I've been watching this closely and have been starting my patients on this over the last few months. As expected I see some significant responses and some that it does nothing at all. Shockingly insurance has been covering it. With the recent press conference about it I figured I would get ahead of the curve a bit and post some information on it.

I've just been prescribing without testing as the test for Cerebral Folate Defiency (CFD) is a spinal tap for CSF and often not covered by insurance. The other potential test is a Folic Acid Recepter alpha antibody test that is again investigational and not covered by insurance and takes a while to get back. Since leucovorin is basically a super vitamin I feel it is quicker, cheaper, and safer to just try it and see. It is estimated from small studies that anywhere from 40-70% of autism patients have CFD.

In full disclosure I am looking at investing in TEVA who is one of the main generic manufacturers of Leucovorin today as it is going to explode in demand.


Here is a summary of the research.

Comprehensive Research Pack
Folinic Acid (Leucovorin), Cerebral Folate Deficiency Syndrome (CFDS), and Autism Spectrum Disorder
This research pack compiles peer-reviewed studies, reviews, and reference materials on folinic acid
(leucovorin), Cerebral Folate Deficiency Syndrome (CFDS), and their relevance to autism spectrum
disorder (ASD). It is designed for broad use across audiences including caregivers, pediatricians, health
departments, legislators, policymakers, media professionals, and advocacy organizations. The goal is to
provide accurate, evidence-based information to support informed decision-making, public education, and
clinical guidance.

Key Takeaways
High prevalence: 58-76% of children with autism test positive for folate receptor alpha autoantibodies
(FRAAs).
Responsiveness: Folinic acid is associated with improvements in expressive language, communication,
and adaptive behavior in select subgroups (e.g., CFDS, FRAA-positive).
Mechanism: CFDS involves low folate levels within the central nervous system, often due to folate
receptor autoantibodies; folinic acid can bypass transport bottlenecks.
Safety & Feasibility: Folinic acid is an FDA-approved medication with decades of safe pediatric use; cost
and availability are not primary barriers.
Equity gap: Absent clear guidance, families face inconsistent access, off-label hesitancy among clinicians,
and unsupervised supplement use.

Clinical Trials
Frye, R. E., Slattery, J. C., Quadros, E. V., et al. (2016). Folinic acid improves verbal communication in
children with autism and language impairment: a randomized double-blind placebo-controlled trial.
Molecular Psychiatry, 21, 241250.
Ramaekers, V. T., et al. (2007). Folinic acid treatment for cerebral folate deficiency associated with autism.
Neuropediatrics, 38(5), 206210.
Moretti, P., et al. (2008). Cerebral folate deficiency with developmental delay, autism, and response to
folinic acid. Neurology, 71(9), 632639.

Reviews & Meta-Analyses
Rossignol, D. A., & Frye, R. E. (2021). Cerebral folate deficiency, folate receptor alpha autoantibodies and
leucovorin treatment in autism spectrum disorders: A systematic review and meta-analysis. Nutrients,
13(3), 818.
Frye, R. E., et al. (2020). Treatment of folate metabolism abnormalities in autism spectrum disorder. NIH
Research Report.
Rossignol, D. A., & Frye, R. E. (2012). A review of research trends in physiological abnormalities in autism
spectrum disorders. Current Opinion in Pediatrics, 24(6), 621627.
Ramaekers, V. T., & Sequeira, J. M. (2011). Autoantibodies to folate receptors in autism spectrum disorder.
Neurochemical Research, 36(2), 341347.
Mechanisms & Folate Pathway Research
Quadros, E. V., et al. (2005). Folate receptor autoimmunity and cerebral folate deficiency. Neurology, 65(3),
512514.
Ramaekers, V. T., & Quadros, E. V. (2004). Cerebral folate deficiency: differential diagnosis and treatment.
Neuropediatrics, 35(6), 325332.
Bliek, E. A., et al. (2017). Folate receptor autoantibodies in autism spectrum disorder and their clinical
correlates. Molecular Autism, 8, 53.
Ramaekers, V. T., Blau, N., et al. (2002). Folate receptor autoimmunity and cerebral folate deficiency in
autism. Neuropediatrics, 33(6), 275281.
Related Research on FRAAs & Neurodevelopment
Wells, E., et al. (2024). Folate receptor alpha autoantibodies in pediatric autoimmune neuropsychiatric
disorders. Journal of Neuroimmunology.
Sequeira, J. M., et al. (2004). Autoantibodies to folate receptors in women with neural tube defect
pregnancies. New England Journal of Medicine, 350, 134142.
Frye, R. E., & James, S. J. (2014). Metabolic pathology of autism spectrum disorder: clinical considerations.
Metabolic Brain Disease, 29, 281292.
Frye, R. E., et al. (2013). Mitochondrial dysfunction in autism spectrum disorder: unique abnormalities and
targeted treatments. Molecular Psychiatry, 18, 196204.
Prevalence & Public Health Context
University of Minnesota, Institute on Community Integration (2025). New Autism Prevalence Findings in
Minnesota: 1 in 28 Children Identified with ASD. MN-ADDM Report.
Maenner, M. J., et al. (2023). Prevalence and characteristics of autism spectrum disorder among children
aged 8 years Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020.
MMWR Surveillance Summaries, 72(2), 114.
Books & Chapters
Frye, R. E., & Rossignol, D. A. (2020). Autism Spectrum Disorder and Metabolism: A Comprehensive
Guide. Springer.
Ramaekers, V. T., & Quadros, E. V. (2019). Cerebral Folate Deficiency Syndrome. In: Handbook of Clinical
Neurology, Vol. 162 (Metabolic Neurology). Elsevier.
Chauhan, A., Chauhan, V., & Brown, W. T. (eds.). (2009). Autism: Oxidative Stress, Inflammation, and
Immune Abnormalities. CRC Press.
Melillo, R. (2015). Disconnected Kids. Penguin.
Notes for Use
This pack is intended for broad distribution: caregivers, clinicians, health departments, legislators,
policymakers, media, and advocacy organizations.
Use the Key Takeaways for quick overviews in meetings, testimony, or interviews; reference detailed
studies when speaking with physicians, researchers, or policy staff.
Supports education on both clinical and policy dimensions: supervised medical treatment, reducing
supplement risks, and improving equity in care access.

Can you share more on "significant responses"? Which symptoms/behaviors (if those are the correct terms to use) are you seeing being modified?

spike427 said:

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Can you share more on "significant responses"? Which symptoms/behaviors (if those are the correct terms to use) are you seeing being modified?

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Speech, Aggression, potty training, stimming.

Are you using it on older kids or just younger? My son is 15 and is high-functioning but has some stimming and minor aggression/tantrums, mostly just when frustrated. He also has almost no situational awareness and struggles to focus on "uninteresting" subjects, although that's probably more a 15 year old boy issue.

jenn96 said:

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Are you using it on older kids or just younger? My son is 15 and is high-functioning but has some stimming and minor aggression/tantrums, mostly just when frustrated. He also has almost no situational awareness and struggles to focus on "uninteresting" subjects, although that's probably more a 15 year old boy issue.

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All ages. If they have CFD it will help at any age. Likely more benefit younger but there is very limited data at this time.

I've seen benefit in pre-adolescents. I've only been prescribing it as they come in for a few months so haven't really seen any concrete benefit in teens at this point.

I appreciate your post - I'll talk to my pediatrician. Anything that can help would be a godsend. Is it being covered under insurance in most cases, in your experience?

ETA Just re-read your post and saw it is.

Will be interesting to see if future investigations on a large scale support this on a population level. Anecdotally I'm sure some benefit, even if the confidence interval crosses 0.

Incidentally, medicaid is supposed to cover this (per RFK), however there have been decent sized medicaid cuts. So not sure where the money is going to come from.

bigtruckguy3500 said:

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Will be interesting to see if future investigations on a large scale support this on a population level. Anecdotally I'm sure some benefit, even if the confidence interval crosses 0.

Incidentally, medicaid is supposed to cover this (per RFK), however there have been decent sized medicaid cuts. So not sure where the money is going to come from.

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NIH.

KidDoc said:

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jenn96 said:

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Are you using it on older kids or just younger? My son is 15 and is high-functioning but has some stimming and minor aggression/tantrums, mostly just when frustrated. He also has almost no situational awareness and struggles to focus on "uninteresting" subjects, although that's probably more a 15 year old boy issue.

---

All ages. If they have CFD it will help at any age. Likely more benefit younger but there is very limited data at this time.

I've seen benefit in pre-adolescents. I've only been prescribing it as they come in for a few months so haven't really seen any concrete benefit in teens at this point.

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is this a once you start taking it you probably have to take it forever type of deal?

Ragoo said:

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KidDoc said:

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jenn96 said:

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Are you using it on older kids or just younger? My son is 15 and is high-functioning but has some stimming and minor aggression/tantrums, mostly just when frustrated. He also has almost no situational awareness and struggles to focus on "uninteresting" subjects, although that's probably more a 15 year old boy issue.

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All ages. If they have CFD it will help at any age. Likely more benefit younger but there is very limited data at this time.

I've seen benefit in pre-adolescents. I've only been prescribing it as they come in for a few months so haven't really seen any concrete benefit in teens at this point.

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is this a once you start taking it you probably have to take it forever type of deal?

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Highly likely as they have a basic biochemical mutation or blocking antibodies. Maybe a bone marrow transplant could get rid of the antibodies but that is high risk.

aa4136 said:

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Can you guys save the leucovorin supply for my colon cancer and CNS lymphoma patients who need it? I really dont want to deal with another shortage of it again...sigh.

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I can guarantee you there are going to be shortages within the next few months.

Curiouswhat strength (5-25 mg seems to be the pill sizes I see) do you prescribe based on age/weight and is this something you can prescribe over the phone or does it require an in-person visit? Also, for those that do see results, how quickly are your patients seeing results?

DeLaHonta said:

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Curiouswhat strength (5-25 mg seems to be the pill sizes I see) do you prescribe based on age/weight and is this something you can prescribe over the phone or does it require an in-person visit? Also, for those that do see results, how quickly are your patients seeing results?

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Start at 0.5 mg/kg/day twice a day up to 2 mg/kg/day divided into two doses. Can see benefit in under a month and maximal benefit around 6 months in the small studies that have been done.