investigate the impact of leucovorin on verbal communication in children with ASD, we conducted a DBPC study, which was recently published in Molecular Psychiatry (detailed below).

How can I determine whether my child requires leucovorin?

A lumbar puncture, often known as a spinal tap, is the only surefire method to determine the amount of folate (5MTHF) in the brain. Many physicians recommend an empirical leucovorin trial to determine whether your child responds, because this is an invasive test.

A blood test known as a FRAT (Folate Receptor Autoantibody Test) is the only alternative testing option. This test checks the blood for autoantibodies that are blocking or binding folate. Autoantibodies detected in the test could indicate that the brain isn’t receiving enough folate. You must order and have the FRAT test kit mailed to you. After receiving it, complete the requisition form and present it to your physician for approval. Then, have the blood drawn and sent to the laboratory. Your doctor will receive the results. For guidance on interpreting these test results, please read the book The Folate Fix by Dr. Frye.

Is leucovorin recognized as a common autism treatment?

No, leucovorin is not yet a recognized, standard treatment for autism. Experts agree that larger, more thorough studies are required to confirm its efficacy and safety before it can be widely recommended for medical practice. Despite the encouraging results of several clinical trials suggesting benefits—particularly for speech and communication in children with cerebral folate deficiency—the FDA is currently reviewing it for this expanded purpose.

The Role of Leucovorin in Autism Therapy in India

Although most clinical studies on leucovorin (folinic acid) and cerebral folate deficiency (CFD) have been conducted in Western countries, the potential relevance of this treatment in India is gaining attention. Research shows that folate and vitamin B12 deficiencies are common in Indian children and women, largely due to dietary factors and limited supplementation.

While CFD is distinct from nutritional folate deficiency, low folate reserves may increase the risk of disrupted folate transport to the brain an issue that leucovorin therapy aims to correct. International studies have reported improvements in speech, language, and social communication in children with autism who tested positive for folate receptor autoantibodies (FRAAs) and received leucovorin treatment. However, India currently lacks large-scale research or clinical trials examining leucovorin’s safety and efficacy in autistic children.

As awareness grows about biomedical interventions for autism in India, there is an urgent need for local studies and clinician-supervised trials to understand how leucovorin can be integrated into autism therapy programs. With careful medical guidance, leucovorin treatment in India could serve as a valuable adjunct to speech, occupational, and behavioral therapies, helping children with autism achieve better communication and developmental outcomes.