Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder

Abstract

Introduction Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Methods Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. Results There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Conclusion Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder.

Endocannabinoid concentrations in hair are associated with PTSD symptom severity

“…Although the small number of studies in humans as well as the inconsistent findings regarding immediate or prolonged effects of ECS stimulation warrant further investigation, these studies indicate that stimulation of the ECS might facilitate extinction learning in humans, too. Since exposure-based psychotherapies for PTSD rely on mechanisms of extinction learning (Anderson and Insel, 2006), it was argued whether stimulation of the ECS might augment therapeutic effects in PTSD (Neumeister et al, 2015). A preliminary randomized controlled trial indicated that treatment with a synthetic cannabinoid (mimicking the effects of THC) significantly reduces the reliving of the traumatic experiences in the form of nightmares in PTSD patients (Jetly et al, 2015).…”

“…While administration of THC in PTSD patients might be problematic due to the associated risk of addiction and abuse, potential cognitive impairments, as well the pleiotropic effectors of THC, these studies demonstrate that targeting the ECS might be a promising avenue for PTSD treatment research. A safer and more specific way to stimulate the ECS could be the administration of fatty acid amide hydrolase inhibitors to counteract endocannabinoid degradation (Neumeister et al, 2015;Papini et al, 2015) or specific inhibitors of N-acylethanolamine acid amidase, the metabolizing enzyme of PEA and OEA (Bandiera et al, 2014).…”

“…Taken together, the summarized literature strongly suggests that reduced endocannabinoid signaling in PTSD, a condition of chronic stress, could contribute to the explanation of the strong difficulties to extinguish fear reactions, the anxiety phenotype, as well as the state of low-grade inflammation observed in PTSD. Accordingly, the ECS has been proposed to play a significant role in PTSD etiology, and could represent a pharmacological treatment option for PTSD (Neumeister et al, 2015).…”

Neurobiological Interactions Between Stress and the Endocannabinoid System

“…Based on these data, there has been a significant interest in therapeutics development around eCB augmenting agents for stress-related neuropsychiatric disorders (see (Gaetani et al, 2009;Hill et al, 2009b;Hill and Patel, 2013c;Neumeister et al, 2015). Results of pending clinical trials with FAAH inhibitors will reveal therapeutic potential of this class of drug for stress-related psychiatric disorder, particularly PTSD and possibly major depression.…”

Circumspectives: Cannabis and Psychiatric Illness: Blunt Thoughts

“…Anecdotes abound of the beneficial effects of cannabis use as a self-medication in PTSD, as do stories of adverse effects. These conflicting reports tie into an emerging realization that endocannabinoid systems are critically important for regulating stress responses, and indeed might offer novel therapeutic targets in PTSD (Neumeister et al, 2015). The question is whether blunt pharmacological actions such as global brain CB1 receptor activation, as occurs with cannabis use, might be beneficial, safe, and well tolerated.…”