Cannabinoid facilitation of fear extinction memory recall in humans

Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA. Electronic address: .
Neuropharmacology (Impact Factor: 5.11). 07/2012; 64(1):396-402. DOI: 10.1016/j.neuropharm.2012.06.063
Source: PubMed


A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 h prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 h after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 h after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

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    • "Indeed, presentation of negative stimuli (pictures of fearful faces) reduces activity in neural structures such as the amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, PFC and regions in the occipital cortex following acute THC exposure, whereas presentation of positive stimuli (pictures of happy faces) increases activity within that network (Bossong et al. 2013). Furthermore, THC facilitates extinction of learned fear in humans and increases activation in the ventromedial PFC and hippocampus upon presentation of the CS relative to subjects that received a placebo (Rabinak et al. 2013, 2014). Cannabidiol, a non-psychoactive cannabinoid found in cannabis, has also been found to enhance consolidation of fear extinction (Das et al. 2013). "
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    ABSTRACT: The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic endocannabinoid signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that endocannabinoid signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic endocannabinoid signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the endocannabinoid system and discuss clinical and rodent models demonstrating endocannabinoid regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the endocannabinoid system in the central nervous system, and models of pharmacological augmentation of endocannabinoid signaling during development in the context of fear learning and anxiety.
    Genes Brain and Behavior 09/2015; DOI:10.1111/gbb.12253 · 3.66 Impact Factor
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    • "The next day, participants were treated with placebo or dronabinol 2 h prior to an extinction session. Those treated with dronabinol had less reinstatement of fear responding 24 h later relative to the placebo group (Rabinek et al, 2013). "
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    ABSTRACT: There have been extensive policy shifts in the legality of recreational and therapeutic use of cannabis in the US, as well as a steady increase in the number of people using the drug on a regular basis. Given these rapid societal changes, defining what is known scientifically about the consequences of cannabis use on mental health takes on added public health significance. The purpose of this Circumspectives piece is to discuss evidence of cannabis' effects on two psychiatric conditions: post-traumatic stress disorder (PTSD) and psychotic disorders. Dr Haney and Dr Evins will discuss two viewpoints regarding the benefit and harm of cannabis use for these conditions, while outlining what remains unproven and requires further testing in order to move the field forward.Neuropsychopharmacology accepted article preview online, 19 August 2015. doi:10.1038/npp.2015.251.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2015; DOI:10.1038/npp.2015.251 · 7.05 Impact Factor
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    • "The primary psychoactive ingredient in cannabis, Δ 9 tetrahydrocannabinol (THC), binds to CB 1 receptors in the brain and produces a variety of acute effects, including subjective feelings of sedation and euphoria (Johns, 2001). Consistent with the role of the endogenous cannabinoid system in the regulation of anxiety and fear learning (Chhatwal and Ressler, 2007), THC and other CB 1 agonists have also been shown to modulate subjective anxiety (Wachtel et al., 2002) and facilitate the extinction of fear responses (Rabinak et al., 2013). The effects of THC on anxiety and fear may be due to changes in amygdala reactivity. "
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    ABSTRACT: Δ(9)-tetrahydrocannabinol (THC) has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex (PFC) is implicated in affective processes, it is possible that THC affects amygdala-PFC functional connectivity, in ways that differ across amygdala subregions: basolateral (AMYG-BL), centromedial (AMYG-CM), and superficial (AMYG-SF). The aim of the study was to examine the effects of THC on functional connectivity between amygdala subregions and the PFC during socio-emotional threat in healthy adults using a double-blind, placebo-controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging (fMRI) task designed to probe amygdala responses to social threat. Amygdala subregion-PFC functional connectivity was compared between THC and placebo using generalized psychophysiological interaction (gPPI) analyses. Findings indicated that THC enhanced AMYG-BL and AMYG-SF connectivity to the rostral anterior cingulate/medial PFC. These effects, including THC's potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect. Published by Oxford University Press on behalf of CINP 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    The International Journal of Neuropsychopharmacology 12/2014; 18(3). DOI:10.1093/ijnp/pyu104 · 4.01 Impact Factor
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