No. However, some individuals with an autism diagnosis may benefit. Those that benefit may show improvements in verbal communication and neurodevelopmental delay.

Research shows that some individuals have a folate (a form of vitamin B9) vitamin deficiency in the brain. This is referred to as a Cerebral Folate Deficiency (CFD), and these individuals may also have an autism diagnosis. CFD can be caused by an autoimmune response where antibodies block folate from entering the brain through the Folate Receptor Alpha (FR⍺). These antibodies can potentially be detected through a blood test that can be ordered by a physician.

Figure 1. (A) Folate can cross the blood brain barrier via the FRα in a healthy brain. (B) This process is inhibited in individuals with folate receptor autoantibodies (FRAA) who have a cerebral folate deficiency which affects neuronal functioning. (C) Folinic acid treatment can bypass the FRα blockade and enter the brain via the reduced folate channel (RFC) and restore folic acid levels and neuronal functioning in the brain.
Folinic acid is a naturally occurring vitamin derivative of folate that uses an alternative pathway to reach the brain, bypassing the blocked receptor. Multiple clinical trials suggest that calcium folinate may help correct this deficiency in individuals with CFD who have these antibodies, potentially improving speech and other symptoms.1,2,3 These trials indicate that calcium folinate is most effective in individuals with high levels of these antibodies, but it may also provide benefits for those with low or no detectable antibodies. It is important to note that folinic acid is required to bypass FR⍺; folate or folic acid supplements are unlikely to be helpful. Calcium folinate is generally considered safe for long-term use in other conditions (megaloblastic anemia, coadministered with methotrexate and 5-FU); it has not been studied for long-term use in CFD.

Four randomized controlled trials, performed in the US, France, India*, and China demonstrated improved verbal communication and other behaviors (daily living skills, irritability, stereotyped behavior and hyperactivity), particularly in individuals with ASD who had the folate- blocking antibodies.1,2,4 Response rates among those receiving calcium folinate ranged from 44-56%, compared to 14-20% in the placebo groups.

*Note: The trial performed in India was retracted from the literature in January 2026.

There is no one measurement of how safe a drug is, but folinic acid is a naturally occurring vitamin that has been used as a medication in people for decades. A recent meta-analysis concluded that “leucovorin [calcium folinate] is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies.” It also indicated “significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%).”6

The best way to determine if calcium folinate could help is to talk to your child’s physician. Some children may be good candidates if they have:

• – A diagnosis of autism
• – Communication difficulties
• – Signs of cerebral folate deficiency:5  Some common symptoms may include agitation, insomnia, slower-than-normal head growth, and delays in movement and coordination, often with low muscle tone and balance issues. Less common signs include stiffness or unusual reflexes in arms and legs, involuntary movements, and/or seizures.
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• Definitive diagnosis of cerebral folate deficiency involves a lumbar puncture procedure (also referred to as a spinal tap) to test for folate and its derivatives in spinal fluid. However, detection of folate receptor autoantibodies in the blood can be a good intermediate step to see if folinic acid is right for your child. The Folate Receptor Antibody Test (FRAT) is a blood test that checks for the presence of autoantibodies that can block folate from entering the brain. If your child has a positive FRAT, it may indicate that folinic acid  could improve verbal communication and/or symptoms of neurodevelopmental delay. However, calcium folinate does not help all children who test positive for FRAT and some children with CFD who test negative for FRAT may still experience benefits from calcium folinate. If your physician is unfamiliar with calcium folinate for CFD, you might suggest they consult a specialist in developmental pediatrics or neurology.

Folate receptor alpha autoantibodies (FRAAs) can be identified in some children with autism and CFD, and calcium folinate has been shown to help some children who test positive.5 However, calcium folinate does not help all children who test positive for FRAAs, and some children with autism who have not been tested—or who test negative for FRAAs—may still experience benefits from calcium folinate. There is more to understand in regards to who may benefit from treatment. As with all treatment decisions, you should speak with your child’s doctor to determine if the likely benefits may outweigh the risks and it might be a good fit.

Available studies have primarily focused on children ages 2-14 and have shown benefits particularly in areas such as verbal communication, social engagement, and attention.1,2,3,4 Available research suggests that earlier intervention may lead to better outcomes. Further research is underway to better understand this treatment in various age populations. If you are considering calcium folinate for your child, speak with your child’s doctor to determine if the likely benefits may outweigh the risks and it might be a good fit.

The dosage of calcium folinate that was used in the four randomized controlled trials to date varied widely. A commonly used dose is 2 mg/kg per day (maximum 50 mg per day), typically given in two divided doses. Individuals are often started at a lower dose, for example 5 mg twice daily (regardless of age and weight), and the dose is increased over a period of time.6 The right dosage for your child should be determined by their doctor.

Every Cure is not currently running clinical trials on calcium folinate for CFD. You may find clinical trials by checking ClinicalTrials.gov.

Every Cure does not maintain a list of providers who offer FRAT and/or prescribe calcium folinate. Some physicians may be more familiar with this test and/or prescribing calcium folinate than others– developmental pediatricians and neurologists specializing in autism may be more familiar with the test. Sharing information with your child’s doctor about research on calcium folinate and its potential benefits for CFD could help them make a decision about testing.

No, folinic acid and folic acid are different.

Folinic acid (calcium folinate) is an active form of folate that can bypass certain antibody blockers present in some individuals and cross into the brain efficiently.

Folic acid is a synthetic form of folate that is not able to bypass certain antibody blockers present in some individuals and cannot readily cross into the brain.

If you or a loved one is interested in learning more about this medication, please talk to your doctor.