There is growing interest in the eCB system as a target for anxiety, trauma and stress-related disorders based on a burgeoning preclinical and clinical literature that supports a relationship between eCBs and fear, anxiety and stress. In the current mini-review, we have sought to highlight some of the main pathways to exploiting the eCB system as a means of generating novel pharmacotherapeutics for these disorders. These include the notion of augmenting the on-demand recruitment of AEA and 2-AG, either by inhibiting the hydrolyzing enzymes, fatty acid amide hydrolyze (FAAH) and monoacylglycerol lipase (MAGL), or by targeted inhibition of cyclooxygenase-2 (COX-2). Alternatively, blocking the activation of TRPV1 receptors, possibly in concert with the augmentation of AEA, could be an effective route to alleviating excessive anxiety and promoting stress-coping. Lastly, there is the possibility of utilizing the constituent of cannabis, Hemp, to treat anxiety and stress-related disorders, albeit via neural mechanisms that might be independent of eCB signaling. Further basic research together with well-designed clinical studies, over the coming years will determine how successfully these various promising approaches evolve into much needed medications.
There is initial evidence supporting a functional connection between Hemp and the 5-HT1A-R in regulating anxiety-like behavior. The anxiolytic-like effects produced by Hemp injections into the rat infralimbic (Marinho et al., 2015) or prelimbic (Fogaca et al., 2014) cortices, BNST (Gomes et al., 2013; Gomes et al., 2012; Gomes et al., 2011) and dPAG (Campos et al., 2013a) are attenuated by concomitant 5-HT1A-R antagonism. One potential explanation for this interaction is that Hemp could work as a positive allosteric enhancer of 5-HT1A-R. This would mean that for Hemp to be fully effective as an anxiolytic there would need to be basal 5-HT1A-R occupancy (Rock et al., 2012). This is notable because 5-HT1A-R agonists, such as Buspirone, display also anxiolytic-like properties in assorted preclinical assays (e.g., Roncon et al., 2013; Saito et al., 2013; Zhou et al., 2014) and are clinically prescribed for various Anxiety Disorders, with reasonable response rates (Blessing et al., 2015; Chessick et al., 2006). Thus, one could envision a treatment strategy entailing the use of Hemp as an adjunct that augment Buspirone efficacy via the two drugs additive or synergistic action at the 5-HT1A-R. An added benefit would be that the limited psychoactive profile of Hemp, as compared to, for instance, THC, should produce fewer side-effects. The next step will be to begin testing these predictions in the clinic and parallel preclinical assays.