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Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders

View Article: PubMed Central - PubMed

ABSTRACT

Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.

No MeSH data available.


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(A) The chemical structure of CBD (National Center for Biotechnology Information, 2016). (B) The different phases of fear memory. In the hours after its acquisition fear memory undergoes consolidation. After a short duration of retrieval, fear memory can become destabilized, after which it undergoes reconsolidation to maintain or update the memory. With longer retrieval and/or repeated exposures extinction can occur, resulting in the acquisition and consolidation of a new extinction memory which competes with the original memory to inhibit fear expression. (C) A summary of the effects of acute CBD administration on different contextual fear memory processes. CBD reduces learned fear expression, disrupts fear memory reconsolidation, and facilitates fear extinction.
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Figure 1: (A) The chemical structure of CBD (National Center for Biotechnology Information, 2016). (B) The different phases of fear memory. In the hours after its acquisition fear memory undergoes consolidation. After a short duration of retrieval, fear memory can become destabilized, after which it undergoes reconsolidation to maintain or update the memory. With longer retrieval and/or repeated exposures extinction can occur, resulting in the acquisition and consolidation of a new extinction memory which competes with the original memory to inhibit fear expression. (C) A summary of the effects of acute CBD administration on different contextual fear memory processes. CBD reduces learned fear expression, disrupts fear memory reconsolidation, and facilitates fear extinction.

Mentions: A promising area of research in this field focuses on repurposing existing and developing novel drugs to enhance the effectiveness of psychological therapies in alleviating fear-related symptoms (Myers and Davis, 2007; Steckler and Risbrough, 2012). One drug showing broad therapeutic potential in various psychiatric diseases is cannabidiol (CBD), the main non-psychotropic constituent of the Cannabis sativa plant (Izzo et al., 2009; see chemical structure of CBD in Figure 1A). Studies in humans demonstrate the promise of CBD for treating anxiety (Blessing et al., 2015) and preclinical studies in rodents are elucidating the pharmacological mechanisms underlying its acute anxiolytic effects. These mechanisms include potentiation of serotonin (5-HT) transmission via 5-HT1A receptor (5-HT1AR) activation and elevation of endocannabinoid levels via inhibition of their metabolism and re-uptake, which indirectly facilitates cannabinoid receptor type1 (CB1R) activation (for a review see Campos et al., 2016).


Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders
(A) The chemical structure of CBD (National Center for Biotechnology Information, 2016). (B) The different phases of fear memory. In the hours after its acquisition fear memory undergoes consolidation. After a short duration of retrieval, fear memory can become destabilized, after which it undergoes reconsolidation to maintain or update the memory. With longer retrieval and/or repeated exposures extinction can occur, resulting in the acquisition and consolidation of a new extinction memory which competes with the original memory to inhibit fear expression. (C) A summary of the effects of acute CBD administration on different contextual fear memory processes. CBD reduces learned fear expression, disrupts fear memory reconsolidation, and facilitates fear extinction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121237&req=5

Figure 1: (A) The chemical structure of CBD (National Center for Biotechnology Information, 2016). (B) The different phases of fear memory. In the hours after its acquisition fear memory undergoes consolidation. After a short duration of retrieval, fear memory can become destabilized, after which it undergoes reconsolidation to maintain or update the memory. With longer retrieval and/or repeated exposures extinction can occur, resulting in the acquisition and consolidation of a new extinction memory which competes with the original memory to inhibit fear expression. (C) A summary of the effects of acute CBD administration on different contextual fear memory processes. CBD reduces learned fear expression, disrupts fear memory reconsolidation, and facilitates fear extinction.
Mentions: A promising area of research in this field focuses on repurposing existing and developing novel drugs to enhance the effectiveness of psychological therapies in alleviating fear-related symptoms (Myers and Davis, 2007; Steckler and Risbrough, 2012). One drug showing broad therapeutic potential in various psychiatric diseases is cannabidiol (CBD), the main non-psychotropic constituent of the Cannabis sativa plant (Izzo et al., 2009; see chemical structure of CBD in Figure 1A). Studies in humans demonstrate the promise of CBD for treating anxiety (Blessing et al., 2015) and preclinical studies in rodents are elucidating the pharmacological mechanisms underlying its acute anxiolytic effects. These mechanisms include potentiation of serotonin (5-HT) transmission via 5-HT1A receptor (5-HT1AR) activation and elevation of endocannabinoid levels via inhibition of their metabolism and re-uptake, which indirectly facilitates cannabinoid receptor type1 (CB1R) activation (for a review see Campos et al., 2016).

View Article: PubMed Central - PubMed

ABSTRACT

Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.

No MeSH data available.


Related in: MedlinePlus