title: FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence.
abstract: 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.
  
  
  
  Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the National Institutes of Health Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid (eCB) 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.
  
  
  
  FAAH C385A allele carriers showed a marked increase in serum anandamide levels at baseline and throughout the stress challenge procedure compared with C allele homozygotes, while levels of eCBs primarily metabolized through other enzymatic activity, such as 2-arachidonoylglycerol, did not differ between genotype groups. FAAH C385A 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.
  
  
  
  This is to our knowledge the first study showing that FAAH C385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the eCB pathway as a promising target for future antistress therapeutics.
authors.affiliation: Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Primavera A
authors.initials: PA
authors.lastname: Spagnolo
authors.affiliation: Section on Human Psychopharmacology, Division of Intramural Clinical and Biomedical Research, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Vijay A
authors.initials: VA
authors.lastname: Ramchandani
authors.affiliation: Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Schwandt
authors.affiliation: Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Kwako
authors.affiliation: Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: David T
authors.initials: DT
authors.lastname: George
authors.affiliation: Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Leah M
authors.initials: LM
authors.lastname: Mayo
authors.affiliation: Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
authors.affiliation: Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. markus.heilig@liu.se.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000150:complications / Q000235:genetics / Q000523:psychology*; D000581:Amidohydrolases / Q000235:genetics*; D001007:Anxiety / Q000235:genetics; D063388:Endocannabinoids / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013313:Stress Disorders, Post-Traumatic / Q000150:complications / Q000235:genetics / Q000523:psychology*; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D000099252:Fatty Acid Amide Hydrolases
keywords: Alcohol Use Disorders; Endocannabinoids; Fatty Acid Amide Hydrolase; Post-traumatic Stress Disorder; Stress