# Confirmatory Double-Blind Placebo-Controlled Efficacy Trial of a Gluten-Free Diet in a Subgroup of Persons with Schizophrenia Who Have High Levels of IgG Anti-Gliadin Antibodies

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $955,279

## Abstract

Summary
 In the past decade extensive research has shown that about one in three persons with schizophrenia
have high levels of anti-gliadin antibodies of the IgG type (AGA IgG). This gluten sensitive group could
represent an as-yet-unrecognized etiology. In the past, removing gluten from the diet has been shown to
diminish or eliminate schizophrenia symptoms in dramatic case reports and small clinical trials, but not
consistently. The ability to screen for AGA IgG was not well developed until the 1990's, so that not a single one
of the previous gluten-free diet trials screened schizophrenia patients for AGA IgG, meaning that 2/3 of the
participants in these studies would have been unlikely to benefit from the gluten-free diet (GFD). We have
completed 2 clinical trials (one open label, one randomized double blind placebo controlled) demonstrating that
people with schizophrenia having this AGA IgG phenotype benefit from a GFD and that strong improvement in
negative symptoms is linked to changes in levels of AGA IgG. We have also shown that AGA IgG is linked to
both peripheral (i.e. cytokines) and central (i.e., magnetic resonance spectroscopy (MRS) neuroimaging)
measures of inflammation. This application proposes a confirmatory double-blind randomized placebo-
controlled trial of the effects of a GFD in an inpatient setting in people with schizophrenia or schizoaffective
disorder who are positive to AGA IgG. We will screen about 600-800 persons with chart diagnosis of
schizophrenia for high levels of AGA IgG, recruiting 50 who meet eligibility criteria into an inpatient unit with
controlled gluten free diet (less than 15 mg of gluten per day) for five weeks. Each day the experimental group
will receive a shake containing rice flour (25 gram), and the control group an identical protein shake containing
gluten flour (25 gram). We will test potential mechanisms of action linking the target engagement (AGA IgG) to
symptoms via alteration in peripheral measures of immune activation (TNF-α and IL-Iβ) and gut permeability
(zonulin and ASCA), as well as neuroimaging techniques related to neuroinflammation (MRS measures of
myoinositol and total choline).
 Our confirmatory study will be adequately powered to establish the utility of the GFD, or to credibly
demonstrate that it is not effective. If the GFD is effective, as we hypothesize, this would add a new treatment
modality for schizophrenia for the first time in over half a century. In addition, the study would suggest
mechanisms of action and etiologic pathways for the effects of gluten withdrawal. If this treatment is effective, it
would revolutionize personalized medicine in schizophrenia by helping to define the gliadin-sensitive illness
phenotype and by stimulating development of additional treatments of medications which block absorption of
gluten. Negative results would redirect interest from this etiologic pathway for understanding and treatment of
schizophrenia pathophysiology, and forestall unp...

## Key facts

- **NIH application ID:** 9996786
- **Project number:** 5R01MH113617-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** WILLIAM W EATON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $955,279
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996786

## Citation

> US National Institutes of Health, RePORTER application 9996786, Confirmatory Double-Blind Placebo-Controlled Efficacy Trial of a Gluten-Free Diet in a Subgroup of Persons with Schizophrenia Who Have High Levels of IgG Anti-Gliadin Antibodies (5R01MH113617-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996786. Licensed CC0.

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