Imaging Fatty Acid Amide Hydrolase Levels in Social Anxiety Disorder: A Replication Study with the PET Tracer [11C]CURB

Introduction: Social Anxiety Disorder (SAD) is becoming an increasingly common condition with worldwide prevalence estimated at 4%. Many individuals undergoing treatment are unable to achieve symptom relief from existing interventions, necessitating new treatment strategies. Fatty acid amide hydrolase (FAAH), a key enzyme involved in metabolizing the endocannabinoid anandamide (AEA), has emerged as a potential risk marker and promising treatment target for SAD. Notably, upregulation of FAAH is observed in rodent models of anxiety, resulting in a reduction of AEA. Elevating AEA levels through FAAH inhibition has shown to decrease anxious behavior and enhance social interaction in rodents.FAAH inhibitors are now being explored to treat SAD in humans_, however, limited research has focused on investigating the status FAAH in individuals with SAD.

Our group has developed an innovative radiotracer ([¹¹C]CURB) to quantify brain FAAH in vivo in humans using positron emission tomography (PET) imaging and have shown in a preliminary sample (SAD n = 16, Healthy Control [HC] n = 46) that whole brain FAAH levels were elevated by 8.8% in the SAD group. While these early findings translate preclinical research into humans and suggest that FAAH may be involved in SAD, the sample size of the SAD group was small, and the HCs were not assessed for social anxiety traits. The current project aims to advance the knowledge of the role of FAAH and extend and replicate the work in a new, larger sample of individuals with SAD compared to HCs who are specifically selected for low social anxiety. This study aims to use PET imaging of [¹¹C]CURB to test the hypothesis that brain FAAH levels are higher in SAD relative to HCs with low social anxiety. This study also aims to investigate if higher FAAH is associated with elevated SAD symptom severity as per the Liebowitz Social Anxiety Scale (LSAS) (Hypothesis 2).

Methods: Unmedicated individuals meeting DSM-5 criteria for primary SAD and psychiatric HCs with LSAS scores below 30 were invited to undergo a PET scan with the FAAH probe, [¹¹C]CURB, and clinical assessments and questionnaires. Blood samples were taken to assess for genetic variability of a FAAH polymorphism (C385A) known to contribute to variability of its expression of activity. In-house software was used for delineation of regions of interest, extraction of time activity curves and kinetic modeling, producing a reliable index of FAAH levels in brain, represented by lk3 values. Mean whole brain FAAH levels were calculated using 9 brain regions of interest encompassing the amygdala; hippocampus; thalamus; ventral and dorsal striatum; and prefrontal, temporal, cingulate and insular cortices.

Results: Three individuals with SAD and eight HCs have completed study procedures thus far. Individuals with SAD (n = 3 [1 male, 2 females]) were 29.7 (± 5.5) years old and had an average LSAS total score of 83.3 (± 8.7). HCs (n = 8 [4 males, 4 females]) were 24.3 (± 2.6) years old and had an average LSAS total score of 11.1 (± 8.8). Regarding the FAAH C385A genotype, the SAD group included 1 individual with the C/C and 2 individuals with the A/C genotype. In the HC group, 5 individuals were characterized for the C/C and 3 for the A/C genotype. Mean whole brain FAAH levels (lk3 values) were higher by 3.5% in the SAD group (SAD mean = 0.176 [range: 0.140 – 0.208]; HC mean = 0.170 [range:0.125 - 0.205]. Statistical analysis has not been completed at this time due to low SAD sample size.

Conclusions: The findings of this project have the potential to improve our understanding of SAD neurobiology and corroborate the results from the preliminary study. If FAAH is elevated in SAD, this knowledge can inform research of FAAH as biological marker and guide clinical trials evaluating ECS-targeting treatments for individuals suffering from SAD.