Over 25 years after the 1990-1991 Gulf War (GW), nearly 250,000 Veterans of that era still suffer from a chronic and debilitating multisymptom illness that they contracted during the war, called Gulf War Illness (GWI). Veterans with GWI experience many seemingly unrelated symptoms, consisting of gastrointestinal problems, chronic pain, fatigue, and memory problems. To date, this illness remains difficult to treat given the complex underlying biology of GWI. We have recently shown that GWI is associated with disturbances in molecules needed to generate energy for performing cellular functions. We found that blood from GWI mice and Veterans with GWI have low levels of energy-related molecules generally found in the sub-cellular compartments known as mitochondria (body’s powerhouse). These mitochondria serve as factories that take in nutrients and convert them into energy. Therefore, lowered availability of these energy-related molecules in Veterans with GWI implies that the mitochondria are functioning abnormally, which would explain why some aspect of GWI can be attributed to low availability of such energy-related molecules. Our recent work also showed that in Veterans with GWI, these energy molecule alterations have repercussions that cause worsened function in other cellular systems relating to energy usage and could contribute to inflammation that manifests as chronic fatigue and memory problems in ill GW Veterans. As such, targeting the mitochondrial energy generation system represents an important avenue to treat the symptoms of GWI.

We recently performed preclinical testing of a naturally occurring dietary supplement, nicotinamide riboside (NR), to determine if such a strategy could be useful for treating GWI in mice. NR is an edible form of NAD+, one of the essential molecules used by the mitochondria to help generate energy molecules. Levels of NAD+ are decreased in our mice models of GWI. NR is also known to have the positive effects of stimulating the mitochondria and reducing inflammation. Our animal studies showed that oral administration of NR for 2 months reduces fatigue-like behavior and encourages weight loss in NR-treated GWI mice compared to untreated GWI mice. Treatment with NR restored normal NAD+ levels, increased markers of mitochondria function, and normalized mitochondria-associated lipids in GWI mice. These studies also showed that NR treatment reduced several markers of inflammation in GWI mice.

Nicotinamide riboside is already known to the Food and Drug Administration (FDA) to be safe for consumption through dietary means in animals or humans. Clinical studies on NR also show that it is safe in individuals who use it as an anti-aging supplement. Based on the promising outcomes of these reports and GWI animal model studies, the work described here is aimed at conducting a pilot clinical trial to test whether a currently available nutraceutical form of NR can be useful as a future treatment for GWI. The key objectives of the proposed work are to test whether NR treatment can restore NAD+ levels to normal, restore the altered lipid levels that are associated with abnormal mitochondria function in GWI, and reduce inflammation. We will also investigate whether these expected outcomes correspond with reducing the fatigue, pain, and memory problems experienced by Veterans with GWI.

Using a double-blind placebo controlled clinical trial design, we will test whether 300 mg of NR once daily can achieve the key objectives of restoring plasma NAD+ levels, correcting lipid profiles, reducing inflammation, and have positive effects on the general heath of ill GW Veterans by decreasing fatigue, pain, and memory problems. We expect that use of NR will substantially improve the activities of daily living of ill GW Veterans. We will administer either NR or placebo to the study participants (26 subjects per group). There will be two phases of the trial. The first phase will be blinded and conducted over a period of 10 weeks and will be followed by a second phase that will consist of an open label period for another 5 weeks, during which all participants will receive NR. Blood samples and clinical data will be collected during in-person visits to assess the proposed study objectives as well as assess NR’s safety.

The proposed work is carefully designed to determine the translational potential of NR in correcting the underlying mitochondria 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 NR as a targeted therapy for GWI. This study will also provide evidence for the potential use of proposed mitochondria-related energy as biomarkers for detecting treatment response to NR, which may then serve as surrogate endpoints in future large-scale clinical trials of NR in Veterans with GWI. This will ultimately help shorten the time required to secure regulatory approvals for using NR as a GWI treatment.