Leucovorin: Is there science behind that?

Elizabeth Hardesty, MA, BCBA, Kassidy Ashbeck, MS, Isabelle Sharp, BA, and Thomas Zane, PhD, BCBA-D
Department of Applied Behavioral Science, University of Kansas

The authors and editors would like to thank Scott Myers, MD and Thomas Challman, MD for their review of the draft of this article.

Is there science behind that Deficits in social communication are a key diagnostic criterion for autism spectrum disorder (ASD), as outlined in the Diagnostic and Skills Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013). Recently, the drug leucovorin has received increasing attention for alleviating symptoms of ASD and was granted fast-tracked approval status from the U.S. Food and Drug Administration for the treatment of cerebral folate deficiency (U.S. Food and Drug Administration, 2026). Interest in leucovorin accelerated dramatically following a White House press briefing in September 2025 that claimed leucovorin may have a role in autism treatment (U.S. Department of Health and Human Services, 2025). In this article, we explore the current research on the use of leucovorin with individuals with ASD, including what leucovorin is, the results of recent clinical evaluations, and other interventions to consider for supporting individuals with challenges related to ASD.

What is Leucovorin?

Leucovorin is a prescription form of folinic acid that has historically been used to buffer the side effects of chemotherapy. Folinic acid is the natural form of folic acid and is found in leafy, green vegetables and is one of a group of substances referred to as “folates.” Folate is a key part of the folate cycle, which is a series of biochemical reactions that play a key role in DNA creation and replication. The folate cycle also supports the growth and survival of each cell by being a mediator of “cleaning up” cell waste (Alam et al., 2020; Vasconcelos et al., 2025). Folic acid is a synthetic form that is used as a dietary supplement and for food fortification in many countries. Due to the importance of the folate cycle in normal cell functioning, dietary guidelines in the United States recommend an intake of 400 micrograms (mcg) of folic acid each day for adults (Office of Dietary Supplements, n.d.). Additional research has shown that daily folic acid intake of 600 mcg during pregnancy helps promote healthy fetal development and prevent brain and spinal cord defects in fetuses (Centers for Disease Control and Prevention, 2025).

In several genetic disorders, levels of folic acid within the central nervous system can reach concentrations low enough to interfere with cell functioning. These genetic disorders limit the ability of folate to pass through the blood-brain barrier (which controls what passes from the bloodstream into the brain) or prevent the absorption of dietary folate in the intestine. When an individual has very low levels of folate in the central nervous system (referred to as cerebral folate deficiency syndrome), the individual may present with severe neurodevelopmental symptoms including tight muscle in the legs, significantly impaired coordination and balance, uncontrolled and involuntary movements, seizures, slowed head growth, and regression in developmental skills (Frye et al., 2013; Pope et al., 2019). Traditionally, this syndrome has been diagnosed using a spinal tap, which allows physicians to directly measure the levels of folic acid in the brain and spinal cord. In 2005, Ramaekers et al. identified two autoantibodies that decrease the amount of folic acid passing through the blood-brain barrier that could be measured with a typical blood sample instead of an invasive spinal tap. In 2013, Sequeira et al. asserted that higher concentrations of these autoantibodies in the blood may correlate with decreased levels of folic acid in the brain and spinal cord. Leucovorin can easily pass through the blood-brain barrier, making it commonly used to treat cerebral folate deficiency syndrome by increasing folic acid levels in the brain (Ramaekers & Blau, 2004; Goldman, 2025).

Why is Leucovorin Considered for Autism?

Some, but not all, individuals with cerebral folate deficiency have been reported as exhibiting symptoms like the listed diagnostic criteria for ASD. Upon receiving treatment with leucovorin, individuals with cerebral folate deficiency have experienced a decrease in these symptoms. This drastic change in behavior for individuals with cerebral folate deficiency has prompted consideration of the use of leucovorin in children with ASD who do not have proven cerebral folate deficiency. Leucovorin has been considered for treating symptoms of ASD based on theories and unknown factors from three areas of research: (1) relative intake levels of folic acid, vitamin B6, and vitamin B12 in individuals with ASD and neurotypical peers, (2) maternal exposure to folic acid and subsequent risk of the child being diagnosed with ASD later in life, and (3) elevated levels of folate receptor autoantibodies in individuals with ASD.

To summarize the findings of the first two areas, Vasconcelos et al. (2025) systematically reviewed 52 scientific articles published between 2013 and 2024 that examined the association between ASD and folic acid. Most studies included in this review were categorized as case-controlled or cross-sectional, meaning that the data were collected from each participant at a single point in time. The collected data were then compared between different groups of participants. The authors’ main findings were that (a) there was no association between mothers taking leucovorin while pregnant and an increased likelihood of the child receiving an ASD diagnosis later in life, (b) individuals with ASD may be at a higher risk of not consuming the recommended levels of folic acid in their daily diet, and (c) individuals with ASD may be more likely to have lower blood concentration levels of folic acid compared to their typically developing peers. With respect to this last point, more research is needed before any true statement could be made relating to levels of folic acid and ASD. For example, Shoffner et al. (2016) directly measured folate levels in the spinal fluid of a sample of children with ASD and found that concentrations of folate in spinal fluid varied significantly over time and did not show any significant relationship to typical clinical features of autism.

All in all, it is unknown if there is any relationship between folic acid levels and ASD. These studies were observational in nature, meaning doctors did not change anything in the participants’ lives to see how participants changed over time. With this type of research, we can establish potential relationships but not determine specific causes. Observational studies are typically used to compare values between groups in the population, meaning this type of research can tell us that individuals with ASD may have lower levels of folic acid than their neurotypical peers. However, this research cannot tell us if ASD causes a lack of folic acid, if low levels of folic acid cause ASD, or if there is a third reason that influences both folic acid and ASD.

Some observational studies have suggested a link between an ASD diagnosis and higher levels of folate receptor autoantibodies. For example, Frye et al. (2013) found that in a sample of 93 children diagnosed with ASD, 75.3% tested positive for at least one of two folate receptor autoantibodies. In 2021, Rossignol & Frye conducted a systematic review of five studies looking at levels of autoantibodies in individuals with ASD and determined that 71% of participants in these studies tested positive for at least one folate receptor autoantibody. A few studies suggest a link between ASD diagnosis and higher levels of folate receptor autoantibodies, but this does not prove that high folate receptor antibodies actually cause ASD or cerebral folate deficiency syndrome—again, observational studies allow scientists to identify possible relationships, but not the cause or direction of the relationship.

In a more recent study, Shi et al. (2024) found that folate receptor autoantibody levels in a group of children with ASD was lower than typically developing counterparts. Folate receptor autoantibodies are also common in the general population and in pregnant women (Berrocal-Zaragoza et al., 2009; Molloy et al., 2009). Rossignol & Frye (2021) also found that these antibodies were extremely common in parents (45%) and neurotypical siblings (61%) of individuals with autism. Overall, it is not clear if high levels of folate receptor autoantibodies cause ASD, if ASD causes high levels of folate receptor autoantibodies, or if the two are affected by a third, unknown cause.

Is There Science Behind the Use of Leucovorin?

In 2013, Frye et al. conducted the first study to evaluate the treatment effects of leucovorin alone and determined that leucovorin may increase communication skills of children with ASD who did not have the severe neurologic impairments associated with cerebral folate deficiency (Frye et al., 2013). After collecting blood samples, the authors separated participants into groups based on folate receptor autoantibody concentration values to determine “high” and “low” concentration levels. It is unclear if these concentration values were determined based on the impact folate receptor autoantibodies may have on the body or were arbitrarily determined. They then evaluated the impact of leucovorin intervention on each group of participants. Among 70 children who were folate receptor autoantibody positive, 44 were treated with oral leucovorin and 26 served as controls. The study found significant improvement in the group of children treated with leucovorin compared to the untreated control group in verbal communication, as well as several secondary outcomes (Frye et al., 2013). The researchers reported that individuals who tested positive for autoantibodies (regardless of concentration level) demonstrated improvements in language and communication domains after leucovorin supplementation. However, as the authors acknowledged, this study was not a clinical trial; the physicians and parents of children who participated in the study knew they were given leucovorin, and the behavioral outcomes were based on subjective parent report rather than direct observation and objective data collection. The authors directly addressed these limitations and requested that more research be conducted to ensure similar outcomes would be observed when physicians and parents are unaware of whether their child received leucovorin treatment and when objective data on behavior changes of participants are collected.

Extending this work, Frye et al. (2018) conducted a double-blind, placebo-controlled, randomized clinical trial comparing changes in language scores on ability-appropriate standardized assessments for 48 children assigned to one of two groups. In other words, neither the physician nor the parents of the children were aware of if their child was taking placebo or leucovorin capsules, and the researchers collected data on scores of standardized language assessments that were selected based on the participant’s current skillset. All participants in the study were diagnosed with ASD, tested for folate autoantibodies, and had documented language impairments. The participants were separated into two groups. Twenty-five children assigned to the control group did not receive any leucovorin supplementation, regardless of folate autoantibody levels or language impairment. Twenty-three children in the experimental group received 12 weeks of leucovorin supplementation. Results indicated that language assessment scores for individuals who received leucovorin supplements significantly improved compared to the control group, 65% of participants (15 of 23) who received leucovorin supplements compared to 24% of participants (6 of 25) from the control group. Further, most of the individuals in the leucovorin group who showed improvements on the language assessment also tested positive for folate autoantibodies.

There are two major strengths to this study. First, Frye et al. (2018) used a direct measure of behavior by directly testing the language abilities of each participant instead of relying on parent reports. Second, the researchers requested that parents not change any medications, interventions, or services for their child over the course of the 12 weeks. Unfortunately, the authors did not share if any parents reported changes during the study, regardless of the request.

Despite these strengths, it is important to note a limitation of Frye et al. (2018) that may influence a caregiver’s decision to give their child leucovorin. Specifically, despite the direct measure of participant responses during language assessments, it is unknown if the statistically significant changes in the assessment scores also represent socially significant changes that would improve a participant’s ability to communicate in their everyday life. Individual-level data that would allow visualization of each participant’s change over the study period were not presented. As with the previous study, Frye et al. reported that these results were preliminary and additional research evaluating the use of leucovorin with a larger number of participants in well-designed trials across clinical locations and over longer periods of time should be evaluated before leucovorin is considered an evidence-based intervention for communication deficits in individuals with ASD.

The largest double-blind study evaluating the effects of leucovorin in 77 children with ASD was published in 2024. However, after concerns about the data and statistical analyses were raised, and post-publication review was unable to replicate the results reported in the article, the journal editor retracted the article (Panda et al., 2026). Retraction means that the article is removed from the scientific record because the findings are no longer considered to be reliable.

Studies comparing pre-treatment to post-treatment scores on the Childhood Autism Rating Scale (CARS) have provided little substantive evidence that leucovorin is an effective treatment for children with ASD. The CARS is a commonly used ASD diagnostic assessment used by trained clinicians to evaluate ASD indicators through direct observation (Schopler et al., 2010). It is also commonly used in research to evaluate changes in ASD symptoms during research. For example, Ramaekers et al. (2019) compared pre-treatment to post-treatment CARS scores in 82 children who were treated with leucovorin and other dietary supplements over a period of 2 years. Before the study, all participants were assessed using the CARS. Following this initial assessment, those in the treatment group received additional vitamin and mineral supplements to meet, but not exceed, daily recommended dietary guidelines. Those receiving leucovorin started at 0.5 mg per kilogram of bodyweight daily, with the dosage potentially increasing to a maximum of 50 mg per day if no clinical response occurred. The authors did not define what constituted a “clinical response.” The control group received no vitamin supplements or leucovorin. After two years, only participants in the treatment were re-evaluated using the CARS. Results of the study suggest that CARS scores improved more for the treatment group, who received leucovorin and dietary supplements, compared to the pre-treatment scores of the control group. This is very different from evaluating the change in CARS score for individuals in both groups over 2 years, as it is unclear if the control group would have shown similar improvements if they were retested. Additionally, the researchers did not account for other variables that were likely to influence the CARS scores, such as the treatment protocol consisting of various supplements in addition to leucovorin, other treatments (e.g., Applied Behavior Analysis [ABA] therapy or other evidence-based interventions), or natural development (physical and psychological) over the two-year period. Because participants may have received a variety of evidence-based interventions that were not controlled for, it is impossible to definitively determine if the changes in the CARS were caused by leucovorin instead of an evidence-based intervention. For more information about these limitations, please see the articles by Frampton (2024), Frampton and Rocheleau (2024), and Rey and O’Neil (2024) from the Association for Science in Autism Treatment.

Last, Vasconcelos et al. (2025) systematically reviewed published research on the relationship between folic acid and ASD. Their review included eight studies that evaluated the effects of leucovorin on blood concentrations of folic acid and measured ASD symptoms via surveys. Participants in these studies had an average age ranging from 2.4 to 16.3 years. Sample sizes of the included research ranged from 12 to 166 participants. All participants were diagnosed with ASD. The studies included in the review varied in procedures and standards for drug trial research. Overall, Vasconcelos et al. (2025) found improvements in expressive communication, irritability, and completion of activities of daily living. Notably, all the studies in the review were group designs that looked at overall outcomes for the group, so the effects of leucovorin on individual behavior changes cannot be determined from this research. Furthermore, the authors highlighted that few standards were present across the reviewed research. For example, the dosage of leucovorin, the assessment tools used, and the skill domains of participants changed across the studies included in the review. Given that researchers were typically looking at different outcome measures and rarely directly observed behavior (in other words, changes in behavior were determined from caregiver reports), it is difficult to determine what, if any, behaviors were directly influenced by leucovorin. It is also not clear if any of the included studies controlled for the presence of additional therapies such as ABA, occupational, physical, or speech-language therapies. We agree with the authors’ conclusion that recommended interventions for ASD should be highly individualized because every person diagnosed with ASD may present with different symptoms.

What is the Gist?

Despite widespread promotion of leucovorin as a “miracle drug” for individuals with ASD, it cannot be considered an evidence-based intervention at this time. Although leucovorin supplements may be beneficial in achieving adequate levels of folic acid for individuals with ASD who have a deficiency, it must be emphasized that there is no firm support for the claim that lower levels of folic acid in the brain or higher levels of autoantibodies in the blood cause ASD. Right now, there is no strong empirical research evidence that treatment with leucovorin improves communication, reduces challenging behavior, or otherwise enhances the lives of children with ASD.

The authors of most published papers evaluating the use of leucovorin for ASD have acknowledged the need for more research to determine whether leucovorin is a safe and effective treatment for children with ASD. In fact, the lack of adequate evidence that leucovorin is safe and effective for ASD-related symptoms has been pointed out in statements from medical professional organizations such as the American Academy of Pediatrics, American Psychiatric Association, Child Neurology Society, and Society for Developmental and Behavioral Pediatrics; and all of these expert groups have recommended against its routine use for this purpose (American Academy of Pediatrics, 2025; American Psychiatric Association, 2025; Child Neurology Society, 2026; Society for Developmental and Behavioral Pediatrics, 2025).

Here, we offer some suggestions for researchers as they attempt to move forward with answering open questions, and for caregivers, who elect to have their children treated with leucovorin.

For researchers: We recommend those interested in leucovorin as an intervention for ASD focus on (1) determining clear diagnostic criteria for cerebral folate deficiency syndrome, (2) evaluating the relationships between folate receptor autoantibodies, CSF folate levels, and ASD to determine causality, (3) conducting well-designed, randomized, controlled clinical trials evaluating observable (measurable) behavior changes for those receiving leucovorin and those receiving placebo, (4) conducting single-subject evaluations to determine possible subsets of the population with ASD who may benefit from leucovorin supplementation the most. It will also be important to determine whether treatment with leucovorin is safe by systematically monitoring for adverse effects in both the short-term and the long-term.

For caregivers: As with all interventions aiming to change behavior for individuals with ASD, we recommend taking the least restrictive, least harmful route to achieve the desired behavior change for your loved one. Based on the current state of research, we recommend that if you are going to use leucovorin, you should work with a behavior analyst to assist you with determining desired behavior change goals, collecting initial data on your primary concerns, and measuring changes in your loved one’s behavior over time to determine if the supplement is supporting or limiting your loved one’s developmental and behavioral goals. We also recommend working with the prescribing healthcare provider to monitor for any side effects that may occur with taking leucovorin.

What Else Should We Consider?

Either in place of leucovorin or in addition to leucovorin supplements, it is important to consider scientific evidence-based behavioral and environmental supports for individuals with ASD. ABA is widely recognized as an evidence-based intervention and considered crucial for supporting individuals with ASD in achieving specific developmental and behavioral goals (American Academy of Pediatrics [AAP], 2020). Specifically, ABA has been shown to be effective in teaching functional communication and can support caregivers in identifying appropriate methods of communication for individuals with ASD (Carr & Durand, 1985; Cicero, 2024; Valentino et al., 2019). There is also over forty-years of behavior analytic research on evaluating various techniques and interventions to decrease common challenging behaviors displayed by individuals with ASD, such as aggression, tantrums, or self-injurious behavior (Melanson & Fahmie, 2023; Tereshko, 2025). If your loved one needs support with communication, challenging behavior, or skill acquisition, you can find a treatment summary on ABA by McKenna (2024) from the Association on Science in Autism Treatment.

Parents or caregivers of individuals with ASD should also consider consulting a pediatrician or primary care provider in identifying any nutritional or biological needs a loved one may need. This may include support in making dietary or medication changes. Current research suggests that individuals with ASD are more likely to consume less protein, vitamins, and minerals compared to neurotypical peers (Alhrbi et al., 2025). Restricted diets, increased mealtime challenging behavior, and gastrointestinal symptoms are likely to contribute to the observed nutritional deficits. Clearly, more research and support for individuals with autism and their loved ones from a biological and behavioral standpoint is necessary. Dietary guidelines as published by the United States Department of Agriculture and the United States Department of Health and Human Services highlight the vital role of meeting nutritional and biological needs. These guidelines may prove useful to ensure your loved one is getting the nutrients they need. We also recommend consulting with your primary care provider before beginning any dietary supplements or changes in medication.

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Reference for this article:

Hardesty, E., Ashbeck, K. Sharp, I., & Zane, T. (2026). Leucovorin: Is there science behind that? Science in Autism Treatment, 23(8).

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Leucovorin: Is There Science Behind That?

Leucovorin:
Is There Science Behind That?