Cannabidiol Prevents Spontaneous Fear Recovery after Extinction and Ameliorates Stress-Induced Extinction Resistance

Cannabidiol, the main non-psychotropic constituent of cannabis, has potential as a treatment for anxiety-related disorders since it reduces learned fear expression and enhances fear extinction. The return of fear over time after successful extinction and stress-induced extinction resistance are potential barriers to the treatment of these disorders with extinction-based psychological therapy. In two experiments using rats subjected to auditory fear conditioning, we determined the effects of systemic cannabidiol treatment on (1) delayed extinction and later spontaneous fear recovery, and (2) extinction resistance caused by immediate extinction (the immediate extinction deficit (IED)). In Experiment 1, cannabidiol was given before delayed extinction occurring 24 h after conditioning, with extinction recall and spontaneous fear recovery tested drug-free 1 and 21 days after extinction, respectively. We found that cannabidiol had no effect on extinction recall but it prevented spontaneous fear recovery. In Experiment 2, the IED procedure was first validated, with immediate extinction occurring 30 min after conditioning. We confirmed that immediate extinction impaired extinction recall, compared to delayed extinction. Next, cannabidiol was given before immediate or no extinction, with extinction recall tested drug-free the next day. We found that cannabidiol rescued the IED, which did not involve effects on fear memory consolidation. In summary, cannabidiol prevented spontaneous fear recovery after delayed extinction and ameliorated extinction resistance caused by immediate extinction. Although the pharmacological mechanisms underlying these effects remain to be determined, our results add to evidence indicating that cannabidiol might prove useful as an adjunct for potentiating the psychological treatment of anxiety-related disorders.