Leucovorin may help with improving verbal communication in certain individuals with ASD who have a vitamin deficiency

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Click the video above to watch a story that ran on CBS Evening News about leucovorin for ASD.

Every Cure is excited to highlight the potential role that leucovorin (folinic acid) may play in improving verbal communication in some individuals with autism spectrum disorder (ASD) who have speech challenges and certain antibodies that cause a vitamin deficiency in the brain. As a nonprofit research organization committed to identifying and elevating potential repurposed treatments, we’ve summarized information about this promising drug repurposing opportunity below.

A vitamin deficiency may contribute to speech challenges in some individuals with ASD

Research shows that some individuals with ASD who experience speech challenges have a folate (folic acid, a form of vitamin B9) deficiency in the brain. This vitamin deficiency is caused by an autoimmune response where antibodies block folate from entering the brain through the Folate Receptor Alpha (FR⍺). These antibodies can be detected through a blood test that can be ordered by a physician. Though only 5-10% of the general population have these antibodies, research suggests that approximately 50-70% of individuals with ASD have these antibodies.

A. Typical CNS folate metabolism

B. Cerebral folate deficiency in FRAA + ASD

C. Correction of folate deficiency in FRAA + ASD

Figure 1. (A) Typical CNS folate metabolism. Folate can cross the blood brain barrier via the FRα in a healthy brain. (B) Cerebral folate deficiency in FRAA+ASD. This process is inhibited in individuals with folate receptor autoantibodies (FRAA) who have a cerebral folate deficiency which affects neuronal functioning. (C) Correction of folate deficiency in FRAA + ASD. Leucovorin 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.

Taking a vitamin may help with speech challenges in some individuals with ASD

Leucovorin (folinic acid) is a naturally occurring vitamin derivative of folate that can use an alternative pathway to reach the brain, bypassing the blocked receptor.¹ Multiple clinical trials suggest that leucovorin may help correct this deficiency in individuals with ASD who have these antibodies, potentially improving speech and other symptoms.^2–4 These trials indicate that leucovorin 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 leucovorin is required to bypass FR⍺ — standard folate or folic acid supplements are unlikely to be helpful. While studies have reported limited side effects, and leucovorin 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 ASD.

Three randomized controlled trials, performed in the US, France, and India, 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. Response rates among those receiving leucovorin ranged from 44-56%, compared to 14-20% in the placebo groups:

A wide range of doses were used in these studies with the lowest dose being 5mg twice daily.

All trials were conducted on children ages 2-15 years old. Further research is underway to better understand this treatment, including a study of 2.5-5 year olds.

Although there is accumulating evidence regarding these antibodies and the potential benefits of leucovorin, testing for these antibodies remains underutilized, and treatment with leucovorin is not widely implemented. We believe limited utilization of the test and medication is related to limited awareness.

What should I do if I’d like more information for myself or a family member?

If you or a loved one is interested in learning more about this medication, please talk to your doctor. Your doctor can order the antibody test from https://www.fratnow.com/.

Everyone with ASD could consider having this test done. A positive test suggests that leucovorin is more likely to help with verbal communication than a negative test.

As with all FDA-approved medications that could be used “off-label” for a different condition, it is important for physicians and patients to evaluate the potential risks and benefits based on an individual’s needs.

How can I share my own experiences with leucovorin?

We love hearing from patients and physicians who have experiences with repurposed medicines like leucovorin. You can share your experiences and ideas here: https://everycure.org/ideas/

You can also sign up as an “expert” to share your expertise on this repurposed treatment and others: https://everycure.org/experts/

Perspectives from Every Cure, Dr Richard Frye, and the Brain Foundation

Perspective from Every Cure’s Co-Founders:

Replenishing a known vitamin deficiency to address speech challenges in individuals with ASD is a powerful example of data-driven drug repurposing—one that we at Every Cure are excited to highlight and share. Every Cure has built an AI platform to identify and prioritize the most promising drug repurposing opportunities for further research and use in patients. We are committed to advancing knowledge and collaborating to improve access to existing treatments that can help patients in need.

Perspective from the leading researcher, Dr Richard Frye, about the significance of this:

“First, this treatment addresses core symptoms of autism, not just behaviors or medical issues associated with autism. Second, this treatment addresses a key abnormality that might be a root biological mechanism that may promote the development of autism symptoms. This means that this treatment may be fixing the underlying biology which, in turn, may be driving autism symptoms to improve. This would, indeed, be considered a significant medical breakthrough in this field. Third, we obtained these results with leucovorin (folinic acid), a vitamin that is a very well tolerated and considered a safe treatment. Leucovorin has been in clinical use in pediatric oncology since the 1950s to rescue the body from the ill effects of a chemotherapy agent known as methotrexate. So the treatment we are giving has been studied for quite some time and the safety profile is well known. This is in contrast to many common treatments used for children with autism with less well-known safety profiles, which are less well studied, and can lead to adverse effects which can sometimes be serious.” Full interview here: https://www.nofone.org/dr-frye-q-and-a-folinic

For more from Dr. Frye and the Autism Discovery and Treatment Foundation, visit https://drfryemdphd.com/folate/ and https://autismdiscovery.org/.

Perspective from the President of The BRAIN Foundation, Pramila Srinivasan, Ph.D.
“These results are promising and from my experience talking to hundreds of parents of children in our community, anecdotally, some parents report remarkable improvement (particularly those with diagnosed antibodies) and a good number saw moderate improvements. However, no one reported any side effects, so it is definitely worth looking into as an adjunct therapy along with speech and behavioral therapy.”

For more from the BRAIN Foundation, visit http://www.brainfoundation.org

A note about terminology: Every Cure is committed to respectful and inclusive language that reflects the perspectives of the communities we aim to support. Our goal is to foster meaningful dialogue and collaboration while advancing research that improves lives. We recognize that preferences vary within the autism community, with some individuals preferring identity-first language (e.g., “autistic person”) and others preferring person-first language (e.g., “individual with autism”). Whenever possible, we defer to the preferences of the community and encourage asking individuals or groups how they wish to be addressed. Please contact us at [email protected] if you have any suggestions for how to improve our language.

Medical Disclaimer

The information provided in this post is for educational and informational purposes only and is not intended as medical advice. Every Cure does not provide medical diagnosis, treatment recommendations, or individualized healthcare guidance. If you or a loved one is considering leucovorin (folinic acid) or any other treatment, please consult with a qualified healthcare provider to discuss potential risks, benefits, and suitability based on your individual medical history.

Any mention of specific tests, treatments, or research studies is for informational purposes and does not constitute an endorsement. The use of FDA-approved medications for conditions not originally approved (off-label use) should be carefully evaluated by a licensed physician.

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