Cannabinoids and the endocannabinoid system in reward processing and addiction: from mechanisms to interventions, Rainer Spanagel, 2020

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

Rainer Spanagel, PhD

Dialogues in Clinical Neuroscience, 2020, 22, (3), 241-250.

doi : 10.31887/DCNS.2020.22.3/rspanagel


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.

Keywords : addiction; alcohol; cannabinoid; CB1/CB2-receptor blockade; cocaine; craving; drug reward; endocannabinoid system; heroin; natural reward; nicotine; phasic dopamine; reward system; substitution therapy; tonic dopamine



The endocannabinoid system is comprised of cannabinoid CB1 and CB2 receptors and endogenous agonists of these receptors—so-called endocannabinoids—and the processes playing a role in biosynthesis, release, transport, and metabolism of these endogenous lipid-signaling molecules. Endocannabinoids such as anandamide and 2-arachidonylglycerol (2-AG) are highly lipophilic compounds that are not stored in vesicles after production. After their release on demand from depolarized postsynaptic neurons, endocannabinoids act retrogradely, activating CB1 receptors on presynaptic terminals, leading to either transient endocannabinoid-mediated short-term depression or long-term depression (LTD) of synaptic transmission.1 Their overall effect is either excitatory or inhibitory depending on the presynaptic inhibition of GABA or glutamatergic transmission. This powerful modulatory action on synaptic transmission of the main transmitter systems has significant functional implications on many physiological functions including reward processing. The last decades have seen a major gain in understanding the involvement of the endocannabinoid system in reward processing and development of addictive behavior.2