Review
Review of the Endocannabinoid System

https://doi.org/10.1016/j.bpsc.2020.07.016Get rights and content

Abstract

The endocannabinoid system (ECS) is a widespread neuromodulatory network involved in the developing central nervous system as well as playing a major role in tuning many cognitive and physiological processes. The ECS is composed of endogenous cannabinoids, cannabinoid receptors, and the enzymes responsible for the synthesis and degradation of endocannabinoids. In addition to its endogenous roles, cannabinoid receptors are the primary target of Δ9-tetrahydrocannabinol, the intoxicating component of cannabis. In this review, we summarize our current understanding of the ECS. We start with a description of ECS components and their role in synaptic plasticity and neurodevelopment, and then discuss how phytocannabinoids and other exogenous compounds may perturb the ECS, emphasizing examples relevant to psychosis.

Section snippets

Cannabinoid Receptors

CB1 and CB2 are the best-characterized cannabinoid receptors. Both are G protein–coupled receptors (GPCRs), primarily coupling to inhibitory G proteins. They inhibit adenylyl cyclase and certain voltage-sensitive calcium channels, stimulate MAP (mitogen-activated protein) kinases and inwardly rectifying potassium channels (GIRKs), and recruit beta-arrestins, among other actions (7). The diversity of CB1 signaling is enhanced by their propensity to heterodimerize with other GPCRs, including

Signaling

As mentioned above, CB1 and CB2 receptors primarily couple to inhibitory G proteins (Gi/o) and engage the pathways associated with Gi/o (7). CB1 and CB2 receptors also recruit beta-arrestins and signal through arrestin-dependent pathways (30,31). Under some conditions, cannabinoid receptors can also stimulate cAMP (cyclic adenosine monophosphate) formation and engage Gq/11 pathways (32,33). Interestingly, astrocyte CB1 receptors strongly couple to Gq/11 (16). Like all GPCRs, CB1 and CB2

Allosteric Modulation

THC and the eCBs interact with CB1 and CB2 receptors at their orthosteric sites. However, the large size of GPCRs gives ample opportunity for sites where other molecules can bind and, under favorable conditions, modulate the function of the receptor. While not much is known about allosteric modulation of CB2 receptors, several positive and negative allosteric modulators of CB1 receptors have been described. Classically, allosteric modulators may affect the kinetics of orthosteric ligand

Multimerization and Cannabinoid Receptor–Interacting Proteins

Like most GPCRs (53), cannabinoid receptors can associate with other GPCRs, a process termed dimerization or multimerization. Association of cannabinoid receptors with other GPCRs has the potential to greatly enrich their signaling repertoire. While both CB1 and CB2 receptors have been found to associate with other GPCRs (54,55), this has been more widely studied with CB1 receptors. Prominent association partners of CB1 receptors include dopamine D2 receptors (56,57), orexin A receptors (58),

Endocannabinoids

Narrowly defined, endogenous cannabinoids (eCBs) are signaling lipids that activate cannabinoid receptors. While 2-AG (72, 73, 74) and anandamide (AEA [N-arachidonoyl ethanolamine]) (75) are the two best known eCBs, other structurally related lipids also engage cannabinoid receptors [e.g., N-arachidonoyl dopamine (76)]. Conversely, 2-AG and AEA have the potential to activate a wide range of GPCRs, nuclear receptors, and ion channels (77, 78, 79), although when considering this literature,

eCB Synthesis

Most of what we know about eCB synthesis comes from investigations of the mature nervous system and heterologous expression systems. These studies have led to the concept that the dominant form of eCB synthesis is “on demand” (81). The principal of on-demand synthesis is that the eCB exists as a precursor in membrane lipids and is liberated by the activation of enzymes, typically lipases, that are triggered by a specific signal (e.g., G proteins or elevation of intracellular calcium [see

eCB Transport

Transport of eCBs across the cell membrane is important following their synthesis and in preparation of their degradation. eCBs are synthesized from phospholipids on the inner leaflet of the membrane; thus, for eCBs to act on adjacent cells, a mechanism for their exit from the cell is necessary (96,97). Similarly, eCB degrading enzymes are primarily intracellular, so a process for eCB entry into cells is necessary to terminate their action. The polar nature of eCBs prevents their passage across

eCB Degradation

eCB signaling is frequently terminated by hydrolysis of the arachidonic group from either the glycerol (2-AG) or ethanolamine (AEA). 2-AG hydrolysis is primarily carried out in the CNS by MAGL (monoacylglycerol lipase) or ABDH6 (alpha/beta-hydrolase domain containing 6) (103,104), while FAAH (fatty acid amino hydrolase) primarily terminates AEA action (105). MAGL is found at the highest levels presynaptically (106), while ABHD6 is mostly found in dendrites (104), suggesting that the two

eCBs as Retrograde Messengers

A major function of the ECS in the mature nervous system is as a retrograde messenger mediating several forms of eCB-mediated synaptic plasticity (110). Here, eCBs synthesized by the postsynaptic cell travel retrogradely across the synapse to activate presynaptic cannabinoid receptors, suppressing neurotransmission from CB1-expressing terminals. There are both transient and long-lasting forms of eCB-mediated synaptic plasticity. Both forms involve stimulation of the postsynaptic neuron (either

Nonretrograde Effects of eCBs on Neuronal Excitability

While much attention is paid to the role of eCBs as retrograde messengers, it is important to appreciate that eCBs modify neuronal excitability in other ways. These can be summarized as 1) direct modulation of ion channels, 2) activation of GIRK channels, and 3) enhancement of a hyperpolarization-activated cation channels (Ih). eCBs also modulate several important ion channels, including 5HT3 (115), TRPV1 (116), GABA-A (79), glycine (117), and many others (118). As always, it is important to

Interactions Between eCBs and Exogenous Cannabinoids (THC and Spice Compounds)

The varying efficacies of 2-AG, AEA, THC, and the synthetic cannabinoids used recreationally (“spice”) gives rise to several potentially important and interesting interactions. For example, THC is a fairly potent, low-efficacy agonist, while 2-AG is a less potent but highly efficacious agonist (121). Thus, under conditions in which either CB1 receptor density or postreceptor coupling is limited, THC may antagonize endogenous 2-AG signaling [e.g., (97)]. On the one hand, this THC/2-AG

Dynamic Expression of ECS During Brain Development

The ECS is present from the earliest stage of pregnancy, in the preimplantation embryo and uterus (127), in the placenta (128), and in the developing fetal brain (129). In human fetal brains, CB1 receptors can be detected at week 14 of gestation, with preferential expression in the cerebral cortex, hippocampus, caudate nucleus, putamen, and cerebellar cortex, mirroring their adult distribution. By week 20, intense expression is evident in CA2 and CA3 of the hippocampus and in the basal nuclear

Summary

The ECS has been implicated in the risk for developing schizophrenia. Perturbingly, the ECS (i.e., through cannabis use) may influence the course of psychoses and acute intoxication with natural or synthetic cannabinoids can induce transient psychotic symptoms. Through the ECS’s role in the developing nervous system, it is well positioned to interact with factors that may predispose an individual to developing psychotic disease and the course of that disease. The ECS’s involvement in multiple

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant Nos. NS086794 (to H-CL), DA043982 (to KM), and DA046196 (to KM).

KM receives consulting fees from Abalone Bio, FSD Pharma, and Nalu Bio. H-CL reports no biomedical financial interests or potential conflicts of interest.

References (150)

  • M. Di Forti et al.

    The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): A multicentre case-control study

    Lancet Psychiatry

    (2019)
  • C.J. Coke et al.

    Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and cannabinoid receptor 2 (CB2) reveals a mechanism for regulation of tumor progression

    J Biol Chem

    (2016)
  • J. Wager-Miller et al.

    Dimerization of G protein-coupled receptors: CB1 cannabinoid receptors as an example

    Chem Phys Lipids

    (2002)
  • J. Ellis et al.

    Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function

    J Biol Chem

    (2006)
  • A. Hajkova et al.

    SGIP1 alters internalization and modulates signaling of activated cannabinoid receptor 1 in a biased manner

    Neuropharmacology

    (2016)
  • S.E. Lee et al.

    SGIP1alpha functions as a selective endocytic adaptor for the internalization of synaptotagmin 1 at synapses

    Mol Brain

    (2019)
  • T. Sugiura et al.

    2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain

    Biochem Biophys Res Commun

    (1995)
  • R. Mechoulam et al.

    Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors

    Biochem Pharmacol

    (1995)
  • A. Tanimura et al.

    The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission

    Neuron

    (2010)
  • J. Liu et al.

    Multiple pathways involved in the biosynthesis of anandamide

    Neuropharmacology

    (2008)
  • E. Leishman et al.

    Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain

    Biochim Biophys Acta

    (2016)
  • S. Nicolussi et al.

    Endocannabinoid transport revisited

    Vitam Horm

    (2015)
  • A. Chicca et al.

    Evidence for bidirectional endocannabinoid transport across cell membranes

    J Biol Chem

    (2012)
  • F.M. Leweke

    Anandamide dysfunction in prodromal and established psychosis

    Curr Pharm Des

    (2012)
  • D.C. D’Souza et al.

    The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis

    Neuropsychopharmacology

    (2004)
  • S. Ganesh et al.

    Psychosis-relevant effects of intravenous delta-9-tetrahydrocannabinol: A mega analysis of individual participant-data from human laboratory studies

    Int J Neuropsychopharmacol

    (2020)
  • A. Minichino et al.

    Measuring disturbance of the endocannabinoid system in psychosis: A systematic review and meta-analysis

    JAMA Psychiatry

    (2019)
  • M. Di Forti et al.

    Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users

    Schizophr Bull

    (2014)
  • A.C. Howlett et al.

    International Union of Pharmacology. XXVII. Classification of cannabinoid receptors

    Pharmacol Rev

    (2002)
  • D. Wootten et al.

    Mechanisms of signalling and biased agonism in G protein-coupled receptors

    Nat Rev Mol Cell Biol

    (2018)
  • A.L. Bodor et al.

    Endocannabinoid signaling in rat somatosensory cortex: Laminar differences and involvement of specific interneuron types

    J Neurosci

    (2005)
  • S.S. Hu et al.

    Distribution of the endocannabinoid system in the central nervous system

    Handb Exp Pharmacol

    (2015)
  • A. Bacci et al.

    Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids

    Nature

    (2004)
  • G. Benard et al.

    Mitochondrial CB(1) receptors regulate neuronal energy metabolism

    Nat Neurosci

    (2012)
  • Allen Brain Map

  • Brain RNA-Seq

  • Mouse Brain Atlas

  • S. Munro et al.

    Molecular characterization of a peripheral receptor for cannabinoids

    Nature

    (1993)
  • S. Galiegue et al.

    Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations

    Eur J Biochem

    (1995)
  • G.A. Cabral et al.

    Endocannabinoids and the immune system in health and disease

    Handb Exp Pharmacol

    (2015)
  • N. Stella

    Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas

    Glia

    (2010)
  • K.J. Spiller et al.

    Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats

    Br J Pharmacol

    (2019)
  • B.K. Atwood et al.

    CB2: A cannabinoid receptor with an identity crisis

    Br J Pharmacol

    (2010)
  • M. Tanaka et al.

    Endocannabinoid modulation of microglial phenotypes in neuropathology

    Front Neurol

    (2020)
  • The health effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

    (2017)
  • E.S. Gouvea et al.

    The role of the CNR1 gene in schizophrenia: A systematic review including unpublished data

    Braz J Psychiatry

    (2017)
  • C. Nogueras-Ortiz et al.

    The multiple waves of cannabinoid 1 receptor signaling

    Mol Pharmacol

    (2016)
  • J.E. Lauckner et al.

    The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins

    Proc Natl Acad Sci U S A

    (2005)
  • M. Glass et al.

    Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: Evidence for a Gs linkage to the CB1 receptor

    J Neurosci

    (1997)
  • T. Kenakin

    Biased receptor signaling in drug discovery

    Pharmacol Rev

    (2019)
  • Cited by (190)

    View all citing articles on Scopus
    View full text