**3. The Endocannabinoid System (ECS) in Health and Disease**

The ECS is widely distributed in the body and is involved in a wide array of physiological functions including pain, sleep, arousal, body temperature, feeding, and emotional regulation [63]. Disequilibrium of the ECS results in a myriad of pathological states. In the nervous system, CB1 activation is anti-emetic, enhances eating, causes changes in short-term and working memory, inhibits the release of neurotransmitters involved in anxiety and depression, attenuates nociception, and is protective against excitotoxicity [64–66]. In neurodegenerative diseases and psychiatric disorders, such as Alzheimer's disease and schizophrenia, CB1 expression is reduced, whereas CB2 is induced in an attempt to halt inflammatory response [67,68]. Indeed, upon injury or inflammation, CB2 is highly induced to dampen inflammatory response [51]. CB2 activation decreases the production of reactive oxygen species (ROS) and the release of inflammatory mediators such as tumour necrosis factor α (TNF-α), and nitric oxide (NO) [68]. It activates immune cell apoptosis and suppresses immune cell activation, proliferation, and migration [69]. In the central nervous system, treatment with CB1 inverse agonists reduces the behavioural effects associated with drugs of abuse [63] and produces appetite suppression decreasing food intake, partially due to drug-induced food aversions such as nausea or vomiting [70]. In contrast, CB2 agonists block defecation, increase urination frequency, and produce

analgesia [71]. Inhibition of EC catabolic enzymes such as FAAH seems also a good strategy to increase EC concentration and treat diseases such as anxiety, sleep disorders, and neuropathic pain [72].

In physiological conditions, the modulation of the ECS has a minor impact on the regulation of the cardiovascular system even though the ECS is widely distributed in the heart and blood vessels [17]. In contrast, ECS dysregulation results in disorders such as hypertension, myocardial infarction (MI), and chronic heart failure [62]. The activation of CB2 is cardioprotective, reducing cardiac fibrosis and infarcted areas during ischemia-reperfusion (I/R) and, at the same time, increasing the activation of cardiac progenitor cells and cardiomyocyte proliferation [73,74].

The ECS also plays a crucial role in lipid and glucose metabolism [63], displays orexigenic effects, and modulates peripheral energy metabolism [20]. In obese mice, stearoyl-CoA desaturase-1 generates monounsaturated fatty acids, which inhibit FAAH, resulting in increased AEA hepatic levels promoting excessive energy storage and insulin resistance [26]. In liver, CB1 stimulation increases de novo lipogenesis [20]. It has been suggested that CB1 has a key role in the development of diet-induced obesity and fatty liver disease [20]. Treatment with a CB1 inverse agonist SR141716 (rimonabant) improves glycaemic control, insulin resistance, and dyslipidemia [75]. However, it has no clinical use due to the significant psychiatric side effects: anxiety, depression, and suicidal ideation [63]. CB2 inverse agonists have also been proposed to modulate the metabolic syndrome, in particular triglycerides, insulin, adipose tissue, and arterial pressure [76].

The ECS also plays important roles in the gastrointestinal tract [77] and in oncology, not only as palliative but also as anti-emetic and anti-tumoural agents (due to their effect in controlling cellular proliferation, angiogenesis, and metastasis in experimental models of cancer [21,41,78]). However, there is controversy regarding their role as oncogenes or tumour suppressors [79,80].
