Understanding Folate and Leucovorin

Now that we’ve defined the key terms, let’s look at why leucovorin has been gaining attention in autism research and treatment.

Studies suggest that about 60–70% of children on the autism spectrum have folate receptor alpha autoantibodies (FRAAs) - proteins that interfere with folate’s ability to cross the blood-brain barrier. When folate can’t reach brain cells effectively, it may lead to cerebral folate deficiency (CFD) - a shortage of active folate in the central nervous system. This shortage can affect communication between neurons contributing to challenges with language, attention, behavior, and emotional regulation.

Leucovorin (calcium folinate) is the prescription form of folinic acid - an active type of folate that can cross into the brain even when folate receptors are blocked. It can bypass this folate transport issue and restore healthy folate activity in the brain.

So how does leucovorin differ from other forms of folate (vitamin B9)?

Compared to Folic Acid:

• Folic acid is the synthetic form of folate that must go through several conversion steps to become active so the body can use it.

• For individuals with MTHFR variants or folate receptor autoantibodies (FRAAs), this process can be less efficient - meaning the brain may not receive enough usable folate.

• Folic acid is what is commonly added to fortified foods and found in most standard multivitamins.

Compared to (OTC) Folinic Acid:

• Folinic acid is a more active form of folate that that body can use more easily.

• This over the counter folinic acid is available in smaller doses, around 800 micrograms (equal to 0.8 milligrams).

• Leucovorin is prescription folinic acid.

  • Leucovorin is produced in a calcium salt form known as calcium folinate, which helps stabilize and improve its absorption.

  • Leucovorin is regulated for medical use and typically prescribed in much higher doses than the OTC folinic acid, usually between 10–50 milligrams.

Because of its strength, stability, and better absorption, leucovorin can reach the brain more effectively. Research shows that for some autistic children, leucovorin may support improvements in:

• Language and communication

• Attention and focus

• Mood regulation and flexibility

• Repetitive or rigid behaviors

Important Considerations

While leucovorin shows promising results for some autistic children, particularly those with folate receptor autoantibodies (FRAAs), there’s still a lot that we don't know. Ongoing research aims to clarify which children benefit most, what dosing is most effective, and how long treatment should continue.

Leucovorin is generally well tolerated, but it can occasionally cause hyperactivity, irritability, sleep changes, or gastrointestinal discomfort, especially when dosing is increased too quickly. Because every child is different, it’s important to work with an experienced and knowledgeable provider who can monitor response and adjust as needed.

More research is needed to better understand who will benefit from leucovorin and why; and how to use leucovorin in the most helpful and safest way possible, maximizing the potential benefits while identifying and minimizing any potential risks.

Once families start learning about folate and leucovorin, a common question is “How do I know if this could help my child?” 

At this time, it is not definitive whether testing is necessary. But it can provide helpful insight into how the body is using folate and whether additional supports may be beneficial.

Standard blood tests don’t always tell the full story. Individuals may have normal folate levels in the blood but still show signs of low folate in the brain. This can happen when folate isn’t crossing the blood-brain barrier effectively.

This could be due to cerebral folate deficiency (CFD). The definitive way to diagnose Cerebral Folate Deficiency (CFD) is through a lumbar puncture (spinal tap) to measure the active folate metabolite 5-methyltetrahydrofolate (5 MTHF) in the cerebrospinal fluid (CSF).

Here are some of the most common tests that may be considered when exploring folate metabolism and brain folate function:

Leucovorin works best as part of a well-rounded approach that supports the brain and body from multiple angles. Nutrition, sleep, exercise, and ongoing therapies all play a vital role in helping your child feel and function their best.

• Pair it with Methyl-B12. Folate and vitamin B12 work hand-in-hand in the methylation cycle. Many providers recommend adding methylcobalamin (Methyl-B12) when starting leucovorin to optimize energy, focus, and neurological function.

• Focus on nutrient-rich whole foods. Offer foods naturally high in folate and antioxidants—such as leafy greens, eggs, citrus, beans, lentils, seeds, and seafood. These foods also provide zinc and selenium, key minerals that support folate and enzyme activity. Try to limit foods fortified with folic acid (often labeled as “enriched”) and consider reducing dairy, which may interfere with folate transport in some children.

• Prioritize sleep. Good, quality sleep plays an important role in neurodevelopment. Morning sunlight exposure helps anchor the circadian rhythm, signaling when to be alert and when to wind down later in the day. A predictable bedtime routine, sensory regulation, consistency, and connection can strengthen sleep quality, which in turn helps the brain process new skills and behaviors more effectively.

• Continue supportive therapies. Provide consistent developmental and neuroaffirming supports. Speech, occupational, and/or behavioral therapy remain the foundation of progress for autism related challenges.