Folate Rechallenge

This study has been completed.
Information provided by (Responsible Party):
Baylor College of Medicine Identifier:
First received: May 5, 2008
Last updated: September 10, 2015
Last verified: September 2015

New evidence suggests that autistic disorder (AD) may be associated with abnormalities in folate metabolism, which is a process that affects genetic expression by facilitating the formation of methyl donors for DNA methylation. Limited data show that some children with AD show behavioral improvements with folic acid (FA) therapy, while others show a worsening effect. If behavioral worsening is linked with abnormalities in folate metabolism, then nutritional modifications could normalize these processes and result in clinical improvements. To address this premise, we propose a randomized, placebo-controlled crossover pilot study with two phases. The first phase will focus on the behavioral and biochemical responses of children with AD to high-dose folic acid supplementation. Because FA is an inactive folate that requires biochemical conversion to become active, and select genotypes impede this conversion, our general hypothesis is that FA will yield behavioral improvements in some children but exacerbate problem behaviors in others. During the second phase, children who had a worsened behavioral response to FA during phase 1 will participate in an open-label trial of high-dose Metafolin® supplementation. The focus here would similarly be on the behavioral and biochemical outcomes of participating children following treatment with the study supplement. Because Metafolin® is an active folate metabolite that should not be affected by genotypes in the folate pathway, our general hypothesis for phase 2 is that Metafolin® would yield behavioral improvements without the risk for behavioral worsening. Results from this project may provide support for continued study of the potential relationship between folate metabolism and problem behaviors among children with AD, potentially justifying the need to examine effects of folate supplementation among a larger sample of affected children.

Condition Intervention Phase
Dietary Supplement: Folic acid
Dietary Supplement: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Folate Rechallenge: A Pilot Study

Resource links provided by NLM:

Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Behavior as measured with the Aberrant Behavior Checklist (ABC) and the Pervasive Developmental Disorder Behavior Inventory (PDDBI). [ Time Frame: Pre-, mid-, and post-treatment during each phase (folic acid and placebo). ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Level of folate metabolites in plasma and site-specific DNA methylation. [ Time Frame: Pre- and post-treatment during each phase (folic acid and placebo). ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: May 2007
Study Completion Date: February 2015
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Dietary Supplement: Folic acid
Compounded capsule, 7.6mg, taken orally, twice daily for 4 weeks.
Other Name: folate
Placebo Comparator: 2 Dietary Supplement: Placebo
Compounded capsule of NaCl, taken orally, twice daily for 4 weeks.

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Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Child participant has a confirmed diagnosis of AD by Autism Diagnostic Observation Schedule and Autism Diagnostic Interview--Revised criteria
  2. Child participant is in stable condition with relatively good control of seizures and no other significant medical problems, including liver, kidney, or heart problems, at the time of entrance to the study. If the child participant is taking medication for a seizure disorder, the investigators will assess his/her eligibility with particular regard to type of seizure medication and other health-related information gleaned during the medical examination
  3. Child participant and parents are willing to comply with the proposed treatments
  4. Child participant is able to take oral medication
  5. Family is fluent in the English language
  6. Parent/caregiver agrees to provide behavioral data on participating children at the requested time points
  7. Family agrees to be contacted weekly by study personnel during the treatment phases

Exclusion Criteria:

  1. Child participant has co-morbid medical and/or genetic disorders, including celiac disease
  2. Child participant has a history of liver or renal disease
  3. Child participant is currently being treated for a serious acute illness
  4. Child participant has a known allergy to any of the proposed supplements
  5. Child participant has uncontrolled seizures
  6. Child participant meets criteria for Asperger's syndrome, PDD-NOS, or does not meet strict criteria for AD
  7. Family is not proficient in the English language
  Contacts and Locations
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Please refer to this study by its identifier: NCT00672360

United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Baylor College of Medicine Identifier: NCT00672360     History of Changes
Other Study ID Numbers: H-20959
Study First Received: May 5, 2008
Last Updated: September 10, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
Autism Spectrum Disorder

Additional relevant MeSH terms:
Vitamin B Complex
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs
Vitamins processed this record on October 13, 2015