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

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.

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

“…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 , ). Emerging preclinical and clinical evidence also indicates that CBD regulates different aversive and appetitive memory processes (Prud'homme et al , ; Jurkus et al , ), 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 , ; Cheng et al , ). 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.…”

“…As alluded to above, there is growing evidence indicating that CBD also regulates learned fear (see Table ). Systemic CBD administration has been shown to reduce the expression of fear memory when given acutely (Zuardi and Karniol, ; Resstel et al , ; Lemos et al , ; Jurkus et al , ). CBD has also been reported to impair the acquisition of fear learning; acute systemic administration before fear conditioning resulted in attenuated fear expression during later memory retrieval testing (Levin et al , ).…”

“…CBD impaired extinction after weak conditioning but enhanced extinction after strong conditioning (Song et al , ). However, CBD given systemically before auditory fear extinction reduced fear expression acutely without affecting extinction memory (Jurkus et al , ). Interestingly, a study in humans also showed that CBD had no effect on the extinction of visual fear memory when given before extinction, but it did enhance extinction memory when given immediately after extinction (Das et al , ).…”

Optimization of recombinant β‐glucuronidase hydrolysis and quantification of eight urinary cannabinoids and metabolites by liquid chromatography tandem mass spectrometry

“…Furthermore, CBD was proposed as pharmacotherapy for the treatment of several diseases including cancer, epilepsy, cerebral ischemia, multiple sclerosis, anxiety, and trauma-related and psychiatric disorders. [22][23][24][25][26][27][28] Measuring CBD in urine would be a useful tool to monitor compliance with prescribed therapy.…”

Cannabidiol provides viable treatment opportunity for multiple neurological pathologies of autism spectrum disorder

“…Acute CBD treatment also protected against hippocampal cell death and improved cognition in mouse models of ischemia and cerebral malaria [41,42]. CBD can also reduce learned fear by decreasing fear expression, disrupting memory reconsolidation, and enhancing extinction in contextual fear memory paradigm as shown in a study involving mice [43]. These findings suggest CBD holds therapeutic potentials for ASD-related behavioral abnormalities.…”