Review articleToward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: A critical review of preclinical research
Introduction
Beginning with California in 1996, twenty-three states in the United States have legalized marijuana for medicinal purposes. Seven of these states have listed posttraumatic stress disorder (PTSD) as an approved condition for treatment with the drug (National Council of State Legislatures, http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx), but unlike other medical conditions for which cannabis is prescribed, there have been no clinical trials testing the efficacy of treating PTSD with cannabis. Moreover, recreational use of cannabis has been associated with a range of poor psychosocial outcomes (Hall, 2014) as well as symptoms of mood, anxiety, and psychotic disorders (Crippa et al., 2009, Moore et al., 2007), suggesting complex effects that require careful assessment of risk alongside any examination of potential benefits. Symptoms of PTSD, including exaggerated reactivity to trauma-related reminders, anxiety, hyperarousal, and avoidant behaviors (American Psychiatric Association, 2013) can undermine functioning for years (Neria et al., 2013), therefore developing novel treatments is crucial, and drawing from research on the behavioral and neurobiological components of PTSD is the best approach for evaluating the therapeutic potential of cannabis.
Several laboratory models have expanded the understanding of PTSD-like symptoms across key levels of analysis (Sullivan, Debiec, Bush, Lyons, & Ledoux, 2009), providing important tools for the rigorous experimentation of potential treatments. Classical fear conditioning (Pavlov, 1927) has been examined at the genetic (Hettema et al., 2003, Jovanovic and Ressler, 2010), synaptic (Amano et al., 2010, Myers and Davis, 2007), neurocircuitry (Rauch et al., 2006, Shin and Liberzon, 2010), and behavioral (Delamater, 2004) levels, and extensively studied in the context of anxiety in humans (Bitterman and Holtzman, 1952, Lissek et al., 2005, Milad and Quirk, 2012). Inhibitory avoidance and fear-potentiated startle paradigms also model behavioral and physiological disturbances relevant to PTSD (Grillon, 2002, Grillon and Morgan, 1999). In all these models, extinction is the learning process during which a conditioned response attenuates after repeated exposure to the conditioned stimulus in the absence of the aversive, unconditioned stimulus (Delamater, 2004, Myers and Davis, 2002).
Several findings point to the applicability of these models in the study of PTSD. Heterogeneous patterns of fear extinction learning have been observed in rats, with rates of rapid, slow, and failed extinction that mirror human trajectories of PTSD symptoms after trauma (Galatzer-Levy, Bonanno, Bush, & LeDoux, 2013). More than with any other psychiatric condition, research has linked PTSD to dysfunctional fear extinction in laboratory paradigms, coupled with impairments in brain regions that are part of the fear circuitry (Fani et al., 2012, Garfinkel et al., 2014, Inslicht et al., 2013, Milad et al., 2008, Milad et al., 2009, Norrholm et al., 2011, Orr et al., 2006, Rougemont-Bücking et al., 2011, Shvil et al., 2014, Sripada et al., 2013). Extinction deficits may be premorbid risk factors for the development of PTSD (Guthrie & Bryant, 2006). Moreover, impaired ability to extinguish fearful associations to trauma-related cues may interfere with treatment response.
In fact, the core mechanism of prolonged exposure therapy (Foa, Hembree, & Rothbaum, 2007), a first-line PTSD treatment (Powers, Halpern, Ferenschak, Gillihan, & Foa, 2010), is extinction learning through behavioral and cognitive techniques (Bouton et al., 2001, Hofmann, 2008, Rothbaum and Davis, 2003). Patients recount their trauma multiple times within sessions (i.e., imaginal exposure) and complete assignments during which avoided situations are repeatedly confronted in a gradual manner (i.e., in vivo exposure). However, some patients who benefit from this empirically-validated treatment experience the relapse of symptoms (Vervliet, Craske, & Hermans, 2013), which is consistent with the phenomenon of spontaneous recovery of conditioned fear in experimental models relevant to PTSD (Bouton et al., 2006, Rescorla, 2004). This has led to the consideration of adjunctive pharmacologic approaches for enhancing extinction learning retention during exposure therapy (Kaplan & Moore, 2011).
A potential pharmacological target for enhancing extinction learning and retention is the endogenous cannabinoid system (ECS), which includes cannabinoid receptors, endocannabinoid neurotransmitters such as anandamide, and enzymes responsible for the breakdown and reuptake of endocannabinoids (Di Marzo, Bifulco, & De Petrocellis, 2004). High densities of endocannabinoid receptors are present in the hippocampus, amygdala, and prefrontal cortex (Glass, Dragunow, & Faull, 1997)—brain regions with key roles in fear acquisition and extinction (Quirk & Mueller, 2008) that have exhibited structural and functional impairments in patients with PTSD (Admon et al., 2013, Garfinkel and Liberzon, 2009). Approaches to understanding the role of the ECS on the acquisition, consolidation, and extinction of fear responses have included the use of transgenic mice lacking cannabinoid type 1 (CB1) receptors, and pharmacological methods including administration of exogenous CB1 antagonists and agonists, and inhibitors of enzymes involved in the breakdown and reuptake of endocannabinoids.
Several reviews have examined the role of the ECS in fear-related processes, highlighting the neurobiological mechanisms derived from animal research (Akirav, 2011, Gunduz-Cinar et al., 2013a, Lutz, 2007, Ruehle et al., 2012), offering concise summaries of cannabinoid research within general expositions of several potential extinction enhancers (de Bitencourt et al., 2013, Fitzgerald et al., 2014), or examining broad therapeutic potential across mood and anxiety disorders (Hill and Patel, 2013, Micale et al., 2013, Neumeister, 2013, Rabinak and Phan, 2014) or schizophrenia (Kucerova, Tabiova, Drago, & Micale, 2014). The present review is focused on the potential role of the ECS in several distinct processes (i.e., fear expression, memory consolidation and reconsolidation, fear extinction, and extinction retention) each with potential implications for risk, early intervention, and treatment of PTSD.
Although the ECS may play a role in processes relevant to several psychiatric disorders, this review focuses on PTSD for several reasons. First, the inclusion of PTSD as one of the approved conditions for treatment with cannabis in several regions of the United States is unique among psychiatric diagnoses, necessitating a careful review of the available scientific evidence. Second, the PTSD diagnosis is unique in DSM nosology in that an etiological stressor (i.e., traumatic event) is one of the diagnostic requirements. The relative unpredictability of human trauma exposure is one of the greatest challenges of experimental research on PTSD, making the use of laboratory paradigms that model stressful events in a controlled environment particularly useful for elucidating pathophysiological mechanisms of PTSD-like symptoms, which include exaggerated reactivity to innocuous cues, avoidance behavior, emotional numbing, and hyperarousal of physiological states.
No laboratory model can fully capture the complex human response to traumatic experiences; however, work with animals and humans has linked several experimental paradigms to PTSD—a necessary step in the evaluation of the translatability of ECS manipulations within these paradigms. Toward this aim, data from animal models and preclinical studies with humans are synthesized in a critical examination of results with cautious attention to inconsistencies, potential risks, and translational value of findings to clinical application. The reviewed research is organized into three sections covering: (1) evidence of the impact of ECS dysfunction on fear-related processes; (2) the feasibility of decreasing the risk of PTSD-like symptoms by modulating endocannabinoid neurotransmission shortly after stress exposure and; (3) the potential to augment existing treatments with a pharmacologic adjunct targeting the ECS.
Section snippets
Methods and materials
A systematic search of the peer-reviewed literature was conducted on PsycINFO, PubMed, and Google Scholar utilizing the key words ‘endocannabinoid’, ‘cannabinoid’, ‘cannabis’, ‘marijuana’, and ‘CB1’ in combination with ‘fear conditioning’, ‘fear extinction’, ‘memory consolidation’, ‘reconsolidation’, ‘PTSD’, ‘inhibitory avoidance’, ‘fear-potentiated startle’, and ‘stress’. Articles from 2002 (year of first experiment in this area) to 2014 were selected that involved manipulation of the ECS in
Animal research
There is strong evidence that disruption of the ECS impairs extinction (Table 1). Genetically altered mice lacking CB1 receptors (i.e., CB1 knockout mice) have consistently demonstrated normal acquisition of conditioned freezing behavior to cues, but a significant impairment in both within-session extinction learning, and subsequent extinction retention, suggesting a critical role of CB1 receptors specific to the extinction of fear (Cannich et al., 2004, Dubreucq et al., 2012, Kamprath et al.,
Discussion
Although PTSD research has predominantly focused on individuals who have already developed the disorder, the use of conditioning and extinction paradigms with animals and, more recently, humans, has made it possible to examine neurobiological factors involved before, during, and after exposure to stress. At every stage of the process (see Fig. 1), emerging data suggest the ECS plays a key role.
First, the reviewed literature provides compelling evidence that disruption of CB1 signaling in
Disclosure statement
G. M. Sullivan has served as a consultant for Ono Pharma USA Inc. and as a consultant and scientific advisory board member for Tonix Pharmaceuticals Inc.; Y. Neria receives funding from Grand Challenges Canada, and Cambridge University Press. S. Papini, D. A. Hien, and E. Shvil report no competing interests.
Acknowledgements
S. Papini receives funding from NIDA R25DA035161-01; D. A. Hien receives funding from NIDA R01DA023187-01, U10DA13035, AA014341, and NIDA R25DA035161-01; E. Shvil receives funding from T32 MH015144-34 and NARSAD; Y. Neria receives funding from NIMH R01MH072833, NIDA R25DA035161, and NHLBI R01HL117832.
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