Cannabinoids: Revealing their complexity and role in central networks of fear and anxiety.

The first aim of the present review is to provide an in-depth description of the cannabinoids and their known effects at various neuronal receptors. It reveals that cannabinoids are highly diverse, and recent work has highlighted that their effects on the central nervous system (CNS) are surprisingly more complex than previously recognized. Cannabinoid-sensitive receptors are widely distributed throughout the CNS where they act as primary modulators of neurotransmission. Secondly, we examine the role of cannabinoid receptors at key brain sites in the control of fear and anxiety. While our understanding of how cannabinoids specifically modulate these networks is mired by their complex interactions and diversity, a plausible framework(s) for their effects is proposed. Finally, we highlight some important knowledge gaps in our understanding of the mechanism(s) responsible for their effects on fear and anxiety in animal models and their use as therapeutic targets in humans. This is particularly important for our understanding of the phytocannabinoids used as novel clinical interventions.