Effects of the endocannabinoid system activation on fear extinction

• Applicants: Professor Dr. Stefan Roepke; Professorin Dr. Katja Wingenfeld
• Subject Area: Biological Psychology and Cognitive Neuroscience
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495478032

Posttraumatic stress disorder (PTSD) is a severe mental disorder with intrusive symptoms such as recurrent, involuntary, intrusive, and distressing memories of the traumatic event. Therefore, processes of learning and memory, such as acquisition, consolidation, and retrieval of autobiographical events are important factors in the development, maintenance, and treatment of these symptoms. Altered fear conditioning and extinction learning are key etiological features of anxiety disorders and PTSD. In particular, reduced fear extinction might be responsible for the maintenance of PTSD symptoms and the success of treatment, for instance via exposure therapy. The endocannabinoid system plays an important role in human cognition and endocannabinoids facilitate fear extinction learning. There is growing evidence for an involvement of the endogenous cannabinoid system in PTSD pathology, with most studies suggesting lower endocannabinoid levels in individuals with PTSD. It is feasible that low endocannabinoid signaling disrupts extinction learning and contributes to the maintenance of PTSD, but this has not been studied. The aim of this study is to investigate the effects of cannabinoid system activation by the exogenous cannabinoid THC on fear extinction learning in individuals with PTSD. In a double-blind placebo-controlled study, we will investigate the effect of exogenous dronabinol (THC) on fear extinction learning in individuals with PTSD and healthy controls. We will recruit 100 individuals with PTSD and 100 sex- and age-matched healthy individuals, who will be randomized to receive either 2.5 mg dronabinol or placebo. First, participants will undergo the fear acquisition part of the fear conditioning paradigm, after which dronabinol or placebo will be administered (120 minutes before extinction learning). The main dependent variable is the skin conductance reaction (SCR). A secondary variable will be the fear potentiated startle (FPS) response. Extinction learning will be operationalized as reduced SCR and FPS to the CS+ during extinction learning compared with during the fear acquisition phase. We hypothesize that fear extinction will be higher in the dronabinol group than in the placebo group (main hypothesis) and that extinction learning will be higher in healthy individuals than in individuals with PTSD in the placebo condition. Dronabinol will increase extinction learning more strongly in individuals with PTSD patients than in healthy individuals (reflected by equal SCR and FPS in healthy individuals and individuals with PTSD). This study will significantly increase our understanding of PTSD symptoms and ways to reduce them by facilitating fear extinction and promoting safety learning. Prospectively, this may help translate basic fear conditioning research to the clinical setting.

• DFG Programme: Research Grants