Fatty Acid Amide Hydrolase Inhibitor Effectively Targets Fear in PTSD

Leah M. Mayo, PhD

New data suggests a fatty acid amide hydrolase (FAAH) inhibitors can improve the recall of fear extinction memories and attenuate the anxiogenic effects of stress in post-traumatic stress disorder (PTSD) patients.

A team led by Leah M. Mayo, PhD, the Center for Social and Affective Neuroscience at Linköping University, conducted a double-blind, placebo-controlled experimental medicine phase IIa single-center clinical trial study of healthy adults given either 4 mg per day of PF-04457845 or a placebo for 10 days.

The drug is a highly selective, orally available irreversible inhibitor that produces a near complete and long-lasting inhibition of FAAH.

A total of 16 participants were given the FAAH inhibitor, while 29 volunteers were given a placebo. On the days 9 and 10, each participant completed a task battery assessing their psychophysiological indices of fear learning, stress reactivity, and stress-induced affective responses.

The primary outcome was measurements of plasma endocannabinoid (eCB) anandamide (AEA) levels, fear extinction (startle electromyography [EMG]), recall of fear extinction, and stress-induced negative affect (corrugator EMG), with secondary outcomes being stress reactivity (skin conductance responses [SCR], subjective stress, cortisol, heart rate) and baseline affect (corrugator EMG).

“FAAH inhibition produced a 10-fold increase in baseline AEA. This was associated with potentiated recall of fear extinction memory when tested 24 hours after extinction training,” the authors wrote. “FAAH inhibition also attenuated autonomic stress reactivity, assessed via electrodermal activity, and protected against stress-induced negative affect, measured via facial electromyography.”

The investigators suggest developing a new class of drugs to treat PTSD, as there are currently very limited options to treat the disorder.

“The beneficial effects of FAAH inhibition on fear extinction, as well as stress- and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for PTSD,” the authors wrote.

PTSD is characterized by a chronic and often severe time course, with a small percentage of patients achieving full remission. Currently, FDA-approved PTSD pharmacotherapies do not target core pathophysiology of dysregulated fear, which are no more effected when used with prolonged exposure (PE) than without PE.

Preclinical evidence suggests that AEA is critical for emotional memory consolidation, which relies on interactions between the amygdala and mPFC, suggesting that elevated AEA signaling could enhance top down cortical control of amygdala activity to enhance the learning of fear extinction., as opposed to modulating fear expression.

Earlier this year, researchers found a lack of studies to draw data from regarding treatments for PTSD.

Heike Gerger, PhD, of the University of Basel (UNIBAS), led a team of investigators, in a meta-analysis comparing psychotherapeutic and pharmacological treatments for PTSD and explained in an interview with MD Magazine® the significance of the lack of available studies.

“One reason for this observation may be that researchers (and clinicians) tend to have a rather strong preference for one or the other kind of treatment,” she said. “In their studies, they then use the treatment they expect to be most efficacious in order to prove its efficacy.

“Therefore, in many cases, only one kind of treatment is compared with control treatments,” she added. “This is particularly problematic if we want to determine which treatment is best suited for which patients.”

The study, “Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase (FAAH): a randomized, controlled experimental medicine trial,” was published in Biological Psychiatry.