In Vivo Characterization of Fatty Acid Amide Hydrolase in Posttraumatic Stress Disorder: A [11C]CURB Positron Emission Tomography Study

Background Posttraumatic stress disorder (PTSD) is associated with impaired fear extinction and dysfunction in amygdala-centered circuits, for which treatments remain insufficient. The endocannabinoid system, particularly anandamide signaling regulated by fatty acid amide hydrolase (FAAH), has been implicated in stress and fear regulation. Preclinical studies suggest increased FAAH is linked to heightened stress responsivity, but FAAH status in PTSD remains unclear. We used [ 11 C]CURB positron emission tomography (PET) to characterize FAAH levels in the amygdala and in corticolimbic regions in PTSD and examine associations with clinical symptoms. Methods Participants with PTSD and controls underwent clinical assessment and PET/MRI. Trauma histories were characterized using clinical interviews and the Traumatic Life Events Questionnaire (TLEQ). FAAH levels ([ 11 C]CURB) were quantified using an irreversible two-tissue compartment model with arterial input function. Associations with PTSD symptoms were examined. Results 86 participants were included (35 PTSD, 51 controls). PTSD participants showed lower amygdala FAAH levels than controls (−10%; p=0.02), with no differences in other corticolimbic regions. Exploratory analyses showed that childhood trauma was associated with higher corticolimbic FAAH levels, irrespective of diagnosis (+11.6%; p=0.014; n=28 vs. 24 with TLEQ data). FAAH levels were not associated with clinical symptoms. Conclusions Despite preclinical evidence linking increased FAAH activity to stress-related phenotypes, we found reduced amygdala FAAH in PTSD. Exploratory analyses showed higher corticolimbic FAAH in individuals with childhood trauma. These findings provide in vivo evidence of altered endocannabinoid signaling in PTSD and may inform interpretation of limited efficacy in FAAH inhibitor trials.