The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 46; no. 5; pp. 1011 - 1019
• Main Authors: Paulus, Martin P., Stein, Murray B., Simmons, Alan N., Risbrough, Victoria B., Halter, Robin, Chaplan, Sandra R.
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2021; Springer International Publishing
• Subjects: Amidohydrolases; Amygdala; Anandamide; Anxiety; Anxiety - drug therapy; Anxiety Disorders; Behavior; Brain mapping; Brain research; Cannabinoid receptors; Cannabinoids; Clinical trials; Cortex (frontal); Dosage; Double-blind studies; Emotions; Enzymes; Extinction behavior; Fatty acids; Fatty-acid amide hydrolase; Fear; Fear conditioning; Functional magnetic resonance imaging; Health care; Humans; Hydrolase; Information processing; Magnetic Resonance Imaging; Male; Mental disorders; Mental health; Neurosciences; Pattern recognition; Pharmacodynamics; Placebos; Post traumatic stress disorder; R&D; Research & development; Respiration
• DOI: 10.1038/s41386-020-00936-w
• ISSN: 0893-133X; 1740-634X

Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), prolongs the regulatory effects of endocannabinoids and reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. However, the neural systems underlying this modulation are poorly understood. A single site, randomized, double-blind, placebo-controlled, parallel study was conducted with 43 subjects assigned to receive once daily dosing of either placebo (n = 21) or JNJ-42165279 (100 mg) (n = 22) for 4 consecutive days. Pharmacodynamic effects were assessed on the last day of dosing and included evaluation of brain activation patterns using BOLD fMRI during an (1) emotion face-processing task, (2) inspiratory breathing load task, and (3) fear conditioning and extinction task. JNJ-42165279 attenuated activation in the amygdala, bilateral anterior cingulate, and bilateral insula during the emotion face-processing task consistent with effects previously observed with anxiolytic agents. Higher levels of anandamide were associated with greater attenuation in bilateral anterior cingulate and left insula. JNJ-42165279 increased the activation during anticipation of an aversive interoceptive event in the anterior cingulate and bilateral anterior insula and right inferior frontal cortex. JNJ-42165279 did not affect fear conditioning or within-session extinction learning as evidenced by a lack of differences on a subjective and neural circuit level. Taken together, these results support the hypothesis that JNJ-42165279 at this dose shares some effects with existing anxiolytic agents in dampening response to emotional stimuli but not responses to conditioned fear.