Elsevier

Biological Psychology

Volume 104, January 2015, Pages 8-18
Biological Psychology

Review article
Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: A critical review of preclinical research

https://doi.org/10.1016/j.biopsycho.2014.10.010Get rights and content

Highlights

  • The endocannabinoid system (ECS) plays a crucial role in the fear circuitry.

  • We reviewed preclinical animal and human research with implications for PTSD.

  • Disruption of the ECS in rodents consistently impaired fear extinction and retention.

  • Targeting the ECS to block consolidation or reconsolidation yielded mixed results.

  • ECS agonism facilitates extinction in rodents, but human data are inconsistent.

Abstract

Despite the lack of clinical research, marijuana and synthetic cannabinoids have been approved to treat posttraumatic stress disorder (PTSD) in several states in the United States. This review critically examines preclinical research on the endocannabinoid system (ECS) in order to evaluate three key questions that are relevant to PTSD: (1) Does ECS dysfunction impact fear extinction? (2) Can stress-related symptoms be prevented by ECS modulation? (3) Is the ECS a potential target for enhancing PTSD treatment? Disruption of the ECS impaired fear extinction in rodents, and ECS abnormalities have been observed in PTSD. Targeting fear memories via the ECS had mixed results in rodents, whereas augmented cannabinoid receptor activation typically facilitated extinction. However, the translational value of these findings is limited by the paucity and inconsistency of human research. Further investigation is necessary to determine whether incorporating cannabinoids in treatment would benefit individuals with PTSD, with cautious attention to risks.

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.

References (154)

  • F.H. Do Monte et al.

    Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors

    Behavioural Brain Research

    (2013)
  • P.J. Fitzgerald et al.

    Can fear extinction be enhanced? A review of pharmacological and behavioral findings

    Brain Research Bulletin

    (2014)
  • E. Ganon-Elazar et al.

    Cannabinoids and traumatic stress modulation of contextual fear extinction and gr expression in the amygdala–hippocampal–prefrontal circuit

    Psychoneuroendocrinology

    (2013)
  • B.P. Genro et al.

    Role of trpv1 in consolidation of fear memories depends on the averseness of the conditioning procedure

    Neurobiology of Learning and Memory

    (2012)
  • M. Glass et al.

    Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain

    Neuroscience

    (1997)
  • C. Grillon

    Startle reactivity and anxiety disorders: Aversive conditioning, context, and neurobiology

    Biological Psychiatry

    (2002)
  • O. Gunduz-Cinar et al.

    Amygdala faah and anandamide: Mediating protection and recovery from stress

    Trends in Pharmacological Sciences

    (2013)
  • S.G. Hofmann

    Cognitive processes during fear acquisition and extinction in animals and humans: Implications for exposure therapy of anxiety disorders

    Clinical Psychology Review

    (2008)
  • S.S. Inslicht et al.

    Sex differences in fear conditioning in posttraumatic stress disorder

    Journal of Psychiatric Research

    (2013)
  • W. Jacob et al.

    Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo

    Neurobiology of Learning and Memory

    (2012)
  • G.B. Kaplan et al.

    The use of cognitive enhancers in animal models of fear extinction

    Pharmacology, Biochemistry and Behavior

    (2011)
  • S. Kuhnert et al.

    Involvement of cannabinoid receptors in the amygdala and prefrontal cortex of rats in fear learning, consolidation, retrieval and extinction

    Behavioural Brain Research

    (2013)
  • D. Laricchiuta et al.

    Effects of endocannabinoid and endovanilloid systems on aversive memory extinction

    Behavioural Brain Research

    (2013)
  • Q.S. Lin et al.

    Hippocampal endocannabinoids play an important role in induction of long-term potentiation and regulation of contextual fear memory formation

    Brain Research Bulletin

    (2011)
  • S. Lissek et al.

    Classical fear conditioning in the anxiety disorders: A meta-analysis

    Behaviour Research and Therapy

    (2005)
  • M. Maćkowiak et al.

    Activation of CB1 cannabinoid receptors impairs memory consolidation and hippocampal polysialylated neural cell adhesion molecule expression in contextual fear conditioning

    Neuroscience

    (2009)
  • V. Micale et al.

    Endocannabinoid system and mood disorders: Priming a target for new therapies

    Pharmacology and Therapeutics

    (2013)
  • M.R. Milad et al.

    Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study

    Journal of Psychiatry Research

    (2008)
  • M.R. Milad et al.

    Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder

    Biological Psychiatry

    (2009)
  • K. Mishima et al.

    Characteristics of learning and memory impairment induced by delta9-tetrahydrocannabinol in rats

    Japanese Journal of Pharmacology

    (2001)
  • N.L. Moore et al.

    Adolescent traumatic stress experience results in less robust conditioned fear and post-extinction fear cue responses in adult rats

    Pharmacology Biochemistry and Behavior

    (2014)
  • T.H. Moore et al.

    Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review

    Lancet

    (2007)
  • H. Abush et al.

    Cannabinoids modulate hippocampal memory and plasticity

    Hippocampus

    (2010)
  • I. Akirav

    The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus

    Frontiers in Behavioral Neuroscience

    (2011)
  • T. Amano et al.

    Synaptic correlates of fear extinction in the amygdala

    Nature Neuroscience

    (2010)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (2013)
  • P. Atsak et al.

    Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

    Proceedings of the National Academy of Sciences

    (2012)
  • M. Bitterman et al.

    Conditioning and extinction of the galvanic skin response as a function of anxiety

    Journal of Abnormal and Social Psychology

    (1952)
  • M. Bouton et al.

    A modern learning theory perspective on the etiology of panic disorder

    Psychological Review

    (2001)
  • M.E. Bowers et al.

    Interaction between the cholecystokinin and endogenous cannabinoid systems in cued fear expression and extinction retention

    Neuropsychopharmacology

    (2014)
  • N. Breslau

    The epidemiology of trauma, PTSD, and other posttrauma disorders

    Trauma, Violence, & Abuse

    (2009)
  • C. Bucherelli et al.

    Aversive memory reactivation engages in the amygdala only some neurotransmitters involved in consolidation

    Learning and Memory

    (2006)
  • P. Campolongo et al.

    Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    Proceedings of the National Academy of Sciences

    (2009)
  • A. Cannich et al.

    CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice

    Learning and Memory

    (2004)
  • J.P. Chhatwal et al.

    Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear

    Neuropsychopharmacology

    (2005)
  • J.P. Chhatwal et al.

    Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning

    Neuropsychopharmacology

    (2009)
  • J.A. Crippa et al.

    Cannabis and anxiety: A critical review of the evidence

    Human Psychopharmacology

    (2009)
  • R.K. Das et al.

    Cannabidiol enhances consolidation of explicit fear extinction in humans

    Psychopharmacology

    (2013)
  • M. Davis

    Neural systems involved in fear and anxiety measured with fear-potentiated startle

    American Psychologist

    (2006)
  • A.R. Delamater

    Experimental extinction in pavlovian conditioning: Behavioural and neuroscience perspectives

    Quarterly Journal of Experimental Psychology. B: Comparative and Physiological Psychology

    (2004)
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