Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder

Abstract

Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the USA, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Finally, we propose 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.

Figure 1

Effects of stress on eCBs and the proposed link to related physiological and behavioral processes. (Top) Stress exposure causes CRH release, which in turn increases FAAH activity to drive down AEA levels within cortico-limbic structures. This reduction in AEA plays a permissive role in the expression of stress-induced anxiety-like behaviors. Pharmacological blockade of FAAH would ‘clamp’ AEA at high levels and thus prevent stress-induced AEA reductions and thereby prevent stress-induced anxiety (not shown). (Bottom) Stress exposure increases 2-AG levels in the amygdala and PFC possibly driven by stress-induced corticosterone release. Upon subsequent stress exposures the 2-AG response shows sensitization via a mechanism which may involve impaired degradation (Sumislawski et al, 2011). This progressive increase in stress-induced 2-AG release in the amygdala is correlated with habituation of the HPA-axis response (red) to repeated homotypic stress exposure (Hill et al, 2010c).

Figure 2

Differential dose–response relationships between cannabis/THC and eCBs augmentation approaches in the regulation of HPA-axis function and anxiety behaviors. THC and cannabis can reduce HPA-axis function in response to stress and decrease anxiety at low doses, however, at higher doses they can increase HPA-axis function and increase anxiety-like behaviors in animals and precipitate anxiety and panic-like symptoms in humans. In contrast, eCB augmentation via FAAH or MAGL inhibition (FAAHi and MAGLi, respectively) generally exerts mono-phasic dose-dependent reductions in HPA-axis activation and anxiety-like behaviors.

Figure 3

Integrative view of eCBs and exogenous cannabinoids in the pathophysiology and potential treatment of PTSD and related processes. Low levels of AEA and/or 2-AG, triggered by stress or pre-existing due to genetic factors, are associated with a myriad of adverse behavioral and physiological consequences including an increase susceptibility to developing trauma-related psychopathology such as PTSD. Therapeutic eCB augmentation may be able to reverse these pre-existing or stress-induced deficiencies via inhibition of FAAH or MAGL activity (FAAHi and MAGLi, respectively). Similarly, this model predicts some people with eCB deficiencies may use cannabis to self-medicate for anxiety and PTSD symptoms. *‘2-AG early’ refers to early relative to stressor onset.