Glutamate Neuro-Excitotoxicity in GWI
Condition: Gulf War Syndrome
MeSH terms: Persian Gulf Syndrome
Study type: Interventional

Summary: 
      The objective of the proposed research is to examine whether dietary exposure to food
      additives containing glutamate may be contributing to symptoms in Gulf War Illness (GWI). The
      rationale for proposed study comes from data in the fibromyalgia field which suggests that
      reducing the consumption of dietary glutamate can reduce over-excitation in the nervous
      system, leading to symptom improvement. In prior research, a low-glutamate diet (restricting
      food additive consumption) was tested in fibromyalgia patients. After one-month on the diet,
      84% of patients had >30% of their symptoms go away (with 11 symptoms remitting on average),
      and 8 subjects had complete remission of all symptoms. Subjects then had a significant return
      of symptoms upon challenge with monosodium glutamate (MSG) as compared to placebo. Since
      there is almost complete symptom overlap between fibromyalgia and GWI, it is of utmost
      importance to test this diet as a low-cost treatment option in GWI patients.

      The findings from this research will ultimately be applicable to all GWI patients and
      potentially to other veterans with a similar symptom profile as well. The ultimate impact of
      this research could be quite profound, as it has the potential to impact all of the symptoms
      of GWI, as opposed to being a proposed treatment for only one of the symptoms. This dietary
      treatment has been shown to dramatically affect symptoms like fatigue, cognitive dysfunction,
      and pain; and thus, has the potential to dramatically improve quality of life for these
      individuals. Potential benefits of the treatment are great, and risks are minimal, as the
      treatment involves shifting the diet to a healthier, whole-food approach.

      First, the study will confirm or negate the idea that abnormal glutamate signaling in the
      nervous system could be causing symptoms in GWI. Second, if found to be successful, then this
      will provide a low-cost, easy-to-implement treatment option for the many veterans suffering
      from this multi-symptom illness. Third, this research could lead to future studies to
      identify potential causes of this abnormal neurotransmission, to help prevent future illness
      onset.
    

Detailed description: 
      Objective/ Hypothesis: The objective of this clinical trial is to test the effectiveness of a
      low-glutamate diet in GWI patients, as a way to mediate symptom occurrence by reducing excess
      glutamatergic neurotransmission.

      Specific Aims:

      Aim 1- Determine if GWI is a glutamate neurotoxicity disorder, by testing whether reduced
      exposure to dietary glutamate can modulate symptoms. Hypothesis: Dietary glutamate
      restriction will significantly reduce GWI symptoms, including fatigue, cognitive dysfunction,
      pain, problems sleeping, headache/migraine, and diarrhea; as measured by symptom
      questionnaire, dolorimetery, computerized cognitive testing, EEG and fMRI memory testing.
      Additionally, brain glutamate levels will be reduced after one month on the diet, as measured
      by magnetic resonance spectroscopy (MRS).

      Aim 2- Confirm that altered dietary glutamate exposure was the cause of symptom improvement.

      Hypothesis: Challenge with MSG, as compared to placebo, in a randomized, double-blind,
      placebo-controlled crossover challenge, will significantly increase the occurrence of
      symptoms, cause increased pain sensitivity as measured by dolorimetry, increased excitatory
      neurotransmission as measured by EEG, and a worsening of cognitive function as measured by
      computerized cognitive testing.

      Study Design: 40 subjects will be recruited from around the US . After phone screening,
      eligible individuals will travel to Washington DC for their first visit, where subjects will
      undergo baseline testing, including assessment of symptoms, cognition, brain glutamate levels
      and working memory testing using fMRI. For phase 1, subjects will be randomized to a
      low-glutamate diet (n=20) or a waitlisted group (n=20 as controls), and symptom occurrence
      will be compared after one month. Waitlisted participants will follow the low-glutamate diet
      over the following month. At the end of phase 1, subjects will return to DC, will undergo
      post-diet assessment of symptoms (same as baseline), and then will move onto Phase 2 of the
      study, a randomized, double-blind, placebo-controlled crossover challenge, to test whether
      symptoms recur upon challenge with MSG and not with placebo. Subjects will be randomized as
      to which contingency (MSG or placebo) is received first, and will receive MSG for 3
      consecutive days on one of the weeks and placebo for 3 consecutive days on the other week.
      Symptoms, EEG and cognition will be assessed on day 3 of challenges each week. All subjects
      will still be following the low-glutamate diet during the challenge period, so their only
      exposure to glutamate will be from the week they receive the MSG.
    

Intervention name(s): Low-glutamate diet
Intervention type(s): Other
Intervention description(s): The dietary intervention consists of a one-month low-glutamate diet, followed by a randomized crossover challenge with MSG and placebo to measure return of symptoms.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Subjects will be randomized to immediately start a one-month dietary intervention restricting consumption of glutamate, or will be waitlisted as a control group for the first month, and then will begin the one-month dietary intervention period (which will be completed at home). Then subjects will return to DC, will complete all measures again, and then will participate in a double-blind, placebo-controlled, crossover challenge with MSG and placebo.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: MSG; Gulf War Syndrome; Diet; Glutamate