Enhancing Fear Extinction: Pharmacological Approaches

Extinction—the process by which a learned conditioned association fades over time and with new learning—is central to fear-related disorders such as phobias, panic disorder, OCD, and PTSD, and underlies gold-standard therapies like prolonged exposure and cognitive processing therapy. Pharmacological modulators of extinction are promising treatment targets. This review covers emerging psychopharmacological agents that may facilitate extinction: D-cycloserine, scopolamine, losartan, ketamine, and MDMA. It also surveys recent advances in molecular pathways relevant to extinction and inhibitory learning, including cannabinoid, BDNF, HPA-axis signaling, and neurosteroid compounds.

Study at a glance

Abstract

Extinction is the process by which the memory of a learned conditioned association decreases over time and with introduction of new associations. It is a vital part of fear learning, and it is critical to recovery in multiple fear-related disorders, including Specific and Social Phobias, Panic Disorder, Obsessive Compulsive Disorder (OCD), and Posttraumatic Stress Disorder (PTSD). The process of extinction is also the underlying mechanism for recovery in gold-standard therapies for PTSD, including prolonged exposure, cognitive processing therapy, eye movement desensitization and procession, as well as other empirically-based paradigms. Pharmacological modulators of extinction are thus promising targets for treatment of fear-related disorders. We focus here on emerging psychopharmacological treatments to facilitate extinction: D-cycloserine, scopolamine, losartan, ketamine, and 3,4-methylenedioxymethamphetamine. We also provide an overview of recent advances in molecular pathways that show promise as targets for extincion and inhibitory learning, including pathways related to cannabinoid, brain-derived neurotrophic factor, hypothalamic-pituitary-adrenal signaling, and promising work in neurosteroid compounds.