Unpack Evidence Behind Using Leucovorin for Autism and “CFD”

Posted October 15, 2025: Article in Progress. We’re releasing this article ahead of our November 2025 issue to quickly provide information to our readers. The information contained in this version is based on the best evidence available to us as of the date of posting. The final version may include revised recommendations.

 

Patients are asking about using leucovorin to treat autism.

We know po leucovorin (folinic acid) is FDA-approved to counteract methotrexate toxicity when treating cancer, autoimmune disorders, etc.

But FDA recently approved leucovorin tabs for patients with cerebral folate deficiency (CFD), stirring up questions about using it for autism.

This is because one theory links autoantibodies against folate receptors in the brain to CFD...and some patients with CFD are shown to have autism features (repetitive behaviors, sensory issues, etc).

Explain that leucovorin’s evidence in CFD and autism is limited.

For example, FDA’s approval is based on about 40 case reports of adults and kids given po leucovorin for genetically confirmed CFD.

Share that several randomized, controlled trials in kids with autism suggest po leucovorin up to 2 mg/kg daily or divided bid (max 50 mg/day) may slightly improve some symptoms (verbal skills, etc) on scoring tools.

Point out that these studies included kids under 13 and enrolled fewer than 100 subjects each...much less than we typically expect for approval. And most trials only lasted up to 12 weeks...we don’t have long-term data.

Stress that leucovorin is well tolerated...but costs can add up. For example, it costs about $600/month to treat a 25 kg child.

Expect patients to ask about using OTC folic acid supplements instead. Folinic acid and folic acid are both used to make DNA components ...but folinic acid doesn’t need enzyme activation in the body to work.

Explain that only one small study used folic acid in autism...plus supplements are NOT regulated by FDA, may have contaminants, etc.

Similarly, anticipate that patients may try to buy leucovorin from gray markets...or get IV doses from “infusion spas” or “hydration clinics.”

Warn about possible counterfeit products and point out that the limited data we have is only for ORAL leucovorin. Caution that IV spas or clinics may be unregulated and IV admin can have complications (infections, etc).

Stay alert for potential supply issues...shortages may occur as leucovorin demand spikes.

Don’t be surprised if patients get conflicting info from social media, family members, etc. Review our Discussing Medical Misinformation chart for resources to help patients make informed decisions.

 

REFERENCES

  • FDA. FDA Takes Action to Make a Treatment Available for Autism Symptoms. September 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms (Accessed September 26, 2025).
  • FDA. Approval of Previously Withdrawn New Drug Application for WELLCOVORIN (Leucovorin Calcium) Tablets. September 24, 2025. https://www.federalregister.gov/documents/2025/09/24/2025-18510/approval-of-previously-withdrawn-new-drug-application-for-wellcovorin-leucovorin-calcium-tablets (Accessed October 2, 2025).
  • 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 Nov 3;11(11):1141.
  • Panda PK, Sharawat IK, Saha S, et al. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024 Nov;183(11):4827-4835.
  • Batebi N, Moghaddam HS, Hasanzadeh A, et al. Folinic Acid as Adjunctive Therapy in Treatment of Inappropriate Speech in Children with Autism: A Double-Blind and Placebo-Controlled Randomized Trial. Child Psychiatry Hum Dev. 2021 Oct;52(5):928-938.
  • Sun C, Zou M, Zhao D, et al. Efficacy of Folic Acid Supplementation in Autistic Children Participating in Structured Teaching: An Open-Label Trial. Nutrients. 2016 Jun 7;8(6):337.
  • Medication pricing by Elsevier, accessed September 2025.