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The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

Despite centuries of recreational use of cannabis, it is only relatively recently that its mechanisms of action, and the existence of endogenous cannabinoids, have been discovered. In this Timeline article, Raphael Mechoulam and colleagues discuss early research on the plant cannabinoids and speculate on the directions this research might take in the future. Isolation and structure elucidation of most of the major cannabinoid constituents — including Δ 9 -tetrahydrocannabinol (Δ 9 -THC), which is the principal psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.

Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system — known as the endocannabinoidome — that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.

The endocannabinoid system (ECS) is a group of neuromodulatory lipids, enzymes, and receptors involved in numerous behavioral and physiological processes such as mood, memory, and appetite. Recently, longitudinal and postmortem studies have shown that the ECS might be involved in neuropsychiatric disorders like schizophrenia. However, despite the large amount of research, our knowledge of the ECS and its implication in this debilitating disorder is still largely limited. This review aims at providing a comprehensive overview of the current state of knowledge of the ECS in schizophrenia and presenting some potential antipsychotic compounds that modulate this system. Findings from animal and human studies, and their implications for pharmacotherapy, will be integrated and discussed in this paper. A closer look will be given at the roles of the cannabinoid receptors type 1 (CB 1 ) and type 2 (CB 2 ), as well as the endogenous ligand N -arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), in the development of psychotic and schizophrenia-like symptoms.

Key Points Cannabinoid receptors and their endogenous ligands are widely expressed throughout the brain, with a particularly strong presence and influence in neuronal circuits such as the mesocorticolimbic pathways highly implicated in reward and addiction. Cannabinoid 1 receptor (CB1R) signalling influences the motivation for both natural and drug rewards. In comparison to most drugs of abuse, CB1Rs exert only modest influence on psychostimulant intake. Brain endocannabinoid (eCB) levels are increased by most drugs of abuse, although the nature of this effect differs between classes of drugs and across brain regions. The response contingency of drug exposure (volitional versus response-independent) seems to influence brain eCB production, suggesting contributions both of drug-related pharmacological effects and of neural activity engaged by active drug-seeking behaviour. Chronic exposure to drugs of abuse generally results in impaired CB1R function, loss of eCB-mediated synaptic plasticity in addiction-related neural circuits, and negative affective states that can be ameliorated through pharmacologically enhanced eCB tone. The eCB system (ECS) has a strong role in modulating relapse-like behaviour induced by conditioned cues or reward priming, and this is evident for both natural and drug rewards. Recent investigations of CNR1 (which encodes CB1R) and fatty acid amide hydrolase ( FAAH ) variants generally suggest an association with endophenotypes implicated in addiction susceptibility, including reward sensitivity, impulsivity and negative affect. However, confounding factors, including restricted sample size, ethnicity and polysubstance use, limit interpretational power, and the functional consequences of the variants (causal or linked) are currently unknown. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, are widely expressed in the brain, particularly in regions that are implicated in mediating reward. In this Review, Parsons and Hurd explore the role of endocannabinoid signalling in natural and drug-induced reward, as well as in addiction. Brain endocannabinoid (eCB) signalling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated eCB signalling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired eCB signalling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states and cravings that propel addiction. Understanding the contributions of eCB disruptions to behavioural and physiological traits provides insight into the eCB influence on addiction vulnerability.

The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ9-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.

Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.

Key Points As gut microorganisms interact with host cells via several mechanisms, targeting the microbiota to treat metabolic disorders is an attractive therapeutic approach The endocannabinoid system is involved in numerous biological processes, such as the regulation of energy homeostasis, inflammation and gut-barrier function The endocannabinoid system is altered during the metabolic syndrome, which contributes to the onset of cardiometabolic disease Gut microorganisms and the endocannabinoid system are intertwined The metabolites, receptors and signalling pathways that couple the gut microbiota with the host endocannabinoid system and eventually metabolism require further investigation Although the endocannabinoid system is currently being targeted in several pathological conditions such as obesity, diabetes mellitus and intestinal inflammation, few candidate drugs have been tested in clinical trials Here, Patrice Cani and colleagues discuss interactions between gut microorganisms, the endocannabinoid system and host metabolism, in the context of both physiology and pathophysiology. The authors highlight the importance of gut barrier function by discussing the role of specific factors involved in intestinal permeability and their role in the gut microbiota–endocannabinoid system axis. The therapeutic potential of targeting the endocannabinoid system to treat cardiometabolic disorders and intestinal inflammation is also discussed. Various metabolic disorders are associated with changes in inflammatory tone. Among the latest advances in the metabolism field, the discovery that gut microorganisms have a major role in host metabolism has revealed the possibility of a plethora of associations between gut bacteria and numerous diseases. However, to date, few mechanisms have been clearly established. Accumulating evidence indicates that the endocannabinoid system and related bioactive lipids strongly contribute to several physiological processes and are a characteristic of obesity, type 2 diabetes mellitus and inflammation. In this Review, we briefly define the gut microbiota as well as the endocannabinoid system and associated bioactive lipids. We discuss existing literature regarding interactions between gut microorganisms and the endocannabinoid system, focusing specifically on the triad of adipose tissue, gut bacteria and the endocannabinoid system in the context of obesity and the development of fat mass. We highlight gut-barrier function by discussing the role of specific factors considered to be putative 'gate keepers' or 'gate openers', and their role in the gut microbiota–endocannabinoid system axis. Finally, we briefly discuss data related to the different pharmacological strategies currently used to target the endocannabinoid system, in the context of cardiometabolic disorders and intestinal inflammation.

During adolescence, both rodent and human studies have revealed dynamic changes in the developmental trajectories of corticolimbic structures, which are known to contribute to the regulation of fear and anxiety-related behaviors. The endocannabinoid (eCB) system critically regulates stress responsivity and anxiety throughout the life span. Emerging evidence suggests that during adolescence, changes in eCB signaling contribute to the maturation of local and corticolimbic circuit populations of neurons, such as mediating the balance between excitatory and inhibitory neurotransmission within the prefrontal cortex. This function of the eCB system facilitates efficient communication within and between brain regions and serves a central role in establishing complex and adaptive cognitive and behavioral processing. Although these peri-adolescent changes in eCB signaling promote brain development and plasticity, they also render this period a particularly sensitive one for environmental perturbations to these normative fluctuations in eCB signaling, such as stress, potentially leading to altered developmental trajectories of neural circuits governing emotional behaviors. In this review, we focus on the role of eCB signaling on the regulation of stress and anxiety-related behaviors both during and after adolescence. Moreover, we discuss the functional implications of human genetic variation in the eCB system for the risk for anxiety and consequences of stress across development and into adulthood.

Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.