BACKGROUND: Obesity is a worldwide epidemic, and severe obesity is a risk factor 
for many diseases, including diabetes, heart disease, stroke, and some cancers. 
Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is 
activated in obesity and plays a role in the regulation of body weight. The main 
research question here was whether quantitative measurement of plasma 
endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined 
with genotyping for mutations in fatty acid amide hydrolase (FAAH) would 
identify circulating biomarkers of ECS activation in severe obesity.
METHODOLOGY/PRINCIPAL FINDINGS: Plasma samples were obtained from 96 severely 
obese subjects with body mass index (BMI) of > or = 40 kg/m(2), and 48 normal 
weight subjects with BMI of < or = 26 kg/m(2). Triple-quadrupole mass 
spectroscopy methods were used to measure plasma ECS analogs. Subjects were 
genotyped for human FAAH gene mutations. The principal analysis focused on the 
FAAH 385 C-->A (P129T) mutation by comparing plasma ECS metabolite levels in the 
FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. 
The main finding was significantly elevated mean plasma levels of anandamide 
(15.1+/-1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 
385 A mutant alleles versus normal subjects (13.3+/-1.0 pmol/ml) with wild-type 
FAAH genotype (p = 0.04), and significance was maintained after controlling for 
BMI.
CONCLUSIONS/SIGNIFICANCE: Significantly increased levels of the endocannabinoid 
anandamide and related NAEs were found in carriers of the FAAH 385 A mutant 
alleles compared with wild-type FAAH controls. This evidence supports 
endocannabinoid system activation due to the effect of FAAH 385 mutant A 
genotype on plasma AEA and related NAE analogs. This is the first study to 
document that FAAH 385 A mutant alleles have a direct effect on elevated plasma 
levels of anandamide and related NAEs in humans. These biomarkers may indicate 
risk for severe obesity and may suggest novel ECS obesity treatment strategies.