Cannabinoid facilitation of fear extinction memory recall in humans

Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA. Electronic address: .
Neuropharmacology (Impact Factor: 4.82). 07/2012; 64(1):396-402. DOI: 10.1016/j.neuropharm.2012.06.063
Source: PubMed

ABSTRACT 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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    • "Recently, several pharmacological agents have been proposed as boosters of exposure therapy (Bentz, Michael, de Quervain, & Wilhelm, 2010; Vervliet, 2008). These new therapeutic approaches are based on the idea that the pharmacological agents facilitate the learning processes underlying the success of exposure therapy (Hofmann, Pollack, & Otto, 2006; Otto, Basden, Leyro, McHugh, & Hofmann, 2007; Rabinak et al., 2013). One agent that has been suggested to improve exposure therapy is cortisol. "
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    ABSTRACT: Previous research in patients with phobia showed that the administration of glucocorticoids reduces fear in phobic situations and enhances exposure therapy. Glucocorticoids underlie a daily cycle with a peak in the morning and low levels during the evening and night. The aim of the present study was to investigate whether exposure is more effective when conducted in the morning when endogenous cortisol levels are high. Sixty patients meeting DSM IV criteria for specific phobia (animal type) were randomly assigned to one-session exposure treatment either at 08.00 a.m. (high cortisol group) or at 06.00 p.m. (low cortisol group). Participants returned for a posttreatment assessment one week after therapy and a follow-up assessment three months after therapy. Both groups showed good outcome, but patients treated in the morning exhibited significantly less fear of spiders in the behavioral approach test (BAT) and a trend for lower scores on the Fear of Spiders Questionnaire (FSQ) than patients treated in the evening. This effect was present at posttreatment and follow-up. Our findings indicate that exposure therapy is more effective in the morning than in the evening. We suggest that this may be due to higher endogenous cortisol levels in the morning group that enhance extinction memory.
    Behaviour Research and Therapy 09/2014; 60. DOI:10.1016/j.brat.2014.06.009 · 3.85 Impact Factor
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    • "There have been various attempts to enhance extinction memory via either pharmacological or behavioral manipulations. The approaches which probably received the most attention involve the partial N-methyl-D-aspartate (NMDA) receptor agonist D-cycloserine (DCS), which has been shown to enhance exposure therapy of anxiety disorders (Ressler et al., 2004; Guastella et al., 2008; Norberg et al., 2008), the endocannabinoid system (de Bitencourt et al., 2013; Rabinak et al., 2013) and the reactivation-extinction approach, in which reactivation of the to be extinguished memory is supposed to render this memory "
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    ABSTRACT: Extinction is not always permanent, as indicated by several types of recovery effects, such as the renewal effect, which may occur after a context change and points towards the importance of contextual cues. Strengthening the retrieval of extinction memory is a crucial aim of extinction-based psychotherapeutic treatments of anxiety disorders to prevent relapse. Stress is known to modulate learning and memory, with mostly enhancing effects on memory consolidation. However, whether such a consolidation-enhancing effect of acute stress can also be found for extinction memory has not yet been examined in humans. In this study, we investigated the effect of stress after extinction learning on the retrieval of extinction memory in a predictive learning renewal paradigm. Participants took the part of being the doctor of a fictitious patient and learned to predict whether certain food stimuli were associated with "stomach trouble" in two different restaurants (contexts). On the first day, critical stimuli were associated with stomach trouble in context A (acquisition phase). On the second day, these associations were extinguished in context B. Directly after extinction, participants were either exposed to a stressor (socially evaluated cold pressor test; n = 22) or a control condition (n = 24). On the third day, we tested retrieval of critical associations in contexts A and B. Participants exposed to stress after extinction exhibited a reduced recovery of responding at test in context B, suggesting that stress may context-dependently enhance the consolidation of extinction memory. Furthermore, the increase in cortisol in response to the stressor was negatively correlated with the recovery of responding in context A. Our findings suggest that in parallel to the known effects of stress on the consolidation of episodic memory, stress also enhances the consolidation of extinction memory, which might be relevant for potential applications in extinction-based psychotherapy.
    Frontiers in Behavioral Neuroscience 08/2013; 7:108. DOI:10.3389/fnbeh.2013.00108 · 4.16 Impact Factor
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    • "In addition to the recreational actions of Cannabis, many anecdotal reports from patients attest its acute antidepressant, anxiolytic and stress-relieving effects, which were recently further supported in a controlled clinical study showing that the synthetic Δ 9 -THC, dronabinol, facilitated fear extinction (Grinspoon & Bakalar, 1998; Iversen, 2003; Ashton et al., 2005; Rabinak et al., 2013). On the other hand, a biphasic effect of cannabinoids in humans, which has already been shown in rodents (Sulcova et al., 1998), is supported by several data since high doses or rapid administration of Δ 9 -THC as well as chronic Cannabis use are associated with transient psychotic syndrome, panicogenisis and bipolar disorders, which could be due to the Δ 9 -THC capacity to modulate several neurotransmitter systems (Piomelli, 2003). "
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    ABSTRACT: The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol [Δ(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.
    Pharmacology [?] Therapeutics 12/2012; 138(1). DOI:10.1016/j.pharmthera.2012.12.002 · 7.75 Impact Factor
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