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

Kathleen S Hodgin, Emily K Donovan, Sophia Kekes-Szabo, Joanne C Lin, Joseph Feick, Rebecca L Massey, Timothy J Ness, Jarred W Younger, Kathleen S Hodgin, Emily K Donovan, Sophia Kekes-Szabo, Joanne C Lin, Joseph Feick, Rebecca L Massey, Timothy J Ness, Jarred W Younger

Abstract

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.

Keywords: fisetin; luteolin; resveratrol.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Study protocol. Each participant completed testing of up to three botanicals. For each botanical, there was a placebo condition, followed by lower-dose botanical and higher-dose botanical conditions. The period of time between visits was 30 ± 3 days. Some participants re-enrolled in the study after completion, receiving up to a maximum of six botanicals.
Figure 2
Figure 2
CONSORT Flow diagram. Twenty-four individuals were randomized to at least one of the treatments covered in this report.
Figure 3
Figure 3
Main treatment effects of resveratrol, luteolin, and fisetin on Gulf War Illness (GWI) symptom severity. Average symptom levels (0–100) are presented for the baseline, placebo, lower-dose, and higher-dose conditions. * Significantly lower than baseline (p < 0.05); *# significantly lower than baseline and placebo (p < 0.05).

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