FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence
Primavera A. Spagnolo,Vijay A. Ramchandani,Melanie L. Schwandt,Laura E. Kwako,David T. George,Leah M. Mayo,Cecilia J. Hillard,Markus Heilig +7 more
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TLDR
This is to the authors' knowledge the first study showing that FAAH C385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity, and points to the eCB pathway as a promising target for future antistress therapeutics.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 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. Results 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. Conclusions 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.read more
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Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?
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Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder.
TL;DR: It is proposed that a state of endocannabinoid deficiency could represent a stress susceptibility endophenotype predisposing to the development of trauma- related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.
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Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial
Leah M. Mayo,Anna Asratian,Johan Lindé,Maria Morena,Maria Morena,Roosa Haataja,Valter Hammar,Gaëlle Augier,Matthew N. Hill,Matthew N. Hill,Markus Heilig +10 more
TL;DR: 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 posttraumatic stress disorder.
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Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice.
Leah M. Mayo,Anna Asratian,Johan Lindé,Lovisa Holm,Daniel Nätt,Gaëlle Augier,Niclas Stensson,Haley A. Vecchiarelli,Georgia Balsevich,Robert J. Aukema,Bijar Ghafouri,Primavera A. Spagnolo,Francis S. Lee,Matthew N. Hill,Markus Heilig +14 more
TL;DR: It is suggested that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.
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