The science behind a promising autism treatment: How d,l-leucovorin calcium (folinic acid) may improve ASD symptoms

03/31/2025 / By Olivia Cook

Research suggests that d,l-leucovorin calcium (folinic acid) significantly improves communication, repetitive behaviors and social function in children with autism spectrum disorder (ASD).
Children with detectable folate-related autoantibodies (FRAAs) responded more strongly to treatment, highlighting the potential for a precision medicine approach in ASD therapy.
The effect of leucovorin on verbal communication was equivalent to hundreds of hours of speech therapy, offering a cost-effective alternative to traditional interventions.
Clinical studies found leucovorin to be well-tolerated, with few adverse side effects, particularly when compounded without additives. Any initial hyperactivity tended to subside over time.
Ongoing trials aim to confirm these findings in larger groups and explore long-term benefits, particularly for young children where early intervention could yield lasting improvements.

A promising new treatment may change the way autism spectrum disorder (ASD) is managed, offering hope for families seeking effective and affordable options.

According to a rigorous study published in Seminars in Pediatric Neurology, d,l-leucovorin calcium (also known as folinic acid) has shown significant benefits in improving communication and reducing autism-related behaviors.

Leucovorin is a metabolically active form of folate, a crucial vitamin for brain function. Unlike folic acid (vitamin B9), which requires multiple steps to be converted into its active form, leucovorin is immediately usable by the body.

Researchers have discovered that some children with autism have difficulty processing folate, particularly due to the presence of folate receptor autoantibodies (FRAAs) – antibodies that block the transport of folate into the brain. This can lead to a condition called cerebral folate deficiency (CFD), which is believed to contribute to ASD symptoms.

The clinical evidence: How leucovorin helps

A series of studies have examined leucovorin’s potential role in improving ASD symptoms:

Gold-standard clinical trial: A double-blind, placebo controlled trial with 48 children with ASD found that those receiving leucovorin for 12 weeks showed significant improvements in verbal communication compared to those given a placebo. The effect was clinically meaningful, with the most dramatic benefits seen in children with FRAAs.
Open-label study: A larger study tracking 82 children taking leucovorin, compared to 84 untreated children, revealed substantial improvements in ASD symptoms. Many children progressed from severe to mild or moderate ASD based on standardized testing.
French study on social interaction: A smaller, single-blind French study of 19 children showed leucovorin led to significant improvements in social behavior and communication, as measured by the Autism Diagnostic Observation Schedule (ADOS).
Case-series study: Research specifically on children with ASD and FRAAs demonstrated improvements in social skills and reductions in repetitive behaviors highlighting the potential of leucovorin as a targeted treatment.

More than just language gains: Behavioral improvements

Beyond enhancing communication, leucovorin was found to reduce core ASD symptoms, such as irritability, repetitive behaviors and social withdrawal. Parents in clinical studies reported noticeable positive changes, reinforcing the idea that folate metabolism dysfunction may play a critical role in autism-related changes.

The number needed to treat (NNT), a measure indicating how many patients must receive a treatment for one to benefit, was just 2.4 overall and 1.8 for those with FRAAs. This suggests leucovorin is highly effective, particularly for children with folate-related abnormalities.

Cost-effectiveness and access

Leucovorin could offer substantial cost savings compared to traditional autism therapies. Researchers estimated that three months of leucovorin treatment equated to approximately 185 hours of speech therapy – valued around $7,400 – while the actual cost of leucovorin for the same period was only about $300. Given the financial and geographic barriers to intensive therapy, leucovorin may become an accessible option for families seeking additional treatment avenues.

Safety profile: A low-risk alternative

Unlike many medications prescribed for autism, such as antipsychotics, which carry risks of significant side effects like metabolic issues and weight gain, among others, leucovorin was well-tolerated in clinical studies. While some children initially experienced mild hyperactivity or agitation, these effects were temporary and generally resolved over time.

Importantly, there was no significant difference in adverse effects between the leucovorin and placebo groups. However, caution is advised when combining leucovorin with the antipsychotic resperidone, as some cases of increased aggression were observed.

The link between folate, mitochondria and brain function

Scientists believe leucovorin’s benefits extend beyond folate metabolism. Mitochondria – the energy-producing structures in cells – play a critical role in brain function. Research suggests that children with autism often exhibit mitochondrial dysfunction, potentially contributing to their symptoms. Leucovorin has been found to support mitochondrial activity, particularly in pathways related to energy production, further strengthening its potential in improving brain function in ASD.

Could leucovorin help prevent autism?

The important of folate in brain development extends to pregnancy. Studies show that adequate folate intake during pregnancy can significantly reduce the risk of autism. One large study found that women who took prenatal folic acid supplements had a 39 percent lower chance of having a child with ASD.

Additionally, animal studies suggest that leucovorin supplementation in pregnant mice prevented autism-like behaviors in offspring exposed to FRAAs, raising the possibility of early intervention benefits. However, human trials are needed to confirm these findings.

The future of leucovorin research

Encouraged by these promising results, researchers are conducting larger, multicenter trials to refine treatment protocols. Future studies aim to determine the optimal dose, duration and long-term effects of leucovorin. Scientists are also investigating whether younger children benefit the most, as early intervention typically yields better development outcomes. Advanced neuroimaging techniques are being employed to study how leucovorin affects brain circuits, providing deeper insights into its therapeutic mechanisms.

A new hope for families

While leucovorin is not a cure for autism, it represents a safe, effective and potentially life-changing treatment for children with ASD – especially those with folate metabolism dysfunction. As research progresses, this simple yet powerful intervention may redefine the landscape of autism therapy, offering families new hope and practical solutions for managing ASD symptoms.

With increasing scientific backing, leucovorin may soon emerge as a vital tool in personalized autism treatment, empowering clinicians to tailor interventions based on each child’s unique biological needs. As the research continues, the future looks bright for families seeking new, evidence-based options to support their children’s development.

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Watch the following video about the hidden key to speech improvement in autism.

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