Functional neuroimaging of fatty acid amide hydrolase inhibition in posttraumatic stress disorder: a randomized clinical trial

TL;DR

A clinical trial found that inhibiting an enzyme involved in anxiety processing did not improve PTSD treatment outcomes, despite increasing a brain chemical linked to fear extinction.

Contribution

This is the first randomized clinical trial to investigate FAAH inhibition's neurobiological effects in PTSD patients undergoing exposure therapy.

Findings

FAAH inhibition did not improve PTSD symptoms compared to placebo.

Symptom improvement correlated with reduced connectivity between brain regions involved in emotional processing.

Increased AEA levels did not translate to changes in brain connectivity or task activation.

Abstract

The endocannabinoid ligand anandamide (AEA) plays a role in fear extinction, the conceptual foundation of the gold standard treatment for posttraumatic stress disorder (PTSD), exposure-based psychotherapy. Converging evidence from animal models and non-clinical human studies highlights the potential to enhance fear extinction pharmacologically by inhibiting the AEA catabolic enzyme, fatty acid amide hydrolase (FAAH). However, in our randomized clinical trial (n = 100), a FAAH inhibitor did no better than placebo at enhancing the response to exposure-based therapy in PTSD. Here, we used functional magnetic resonance imaging to investigate the neurobiological effects of FAAH inhibitor treatment on resting-state functional connectivity and the neural correlates of emotional processing (n = 76 scanned). We found that greater symptom improvement was significantly related to lower functional connectivity between ventromedial prefrontal cortex (vmPFC) and right dorsolateral prefrontal cortex (dlPFC), as well as lower task activation of the right dlPFC. Further, we found that self-reported symptoms at the time of scan were associated with increased functional connectivity of the vmPFC and the amygdala across the cortex (mainly in the ventral attention network and sensorimotor network, respectively). However, while we confirmed that 4 weeks of FAAH inhibition significantly increased AEA, there were no significant differences in functional connectivity or task activation between treatment groups. These findings suggest that FAAH inhibition does not affect intrinsic functional connectivity or emotional task response in PTSD, and that the dlPFC may play an important role in the response to exposure-based psychotherapy.

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