Tier 2 — strong

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
International Journal of Environmental Research and Public Health 2021 18(5):2483

Bibliography

PubMed
PMID 33802381
PubMed Central
PMC7967624
DOI
10.3390/ijerph18052483
Trial registry
View on ClinicalTrials.gov Registered trial — results not yet published in a peer-reviewed journal.
Funding
Funded by U.S. Department of Defense Congressionally Directed Medical Research Programs grants W81XWH-14-1-0623 and W81XWH-19-1-0725, with support from NIH NCATS award UL1TR003096. The funders were not involved in study design, data collection/analysis, or manuscript preparation.
Competing interests
The authors declared no conflicts of interest.

Study snapshot

DesignPlacebo-controlled, pseudo-randomized crossover botanical screening trial.
ModelMale U.S. Gulf War veterans with Gulf War Illness.
Sample21 participants completed the protocol; participants could complete up to three botanical cycles.
InterventionFisetin 200 mg/day for one month, then 800 mg/day for one month, with doses split morning/evening; compared with a preceding placebo month. Resveratrol and luteolin were tested in separate cycles.
DurationFor each botanical: approximately 1 month placebo, 1 month lower dose, and 1 month higher dose, after a baseline reporting period.
EndpointsOverall Gulf War Illness symptom severity; Pain severity; Fatigue severity; Safety/tolerability

What the study showed, in plain terms

This small human crossover study screened fisetin, resveratrol and luteolin as possible treatments for Gulf War Illness. For fisetin, participants received a placebo period followed by 200 mg/day and then 800 mg/day.

Fisetin did not significantly reduce overall Gulf War Illness symptom severity versus placebo at either dose. This is important negative human evidence: it shows that biologically plausible anti-inflammatory activity does not automatically translate into symptom improvement in a clinical population.

Key findings

  • Fisetin did not reduce overall Gulf War Illness symptom severity versus placebo at 200 mg/day (p=0.504).
  • Fisetin also did not reduce symptom severity versus placebo at 800 mg/day (p=0.616).
  • The trial was designed as a rapid botanical screening study, so null results are especially useful for prioritizing which compounds warrant larger efficacy trials.

What this study can and cannot tell us

  • Small sample size and pseudo-randomized crossover design limit precision and generalizability.
  • Participants were male Gulf War veterans with a specific multisymptom illness; results cannot be generalized to healthy adults or other diseases.
  • Botanical sourcing, purity and multi-agent screening introduce additional complexity compared with a dedicated confirmatory fisetin trial.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology