

April 2020

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420 

Prepared by:

Evidence Synthesis Program (ESP) Center

Portland VA Medical Center

Portland, OR 

Devan Kansagara, MD, MCR, Director 

Gulf War Illness: A Systematic 

Review of Therapeutic Interventions 

and Management Strategies 



Authors: 

Principal Investigator: 

Michele Freeman, MPH

Shannon M. Nugent, PhD

Co-Investigators: 

Chelsea K. Ayers, MPH

Kara A. Winchell, MA

Ashlyn Press, MPH 

Maya E. O’Neil, PhD

Devan Kansagara, MD, MCR

Evidence Synthesis Program
GWI Interventions Evidence Synthesis Program

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PREFACE

The VA Evidence Synthesis Program (ESP) was established in 2007 to provide timely and accurate 

syntheses of targeted health care topics of importance to clinicians, managers, and policymakers as they 

work to improve the health and health care of Veterans. These reports help: 

• Develop clinical policies informed by evidence;

• Implement effective services to improve patient outcomes and to support VA clinical practice 

guidelines and performance measures; and 

• Set the direction for future research to address gaps in clinical knowledge.

The program is comprised of 4 ESP Centers across the US and a Coordinating Center located in 

Portland, Oregon. Center Directors are VA clinicians and recognized leaders in the field of evidence 

synthesis with close ties to the Agency for Healthcare Research and Quality (AHRQ) Evidence-based 

Practice Center Program and Cochrane Collaboration. The Coordinating Center was created to manage 

program operations, ensure methodological consistency and quality of products, and interface with 

stakeholders. To ensure responsiveness to the needs of decision-makers, the program is governed by a 

Steering Committee comprised of health system leadership and researchers. The program solicits 

nominations for review topics several times a year via the program website. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, Deputy Director, ESP 

Coordinating Center at Nicole.Floyd@va.gov.

Recommended citation: Freeman M, Nugent SM, Ayers CK, Winchell KA, Press A, O’Neil ME, 

Kansagara D. Gulf War Illness – A Systematic Review of Therapeutic Interventions and Management 

Strategies. Washington, DC: Evidence Synthesis Program, Health Services Research and 

Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP 

Project #05-225; 2020. Available at: https://www.hsrd.research.va.gov/publications/esp/reports.cfm. 

This report is based on research conducted by the Evidence Synthesis Program (ESP) Center located at the located 

at the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans 

Health Administration, Health Services Research and Development. The findings and conclusions in this document 

are those of the author(s) who are responsible for its contents; the findings and conclusions do not necessarily 

represent the views of the Department of Veterans Affairs or the United States government. Therefore, no statement 

in this article should be construed as an official position of the Department of Veterans Affairs. No investigators 

have any affiliations or financial involvement (eg, employment, consultancies, honoraria, stock ownership or 

options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented 

in the report.
GWI Interventions Evidence Synthesis Program

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ACKNOWLEDGMENTS 

This topic was developed in response to a nomination by Karen Block, PhD, Director of Gulf 

War Research in the Veterans Affairs (VA) Office of Research and Development (ORD) Gulf 

War Research Program, for the purpose of informing the planning for a state-of-the-art meeting 

on Gulf War Research and providing guidance for ORD funding priorities in Gulf War research. 

The scope was further developed with input from the topic nominators (ie, Operational Partners), 

the ESP Coordinating Center, the review team, and the Technical Expert Panel (TEP).

In designing the study questions and methodology at the outset of this report, the ESP consulted 

several technical and content experts. Broad expertise and perspectives were sought. Divergent 

and conflicting opinions are common and perceived as healthy scientific discourse that results in 

a thoughtful, relevant systematic review. Therefore, in the end, study questions, design, 

methodologic approaches, and/or conclusions do not necessarily represent the views of 

individual technical and content experts. 

The authors gratefully acknowledge Robin Paynter, MLIS, and the following individuals for 

their contributions to this project: 

Operational Partners

Operational partners are system-level stakeholders who have requested the report to inform 

decision-making. They recommend TEP participants; assure VA relevance; help develop and 

approve final project scope and timeframe for completion; provide feedback on draft report; and 

provide consultation on strategies for dissemination of the report to field and relevant groups.

Karen Block, PhD

Office of Research and Development (ORD) (10P9) – Gulf War Research Program

Washington, DC

Drew Helmer, MD, MS

Deputy Director, Center for Innovations in Quality, Effectiveness and Safety (IQuESt)

Houston, TX

Technical Expert Panel (TEP)

To ensure robust, scientifically relevant work, the TEP guides topic refinement; provides input 

on key questions and eligibility criteria, advising on substantive issues or possibly overlooked 

areas of research; assures VA relevance; and provides feedback on work in progress. TEP 

members are listed below:

Peter Rumm, MD, MPH, FACPM 

Pre-9/11 Era-Program Post-Deployment Health Services 

Washington, DC

Matthew Reinhard, PsyD 

DC War Related Illness and Injury Study Center

Washington, DC
GWI Interventions Evidence Synthesis Program

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Lisa McAndrew, PhD 

NJ War Related Illness and Injury Study Center 

East Orange, NJ 

Francis (Fran) Murphy, MD, MPH 

Sigma Health Consulting 

Washington, DC area

Peter Bayley, PhD 

CA War Related Illness and Injury Study Center

Palo Alto, CA 

Rebekah (Ryanne) Wu, MD, MHS

Durham VA Health Care System

Durham, NC

Stephen C. Hunt, MD, MPH 

VA Puget Sound Health Care System 

Seattle, WA 

Eva Lee, PhD

Georgia Institute of Technology 

Atlanta, GA

Peer Reviewers

The Coordinating Center sought input from external peer reviewers to review the draft report and 

provide feedback on the objectives, scope, methods used, perception of bias, and omitted 

evidence. Peer reviewers must disclose any relevant financial or non-financial conflicts of 

interest. Because of their unique clinical or content expertise, individuals with potential conflicts 

may be retained. The Coordinating Center and the ESP Center work to balance, manage, or 

mitigate any potential nonfinancial conflicts of interest identified. 
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TABLE OF CONTENTS 

Acknowledgments ......................................................................................................................... ii

Abstract .......................................................................................................................................... 1

Executive Summary ...................................................................................................................... 2

Aim ............................................................................................................................................. 2

Methods....................................................................................................................................... 2

Results ......................................................................................................................................... 2

Figure i. Summary of findings .................................................................................................... 3

Conclusion .................................................................................................................................. 4

Abbreviations Table .................................................................................................................... 5

Evidence Report ............................................................................................................................ 9

Introduction ................................................................................................................................... 9

Methods ........................................................................................................................................ 10

Topic Development ................................................................................................................... 10

Search Strategy ......................................................................................................................... 11

Study Selection ......................................................................................................................... 11

Data Abstraction ....................................................................................................................... 13

Quality Assessment ................................................................................................................... 13

Data Synthesis ........................................................................................................................... 13

Rating the Body of Evidence .................................................................................................... 13

Results .......................................................................................................................................... 14

Key Question 1: What are the benefits and harms of pharmacological and nonpharmacological interventions and management strategies for Veterans with GWI? .............. 16

Medications ........................................................................................................................... 21

Nutritional supplements ........................................................................................................ 22

Psychological, exercise, and multi-component interventions ............................................... 23

Other interventions (acupuncture, CPAP) ............................................................................ 26

Key Question 2: Do the effectiveness or harms of the interventions/strategies differ among 

subgroups of Veterans with GWI, such as female Veterans or cases defined by specific 

criteria, in comparison with Veterans with GWI overall? ........................................................ 28

Key Question 3: What interventions for GWI have been examined in noncomparative studies 

and ongoing/unpublished trials or cohort studies? .................................................................... 28

Summary of Findings ............................................................................................................ 28

Ongoing and Unpublished Studies – Detailed Findings ....................................................... 31

Single-arm Studies with Published Results .......................................................................... 33
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Discussion..................................................................................................................................... 34

Limitations ................................................................................................................................ 35

Heterogeneity ........................................................................................................................ 36

Publication Bias .................................................................................................................... 37

Applicability of Findings to the VA Population ................................................................... 37

Implications for VHA ............................................................................................................... 37

Research Gaps/Future Research ............................................................................................... 37

Conclusions .................................................................................................................................. 39

Summary Table. Visual representation of findings .................................................................. 39

References .................................................................................................................................... 41

TABLES

Table 1. PICOTS by Key Question ........................................................................................... 12

Table 2. Characteristics of randomized controlled trials of interventions for Gulf War Illness17

Table 3. Summary of the effectiveness and strength of evidence from placebo-controlled trials 

of medications for treating symptoms of Gulf War Illness ....................................................... 21

Table 4. Summary of the effectiveness and strength of evidence from placebo-controlled 

trials of nutritional supplements for treating Gulf War Illness, by symptom domain .............. 23

Table 5. Summary of the effectiveness and strength of evidence from trials of 

psychological, exercise, or multi-component interventions for treating GWI, by 

symptom domain ....................................................................................................................... 25

Table 6. Summary of the effectiveness and strength of evidence from trials of 

acupuncture and CPAP in Veterans with Gulf War Illness ...................................................... 26

Table 7. Interventions for GWI in ongoing/unpublished clinical trials and single-arm studies 29

Table 8. Risk of bias in trials of interventions for Gulf War Illness ......................................... 55

Table 9. Results for physical health, pain, and fatigue outcomes in intervention trials for Gulf 

War Illness ................................................................................................................................ 57

Table 10. Results for cognitive, mental health, PTSD symptoms, and global outcomes in 

intervention trials for Gulf War Illness ..................................................................................... 61

Table 11. Results for gastrointestinal symptoms and sleep outcomes in intervention trials for 

Gulf War Illness ........................................................................................................................ 66

Table 12. Adverse events in published intervention studies for Gulf War Illness ................... 68

Table 13. Details of ongoing and unpublished controlled trials of interventions/management 

strategies for Gulf War Illness .................................................................................................. 69

Table 14. Details of single-arm studies of interventions/management strategies for Gulf War 

Illness ........................................................................................................................................ 80

Table 15. Available results of unpublished randomized controlled trials of interventions for 

Gulf War Illness ........................................................................................................................ 81
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Table 16. Results of single-arm studies of interventions/management strategies for Gulf War 

Illness ........................................................................................................................................ 83

FIGURES

Figure 1. Conceptual framework .............................................................................................. 10

Figure 2. Literature Flow Chart ................................................................................................ 14

Figure 3. Frequency of intervention categories* among published (KQ1) and 

unpublished (KQ3) studies of treatments for GWI ................................................................... 35

Appendix A. Search Strategies .................................................................................................. 46

Appendix B. Study Selection ...................................................................................................... 52

Appendix C. Quality Assessment Criteria ................................................................................ 54

Appendix D. Data Supplement .................................................................................................. 57

APPENDIX E. Peer Review Comments/Author Responses ................................................... 85
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ABSTRACT

Aim: We conducted a systematic review of therapeutic interventions for Gulf War Illness (GWI) 

to evaluate effectiveness and harms and identify potentially promising treatments.

Methods: We searched electronic databases, trial registries, and reference lists through 

September 2019 for randomized and non-randomized controlled trials and cohort studies directly 

comparing interventions for Veterans with GWI to each other, placebo, or usual care. We 

abstracted data on study design, demographics, interventions, and outcomes. Two reviewers 

independently assessed studies for inclusion, quality, and strength of evidence using prespecified criteria. We resolved discordant ratings by discussion and consensus. 

Results: We identified 12 RCTs, each of which examined a different intervention for GWI. We 

found moderate-strength evidence that cognitive behavioral therapy (CBT) and exercise, 

separately and in combination, were associated with improvements in several GWI symptom 

domains. There was low-strength evidence of benefit from 2 mindfulness-based interventions 

and Continuous Positive Airway Pressure (CPAP). Mindfulness-based stress reduction improved 

pain, cognitive functioning, fatigue, depression, and posttraumatic stress disorder (PTSD), while 

mind-body bridging improved fatigue, depression, PTSD, and sleep, although pain and other 

outcomes did not improve. CPAP improved overall physical health, pain, cognitive functioning, 

fatigue, mental health, and sleep quality in a small study of Veterans with sleep-disordered 

breathing and GWI. We found moderate-strength evidence that doxycycline is ineffective for 

GWI in mycoplasma DNA-positive Veterans and increases the risk of adverse effects compared 

with placebo. We also found 33 ongoing, single-arm pilot, or unpublished studies examining a 

variety of interventions.

Conclusion: There is moderate-strength evidence of benefit from CBT and exercise, and lowstrength evidence of benefit from 2 distinct mindfulness-based interventions as well as CPAP. 

Doxycycline was ineffective and associated with harms (moderate-strength evidence). Emerging 

evidence examines a wide array of treatments. Larger, more rigorous studies are needed to 

reproduce and characterize positive findings. 
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EXECUTIVE SUMMARY 

AIM 

We conducted a systematic review to evaluate the effectiveness and harms associated with 

therapeutic interventions for Gulf War Illness (GWI) and its related symptoms. This review helps 

to identify treatments that warrant further inquiry, as well as treatments with a moderate base of 

evidence showing lack of effect and potential for harm.

METHODS

We searched electronic databases, clinical trial registries, and reference lists through September 

2019 for randomized and non-randomized controlled trials (RCT/nRCT) and cohort studies 

directly comparing interventions for Veterans with GWI to each other, placebo, or usual care. 

We excluded studies that compared interventions in Veterans without GWI to those with GWI, 

unless there was a separate analysis of the comparison in only those with GWI. We also 

excluded non-comparative studies except when summarizing emerging research. We abstracted 

data on study design, demographics, interventions, and outcomes. Two reviewers independently 

assessed studies’ full text for inclusion, quality (risk of bias [ROB]), and strength of evidence

(SOE) using published criteria and resolved discordant ratings by discussion and consensus. 

RESULTS

We identified and synthesized the evidence from 12 RCTs, each of which examined a different 

intervention for GWI (Figure i). We found several promising – but not definitive – treatments for 

various symptoms associated with GWI. We found moderate-strength evidence that cognitive 

behavioral therapy (CBT), exercise, and the combination of the 2 were associated with 

improvements in several GWI symptom domains. We found low-strength evidence that the 

following interventions improved 1 or more outcomes in patients with GWI:

• Mindfulness-based stress reduction (MBSR) improved*

 pain, cognitive functioning, 

fatigue, depression, and posttraumatic stress disorder (PTSD). 

• Mind-body bridging (MBB) – another type of mindfulness intervention – improved*

fatigue, depression, PTSD, and sleep, though it did not improve overall physical or 

mental health, pain, or cognitive functioning. 

• Continuous Positive Airway Pressure (CPAP) improved* overall physical health, pain, 

cognitive functioning, fatigue, mental health, and sleep quality in a small study of 

Veterans with sleep-disordered breathing and GWI. 

We found moderate-strength evidence that doxycycline is ineffective for GWI in mycoplasma 

DNA-positive Veterans and increases the risk of adverse effects compared with placebo. We 

found no effects of treatment with mifepristone, naltrexone, or rifaximin on GWI-associated 

symptoms, and some indications of benefit with carnosine, Coenzyme Q10 (CoQ10), 

acupuncture, and detoxification, though the SOE for these findings was insufficient to draw 

*

Specifics on improvement for these outcomes are defined in the subsequent full report
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conclusions due to methodical limitations of the studies. No studies examined the effects of 

interventions on respiratory or dermatologic outcomes. 

Most of this evidence base consists of small studies each examining a different intervention, and 

the findings described are likely to change as more research is conducted. We identified 31 

ongoing or unpublished studies, 2 published single-arm studies, and 2 studies that were 

terminated prior to completion. Few of these ongoing studies examine an intervention that has 

previously been studied: 2 of cognitive behavioral approaches, 1 of MBSR, and 1 with an 

acupuncture component. Aside from 2 ongoing studies examining forms of transcranial direct 

current stimulation (tDCS), and 3 examining repetitive transcranial magnetic stimulation 

(rTMS), no 2 ongoing studies address the same intervention, and the interventions examined by 

the remaining 22 studies vary widely. 

Figure i. Summary of findings

Treatment

Subpopulation if 

applicable

Outcome domain Physical health overall Pain Cognitive

FatigueMental health overallDepressionGlobal outcomes (function, QoL)PTSD symptomsSleepGI symptomsAdverse events

Medications vs placebo

Doxycycline1

Positive mycoplasma

     --- --- --- --- --- 

Mifepristone2 Ø --- Ø Ø Ø Ø --- Ø --- --- Ø

Naltrexone3 Ø --- Ø --- --- --- --- --- --- --- Ø

Rifaximin4

IBS (Rome III)

--- --- --- --- --- --- Ø --- --- Ø Ø

Nutritional supplements vs placebo

Carnosine5 --- Ø Ø Ø --- --- --- --- --- Ø Ø

CoQ106 Ø --- Ø --- --- --- --- --- --- --- Ø

Psychological, exercise, or multi-component interventions

CBTa7      --- --- --- --- --- Ø

Exercisea7      --- --- --- --- --- Ø

CBT + Exercise in 

combinationa7

     --- --- --- --- --- Ø

Detox regimenb8 Ø Ø --- Ø Ø --- Ø --- --- --- Ø

Mindfulness-based stress 

reductionb9

---    ---  ---  --- --- ---

Sleep focused mind-body 

bridgingc10

Ø Ø Ø  Ø  Ø   --- ---

Other interventions

Acupuncturea11 Ø Ø --- --- --- --- --- --- --- --- Ø

CPAPd12      --- --- ---  --- ---
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Shading represents the direction of effect: Pale yellow=Mixed Findings/Unclear, Green=Evidence of 

benefit, Gray=No association, Red=Favors usual care

Symbols represent the strength of the evidence: --- No evidence, Ø Insufficient, Low,  Moderate,  High a Versus usual care/TAU

b Versus waitlist

c Versus sleep education

d Versus sham CPAP

CONCLUSION

We found a small but growing body of evidence examining a disparate array of treatments for 

Veterans with GWI. There is low- to moderate-strength evidence that suggests several treatments 

may hold promise for improving symptoms related to GWI: the evidence was moderate-strength 

for benefits of a combination of CBT and exercise and low-strength for 2 distinct mindfulnessbased interventions and CPAP for Veterans with GWI who have sleep-disordered breathing. 

Doxycycline, on the other hand, is likely to be an ineffective treatment and is associated with 

harms (moderate-strength evidence). There are 33 ongoing, single-arm pilot, or unpublished 

studies examining a variety of interventions: some of these studies will help strengthen the 

evidence base for interventions that have already been examined on a small scale (eg, CBT and 

mindfulness-based stress reduction). However, many of these studies examine interventions that 

are both different from each other and different from interventions that have been studied before.

While this approach may help identify potentially promising interventions, the variety of 

treatments examined will make it challenging to develop enough of an evidence base to guide 

clinicians about which treatments are most likely to be effective in clinical practice and which 

treatments should be avoided. Part of the challenge in studying treatment of GWI is the lack of 

an agreed-upon case definition, and the heterogeneity of symptoms and differing degrees of 

functional impairment experienced by those with GWI. Addressing these issues will help 

researchers to better target intervention-focused research.
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ABBREVIATIONS TABLE

Abbreviation Definition

A Actual

AA African American

AMED Allied and Complementary Medicine Database

BAC-A Brief Assessment Checklist for Adolescents

BDI Beck Depression Inventory

BID bis in die

BPI Brief Pain Inventory

BPI-SF Brief Pain Inventory-Short Form

BSI Brief Symptom Inventory

BSS Bowel Symptom Scale

BVMT-R Brief Visuospatial Memory Test-Revised

CAPS-5 Clinician-Administered PTSD Scale for DSM-5

CBC Complete Blood Count

CBT Cognitive Behavioral Therapy

CBTi Cognitive Behavioral Therapy for Insomnia

CCRCT Cochrane Central Register of Controlled Trials

CDC Centers for Disease Control and Prevention

CDMRP Congressionally Directed Medical Research Programs

CDSMP Chronic Disease Self-Management Program

CDSR Cochrane Database of Systematic Reviews

CES-D Center for Epidemiological Studies-Depression Scale

CFQ Cognitive Failures Questionnaire

CFQ11 Chalder Fatigue Scale

CFS Chronic Fatigue Syndrome

CI Confidence Interval

CINAHL Cumulative Index to Nursing and Allied Health Literature

CMI Chronic Multisymptom Illness

CoE Center of Excellence for Research on Returning War Veterans

CoQ10 Coenzyme Q10

COWAT Controlled Oral Word Association Test

CPAP Continuous Positive Airway Pressure

CPT Connors Continuous Performance Test

CPT-3 Conner’s Continuous Performance Test - 3rd Edition

CRS Chronic Rhinosinusitis

CVLT-II California Verbal Learning Test Second Edition

DB-RCT Double-Blind Randomized Controlled Trial

DCS D-cycloserine

D-KEF Delis-Kaplan Executive Function System

DoD Department of Defense

DTI Diffusion Tensor Imaging
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Abbreviation Definition

DTS Davidson Trauma Scale

E Estimated

EBM Evidence-based Medicine

EEG Electroencephalogram

AE Adverse event

EHR Electronic health record

EMG Electromyography

ERP Event Related Potential

ESP Evidence Synthesis Program

f Cohen’s f Value

FIQR Revised Fibromyalgia Impact Questionnaire

FIT Rey 15-Item Test

FODMAP Fermentable Oligo-, Di-, Mono-saccharides And Polyols

FSS Fatigue Severity Scale

GAD-7 Generalized Anxiety Disorder 7-item

GI Gastrointestinal

GW Gulf War

GWHE Gulf War Health Education

GWI Gulf War Illness

GWV Gulf War Veteran

GWVI Gulf War Veterans Illness

HA Headache

HADS Hospital Anxiety and Depression Scale

HAM-A Hamilton Anxiety Rating Scale

HAM-D Hamilton Depression Rating Scale

HD-tDCS High Definition transcranial Direct Current Stimulation

HIT-6 Headache Impact Test

HPG Hypothalamic-Pituitary-Gonadal

HPT Hypothalamic–Pituitary–Thyroid

HRQoL Health-Related Quality of Life

HVLT-R Hopkins Verbal Learning Test – Revised

IBS Irritable Bowel Syndrome

IBS-QoL Irritable Bowel Syndrome Quality of Life

ICTRP International Clinical Trials Registry Platform

IQR Interquartile Range

ISI Insomnia Severity Index

LDLPFC Left Dorsolateral Prefrontal Cortex

LED Light Emitting Diode

LMC Left Motor Cortex

MA Meta-Analysis

MAP Mean Arterial Pressure

MASQ Mood and Anxiety Symptoms Questionnaire
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Abbreviation Definition

MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia

MBB Mind-Body Bridging

MBSR Mindfulness-based Stress Reduction

MCS Mental Component Summary

MFI-20 Multidimensional Fatigue Inventory-20

MFSI Multidimensional Fatigue Symptom Inventory

MPI Multidimensional Pain Inventory

MPQ McGill Pain Questionnaire

MRI Magnetic Resonance Imaging

MRS Magnetic Resonance Spectroscopy

MSG Monosodium glutamate

NI Nasal Irrigation

NR Not Reported

NRCT non-Randomized Controlled Trial

NSI Neurobehavioral Symptom Inventory

ORD Office of Research and Development

P P-Value

PCL PTSD Checklist

PCS Physical Component Summary

PDI Pain Disability Index

PFS Piper Fatigue Scale

PHQ Patient Health Questionnaire

PICOTS Population, interventions, comparators, outcomes, timing, and setting

preSMA Presupplementary Motor Area

PRESS Peer Review of Search Strategies

PROMIS Patient Reported Outcomes Measurement Information System

PSQI Pittsburgh Sleep Quality Index

PSS-I PTSD Symptom Score interview

pts Participants

PTSD Post-Traumatic Stress Disorder

QoL Quality of Life

RCT Randomized Controlled Trial

ROB Risk of Bias

rTMS Repetitive Transcranial Magnetic Stimulation

SAT Symptoms Assessment Tool

SCL-90R Symptom Checklist-90-Revised

SD Standard Deviation

SE Standard Error

SED Sleep Education

SF-12V Standard Form 12-Veteran version

SF-36 36-Item Short Form Health Survey

SF-MPQ Short-Form McGill Pain Questionnaire
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Abbreviation Definition

SNOT-20 Sinonasal Outcome Test-20

SOE Strength of Evidence

SORT Semantic Object Retrieval Test

SR Systematic Review

TAU Treatment as Usual

tDCS Transcranial Direct Current Stimulation

TEP Technical Expert Panel

TMT Trail Making Test

Tx Treatment

USA United States of America

VA Veterans Affairs

VAMC Veterans Affairs Medical Center

VAS Visual Analog Scale

VHA Veterans Health Administration

VNS Vagus Nerve Stimulation

VSF-36 Veterans 36-Item Short Form

VSL Very Safe Lactobacilli

WAIS-IV Wechsler Adult Intelligence Scale-Fourth Edition

WHO World Health Organization

WHODAS World Health Organization Disability Assessment Schedule

WRIISC War Related Illness and Injury Study Center
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EVIDENCE REPORT

INTRODUCTION

After the 1990-1991 conflict in the Persian Gulf, many Gulf War Veterans began reporting

numerous unexplained symptoms including, but not limited to, systemic pain, fatigue, flu-like 

symptoms and difficulty with memory/concentration. These symptom clusters were initially 

classified as Persian Gulf War Syndrome, then more generally under the broader umbrella of

Chronic Multisymptom Illness (CMI), and most recently as Gulf War Illness (GWI).

13 The 2

most widely recognized case definitions of GWI —recommended for use by the Department of 

Defense (DoD) and Department of Veterans Affairs (VA)—are the Centers for Disease Control 

and Prevention (CDC)14 and Kansas15 definitions. The CDC definition defines a case as having 

at least 1 symptom from 2 of 3 categories (fatigue, mood and cognition, and musculoskeletal) for 

6 months or longer.14 The Kansas approach defines a case as having 1 moderately severe, or 2 or 

more chronic, symptoms in at least 3 of 6 domains (including fatigue or sleep, pain, neurologic 

or cognitive or mood, gastrointestinal, respiratory, and skin).15 While both case definitions 

require the onset of symptoms to be within 6 months of deployment, this onset criteria is not 

consistently applied. In addition, a wide range of symptom severity and functional impairment is

captured by the current case definitions. The proportion of Gulf War-deployed Veterans who 

meet case criteria for GWI is approximately 34% (based on the Kansas case definition) to as high 

as 60% (based on the less-restrictive CDC case definition).

16 While the etiology of GWI is still 

debated, as many as 250,000 former service members may suffer from GWI,17 making the need 

for treatment urgent. 

Identification and treatment of GWI is a top research priority for the VA Office of Research and 

Development (ORD). Although the VA and DoD developed an evidence-based clinical practice 

guideline for the management of CMI in 2014,18 only 3 of the identified trials investigated 

treatment of GWI specifically (other CMI conditions reviewed included chronic fatigue 

syndrome, irritable bowel syndrome, and fibromyalgia, and included non-Veteran populations).

The VA and other institutions have recently provided funding for numerous trials of treatments 

and management strategies for GWI, and the research in this area is rapidly expanding. An 

updated, systematic evidence review that focuses on the treatment of GWI in Gulf War Veterans 

is needed to understand this emerging body of evidence and assist Veterans Health 

Administration (VHA) leadership in developing and funding future clinical and research 

priorities.

This systematic review seeks to expand on recent work by identifying potentially promising 

interventions for the treatment of GWI and its related symptoms as well as identifying any areas 

that have been relatively well-studied and shown to be ineffective or harmful. Together, this will

help target resources for further inquiry.
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METHODS 

TOPIC DEVELOPMENT

The key research questions for the review were as follows: 

1. Evidence on effectiveness/harms: What are the benefits and harms of pharmacological 

and non-pharmacological interventions and management strategies for Veterans with 

GWI? 

2. Evidence about subgroups: Do the effects of the interventions differ among subgroups 

Veterans with GWI in direct comparison with a larger sample of GWI patients?

3. Emerging research: What interventions for GWI have been examined in: 

a) noncomparative studies only? 

b) ongoing/unpublished trials or cohort studies? 

Our approach was guided by the conceptual framework we developed in consultation with our 

operational partners (Figure 1). 

Figure 1. Conceptual framework

Note. Numbers in grey bubbles refer to Key Questions

Abbreviations: GWI=Gulf War Illness; QoL=quality of life

Veterans with GWI Outcome 

Domains

Cognitive function

Fatigue 

Pain

Sleep 

Mood

Musculoskeletal

Gastrointestinal

Respiratory

Dermatological

Global (eg, QoL)

Present in the 

Persian Gulf during 

1990-1991 and meet 

inclusion criteria for 

chronic 

multisymptom 

illness/GWI based on 

the instrument. 

Therapeutic 

interventions or 

management 

strategies 

for GWI

Patient 

subgroups 

eg, GWI inclusion 

instrument, 

gender

Harms

1, 3

2
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SEARCH STRATEGY

We conducted a primary review of the literature by systematically searching, reviewing, and 

analyzing the scientific evidence as it pertains to the research questions. To identify relevant 

articles, we searched Ovid MEDLINE, Ovid PsycINFO, Ovid EBM Reviews (Cochrane 

Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), CINAHL, 

and Allied and Complementary Medicine Database (AMED) through September 17, 2019. 

Search strategies were developed in consultation with a research librarian, and peer reviewed by 

a second research librarian using the instrument for Peer Review of Search Strategies (PRESS).

19

The search strategy included terms to identify Veterans from the Gulf War era (eg, Desert

Shield, Desert Storm, Kuwait War, Operation GRANBY) combined with past and present terms 

to identify Gulf War Illness (eg, chronic multisymptom illness, chronic fatigue, Gulf War 

Syndrome). We limited our search to English-language publications but did not limit by

publication status or study design. To identify in-progress or unpublished studies, we searched

ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials 

Registry Platform (ICTRP; the full search strategies are in Appendix A). We reviewed the 

bibliographies of relevant articles and contacted experts to identify additional studies.

STUDY SELECTION

Criteria for population, interventions, comparators, outcomes, timing, and setting (PICOTS; 

Table 1) were developed in collaboration with our operational partners and Technical Expert 

Panel. Two ESP-reviewers independently assessed studies for inclusion based on pre-specified 

criteria. All discordant results were resolved through consensus or consultation with a third ESPreviewer. Articles meeting eligibility criteria were included for data abstraction.

For evidence on effectiveness, harms, and subgroups, eligible study designs included RCTs, 

nRCTs, and cohort studies in Veterans with GWI that directly compared interventions against 

each other, placebo, or usual care. To be included, both the intervention and comparator groups 

had to consist of a population of Veterans with GWI. If there was a mix of participants with and 

without GWI, we only included the study if the GWI population was analyzed separately. For 

Key Question (KQ) 3 on emerging research, we also included noncomparative intervention 

studies such as pilot/feasibility studies or case series.
GWI Interventions Evidence Synthesis Program

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Table 1. PICOTS by Key Question

Key 

Question: 

KQ1. evidence on effectiveness and 

harms: 

What are the (a) benefits and (b) harms of 

interventions and management strategies 

for Veterans with GWI? 

KQ2. evidence about subgroups: 

Do the effects of the interventions differ 

among subgroups in direct comparison 

with a larger sample of GWI patients? 

KQ3. emerging research: 

What interventions for GWI have been examined 

in: 

a) noncomparative studies only?

b) ongoing/unpublished trials or cohort studies? 

Population Veterans with GWI who were deployed to 

the Persian Gulf region between Aug 2, 1990 

- Nov 1991. Include international Veteran 

populations (countries that deployed troops 

there*; but limit to English-language 

publications). Include studies of civilian 

contractors present during the conflict, if 

available. Include studies where deployment 

status is unclear because diagnosis was 

made according to CDC/Fukuda 1998 

criteria.14

Subpopulations may include but are not 

limited to the following:

- Gender

- Case definition

- Severity of symptoms

- Branch of military

Studies that include only members of a 

specific subgroup and do not compare 

findings to Veterans with GWI overall 

would address KQ1 only.

Veterans with GWI who were deployed to the 

Persian Gulf region between Aug 2, 1990 - Nov 

1991. Include international veteran populations 

(countries that deployed troops there*; but limit to 

English-language publications). Include studies of 

civilian contractors present during the conflict, if 

available. Include studies where deployment status 

is unclear because diagnosis was made according to 

CDC/Fukuda 1998 criteria.14

Intervention Pharmacological and nonpharmacological interventions or management strategies for Gulf War Illness

Comparators Another active intervention, placebo, or usual care. Another active intervention, placebo, usual care, or 

no comparator (eg, single-arm pilot study).

Outcomes Outcomes of interest are the 3 symptom domains that occur in both the CDC and Kansas case definitions: cognitive function, fatigue, and pain.

Other outcomes of interest: 

• Additional symptom domains used in the Kansas case definition (sleep, mood, musculoskeletal, gastrointestinal, respiratory, dermatological)

• Global outcomes (eg, QoL and measures of function)

• PTSD

• Adverse effects of treatment

Timing No limits

Settings No limits

Study Design RCT, nRCT, cohort, SRs/MAs Unpublished or in-progress comparative studies 

(RCT, nRCT, cohort, SRs/MAs) and case 

series/single-arm pilot studies of interventions not 

examined in comparative studies. Exclude case 

reports.

*We recognize other countries may use different case definitions

Abbreviations: CDC=Centers for Disease Control and Prevention; GWI=Gulf War Illness; KQ=Key Question; MA=Meta-Analysis; nRCT=non-Randomized Controlled Trial; 

PTSD=Posttraumatic Stress Disorder; QoL=Quality of Life; RCT=Randomized Controlled Trial; SR=Systematic Review 
GWI Interventions Evidence Synthesis Program

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DATA ABSTRACTION

Data from studies meeting inclusion criteria were abstracted by 1 ESP reviewer and confirmed 

by at least 1 additional ESP reviewer. From each study, we abstracted the following where 

available: study design, sample size, setting, population characteristics, participant inclusion and 

exclusion criteria, the study and comparator interventions including dosage, timing, and duration 

of treatment, duration of follow-up, adjunctive interventions, adverse effects, and findings 

according to GWI outcome domains (cognitive function, fatigue, pain, sleep, mood, QoL, 

musculoskeletal, gastrointestinal, respiratory, and dermatological).

QUALITY ASSESSMENT

Two ESP-reviewers independently assessed the risk of bias (ROB) of each study. To assess the 

ROB of RCTs we used the Revised Cochrane Risk-of-Bias criteria, RoB 2.0.

20 Disagreements 

were resolved by consensus or a third ESP-reviewer. The ROB assessment criteria and our

ratings for each study are shown in Appendix C.

DATA SYNTHESIS

We qualitatively synthesized the evidence and compiled evidence tables of study characteristics 

and findings for each key question, grouping outcomes and interventions across studies when 

indicated. We were not able to conduct meta-analyses of interventions because there were not 

enough studies with similar characteristics of similar interventions to allow meaningful 

quantitative analysis.

RATING THE BODY OF EVIDENCE

We assessed the overall strength of evidence (SOE) for each outcome using a method developed 

for the Agency for Healthcare Research and Quality’s (AHRQ) Evidence-based Practice Centers 

(EPCs).

21 The AHRQ EPC method considers study limitations, directness, consistency, 

precision, and reporting bias to classify the SOE for individual outcomes independently for 

RCTs and observational studies, with supplemental domains of dose-response association, 

plausible confounding that would decrease the observed effect, and strength of association, as 

well as separate guidance for applicability.22 Ratings were categorized as follows: 

• High=Very confident that the estimate of effect lies close to the true effect for this 

outcome. The body of evidence has few or no deficiencies, the findings are stable, and 

another study would not change the conclusions.

• Moderate=Moderately confident that the estimate of effect lies close to the true effect for 

this outcome. The body of evidence has some deficiencies and the findings are likely to 

be stable, but some doubt remains. 

• Low=Limited confidence that the estimate of effect lies close to the true effect for this 

outcome. The body of evidence has major or numerous deficiencies (or both). Additional 

evidence is needed before concluding either that the findings are stable or that the 

estimate of effect is close to the true effect.

• Insufficient=Unable to estimate an effect, typically because there were too few studies, 

with very small sample sizes, and often with methodologic flaws.

• No evidence=No studies.
GWI Interventions Evidence Synthesis Program

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RESULTS 

We reviewed a total of 4,621 citations. After title and abstract review, 155 met inclusion criteria. 

After we reviewed the full text of these studies, we included a total of 45 studies. A diagram of 

the literature yield is shown in Figure 2. 

Figure 2. Literature Flow Chart

155 Potentially relevant 

articles for full-text review

14 Citations identified from reference lists of

relevant articles and reviews, key experts, 

and other sources

4,621 Citations compiled for 

review of titles and abstracts

45 included studies

4,607 Citations identified from electronic databases: 

3,426 PubMed/Ovid MEDLINE (Sept 19, 2019)

691 PsycINFO (Sept 17, 2019)

259 Scopus (Sept 17, 2019)

123 CINAHL (Sept 17, 2019)

55 WHO International Clinical Trials Registry Platform (Oct 1, 2019)

26 Ovid EBM Reviews (CDSR, CCRCT; Sept 17, 2019)

15 Clinicaltrials.gov (Oct 1, 2019)

12 Allied and Complementary Medicine Database (Oct 1, 2019)

4,466 Titles and abstracts 

excluded for lack of relevance

KQ 1:

12 RCTs

KQ 2:

No evidence

KQ 3:

31 unpublished studies

2 published single-arm studies

110 Excluded publications:

77 Used for background or discussion

 5 Excluded populations

 3 No relevant interventions

 2 Excluded study design or publication type

23 duplicate or preliminary publications of 

another study

Abbreviations: CCRCT=Cochrane Central Register of Controlled Trials; CDSR=Cochrane Database of 

Systematic Reviews; CINAHL=Cumulative Index to Nursing and Allied Health Literature; EBM=Evidencebased Medicine; KQ= Key Question; RCT=Randomized Controlled Trial; WHO=World Health Organization
GWI Interventions Evidence Synthesis Program

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Twelve RCTs addressed KQ1. The interventions included 4 medications (doxycycline,1

mifepristone,2 naltrexone,3 and rifaximin4); 2 nutritional supplements (carnosine5 and CoQ106); 4 

studies with a behavioral or psychological treatment component (cognitive behavioral therapy 

[CBT] with and without exercise,7 a detox regimen,

8

 and 2 mindfulness-based interventions9,10); 

acupuncture11; and continuous positive airway pressure therapy (CPAP).12 

Four interventions were examined in specific subpopulations of GWI patients: doxycycline in 

patients positive for mycoplasma DNA,1 rifaximin in patients with irritable bowel syndrome 

(IBS),4 mind-body bridging (MBB) in patients with sleep disturbance,10 and CPAP in patients 

with sleep-disordered breathing.12 In a study of mindfulness-based stress reduction (MBSR), 

patients diagnosed with posttraumatic stress disorder (PTSD) made up a large proportion 

(81.8%) of the sample, and the effect of the intervention on PTSD symptoms was evaluated 

specifically in this subgroup.9

 

Although the findings of these studies may be most applicable to the targeted subpopulations, 

none of the studies identified in our search addressed KQ2 by comparing the effects of an 

intervention in the subpopulation with a broader sample of GWI patients. Additionally, although 

considered eligible in our selection criteria, our search did not yield any cohort studies that 

addressed the key questions. 

For KQ3, we compiled information from 31 intervention studies that are ongoing or unpublished, 

as well as 2 published single-arm intervention studies. In describing the current research on 

interventions, we also included 2 studies that were terminated before completion23,24 due to low 

enrollment or for unspecified reasons. 

The findings for each KQ are presented in the sections that follow. 
GWI Interventions Evidence Synthesis Program

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KEY QUESTION 1: What are the benefits and harms of 

pharmacological and non-pharmacological interventions and 

management strategies for Veterans with GWI? 

Table 2 provides descriptive characteristics about each of the 12 trials that addressed KQ1, 

including the interventions and comparators used, the duration of treatment, the duration of 

observation (which includes the treatment period), the populations studied, and the outcomes 

reported. 

The outcomes measured varied among the studies (Table 2). Measures of physical health, pain, 

and cognitive function were reported most frequently. None of the included studies reported 

outcomes specifically for respiratory, dermatological, or musculoskeletal symptoms measured 

separately from overall pain. 

Most of the studies used the CDC or Kansas criteria for defining GWI. Some studies used 

equivalent criteria or modified the CDC or Kansas criteria. One study of rifaximin4

 included 

Gulf War Veterans with IBS. 

Following Table 2, we provide a summary of the findings for each intervention, organized into 4 

categories: medications, nutritional supplements, behavioral/exercise/multicomponent, and other 

interventions. Detailed findings on effectiveness and adverse events are provided in Appendix D, 

Tables 9-12. 
GWI Interventions Evidence Synthesis Program

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Table 2. Characteristics of randomized controlled trials of interventions for Gulf War Illness

Study 

Design

Setting

Years of enrollment

N=total participants

Overall ROB

Intervention vs comparator

Dose

N randomized Tx vs C

Duration of treatment and observation 

(includes treatment period)

Population

GWI case definition 

Subpopulation, if applicable

Age: Mean (SD)

Female: %

Race: % White/Afr Am/Other 

Hispanic: %

Employed full-time: %

Clinical characteristics

Outcomes reporteda

Physical health overallPainCognitiveFatigueMental health overallDepressionGlobal outcomesbPTSD symptomsSleepGI symptomsAdverse events

Medications

Doxycycline1

DB-RCT

Multisite: 26 VA and 2 

DoD medical centers

Years: April 1999-Nov 

2001

N=491

ROB: Low 

Doxycycline 200 mg/day vs placebo

N=245 vs 246

Tx duration: 12 months

Observation: 18 months

CDC criteria

Subpop: mycoplasma DNA positive

Tx group only:

Age: 41.1 (9.2)

Female: 15.5

Race: 61.6 / 26.5 / 7.8

Hispanic: NR

Employed: 73.5

X X X X X --- --- --- --- --- X

Mifepristone2

DB-RCT, crossover

Single site, VA 

hospital 2008-2011

N=36

ROB: Some concerns

Mifepristone 200 mg/day vs placebo

Two, 3-week crossover Tx phases with 

1-month washout

N=18 vs 18 in phase 1

18 vs 15 in phase 2

Tx duration: 6 weeks

Observation: 4 months

Kansas criteria

Age: 49.1 (7.2)

Female: 0.0

Race: 40.6 / 50.0 / 9.4

Hispanic: 50.0

Employed: 56.3

X --- X X X X --- X --- --- X

Naltrexone3

RCT, Pts blinded

Setting: NR

Years: NR

N=40

ROB: High

Naltrexone 4.5 mg/day vs placebo

3-month crossover Tx phases separated 

by 1-month washout.

N=37 (completed both phases)

Tx duration: 3 months

Observation: 7 months

Kansas, modified

Age: 54 (SD NR)

Female: 2.7 (completed study) 

Race: NR

Employed: NR

X --- X --- --- --- --- --- --- --- X

Rifaximin4

DB-RCT

Setting: NR

Years: NR

N=50

ROB: Some concerns

Rifaximin (550 mg 2x/d) vs placebo

N=27 vs 23 

Tx duration: 2 weeks

Observation: 2 weeks

GWI criteria: NR

Subpopulation: IBS (Rome III)

Tx group only:

Age, median: 53

Female: 13.6

Race: NR

Employed: NR

--- --- --- --- --- --- X --- --- X X
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Study 

Design

Setting

Years of enrollment

N=total participants

Overall ROB

Intervention vs comparator

Dose

N randomized Tx vs C

Duration of treatment and observation 

(includes treatment period)

Population

GWI case definition 

Subpopulation, if applicable

Age: Mean (SD)

Female: %

Race: % White/Afr Am/Other 

Hispanic: %

Employed full-time: %

Clinical characteristics

Outcomes reporteda

Physical health overallPainCognitiveFatigueMental health overallDepressionGlobal outcomesbPTSD symptomsSleepGI symptomsAdverse events

Nutritional supplements

Carnosine5

DB-RCT

Single site: 

Georgetown Univ 

Hospital 

2008-2011

N=34

ROB: High 

L-carnosine (dose of 500, 1,000, 1,500 

mg/d increasing at 4-week intervals) vs 

placebo

N=34 (only 12 vs 13 finished study)

Tx duration: 12 weeks

Observation: 14 weeks

CDC criteria, or GW Vet diagnosed 

with post-GW CFS

Of 25 study completers:

Age: 49.4

Female: 32

Race: NR

Employed: NR

--- X X X --- --- --- --- --- X X

CoQ106

DB-RCT

Setting: Southern 

California Hospital

Years: NR

N=46

ROB: High

CoQ10 (2 dosage arms, 100 mg/day vs 

300 mg/day) vs placebo

N=11 vs 12 vs 23

Tx duration: 3.5 +/- 0.5 months

Observation: 3.5 +/- 0.5 months

Required both CDC & Kansas criteria

Placebo vs Q100 vs Q300:

Age: 48 vs 50 vs 44

Female: 9 vs 27 vs 17

White: 55 vs 73 vs 58

Latino: 18 vs 0 vs 17

Afr Am: 9.1 vs 9.1 vs 25

Employed: NR

X --- X --- --- --- --- --- --- --- X

Psychological, exercise, or multi-component interventions

CBT + Exercise7

2x2 factorial RCT, Pts 

not blinded

Multi-site: 18 VAs and 

2 DoD medical 

centers

April 1999-September 

2001

N=1092

ROB: Some concerns

4 arms:

CBT+Exercise (n=266)

CBT only (n=286)

Exercise only (n=265)

TAU (n=270)

Exercise sessions were 60 minutes and 

CBT sessions were 60 to 90 minutes; 

Each type of session held 1x/week.

Tx duration: 12 weeks

Observation: 12 months

CDC equivalent

Age: 40.67

Female: 14.8

Race: 52.5 / 24.4 / 3.4

Hispanic: 19.6

Employed: NR

X X X X X --- --- --- --- --- X

Detox regimen8

RCT, Pts not blinded

Commercial rehab 

center

Detox regimen: niacin immediate release 

(dose NR); then 20-30 min moderate 

aerobic exercise; then low temperature 

sauna (60-80 Celsius) 2-4 hours; other 

Kansas criteria

Sex: 66% Male, 34% Female

Age: 51 (6.5)

Race: 81 / 19 / 3

X X --- X X --- X --- --- --- X
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Study 

Design

Setting

Years of enrollment

N=total participants

Overall ROB

Intervention vs comparator

Dose

N randomized Tx vs C

Duration of treatment and observation 

(includes treatment period)

Population

GWI case definition 

Subpopulation, if applicable

Age: Mean (SD)

Female: %

Race: % White/Afr Am/Other 

Hispanic: %

Employed full-time: %

Clinical characteristics

Outcomes reporteda

Physical health overallPainCognitiveFatigueMental health overallDepressionGlobal outcomesbPTSD symptomsSleepGI symptomsAdverse events

2013-2015

N=32

ROB: Some concerns

vitamin/mineral supplements in calciummagnesium drink throughout;

vs waitlist

N=22 vs 10

Tx duration: 4-6 weeks

Observation: 3 months 

Hispanic: NR

Employed: 59

Mindfulness-based 

stress reduction9

RCT, Pts not blinded

Setting: VA Hospital

Years: NR

N=55

ROB: Some concerns 

MBSR: 2.5 sessions 1x/week for 8 

weeks + single 7-hour weekend session 

vs TAU 

N=26 vs 29

Tx duration: 8 weeks

Observation: 6 months

CDC criteria

Subpopulation: PTSD 81.8%;

≥50% service-connected disability 

79.6% 

Age: 49.9

Female: 14.5

Race: 61.8 / 18.2 / 14.5

Hispanic: NR 

Employed: NR

--- X X X --- X --- X --- --- ---

Sleep-focused MindBody Bridging10

Study design: 

Prospective RCT

Single site: VA Salt 

Lake City

2012-2015

N=60

ROB: Some concerns

Sleep-focused MBB vs sleep education 

(SED; lectures, group discussions)

N=33 vs 27

Tx duration: 3 sessions over 3 weeks

Observation: 3 months

Pts could remain on previously 

prescribed sleep medications. 

CDC equivalent

Subpopulation: sleep disturbance 

Age: 50.7

Female: 10.0

Race: 88.0 / 7.0 / 8.6

Hispanic: 8.3

Employed: NR

X X X X X X X X X --- ---

Other interventions

Acupuncture11

RCT, Pts not blinded

30 treatment sites

Enrolled 2010-2013

N=104

ROB: Some concerns 

Acupuncture 2x/week for 6 months vs 

waitlist 2 months, then acupuncture 

1x/week for 4 months

N=52 vs 52

Tx duration: 6 months

Observation: 6 months

CDC criteria

Age: 48.2

Female: 13.0

Race: 80.7 / 9.6 / 9.6

Hispanic: 5.8

Employed: NR

X X --- --- --- --- --- --- --- --- X

CPAP12

RCT, Pts blinded

Active nasal CPAP (using individualized 

pressure level that eliminated inspiratory 

Kansas equivalent

Subpopulation: sleep-disordered 

X X X X X --- --- --- X --- ---
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Study 

Design

Setting

Years of enrollment

N=total participants

Overall ROB

Intervention vs comparator

Dose

N randomized Tx vs C

Duration of treatment and observation 

(includes treatment period)

Population

GWI case definition 

Subpopulation, if applicable

Age: Mean (SD)

Female: %

Race: % White/Afr Am/Other 

Hispanic: %

Employed full-time: %

Clinical characteristics

Outcomes reporteda

Physical health overallPainCognitiveFatigueMental health overallDepressionGlobal outcomesbPTSD symptomsSleepGI symptomsAdverse events

Single site, VA 

hospital. 

January 2006-July 

2008

N=18

ROB: Low 

airflow limitation) vs sham CPAP 

(pressure below 1 cm H20)

N=9 vs 9

Tx duration: 5+ hours/ night for 3 weeks

Observation: 3 weeks

breathing

Age: 42 (4)

Female/Race/Employed: NR 

Apnea Hypopnea Index: 19 (25)

Respiratory event-related arousal: 15 

(10) 

Ptherapeutic (parallel level of nasal 

CPAP that eliminates inspiratory 

airflow limitation): 9 (2) cmH2O

Total studies reporting outcome 9 9 9 8 7 4 4 3 2 2 9 a No outcomes were reported for musculoskeletal, respiratory, or dermatological symptoms. 

b Include measures of functional status and quality of life.

Abbreviations: CBT=Cognitive Behavioral Therapy; CDC=Centers for Disease Control and Prevention; CFS=Chronic Fatigue Syndrome; CoQ10=Coenzyme Q10;

CPAP=Continuous Positive Airway Pressure; DB-RCT=Double Blind Randomized Controlled Trial; DoD=Department of Defense; GI=Gastrointestinal; GW=Gulf War; 

GWI=Gulf War Illness; IBS=Irritable Bowel Syndrome; MBB=Mind-Body Bridging; MBSR=Mindfulness-based Stress Reduction; NR=Not Reported; Pts=Participants; 

PTSD=Posttraumatic Stress Disorder; QoL=Quality of Life; ROB=Risk of Bias; SD=Standard Deviation; SED=Sleep Education; TAU=Treatment as Usual; Tx=Treatment; 

VA=Veterans Affairs
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Medications

We found 4 trials of medications (doxycycline,1 mifepristone,2

 naltrexone,3 and rifaximin4; Table 

3; Study characteristics in Table 2; Detailed results in Appendix D, Tables 9-11). A large 

(N=491), adequately-powered, 12-month study of doxycycline (200 mg/day) provided moderatestrength evidence of no benefit and greater risk of adverse effects, such as nausea and 

photosensitivity, with treatment compared with placebo.1 Study retention in the doxycycline 

group was similar to that of the placebo group (80% versus 82.5%), and adherence was rated 

“good or excellent” in 77.5% versus 74.5% of participants at 6 months, and 65.6% versus 66.6% 

at 12 months.1 A 2-week study of rifaximin4

 (550 mg twice per day) in patients with IBS found 

no effect on IBS symptoms or quality of life; we rated the evidence insufficient because there 

was only 1 small study that analyzed only the participants who completed treatment (92.6% in 

rifaximin vs 82.6% placebo). Studies of mifepristone2 (200 mg/day for 3 weeks) and naltrexone3

(4.5 mg/day for 3 months) were rated as insufficient due to methodologic limitations such as 

small sample size2 and concerns with allocation concealment3 (more details on quality are 

presented in Appendix C, Table 8; Information on harms is in Table 12). Attrition was low in 

both studies, with 97% of randomized participants completing treatment in the mifepristone 

study2

 and 92.5% completion in the naltrexone study.3

Table 3. Summary of the effectiveness and strength of evidence from placebo-controlled 

trials of medications for treating symptoms of Gulf War Illness 

Doxycycline1 Mifepristone2 Naltrexone3 Rifaximin4

Study characteristics

Sample size

ROB

N=491

Low

N=36

Some concerns

N=40

High

N=50

Some concerns

Summary of effectiveness (strength of evidence) of treatment vs placebo, by symptom domain

Physical health 

overall

No difference 

(Moderate)

No difference 

(Insufficient)

No difference 

(Insufficient)

---

Pain No difference 

(Moderate)

--- --- ---

Cognitive No difference 

(Moderate)

Mixed findings 

(Insufficient)

No difference 

(Insufficient)

---

Fatigue No difference 

(Moderate)

No difference 

(Insufficient)

--- ---

Mental health overall No difference 

(Moderate)

No difference 

(Insufficient)

--- ---

Depression --- No difference 

(Insufficient)

--- ---

Global outcomes 

function, QoL

--- --- --- No difference 

(Insufficient)

PTSD symptoms --- No difference 

(Insufficient)

--- ---
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Doxycycline1 Mifepristone2 Naltrexone3 Rifaximin4

Sleep --- --- --- ---

GI symptoms --- --- --- No difference 

(Insufficient)

Adverse events Favors placebo 

(Moderate)

Unclear 

(Insufficient)

Unclear 

(Insufficient)

No difference 

(Insufficient)

Abbreviations: GI=Gastrointestinal; N=Number of participants; PTSD=Posttraumatic Stress Disorder; QoL=Quality 

of Life; ROB=Risk of bias; SOE=Strength of Evidence

Nutritional supplements

Two high-ROB trials of nutritional supplements (carnosine5 and CoQ106) found some evidence 

of benefit on various GWI symptoms (Table 4; Study characteristics in Table 2; Detailed results 

in Appendix D). The SOE for these findings is insufficient due to methodologic limitations 

including selective outcome reporting in the CoQ10 trial6

 and potential deviation from the 

intended interventions in the carnosine trial.5 

The trial of carnosine (500 mg/day increasing to 1500 mg/day over 12 weeks) in 34 patients with 

IBS found positive effects on cognitive function and gastrointestinal (GI) symptoms, but no 

difference on pain and fatigue (see Appendix D).

5

 At 12 weeks, the proportion of participants

with no IBS symptoms increased from 30% to 43% compared with baseline in the carnosine 

group, but remained 33% in the placebo group (P = 0.019). Symptoms of stool frequency and 

watery consistency reduced with carnosine but did not change with placebo. The carnosine group 

had significantly lower WAIS-R scores at week 12 compared with placebo (P = 0.013). Because 

the WAIS-R scores were lower in the carnosine group at baseline, the effect of carnosine on 

cognitive symptoms is inconclusive. The authors report that study compliance was excellent 

based on diaries and pill counts, though this was not biologically verified. With regard to 

attrition, 9 of the 34 participants dropped out prior to the study ending (5 from the carnosine 

group and 4 from placebo). Two were terminated due to health issues determined to be unrelated 

to treatment, 4 were lost to follow-up, and 3 dropped out after 6 weeks due to “frustration about 

lack of improvement”.

5

A 4-month trial of CoQ10 (N = 46; n = 11 on 100 mg/day, n = 12 on 300 mg/day for 4 months) 

found improvement on overall physical health (differences in Summary Performance Score of 

42% for 100 mg/day versus placebo [P = 0.025] and 15% for 300 mg/day versus placebo [P = 

0.44]) but the threshold for improved versus not improved was not clearly defined.6 No 

difference in cognitive symptoms was observed. Adherence was not reported for this trial. 

Attrition was minimal; 1 dropout in the treatment arm due to a stroke, and 3 in the placebo arm 

due to logistical reasons (2) and lost to follow-up (1).
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Table 4. Summary of the effectiveness and strength of evidence from placebo-controlled 

trials of nutritional supplements for treating Gulf War Illness, by symptom domain 

Carnosine5 CoQ106

Study characteristics

Sample size

ROB

N=34

High ROB

N=46

High ROB

Summary of effectiveness (strength of evidence) of treatment vs placebo

Physical health overall --- Favors CoQ10 (Insufficient)

Pain No difference (Insufficient) ---

Cognitive Favors carnosine (Insufficient) No difference (Insufficient)

Fatigue No difference (Insufficient) ---

Mental health overall --- ---

Depression --- ---

Global outcomes (function, QoL) --- ---

PTSD symptoms --- ---

Sleep --- ---

GI symptoms Favors carnosine (Insufficient) ---

Adverse events No difference (Insufficient) No difference (Insufficient)

Abbreviations: GI=Gastrointestinal; N=Number of Participants; PTSD=Posttraumatic Stress Disorder; QoL=Quality 

of Life; ROB=Risk of Bias; SOE=Strength of Evidence

Psychological, exercise, and multi-component interventions

This category of treatments for GWI includes 2 mindfulness-based interventions,9,10 a detox 

regimen,8 and a multi-arm trial of CBT with and without exercise7 (see Table 2 for study 

characteristics; Table 5 for a summary of the evidence; and Appendix D, Tables 9-11 for detailed 

results). The 2 mindfulness approaches had somewhat inconsistent results. The first was a trial of 

MBSR (N = 55) – a program focused on increasing present moment awareness and acceptance of 

thoughts, emotions and sensations – which was delivered in 8 weekly, 2.5-hour sessions, plus 1 

7-hour session.9 It found that MBSR improves pain, cognitive functioning, fatigue, depression 

and PTSD symptoms among those with GWI compared to treatment as usual (TAU; low SOE). 

Improvements on all outcomes were retained at the 6-month follow up, with the exception of 

PTSD symptoms (detailed study information located in Table 2 and Appendix D).9 Seventy-three 

percent of the intervention arm were classified as completers, defined as having attended 4 out of 

8 classes. Attrition for TAU was not reported. Intention-to-treat (ITT) and completer analyses 

were performed and had similar results. With regard to follow-up data, 22 (85%) of those in the 

MBSR arm contributed 6-month follow-up data compared to 23 (79%) of those in the TAU arm.

9

 

Another trial of a mindfulness-based approach, MBB (N = 60) taught participants to stay in the 

present moment when trying to fall asleep, as well as skills to manage stress and emotional 

reactivity to stressful thoughts over 3 sessions.

10 The comparator group received 3 Sleep Hygiene 

Educational (SED) sessions focused on improving routine and habits around sleep. MBB was

found to improve fatigue, depression, PTSD and sleep, but did not improve overall physical or 

mental health, pain or cognitive functioning compared to SED. Of the initial 60 participants who 

were randomized to MBB (33) versus SED (27), 57 participants completed the intervention, 

indicated by their attending at least 2 sessions (31 [93.9%] versus 26 [96.3%]). A total of 55
GWI Interventions Evidence Synthesis Program

24

completed the post assessment (29 [87.9%] versus 26 [93.9%]), and 49 completed the follow-up 

assessment (24 [72.7%] versus 25 [92.6%]). Reasons for attrition were not reported.10

In the trial of CBT and exercise,

7 1,092 Veterans were randomly assigned to 1 of 4 groups: (1) 

TAU (n=271), which consisted of any and all care received from inside and outside the VA; (2) 

CBT and TAU (n=286) which added 12 weekly, 60-90 minute CBT group sessions that taught 

behavioral and cognitive skills to enhance coping and problem-solving; (3) TAU and exercise

(n= 269) which added 12 weekly, 60-minute low-intensity aerobic exercise sessions; and (4) 

TAU with CBT and exercise (n= 266). Global physical health improvement was defined as a 7-

point or greater increase on the Physical Component Scale (PCS) of the Veteran Short Form 36-

Item Health Survey (VF-36). Among those who received CBT, exercise, or a combination of the 

2, there was evidence of modest benefit (marginal effect) for up to 1 year after the intervention 

completion on several GWI symptom domains, including measures of physical health fatigue, 

cognitive functioning, distress, and mental health functioning (moderate SOE). The intervention 

adherence rates, defined as attending two-thirds of sessions, ranged from a low of 36% among 

those in the CBT only arm to a high of 47% for exercise only. Table 2 contains detailed study 

information, and results are in Appendix D.

Finally, the detox regimen study used a pragmatic, parallel design, to randomize 32 participants 

to either a daily regimen of exercise, sauna-induced sweating, crystalline nicotinic acid, and 

other supplements for 4-6 weeks (n=22) or waitlist control (n=10; Detailed study information 

located in Table 2, and results in Appendix D).

8 The intervention was found to improve pain, 

fatigue, and overall mental health, yet there was no difference on global QoL compared to 

placebo; methodological limitations such as limited sample size and selective outcome reporting 

inhibited our ability to have confidence in the conclusions. As such, outcomes from this detox 

regimen were all rated insufficient SOE. All 32 participants completed the intervention and 21 

completed the 3-month follow up.8

The ROB for all psychosocial intervention studies was classified as “some concerns” primarily 

because of utilizing self-reported outcomes without blinding of participants as to which 

intervention group they were in. There are methodical ways to do this including using sham 

treatment as a control in some cases. We outline the pros and cons of such blinding procedures in 

the discussion. Another limitation of this body of literature is that the potential harms of these 

interventions were not well characterized – as was the case in the MBSR trial – or it was unclear 

whether the AEs were related to the intervention or not – as was the case in the CBT/Exercise

trial. The detox intervention may place individuals at a higher risk of AEs; yet there may be 

promising effects of the mindfulness-based approaches and the combination of CBT and exercise

(See Appendix C, Table 8 for ROB ratings, and Appendix D, Table 12 for AE details). 
GWI Interventions Evidence Synthesis Program

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Table 5. Summary of the effectiveness and strength of evidence from trials of psychological, 

exercise, or multi-component interventions for treating GWI, by symptom domain 

CBT/Exercise/

combined CBT + 

Exercise7

Detox regimen8 Mindfulnessbased stress 

reduction9

Sleep focused 

mind-body 

bridging10

Study characteristics

Comparator

Sample size

ROB

TAU

N=1092

Some concerns

Waitlist

N=32

Some concerns

TAU

N=55

Some concerns

Sleep education

N=60

Some concerns

Summary of effectiveness (strength of evidence) of treatment vs comparator

Physical health 

overall

Favors CBT 

(Moderate)

Mixed findings 

(Insufficient)

--- No difference 

(Insufficient)

Pain Favors CBT; Favors 

combined CBT + 

exercise

(Moderate) 

Favors detox 

(Insufficient)

Favors MBSR 

(Low)

No difference 

(Insufficient)

Cognitive Favors CBT; Favors 

exercise; Favors 

combined CBT + 

exercise

(Moderate)

--- Favors MBSR 

(Low)

No difference 

(Insufficient)

Fatigue Favors combined 

CBT + exercise 

(Moderate)

Favors detox 

(Insufficient)

Favors MBSR 

(Low)

Favors MBB 

(Low)

Mental health 

overall

Favors exercise; 

Favors combined 

CBT + exercise; 

Mixed findings CBT

(Moderate)

Favors detox 

(Insufficient)

--- No difference 

(Insufficient)

Depression --- --- Favors MBSR 

(Low)

Favors MBB 

(Low)

Global outcomes

(function, QoL)

--- No difference 

(Insufficient)

--- No difference 

(Insufficient)

PTSD symptoms --- --- Favors MBSR 

(Low)

Favors MBB 

(Low)

Sleep --- --- --- Favors MBB 

(Low)

GI symptoms --- --- --- ---

Adverse events Unclear

(Insufficient)

Favors usual 

care

(Insufficient)

--- ---

Abbreviations: CBT=Cognitive Behavioral Therapy; GI=Gastrointestinal; MBB=Mind-body Bridging; 

MBSR=Mindfulness-based Stress Reduction; N=Number of Participants; PTSD=Posttraumatic Stress Disorder; 

QoL=Quality of Life; ROB=Risk of Bias; SOE=Strength of Evidence; TAU=Treatment as Usual
GWI Interventions Evidence Synthesis Program

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Other interventions (acupuncture, CPAP)

Two other interventions were identified (Table 6; Detailed study information in Table 2; and 

results in Appendix D). A trial of acupuncture11 (N = 104) with some concerns for ROB found 

that overall physical health (P = 0.03; SE 3.76 [95% CI: 1.03 to 15.76]) and pain (P = 0.04; SE 

1.71 [95% CI: -6.95 to -0.2]) significantly improved in the treatment arm versus wait list. 

Treatment consisted of individualized acupuncture protocols twice a week for 6 months 

compared to 2 months on a waitlist followed by once-weekly individualized acupuncture 

protocols. After 2 months, 90% of participants randomized to 2 sessions per week remained in 

the study, and 84.6% of those randomized to waitlist were available to receive treatment. Eightytwo percent (85 out of 104 randomized) completed the 6-month follow up assessment. Pain on 

needling was reported as an AE, but despite that, 96% of participants reported that they would 

recommend acupuncture.11 The SOE was insufficient owing to lack of blinding with selfreported outcomes. 

A low-ROB trial of CPAP among Veterans with GWI and sleep disordered breathing reported 

favorable results on multiple outcomes (low SOE).12 The trial compared the use of CPAP at 

individualized pressure levels with sham CPAP (pressure below 1 cmH2O) for 5 hours per night 

over 3 weeks. Although CPAP is an evidence-based treatment for sleep apnea, CPAP was also 

associated with improvement among a broader range of GWI symptoms in this study than just 

sleep outcomes. Specifically, significant improvements were found for pain (effect size: 2.14; P 

= 0.0008), fatigue (effect size: 2.55; P = 0.0002), cognitive function (effect size: 1.67; P = 

0.004), sleep quality (effect size: 2.67; P = 0.0003), physical health (effect size: 2.79; P = 

0.0003), and mental health (effect size: 1.29; P = 0.03). Compliance with assigned treatment was 

comparable between the active and sham groups (265.1 ± 90.2 minutes/night versus 266.6 ± 

100.8 minutes/night, respectively; P = 0.98). Participants were 100% compliant with mailing 

back their questionnaires. One participant assigned to active treatment was enrolled in a PTSD 

treatment program and excluded. While methodologically the CPAP trial had low ROB, because 

the trial was small (N=18) more trials are needed to characterize the benefits with confidence. 

Table 6. Summary of the effectiveness and strength of evidence from trials of acupuncture 

and CPAP in Veterans with Gulf War Illness 

Acupuncture11 CPAP12

Study characteristics

Comparator

Sample size

ROB

Waitlist

N=104

Some concerns

Sham CPAP

N=18

Low ROB

Summary of effectiveness (strength of evidence) of treatment vs comparator

Physical health overall Favors acupuncture (Insufficient) Favors CPAP (Low)

Pain Favors acupuncture (Insufficient) Favors CPAP (Low)

Cognitive --- Favors CPAP (Low)

Fatigue --- Favors CPAP (Low)

Mental health overall --- Favors CPAP (Low)

Depression --- ---

Global outcomes 

(function, QoL)

--- ---
GWI Interventions Evidence Synthesis Program

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PTSD symptoms --- ---

Sleep --- Favors CPAP (Low)

GI symptoms --- ---

Adverse events Unclear (Insufficient) ---

Abbreviations: CBT=Cognitive Behavioral Therapy; GI=Gastrointestinal; MBB=Mind-body Bridging; 

MBSR=Mindfulness-based Stress Reduction; N=Number of Participants; PTSD=Posttraumatic Stress Disorder; 

QoL=Quality of Life; ROB=Risk of Bias; SOE=Strength of Evidence
GWI Interventions Evidence Synthesis Program

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KEY QUESTION 2: Do the effectiveness or harms of the 

interventions/strategies differ among subgroups of Veterans with 

GWI, such as female Veterans or cases defined by specific criteria, in 

comparison with Veterans with GWI overall?

We found no studies that compared the effects of an intervention in a subpopulation with a 

broader sample of GWI patients. Four studies included in KQ1 limited their inclusion criteria to 

specific symptoms or subpopulations (IBS in a study of rifaximin,

4 sleep-disordered breathing in 

a study of CPAP,

12 sleep disturbance in a study of mind-body bridging,10 and patients positive 

for mycoplasma DNA in a study of doxycycline1

). Although the findings of these studies may be 

most applicable to the targeted subpopulations, we are not able to draw conclusions about 

whether the treatments affect symptoms differently in these subpopulations compared with GWI 

patients overall.

KEY QUESTION 3: What interventions for GWI have been examined in 

noncomparative studies and ongoing/unpublished trials or cohort 

studies?

Summary of Findings

We found 31 ongoing or unpublished trials and 2 published noncomparative intervention studies.

Although 2 of the clinical trials were terminated before completion, we have included them in

the characterization of current research in this area so that future researchers are aware of what 

interventions have been attempted. A brief list of the interventions, comparators, projected 

sample sizes, and targeted symptom or subpopulations are shown in Table 7. Detailed 

information about each study is provided in Appendix D, Table 13.

We identified 33 ongoing, single-arm pilot, or unpublished studies of treatments for GWI 

symptoms in the following areas: behavioral and psychological interventions (4), various forms 

of central nervous system stimulation devices (5), complimentary and integrated health 

interventions including movement therapies (4), dietary interventions (2), exercise (1), 

medications (7), nutritional supplements (7), stochastic noise electrical stimulation (1), nasal 

irrigation (1), and light-emitting diode (LED) therapy (1). These represent a much broader range 

of interventions than completed trials included in our question about effectiveness (KQ1) with 

only a few treatments that have been tested in earlier trials: 2 of cognitive behavioral approaches, 

1 of MBSR, and 1 with an acupuncture component. Aside from 2 ongoing studies examining 

forms of transcranial direct current stimulation (tDCS), and 3 examining repetitive transcranial 

magnetic stimulation (rTMS), no 2 ongoing studies address the same intervention, and the 

interventions examined by the remaining 22 studies vary widely (See Appendix D, Table 13).

Because many of these studies are ongoing, we were not able to rate the ROB for the individual 

studies or draw conclusions. Four RCTs have made results publicly available, although 3 did not 

report between-group statistical analyses. Preliminary results (N=17) from 1 crossover RCT of a 

low-glutamate diet found significant improvement in PTSD and anxiety (see Appendix D, Table 

15).

25
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Two additional single-arm pilot studies also showed a pre-post treatment effect, but these results 

would need to be replicated in a larger sample and may suggest future areas of research (see 

Appendix D, Table 16). 

Table 7. Interventions for GWI in ongoing/unpublished clinical trials and single-arm 

studies 

Intervention 

category Treatment Comparator Sample size*

Targeted 

symptom or 

subpopulation

Status

Behavioral CBT26 Waitlist 80 Insomnia Ongoing

Cognitive 

rehabilitation27

Health 

education

268 --- Completed, no 

results posted

MindfulnessBased Stress 

Reduction28

Adapted 

CDSMP

308 --- Ongoing

Behavioral, 

multicomponent 

Specialized 

Care Program29

No 

comparator

109 --- Published

CNS stimulation (HD) tDCS30 Sham HD 

tDCS

120 --- Ongoing

rTMS23 Sham rTMS --- Chronic 

musculoskeletal 

pain

Terminated 

before 

completion

rTMS31 Sham rTMS 90 Migraines, and 

muscle/ joint pain

Ongoing

rTMS32 Sham rTMS 80 Migraines, muscle/ 

joint pain, and 

depression

Ongoing

rTMS33 Sham rTMS 150 Headaches and 

pain

Ongoing

tDCS34 Sham tDCS 120 --- Ongoing

VNS35 Placebo 40 Widespread pain 

and migraines

Ongoing

Complementary 

and integrative 

health

Acupressure36 Reiki 7 Pain and fatigue Completed, no 

results posted

Meditation + 

acupuncture37

GW Health 

education

172 --- Ongoing

Tai Chi38 Wellness 

intervention 

(video and 

mindfulness)

120 Joint pain/stiffness Ongoing

Yoga39 CBT 75 Chronic pain Completed, 

results posted

Diet Low-FODMAP 

diet40

HighFODMAP 

diet

68 IBS Completed, no 

results posted

Low-glutamate 

diet41,42

Waitlist 40 --- Ongoing
GWI Interventions Evidence Synthesis Program

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Intervention 

category Treatment Comparator Sample size*

Targeted 

symptom or 

subpopulation

Status

Exercise Exercise 

training43

Waitlist 77 Chronic 

musculoskeletal 

pain

Completed, no 

results posted

Medication D-cycloserine44 Placebo 56 Cognitive 

symptoms

Ongoing

Duloxetine vs 

pregabalin24

Placebo --- Pain Terminated 

before 

completion

Etanercept+ 

mifepristone45

No 

comparator

20 Safety Ongoing

Intranasal 

insulin46

Placebo 114 Cognitive 

symptoms

Ongoing

Prednisone47 Placebo 100 --- Ongoing

Pregnenolone48 Placebo 170 --- Completed, no 

results posted

Rituximab49 Placebo NR --- Ongoing

Medication + 

nutritional 

supplement 

Nutrient formula 

+ 

methylphenidate

50

No 

comparator

15 --- Published

Nutritional 

supplement

Botanical 

Microglia 

Modulators51

Placebo 64 --- Ongoing

Concord grape 

juice52

Placebo 36 --- Completed, no 

results posted

Mitochondrial 

cocktail53

Placebo NR --- Ongoing

Resveratrol54 Placebo 68 --- Ongoing

Ubiquinol 

(CoQ10)55

Placebo 200 --- Ongoing

Visbiome vs 

VSL#356

Placebo 60 IBS Ongoing

Other Electrical 

stimulation 

(stochastic 

noise)57

Sham 

electrical 

stimulation

60 Vestibular function; 

postural sway

Completed; 

unpublished

LED therapy58 Sham LED 160 Neuropsychological 

symptoms

Ongoing

Nasal irrigation 

(Xylitol)59,60

Saline NI; 

Usual care

40 Chronic 

rhinosinusitis

Completed, 

results posted

*projected sample size, actual size may differ

Abbreviations: CDSMP=Chronic Disease Self-Management Program; CN =Central Nervous System; 

CoQ10=Coenzyme Q10; FODMAP=Fermentable Oligo-, Di-, Mono-saccharides and Polyols; GW=Gulf War; HD 

tDCS=High Definition Transcranial Direct Current Stimulation; LED=Light-emitting Diodes; NI=Nasal Irrigation; 

NR=Not Reported; rTMS=Repetitive Transcranial Magnetic Stimulation; tDCS=Transcranial Direct Current 

Stimulation; VNS=Vagus Nerve Stimulation; VSL=Very Safe Lactobacilli 
GWI Interventions Evidence Synthesis Program

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Ongoing and Unpublished Studies – Detailed Findings

Behavioral interventions

Two randomized controlled trials (1 in progress26 and 1 unpublished but completed27) are testing 

CBT for GWI. The ongoing study26 is testing telephone-delivered, insomnia-focused CBT for 

Veterans with GWI and insomnia compared to usual care, and the other trial tested problemsolving therapy for cognitive rehabilitation compared to health education in GWI Veterans.27 A 

third, ongoing behavioral study is comparing MBSR to a Chronic Disease Self-Management 

Program (CDSMP) in Veterans with CMI.28 A subset of the study population will be Gulf War 

Veterans. No results are available yet for these studies (Appendix D, Table 13).

Brain stimulation therapy

Six RCTs are testing brain stimulation therapies (Appendix D, Table 13).

30-35 Three studies are 

examining rTMS versus sham rTMS, 2 are investigating tDCS versus sham tDCS,

30,34 and 1 is 

studying vagus nerve stimulation (VNS) versus sham VNS.

35 Three of the 6 trials required 

participants have migraines in addition to GWI in their inclusion criteria.

31,32,35 One additional 

study of rTMS was terminated due to low enrollment.23 Results have not been reported for any of 

these RCTs. 

Complementary and integrative health (CIH)

Four trials examined CIH interventions (Appendix D, Table 13).

36-39 One nRCT of acupressure

versus reiki for GWI-related fatigue and pain36 was completed in 2017, but has not posted 

results; an ongoing RCT is examining Tai Chi compared to a wellness intervention for pain and 

other GWI symptoms38; and 1 ongoing RCT is studying meditation (iRest Yoga Nidra) with 

auricular acupuncture compared to a GW health education control for improving sleep quality in 

Veterans with GWI.37

The fourth study is an RCT completed in early 2018 comparing yoga to CBT for pain in 

Veterans with GWI.

39,61 This trial reported results for change in within-group mean pain scores 

measured by the Brief Pain Inventory-Short Form (BPI-SF) from baseline to end of treatment 

and found that the yoga group improved significantly (P < 0.001), but the CBT group did not (P

> 0.05).39,62 At 6-month follow-up the yoga group still had significantly improved pain scores 

compared to baseline (P = 0.02), while CBT mean change scores were not reported.39,62 No 

between-groups analysis was reported (Results in Appendix D, Table 15).

Diet

Two RCTs are examining the effects of dietary interventions on Veterans with GWI (Appendix 

D, Table 13).

40,41 One study, that was estimated to have been completed in 2018, compared a 

low-FODMAP (Fermentable Oligo-, Di-, Mono-saccharides And Polyols) diet to a typical 

healthy (high-FODMAP) diet for IBS in GW Veterans, but results are not yet reported.40

The other dietary RCT is a crossover study examining a low-glutamate diet and subsequent 

monosodium glutamate (MSG) challenge.41 This trial is ongoing but has reported some 

preliminary results for 17 participants.

25,41 The outcomes analyzed were PTSD symptoms 

measured by the PTSD Checklist – Civilian version (PCL-C) and anxiety measured by the 
GWI Interventions Evidence Synthesis Program

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Generalized Anxiety Disorder 7-item scale (GAD-7). Median scores were reduced significantly 

over 1-month intervention (PCL-C score P = 0.04; GAD-7 score P = 0.01; Appendix D, Table 

15).

Electrical stimulation

In 1 trial, the investigators developed a novel portable electrical stimulation device that provides 

random, imperceptible stochastic noise via ear clips, intended to improve vestibular function

(Appendix D, Table 13).

57,63 Worn constantly during the 12-week trial, it improved ocular 

torsion (OT) and sway compared to a sham stimulator (Appendix D, Table 15).

57,63

Exercise

One RCT tested 16 weeks of resistance exercise training compared to a waitlist control for 

physical symptoms including chronic pain in Veterans with GWI.43 Completed at the end of 

2018, results of the trial are not yet available. 

Light-Emitting Diodes therapy

One crossover RCT is comparing a course of LED treatment to sham LED treatment for 

cognitive symptoms in GWI Veterans (Appendix D, Table 13).

58 The study is ongoing. 

Medications

Seven RCTs examined pharmacological interventions for Veterans with GWI symptoms

(Appendix D, Table 13).

24,44-49 One RCT studying adjunctive pregnenolone for fatigue, 

musculoskeletal pain, and cognitive decline in GW veterans48 was completed in 2018, but has 

not posted results; 1 small Phase I trial of the combination of etanercept and mifepristone is 

testing 2 doses of mifepristone (300mg and 600mg) and the primary outcome is safety45; 1 RCT,

estimated to have been completed in 2017, examined whether intranasal insulin improves 

cognitive function and other CMI symptoms in GW veterans with CMI46; an ongoing RCT of 

treatment with delayed-release prednisone seeks to determine if it improves the health-related 

QoL of Veterans with GWI47; 1 ongoing RCT is investigating the efficacy of d-cycloserine 

treatment for GWI44; and 1 ongoing RCT is evaluating GWI symptom improvement with the use 

of b-cell depletion therapy with rituximab.

49 One RCT was testing the treatments of duloxetine 

and pregabalin for Veterans with GWI, but the study was terminated by the funder in 2019, and 

no reason was given.

24

Nasal irrigation

One RCT examined the effectiveness of nasal irrigation with either xylitol or saline versus 

placebo for chronic rhinosinusitis (CRS) in Veterans with GWI (Appendix D, Table 13).

60

Changes from baseline in fatigue (measured by the Multidimensional Fatigue Inventory [MFI]) 

and respiratory scores (measured by the 20-item Sinonasal Outcome Test [SNOT-20]) were 

reported for the 40 participants at weeks 8 and 26 of treatment, but no statistical analyses were 

presented (Appendix D, Table 15).

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Nutritional supplements

Six recent trials examined the effects of nutritional supplements on veterans experiencing GWI 

symptoms (Appendix D, Table 13).

51-56 One RCT tested the consumption of Concord grape juice 

for treating cognitive deficits and chronic fatigue in Veterans with GWI52 was completed in 

2019, but has not posted results; 1 controlled trial estimated to have been completed in 2019 

examined the benefit of a mitochondrial supplement with an individualized correction or citric

acid cycle (CAC) intermediates and amino acid (AA) abnormalities as part of a 

mitochondrial/oxidative stress treatment approach in GWI53; 1 RCT estimated to have been 

completed in 2018 examined Visbiome and its effects on IBS and non-intestinal symptoms such 

as fatigue, joint pain, insomnia, general stiffness and headache, associated with IBS56; 1 ongoing 

RCT is using resveratrol as a treatment to improve memory issues, difficulties with thinking and 

mood problems in Veterans with GWI54; 1 ongoing RCT is determining the use of ubiquinol and 

its effectiveness to improve the physical function in Veterans with GWI55; and 1 ongoing 

crossover RCT is examining various botanical compounds and their effectiveness in suppressing 

symptoms of GWI.51

Single-arm Studies with Published Results

Two published single-arm pre-post studies of interventions for GWI were identified in our search

(Appendix D, Tables 14 and 16).

29,50 First, in a specialized care program (SCP) of 109 Veterans, 

improvements were seen on global physical health outcomes that were maintained at 3-month 

follow-up.29 The program was a 3-week intensive outpatient group program that included the 

development of an individualized symptom-management plan that combined regular primary 

medical care, exercise, self-care, and other active coping strategies.

29

The other single-arm study was of 15 Veterans with GWI treated with a nutrient formula and 

methylphenidate for 12 weeks.50 Participants improved on measures of fatigue, sleep, cognitive 

symptoms, and an assessment of GWI symptoms overall, but the small size and lack of 

comparison group precludes drawing any conclusions from results.
GWI Interventions Evidence Synthesis Program

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DISCUSSION

We conducted a comprehensive review of treatments for GWI and found studies of several 

interventions that reported improvements in various GWI symptom domains. A large multi-arm 

study of CBT and exercise found moderate-strength evidence of benefit with CBT and exercise 

alone and in combination.

7 Studies of mindfulness-based interventions (MBB and MBSR) also 

found low-strength evidence of improvement on several outcome measures.9,10 CPAP improved 

overall physical health, pain, cognitive functioning, fatigue, mental health, and sleep quality in 

participants with GWI and sleep-disordered breathing (low SOE).

12 Studies of nutritional 

supplements5,6 and acupuncture11 showed some indications of benefit, though the evidence was 

insufficient due to methodological issues (Appendix C). Several interventions were found to 

have no treatment effect, including doxycycline, mifepristone, and naltrexone. 

Several trials found promising effects on some outcomes but no treatment effects on other 

outcome measures. Among the interventions, it is important to also consider potential for harms. 

Adverse events occurred more frequently with 2 interventions: doxycycline1 and a detoxification 

and sauna regimen.8 It is unclear whether the psychosocial and exercise interventions are 

associated with increased risk of adverse events. This will be important information to ascertain 

with greater certainty in future, larger trials.

Among the ongoing studies, there appears to be emerging interest in central nervous system 

(CNS) stimulation therapies and complementary and integrative health (CIH) approaches for 

treating GWI. Medications and nutritional supplements continue to be evaluated, although no 

particular medication has been studied in more than 1 trial in either KQ1 or KQ3. Figure 3 shows 

the types of interventions examined among the 12 published RCTs in KQ1 and the 32 

ongoing/unpublished/single-arm studies in KQ3.
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Figure 3. Frequency of intervention categories* among published (KQ1) and unpublished 

(KQ3) studies of treatments for GWI

*Because 1 study had 3 active treatment arms,7 there are 47 intervention arms represented among 45 total studies.

Abbreviations: CNS=Central Nervous System; KQ=Key Question.

It has been almost 7 years since the Institute of Medicine’s (IOM) Committee on Gulf War and 

Health: Treatment for Chronic Multisymptom Illness’ review, which also included studies in 

non-Veterans and treatments for conditions and comorbidities other than GWI (eg, fibromyalgia, 

IBS, depression, etc.). The IOM report did not conclusively recommend any interventions but 

advised that antidepressant medications (SSRIs and SNRIs) as well as CBT may be helpful for 

some. Authors of the report also emphasized that this is a complex illness and individualized 

health care management plans are necessary. More recently, a narrative review of interventionfocused GWI research was published in 2019,17 which included 7 studies that also met our 

inclusion criteria for this review. We have added to the findings of that 2019 review by 

performing a critical appraisal of the 7 included studies and identifying 5 additional treatment 

studies. We further conducted a comprehensive search for VA- and DoD-funded studies and 

found many studies that are ongoing or completed but unpublished. The expanded scope of this 

review helps to characterize what is currently known about GWI interventions, and to inform 

future directions for GWI research. 

LIMITATIONS

There are several limitations that should be considered, both of our review, as well as of the body 

of literature that we reviewed. Regarding our review, we were not able to combine results into a 

meta-analysis due to the heterogeneity of outcomes and interventions assessed. 
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With regard to the body of literature, there are several limitations to this evidence base. The 

absence of participant blinding was a frequent limitation, particularly among the psychosocial 

interventions, which results in potential bias for self-reported outcomes. The magnitude of 

treatment effect was not always reported, and documentation of adverse events was inconsistent 

among the trials. Of all the GWI treatment studies we reviewed, only 2 are low ROB

(Doxycycline1 and CPAP12) and 1 of them had a very small sample size (CPAP, N=18).

12

Moreover, while CPAP is an evidence-based treatment for sleep apnea, it was also associated 

with improvement on a broader range of GWI symptom in this study, not just sleep outcomes, so 

it is important to include. 

Heterogeneity

Heterogeneity among the interventions, outcome measures, and other study characteristics 

limited our ability to draw conclusions. Because we identified only 1 study each of the 12 

different interventions included in KQ1, we were unable to conduct meta-analyses. 

There are many methodologic challenges in studying treatments for GWI all of which drive the 

issues of heterogeneity. These include variation in case definition, lack of common and diseasespecific outcome measures for GWI, as well as differing interpretations of the pathophysiology 

of GWI itself. With regard to variation in case definitions, it is a major challenge to develop an 

evidence base for treating an illness that does not yet have an agreed upon set of symptoms, 

clinical presentation or measurement tools.

63 While there is overlap in some of the symptoms 

required to meet either the CDC or Kansas case definitions, individuals with GWI often present 

with wide range and variability in their symptoms, potentially resulting in too heterogeneous of a 

sample to see a treatment effect. Luckily 2 ongoing studies both leveraging VA administrative 

data (one employing a comprehensive chart review; PI: Helmer) and the other is employing a 

machine learning approach to identify health care data clusters that are associated with GWI (PI: 

Dursa), both will provide additional clarity on a case definition. Finally, there is a range of 

illness severity that is not well captured by the current measurement of GWI and not consistently 

measured and/or reported across the studies. Lack of a standard measure of global GWI 

symptoms and symptom clusters to measure a potential global reduction also resulted in a high 

degree of heterogeneity in outcome measures across studies (can cite McNeil 2013 again here). 

To try and address this challenge, in 2018, the Gulf War Illness Common Data Elements 

Symptoms Work Group64 developed a recommendation for the battery of measures to be used to 

assess symptom frequency, severity, and functional impairment.65 Ideally, moving forward, trials 

could use these recommended measures in order to combine results into larger meta-data from 

which to draw stronger conclusions about effectiveness of treatments. 

A common limitation of the psychosocial and exercise intervention literatures was the use of 

self-reported outcomes accompanied with a lack of participant blinding. The role and necessity 

of patient blinding in studies of these types of interventions has been debated. There are 

techniques even for complex nonpharmacologic interventions to blind patients to some degree.66

Some argue that lack of patient blinding in trials of non-pharmacologic therapies may 

considerably exaggerate treatment effects.

67 In which case, it would be difficult to determine 

whether and to what extent positive treatment effects – especially for the findings with only low 

level confidence – were due to an independent effect of treatment, expectancy as a mechanism of 

change, placebo effect, or a combination of these factors. On the other hand, others have argued 
GWI Interventions Evidence Synthesis Program

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that blinding is not only challenging but also potentially counterproductive as expectancy for 

change is thought to be an integral part of the intervention itself.68

Publication Bias

For KQ3, we identified lists of funded trials from the DoD69 and VA and searched for 

publications based on these funded trials. We found 31 studies that have not been published. 

Results of 3 of these studies have been posted publicly. No findings have been posted for 5 

studies, of which 2 were completed in 2017, and 2 in 2018. The absence of published findings 

from completed studies suggests the potential for publication bias or other barrier to publication. 

Applicability of Findings to the VA Population

All of these studies were conducted in Veteran participants with GWI, and many of the studies 

that showed effectiveness were conducted in a VA setting, so there is a high degree of 

applicability to Veterans who receive care at the VA. Also, some of the studies include important 

subpopulations (eg, those with sleep-disordered breathing, PTSD, or IBS). Yet, there may be less 

applicability to Veterans who do not receive care in the VA or who do not have access to 

specialty medical, post-deployment, or mental health care.

IMPLICATIONS FOR VHA

The findings of this report can help to inform priorities for future funding and clinical inquiry. 

There are several promising interventions including mindfulness-based approaches, CBT and 

exercise (separately or together), and the use of a CPAP among those with sleep-disordered 

breathing and GWI. The VA is in a unique position to offer integrated specialty and mental 

health care, which may be the ideal care model to effectively manage those with GWI. 

RESEARCH GAPS/FUTURE RESEARCH

There are many areas of future inquiry that should be considered. Several potentially promising 

interventions that have demonstrated effectiveness to improve 1 or more symptoms include:

mindfulness-based approaches, CBT and exercise (separate or together), and the use of a CPAP 

among those with GWI who have sleep-disordered breathing. The implementation of these in 

VA should be studied. We identified a broader literature of ongoing or single-arm studies from 

which we could not draw conclusions, but which may point us in the direction of promising 

novel therapies. Notable among these was a Specialized Care Program, and dietary interventions 

(low-glutamate diet; nutrient formula combined with methylphenidate), which warrant further 

investigation and movement to effectiveness trials.

In the context of an aging population of Gulf War Era Veterans, especially those with GWI, 

symptoms may be exacerbated either by the aging process or by the development of other 

medical comorbidities. Interventions with low risk of adverse effects are an important 

consideration. Studies examining GWI sub-populations were quite limited. Only 3 trials 

examined effects on Veterans with GWI who also had a specific comorbidity (1 each of IBS, 

PTSD, and sleep-disordered breathing), leaving many subpopulations in need of future research. 

In sum, research gaps and future ways to improve the evidence base include: 
GWI Interventions Evidence Synthesis Program

38

(1) Consolidation of intervention work, replicating promising interventions and conducting 

studies of a hybrid design to assess effectiveness and feasibility of implementation of

promising interventions in VA settings; 

(2) Development of a single case definition that considers the onset of other chronic health 

conditions in this aging population; 

(3) Development and use of consistent outcome measures capable of assessing the depth and 

breadth of GWI symptoms, considering the severity of illness to differentiate those with 

severe and less severe disease, and measuring longitudinal change in symptom severity. 
GWI Interventions Evidence Synthesis Program

39

CONCLUSIONS

We found a small but growing body of evidence examining a disparate array of treatments for 

Veterans with GWI (see Summary Table). There is low- to moderate-strength evidence that 

suggests several treatments may hold promise for improving symptoms related to GWI. The 

evidence was moderate-strength for benefits of a combination of CBT and exercise and lowstrength for 2 distinct mindfulness-based interventions and CPAP for Veterans with GWI who 

have sleep-disordered breathing. Doxycycline, on the other hand, is likely to be an ineffective 

treatment and is associated with harms (moderate-strength evidence). There are 33 ongoing, 

single-arm pilot, or unpublished studies examining a variety of interventions; some of these 

studies will help strengthen the evidence base for interventions that have already been examined 

on a small scale (eg, CBT and mindfulness-based stress reduction). However, many of these 

studies examine interventions that are both different from each other and different from 

interventions that have been studied before. While this approach may help identify potentially 

promising interventions, the variety of treatments examined will make it challenging to develop 

enough of an evidence base to guide clinicians about which treatments are most likely to be 

effective in clinical practice and which treatments should be avoided. Part of the challenge in 

studying treatment of GWI is the lack of an agreed-upon case definition, and the heterogeneity of 

symptoms and differing degrees of functional impairment experienced by those with GWI. 

Addressing these issues will help researchers to better target intervention-focused research.

Summary Table. Visual representation of findings

Treatment

Subpopulation if 

applicable

Outcome domain Physical health overall Pain Cognitive

FatigueMental health overallDepressionGlobal outcomes (function, QoL)PTSD symptomsSleepGI symptomsAdverse events

Medications vs placebo

Doxycycline1

Positive mycoplasma

     --- --- --- --- --- 

Mifepristone2 Ø --- Ø Ø Ø Ø --- Ø --- --- Ø

Naltrexone3

Ø

---

Ø

--- --- --- --- --- --- --- Ø

Rifaximin4

IBS (Rome III)

--- --- --- --- --- --- Ø --- --- Ø Ø

Nutritional supplements vs placebo

Carnosine5 --- Ø Ø Ø --- --- --- --- --- Ø Ø

CoQ106 Ø --- Ø --- --- --- --- --- --- --- Ø

Psychological, exercise, or multi-component interventions

CBTa7      --- --- --- --- --- Ø

Exercisea7      --- --- --- --- --- Ø
GWI Interventions Evidence Synthesis Program

40

Treatment

Subpopulation if 

applicable

Outcome domain Physical health overall Pain Cognitive

FatigueMental health overallDepressionGlobal outcomes (function, QoL)PTSD symptomsSleepGI symptomsAdverse events

CBT + Exercise in 

combinationa7

     --- --- --- --- --- Ø

Detox regimenb8 Ø Ø --- Ø Ø --- Ø --- --- --- Ø

Mindfulness-based stress 

reductionb9

---    ---  ---  --- --- ---

Sleep focused mind-body 

bridgingc10

Ø Ø Ø  Ø  Ø   --- ---

Other interventions

Acupuncturea11 Ø Ø --- --- --- --- --- --- --- --- Ø

CPAPd12      --- --- ---  --- ---

Shading represents the direction of effect: Pale yellow=Mixed Findings/Unclear, Green=Evidence of 

benefit, Gray=No association, Red=Favors usual care

Symbols represent the strength of the evidence: --- No evidence, Ø Insufficient, Low,  Moderate,  High a Versus usual care/TAU

b Versus waitlist

c Versus sleep education

d Versus sham CPAP
GWI Interventions Evidence Synthesis Program

41

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GWI Interventions Evidence Synthesis Program

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APPENDIX A. SEARCH STRATEGIES

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations 

and Daily 1946 to September 16, 2019 

Date searched: September 17, 2019 

# Searches Results

1 Persian Gulf Syndrome/ or Gulf War/ 1069

2 (("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or 

"Kuwait War" or "Operation GRANBY" or "Op GRANBY") adj7 (bioassay* or bio-assay* 

or biomarker* or bio-marker* or CFS or (chronic adj (fatigue or headache* or pain or 

"physical symptom*" or multisymptom or multi-symptom or multisystem or multi-system)) 

or cluster or cognit* or deployment or detect* or diagnos* or disease* or disorder* or 

expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal or gastrointestinal or headache* or identif* or illness or "irritable bowel syndrome*" or ME?CFS or 

"medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal or musculoskeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuro-psych* or 

((nonspecific or non-specific) adj ("chest pain*" or symptom*)) or psychosomatic or 

pulmonar* or respirator* or sickness or syndrome or somatization or somatoform or 

temporomandibular or temporo-mandibular or therap* or treat* or war-related)).ti,ab,kf.

1044

3 ("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or 

"Kuwait War" or "Operation GRANBY" or "Op GRANBY").ti,ab,kf. and (di or dg or dt or rt 

or rh or su or tu or th).fs.

583

4 (GWI or GWIs or GWVI or GWVIs or "Iowa Persian Gulf Study" or "War Related Illness 

and Injury Study Center*").ti,ab,kf.

200

5 (((Kuwait or Iraq or "Persian Gulf" or "Southwest Asia" or "SW Asia") adj7 ("air force" or 

"armed forces" or army or marines or "military personnel" or "national guard*" or naval or 

navy or "service members" or servicemembers or soldier* or veteran*)) and (bioassay* or 

bio-assay* or biomarker* or bio-marker* or CFS or (chronic adj (fatigue or headache* or 

pain or "physical symptom*" or multisymptom or multi-symptom or multisystem or multisystem)) or cluster or cognit* or deployment or detect* or diagnos* or disease* or 

disorder* or expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal 

or gastro-intestinal or headache* or identif* or illness or "irritable bowel syndrome*" or 

ME?CFS or "medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal 

or musculo-skeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuropsych* or ((nonspecific or non-specific) adj ("chest pain*" or symptom*)) or 

psychosomatic or pulmonar* or respirator* or sickness or syndrome or somatization or 

somatoform or temporomandibular or temporo-mandibular or therap* or treat* or warrelated)).ti,ab,kf.

1566

6 or/1-5 3087

7 6 not ("Enduring Freedom" or "Iran-Iraq" or "Iraq-Iran" or (Iraq adj2 Afghanistan) or "Iraqi 

Freedom" or OEF or OIF or "Op TELIC" or "Operation TELIC").ti,ab,kf.

1972

8 7 not ((exp animals/ not humans/) or (cat or cats or dog or dogs or mice or mouse or rat 

or rats or rodent).ti.)

1849

9 limit 8 to english language 1809

10 limit 9 to yr="1990 -Current" 1806
GWI Interventions Evidence Synthesis Program

47

EBM Reviews: Cochrane Central Register of Controlled Trials August 2019 

Cochrane Database of Systematic Reviews 2005 to September 11, 2019 

Date searched: September 17, 2019 

# Searches Results

1 (("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or 

"Kuwait War" or "Operation GRANBY" or "Op GRANBY") adj7 (bioassay* or bio-assay* 

or biomarker* or bio-marker* or CFS or (chronic adj (fatigue or headache* or pain or 

"physical symptom*" or multisymptom or multi-symptom or multisystem or multi-system)) 

or cluster or cognit* or deployment or detect* or diagnos* or disease* or disorder* or 

expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal or gastrointestinal or headache* or identif* or illness or "irritable bowel syndrome*" or ME?CFS or 

"medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal or musculoskeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuro-psych* or 

((nonspecific or non-specific) adj ("chest pain*" or symptom*)) or psychosomatic or 

pulmonar* or respirator* or sickness or syndrome or somatization or somatoform or 

temporomandibular or temporo-mandibular or therap* or treat* or war-related)).ti,ab.

81

2 ("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or 

"Kuwait War" or "Operation GRANBY" or "Op GRANBY").ti,ab.

97

3 (GWI or GWIs or GWVI or GWVIs or "Iowa Persian Gulf Study" or "War Related Illness 

and Injury Study Center*").ti,ab.

45

4 (((Kuwait or Iraq or "Persian Gulf" or "Southwest Asia" or "SW Asia") adj7 ("air force" or 

"armed forces" or army or marines or "military personnel" or "national guard*" or naval or 

navy or "service members" or servicemembers or soldier* or veteran*)) and (bioassay* or 

bio-assay* or biomarker* or bio-marker* or CFS or (chronic adj (fatigue or headache* or 

pain or "physical symptom*" or multisymptom or multi-symptom or multisystem or multisystem)) or cluster or cognit* or deployment or detect* or diagnos* or disease* or 

disorder* or expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal 

or gastro-intestinal or headache* or identif* or illness or "irritable bowel syndrome*" or 

ME?CFS or "medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal 

or musculo-skeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuropsych* or ((nonspecific or non-specific) adj ("chest pain*" or symptom*)) or 

psychosomatic or pulmonar* or respirator* or sickness or syndrome or somatization or 

somatoform or temporomandibular or temporo-mandibular or therap* or treat* or warrelated)).ti,ab.

173

5 or/1-4 264

6 5 not ("Enduring Freedom" or "Iran-Iraq" or "Iraq-Iran" or (Iraq adj2 Afghanistan) or "Iraqi 

Freedom" or OEF or OIF or "Op TELIC" or "Operation TELIC").ti,ab.

117

PsycINFO 1806 to September Week 2 2019 

Date searched: September 17, 2019 

# Searches Results

1 (("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or 

"Kuwait War" or "Operation GRANBY" or "Op GRANBY") adj7 (bioassay* or bio-assay* 

or biomarker* or bio-marker* or CFS or (chronic adj (fatigue or headache* or pain or 

"physical symptom*" or multisymptom or multi-symptom or multisystem or multi-system)) 

or cluster or cognit* or deployment or detect* or diagnos* or disease* or disorder* or 

expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal or gastrointestinal or headache* or identif* or illness or "irritable bowel syndrome*" or ME?CFS or 

"medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal or musculo375
GWI Interventions Evidence Synthesis Program

48

skeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuro-psych* or 

((nonspecific or non-specific) adj ("chest pain*" or symptom*)) or psychosomatic or 

pulmonar* or respirator* or sickness or syndrome or somatization or somatoform or 

temporomandibular or temporo-mandibular or therap* or treat* or war-related)).ti,ab.

2 ("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or 

"Kuwait War" or "Operation GRANBY" or "Op GRANBY").ti,ab.

1122

3 (GWI or GWIs or GWVI or GWVIs or "Iowa Persian Gulf Study" or "War Related Illness 

and Injury Study Center*").ti,ab.

57

4 (((Kuwait or Iraq or "Persian Gulf" or "Southwest Asia" or "SW Asia") adj7 ("air force" or 

"armed forces" or army or marines or "military personnel" or "national guard*" or naval or 

navy or "service members" or servicemembers or soldier* or veteran*)) and (bioassay* or 

bio-assay* or biomarker* or bio-marker* or CFS or (chronic adj (fatigue or headache* or 

pain or "physical symptom*" or multisymptom or multi-symptom or multisystem or multisystem)) or cluster or cognit* or deployment or detect* or diagnos* or disease* or 

disorder* or expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal 

or gastro-intestinal or headache* or identif* or illness or "irritable bowel syndrome*" or 

ME?CFS or "medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal 

or musculo-skeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuropsych* or ((nonspecific or non-specific) adj ("chest pain*" or symptom*)) or 

psychosomatic or pulmonar* or respirator* or sickness or syndrome or somatization or 

somatoform or temporomandibular or temporo-mandibular or therap* or treat* or warrelated)).ti,ab.

1314

5 or/1-4 2310

6 5 not ("Enduring Freedom" or "Iran-Iraq" or "Iraq-Iran" or (Iraq adj2 Afghanistan) or "Iraqi 

Freedom" or OEF or OIF or "Op TELIC" or "Operation TELIC").ti,ab.

1318

7 6 not ((exp animals/ not humans/) or (cat or cats or dog or dogs or mice or mouse or rat 

or rats or rodent).ti.)

1291

8 limit 7 to english language 1243

9 limit 8 to yr="1990 -Current" 1242

CINAHL with Full Text

Date searched: September 17, 2019 

S1 (MH "Persian Gulf Syndrome") 264

S2 TI ( (("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or

"Kuwait War" or "Operation GRANBY" or "Op GRANBY") N7 (bioassay* or bio-assay* or

biomarker* or bio-marker* or CFS or (chronic N1 (fatigue or headache* or pain or

"physical symptom*" or multisymptom or multi-symptom or multisystem or multi-system))

or cluster or cognit* or deployment or detect* or diagnos* or disease* or disorder* or

expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal or gastrointestinal or headache* or identif* or illness or "irritable bowel syndrome*" or ME?CFS or

"medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal or musculoskeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuro-psych*

or ((nonspecific or non-specific) N1 ("chest pain*" or symptom*)) or psychosomatic or

pulmonar* or respirator* or sickness or syndrome or somatization or somatoform or

temporomandibular or temporo-mandibular or therap* or treat* or war-related)) ) OR AB ( 

(("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or

"Kuwait War" or "Operation GRANBY" or "Op GRANBY") N7 ((bioassay* or bio-assay* or

biomarker* or bio-marker* or CFS or (chronic N1 (fatigue or headache* or pain or

"physical symptom*" or multisymptom or multi-symptom or multisystem or multi-system))

313
GWI Interventions Evidence Synthesis Program

49

or cluster or cognit* or deployment or detect* or diagnos* or disease* or disorder* or

expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal or gastrointestinal or headache* or identif* or illness or "irritable bowel syndrome*" or ME?CFS or

"medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal or musculoskeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuro-psych* or

((nonspecific or non-specific) N1 ("chest pain*" or symptom*)) or psychosomatic or

pulmonar* or respirator* or sickness or syndrome or somatization or somatoform or

temporomandibular or temporo-mandibular or therap* or treat* or war-related)) )

S3 TI ( ("Desert Shield" or "Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or

"Kuwait War" or "Operation GRANBY" or "Op GRANBY") ) OR AB ( ("Desert Shield" or

"Desert Storm" or "Gulf War" or "Gulf Conflict" or "Gulf Crisis" or "Kuwait War" or

"Operation GRANBY" or "Op GRANBY") )

629

S4 TI ( (GWI or GWIs or GWVI or GWVIs or "Iowa Persian Gulf Study" or "War Related

Illness and Injury Study Center*") ) OR AB ( (GWI or GWIs or GWVI or GWVIs or "Iowa

Persian Gulf Study" or "War Related Illness and Injury Study Center*") )

44

S5 TI ( (veteran* N15 ("chronic fatigue" or fibromyalg* or "medically unexplained" or

multisymptom or multi-symptom or multisystem or multi-system or myalgi* or ME/CFS)) ) 

OR AB ( (veteran* N15 ("chronic fatigue" or fibromyalg* or "medically unexplained" or

multisymptom or multi-symptom or multisystem or multi-system or myalgi* or ME/CFS)))

52

S6 TI ( (((Kuwait or Iraq or "Persian Gulf" or "Southwest Asia" or "SW Asia") N7 ("air force"

or "armed forces" or army or marines or "military personnel" or "national guard*" or naval

or navy or "service members" or servicemembers or soldier* or veteran*)) and (bioassay*

or bio-assay* or biomarker* or bio-marker* or CFS or (chronic N1 (fatigue or headache*

or pain or "physical symptom*" or multisymptom or multi-symptom or multisystem or

multi-system)) or cluster or cognit* or deployment or detect* or diagnos* or disease* or

disorder* or expos* or fibromyalgi* or "functional somatic syndrome*" or gastrointestinal

or gastro-intestinal or headache* or identif* or illness or "irritable bowel syndrome*" or

ME?CFS or "medically unexplained" or "multiple chemical sensitivit*" or musculoskeletal

or musculo-skeletal or myalgi* or neurocognit* or neuro-cognit* or neuropsych* or neuropsych* or ((nonspecific or non-specific) N1 ("chest pain*" or symptom*)) or

psychosomatic or pulmonar* or respirator* or sickness or syndrome or somatization or

somatoform or temporomandibular or temporo-mandibular or therap* or treat* or warrelated)) ) OR AB ( (((Kuwait or Iraq or "Persian Gulf" or "Southwest Asia" or "SW Asia")

N7 ("air force" or "armed forces" or army or marines or "military personnel" or "national

guard*" or naval or navy or "service members" or servicemembers or soldier* or

veteran*)) and (bioassay* or bio-assay* or biomarker* or bio-marker* or CFS or (chronic

N1 (fatigue or headache* or pain or "physical symptom*" or multisymptom or multisymptom or multisystem or multi-system)) or cluster or cognit* or deployment or detect*

or diagnos* or disease* or disorder* or expos* or fibromyalgi* or "functional somatic

syndrome*" or gastrointestinal or gastro-intestinal or headache* or identif* or illness or

"irritable bowel syndrome*" or ME?CFS or "medically unexplained" or "multiple chemical

sensitivit*" or musculoskeletal or musculo-skeletal or myalgi* or neurocognit* or neurocognit* or neuropsych* or neuro-psych* or ((nonspecific or non-specific) N1 ("chest

pain*" or symptom*)) or psychosomatic or pulmonar* or respirator* or sickness or

syndrome or somatization or somatoform or temporomandibular or temporo-mandibular

or therap* or treat* or war-related)) )

804

S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6 1,434

S8 S7 NOT ("Enduring Freedom" or "Iran-Iraq" or "Iraq-Iran" or (Iraq N2 Afghanistan) or

"Iraqi Freedom" or OEF or OIF or "Op TELIC" or "Operation TELIC") 

Limiters –

167
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Published Date: 19900101-20191231;

English Language; 

Exclude MEDLINE records;

Human

Scopus

Date searched: September 17, 2019 

TITLE-ABS-KEY ( "Desert Shield" OR "Desert Storm" OR "Gulf War" OR "Gulf Conflict" OR "Gulf 

Crisis" OR "Kuwait War" OR "Operation GRANBY" OR "Op GRANBY" OR "Iowa Persian Gulf Study"

OR "War Related Illness and Injury Study Center" ) 

AND DOCTYPE ( cp ) 

AND PUBYEAR > 1989 

AND ( LIMIT-TO ( LANGUAGE , "English" ) ) 

= 308 results

Allied and Complementary Medicine (AMED)

Date searched: October 1, 2019 

# Searches Results 

S8 S6 NOT S7 

Limiters - Published Date: 19900101-20200131; Language: English 

55

S7 TI (cat OR cats OR dog OR dogs OR mice OR mouse OR rat OR rats OR rodent) 7,158

S6 S4 NOT S5 58

S5

TI ("Enduring Freedom" OR "Iran-Iraq" OR "Iraq-Iran" OR (Iraq N2 Afghanistan) OR "Iraqi 

Freedom" OR OEF OR OIF OR "Op TELIC" OR "Operation TELIC") OR AB ("Enduring 

Freedom" OR "Iran-Iraq" OR "Iraq-Iran" OR (Iraq N2 Afghanistan) OR "Iraqi Freedom" OR 

OEF OR OIF OR "Op TELIC" OR "Operation TELIC")

191

S4 S1 OR S2 OR S3 116

S3

TI (((Kuwait OR Iraq OR "Persian Gulf" OR "Southwest Asia" OR "SW Asia") N7 ("air 

force" OR "armed forces" OR army OR marines OR "military personnel" OR "national 

guard*" OR naval OR navy OR "service members" OR servicemembers OR soldier* OR 

veteran*)) AND (bioassay* OR bio-assay* OR biomarker* OR bio-marker* OR CFS OR 

(chronic N1 (fatigue OR headache* OR pain OR "physical symptom*" OR multisymptom 

OR multi-symptom OR multisystem OR multi-system)) OR cluster OR cognit* OR 

deployment OR detect* O ... 

74

S2

TI (GWI OR GWIs OR GWVI OR GWVIs OR "Iowa Persian Gulf Study" OR "War Related 

Illness and Injury Study Center*") OR AB (GWI OR GWIs OR GWVI OR GWVIs OR "Iowa 

Persian Gulf Study" OR "War Related Illness and Injury Study Center*") 

7

S1

TI (("Desert Shield" OR "Desert Storm" OR "Gulf War" OR "Gulf Conflict" OR "Gulf Crisis" 

OR "Kuwait War" OR "Operation GRANBY" OR "Op GRANBY") N7 (bioassay* OR bioassay* OR biomarker* OR bio-marker* OR CFS OR (chronic N1 (fatigue OR headache* 

OR pain OR "physical symptom*" OR multisymptom OR multi-symptom OR multisystem 

OR multi-system)) OR cluster OR cognit* OR deployment OR detect* OR diagnos* OR 

45 
GWI Interventions Evidence Synthesis Program

51

disease* OR disorder* OR expos* OR fibromyalgi* OR "functional somatic syndrome*" 

OR gastrointest ... 

ClinicalTrials.gov 

Date searched: September 17, 2019 

OTHER TERMS: "Desert Shield" OR "Desert Storm" OR "Gulf War" OR "Gulf Conflict" OR "Gulf 

Crisis" OR "Kuwait War" OR "Operation GRANBY" OR "Op GRANBY" OR "Iowa Persian Gulf Study" 

OR "War Related Illness and Injury Study Center"

= 71 results

WHO ICTRP

Date searched: September 17, 2019 

TITLE: "Desert Shield" OR "Desert Storm" OR "Gulf War" OR "Gulf Conflict" OR "Gulf Crisis" OR 

"Kuwait War" OR "Operation GRANBY" OR "Op GRANBY" OR "Iowa Persian Gulf Study" OR "War 

Related Illness and Injury Study Center"

RECRUITMENT STATUS=ALL

DATE OF REGISTRATION= 01/01/1990 – 17/09/2019

= 56 results
GWI Interventions Evidence Synthesis Program

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APPENDIX B. STUDY SELECTION

Inclusion codes, code definitions, and criteria

1. Is the full-text of the article in English? 

Yes  Proceed to 2.

No  Code X1 (Non-English-language publication). STOP.

2. Does the population include Veterans with Gulf War Illness?

Include: Veterans (either U.S. or international) deployed to the Persian Gulf region 

between Aug 2, 1990 - Nov 1991, defined by the authors as having Gulf War Illness 

according to a recognized case definition (CDC or Kansas), or defines cases using 

similar criteria to CDC/Kansas, or using illness definitions prior to CDC/Kansas criteria 

(Chronic Multisymptom/multisystem) Illness (CMI), Irritable Bowel Syndrome (IBS), 

Chronic Fatigue Syndrome (CFS)/Myalgic Encephalitis (EM), fibromyalgia (FM), Gulf 

War Syndrome). Also include studies of civilian contractors present during the conflict, if 

available. Include studies where deployment status and/or time of deployment is unclear.

Yes  Proceed to 3.

No  Code X2 (Excluded population). STOP.

3. Does the study examine the benefits and/or harms of an intervention or management 

strategy (pharmacological, supplement, non-pharmacological, behavioral, etc. – no 

exclusions) for treating symptoms of Gulf War Illness?

Yes  Proceed to 4.

No  Is the study about a potential biomarker for GWI? 

Yes  Code Biomarker. STOP.

No  Code X3 (Not relevant to GWI interventions or biomarkers). STOP.

4. Is the study a published randomized controlled trial, non-randomized controlled trial, or 

cohort study that compares the intervention to placebo, usual care, or another active 

intervention, among Veterans with GWI? 

Yes  Code Tx-KQ1-[specify intervention, specify condition if subset of GWI].

Proceed to 6.

No, compares GWI with a non-GWI population  Code X4 (non-GWI comparator). 

STOP.

No, it is a systematic review/meta-analysis of GWI interventions  Code Tx-SR. 

STOP.

No, it is a protocol/abstract/unpublished report that otherwise meets these criteria 

Code Tx-KQ3 emerging research [specify intervention]. STOP.

No, for none of the reasons above  Proceed to 5.
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5. Is the GWI intervention study a single-arm study or case series in which all participants 

received the same intervention for GWI?

Yes  Code Tx-KQ3 single-arm [specify intervention]. STOP.

No  Code X5 (excluded study design or publication type). STOP.

Exclude: case studies, editorials, letters, and review articles that are non-systematic.

Mark “B” any X5’s that may contain useful content for background/discussion, eg: 

B-X5 – Narrative review with good background

B-X5 – May be useful for discussion

6. Does the study examine effectiveness or harms in a subgroup (defined by gender, 

symptom severity, case definition, or branch of military, as examples) compared with a 

larger population of Veterans with GWI? 

Yes  Add code KQ2 (eg, Tx-KQ1-KQ2). STOP.

No  STOP.

Key Questions:

1. Evidence on effectiveness/harms: What are the benefits and harms of pharmacological 

and non-pharmacological interventions and management strategies for Veterans with 

GWI?

2. Evidence about subgroups: Do the effectiveness or harms of the interventions/strategies 

differ among subgroups of Veterans with GWI, such as female Veterans or cases defined 

by specific criteria, in comparison with Veterans with GWI overall?

3. Emerging research: What interventions for GWI have been examined in 

a) noncomparative studies only?

b) ongoing/unpublished trials or cohort studies?

Exclusion Codes:

X1: Non-English-language publication

X2: Excluded population

X3: Not relevant to GWI interventions or biomarkers

X4: Non-GWI comparator

X5: Excluded study design or publication type

X9: Duplicate or preliminary publication of a more recent study

X99: Study terminated
GWI Interventions Evidence Synthesis Program

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APPENDIX C. QUALITY ASSESSMENT CRITERIA 

Cochrane Rob 2.0:20 Five domains through which bias may be introduced

1. Risk of bias arising from the randomization process:

1.1. Was the allocation sequence random?

1.2. Was the allocation sequence concealed until participants were enrolled and assigned to 

interventions?

1.3. Did baseline differences between intervention groups suggest a problem with the 

randomization process?

2. Risk of bias due to deviations from the intended interventions (effect of assignment to intervention):

2.1. Were participants aware of their assigned intervention during the trial?

2.2. Were carers and people delivering the interventions aware of participants' assigned 

intervention during the trial?

2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose 

because of the experimental context?

2.4. If Y/PY to 2.3: Were these deviations from intended intervention balanced between groups?

2.5. If N/PN/NI to 2.4: Were these deviations likely to have affected the outcome? 

2.6. Was an appropriate analysis used to estimate the effect of assignment to intervention? 

2.7. If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to 

analyse participants in the group to which they were randomized?

3. Risk of bias due to missing outcome data:

3.1. Were data for this outcome available for all, or nearly all, participants randomized? 

3.2. If N/PN/NI to 3.1: Is there evidence that the result was not biased by missing outcome data? 

3.3. If N/PN to 3.2: Could missingness in the outcome depend on its true value? 

3.4. If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?

4. Risk of bias in measurement of the outcome:

4.1. Was the method of measuring the outcome inappropriate? 

4.2. Could measurement or ascertainment of the outcome have differed between intervention 

groups? 

4.3. If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study 

participants ? 

4.4. If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of 

intervention received? 

4.5. If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of 

intervention received?

5. Risk of bias in selection of the reported result:

5.1. Were the data that produced this result analysed in accordance with a pre-specified analysis 

plan that was finalized before unblinded outcome data were available for analysis?

 

Is the numerical result being assessed likely to have been selected, on the basis of the results, 

from... 

5.2. ...multiple outcome measurements (eg, scales, definitions, time points) within the outcome 

domain? 

5.3. ...multiple analyses of the data?

Overall risk-of-bias judgement

Low ROB The study is judged to be at low risk of bias for all domains for this result. 

Some Concerns The study is judged to raise some concerns in at least 1 domain for this result, but 

not to be at high risk of bias for any domain.

High ROB The study is judged to be at high risk of bias in at least one domain for this result. 

OR 

The study is judged to have some concerns for multiple domains in a way that 

substantially lowers confidence in the result.
GWI Interventions Evidence Synthesis Program

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Table 8. Risk of bias in trials of interventions for Gulf War Illness

Experimental 

intervention Comparator Randomization process 

Deviations 

from intended 

interventions

Missing 

outcome 

data

Measurement 

of the

outcome

Selection of 

the reported 

result

Overall Bias Comment

Medications

Doxycycline1 Placebo Low Low Low Low Low Low ---

Mifepristone2 Placebo Low Low Low Some 

concerns

Low Some 

concerns

Analyzed completers only. 

Statistically underpowered: 

the intended sample size of 

40 not reached due to 

recruitment difficulties. 

Naltrexone3 Placebo Some concerns Low Low High High High Randomization and allocation 

concealment (cards drawn 

from box. Analyzed CGISresponders vs non 

responders, not by 

randomization (Tx vs 

placebo).

Rifaximin4 Placebo Low Some concerns Low Low Low Some 

concerns

Analyzed completers only.

Nutritional supplements

CoQ106 Placebo Low Low Low Low High High Post-protocol changes in 

analytic approach; 

threshold/magnitude of 

change not defined for binary 

analyses of improvement. 

Carnosine5 Placebo Low Some concerns High Low Low High Differential loss to follow-up: 

37% vs 13.3% Analyzed 

completers only.

Psychological, exercise, and multi-component interventions

CBT + 

Exercise7

TAU Low Low Low Some 

concerns

Low Some 

concerns

Self-reported outcomes, 

subjects not blinded

Detox 

regimen8

Waitlist Some concerns Low Low Some 

concerns

Low Some 

concerns

Baseline differences in % 

disabled vs employed selfreported outcomes, subjects 

not blinded.

Mindfulnessbased 

therapy9

TAU Low Low Low Some 

concerns

Low Some 

concerns

Self-reported outcomes, 

subjects not blinded.
GWI Interventions Evidence Synthesis Program

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Experimental 

intervention Comparator Randomization process 

Deviations 

from intended 

interventions

Missing 

outcome 

data

Measurement 

of the

outcome

Selection of 

the reported 

result

Overall Bias Comment

Sleep-focused 

Mind-Body 

Therapy10

Sleep 

education

Low Low Low Some 

concerns

Low Some 

concerns

Self-reported outcomes, 

subjects not blinded

Other interventions

Acupuncture 

(bi-weekly)11

Waitlist/ 

acupuncture 

(weekly)

Low Some concerns Low Some 

concerns

Low Some 

concerns

Self-reported outcomes; 

participants and intervention 

staff not blinded

CPAP12 Sham CPAP Low Low Low Low Low Low ---

Abbreviations: CBT=Cognitive Behavioral Therapy; CoQ10=Coenzyme Q10; CPAP=Continuous Positive Airway Pressure; IBS=Irritable Bowel Syndrome; MBB=Mind-body 

Bridging; MBSR=Mindfulness-based Stress Reduction; QoL=Quality of Life; ROB=Risk of Bias; SF-36=36-Item Short Form Health Survey; Sx=symptom; TAU=Treatment as 

Usual; Tx=Treatment; WAIS-R=Wechsler Adult Intelligence Scale-Revised. 
GWI Interventions Evidence Synthesis Program

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APPENDIX D. DATA SUPPLEMENT 

Table 9. Results for physical health, pain, and fatigue outcomes in intervention trials for Gulf War Illness

Intervention and

study characteristicsa Physical Health Overall Pain Fatigue 

Medications

Doxycycline1 (n=245) vs 

placebo (n=246)

Total N=491

Subpopulation: positive 

mycoplasma DNA test

Tx duration: 12 months

Observation: 18 months

ROB: Low

Veterans SF-36 PCS Pt score

N analyzed: 199 vs 212

Least-square mean difference (95% CI; Tx 

minus C) at 12 months: 1.0 (-0.3 to 2.4), 

P=0.12

McGill Pain Questionnaire (N analyzed), 

least-square mean difference (95% CI; Tx 

minus C) at 12 months:

Sensory (207 vs 214): -0.6 (-1.8 to 0.6), P 

> 0.2

Affective (206 vs 214): 0.0 (-0.5 to 0.5), P 

> 0.2

Pain now (207 vs 213): -0.3 (-0.7 to 0.1), 

P=0.18

Typical pain (206 vs 213): 0.0 (-0.4 to 

0.3), P > 0.2

MFI (N analyzed), least-square mean 

difference (95% CI; Tx minus C) at 12 

months:

General fatigue (206 vs 214): 

-0.1 (-0.7 to 0.5), P > 0.2

Physical fatigue (206 vs 214): 

-0.1 (-0.6 to 0.5), P > 0.2

Reduced activity (207 vs 214): 

0.0 (-0.6 to 0.7), P > 0.2

Reduced motivation (206 vs 214): 

-0.2 (-0.8 to 0.4), P > 0.2

Mental fatigue (206 vs 213): 

0.0 (-0.6 to 0.6), P > 0.2

Mifepristone2 (n=18 in 

each phase 1 and 2) 

vs placebo (n=18 in phase 

1, n=15 in phase 2), 6-

week crossover phases, 

1m washout

Phase 1 Total N=36

Phase 2 Total N=33

Tx duration: 6 weeks

Observation: 4 months

ROB: Some concerns

Veterans SF-36 (acute form) PCS score: 

Mifepristone treatment was not associated 

with improvement in self-reported physical 

health status (p=0.838)

Overall mean change, ΔT minus ΔC (SD): -

0.46 (7.76), P=0.738

NR General fatigue (MFI-20) Overall mean 

change, ΔT minus ΔC (SD): 0.63 (3.37), 

P=0.302 

Naltrexone3

vs placebo (n’s=NR), 

crossover phases 

separated by 1-month 

washout.

Total N=40

Tx duration: 3 months

Observation: 7 months

ROB: High

Change in CGIS favored naltrexone: 14 

(35%) 

Change in CGIS favored placebo: 5 (12.5%)

No change from baseline: 18 (45%)

(Tx vs C not significant)

 

NR NR

Nutritional supplements
GWI Interventions Evidence Synthesis Program

58

Intervention and

study characteristicsa Physical Health Overall Pain Fatigue 

Carnosine5 (n=12 finished 

study) vs placebo (n=13 

finished study)

Total N=34

Tx duration: 12 weeks

Observation: 14 weeks

ROB: High

NR No changes in average (dolorimetry) pain 

thresholds, and no differences between 

groups.

CFS severity score: no differences 

between groups. 

Instantaneous fatigue scores: no 

treatment effects.

CoQ106

100 mg/d (n=11) vs 300 

mg/d (n=12) vs placebo 

(n=23)

Total N=46

Tx duration: 3.5 +/- 0.5 

months

Observation: 3.5 +/- 0.5 

months

ROB: High

GSRH: improved from baseline (threshold not 

defined for improved/not improved):

Q100 (N=10) vs placebo (N=19): OR (95% 

CI):

All Pts (N=46): 1.88 (0.26 to 13.4), P=0.53

Physical function assessed by Summary 

Performance Score:

Q100 vs Placebo, % Pts Improved from 

baseline: 82% vs 40% 

Absolute difference: 42% (P=0.025). Women 

contributed to this benefit. 

Q300 vs Placebo, % Pts Improved from 

baseline: 55% vs 40% 

Absolute difference: 15% (P=0.44). 

SPS improvement on Q300 was not 

significant, though the effect on Q100 did not 

differ significantly from that on Q300 

(P=0.17).

NR NR

Psychological, exercise, or multi-component interventions

CBT+Exercise7 (n=266) vs 

CBT (n=286) vs Exercise 

(n=265) vs TAU (n=270)

Total N=1092

Tx duration: 12 weeks

Observation: 12 months

ROB: Some concerns

VSF-36 PCS Score: % of Pts with 7+ points 

improvement vs baseline at 3 months, 6 

months, 12 months:

CBT + exercise (n=266): 16.5, 16.2, 18.4

CBT alone (n=286): 15.0, 12.9, 18.5

Exercise alone (n=265): 12.8, 13.6, 11.7 

TAU (n=270): 9.3. 12.2, 11.5 

OR (95%CI) for 7+ points PCS improvement 

vs TAU, adjusted for study design, pending 

disability claims, and baseline V/SF-36 

physical component summary score:

Exercise: 1.07 (0.63 to 1.82)

CBT: 1.72 (0.91 to 3.23)

Exercise + CBT: 1.84 (0.95 to 3.55)

MPQ-S: Of the 4 subscales: sensory, 

affective, pain right now, typical level of 

pain, affective pain was significantly 

reduced (P < 0.025) vs TAU in CBT 

arms:

CBT alone: -0.43

CBT + Exercise: -0.50

All other findings not significant. 

MFI: Both exercise arms (exercise, 

CBT+Exercise) significantly improved 

fatigue (P < 0.05) vs TAU on all 5 

domains (general, physical, reduced 

activity, reduced motivation, mental 

fatigue).

CBT alone: No significant changes from 

baseline on any of the 5 MFI domains.
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Intervention and

study characteristicsa Physical Health Overall Pain Fatigue 

Overall (marginal) effect, OR (95%CI) for 7+ 

points PCS improvement vs TAU:

CBT (n=552) vs no CBT (n=535): 1.71 (95% 

CI, 1.15 to 2.53) 

Exercise (n=531) vs no exercise (n=556): 

1.07 (95% CI, 0.76-1.50)

Detox regimen8 (n=22) vs 

waitlist (n=10)

Total N=32

Tx duration: 4-6 weeks

Observation: 3 months 

ROB: Some concerns

VF-36 PCS: Difference in score (95% CI) 

between Waitlist and Tx at Week 6, adjusted 

for baseline (Positive changes indicate 

improvement): 6.9 (-0.3 to 14.2); P=0.06

Subscales of VF-36 physical:

Physical functioning : 2.7 (-18.1 to 23.5) 

P=0.8

Role-physical: 27.6 (6.9, to 48.3) P=0.009

General health: 20.7 (9.2 to 32.3) P < 0.001

Vitality: 31.2 (15.6 to 46.9) P < 0.001

MPQ-2-SF: Difference in score (95% CI) 

between Waitlist and Tx at Week 6, 

adjusted for baseline (Negative changes 

indicate improvement):

Total pain score: -1.1 (-2.0 to -0.2); 

P=0.02. 

VR-36 bodily pain subscale score: 26.4 

(8.5, 44.4) P=0.004

MFI: Difference in score (95% CI) 

between Waitlist and Tx at Week 6, 

adjusted for baseline (Negative changes 

indicate improvement):

General fatigue: -4.3 (-7.4 to -1.3); 

P=0.006

Physical fatigue: -3.5 (-6.9 to -0.2); 

P=0.04

Reduced activity: -4.0 (-7.3 to -0.7); 

P=0.02

Reduced motivation: -3.1 (-5.6 to -0.5); 

P=0.02

Mental fatigue: -5.7 (-8.7 to -2.7); P < 

0.001

Mindfulness-based stress 

reduction9 (n=26) vs TAU 

(n=29)

Total N=55

Tx duration: 8 weeks

Observation: 6 months

ROB: Some concerns

NR MPQ-2: Tx group reported greater 

reductions in pain at 6 months compared 

to TAU:

Post-treatment: f=0.13; P=.45

6 months: f=0.33; P=.05

MFI General Fatigue: 

Tx group reported significant 

improvement in fatigue at 6 months 

compared to TAU: 

Post-treatment: f=0.18; P=0.27

6 months: f=0.32; P=0.03

PROMIS fatigue: significant improvement 

with Tx vs TAU at both timepoints:

Post-treatment: f=0.35; P=0.02

6 months: f=0.26; P=0.05

Sleep focused mind-body 

bridging10 (n=33) vs sleep 

education (n=27)

Subpopulation: sleep 

disturbance 

Total N=60

Tx duration: 3 sessions 

over 3 weeks

Observation: 3 months

ROB: Some concerns

PA-assessed physical condition (N (%) 

improved): 8 (32%) vs 3 (13.6%); P=NS

QoL (SF-36 pain): 

Pre: 38.9 (30.8–47.0) vs 37.9 (29.5–46.2)

Post: 46.6 (37.9–55.4) vs 39.1 (30.0–

48.3)

Observation: 45.0 (36.6–53.5) vs 39.5 

(28.6–50.4)

Post-randomization treatment by period 

interaction: effect size 0.47 (P=0.032).

The 2 interventions differed at 

Observation (p=.052), in which 

improvement in mental fatigue for MBB 

(1.99) was greater than that for SED 

(.36), from the baseline covariate (17.74).

MFI, unadjusted mean (95% CI):
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Intervention and

study characteristicsa Physical Health Overall Pain Fatigue 

General fatigue:

Pre: 21.0 (20.1 to 21.9) vs 20.7 (19.3 to 

22.0) 

Post: 19.4 (18.1 to 20.8) vs 20.0 (18.7 to 

21.3) 

Observation: 18.8 (17.3–20.4) vs 20.2 

(18.4–22.0) 

Mental fatigue:

Pre: 18.3 (17.2 to 19.5) vs 17.4 (15.9 to 

18.9)

Post: 16.2 (14.7 to 17.7) vs 16.2 (14.5 to 

17.9)

Observation: 16.1 (14.5 to 17.7) vs 17.1 

(15.4 to 18.8)

Other interventions

Acupuncture11 2x/week 

(n=52) vs 2-month waitlist 

then acupuncture 1x/week 

(n=52)

Total N=104

Tx duration: 6 months

Observation: 6 months

ROB: Some concerns

SF-36P significantly improved by mean 9.4 

points with T vs waitlisted group at month 6, 

adjusted for baseline pain. (P=0.03).

MPQ: at 6 months, treatment group had 

an average reduction of 3.6 points 

(p=0.04) compared to the comparator 

group.

NR

CPAP12 (n=9)

vs sham CPAP (n=9)

Subpopulation: sleepdisordered breathing

Total N=18

Tx duration: 3 weeks

Observation: 3 weeks

ROB: Low

Treatment group experienced 34% 

improvement in physical health.

SF-36 PCS: between groups effect size 2.79 

(P=0.0003) 

Correlation with sleep stage shifts: -0.41 

(P=0.104)

Treatment group experienced 34% 

reduction in pain.

Pain VAS (0-10, daily): between groups 

effect size 2.14 (P=0.0008)

Correlation with sleep stage shifts: 0.51 

(P=0.037)

Treatment group experienced 38% 

reduction in fatigue.

FSS (increasing impact was rated 1–7 

days 1 and 7 (averaged)): between 

groups effect size 2.55 (P=0.0002)

Correlation with sleep stage shifts: 0.71 

(P=0.0002)

a

Study characteristics include number randomized per treatment arm, subpopulation if applicable, total sample size, duration of treatment, duration of observation (includes 

treatment period unless otherwise specified), and risk of bias (ROB).

Abbreviations: CBT=Cognitive Behavioral Therapy; CFS=Chronic Fatigue Syndrome; CGIS=Clinical Global Impressions Scale; CI=Confidence Interval; CPAP=Continuous 

Positive Airway Pressure; f=Cohen’s f value (0 .10=small; 0.25=medium; 0.40=large effect size); FSS=Fatigue Severity Scale; GSRH=General Self-Reported Health; 

IBS=Irritable Bowel Syndrome; MBB=Mind-Body Bridging; MFI=Multidimensional Fatigue Inventory; MPQ=McGill Pain Questionnaire; NR=Not Reported; NS=Not 

Significant; P=P-value; PA=Physician’s Assistant; PCS=Physical Component Summary; PROMIS=Patient-Reported Outcomes Measures Information System; ROB=Risk of Bias; 

QoL=Quality of Life; ROB=Risk of Bias; SED=Sleep Education; SF-36=36-item Short Form Survey (SF-36P=physical component); TAU=Treatment as Usual; Tx=Treatment; 

VAS=Visual Analog Scale; VSF-36 (also VF-36)=Veterans 36-Item Short Form Survey
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Table 10. Results for cognitive, mental health, PTSD symptoms, and global outcomes in intervention trials for Gulf War Illness

Intervention and study 

characteristics Cognitive symptoms Mental health overall Depression Global outcomes (Function, QoL) PTSD symptoms

Medications

Doxycycline1 (n=245) vs 

placebo (n=246)

Subpopulation: positive 

mycoplasma DNA test

N=491

Tx duration: 12 months

Observation: 18 months

ROB: Low

CFQ:

N analyzed: 207 vs 214

Least-square mean difference 

at 12 months, Tx minus C 

(95% CI): -1.2 (-3.7 to 1.4), 

P > 0.2

Veterans SF-36 MCS:

N analyzed: 199 vs 212

Least-square mean 

difference at 12 months, 

Tx minus C (95% CI): 0.0 

(-1.8 to 1.8), P > 0.2

NR NR NR

Mifepristone2 (n=18 in 

each phase 1 and 2) 

vs placebo (n=18 in phase 

1, n=15 in phase 2), 6-week 

crossover Tx phases 

separated by 1-month 

washout

Phase 1 N=36

Phase 2 N=33

Tx duration: 6 weeks

Observation: 4 months

ROB: Some concerns

MATRICS Consensus 

Cognitive Battery (Overall 

mean change, ΔT minus ΔC 

(SD)): 0.10 (6.83), P=0.937

Working memory: 0.16 (8.26), 

P=0.914

Verbal learning: 5.23 (10.29), 

P=0.008

Visual learning: -0.94 (11.12), 

P=0.643

Overall: 0.10 (6.83), P=0.937

CFQ Overall mean change, ΔT 

minus ΔC (SD): 1.06 (15.46), 

P=0.700

SF-36 MCS overall mean 

change, ΔT minus ΔC 

(SD): 

-1.89 (12.49), P=0.423

BDI overall mean 

change, ΔT minus ΔC 

(SD): 0.88 (9.22), 

P=0.595

NR PCL overall mean 

change, ΔT minus ΔC 

(SD): -3.38 (12.26), 

P=0.130

Naltrexone3

vs placebo (n’s=NR), 

crossover phases separated 

by 1-month washout.

Total N=40

Tx duration: 3 months

Observation: 7 months

ROB: High

Attention-related problems 

(CPT; mean change in hit 

response time): −7.33 ± 6.92 

(95% CI: −21.49 to 6.72)

vs −0.88 ± 7.98 

(95% CI: −15.3 to 17.09)

(P=0.43)

NR NR NR NR

Rifaximin4 (n=27) vs 

placebo (n=23)

Subpopulation: IBS (Rome 

III)

NR NR NR IBS-QoL, change mean 

(SE), Tx vs C:

Dysphoria: 6.62 (4.31) 

vs 11.30 (4.82), P=0.50 

Interference with 

activity: 8.40 (5.10) vs 

NR
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Intervention and study 

characteristics Cognitive symptoms Mental health overall Depression Global outcomes (Function, QoL) PTSD symptoms

N=50 

Tx duration: 2 weeks

Observation: 2 weeks

ROB: Some concerns

4.95 (4.76), P=0.52

Body image: 8.09 (4.14) 

vs 12.02 (4.93), P=0.83

Health worry: 3.92 

(4.29) vs 10.26 (5.35), 

P=0.39

Food avoidance: 7.35 

(6.35) vs 6.41 (5.27), 

P=0.26

Social reaction: 4.78 

(4.14) vs 0.48, P=0.28

Sexual score: 3.68 

(6.59) vs −3.85 (4.98), 

P=0.77

Relationships: 2.19 

(3.54) vs −3.65, P=0.17

Overall (all items): 6.23 

(4.00) vs 6.50 (3.82), 

P=0.86

Nutritional Supplements

Carnosine5 (n=12 finished 

study) vs placebo (n=13 

finished study)

N=34

Tx duration: 12 weeks

Observation: 14 weeks

ROB: High

Cognition (WAIS-R digit 

symbol substitution test): 

Significant improvement within 

carnosine group between 

week 0 - 12 (P=0.046) vs no 

change with placebo.

Trail Making Tests: No 

difference between groups 

NR NR NR NR

CoQ106

Q100 (n=11) vs Q300 

(n=12) vs placebo (n=23)

N=46

Tx duration: 3.5 +/- 0.5 

months

Observation: 3.5 +/- 0.5 

months

ROB: High

Backward digit span, change 

from baseline, mean diff (SE):

Q100 (n=11) vs placebo 

(n=20): -0.13 (0.71); 95% CI -

1.57 to 1.32, P=0.86

Q300 (n=11) vs placebo 

(n=20): -0.22 (0.85); 95% CI -

1.96 to 1.53, P=0.80

NR NR NR NR
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Intervention and study 

characteristics Cognitive symptoms Mental health overall Depression Global outcomes (Function, QoL) PTSD symptoms

Psychological, exercise, or multi-component interventions

CBT+Exercise7 (n=266) vs 

CBT (n=286) vs Exercise 

(n=265) vs TAU (n=270)

Total N=1092

Tx duration: 12 weeks

Observation: 12 months

ROB: Some concerns

CFQ (positive changes 

indicate improvement)

Mean changes from baseline, 

adjusted for study design, 

pending disability claims, and 

baseline values:

TAU: -0.67 (P=NS) 

CBT + Exercise: 3.38 

(P < 0.01)

Exercise: 2.98 (P < 0.01)

CBT: 2.66 (P < 0.025)

VSF-36 MCS score: 

Mean change from 

baseline, adjusted for 

study design, pending 

disability claims, and 

baseline values ((positive

changes indicate 

improvement):

TAU: -1.03 (P=NS)

CBT + Exercise: 2.30 (P 

< 0.01)

Exercise: 2.33 (P < 0.01)

CBT: 0.97 (P < 0.025)

VSF-36 Mental Health 

Index:

TAU: -1.60 (P=NS)

CBT + Exercise: 2.95 (P 

< 0.01)

Exercise: 3.27 (P < 0.01)

CBT: 1.37 (P=NS)

NR NR NR

Detox regimen8 (n=22) vs 

waitlist (n=10)

N=32

Tx duration: 4-6 weeks

Observation: 3 months 

ROB: Some concerns

NR VF-36 MCS (Positive 

changes indicate 

improvement): Difference 

in score (95% CI) 

between Waitlist and Tx 

at Week 6, adjusted for 

baseline: 9.5 (3.1 to 

15.8); P=0.003 

Role-emotional: 15.2 (-

4.9 to 35.2) P=0.1

Mental health: 17.7 (5.3 

to 30.0) P=0.005

NR Subscales of VF-36 

mental:

Social functioning: 15.9 

(-3.9 to 35.7) P=0.1

NR

Mindfulness-based stress 

reduction9 (n=26) vs TAU 

(n=29)

N=55

Tx duration: 8 weeks

Observation: 6 months

CFQ: intervention group 

reported more cognitive 

failures post-treatment: f=0.44; 

P=.002

6 months: f=0.40; P < .001

NR PHQ-9: reduction in 

depressive symptoms 

greater for treatment 

group, at both posttreatment and 6 

months:

NR PSS-I: reduction in 

PTSD symptoms 

greater for treatment 

group post-treatment, 

but not 6 months: 

Post-treatment: 
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Intervention and study 

characteristics Cognitive symptoms Mental health overall Depression Global outcomes (Function, QoL) PTSD symptoms

ROB: Some concerns Post-treatment: f=0.22; 

P=.050

6 months: f=0.27; 

P=.031

f=0.40; P=0.004

6 months: f=0.27; 

P=0.08

Veterans with PTSD 

at baseline (N=45) 

randomized to 

treatment group had 

significantly greater 

reductions in PTSD 

symptoms vs TAU 

post-treatment, but 

not 6 months: 

Post: f=0.44; P=.005

6 months: f=0.31; 

P=.082

Sleep focused mind-body 

bridging10 (n=33) vs sleep 

education (n=27)

Subpopulation: sleep 

disturbance 

N=60

Tx duration: 3 sessions over 

3 weeks

Observation: 3 months

ROB: Some concerns

Cognitive failure (CFQ total 

score), unadjusted means 

(95% CI):

Pre: (51.7 to 62.5) vs 55.9 

(46.2 to 65.6)

Post: 49.9 (42.4 to 57.3) vs 

46.0 (35.1 to 57.0)

At 3 months: 50.6 (40.6 to

60.6) vs 46.7 (35.6 to 57.9) 

“no reliable treatment effects”

BSI (global severity 

index), unadjusted 

means (95% CI):

Pre: 24.8 (20.5 to 29.0) 

vs 25.4 (20.3 to 30.4)

Post: 23.0 (18.2 to 27.9) 

vs 20.4 (14.1 to 26.6)

At 3 months: 20.2 (15.6 

to 24.9) vs 23.5 (16.1 to 

30.9)

“no reliable treatment 

effects”

Depression (CES-D 

total score), 

unadjusted means 

(95% CI):

Pre: 27.4 (25.2 to 

29.5) vs 26.2 (23.2 to 

29.2)

Post: 25.4 (22.5 to 

28.3) vs 24.9 (21.5 to 

28.2)

Observation: 22.8 

(20.5 to 25.2) vs 27.0 

(22.6 to 31.4)

No between-groups 

difference for 

post randomization 

treatment (p=.17) or 

treatment by period 

interaction (p=.080). 

Observation: 

significantly greater 

improvement with 

MBB in customized 

No treatment effects

QoL (SF-36 total score), 

unadjusted means (95% 

CI):

Pre: 43.8 (38.6 to 48.9) 

vs 43.0 (35.8 to 50.1)

Post: 48.4 (42.6 to 54.1) 

vs 46.4 (39.6 to 53.2)

Observation: 48.2 (42.0 

to 54.4) vs 44.2 (35.82 

to 52.5)

QoL (SF-36 pain),

unadjusted means (95% 

CI):

Pre: 38.9 (30.8 to 47.0) 

vs 37.9 (29.5 to 46.2)

Post: 46.6 (37.9 to 55.4) 

vs 39.1 (30.0 to 48.3)

Observation: 45.0 

(36.6.0 to 53.5) vs 39.5 

(28.6 to 50.4)

PCL-M total score

adjusted mean 

improvement: 

MBB

Post-Tx: 3.30 (p=.027)

3m observation: 5.45 

(p=.001)

SED

Post-Tx: not 

significant (P=0.72)

3m observation: not 

significant (P=0.19).

The 2 groups differed 

for the post 

randomization

treatment effect 

(p=.038). 

MBB was more 

effective than SED in 

decreasing PCL-M 

scores.
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Intervention and study 

characteristics Cognitive symptoms Mental health overall Depression Global outcomes (Function, QoL) PTSD symptoms

between-groups 

contrasts (adjusted 

mean): effect 

size=0.71 (P=.038)

Other interventions

CPAP active12 (n=9)

vs sham CPAP (n=9)

Subpopulation: sleepdisordered breathing

N=18

Tx duration: 3 weeks

Observation: 3 weeks

ROB: Low

Treatment group experienced 

33% improvement in cognitive 

function.

Cognitive VAS (0-10 daily): 

between groups effect size 

1.67 (P=0.004)

Cognition correlation with 

sleep stage shifts: 0.64 

(P=0.006)

Treatment group 

experienced 16% 

improvement in mental 

health.

SF-36 mental: between 

groups effect size 1.29 

(P=0.03) 

Correlation with sleep 

stage shifts: -0.58 

(P=0.015)

NR NR NR

a

Study characteristics include number randomized per treatment arm, subpopulation if applicable, total sample size, duration of treatment, duration of observation (includes 

treatment period unless otherwise specified), and risk of bias (ROB).

Abbreviations: BDI=Beck Depression Inventory; BSI=Brief Symptom Inventory; CBT=Cognitive Behavioral Therapy; CES-D=Center for Epidemiological Studies-Depression 

Scale; CFQ=Cognitive Failures Questionnaire; CI=Confidence Interval; CPAP=Continuous Positive Airway Pressure; CPT=Connors Continuous Performance Test; f=Cohen’s f 

value (0 .10=small; 0.25=medium; 0.40=large effect size); IBS-QoL=Irritable Bowel Syndrome Quality of Life; MATRICS=Measurement and Treatment Research to Improve 

Cognition in Schizophrenia; MBB=Mind-Body Bridging; MCS=Mental Component Score; NR=Not Reported; P=P-Value; PCL=PTSD Checklist; PHQ-9=Patient Health 

Questionnaire 9-item; PSS-I=PTSD Symptom Score interview; PTSD=Post-Traumatic Stress Disorder; QoL=Quality of Life; ROB=Risk of Bias; SE=Standard Error; SED=Sleep 

Education; SF-36=36-Item Short Form Survey; TAU=Treatment as Usual; Tx=Treatment; VAS=Visual Analog Scale; VSF-36 (also VF-36)=Veterans 36-Item Short Form;

WAIS-R-Wechsler Adult Intelligence Scale-Revised
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Table 11. Results for gastrointestinal symptoms and sleep outcomes in intervention trials for Gulf War Illness

Intervention and study 

characteristicsa Gastrointestinal Symptoms Sleep Outcomes

Medications

Rifaximin4 (n=27) vs placebo 

(n=23)

Subpopulation: IBS (Rome III)

N=50 

Tx duration: 2 weeks

Observation: 2 weeks

ROB: Some concerns

IBS symptoms (BDQ) - difference (T minus C, change 

from baseline), (95% CI), P value:

Stool frequency: 0.2 (−0.2, 0.6), P=0.38

Stool consistency: 0.3 (− 0.2, 0.9), P=0.25

Urgency: 0.0 (−0.2, 0.3), P=0.88

Abdominal pain: 0.1 (− 0.4, 0.7), P=0.71

Bloating: 0.1 (−0.5, 0.6), P=0.86

Global improvement: 0.0 (−0.6, 0.6), p > 0.99

NR

Nutritional Supplements

Carnosine5 (n=12 finished 

study) vs placebo (n=15 finished 

study)

N=27

Subpopulation: IBS (Rome II)

Tx duration: 12 weeks

Observation: 14 weeks

ROB: High

Within groups: Tx group had reduced stool frequency and 

watery consistency from weeks 0 to 12 (P=0.019) vs no 

changes in placebo group. 

NR

Psychological, exercise, or multi-component interventions

Sleep focused mind-body 

bridging10 (n=33) vs sleep 

education (n=27)

Subpopulation: sleep 

disturbance 

N=60

Tx duration: 3 sessions over 3 

weeks

Observation: 3 months

ROB: Some concerns

NR Adjusted mean SPI-II scores were similar between SED and MBB 

for the overall treatment effect (p=.32). 

Sleep problems in MBB declined to a greater extent than did 

those in SED (p=.046, effect size=.70). 

The adjusted mean improvements, MBB vs SED:

Post-treatment: 16.88 vs 14.69 

At 3 months: 20.70 vs 12.63 

All were sig. different from baselines (p < .001).

PA-assessed changes in sleep, SED vs MBB (P for between 

group difference):

Improved: 7 (26.9%) vs 17 (58.6%), P <0.05 

Other interventions

CPAP active12 (n=9) vs sham 

CPAP (n=9)

Subpopulation: sleep-disordered 

breathing

NR Quality of sleep (PSQI; rated 0–21 on days 1 and 7 (averaged)): 

Treatment group experienced 41% improvement. Slightly poorer 

in sham group (assessed by sleep parameters), but no significant 

between-group differences. 
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Intervention and study 

characteristicsa Gastrointestinal Symptoms Sleep Outcomes

N=18

Tx duration: 3 weeks

Observation: 3 weeks

ROB: Low

PSQI: between groups effect size 2.67 (P=0.0003)

Correlation with sleep stage shifts: 0.59 (P=0.016)

a

Study characteristics include number randomized per treatment arm, subpopulation if applicable, total sample size, duration of treatment, duration of observation (includes 

treatment period unless otherwise specified), and risk of bias (ROB).

Abbreviations: BDQ=Bowel Disease Questionnaire; CBT=Cognitive Behavioral Therapy; CI=Confidence Interval; CPAP=Continuous Positive Airway Pressure; IBS=Irritable 

Bowel Syndrome; MBB=Mind-Body Bridging; NR=Not Reported; P=P-value; PSQI=Pittsburgh Sleep Quality Index; ROB=Risk of Bias; SED=Sleep Education; SPI-II=Stroke 

Prognosis Instrument 2.
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Table 12. Adverse events in published intervention studies for Gulf War Illness

Treatment (Sample size) N participants Adverse events

Acupuncture11 104 1 in biweekly treatment group reported pain on 

needling; 

1 in weekly treatment group reported suicidal 

thoughts

Carnosine5 34 1 asymptomatic elevation of alanine-serine 

transaminase plus interval increase in CRP, 

considered not related to study drug.

CBT, Exercise, CBT + Exercise7 1092 112 serious AEs, mostly “hospitalizations

unrelated to the study”: 

23 CBT + exercise 

27 exercise 

30 CBT

32 TAU

3 AEs possibly related: 

2 TAU (psychosis and angina)

1 back surgery (exercise arm)

CoQ106 46 2 neurological events, both placebo.

CPAP12 18 ---

Detox regimen8 32 Discomfort and nausea from sauna; flushing 

and itching from niacin; pre-syncope; IBS; 

hypokalemia

Doxycycline1 491 Significantly more nausea and photosensitivity 

with doxycycline vs placebo.

No significant difference in myalgia.

Mifepristone2 36 1 on mifepristone developed a rash that 

resolved after ceasing drug

Mindfulness-based stress 

reduction9

55 ---

Naltrexone3 40 1 w/d due to dizziness with naltrexone.

Rifaximin4 50 No differences

Sleep focused mind-body 

bridging vs sleep education10

60 ---

Abbreviations: CBT=cognitive behavioral therapy; CPAP=continuous positive airway pressure; CoQ10= coenzyme 

Q10; TAU=treatment as usual.
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Table 13. Details of ongoing and unpublished controlled trials of interventions/management strategies for Gulf War Illness

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

Behavioral

CBT26

NCT02782780

RCT

VA ORD;

San Francisco 

VAMC

Cognitive 

Behavioral 

Therapy for 

Insomnia for Gulf 

War Illness

Recruiting 

as of July 

2019;

E: May 30, 

2020

"examine the efficacy of 

telephone-delivered CBTi 

for alleviating sleep and 

non-sleep GWI 

symptoms in a 2-arm 

randomized controlled 

trial"

80 deployed GW Veterans 

meeting Gulf War Registry 

criteria, Kansas definition, 

and Insomnia severity index 

score of 14 or greater

8 weekly, individual sessions 

of Cognitive Behavioral 

Therapy for Insomnia (CBTi) 

vs usual care/waitlist

Kansas 1°: Insomnia severity (ISI); sleep 

quality (PSQI); GWI symptoms 

(modified Kansas questionnaire); 

sleep latency, minutes of wake 

after sleep onset, sleep efficiency 

(self-report sleep diary)

2°: fatigue (FSS); pain (BPI); 

cognitive function (MASQ); anxiety 

and depressive symptoms (HADS)

Time frame: baseline, 8 weeks, 

and 6-month follow-up

Cognitive 

rehabilitation27

NCT02161133

RCT

VA ORD; VAMCs 

Bedford, MA; East 

Orange, NJ; 

Canandaigua, NY

Cognitive 

Rehabilitation for 

Gulf War Illness

Completed 

Sept 2019. 

No results;

A: 

September 

1, 2019

"to determine whether 

Problem-Solving 

Therapy, a patient 

centered cognitive 

rehabilitation therapy, 

can reduce disability by 

compensating for 

problem-solving deficits"

268 GW Veterans with GWI, 

scores at least half a 

standard deviation worse 

than the mean on the 

WHODAS 2.0

Cognitive rehab (problemsolving therapy) vs

Health education

Kansas 1°: Disability (WHODAS 2.0)

2°: problem-solving inventory (selfreport), problem-solving ability 

(Neuropsychological Battery 

includes: Halstead Category Test, 

Russell Revised Version; CPT-3,

Stroop Color and Word Test, 

executive functioning (TMT parts A 

and B), FIT, fatigue (FSS), and 

pain (PDI and MPI composite 

score)

Time frame: 12 weeks

MBSR28

NCT03058952

RCT

VA ORD; 

VAPSHCS, Seattle, 

WA

Evaluation of a 

MindfulnessBased 

Intervention for 

Gulf War Illness

Recruiting 

as of July 

2017; E: 

April 30, 

2021

“to evaluate outcomes 

of... Mindfulness-Based 

Stress Reduction and an 

adapted version of the 

Chronic Disease SelfManagement Program 

(CDSMP)...for Veterans 

with Chronic 

Multisymptom Illness 

(CMI).”

308 Veterans with CMI (50% 

will be GWV*)

MBSR vs adapted CDSMP

N/A (used 

CMI as 

criteria)

1°: Pain (SF-MPQ-2); Fatigue 

(MFI); concentration and memory 

(CFQ); satisfaction with 

intervention (CSQ-8)

2°: Depression (PHQ-9); PTSD 

(PCL-C); SF-36; alcohol use 

disorder (NIH PROMIS Alcohol 

Use and Negative Consequences, 

short form)
GWI Interventions Evidence Synthesis Program

70

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

Central Nervous System (CNS) Stimulation

rTMS23

NCT01608321

RCT

VA ORD; VA Palo 

Alto Health Care 

System

rTMS for the 

Treatment of 

Chronic Pain in 

GW1 Veterans 

(rTMS)

Terminated 

(Did not 

meet 

recruitment 

goals as of 

June 2015)

“to engage in a clinical 

trial of rTMS in chronic 

pain that occurs in the 

context of multiple 

medical symptoms ...in 

GWI diagnosed patients 

[with] symptoms of 

chronic pain in the 

musculoskeletal category 

and at least two 

additional symptoms.”

206 (initially estimated)

Chronic pain >= 4 on the pain 

severity scale of the BPI-SF

Active vs sham rTMS, 20 

sessions

Kansas 1°: Change in pain (BPI-SF)

Time Frame: Baseline and 3-4 

weeks

rTMS31

NCT03030794

RCT

Veterans Medical 

Research 

Foundation, in 

collaboration with 

DoD; Naval 

Medical Center and 

Veterans Affairs 

Hospital, San 

Diego, CA

Alleviating 

Headache and 

Pain in GWI With

Neuronavigation 

Guided rTMS

recruiting as 

of Aug 

2018;

E: 

December 

2018

"assess the effect of 

repetitive transcranial 

magnetic stimulation 

(rTMS) on Gulf War 

illness related headaches 

and pain"

90 pts meeting CDC and 

Kansas criteria with 

Migraines and muscle pain 

and joint pain

Repetitive transcranial 

magnetic stimulation (rTMS), 

11 visits over 2 months vs

Sham rTMS at same intervals

CDC and 

Kansas

1°: Self-reported headache and 

pain (daily log); HA pain severity 

(HIT-6); pain level; opioid 

medication assessment; 

headache, muscle, and joint pain 

(VAS)

2°: Neurobehavioral symptoms 

(NSI); Pain (SF-MPQ); widespread 

pain (New Clinical Fibromyalgia 

Diagnostic Criteria); FIQR; HVLT; 

TMT A&B; executive function; 

depression (HAM-D); SF-36; sleep 

quality (PSQI); insomnia fatigue 

scale

Time Frame: 2 months for each 

subject (11 visits)

rTMS32

NCT04046536

RCT

VA ORD;

VA San Diego, 

Palo Alto, and 

Atlanta

rTMS in 

Alleviating Pain 

and Co-Morbid 

Symptoms in 

Gulf War 

Veterans Illness 

(GWVI)

Recruiting 

as of Nov 

2019

E: 

September 

30, 2024

Assess "effectiveness of 

using repetitive 

transcranial magnetic 

stimulation (rTMS) in 

relieving pain and other 

co-morbid symptoms of 

Gulf War Illness"

80 GW Veterans meeting 

CDC and Kansas, with 

migraines, muscle and joint 

pain, and depression 

4 arms:

1. rTMS at the LDLPFC

2. rTMS at the LMC vs

CDC and 

Kansas

1°: Self-reported headache and 

pain by daily log; SF-MPQ; HIT-6; 

HAM-D; SF-36; BPI-SF; pain (New 

Clinical Fibromyalgia Diagnostic 

Criteria); FIQR; sleep quality 

(PSQI); insomnia severity index; 

Flinders Fatigue Scale

2°: PTSD symptoms (CAPS-5); 

opioid-based pain medication 

usage; supraspinal resting state 
GWI Interventions Evidence Synthesis Program

71

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

3. Sham rTMS at the 

LDLPFC 

4. Sham rTMS at the LMC 

functional connectivity (MRI)

Time Frame: Baseline, 1-week, 1-

month, 2-month, and 3-month

rTMS33

NCT04182659

RCT

Veterans Medical 

Research 

Foundation & 

DoD; VA Palo Alto, 

San Diego, Atlanta

Long Term 

Efficacy of 

Neuronavigation 

Guided rTMS in 

Alleviating Gulf 

War Illness 

Related 

Headaches and 

Pain Symptoms

Recruiting 

as of Dec 

2019; E: 

Sept 2022

Assess “the effectiveness 

of repetitive transcranial 

magnetic stimulation 

(rTMS), non-invasive 

treatment option, in 

alleviating headaches, 

muscle, and joint pain 

symptoms of GWI.”

150 GW Veterans with 

migraines, under age 65, who

served at least 30 days in the 

conflict

Transcranial Magnetic 

Stimulation (rTMS) vs sham 

rTMS at the left motor cortex 

(LMC)

CDC & 

Kansas

1°: pain (SF-MPQ; BPI-SF), 

headaches (Self-report journal; 

HIT-6), QoL (SF-36); fibromyalgia 

(New Clinical Fibromyalgia 

Diagnostic Criteria - Part 1; 

Revised Fibromyalgia Impact 

Questionnaire); neurobehavioral 

(NSI); sleep (PSQI; Insomnia 

Severity Index); fatigue (Flinders 

Fatigue Scale). 

2°: PTSD (CAPS-5); opioid-based 

pain medication usage; 

supraspinal resting state functional 

connectivity

(HD) tDCS30

NCT03542383

RCT

The University of 

Texas at Dallas; 

Callier Center for 

Communication 

Disorders

Treatment of 

Memory 

Disorders in Gulf 

War Illness with 

High Definition 

Transcranial 

Direct Cortical 

Stimulation

Recruiting 

as of May 

2018;

E: Sept 29, 

2019

"determine if delivery of 

[High Definition 

transcranial Direct 

Current Stimulation] HD 

tDCS over the 

[PreSupplementary Motor 

Area] preSMA will 

improve performance in 

GWI veterans with a 

verbal retrieval deficit"

120 deployed GW Veterans

HD tDCS: 10 20-minute 

sessions of 1 mA anodal High 

Definition Transcranial Direct 

Current Stimulation to the 

preSMA region over a 2-week 

period vs sham HD tDCS at 

same duration

Not 

specified

1°: Verbal fluency (COWAT; timing 

note: also applied at initial phone 

screen), and Verbal learning and 

memory (CVLT)

2°: Semantic memory (SORT); 

Semantic Selection Task 

Time Frame: Baseline, after Tx (2 

weeks), and 3- and 6-months 

follow-up

tDCS34

NCT03547869

RCT

The University of 

Texas at Dallas;

University of Texas 

Southwestern 

Medical Center

Transcranial 

Direct Current 

Stimulation for 

Pain Treatment 

in Gulf War 

Illness.

Recruiting 

as of July 

2019;

E: March 

12, 2021

"investigate long-term 

modulation of pain 

pathways leading to a 

suppression of pain 

symptoms in Gulf War 

Illness patients by 

applying transcranial 

direct current stimulation"

120 GW Veterans

tDCS vs sham tDCS, 10 

sessions

Not 

specified

1°: Pain (VAS)

2°: Brain activity (EEG)

Time frame: baseline, immediately 

after tDCS, and 1, 4, 12, 24 weeks 

after the last tDCS session

VNS35

NCT02791893

RCT

Vagus Nerve 

Stimulation: 

Treatment for 

Recruiting 

as of Nov 

2019;

"Besides their pain, the 

researchers will also 

assess the effect of 

40 GWV with GWI, 

widespread pain, has 

migraine headaches

Kansas 1°: Widespread pain (VAS); 

2°: Overall improvement (patient 

global improvement of change), 
GWI Interventions Evidence Synthesis Program

72

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

Benjamin Natelson

VA East Orange, 

NJ; Icahn School of 

Medicine at Mount 

Sinai

Gulf Veterans 

with Gulf War 

Illness

E: March 

2020

vagus nerve stimulation 

(VNS) in alleviating 

migraine headache"

VNS hand-held device (20 

weeks total, 120 second 

period 3x/day) vs placebo 

(inactive device at same 

frequency/duration) 

SF-36, number of migraine 

headache days 

Time frame: baseline, 10 and 20 

weeks

Complementary and integrative health

Acupressure36

NCT02075489

NRCT

The Cleveland 

Clinic

Acupressure for 

Pain 

Management and 

Fatigue Relief in 

Gulf War 

Veterans

Completed 

Oct 2017. 

No results;

A: October 

2017

"determine the 

effectiveness of 

acupressure treatment in 

symptomatic veterans in 

fatigue relief and pain 

management for Gulf 

War Illness (GWI)"

7 GW Veterans with GWI, 

severity and interference 

scores of 5+ by BPI, score of 

3+ by Piper Fatigue Scale

Acupressure treatment (40 

minutes/day, 2days/week for 

6 weeks) vs

Reiki (40 mins/day, 2 

days/week for 6 weeks)

Not 

specified

1°: Fatigue (revised PFS)

2°: changes in corticomuscular 

coherence (EEG and EMG surface 

signals), SF-36

Timing: baseline and 6 weeks 

Meditation + 

acupuncture37

NCT02180243

RCT

VA ORD;

VAMC, 

Washington, DC

CAM in Veterans 

with Gulf War 

Illnesses

Recruiting 

as of Nov 

2019;

E: October 

1, 2021

"to explore the 

effectiveness Gulf War 

Health Education 

(GWHE) and iRest Yoga 

Nidra (meditation)/ 

auricular (ear) 

acupuncture for Veterans 

with Gulf War Veterans' 

Illnesses (GWVI)"

172 GW Veterans with GWI 

(ie fatigue, pain, cognitive 

impairment)

iRest Yoga Nidra and 

auricular acupuncture vs

Gulf War Health education

Not 

specified

1°: Sleep quality (objective and 

self-report sleep measures will be 

taken)

Time frame: 1 year

Tai Chi38

NCT02661997

RCT

VA ORD; 

VAMC Boston

Novel 

Interventions for 

GWVI

Recruiting 

as of Aug 2, 

2019;

E: March 

31, 2021

"examine the beneficial 

effects of two novel 

treatments for Gulf War 

Veteran's Illness (Tai Chi 

and Wellness 

intervention) and to 

establish the efficacy of 

these mind-body 

approaches to symptom 

reduction"

120 GW veterans with joint 

pain or stiffness over 6 

months and meeting CDC 

CMI criteria

Tai Chi: 60 minutes, twice a 

week for 12 weeks + 

30min/day home practice vs

Wellness Intervention: same 

dose/duration + VA Whole 

Health video and brief 

mindfulness practice

CDC 1°: Change in pain (BPI-SF)

2°: Fatigue (MFI-20); PROMIS 

Global Health Scale; 50-foot walk 

test; Short Physical Performance 

Battery; executive functioning 

(TMT); verbal learning (HVLT-R) 

Other outcomes: various

Time frame: baseline and 12 

weeks 
GWI Interventions Evidence Synthesis Program

73

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

Yoga39

NCT02378025

RCT

Palo Alto Veterans 

Institute for 

Research, DoD

VAMC, Palo Alto

Treating Chronic 

Pain in Gulf War 

Illness

Completed; 

A: March 

2018

Results 

shown in 

Table 14

"The purpose of this 

study is to determine 

whether yoga is effective 

for the treatment of 

chronic pain in Gulf War 

Illness"

75 Veterans (served 1990-91 

regardless of deployment) 

with chronic pain

Yoga (10 weeks) vs

CBT (10 weeks)

CDC 1°: Pain (BPI-SF) 

Time frame: Weeks 0, 2, 4, 8, 10, 

18, 26, and 34

2°: SF-36, Fatigue (6-minute walk 

test), Changes in medication.

Time frame: Weeks 0, 10, and 34

Diet

Low-FODMAP 

diet25,40

NCT02881944

RCT

Ashok Tuteja

VAMC Salt Lake 

City, UT

Effect of Diet on 

Gulf War Illness

Completed

E: 

September 

2018

Results 

shown in 

Table 14

"compare a low FODMAP 

diet to a high FODMAP 

diet for effect on 

Veterans with IBS and 

symptoms of Gulf War 

Illness"

68 GW Veterans with IBS 

and 2 or more of the nonintestinal symptom groups 

(chronic-once a week or more 

often-fatigue, insomnia, joint 

pains, general stiffness, and 

headache, neurological and 

mood, respirator and skin 

symptoms) for > 6 months

Low-FODMAP diet vs highFODMAP (typical healthy) 

diet for 3 weeks

Not 

specified

1°: Bowel symptom score (selfreported) 

2°: IBS-QoL score (self-reported) 

Time frame: baseline and 3 weeks

Low-glutamate 

diet41,42

NCT03342482

Crossover RCT

American 

University, 

Washington, DC

Glutamate 

NeuroExcitotoxicity in 

GWI

Recruiting 

as of July 4, 

2019;

E: August 

31, 2020

"test the effectiveness of 

a low-glutamate diet in 

GWI patients, as a way to 

mediate symptom 

occurrence by reducing 

excess glutamatergic 

neurotransmission"

40 Veterans deployed during 

GW with GWI

Phase 1: Low-glutamate diet 

vs waitlist (1 month)

Phase 2: MSG challenge (3 

consecutive days) vs placebo 

(2 weeks: one 3-day 

challenge per week, then 

crossover) 

Kansas 

and CDC

1°: Change in Brain Glutamate 

Levels ( MRS) at baseline and 1 

month

2°: Symptom change, and 

Cognitive function (computerized 

battery)

Other: Change in brain excitation 

(EEG) 

Timing (2° and other): baseline, 1 

month, and weeks 5 & 6

Exercise

Exercise 

training43

NCT01350492

RCT

Impact of 

Exercise Training 

on Pain and 

Brain Function in 

Completed. 

No results 

posted as of 

April 5, 

2019; 

"test the influence of 

weight training on 

physical symptoms, 

physical activity and brain 

structure and function in 

77 Gulf War Veterans with 

chronic musculoskeletal pain

Resistance exercise training 

(16 weeks) vs

Not 

specified

1°: Symptoms (self-report and 

EHR)

2°: Physical activity 

(accelerometer and self-report), 
GWI Interventions Evidence Synthesis Program

74

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

VA ORD; VAMC 

Madison, WI

Gulf War 

Veterans

A: 

December 

31, 2018

Gulf War Veterans with 

chronic widespread 

muscle pain"

Waitlist brain structure and function (6 MRI 

scans over course of study)

Time frame: baseline, during 

exercise phase, and 6- and 12-

months post-exercise

Medications

D-cycloserine44

NCT02983734

RCT

Boston University 

Charles River 

Campus

D-cycloserine: A 

Novel Treatment 

for Gulf War 

Illness (GWDCS)

Recruiting 

Jan 2019; 

September 

2019

"investigate the efficacy 

of d-cycloserine (DCS) 

treatment for Gulf War 

Illness (GWI)"

56 GW Veterans meets GWI 

criteria with cognitive 

symptom domain

D-cycloserine 100mg/day for 

4 weeks vs placebo

Not 

specified

1°: Neuropsychological Test 

Battery

2°: Symptom Questionnaires

Time frame: 8 weeks per subject

Etanercept+ 

mifepristone45

NCT04254627

Phase I 

Nova Southeastern 

University, RTI 

International, 

Rochester General 

Hospital

Tumor Necrosis 

Factor (TNF) and 

Glucocorticoid 

Antagonist for 

Gulf War Illness 

(GWI)-

Associated Multisymptom 

Disease 

Homeostasis 

Reset

Not yet 

recruiting as 

of Mar 

2020; E: 

July 2021

“assess the safety and 

mechanistic efficacy of a 

sequential etanerceptmifepristone intervention 

for Gulf War Illness” 

20 males, 45-70 yrs, with 

trauma, meeting CDC & 

Kansas criteria for GWI

Etanercept 50 mg weekly 

injection for 12 weeks, 

followed by 1 week of 

mifepristone at either 300 or

600 mg/day 

CDC & 

Kansas

1°: Safety

Duloxetine vs 

pregabalin24

NCT01846182

RCT

VA ORD; Central 

Texas Health Care 

System and 

Central Texas 

VAMC (Waco, TX)

RCT of 

Duloxetine & 

Pregabalin for 

the treatment of 

Gulf War Illness 

in Veterans 

Terminated 

Jan 2020

“Test the efficacy of 

Duloxetine and 

Pregabalin for treating 

Gulf War Veterans who 

suffer from GWI”

162 English-speaking GW 

Veterans with pain and GWI

3 arms: 60mg duloxetine 

(taken daily in AM) vs 300mg 

pregabalin (taken daily in PM) 

vs placebo (taken daily AM & 

PM), for 20 weeks

Kansas 1° Pain (10-point VAS; PCS of SF36)

2°: Side effects (checklist)

Time frame: every 2 weeks up to 

34 weeks

Intranasal 

insulin46

NCT01802944

RCT

Bronx Veterans 

Medical Research 

Intranasal 

Insulin: A Novel

Treatment for 

Gulf War

Multisymptom 

Illness

Unknown as 

of Oct 2017;

E: 

December 

2017

Examine whether 

intranasal insulin 

improves cognitive 

function and other CMI 

symptoms in GW 

Veterans with CMI

114 GW veterans with CMI, 

must include cognitive 

domain (Kansas)

Kansas 1°: Memory functioning (CVLT), 

and attention functioning (Stroop 

Color-Word Interference Task).

Secondary: Physical health (PCS 

of the SF-12V), mood (POMS 

vigor scale)
GWI Interventions Evidence Synthesis Program

75

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

Foundation, Inc.; 

Bronx and Boston 

VAMCs 

2 dose groups: 10 IU BID and 

20 IU BID intranasal insulin 

vs placebo

Time frame: baseline, 8 weeks, 

and 1-month follow-up 

Prednisone47

NCT02506192

RCT

Minneapolis 

VAMC; DoD is a 

collaborator

Gulf War Illness 

Inflammation 

Reduction Trial

Recruiting 

as of Aug 

2019;

E: October 

2020

"determine if treatment 

with an anti-inflammatory 

drug (delayed-release 

prednisone) improves the 

health-related quality of 

life (HRQoL) of veterans 

with Gulf War Illness 

(GWI)"

100 GW vets deployed to 

Kuwaiti Theater of Operation, 

and scores moderate-severe 

on at least 3 out of 6 domains 

from the Kansas GWI case 

definition

Delayed-Release Prednisone 

oral tablets (2x5mg) daily for 

8 weeks vs placebo

Kansas 1°: SF-36 PCS. 

Time frame: 0, 8, and 16 weeks

2°: Pain (MPQ); Fatigue (MFI); 

Cognitive symptoms (CFQ); SF-36 

MCS; blood biomarkers (MAP and 

CBC)

Pregnenolone48

NCT01956279

RCT

VA ORD; VA 

Durham, NC

Complementary 

Neurosteroid

Intervention in 

Gulf War 

Illnesses (GWVI)

Completed 

Oct 2018;

A: October 

10, 2018

"investigate the use of 

adjunctive pregnenolone 

for" fatigue, 

musculoskeletal pain, 

and cognitive decline

170 GW deployed Veterans

Pregnenolone: 250 mg BID 

for 28 days after titration 

phase (titration starting at 

50mg BID increasing by 

100mg every 2 wks) vs

placebo

modified 

CDC

1°: SF-36 Physical component

2°: Pain (BPI); executive 

functioning (Tower of London from 

BAC-A); Fatigue (MFSI); 

psychiatric symptoms (SCL-90R)

Time frame: baseline (2 weeks), 6 

and10 weeks

Rituximab49

GW160123

RCT

DoD; Nova 

Southeastern 

University

The Use of BCell Depletion 

Therapy (BCDT) 

in Gulf War 

Illness: A Phase 

1/2 Study

NR;

NR

"to evaluate the efficacy 

and safety of rituximab, 

validate the presence of 

central nervous system 

autoantibodies and 

decrease their presence 

with B-cell depleting 

therapy such as 

rituximab, and reset 

underlying mechanisms 

of disease to improve 

symptoms and reset 

homeostasis.

NR

Rituximab (2 infusions with 2 

weeks’ interval (500 mg/m2, 

max. 1000 mg)) vs

Placebo: Saline infusion

Not 

specified

1°: SF-36 (PCS and vitality), and 

levels of autoantibodies against 

neuronal glial proteins

Time frame: 6 weeks, and 3, 6, 

and 9 months after initial 

administration of rituximab or 

placebo

Nutritional supplements
GWI Interventions Evidence Synthesis Program

76

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

Botanical 

Microglia 

Modulators51

NCT02909686

Crossover RCT

University of 

Alabama at 

Birmingham; 

CDMRP is a 

collaborator

Effects of 

Botanical 

Microglia 

Modulators in 

Gulf War Illness

Active as of 

Oct 2019;

E: Sept

2020

test if any botanical 

agents that "suppress 

microglia function in a 

way that is antiinflammatory and 

neuroprotective...suppre

ss symptoms in GWI"

64 male GW Veterans with 

GWI

Botanical compounds daily 

values: Boswellia serrata 

400-800mg, curcumin 1000-

2000mg, Epimedium 1000-

2000mg, fisetin 200-800mg, 

luteolin 200-400mg, nettle 

435-1305mg, Pycnogenol 

200-400mg, reishi mushroom 

1600-3200mg, resveratrol 

200-600mg vs placebo

Kansas 1°: GWI severity (self-report scale: 

0-100 2x/day)

2°: self-reported pain, fatigue, 

cognitive symptoms, mood, 

dermatological symptoms, 

respiratory symptoms, and GI 

symptoms 

Time frame: the last 2 weeks of 

each treatment, compared to 

average severity during the last 2 

weeks of placebo; baseline

Concord grape 

juice52

NCT02915237

RCT

Icahn School of 

Medicine at Mount 

Sinai in 

collaboration with 

DoD; VA East 

Orange, NJ

Development of 

a Polyphenol-rich 

Dietary 

Preparation for 

Treating 

Veterans with 

Gulf War Illness

Completed 

Mar 2019. 

No results 

posted;

A: January 

17, 2019 

"the goal is to test 

whether daily 

consumption of 

commercially available 

Concord grape juice is 

effective for treating 

cognitive deficits and 

chronic fatigue in 

Veterans with GWI"

36 GW Veterans with GWI

Concord grape juice (low 4oz 

dose, moderate 8oz dose, 

and high 16oz dose) vs 

placebo beverage

Kansas 1°: Safety and tolerability to 

treatment (BSI and PHQ-15), 

cognitive functioning (CVLT-II), 

chronic fatigue (CFQ11)

2°: Auditory attention (WAIS-IV - 

digit span subtest), attention (CPT3), graphomotor speed and 

executive functioning (TMT), 

intelligence level (WAIS-IV block 

design subtest), color and word 

test (Stroop test), Halstead 

Category Test, learning and 

memory (BVMT-R), auditory 

memory and attention (WAIS-IV)

Time frame: 6 months

Mitochondrial 

cocktail53

NCT02804828/ 

GW140146 

Controlled trial (not 

clear if 

randomized)

University of 

California, San 

Diego

Mitochondrial 

Cocktail for Gulf 

War Illness

Not yet 

recruiting as 

of Dec 

2018;

E: Sept 

2019

"assess the benefit of a 

mitochondrial cocktail 

plus individualized 

correction of citric acid 

cycle (CAC) 

intermediates and amino 

acid (AA) abnormalities 

as part of a 

mitochondrial/ oxidative 

stress treatment 

Meet CDC and Kansas GWI 

criteria

Individualized mitochondrial 

cocktail & Arctic cod liver oil 

capsules vs placebo

CDC and 

Kansas

1°: Predictive GWI biomarkers (αketoglutarate, fumarate, malate, 

citrate, and isocitrate) 

Time Frame: baseline, 6, and 12 

months
GWI Interventions Evidence Synthesis Program

77

Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

approach in Gulf War 

Illness (GWI)."

Resveratrol54

NCT03665740

RCT

VISN 17 CoE, 

Waco, Texas

Multimodal 

Investigation of 

the 

Neuroprotective 

Effects of 

Resveratrol 

(MINER)

Recruiting 

as of Sept 

2018; 

E: August 

31, 2022

Examine whether 

"resveratrol treatment will 

improve memory issues, 

difficulties with thinking 

and mood problems in 

Veterans with GWI "

68 veterans deployed in GW 

meeting criteria Kansas and 

CDC criteria for GWI

2000mg Resveratrol for 6 

weeks (following titration from 

500mg in 500mg increments 

every 6 weeks) vs identical 

placebo

Kansas 

and CDC

1°: Cognitive function (CVLT-II), 

mood (BDI-II), and daily 

functioning (WHODAS 2.0)

2°: hippocampus scans (MRI and 

DTI) 

Time frame: baseline and 26 

weeks

Ubiquinol55

NCT02865460

RCT

VA Office of 

Research and 

Development;

VA Miami, Boston, 

Minneapolis, and 

Bronx Health Care 

Systems

CoQ10 in Gulf 

War Illness

Recruiting 

as of Oct 

2019;

E: Sept 30, 

2020

"determine if treatment 

with ubiquinol improves 

the physical function of 

men and women 

Veterans suffering from 

GWI"

200 GWV who were in good 

health prior to 1990. currently 

with moderate-severe GWI

Ubiquinol: 2x200mg for 2 

months; 1x200mg for 4 

months vs placebo

Kansas 1°: SF-36 every 4 wks to 28 wks

2°: Fatigue (MFI), GWI symptoms, 

pain (BPI), Sleep (PSQI), anxiety 

(HAM-A), physical activity (FitBit), 

trauma (DTS), cognitive symptoms 

(CPT-3), recall and memory 

(CVLT-II), visual memory (BVMT), 

GWI associated blood biomarkers 

(CBC), depression (HAM-D), 

circadian rhythm (cortisol levels 

through saliva), thyroid status 

(HPT axis levels), HPG axis levels

Visbiome vs 

VSL#356

NCT03078530

RCT

Ashok Tuteja; DoD

VAMC Salt Lake 

City, UT

Probiotic 

(Visbiome) for 

Gulf War Illness

Recruiting 

as of Dec 

2017;

E: May 31, 

2018

"determine whether 

Visbiome will improve 

intestinal symptoms of 

IBS and non-intestinal 

symptoms (fatigue, joint 

pain, insomnia, general 

stiffness and headache) 

associated with IBS"

60 GW Veterans with IBS 

and 2 or more non-intestinal 

symptoms > 6 months 

Three arms: Visbiome vs 

VSL#3 vs placebo

Not 

specified

1°: IBS-related symptoms (BSS at 

8 weeks)

2°: chronic fatigue (1-5 scale; 

Baseline to 4 and 8 weeks)

Other

Electrical 

stimulation

(stochastic 

noise)57,70

Proposal: 

GW130093

Use of a Portable 

Stimulator to 

Treat GWI 

Completed; 

poster 

presented at 

Neuroscienc

e Nov 2018. 

“We hypothesize that 

stimulation of the 

vestibular system with 

electrical stochastic noise 

via surface electrodes will 

produce immediate and 

60 GW Veterans with GWI 

and vestibular loss

Stochastic noise electrical 

stimulation vs sham electrical 

Not 

specified

1°: Ocular torsion; sway; balance; 

dizziness
GWI Interventions Evidence Synthesis Program

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Intervention; 

Registration; 

Study Design; 

Sponsors; Setting Study Title

Status; 

completion 

date Purpose of study

Participants; 

Intervention(s)/ 

Comparator

GWI case 

definition Outcome(s) and timing

DoD CDMRP; 

Rutgers, Newark, 

NJ

Results 

shown in 

Table 14

long-term improvements 

in vestibular function and 

balance.”

stimulation bilaterally through 

ear clips for 12 weeks

LED therapy58

NCT01782378

Crossover RCT

VA ORD; VA San 

Francisco and 

Boston

Scalp Application 

of Red and NearInfrared Light, 

From LightEmitting Diodes 

(LED) to Improve 

Thinking and 

Memory in 

Veterans with 

Gulf War 

Illnesses

Active - not 

recruiting. 

Mar 2019. 

Results 

submitted;

E: 

December 

31, 2019

"learn if an experimental 

[LED] treatment can help 

thinking ability, and 

memory in Veterans with 

Gulf War Veterans 

Illnesses (GWVI)"

160 GW Veterans meeting 

CDC and Kansas criteria, and 

with neuropsychological 

symptoms

Real LED Treatment Series 

First vs Sham LED Treatment 

Series First. 15 sessions with 

helmet (real or sham) and 

intranasal devices

CDC and 

Kansas

1°: Attention/Executive Function 

(Stroop Test)

2°: Additional Attention/Executive 

Function (WAIS-IV and D-KEF); 

learning and memory (CVLT-II); 

Mood (BDI); SF-36 physical; blood 

tests: mitochondrial function, 

inflammation, coagulation

Nasal Irrigation 

(Xylitol vs 

saline)59,60

NCT01700725

RCT

University of 

Wisconsin, 

Madison

Effectiveness of 

nasal irrigation 

for chronic 

rhinosinusitis and 

fatigue in 

patients with Gulf 

War illness: 

protocol for a 

randomized 

controlled trial

Completed;

A: May 

2017

Results 

shown in 

Table 15

"to determine whether 

nasal irrigation with 

Xylitol or saline are 

effective in the treatment 

of chronic rhinosinusitis 

and fatigue symptoms 

associated with Gulf War 

Illness"

40 deployed GW Veterans 

with GWI and chronic 

rhinosinusitis (CRS)

Three arms: Nasal Irrigation 

(NI) with saline vs NI with 

xylitol vs usual care

modified 

Kansas

1°: QoL (SNOT-20)

2°: Fatigue (MFI); HRQoL (SF-36); 

cost-effectiveness ratio; treatment 

satisfaction (7-point Likert)

Other: laboratory stress- and 

illness-related biomarkers

*Only analyses of this subpopulation alone would be included for purposes of answering our key questions

Abbreviations: A=Actual; BAC-A=Brief Assessment Checklist for Adolescents; BID=bis in die; BPI=Brief Pain Inventory; BPI-SF=Brief Pain Inventory-Short Form; BSI=Brief 

Symptom Inventory; BSS=Bowel Symptom Scale; BVMT-R=Brief Visuospatial Memory Test-Revised; CAPS-5=Clinician-Administered PTSD Scale for DSM-5; 

CBC=Complete Blood Count; CBTi=Cognitive Behavioral Therapy for Insomnia; CDC=Centers for Disease Control and Prevention; CDMRP=Congressionally Directed Medical 

Research Programs; CDSMP=Chronic Disease Self-Management Program; CFQ11=Chalder Fatigue Scale; CMI=Chronic Multisymptom Illness; CoE=Center of Excellence for 

Research on Returning War Veterans; CoQ10=Coenzyme Q10; COWAT=Controlled Oral Word Association Test; CPT-3=Conner’s Continuous Performance Test - 3rd Edition; 

CRS=chronic rhinosinusitis; CVLT-II=California Verbal Learning Test Second Edition; DCS=d-cycloserine; D-KEF=Delis-Kaplan Executive Function System; DTI=Diffusion 

Tensor Imaging; DTS=Davidson Trauma Scale; E=Estimated; EHR=Electronic Health Record; EEG=Electroencephalogram; EMG=Electromyography; ERP=Event Related 

Potential; FIQR=Revised Fibromyalgia Impact Questionnaire; FIT=Rey 15-Item Test; FODMAP=Fermentable Oligo-, Di-, Mono-saccharides And Polyols; FSS=Fatigue Severity 

Scale; GI=Gastrointestinal; GW=Gulf War; GWHE=Gulf War Health Education; GWI=Gulf War Illness; GWV=Gulf War Veteran; GWVI=Gulf War Veterans Illness; 

HA=Headache; HADS=Hospital Anxiety and Depression Scale; HAM-A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Depression Rating Scale; HD-tDCS=High 

Definition transcranial Direct Current Stimulation; HIT-6=Headache Impact Test; HPG=Hypothalamic-Pituitary-Gonadal; HPT=Hypothalamic–Pituitary–Thyroid; 

HRQoL=Health-related Quality of Life; HVLT-R=Hopkins Verbal Learning Test – Revised; IBS=Irritable Bowel Syndrome; ISI=Insomnia Severity Index; LDLPFC=Left 

Dorsolateral Prefrontal Cortex; LED=Light Emitting Diode; LMC=Left Motor Cortex; MAP=Mean Arterial Pressure; MASQ=Mood and Anxiety Symptoms Questionnaire; 

MBSR=Mindfulness-based Stress Reduction; MCS=Mental Component Summary; MFI-20=Multidimensional Fatigue Inventory-20; MFSI=Multidimensional Fatigue Symptom 
GWI Interventions Evidence Synthesis Program

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Inventory; MPI=Multidimensional Pain Inventory; MPQ=McGill Pain Questionnaire; MRI=Magnetic Resonance Imaging; MRS=Magnetic Resonance Spectroscopy; 

MSG=Monosodium Glutamate; NI=Nasal Irrigation; NIH=National Institutes of Health; NR=Not Reported; nRCT=non-Randomized Controlled Trial; NSI=Neurobehavioral 

Symptom Inventory; ORD=Office of Research and Development; PCS=Physical Component Summary; PDI=Pain Disability Index; PFS=Piper Fatigue Scale; PHQ-9=Patient 

Health Questionnaire 9-item; PHQ-15 Patient Health Questionnaire 15-item; PI=Principal Investigator; preSMA=PreSupplementary Motor Area; PROMIS=Patient Reported 

Outcomes Measurement Information System; PSQI=Pittsburgh Sleep Quality Index; PTSD=Posttraumatic Stress Disorder; QoL=Quality of Life; rTMS=Repetitive Transcranial 

Magnetic Stimulation; SCL-90R=Symptom Checklist-90-Revised; SF-12V=Standard Form 12-Veteran Version; SF-36=36-Item Short Form Health Survey; SF-MPQ=Short-Form 

McGill Pain Questionnaire; SNOT-20: Sinonasal Outcome Test-20; SORT=Semantic Object Retrieval Test; tDCS=Transcranial Direct Current Stimulation; TMT=Trail Making 

Test; VAMC=Veterans Affairs Medical Center; VAPSHCS=Veterans Affairs Puget Sound Health Care System; VAS=Visual Analog Scale; VNS=Vagus Nerve Stimulation; 

VSL=Very Safe Lactobacilli; WAIS-IV=Wechsler Adult Intelligence Scale-Fourth Edition; WHODAS=World Health Organization Disability Assessment Schedule
GWI Interventions Evidence Synthesis Program

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Table 14. Details of single-arm studies of interventions/management strategies for Gulf War Illness

Intervention;

Study Design; 

Sponsors; Setting Study Title Purpose of study Participants; Intervention(s)

GWI case 

definition(s) Outcome(s) and timing

Specialized Care 

Program29

Single-arm pilot 

intervention

Sponsors not 

specified: 

Acknowledgements 

included - US Army 

Lieutenant General 

Ronald R. Blanck

Setting not specified

Rehabilitative care 

of war-related 

health concerns

"to present SCP data 

comparing longitudinal 

health outcomes with 

baseline health status 

among a series of Gulf 

War veterans with 

persistent symptoms"

109 veterans

Specialized Care Program (SCP): 3-

week intensive outpatient group 

program. Medical assessment; 

collaboration with providers and other 

GW veterans to develop "symptommanagement plan - an individualized 

combination of regular primary medical 

care, exercise, self-care, and other 

active coping strategies"

Not specified SF-36; Physical symptoms 

(PRIME-MD patient 

questionnaire), quality of life, 

physical health concern (Whitely 

Index), and psychosocial distress 

(Somatization, Depression, and 

Anxiety scales of the BSI) 

contrasted across time and 

demographic groups 

Time frame: SCP entry, exit, and 

at 1 and 3 months after exit.

Nutrient formula + 

methylphenidate50

DoD grant to K-PAX 

Pharmaceuticals; 

VA Palo Alto Health 

Care System, Palo 

Alto, CA

Treatment for Gulf 

War Illness (GWI) 

with KPAX002 

(methylphenidate

hydrochloride + 

GWI nutrient 

formula) in subjects 

meeting the 

Kansas case

definition: A 

prospective, openlabel trial

“tested the safety, 

tolerability, and 

efficacy of KPAX002--

a combination of 

methylphenidate 

hydrochloride plus a 

micronutrient formula 

designed to support 

mitochondrial 

function—as a 

treatment for Gulf War

Illness (GWI)”

15 Veterans with GWI

GWI Nutrient Formula (4 tablets twice 

daily) and methylphenidate 

hydrochloride (5mg twice daily for 

Week 1 and 10mg twice daily for Week 

2-12)

Kansas 1°: Symptoms (GWI SAT; quant 

scores 0-87)

2°: symptomatology and disability 

potential (CIS; scores 20-40); 

fatigue, cognitive symptoms, pain, 

and sleep problems (0 -100 VAS)

Time frame: baseline to Week 12

Abbreviations: BSI=Brief Symptom Inventory; CIS=Checklist Individual Strength; GW=Gulf War; GWI=Gulf War Illness; PRIME-MD=Primary Care Evaluation of Mental 

Disorders; SAT=Symptoms Assessment Tool; SCP=Specialized Care Program; SF-36=36-Item Short Form Health Survey
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Table 15. Available results of unpublished randomized controlled trials of interventions for Gulf War Illness

Electrical stimulation57,70 Low-glutamate diet25,41 Xylitol nasal irrigation59 Yoga39,62

Descriptive characteristics

N total N=60 N=17* N=40 N=68 (treated) 

N per arm Electrical stimulation 

(stochastic noise) vs

Sham electrical stimulation

Low- vs high-glutamate 

diet

Saline vs xylitol vs usual 

care: 14 vs 14 vs 12

Yoga vs CBT: 37 vs 31

Duration of treatment 

and observation

Tx and Obs: 12 weeks Tx and Obs: 1 month Tx: 8 weeks

Obs: 26 weeks

Tx: 10 weeks 

Obs: 6 months

Demographics NR 12% Female 

Age: 50 (4)

20% Female 

Age: 53.8 (SD 7.8) 

Race: 77.5% non-Hispanic 

White; 10% White Hispanic; 

5% AA/Black; 2.5% Asian; 

2.5% Pacific 

Islander/Hawaiian; 2.5% 

multiple races Educ: 7.5% 

high school or less

NR

Findings (change from baseline), Treatment vs Comparator

Pain --- --- BPI-SF pain (within group 

mean ± SD) 

End-of-treatment 

Yoga: pre- 5.44 ± 2.00 vs 

post- 4.00 ± 2.08; P < 0.001 

CBT: pre- 5.09 ± 1.62 vs 

post- 4.95 ± 2.35; P > 0.05 

6-month f/u pain: 

Yoga: 4.70 ± 2.17; P=0.02 

CBT: NR

Fatigue --- MFI score (mean (SD)): 

Week 8: 

Xylitol 0.6 (2.4) vs saline 0.9 

(2.3) vs control 0.5 (2.5) 

Week 26: Xylitol 1.9 (2.8) vs 

saline -1.4 (2.4) vs control 

10.4 (3.0) 

---
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Mental Health --- Anxiety (GAD-7) (median 

(IQR)): reduced from 9 

(13) to 5 (10); P=0.01*

--- ---

PTSD --- PCL-C score (median 

(IQR)): reduced from of 58 

(33) to 43 (28); P=0.04*

--- ---

Respiratory --- SNOT-20 score (mean 

(SD)): Week 8: 

Xylitol -16.9 (4.9) vs saline -

8.8 (5.0) vs control -3.4 (5.3) 

Week 26: 

Xylitol -18.9 (4.9) vs saline -

16.9 (5.3) vs control -3.5 

(5.6)

---

Vestibular function Ocular torsion (OT): improved 

in 53% of pts; mean increases 

of 25% (range 1-81)

Sway: improved in 100% of 

participants; reduced by mean 

of 42% (Range 21-63).

Adverse events NR NR No AEs or SAEs NR

 * Preliminary results, study ongoing

Abbreviations: AA=African American; BPI-SF=Brief Pain Inventory-Short Form; CBT=Cognitive Behavioral Therapy; GAD-7=Generalized Anxiety Disorder 

7-item; IQR=Interquartile Range; MFI=Multidimensional Fatigue Inventory; NI=Nasal Irrigation; NR=Not Reported; Obs=Observation; PCL-C=PTSD 

Checklist – Civilian version; PTSD=Posttraumatic Stress Disorder; SAT=Symptoms Assessment Tool; SD=Standard Deviation; SNOT-20: Sinonasal Outcome 

Test-20
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Table 16. Results of single-arm studies of interventions/management strategies for Gulf 

War Illness

Intervention Specialized Care Program29

(Multicomponent group program)a

KPAX00250 (Nutrient formula 

plus methylphenidate)

Descriptive characteristics

Total N N=109 N=15

Duration of treatment 

and total observation

Tx: 3 weeks 

Obs: 1 & 3 months

Tx and Obs: 12 weeks

Demographics 18.3% Female 

Age: 56% younger than 40 years of age 

Race: 50.5% White; 30.3% Black; 19.3% 

Others

12% Female 

Age: 53.0 (6.15) 

Race: 12% AA/Black, 6% 

Hispanic, 6% Native American, 

71% white, 6% other 

Findings (mean difference from baseline)

Physical Health 

Overall

SF-36 PCS 

End-of-treatment (N=93): 1.08 (P=NS) 

1-mo f/u (N=48): 0.96 (P=NS) 

3-mo f/u (N=37): 1.49 (P=NS) 

No. of physical symptoms 

End-of-treatment (N=102): -2.54 (P < 0.01) 

1-mo f/u (N=51): -0.80 (0.01 < P < 0.05) 

3-mo f/u (N=37): -1.14 (0.01 < P < 0.05)

---

Fatigue --- CIS: -14 (±19.59) 95% CI, −22.3 

to −5.7; P < 0.001 

VAS: -1.3 (±2.41); P=0.019 

GWI Symptoms 

Overall

--- SAT: -8.8 (±12.54); 95% CI 

−13.2 to −4.5; P < 0.001

Mental Health Overall SF-36 MCS

End-of-treatment (N=93): 5.17 (P < 0.01) 

1-mo f/u (N=48): -0.69 (P=NS) 

3-mo f/u (N=37): 0.70 (P= NS) 

Physical Health Concern (Whitely Index 

score): End-of-treatment (N=97): -0.65 (0.01 

< P < 0.05) 

1-mo f/u (N=49): -0.78 (P=NS) 

3-mo f/u (N=37): -1.41 (P < 0.01)

---

Psychosocial distress Somatization score (BSI) 

End-of-treatment (N=97): -4.75 (P < 0.01) 

1-mo f/u (N=49): -2.77 (P=NS) 

3-mo f/u (N=37): -7.74 (0.01 < P < 0.05) 

Depression score (BSI) 

End-of-treatment (N=97): -3.05 (0.01 < P < 

0.05) 

1-mo f/u (N=49): 1.96 (P=NS) 

3-mof/u (N=37): 1.38 (P=NS) 

Anxiety Score (BSI) 

End-of-treatment (N=97): -3.52 (P < 0.01) 

1-mo f/u (N=49): -1.19 (P=NS) 

3-mo f/u (N=37): -2.90 (P=NS)

---

Other --- Sleep VAS: -1.4 (±2.47); 

P=0.026 Pain VAS: -1 (±2.62); 

P=0.054 Cognitive
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Intervention Specialized Care Program29

(Multicomponent group program)a

KPAX00250 (Nutrient formula 

plus methylphenidate)

disturbance VAS: -1.5 (±2.45); 

P=0.006

Severe AEs/ dropouts 

due to AEs

--- No SAEs; 2 dropouts due to 

AEs a An intensive outpatient program that included medical assessment and collaboration with providers and other GW 

Veterans in the development of an individualized symptom management plan combining primary medical care with 

exercise, self-care, and other active coping strategies. 

Abbreviations: AA=African American; AE=Adverse Event; BSI=Brief Symptom Inventory; CIS=Checklist 

Individual Strength; F/U=Follow-up; MCS=Mental Component Summary; NS=Not Significant; P=P-value; 

PCS=Physical Component Summary; SAE=Severe Adverse Event; SAT=Symptoms Assessment Tool;

SCP=Specialized Care Program; SF-36=36-Item Short Form Health Survey; Tx=Treatment; VAS=Visual Analog 

Scale
GWI Interventions Evidence Synthesis Program

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APPENDIX E. PEER REVIEW COMMENTS/AUTHOR 

RESPONSES 

# Reviewer Comment ESP response

Are the objectives, scope, and methods for this review clearly described?

1 Yes 

2 No - yes they are in sufficient detail

3 Yes

4 Yes

5 Yes

6 Yes

8 Yes

Is there any indication of bias in our synthesis of the evidence?

1 No

2 No 

3 No

4 No

5 Yes - the review seems to be done fairly, and in an 

unbiased way

6 No

8 No

Are there any published or unpublished studies that we may have overlooked?

1 No

2 No

3 No

4 No

5 No

6 No

8 Yes - Maybe, please see comments in attached review.

Additional suggestions or comments can be provided below. If applicable, please indicate the page and 

line numbers from the draft report.

1 This systematic review of interventions for Gulf War 

Illness (GWI) was reasonably well done and is timely 

given the ongoing interest and need for improved 

management of GWI. I have no concerns or critique of 

the actual systematic review itself (procedures and 

write-up) but do have two major concerns, one 

methodological and the other is more philosophical.

First, philosophically I think this review is probably 

premature. Mainly, because a clinical definition of what 

GWI remains elusive and there is no consensus or 

diagnostic definition. As a consequence, this review is 

really nothing more than a review some treatments for 

diseases that may (or may not) be part of a more 

"global" disease/disorder that we refer to as GWI. Until 

We agree that there are many challenges 

inherent in the study of an illness that is 

poorly defined. We do cite some of these 

limitations in the discussion section. Our 

hope and goal was to identify treatments 

that might be promising and worthy of 

further inquiry as well as identify 

treatments that may be ineffective or 

harmful. We have modified our aim to 

clarify this point.
GWI Interventions Evidence Synthesis Program

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# Reviewer Comment ESP response

such time that we get to consensus agreement on 

exactly what GWI is and what 

diseases/disorders/symptoms define GWI we doing 

nothing more than "guessing" about managing GWI by 

using treatments for specific diseases/disorders that we 

"believe" are part of GWI and may have shown efficacy 

in the past, and hoping that they work similarly in those 

we define as GWI by the CDC/Kansas definition. 

1 Which brings me to my second major concern. In the 

Executive Summary (pg. 1) and in the "Study Section" 

(pg. 10) you state that: "We excluded studies that 

compared interventions in Veterans with versus those 

without GWI.". I believe that exclusion of these types of 

studies is a catastrophic limitation to this report for 

several reasons. One, relates to the concern raised 

above in that, since we do not have a clinical 

definition/criteria to define/diagnose GWI (other than 

CDC & Kansas criteria) we really do not know what we 

are dealing with. Thus, the treatments evaluated are not 

treatments for GWI, but rather for specific other 

diseases/disorders that may, or may not, be part of the 

GWI. It would have been inherently interesting and 

informative to have included studies that compared GWI 

versus no GWI. If for example, those designated as 

GWI (by CDC/Kansas) failed to show a favorable 

response to CBT or CPAP compared to those without 

GWI would suggest that simply using existing 

treatments/interventions for the symptom domains of 

GWI is not effective and that at present we have a great 

deal of work yet to do to develop 

treatments/interventions in and for GWI. By not 

including the non-GWI comparative studies we have 

limited information as to whether the 

treatments/interventions evaluated in this review work 

as well for the target disorder/symptom domain in those 

with GWI.

All of the studies compared treatment and 

placebo in a cohort of Veterans who were 

identified to have GWI. We did not 

exclude any studies for including a 

population other than GWI (and we were 

open to the possibility of including such 

as study had they met all of our other 

inclusion criteria e.g., also included a 

control group with GWI). We have revised 

the Study Selection section to be clear 

that we would have included studies that 

compare the same intervention in GWI 

and another illness as long as that study 

also had a control treatment had we 

found any. 

1 Since one of the purposes of this type of review is to 

summarize a literature with aim of providing some 

clinical guidance regarding best practice. That aim was 

not achieved, in part due to the wide variability in the 

science, lack of a consensus clinical definition of GWI, 

and exclusion of studies that employed non-GWI 

comparison group. Until such time that a clinical 

diagnostic criteria is ratified, the within and between 

groups variability will never afford the stability necessary 

to generate meaningful information from systematic 

reviews.

We agree that there are many challenges 

inherent in the study (and evidence 

synthesis) of an illness that is poorly 

defined. We do cite some of these 

limitations in the discussion section. We 

clarify that our aim was not to 

characterize literature in the spirit of 

developing treatment guidelines, rather 

we sought to identify treatments that

might be promising and worthy of further 

inquiry as well as to identify treatments 

that may be ineffective or harmful. This 

would help streamline future resources to 

build an evidence base to develop clinical 

guidelines. The use of the report would 

be up to the stakeholders.
GWI Interventions Evidence Synthesis Program

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# Reviewer Comment ESP response

1 Research with an emphasis on defining GWI is 

paramount. Fortunately, there are two such studies, 

currently in their first year, underway. One is using a 

comprehensive chart review process to better 

understand the clinical manifestations in those with 

presumed GWI and the other is employing a "machine 

learning" approach mining VHA healthcare data to try 

and identify clusters of healthcare data that may 

correlate with clinical classifications of GWI.

Thank you for this information. We have 

now specifically referenced these 

ongoing studies in the discussion section.

1 This systematic review was done with rigor and is well 

written however, for the reasons noted above, I believe 

it is premature and offers clinicians little with regard to 

management of their patients with believed to be 

suffering with GWI.

Thank you, we have clarified in our Aims 

that our goal was not to develop clinical 

guidelines rather to review current 

evidence to (1) identify treatments that 

might be promising and worthy of further 

inquiry and (2) identify treatments that 

may be ineffective or harmful.

2 This is extremely well done and will prove very valuable. 

I have no concerns. While there may be other studies 

out there, they are not of major importance or relevance.

Noted, thank you.

3 Thank you for the opportunity to review this evidence 

based synthesis. I read this over a few times and had 

very few comments. This was excellently done, easy to 

read and clear. Thank you.

I had one main comment. I think the reviewers should 

include information on adherence. Adherence to these 

treatments were generally low. I know that this wasn’t a 

primary purpose of the study – but it would be easy to 

include it in the tables and I think it would be 

informative. If a Veteran won’t use the treatment, this is 

important to know.

We agree this is important, especially 

when considering feasibility of patient 

engagement in psychosocial and 

exercise interventions that are time 

intensive. We have now added 

information about adherence for all 

studies that reported it.

3 Minor comment: First table – what does PTSD mean in 

the label for the table under mindfulness?

This was originally to display a 

subpopulation that was examined in the 

study, we have removed it to reduce 

confusion.

4 I think that this is an excellent review. Well done. Thank you.

Page 25: I would comment on the Study of Amin et al. 

on the use of CPAP in GWI and sleep disordered 

breathing. DOI 10.1007/s11325-010-0406-8.(12)

This study of GWI and sleep disordered breathing 

(SDB) appears to confirm the effectiveness of nasal 

CPAP in treating the symptoms of SDB and obstructive 

sleep apnea. According to the AASM criteria, as listed in 

the International Classification of Sleep Disorders: 

Diagnostic and Coding Manual, Second Edition. At least 

1 of the following criteria must apply for obstructive 

sleep apnea (OSA) to be diagnosed:

• The patient reports daytime sleepiness, unrefreshing 

sleep, fatigue, insomnia, and/or unintentional sleep 

episodes during wakefulness. The patient awakens with 

breath holding, gasping, or choking. The patient’s bed 

partner reports loud snoring, breathing interruptions, or 

both during the patient’s sleep.

This is a valid point. CPAP is an 

evidence-based treatment used to treat 

sleep apnea. The patients in the study all 

had sleep-disordered breathing in 

addition to GWI. We think this 

intervention is important to include 

because the study found improvement in 

broader range of GWI symptoms (not just 

sleep outcomes) with CPAP treatment. It 

therefore may be worthwhile for clinicians 

to determine whether Veterans with GWI 

have sleep-disordered breathing and use 

a CPAP to address both sleep disordered 

breathing as well as a broader range of 

GWI symptoms. 
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# Reviewer Comment ESP response

• Polysomnography (PSG) shows more than 5 

scoreable respiratory events (eg, apneas, hypopneas, 

RERAs) per hour of sleep and/or evidence of respiratory 

effort during all or a portion of each respiratory event.

• PSG shows more than 15 scorable respiratory events 

(eg, apneas, hypopneas, RERAs) per hour of sleep 

and/or evidence of respiratory effort during all or a 

portion of each respiratory event.

• Another current sleep disorder, medical or neurologic 

disorder, medication use, or substance use does not 

better account for the patient’s condition.

Many of the GW Veterans included in this study fit the 

OSA criteria; it is not a surprise that symptoms improved 

with CPAP. 

I don’t think this study adds valuable knowledge about 

treatment of GWI. This study uses an evidence-based 

intervention, CPAP, to treat SDB/OSA. The patients in 

this study had symptoms that were readily attributed to 

a diagnosable condition other than to GWI, that is OSA.

I think your review should provide this information in 

your discussion of the study results. It is a source of 

bias in the study.

5 Overall I found the Evidence Synthesis Program to be a 

very well organized review of a complex literature. I 

think it will be a valuable resource for those working in 

the field of Gulf War Illness. Specific comments follow;

Thank you. See responses below.

p. 23 line 11: typo “delivered a in 8 weekly...” should 

read “delivered in 8 weekly...”

Corrected.

p.23, line 41 states that participants used self-reported 

outcomes without blinding of participants. Since blinding 

of participants is not possible in psychological and 

exercise interventions, I suggest clarifying the statement 

to say this. 

The role and necessity of patient blinding 

in studies of these types of interventions 

has been debated. There are techniques 

even for complex nonpharmacologic 

interventions to blind patients to some 

degree. Some argue that lack of patient 

blinding in trials of non-pharmacologic 

therapies may considerably exaggerate 

treatment effects; in which case, it would 

be difficult to determine whether and to 

what extent positive treatment effects – 

especially for the findings with only low 

level confidence – were due to an 

independent effect of treatment, 

expectancy as a mechanism of change, 

placebo effect, or a combination of these 

factors. On the other hand, others have 

argued that blinding is not only 

challenging but also potentially 

counterproductive as expectancy for 

change is thought to be an integral part of 

the intervention itself. We have added 

this to the discussion.
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# Reviewer Comment ESP response

p. 29, line 35 describes the study done by my group (I 

am the P.I.). The manuscript giving details of the study 

and the results is still under peer review, and is 

described in the Evidence Synthesis Program using ref 

#37 (clinicaltrials.gov identifier) and ref #58 (an 

abstract). The information from these references is 

incomplete. I don’t know if the manuscripts will be 

excepted for puplication before the Evidence Synthesis 

Program is published, here is the reference for the 

manuscript currently under review. 

Bayley, P. J., Cho, R. Schulz-Heik, R. J., Mathersul, D. 

C., Collery L., Shankar, K. Ashford, J. W. Jennings, J. 

Tang, J. Wong, M. Avery, T. J. Stanton, M. Meyer, H. 

Friedman, M. Kim, S. Jo, B. Younger, J. Mathews B., 

Majmundar M. & Mahoney L. Yoga is effective in 

treating symptoms of gulf war illness: a randomized 

clinical trial (in review).

I do not want to list all the results in the paper before it is 

published, but you may want to cite it (e.g., p.29, in the 

paragraph starting on line 35). For accuracy, I suggest 

making the following edits to the existing text;

i. The comparator group in the study is more accurately 

described as CBT. I recommend changing Table 7 the 

comparator group from a “pain management wellness 

group” to “CBT”. Similarly, p.29, line 35 should refer to a 

“CBT” group rather than a “CBT-based pain 

management wellness group for pain”. Similarly, p. 69 

line 24-25 “pain management wellness group” should be 

changed to “CBT”

ii. the study used the CDC GWI case definition, so I 

suggest changing p.68, line 56 from “not specified” to 

“CDC”

We have made these changes as 

suggested. 

p. 33, line 45 refers to publication #4 as “a narrative 

review of ...GWI research”. It doesn’t look like a review 

to me, and the abstract calls it “a double-blind, placebocontrolled study”.

Thank you, that citation was incorrect. 

We have replaced it with the correct 

citation: Chester JE, Rowneki M, Van 

Doren W, Helmer DA. Progression of 

intervention-focused research for Gulf 

War illness. Mil Med Res. 2019;6(1):31.

The Summary Table (p.36-37) describes the results 

from a large RCT by Donta et al (2003). The table 

shows the results for the CBT (line 54) and CBT + 

Exercise (line 56) interventions, coded to show evidence 

of benefit for pain. I am not sure this is accurate. Donta 

et al stated that “only 1 of the 4 measures of pain 

(affective) showed significant treatment differences for 

CBT alone and CBT plus exercise compared with usual 

care” As a result, Donta et al state several times that 

“neither treatment had a significant impact on pain” 

(Abstract, Comment). In my opinion, it would be more 

accurate to recode the findings for pain in this study to 

be either Mixed/Unclear (which would then match how 

they are reported in Table 5), or even No Benefit.

Thank you for pointing out this 

discrepancy between tables. We meant 

for it to be mixed/unclear findings for CBT 

and CBT+Exercise for pain and have 

updated the summary table to reflect this. 
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# Reviewer Comment ESP response

8 Overall, this manuscript provides a comprehensive 

National overview of published and currently active Gulf 

War studies with focus on treatments and therapeutics. 

Inclusion of Risk of Bias (ROB), Strength of Evidence 

(SOE), and discussion of studies focused on GWI vs. 

symptoms of GWI are strengths of this review. 

This manuscript will no doubt provide important Gulf 

War field-forward objectives and guidance for 

investigators and funding agencies.

Noted, thank you.

Could the authors include a paragraph or discussion of 

a Standard Operation Procedure (SOP) or an outline of 

how clinical trials should be experimentally and 

methodologically assembled for subsequent good 

synthesis review? This could be a nice value added to 

this manuscript as VA often contracts with NASEM and 

inclusion of studies are important for overall 

interpretation.

This is a very important point, but it is 

beyond the scope of this report. We have 

asked the ESP Coordinating Center to 

examine this issue and have had follow 

up correspondence about a plan to help 

develop some guidance about this. We 

also include in our discussion very broad 

points about future research needs and 

approaches, but these are by no means 

comprehensive.

Could the authors include a discussion of literature not 

included in the ESP that maybe a promising treatment 

on the horizon if the experimental approach were solid.

Unfortunately, for the systematic review, 

we are only able to include literature 

captured by our search and that meets 

our inclusion criteria. Key Question 3 

does capture ongoing studies of 

treatments, but anything beyond that is 

outside the scope of this review.

Executive Summary (pg1)

...We excluded studies that compared interventions in 

Veterans with versus without GWI... why? Were there 

treated and untreated numbers in each group? If so, 

wouldn’t that include GWI Veterans with and without 

treatment?

We have clarified that this exclusion 

would only be in the case where both 

treated and untreated groups contained 

GWI and non-GWI participants, and there 

was no separate analysis. However, no 

studies were excluded for this reason.

Executive Summary (pg1): Were there any nRCTs in 

the literature and considered or not for evidence 

synthesis?

The study design was allowed, but none 

met our inclusion criteria, with the 

exception of one ongoing study on 

acupressure (see Table 13).

Executive Summary (pg1)

MBSR, MBB, and CPAP results: “improved” outcomes 

including fatigue, depression, PTSD, pain cognitive, and 

sleep. How was improved defined? Was this a 

qualitative conclusion by the authors or was it based on 

objective quantitative measures?

We are trying to be brief in the Executive 

Summary, but we have added a footnote 

referring readers to the full report for how 

improvement was defined in the relevant 

studies.

Abbreviations Table (pg4) Please add:

•AE = Adverse Effect

•PICOTS = ?

•SOE = Strength of Evidence

We have made the suggested changes. 

Evidence Report (pg8)

Introduction:

•Add symptoms within 6-month deployment were 

applicable

We have added this in the introduction.
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# Reviewer Comment ESP response

Methods (pg9) Figure 1. Conceptual Framework

We may need to tweak this figure. Suggestions: 

• Remove “case definition” under Patient Subgroups. 

There is no clinical case definition.

• Remove “case definition” under Veterans with GWI. 

Include: ... and meet inclusion/exclusion criteria based 

on the instrument.

Thank you, we have made this change to 

the Figure 1.

Study Selection (pg10): We excluded studies that 

compared interventions in Veterans with versus 

Veterans without GWI: How many studies were 

excluded?

We did not count how many were 

excluded for this exact reason, but they 

would fall under “excluded populations” in 

our full text review (see literature flow 

diagram). Since there were 5 exclusions 

for population, there are 5 or less studies 

that were excluded for this reason.

Table 1 PICOTS by Key Question (pg 11): Key Question 

(KQ2 – hard to understand based on current wording. 

Please rephrase.

We have edited the wording of the 

question for clarity.

Data Abstraction, Quality Assessment (pg12): In lieu of 

“investigator” or reviewer(s), Consider changing to ESPreviewing member or ESP-reviewer where applicable.

We have made this change.

Quality Assessment: ROB should be on the first 

sentence, not sentence 2.

Correction made.

Table 3. (pg21). Table 4 (pg22): Remove ROB after low, 

high.

Correction made.

# = anonymous reviewer number