FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence

Abstract

BACKGROUND A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase (FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses. METHODS Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the NIH Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSD symptom severity. RESULTS FAAH 385A allele carriers showed a marked increase in serum anandamide levels throughout the stress challenge procedure compared with C allele homozygotes, while levels of endocannabinoids primarily metabolized through other enzymatic activity, such as 2-AG, did not differ between genotype groups. FAAH 385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAH C385A genotype were found at the level of clinical PTSD symptom severity, in particular in the arousal domain. CONCLUSIONS This is to our knowledge the first study showing that FAAH 385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the endocannabinoid pathway as a promising target for future anti-stress therapeutics.

Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice

“…These emotional states, and the search for the anxiolytic and antidepressant-like effects of alcohol, might in turn contribute to promoting the high levels of alcohol intake and preference that characterize the escalation drinking observed in the present study in mice [Colombo et al 1995; Koob and Volkow 2010]. The stress-response eCB system is critically involved in “anxiety”-related behaviors [Dincheva et al 2015; Parsons & Hurd 2015; Pardini et al et al 2012; Spagnolo et al 2016], and FAAH inhibition reverses enhanced anxiety-like behavior present during alcohol withdrawal [Cippitelli et al 2008]. Our mouse escalation model suggests a role for FAAH activity in the alcohol withdrawal-induced tendency of mice towards “anxiety”- and “depression”- like states.…”

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

“…Additionally, alcohol-dependent patients with the C allele exhibit enhanced PFC, orbitofrontal cortex, and NAc activation in response to alcohol-associated cues and report larger subjective reward following the consumption of several alcoholic beverages (Hutchison et al, 2008). In addition, the CNR1 C allele (Marcos et al, 2012) and the FAAH C385A single nucleotide polymorphism (Buhler et al, 2014;Spagnolo et al, 2016) have been identified as likely indicators of individuals who are at higher risk for alcohol abuse. Furthermore, the FAAH Pro129Thr missense variant (rs324420) has also been shown to be associated with alcohol dependence severity in European Americans (Sloan et al, 2018).…”

FAAH, SLC6A4, and BDNF variants are not associated with psychosocial stress and mental health outcomes in a population of Syrian refugee youth

“…Altered FAAH enzyme activity has been directly linked to neurological changes that increase excitability and anxiety (Gunduz-Cinar et al, 2013). Furthermore, the specific genetic variant of FAAH assayed in our study (rs324420) has been previously associated with several anxiety disorders, particularly in association with psychosocial stress (Lazary et al, 2016;Spagnolo et al, 2016).…”

“…FAAH has been previously associated with psychosocial stress and anxiety, for which we have multiple measures including generalized scales developed for use globally (PSS) and specialized scales designed for use in the region (HD and AYMH; Spagnolo et al, 2016). However, few studies have linked FAAH specifically with childhood trauma, Lazary et al (2016) being the notable exception that led us to assay the gene.…”

“…Individuals were coded based on the presence or absence of the minor allele (i.e. Pro/Pro vs. Pro/Thr + Thr/Thr), consistent with previous findings in this gene (Bühler et al, 2014;Lazary et al, 2016;Spagnolo et al, 2016).…”