The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses

Abstract

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.

Keywords: Anxiety; CB1; FAAH; MAGL; PTSD; autism; cannabis; endocannabinoid; psychiatric illness; substance use disorder.

Figure 1.

Pharmacotherapeutic targets of the endocannabinoid system. A schematic showing potential therapeutic targets of the endocannabinoid system in the central nervous system displayed in their pre- and postsynapse localization in neurons (this is not to say that central mechanisms of action could also occurs through nonneuronal cell types). Compounds include: CB1R orthosteric targets (including agonists and antognists), CB1R modulators (signaling specific inhibitors, PAMs and NAMs), FAAH inhibitors, MAGL inhibitors, FABP inhibitors and membrane transporter inhibitors. CB1R-cannabinoid receptor type 1; PAM-positive allosteric modulator; NAMnegative allosteric modulator; FAAH-fatty acid amide hydrolase; MAGL-monoacylglycerol lipase; FABP-fatty acid binding protein. Created in Biorender.