Objective

A recent phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 might have played a role. Here, we used activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues, revealing that the drug inhibited several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced widespread alterations in lipid networks in human cortical neurons, showing the potential for promiscuous lipase inhibitors to cause metabolic dysregulation in the nervous system.