For over 25 years now, 250,000 Veterans from the 1990-1991 Gulf War (GW) have suffered from a chronic and debilitating multisymptom illness, called Gulf War Illness (GWI). Veterans with GWI experience heterogeneous symptoms consisting of chronic pain, fatigue, and memory problems. To date, this illness remains difficult to treat given its complex underlying biology. We have recently shown that disturbances in fat (lipid) breakdown may be a feature of GWI, present in both animal models of GWI and in blood from Veterans suffering from this condition. We found that these lipids were associated with the sub-cellular compartments (peroxisomes) that perform the initial breakdown of certain lipids and then transfer them to mitochondria (the body’s powerhouse) where they are further metabolized to serve as an alternative energy source. Our recent work shows that lipids regulated by peroxisomes are abnormally elevated in Veterans with GWI. As such, targeting peroxisomal lipid metabolism represents an important avenue for treating the symptoms of GWI.

We recently performed preclinical testing of a naturally occurring lipid, oleoylethanolamide (OEA), that targets peroxisomes to determine if such a strategy could be useful for treating GWI. Our animal studies showed that oral administration of OEA for 6 months improves learning and memory and reduces fatigue-like behavior in OEA-treated GWI mice compared to untreated GWI mice. These studies also showed that OEA treatment restores lipid metabolism and reduces immune cell activation and other markers associated with inflammation in the brains of GWI mice. OEA appeared safe as there was no overt toxicity as quantified by weight change and no physical signs of distress observed in mice. Clinical studies and consumer testimonials on the web for OEA use also show that it is safe in individuals who used it as a weight loss supplement. The key objective of the proposed work is to test whether OEA treatment can restore lipid levels that were associated with abnormal peroxisome function in GWI and whether correcting lipid profiles corresponds with improvements in memory function and reductions in fatigue and pain experienced by Veterans with GWI.

Using a double-blind placebo controlled clinical trial design, we will test whether 200 mg of OEA twice daily can achieve the key objectives of correcting lipid profiles and reducing inflammation and have positive effects on the general health of ill GW Veterans by boosting memory function and decreasing fatigue and pain. We expect that use of OEA will substantially improve the activities of daily living of ill Veterans. We will administer either OEA or placebo to the study participants. There will be two phases of the trial. The first phase will be blinded and conducted over a period of 10 weeks followed by a second phase, which will consist of an open label period for another 5 weeks where all participants will receive OEA. Blood samples and clinical data will be collected during in-person visits to assess the proposed study objectives as well as address OEA’s safety in Veterans with GWI.

The proposed work is carefully designed to determine the translational value of OEA in correcting the underlying peroxisomal and mitochondria-associated lipid disturbances observed in Veterans with GWI. We expect that the results from this trial will guide the design of future Phase III clinical trials for developing OEA as a targeted therapy for GWI. This study will also provide evidence for a potential use of lipid biomarkers as surrogates for detecting treatment response that may serve as end-points in future trials in Veterans with GWI, which will ultimately help shorten the time required for securing regulatory approvals for using OEA as a GWI treatment.