Effects of Botanical Microglia Modulators in Gulf War Illness

The overall objective of this protocol is to test if Gulf War Illness (GWI) involves chronic inflammation that cannot be measured with typical techniques. The investigators will be observing the effects of nine different botanical compounds (supplements) that are known to suppress inflammation. If one of those supplements helps the symptoms of GWI, it will give the investigators information about what is wrong in people with GWI.

Study Overview

• Status: Completed
• Conditions: Gulf War Illness
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Resveratrol; Dietary supplement: Curcumin; Dietary supplement: Boswellia Serrata; Dietary supplement: Epimedium; Dietary supplement: Fisetin; Dietary supplement: Luteolin; Dietary supplement: Nettle; Dietary supplement: Pycnogenol; Dietary supplement: Reishi Mushroom

Detailed Description

There is still a poor understanding of the pain, fatigue, and other symptoms that affect approximately 250,000 veterans. The precise mechanism of Gulf War Illness (GWI) is not understood, and there is no targeted treatment for the condition. A current model for GWI points to the central nervous system, immune cells, called microglia that may be hyperactive in patients with GWI. Discovering effective treatments for this disorder is a top priority of GWI research.

Given the investigator's preliminary data, it is suspected that GWI is a form of low-level neuroinflammation that involves hypersensitivity of receptors on microglia. In order to help test that hypothesis, the investigators will be administering supplements that have been shown in vitro or animal in vivo to suppress microglia function in a way that is anti-inflammatory and neuroprotective. If any of these agents suppress symptoms in GWI, it will give the investigators important information about the disease that may allow for creation of better diagnostic tools and treatments in future research studies. Observing the effects of the selected nine anti-inflammatory botanical compounds, in this clinical study, is a strong compliment to the ongoing mechanistic GWI research.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male
2. Age 39-65, inclusive
3. Veterans who meet the Kansas inclusion criteria for GWI
4. Present in Persian Gulf between 1990 and August 1991
5. Patient completes daily report during 2 week baseline period (at least 80% completion rate)
6. Able to receive a venous blood draw

Exclusion Criteria:

1. Positive rheumatoid factor at screening
2. Positive anti-nuclear antibody at screening
3. C-reactive protein> 3mg/L at screening
4. Erythrocyte Sedimentation Rate> 40mm/hr at screening
5. Auto-immune disorder
6. Diagnosed Rheumatologic Condition
7. Major PTSD symptoms
8. Hypotension (under 90/60 mm Hg) or history of cardiovascular disease
9. Antihypertensive, anticoagulant medication, nitroglycerine, lithium medication use
10. Diabetes with Hemoglobin A1C >9%
11. History of anaphylaxis to study botanical compounds
12. Current daily use of opioid medication
13. Hospital Anxiety and Depression Scale, Depression subscale score of 16 or higher at baseline
14. Current litigation of worker's compensation claim
15. Blood or clotting disorder
16. Acute infection (body temperature over 100 degrees F)
17. Current daily use of confounding-anti-inflammatory medication as part of regular medication regimen
18. Individuals that are not able to read & understand English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Boswellia Serrata; 400-800mg in capsule form by mouth every day	Dietary supplement: Boswellia Serrata; Other Names: Indian frankincense
Experimental: Curcumin; 1000-2000mg in capsule form by mouth every day	Dietary supplement: Curcumin; Other Names: Curcumasorb; Turmeric extract; Meriva
Experimental: Epimedium; 1000-2000mg in capsule form by mouth every day	Dietary supplement: Epimedium; Other Names: Horny Goat Weed; Barrenwort; Bishop's Hat; Fairy Wings; Yin Yang Huo
Experimental: Fisetin; 200-800mg in capsule form by mouth every day	Dietary supplement: Fisetin
Experimental: Luteolin; 200-400mg in capsule form by mouth every day	Dietary supplement: Luteolin
Experimental: Nettle; 435-1305mg in capsule form by mouth every day	Dietary supplement: Nettle; Other Names: Common Nettle; urtica dioica; Stinging Nettle
Experimental: Pycnogenol; 200-400mg in capsule form by mouth every day	Dietary supplement: Pycnogenol; Other Names: Maritime Pine Extract; Pine Bark Extract
Experimental: Reishi Mushroom; 1600-3200mg in capsule form by mouth every day	Dietary supplement: Reishi Mushroom
Experimental: Resveratrol; 200-600mg in capsule form by mouth every day	Dietary supplement: Resveratrol; Other Names: Red Wine Extract
Placebo Comparator: Placebo; in capsule form by mouth every day	Dietary supplement: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Overall Gulf War Illness Disease Severity	Self reported Gulf War Illness symptom severity evening reports were collected for the duration of the study. Scale= change from baseline in overall GWI Disease severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pain Severity	Self reported pain symptom severity evening reports were collected for the duration of the study. Scale= change from baseline in overall GWI pain severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17
Change From Baseline in Fatigue Severity	Self reported fatigue symptom severity evening reports were collected for the duration of the study. Scale= change from baseline in overall GWI fatigue severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17
Change From Baseline in Cognitive Symptom Severity	Self reported Cognitive Symptom Severity evening reports were collected for the duration of the study. Scale= change from baseline in overall Cognitive Symptom Severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17
Change From Baseline in Mood Symptom Severity	Self reported Mood Symptom Severity evening reports were collected for the duration of the study. Scale= change from baseline in overall Mood Symptom Severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17
Change From Baseline in Dermatological Symptom Severity	Self reported Dermatological Symptom Severity evening reports were collected for the duration of the study. Scale= change from baseline in overall Dermatological Symptom Severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17
Change From Baseline in Respiratory Symptom Severity	Self reported Respiratory Symptom Severity evening reports were collected for the duration of the study. Scale= change from baseline in overall Respiratory Symptom Severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17
Change From Baseline in Gastrointestinal Symptom Severity	Self reported Gastrointestinal Symptom Severity evening reports were collected for the duration of the study. Scale= change from baseline in overall Gastrointestinal Symptom Severity (-100 to +100, with positive numbers indicating how much the symptom improved).	Week 17

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Congressionally Directed Medical Research Programs
• Investigators: Principal Investigator: Jarred W Younger, PhD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Younger J, Donovan EK, Hodgin KS, Ness TJ. A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Reishi Mushroom (Ganoderma lucidum), Stinging Nettle (Urtica dioica), and Epimedium (Epimedium sagittatum). Int J Environ Res Public Health. 2021 Apr 1;18(7):3671. doi: 10.3390/ijerph18073671.
• Hodgin KS, Donovan EK, Kekes-Szabo S, Lin JC, Feick J, Massey RL, Ness TJ, Younger JW. A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Resveratrol (Polygonum cuspidatum), Luteolin, and Fisetin (Rhus succedanea). Int J Environ Res Public Health. 2021 Mar 3;18(5):2483. doi: 10.3390/ijerph18052483.
• Donovan EK, Kekes-Szabo S, Lin JC, Massey RL, Cobb JD, Hodgin KS, Ness TJ, Hangee-Bauer C, Younger JW. A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Curcumin (Curcuma longa), Boswellia (Boswellia serrata), and French Maritime Pine Bark (Pinus pinaster). Int J Environ Res Public Health. 2021 Mar 3;18(5):2468. doi: 10.3390/ijerph18052468.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 16, 2016
• First Posted (Estimated): September 21, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 9, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Gulf War Syndrome; Chronic Multisymptom Illnesses; Medically Unexplained Illnesses
• Additional Relevant MeSH Terms: Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Platelet Aggregation Inhibitors; Antioxidants; Protective Agents; Adjuvants, Immunologic; Resveratrol; Curcumin; Turmeric extract; Pycnogenols
• Other Study ID Numbers: F150318011; CDMRP-GW130015 (Other Grant/Funding Number: Congressionally Directed Medical Research Programs)