Cannabinoids and the endocannabinoid system in reward processing and addiction: from mechanisms to interventions

Abstract

The last decades have seen a major gain in understanding the action of cannabinoids and the endocannabinoid system in reward processing and the development of addictive behavior. Cannabis-derived psychoactive compounds such as Δ9-tetrahydrocannabinol and synthetic cannabinoids directly interact with the reward system and thereby have addictive properties. Cannabinoids induce their reinforcing properties by an increase in tonic dopamine levels through a cannabinoid type 1 (CB1 ) receptor–dependent mechanism within the ventral tegmental area. Cues that are conditioned to cannabis smoking can induce drug-seeking responses (ie, craving) by eliciting phasic dopamine events. A dopamine-independent mechanism involved in drug-seeking responses involves an endocannabinoid/glutamate interaction within the corticostriatal part of the reward system. In conclusion, pharmacological blockade of endocannabinoid signaling should lead to a reduction in drug craving and subsequently should reduce relapse behavior in addicted individuals. Indeed, there is increasing preclinical evidence that targeting the endocannabinoid system reduces craving and relapse, and allosteric modulators at CB1 receptors and fatty acid amide hydrolase inhibitors are in clinical development for cannabis use disorder. Cannabidiol, which mainly acts on CB1 and CB2 receptors, is currently being tested in patients with alcohol use disorder and opioid use disorder.

The Impact of Cannabidiol on Human Brain Function: A Systematic Review

“…Based on a mechanistic account of these networks, these findings suggest that CBD might prove useful as treatment by restoring imbalanced networks in these and probably other neurological ( Nenert et al, 2020 ) and psychiatric conditions, such as substance use disorders ( Freeman et al, 2020 ). Regarding the last, converging preclinical and clinical evidence have shown promising effects of CBD on reducing craving, negative affect and motivation for substance use ( Chye et al, 2019 ; Hurd et al, 2019 ; Freeman et al, 2020 ; Spanagel, 2020 ), phenomena associated with fronto-striatal and limbic network disbalances ( Koob and Volkow, 2016 ; Volkow and Boyle, 2018 ).…”

Co-exposure of cannabinoids with amphetamines and biological, behavioural and health outcomes: a scoping review of animal and human studies

“…This situation underscores a need for the examination of potentially effective therapeutic strategies or interventions for psychostimulant and specifically problematic amphetamine use or use disorders (Fischer et al 2015b ; Kogan and Mechoulam 2007 ; Shorter et al 2015 ). Recently, there has been increased focus on the endocannabinoid system as a possible target for treating drug dependence, craving or withdrawal (Chye et al 2019 ; Manzanares et al 2018 ; Parsons and Hurd 2015 ; Spanagel 2020 ), with a growing number of studies examining the therapeutic effects of cannabinoid agents for addictive disorders (Batalla et al 2019 ; Calpe-López et al 2019 ; Prud'homme et al 2015 ; Turna et al 2019 ).…”

“…serotonin, dopamine) essential in the reward system and drug addiction. Of special interest is the role of CB1 receptors, expressed in brain regions involved in decision-making, withdrawal and relapse, and therefore, essential for modulating the rewarding effects of drugs (Chye et al 2019 ; Maldonado et al 2006 ; Manzanares et al 2018 ; Parsons and Hurd 2015 ; Spanagel 2020 ). Moreover, there is increasing evidence and practice of medical usage for some indications (e.g.…”

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…CB 1 receptors are mainly located in the central nervous system, thus covering most of the psychoactive effects of SCRAs. Due to the distribution of CB 1 and CB 2 receptors on the terminals of neuron, which mediate a modulation and inhibition of synaptic transmission, cannabinoids have effects on neuronal development, motor function, cognition, and memory, appetite, sleep, thermoregulation, analgesia, reward processes, cardiovascular, respiratory, immune, and reproductive functions [ 7 , 52 , 53 , 54 , 55 ]. Reward, euphoria, memory loss, altered vigilance, anxiety and cognitive deficit, proconvulsant, antinociceptive, cataleptic, hypolocomotion, and hypothermic effects of SCRAs, such as JWH-018, JWH-073, 5F-AMB, 5F-AB-PINACA, and Cumyl-4CN-BINACA, are mediated by CB 1 receptor activation, as demonstrated in CB 1 knock-out mice or by CB 1 -blocking agents [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ].…”