Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that develops in a subset of people following a traumatic event. Exposure-based psychological treatments and antidepressants are the current first-line treatments for PTSD symptoms. However, many patients fail to receive effective treatments, drop out treatments, or are non-responsive to existing treatments (Watts et al, 2013), highlighting an urgent unmet need to develop novel therapeutics. Part of the challenge in developing effective therapies has been the biological heterogeneity in PTSD pathophysiology. ‘Broad-spectrum’ therapies such as antidepressants and standardized exposure therapies may not account for the biological diversity of the underlying deficits in neurotransmitter mechanisms, stress resiliency, and learning deficits.

One of the novel targets that has emerged as being involved in PTSD with strong preclinical and human data is the endocannabinoid system. The endocannabinoid system includes two principal cannabinoid receptors (CB1R and CB2R), their several endogenous ligands, including the two key ligands anandamide and 2- arachidonoylglycerol (2-AG), and enzymes responsible for endocannabinoid biosynthesis and inactivation. Although there are some conflicting findings, perhaps due to differences in experimental conditions, preclinical studies of fear disorder models generally support the concept that selective agonists of CB1R facilitate fear extinction. Subjects with PTSD are reported to have significantly lower CB1R availability and reduced peripheral concentration of anandamide (Pietrzak et al, 2014; Neumeister et al, 2015) and appears to be associated with threat processing in trauma survivors (Pietrzak et al, 2014). These data suggest that low anandamide levels and upregulation of endocannabinoid receptors in the amygdale-hippocampal-cortico-striatal circuitry could result in the enhanced reactivity to threat stimuli, and endogenous cannabinoid would ameliorate such responses (Neumeister et al, 2015).

Despite this strong mechanistic rationale, utilizing direct agonists of CB1R receptors has several disadvantages. The CB1 receptors regulate many opposing functions in brain, especially in the regulation of fear regulation circuitry and downregulation of receptors are seen after chronic exposure to agonists. Agonists could also have adverse effects from off-target CB1 activation. Therefore, alternative approaches to augment endocannabinoid signaling need to be explored. One such promising approach is through inhibition of fatty acid amide hydrolase (FAAH) involved in endocannabinoid catabolism that would increase the availability of endogenously generated endocannabinoids (Gunduz-Cinar et al, 2013).

A second approach is to utilize positive allosteric modulators (PAMs) that selectively increase the CB1R effects. CB1R has allosteric sites spatially distinct from the orthosteric ligand-binding pocket, and engagement of CB1R by allosteric modulators induce a conformational change in the receptor that may be difficult to achieve with orthosteric ligands alone and thus one can ‘fine-tune’ the pharmacological activity of the endogenous ligand. Such compounds could offer not only enhanced CB1R selectivity, but also reduced receptor downregulation and inter-receptor promiscuity (Kulkarni et al, 2016). One such compound GAT211 increases CB1R effects, demonstrates good efficacy in rodent models of chronic pain without demonstrating acute tolerance, rewarding properties or dependence (Slivicki et al, 2017). Our preliminary data show that GAT211 also enhances fear extinction in auditory cue-induced fear conditioning model and could potentially provide a novel approach to PTSD drug development.

Funding and Disclosure

The work was supported by National Institutes of Health grants MH52619 to AS and DA027113 and EY024717 to G.A.T. GAT is a co-inventor on the patents filed by Northeastern University for the CB1 PAMS. The remaining author declares no conflict of interest.