Metabolism of N-acylethanolamines: To Phase II and Back Again

N-acylethanolamines (NAEs) are a family of endogenous signalling molecules involved in various effects of the body including pain, inflam- mation, appetite and sleep. NAEs are mainly degraded by fatty acid amide hydrolase (FAAH) andN-acylethanolamine acid amidase (NAAA). FAAH inhibitors have shown promising results in pre- clinical studies of pain, inflammation and anxiety, mediating effects mainly via increased cannabi- noid receptor activity. However, FAAH inhibitors have failed in clinical pain trials, and in a recent phase I trial, an irreversible compound caused one death and sustained impairments in healthy vol- unteers. The latter is most likely due to off-target effects of that compound, rather than an FAAH-mediated effect, and design of dual-action FAAH-NAAA, -TRPV1 or -cyclooxygenase-2 inhibitory compounds may solve the pain efficacy issue. NAAA inhibitors are still in preclinical testing and show a promising anti-inflammatory profile mainly due to increased palmitoylethanolamide and oleoylethanolamide levels.