Cannabidiol regulation of emotion and emotional memory processing : relevance for treating anxiety-related and substance abuse disorders

Jonathan L.C. Lee, Leandro J. Bertoglio, Francisco S. Guimarães and Carl W. Stevenson

British Journal of Pharmacology, 2017, 174, 3242–3256

DOI : 10.1111/bph.13724

Abstract
Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotionalmemories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders.

LINKED ARTICLES
This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc

Introduction
Anxiety (e.g. generalized and social anxiety, panic and phobias), trauma-related [i.e. post-traumatic stress disorder (PTSD)] and substance abuse disorders are serious forms of mental illness associated with a significant lifetime prevalence. These disorders pose an enormous social and financial burden as they are often chronic in nature and inadequately treated (Di Luca et al., 2011). Certain anxiety-related disorders (e.g. phobias and PTSD) and addiction are characterized by aberrant and persistent emotional memories of fear- and drug-related stimuli. These discrete or contextual cues can trigger the emergence of symptoms or even their re-emergence after treatment, highlighting the limited effectiveness of the psychological and pharmacological therapies currently available to curtail symptom relapse over the long-term (Tronson and Taylor, 2013; Everitt, 2014; Kindt, 2014; Singewald et al., 2015). Moreover, there is also significant co-morbidity between substance abuse disorders and PTSD, which can further complicate how PTSD develops and is treated. For example, the learning and memory processes involved in the psychological therapies that are used for treating PTSD can be adversely affected by different drugs of abuse, which may also have complex drug–drug interactions with pharmacological treatments for PTSD (Tipps et al., 2014). Thus, there is an urgent need to improve the treatment of these disorders.

An area of real promise in this field involves the use of existing or novel medications as adjuncts to psychological therapies to enhance the efficacy of treatment. Cannabidiol (CBD) is one such drug that shows therapeutic potential in a broad range of neurological and psychiatric diseases (Campos et al., 2012b). This phytocannabinoid is the main non-psychotomimetic constituent of the Cannabis sativa plant, and mounting evidence indicates that CBD has anxiolytic properties (Blessing et al., 2015). Emerging preclinical and clinical evidence also indicates that CBD regulates different aversive and appetitive memory processes (Prud’homme et al., 2015; Jurkus et al., 2016), in keeping with the findings of recent studies showing a role for CBD in modulating other types of memory, such as novel object and social recognition, in cognitively-impaired animals (Fagherazzi et al., 2012; Cheng et al., 2014). In this paper, we begin with a brief historical account of the discovery of CBD and touch on the first studies that investigated its behavioural effects in rodents and humans. We then review the literature on CBD regulation of anxiety and the pharmacological and brain mechanisms involved. The bulk of the paper focuses on discussing the findings from the growing number of studies, mostly preclinical, that have examined the regulation of learned fear and, more recently, addictive drug memory processing by CBD. Importantly, these studies have used experimental procedures with clinical relevance for understanding the psychological and neurobiological mechanisms involved in the pathophysiology and treatment of anxiety-related and substance abuse disorders.

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BPH-174-3242