FDA Recognizes Leucovorin As A Treatment For Some Autistic Children

The U.S. Food and Drug Administration (FDA) has officially updated the indications for leucovorin, enabling its use to address speech-related deficits in children with autism spectrum disorder (ASD), as announced by RFK on Monday. This new categorization will permit state Medicaid programs to cover leucovorin treatment, thus providing an option for addressing cerebral folate deficiency commonly observed in autistic children. Let’s delve into what leucovorin is and its potential role in treating autism.

Understanding Leucovorin

Leucovorin is a pharmacological form of vitamin B9 (folinic acid) that has been in use since the 1950s. Medical professionals typically prescribe it to treat specific types of anemia caused by folate deficiency and also to safeguard healthy cells during chemotherapy treatments.

Clinical Observations of Leucovorin in Autism

Dr. Donna Kirchoff, an integrative developmental and behavioral pediatrician based in Portland, Oregon, comments on the application of leucovorin, noting, “I have observed improvements in expressive language among my patients.” She highlights its safety, allowing her to employ lab tests to identify children who may benefit the most from its use. However, she expresses caution regarding the considerable excitement surrounding leucovorin, underscoring that while some children have indeed made progress in language, challenges in communication remain.

For non-verbal children with autism, any advance in speech can represent a substantial breakthrough. Nonetheless, these children continue to require support for their unique communication needs.

Mechanism of Action of Leucovorin in the Brain

Naturally occurring folate is transported into the brain via the folate receptor alpha (FRα), which facilitates the movement of folate from the bloodstream into the cerebral spinal fluid (CSF)—a crucial environment for optimal brain function. Folate aids in the production of vital neurotransmitters such as serotonin, norepinephrine, and dopamine and plays a role in significant developmental processes, including the synthesis of DNA and RNA. A deficit in folate can lead to behavioral and developmental complications.

In some individuals, an autoimmune response produces folate receptor alpha autoantibodies (FRAAs), impeding folate transport despite normal blood levels. This results in a functional deficiency within the brain. Leucovorin circumvents this blockade by utilizing an alternative transporter, the reduced folate carrier (RFC1), effectively ensuring adequate folate levels within the brain.

Research Background: Why Investigate Leucovorin for Autism?

Research indicates that many autistic children suffer from cerebral folate deficiency (CFD), often correlated with the presence of FRAAs. A 2021 meta-analysis led by Dr. Richard Frye, a behavioral child neurologist, revealed that approximately 70% of children with autism tested positive for FRAAs—a stark contrast to neurotypical peers, where such positivity was significantly lower. Elevated levels of FRAAs were associated with decreased brain folate levels.

Given that leucovorin can bypass the blocked receptor and restore brain folate levels, various research studies have assessed its impact on autistic children. In a comprehensive review of 21 studies, leucovorin treatment correlated with enhancements in communication, irritability, seizures, and motor skills, particularly among those with FRAA positivity.

A pivotal 2018 clinical trial involved administering high doses of leucovorin to 48 autistic children experiencing language delays. After 12 weeks, substantial improvements were noted in verbal communication and adaptive behaviors in those receiving leucovorin compared to the placebo group. Similar positive outcomes have been reported in recent studies conducted in India and China.

Identifying Candidates for Leucovorin Treatment

It is essential to note that not all autistic children experience cerebral folate deficiency, which leucovorin targets. Diagnosis typically involves a lumbar puncture to assess CSF folate levels, a procedure that may not be practical for widespread screening. Identifying subgroups most likely to benefit includes those testing positive for FRAAs, confirmed cases of CFD, as well as children with mitochondrial overlaps.

Assessing the Safety of Leucovorin for Autistic Children

Leucovorin should be prescribed and monitored by medical professionals. While some may consider acquiring it over the counter, self-treatment could lead to imbalances. Excessive intake of folic acid can result in detrimental effects, including possible delays in brain development in children and accelerated cognitive decline in older adults.

When managed by healthcare providers, leucovorin is typically well-tolerated, with any side effects being mild and generally resolving with discontinuation of the drug. Potential side effects may include irritability, hyperactivity, headaches, sleep disturbances, or gastrointestinal upset, many of which diminish as patients acclimate.

The Future of Leucovorin in Treating Autism

Leucovorin presents a promising avenue for treatment among certain children with autism, especially those with the most severe symptoms. For parents, this could be a new and viable component of a broader support strategy for their child. Nevertheless, research thus far remains limited, necessitating further exploration into leucovorin’s efficacy and its potential applications for autistic adults.