FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.0R790.
Gulf War Illness (GWI) corresponds to an array of symptoms that includes chronic fatigue, musculoskeletal pain, cognitive dysfunction, sleep disturbance, gastrointestinal, respiratory, and dermatological symptoms that affect ~250,000 U.S. military veterans that served in Operation Desert Storm/Desert Shield (1990-1991). Mitochondrial function impairments have been shown in GWI patients. GWI patients report partial amelioration of chronic fatigue and brain fog after medicinal marijuana and CBD oils. Interestingly, cannabidiol (CBD) modulates mitochondrial physiology though this has not been characterized in detail. We hypothesize that GWI mitochondrial pathology can be recapitulated in dermal fibroblasts (DF) from subjects to help define and develop a cell-based model to study GWI and CBD treatment of DF promotes energy production by improving mitochondrial physiology. GWI patients (gender/age matched to healthy controls) were recruited to collect skin punch biopsy explants that were processed and cultured in DMEM FBS 10% for 30-days to obtain dermal fibroblasts. DF were treated with serial dilutions of Verséa™ CBD (50mg/mL) lipid formulation (VESIsorb® that increases 4.4-fold Cmax ). Using real time mitochondrial analysis by Seahorse, energy phenotype and mitochondrial function was analyzed in control and GWI DF. Mitochondrial networks and ultrastructure were studied by live-imaging using MitoTracker™ and transmission electron microscopy, respectively. Energy phenotype studies suggest that GWI DF present with lower mitochondrial metabolism and higher glycolytic activity, compared with controls. Additionally, mitochondrial stress suggests a significant reduction in mitochondrial maximal capacity. Such data establish GWI derived DF as a personalized model system to study mitochondrial pathology in GWI. After 18h treatment with Verséa™ CBD, GWI DF show a significant improvement in mitochondrial and glycolytic metabolism; control patients show no increases in mitochondrial metabolism but improved glycolysis. Verséa™ CBD treatment induced mitochondrial networks re-organization in DF. These findings suggest that CBD improves GWI DF mitochondrial physiology, thus improving energy homeostasis. Our data provide new evidence that will validate the potential of cannabinoids as a therapeutic strategy to mitigate energy imbalance that may contribute to detrimental symptomatology (i.e., chronic fatigue, brain fog, cognitive dysfunction, etc.) in GWI patients.