Glutamate Neuro-Excitotoxicity in GWI
| Status: | Recruiting |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 1/11/2018 |
| Start Date: | November 14, 2017 |
| End Date: | August 31, 2020 |
| Contact: | Kathleen Holton, PhD |
| Email: | holton@american.edu |
| Phone: | 202-885-3797 |
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.
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.
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.
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.
Inclusion Criteria:
- Males & Females
- Served (and was deployed) in the Persian Gulf War
- Fulfill both Kansas and CDC definitions of GWI
- Stable medication regimen for 3 or more months
Exclusion Criteria:
- Active Duty Military
- Current substance use disorder
- Unwilling to change diet for 2 months
- Severe asthma requiring past hospitalization
- Seizure disorder
We found this trial at
1
site
Washington, District of Columbia 20014
Principal Investigator: Kathleen F Holton, PhD
Phone: 202-885-3810
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