How A Cancer Drug May Help Some Children with Autism

For decades, oncologists have relied on leucovorin to help reduce the side effects of chemotherapy and to enhance the power of cancer drugs. But it is also being repurposed as a potential treatment for a subset of children with autism. What is the science behind this connection?

Leucovorin or folinic acid is a reduced form of folate, a naturally occurring type of vitamin B9, that is already in an active form and can directly enter cellular metabolism without requiring the reduction steps needed by folic acid. It differs from folic acid, a synthetic form of folate that requires enzymatic conversion to become biologically active. For years, leucovorin was confined mostly to the outpatient oncology wings in the following ways:

1.    As a rescue agent: Chemotherapeutics such as methotrexate block dihydrofolate reductase (DHFR), which is essential for DNA synthesis. While this harms cancerous cells, it also affects healthy cells. Leucovorin, in turn, bypasses this enzyme blockade, thereby diminishing lethal toxicity on healthy cells from folate depletion.

2.    As a chemotherapy enhancer: In regimens with 5-fluorouracil (5-FU), leucovorin boosts its tumor-killing effects. It does so by stabilizing the interaction between 5-FU and thymidylate synthase, making the chemotherapy more effective^1. This stabilization prolongs the thymidylate synthase blockade, extending nucleotide depletion and favoring tumor cell death. Numerous clinical protocols for colorectal cancer rely on this synergy².

Leucovorin’s dual role—rescuing folate metabolism while enhancing fluoropyrimidine efficacy—established a unique therapeutic profile in cancer care. Because the drug is well-tolerated, it has been widely used in cancer regimens, showing low toxicity in most patients. Notably, the mechanisms that render leucovorin effective in cancer treatment may also enhance brain function in individuals experiencing specific metabolic and immune-related folate deficiencies. What are the potential reasons?

Folate and the brain: Is there a link to autism?

Over the past decade, researchers discovered that some children with autism spectrum disorder (ASD) have insufficient folate transport into the brain. This is often associated with autoantibodies, i.e., our own immune system erroneously forming antibodies against the folate receptor alpha (FRAAs), resulting in blocking the primary pathway of vitamin B9 into the brain. Even when its blood levels are normal, brain development is affected, a condition referred to as cerebral folate deficiency³. Healthy brain function requires folate, supporting DNA synthesis, methylation, neurotransmitter metabolism, and antioxidant defense. When its transport or metabolism is impaired, these biochemical functions can break down, especially in developing brains.

Potentially, the neurological benefit of leucovorin’s rescue of folate metabolism lies in that it allows cells to carry on one-carbon metabolism, nucleotide synthesis, and DNA repair, among others, processes fundamental to neural development, synaptic function, and gene regulation. If cerebral folate deficiency impairs these pathways in specific neural circuits, supplemental reduced folate may help alleviate deficits.

Accumulating evidence

While likely not a universal treatment for autism, those with specific metabolic and immune dysfunctions affecting folate supply may benefit from leucovorin therapy. Physicians are increasingly using folate receptor autoantibody testing to identify potential responders. Theoretically, leucovorin should bypass the blocked transport route, as it differs from regular folic acid in that it can utilize alternative transport systems, such as the reduced folate carrier, to cross into the brain. This has opened a therapeutic option for children with autism who test positive for FRAAs or show other signs of vitamin B9-related issues. Clinical and observational data in autism lend some support. For instance:

•    A systematic review and meta-analysis identified ~20 studies, which found that d,l leucovorin (typically 0.5 to 2.5 mg/kg/day) significantly improved communication skills in ASD children, with medium to large effect sizes. Some studies also reported improvements in irritability and social behavior⁴.
•    A retrospective study involving 110 ASD children found that those with higher levels of folate-blocking autoantibodies responded best to leucovorin treatment, particularly in social responsiveness and irritability scores⁵.
•    An open-label study confirmed improvements in core autism symptoms and overall behavior with few adverse effects⁶.

These findings suggest a mechanistic analogy to how leucovorin may aid a subset of autistic children with folate receptor dysfunction, much like it does in oncology patients, by circumventing folate pathway blockades. Backed by decades of pharmacology, leucovorin’s safety record in clinical oncology regimens has been long established, whereas the autism application remains an emerging hypothesis supported by small, controlled trials and biomarker-guided observational data. Larger randomized trials, longer follow-up, and careful biomarker stratification will be essential to validate safety, dosing, and efficacy in this context.

Efforts to find new therapeutic uses for existing drugs have many precedents. Successful examples within the past decade include remdesivir⁷, metformin and propranolol⁸, to name a few. If it can be fully established that this cancer drug can help some children with autism, it underlines the importance of drug repurposing combined with personalized medicine.

References:
1.    Grogan L, Sotos GA, Allegra CJ. Leucovorin modulation of fluorouracil. Oncology (Williston Park), 1993, 7:63-72; discussion 75-6. https://pubmed.ncbi.nlm.nih.gov/8398636/.
2.    Machover D. A comprehensive review of 5-Fluorouracil and leucovorin in patients with metastatic colorectal carcinoma. Cancer, 1997, 80:1179-1187. doi: 10.1002/(SICI)1097-0142(19971001)80:7%3C1179::AID-CNCR1%3E3.0.CO;2-G
3.    Frye RE, Rossignol DA, Scahill L, et al. Treatment of folate metabolism abnormalities in autism spectrum disorder. Semin Pediatr Neurol. 2020, 35:100835. doi: 10.1016/j.spen.2020.100835.
4.    Rossignol DA, Frye RE. Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: a systematic review and meta-analysis. J Pers Med., 2021, 11:1141. doi: 10.3390/jpm11111141.
5.    Frye RE, McCarty PJ, Werner BA, et al. Binding folate receptor alpha autoantibody is a biomarker for leucovorin treatment response in autism spectrum disorder. J Pers Med., 2024, 14:62. doi: 10.3390/jpm14010062.
6.    Frye RE, Lane A, Worner A, et al. The soluble folate receptor in autism spectrum disorder: relation to autism severity and leucovorin treatment. J Pers Med., 2022, 12:2033. doi: 10.3390/jpm12122033.
7.    Santoro MG, Carafoli E. Remdesivir: from ebola to COVID-19. JBiochem Biophys Res Commun., 2021, 538:145-150. doi: 10.1016/j.bbrc.2020.11.043.
8.    Ioakeim-Skoufa I, Tobajas-Ramos N, Menditto E, et al. Drug repurposing in oncology: a systematic review of randomized controlled clinical trials. Cancers, 2023, 15:2972. doi: 10.3390/cancers15112972.