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)

This report is third in a three-part clinical trial series screening potential treatments for Gulf War Illness (GWI). The goal of the project was to rapidly identify agents to prioritize for further efficacy research. We used a placebo-controlled, pseudo-randomized, crossover design to test the effects of reishi mushroom (Ganoderma lucidum), stinging nettle (Uritca dioica), and epimedium (Epimedium sagittatum) in 29 men with GWI. Participants completed 30 days of symptom reports for baseline, then a botanical line consisting of 30 days of placebo, followed by 30 days each of lower-dose and higher-dose botanical. After completing a botanical line, participants were randomized to complete the protocol with another botanical, until they completed three botanical trials. GWI symptom severity, pain, and fatigue were contrasted between the four conditions (baseline, placebo, lower-dose, higher dose) using linear mixed models. GWI symptom severity was unchanged from placebo in the reishi lower-dose condition (p = 0.603), and was higher in the higher-dose condition (p = 0.012). Symptom severity was not decreased from placebo with lower-dose stinging nettle (p = 0.604), but was significantly decreased with higher-dose stinging nettle (p = 0.048). Epimedium showed no significant decreases of GWI symptoms in the lower (p = 0.936) or higher (p = 0.183) dose conditions. Stinging nettle, especially at higher daily dosages, may help reduce the symptoms of GWI. Epimedium does not appear to beneficially affect GWI symptom severity, and reishi may exaggerate symptoms in some GWI sufferers. These results are in a small sample and are preliminary. Further research is required to determine if stinging nettle is indeed helpful for the treatment of GWI, and what dosage is optimal. This trial was registered on ClinicalTrials.gov (NCT02909686).

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A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Resveratrol (Polygonum cuspidatum), Luteolin, and Fisetin (Rhus succedanea)

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052483 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2483

Author(s):

Kathleen S. Hodgin ◽

Emily K. Donovan ◽

Sophia Kekes-Szabo ◽

Joanne C. Lin ◽

Joseph Feick ◽

...

Keyword(s):

Symptom Severity ◽

Gulf War ◽

Unknown Etiology ◽

Optimal Dosage ◽

Polygonum Cuspidatum ◽

Gulf War Illness ◽

Male Veterans ◽

Symptom Reports ◽

Screening Study ◽

Rhus Succedanea

A chronic multi-symptom illness of unknown etiology, Gulf War Illness (GWI) affects 175,000 to 250,000 veterans of the Gulf War. Because inflammation has suspected involvement in the pathophysiology of GWI, botanical treatments that target inflammation may be beneficial in reducing symptoms. No FDA-approved treatments currently exist for GWI, and rapid prioritization of agents for future efficacy testing is important. This study is part of a larger project that screened nine different botanical compounds with purported anti-inflammatory properties for potential treatment of GWI. We tested three botanicals (resveratrol [Polygonum cuspidatum], luteolin, and fisetin [Rhus succedanea]) on symptom severity of GWI in this placebo-controlled, pseudo-randomized clinical trial. Twenty-one male veterans with GWI completed the study protocol, which consisted of 1 month (30 days ± 3) of baseline symptom reports, 1 month of placebo, 1 month of lower-dose botanical, and 1 month of higher-dose botanical. Participants completed up to 3 different botanicals, repeating the placebo, lower-dose, and higher-dose cycle for each botanical assigned. Linear mixed models were used for analyses. Resveratrol reduced GWI symptom severity significantly more than placebo at both the lower (p = 0.035) and higher (p = 0.004) dosages. Luteolin did not decrease symptom severity more than placebo at either the lower (p = 0.718) or higher dosages (p = 0.492). Similarly, fisetin did not reduce symptom severity at either the lower (p = 0.504) or higher (p = 0.616) dosages. Preliminary findings from this screening study suggest that resveratrol may be beneficial in reducing symptoms of GWI and should be prioritized for future testing. Larger trials are required to determine efficacy, response rates, durability of effects, safety, and optimal dosage. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016.

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The relationship between Gulf War Illness symptom severity and heart rate variability: A pilot study

Life Sciences ◽

10.1016/j.lfs.2021.119663 ◽

2021 ◽

pp. 119663

Author(s):

Kyle J. Jaquess ◽

Nathaniel Allen ◽

Timothy J. Chun ◽

Lucas Crock ◽

Alexander A. Zajdel ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Pilot Study ◽

Symptom Severity ◽

Gulf War ◽

Gulf War Illness ◽

The Relationship

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Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study

Neural Computation ◽

10.1162/neco_a_00659 ◽

2014 ◽

Vol 26 (11) ◽

pp. 2594-2651 ◽

Cited By ~ 28

Author(s):

Beatrice A. Golomb ◽

Matthew Allison ◽

Sabrina Koperski ◽

Hayley J. Koslik ◽

Sridevi Devaraj ◽

...

Keyword(s):

Physical Function ◽

Coenzyme Q10 ◽

Gulf War ◽

Small Sample ◽

Controlled Study ◽

Double Blind Study ◽

Gulf War Illness ◽

War Veterans ◽

Double Blind ◽

Gulf War Veterans

We sought to assess whether coenzyme Q10 (CoQ10) benefits the chronic multisymptom problems that affect one-quarter to one-third of 1990–1 Gulf War veterans, using a randomized, double-blind, placebo-controlled study. Participants were 46 veterans meeting Kansas and Centers for Disease Control criteria for Gulf War illness. Intervention was PharmaNord (Denmark) CoQ10 100 mg per day (Q100), 300 mg per day (Q300), or an identical-appearing placebo for 3.5 [Formula: see text] 0.5 months. General self-rated health (GSRH), the primary outcome, differed across randomization arms at baseline, and sex significantly predicted GSRH change, compelling adjustment for baseline GSRH and prompting sex-stratified analysis. GSRH showed no significant benefit in the combined-sex sample. Among males (85% of participants), Q100 significantly benefited GSRH versus placebo and versus Q300, providing emphasis on Q100. Physical function (summary performance score, SPS) improved on Q100 versus placebo. A rise in CoQ10 approached significance as a predictor of improvement in GSRH and significantly predicted SPS improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on Q100 versus placebo was favorable for all except sleep problems; sign test 19:1, [Formula: see text]) with several symptoms individually significant. Significance for these symptoms despite the small sample underscores large effect sizes, and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. In conclusion, Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness. Examination in a larger sample is warranted, and findings from this study can inform the conduct of a larger trial.

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Gulf War Illness Symptom Severity and Onset: A Cross-Sectional Survey

Military Medicine ◽

10.1093/milmed/usz471 ◽

2020 ◽

Vol 185 (7-8) ◽

pp. e1120-e1127

Author(s):

Cayla M Fappiano ◽

James N Baraniuk

Keyword(s):

Burden Of Disease ◽

Symptom Severity ◽

Sleep Disturbances ◽

Gulf War ◽

Gulf War Illness ◽

Cross Sectional ◽

Duration Of Symptoms ◽

The Past ◽

Abdominal Symptoms ◽

Severity Scores

Abstract Introduction: Gulf War illness (GWI) affects 25 to 32% of the 693,826 veterans of the First Persian Gulf War. The etiology and pathophysiology of GWI remain controversial, but the condition is attributed to toxic exposures and stress in the deployed setting. The Kansas criteria used for GWI diagnosis highlight 37 symptoms that were more prevalent in deployed compared to nondeployed veterans. This study employed the Kansas criteria to identify recent symptom severity, assess the perceived burden of disease for veterans with GWI, and characterize disease course over the past three decades. Materials and Methods: The Kansas criteria were operationalized into a questionnaire to provide a summary of symptom severity, approximate year of onset, and an aid for diagnosis. The online version of the questionnaire was completed by 485 veterans with GWI. Symptom data were grouped for analysis based on observed trends. This study received approval from the Georgetown University Institutional Review Board (IRB 2018–0430). RESULTS: Symptom severity for the past 6 months demonstrated a high burden of disease for veteran participants. Frequency analysis of total severity scores (out of 148) showed a unimodal distribution with a median score of 95 (1st quartile = 78, 3rd quartile = 110), minimum score of 19, and maximum of 146. Over 89% of respondents had moderate or severe fatigue, sleep disturbances, pain, and abdominal symptoms over the past 6 months. The veterans who participated in this study reported cumulative frequencies higher than those in a meta-analysis of 21 GWI large epidemiologic cross-sectional studies for symptoms around 1998. The cumulative frequency of symptoms indicated long duration of symptoms, although recall bias must be taken into consideration. Conclusions: This cross-sectional sample of self-selected veterans with GWI demonstrates a high current burden of disease and reveals symptom onset patterns. The information from this study can be used to better understand the long-term trajectory of GWI and be integrated into the treatment and diagnosis of impacted veterans. It can also be used as historical deployed health data and inform the future medical care of combat veterans experiencing health effects from war exposures.

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Gulf War Illness and Inflammation: Association of symptom severity with C-reactive protein

Journal of Neurology and Neuromedicine ◽

10.29245/2572.942x/2019/2.1245 ◽

2019 ◽

Vol 4 (2) ◽

pp. 15-19 ◽

Cited By ~ 1

Author(s):

Lisa James ◽

Brian Engdahl ◽

Rachel Johnson ◽

Apostolos Georgopoulos

Keyword(s):

Symptom Severity ◽

Gulf War ◽

C Reactive Protein ◽

Gulf War Illness ◽

Reactive Protein

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Brain and Physiological Markers of Autonomic Function Are Associated With Treatment-Related Improvements in Self-Reported Autonomic Dysfunction in Veterans With Gulf War Illness: An Exploratory Pilot Study

Global Advances in Health and Medicine ◽

10.1177/2164956120922812 ◽

2020 ◽

Vol 9 ◽

pp. 216495612092281 ◽

Cited By ~ 1

Author(s):

Danielle C Mathersul ◽

Carla M Eising ◽

Danielle D DeSouza ◽

David Spiegel ◽

Peter J Bayley

Keyword(s):

Heart Rate ◽

High Frequency ◽

Behavioral Therapy ◽

Small Sample Size ◽

Controlled Trial ◽

Low Frequency ◽

Physical Symptoms ◽

Gulf War ◽

Small Sample ◽

Gulf War Illness

Background Gulf War Illness (GWI) is a poorly understood condition characterized by a constellation of mood, cognitive, and physical symptoms. A growing body of evidence demonstrates autonomic nervous system (ANS) dysfunction. Few published treatment studies exist for GWI. Method We recently completed a randomized controlled trial comparing a 10-week group yoga intervention to 10-week group cognitive behavioral therapy (CBT) for veterans with GWI. Here, we present exploratory data on ANS biomarkers of treatment response from a small pilot exploratory neurophysiological add-on study (n = 13) within that larger study. Results Findings suggest that veterans with GWI receiving either yoga or CBT for pain improved following treatment and that changes in biological ANS—especially for the yoga group—moved in the direction of healthy profiles: lower heart rate, higher square root of the mean squared differences between successive R-R intervals (RMSSD), greater parasympathetic activation/dominance (increased high-frequency heart rate variability [HF-HRV], decreased low-frequency/high-frequency [LF/HF] ratio), reduced right amygdala volume, and stronger amygdala-default mode/amygdala-salience network connectivity, both immediately posttreatment and at 6-month follow-up. Biological mechanisms of CBT appeared to underlie improvements in more psychologically loaded symptoms such as self-reported fatigue and energy. Higher tonic arousal and/or more sympathetic dominance (higher skin conductance, lower RMSSD, lower HF-HRV, higher LF/HF ratio) pretreatment predicted greater treatment-related improvements in self-reported ANS for both the yoga and CBT group. Conclusion These exploratory pilot data provide preliminary support for the suggestion that treatment (yoga, CBT) is associated with improvements in both biological and self-reported ANS dysfunctions in GWI. The major limitation for these findings is the small sample size. Larger and more controlled studies are needed to replicate these findings and directly compare biomarkers of yoga versus CBT.

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