Stay Alert for Leucovorin Rxs to Treat 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.

 

You may start to see Rxs for leucovorin to treat autism.

Oral 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)...or low folate levels in the brain. And FDA’s move has stirred questions about using leucovorin for autism.

This is because one theory links CFD to autism...since some patients with CFD are shown to have autism features (repetitive behaviors, sensory processing issues, etc). Be aware 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 confirmed CFD.

Know that several clinical 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.

These studies included kids under 13 and enrolled fewer than 100 people...much less than we typically expect for FDA approval. And most trials only lasted up to 12 weeks...we don’t have long-term data.

Keep in mind that leucovorin can also be costly. For example, it costs about $600/month to give 50 mg/day to a 25 kg (55 lb) child.

If you get an Rx for leucovorin, watch for mix-ups.

For instance, it’s easy to confuse folINIC acid...leucovorin’s other name...with folIC acid. They’re similar...but they are NOT the same med.

Confirm the patient’s weight so your RPh can verify doses. Remember that 1 kg equals 2.2 lbs when converting weights or calculating doses.

Use barcode-scanning technology to double-check tablet strengths, since leucovorin comes as 5, 10, 15, and 25 mg tabs.

Expect patients to ask your RPh about using OTC folic acid products instead. But 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.”

But 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 you hear conflicting info from social media, family members, etc. Review our Discussing Medical Misinformation chart for resources that can help clear up confusion.

 

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.