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.

Unraveling the Endocannabinoid System: Exploring Its Therapeutic Potential in Autism Spectrum Disorder

“…Increasing anandamide levels lessened cognitive abnormalities, while blocking amygdalar 2-AG transmission improved sociability in the rats, as demonstrated by behavioral tests (Schiavi et al, 2023 ). Considering the pivotal role of endocannabinoids in the etiopathology of ASD described in this article, it is not astonishing that researchers have investigated the therapeutic potential of certain phytocannabinoids, such as cannabidiol (Hill et al, 2023 ; Parrella et al, 2023 ; Shani Poleg et al, 2019 ). Although cannabidiol has only a weak affinity for CB1 receptors, it has been found to inhibit FAAH, which is responsible for the breakdown of AEA (Cristino et al, 2020 ; Parrella et al, 2023 ).…”

Predator odor stress reactivity, alcohol drinking and the endocannabinoid system

“…The endocannabinoid system has been implicated in modulating many aspects associated with PTSD (for review see ( Hill et al, 2023 ; Mayo et al, 2022 ; Hill et al, 2018 ; Patel et al, 2017 ; Neumeister et al, 2015 ; Lutz et al, 2015 ; Gunduz-Cinar, 2021 ; Bedse et al, 2020 )). For example, the endocannabinoid system can act as an endogenous protective or defense mechanism against stress (for review see ( Morena et al, 2016 )) by regulating stress signaling in the brain ( McLaughlin et al, 2012 ) including the balance of inhibitory and excitatory transmission during stressor exposure and allowing for appropriate cortical control of stress responses ( Fitzgerald et al, 2019 ; Kiritoshi et al, 2013 ; Rey et al, 2012 ).…”

Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs

“… 30 Inhibition of MAGL activity enhances central synaptic 2-AG-mediated phasic and tonic signaling, which has positive implications in anxiety relief, reduction of stress-induced anxiety susceptibility, and fear extinction. 31 …”