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Publicly Available Published by De Gruyter March 30, 2018

Cannabinoids in health and disease: pharmacological potential in metabolic syndrome and neuroinflammation

  • Andrea Mastinu ORCID logo EMAIL logo , Marika Premoli , Giulia Ferrari-Toninelli , Simone Tambaro , Giuseppina Maccarinelli , Maurizio Memo and Sara Anna Bonini


The use of different natural and/or synthetic preparations of Cannabis sativa is associated with therapeutic strategies for many diseases. Indeed, thanks to the widespread diffusion of the cannabinoidergic system in the brain and in the peripheral districts, its stimulation, or inhibition, regulates many pathophysiological phenomena. In particular, central activation of the cannabinoidergic system modulates the limbic and mesolimbic response which leads to food craving. Moreover, cannabinoid agonists are able to reduce inflammatory response. In this review a brief history of cannabinoids and the protagonists of the endocannabinoidergic system, i.e. synthesis and degradation enzymes and main receptors, will be described. Furthermore, the pharmacological effects of cannabinoids will be outlined. An overview of the involvement of the endocannabinoidergic system in neuroinflammatory and metabolic pathologies will be made. Finally, particular attention will also be given to the new pharmacological entities acting on the two main receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), with particular focus on the neuroinflammatory and metabolic mechanisms involved.


The endocannabinoid (EC) system is closely involved in inflammatory and metabolic processes in peripheral and central districts [1]. Indeed, Cannabis sativa, the natural source of cannabinoids, has been used for many medical applications since ancient times, including those related to inflammation, pain, anxiety and food intake [2]. In particular, the genesis of metabolic syndrome and especially obesity begins with a hypothalamic signalling altered where the ECs play an important role. Indeed, the pathways of leptin, insulin, adiponectin, cholecystokinin and ghrelin, hormones involved in obesity development, are altered, as has been reported by many authors [3]. Moreover, in the bloodstream of murine models and obese patients there is a high presence of cytokines and chemokines [4]. This inflammatory condition is common to many chronic diseases and in particular those of the central nervous system (CNS) such as Parkinson’s disease (PD) [5], Alzheimer’s disease (AD) [6], depression [7] or anxiety [8]. Moreover, to date, the therapeutic strategies that can rebalance the metabolic and neuroinflammatory homeostasis are few. This review will give an overview of the role of cannabinoids in neuroinflammatory and metabolic mechanisms. Furthermore, the neuroinflammatory and metabolic basis of some neurological diseases will be explored. Finally, the pharmacological potential of cannabinoid agents in metabolic syndrome and neuroinflammation will be discussed.


Brief history of Cannabis sativa

The C. sativa plant has been used for medicinal reasons for thousands of years by different cultures [9]. The first documentation of cannabis as a medicine appeared in China 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and, mixed with wine, as a surgical analgesic [10]. In India, more than 1000 years BC, the plant was used for various functions, such as as a hypnotic and a tranquiliser useful in the treatment of anxiety, mania and hysteria [11]. Also the Assyrians inhaled cannabis to relieve symptoms of depression [12]. Pedacius Dioscorides, a Greek physician, between 50 and 70 AD classified different plants, including C. sativa, and described the benefits derived from its use in De Materia Medica (Figure 1). Only in the 19th century was cannabis introduced into Western medicine for its analgesic, anti-inflammatory, anti-emetic and anticonvulsant properties [13]. In the beginning of the 20th century, cannabis extracts were used for the treatment of mental disorders, especially as sedatives and hypnotics [12]. After the 1930s, the medical use of cannabis significantly decreased [9]: as it was considered to be an illegal substance, its use in psychiatry was limited further. However, after the identification of the main components of cannabis and the discovery that the EC system is able to modulate different processes in psychiatric disorders, has the interest in the use of cannabinoids been renewed [14].

Figure 1: Cannabis sativa. Illustration from the “Vienna Dioscorides” 512 AD adapted from De Materia Medica by Dioscorides, 1st century BC.
Figure 1:

Cannabis sativa. Illustration from the “Vienna Dioscorides” 512 AD adapted from De Materia Medica by Dioscorides, 1st century BC.

Endocannabinoids: synthesis and degradation

ECs are lipid molecules produced from fatty acid metabolism [15]. The most studied are N-arachidonoylethanolamine (AEA), or anandamide, and 2-arachidonoyl glycerol (2-AG) [16]. AEA and 2-AG which are members of the fatty acid amide (FAA) and monoacylglycerol (MAG) families of neutral lipids, respectively, are produced from cell membrane phospholipids and are immediately released [16]. Complex enzymatic mechanisms regulate the synthesis and degradation of these endogenous molecules. In particular, several pathways have been proposed to mediate AEA synthesis, among these the hydrolysis of N-acylphosphatidylethanolamine (NAPE) by NAPE-selective phospholipase D or the synergic action of α,β-hydrolase domain-containing 4 and glycerophosphodiesterase 1 on NAPE precursors [17]. 2-AG synthesis occurs from the sequential hydrolysis of 2-arachidonic acid, containing diacylglycerol (DAG) membrane phospholipids, by means of phospholipase C (PLC) and diacylglycerol lipase α (DAGLα) or β (DAGLβ) [18]. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are degradation enzymes of AEA and 2-AG, respectively, which through their hydrolysis generate arachidonic acid and ethanolamine or glycerol [18].

Endocannabinoids: receptors

The endogenous cannabinoids act mainly at the level of two receptors: the type 1 cannabinoid receptor (CB1R) and the type 2 cannabinoid receptor (CB2R) [19]. On the one hand, CB1Rs are significantly distributed in some brain areas such as the basal ganglia, cerebellum, hippocampus and cortex [19]. On the other hand, less concentration is localised in other areas, for example, in the brainstem where the regulatory centres of respiration and cardiac function are located [20]. They have also been localised in peripheral areas such as the intestine, liver, adipose tissue and immune cells [21]. CB1R belongs to the G protein-coupled receptors, consisting of seven transmembrane segments and with the intracellular C-terminal and N-terminal portions [19]. In neurons, where CB1R expression is mostly localised, the stimulation of presynaptic CB1R inhibits neurotransmitter release. In particular, CB1R plays a key role in signal transduction where the interaction between receptors associated with inhibitor G protein and cannabinoidergic ligand generates the inhibition of adenylyl cyclase and of calcium channels N and P/Q, activates those with potassium and stimulates MAP kinases [22], [23]. In the liver, where CB1R is normally expressed at low levels, its stimulation leads to the enhanced expression of acetyl-CoA carboxylase-1 and fatty acid synthase and thus increases lipogenesis [24]. Also CB2Rs are G protein-associated receptors and are mainly distributed in the spleen, tonsils and immune cells [25], [26]. Recently, they have been identified in the CNS (glial and neuronal cells) [27], [28], [29]. CB2R seems to have several immunosuppressive effects, including inhibition of proinflammatory cytokine production [30], [31]. In addition, AEA and 2-AG show an affinity for non-CBs. Indeed, AEA interacts with the transient receptor potential vanilloid 1 (TRPV1) channel and increases intracellular Ca2+ levels by miming CB1R and CB2R activation [32], [33], [34]. Moreover, high concentrations of AEA interact with the nuclear receptor, the peroxisome proliferator-activated receptor-gamma (PPARγ) [35]. PPARs are transcription factors activated by ligands that belong to the nuclear receptor super family, which also includes steroid and thyroid hormone receptors [36]. As transcription factors, PPARs regulate the expression of numerous genes and intervene on the control of glycaemia, lipid metabolism, vascular tone and inflammation [37]. Activation of the PPAR-γ isoform improves sensitivity to insulin, reduces inflammation, plasmatic levels of free fatty acids and consequently inhibits atherogenesis, improves endothelial function and reduces cardiovascular events [37], [38]. The main components of the EC system are shown in Figure 2.

Figure 2: Endocannabinoid system.
Figure 2:

Endocannabinoid system.

Cannabinoids and brain

Increasing literature suggests that the long-term use of cannabis is associated with different adverse effects. From animal studies delta-9-tetrahydrocannabinol (THC) has been shown to induce dose-dependent toxicity and structural changes in brain regions rich in CB1R, such as the hippocampus, amygdala, cerebellum, prefrontal cortex and striatum [39]. In contrast, much less is known about the neurobiological consequences of long-term cannabis exposure in humans. Long-term cannabis use has been correlated with morphological alterations in regions linked to memory and executive/affective processing, such as the hippocampus and amygdala [39], [40]. In regular cannabis smokers, a decrease in hippocampal volume correlated with lifetime consumption and psychotic symptoms and also a bilateral reduction in amygdala volume have been found [39]. Yücel and colleagues suggested that there are complex associations between cannabis exposure, hippocampal volume reductions and psychotic symptoms [39]. Given that cannabis use typically begins during adolescence, an important question is whether cannabis consumption is linked with differential effects on brain structure according to the age of first use (during/after adolescence). Adolescence is an important period for brain maturation and for the development of cognitive, motor and sensory functions [41]. Environmental factors, such as drugs, can alter adolescent brain development, increasing the occurrence of psychiatric disorders and substance abuse. During adolescence white matter structures are still rich of CBs, and long-term cannabis exposure can downregulate the EC system, thus provoking apoptosis of oligodendrocyte progenitors and altering white matter development [40]. For these reasons, the age of onset of regular cannabis use is a key factor defining the intensity of white matter alterations and long-term cannabis use is toxic to white matter development [40]. Finally another interesting question is relative to the importance of these changes and the quantity of cannabis consumed. Regular cannabis users showed a lower gray matter volume in the medial temporal cortex, temporal pole, parahippocampal gyrus, left insula and orbitofrontal cortex compared with occasional drug users [42]. The magnitude of alterations in these regions is linked with the frequency of cannabis use and is modulated by the age of first use [42]. These structural variations also have implications in many processes, such as gray matter volume reduction in insula and orbitofrontal cortex linked to affective/emotional processes and alterations in the temporal pole correlated with changes in personality and social behaviour [43]. Changes in the hippocampus are related to reduced memory performance [44] and psychotic symptoms [39]. In contrast, the increased gray matter volume in the cerebellum found in regular drug users without correlation with the amount of cannabis use may be associated with developmental processes during adolescence [42].

Given the expression of cannabinoids receptors in the nervous system, and the interactions between cannabinoids with neurotransmitters, such as dopamine, glutamate, serotonin and gamma-aminobutyric acid, it might be possible that cannabis has medical potential [45]. A meta-analysis study performed by Whiting and colleagues [46] showed that there is evidence to support the use of cannabinoids for the treatment of chronic neuropathic or cancer pain (smoked THC and nabiximols) and spasticity due to multiple sclerosis (MS) [nabiximols, nabilone, THC/cannabidiol (CBD) capsules and dronabinol]. There is evidence to suggest that cannabinoids can be useful for nausea and vomiting due to chemotherapy (dronabinol and nabiximols), weight gain in HIV (dronabinol), sleep disorders (nabilone, nabiximols) and Tourette’s syndrome (THC capsules). Cannabinoids are associated with an increased risk of short-term adverse events such as asthenia, balance problems, confusion, dizziness, disorientation, diarrhoea, euphoria, drowsiness, dry mouth, fatigue, hallucination, nausea, somnolence, vomiting [46] and also anxiety [47]. Recent studies have demonstrated that cannabis can have both anxiogenic and anxiolytic effects. This is due to the fact that C. sativa contains THC and CBD, with different psychoactive properties, able to modulate anxiety. Animal studies reported that low doses of THC have anxiolytic effects, instead high doses are anxiogenic. In contrast, CBD has anxiolytic effects in both animals and humans due to activation patterns in limbic and paralimbic areas [48]. This anxiolytic effect of CBD can explain why many patients with anxiety disorders use cannabis as a “self-medication” to obtain relief from anxiety symptoms [47]. These data suggest a potential usefulness of CBD in the treatment of anxiety disorders, though further studies are necessary to confirm these observations [49]. Preclinical evidence support the use of cannabinoids in the treatment of epilepsy. CBD is the only non-THC phytocannabinoid that has been evaluated in preclinical and clinical studies for anticonvulsant effects [50]. Recently in vitro and in vivo models have shown that CBD have anti-epileptiform and anticonvulsant effects. Also cannabidivarin, the propyl variant of CBD, has significant anticonvulsant properties. The mechanisms by which these drugs exert their anti-seizure effects are not well understood. CBD may reduce neuronal excitability and neuronal transmission modulating intracellular calcium through interactions with many targets such as TRP channels, GPR55 or VDAC1. Alternatively CBD anti-inflammatory effects may also be involved in anti-ictogenesis [50]. These data support the potential for use CBD in the treatment of seizures and epilepsy, but further studies and clinical trials are required.

Cannabinoids and disease

The EC system is involved in many peripheral and central disorders, between these, the main ones are the metabolic and neuroinflammatory pathologies. Indeed, on the one hand, cannabinoids modulate the hunger/satiety and neuroinflammation in the brain and on the other hand, they are involved in peripheral metabolic reactions in the liver, fat, muscles and anti-inflammatory response in the blood cells. This signalling is altered in subjects with metabolic syndrome. Indeed, they show a white fat tissue increase with impairments in the hormones (leptin and insulin), cytokines and cannabinoids signalling. Therefore, metabolic syndrome is strictly associated to a systemic inflammation changed where the cannabinoids play a key role.

Metabolic syndrome

Metabolic syndrome: definition and pathogenetic mechanisms

Metabolic syndrome is a complex pathology that includes several cardiometabolic diseases, insulin resistance and obesity with the accumulation of abdominal white fat [51]. Metabolic syndrome, also named “insulin resistance syndrome” or “syndrome X”, is a group of risk factors for cardiovascular disease and type 2 diabetes, which includes abdominal obesity, hyperglycaemia, dyslipidemia (high triglycerides and low high density lipoprotein cholesterol) and hypertension (Figure 3) [52], [53], [54], [55]. It has a strong inflammatory and endocrine base [56]. Metabolic syndrome pathogenesis seems to originate from visceral adiposity due to the high caloric intake and culminates in the final pathway of inflammation [57]. Genetic factors may account for 50% of the variation of metabolic syndrome susceptibility. Insulin resistance is believed to play a pivotal role in the pathogenesis of metabolic syndrome. Insulin increases glucose uptake in muscle and liver, and inhibits lipolysis and hepatic gluconeogenesis. In response to the insulin resistance, pancreatic cells produce higher insulin levels generating a hyperinsulinaemic state to maintain euglycaemia. When the compensation fails insulin secretion decreases an increase in serum viscosity occurs, together with the induction of a prothrombotic state, and the release of pro-inflammatory cytokines from the adipose tissue that contribute to an increased risk of cardiovascular diseases (CVD). Finally, the insulin-mediated inhibition of lipolysis is lost, leading to an increase in circulating free fatty acids that are responsible for vasoconstriction and toxicity for pancreatic beta cells, thus further inhibiting insulin production. Also, free fatty acids induce triglycerides synthesis and the production of apolipoprotein B containing low density lipoprotein (LDL) [58], [59], [60]. Visceral fat is more involved in this mechanism than subcutaneous fat, because visceral lipolysis leads to an increased delivery of free fatty acids to the liver through the splanchnic circulation; visceral adipose tissue synthesises also a higher amount of prothrombotic proteins and of protein which promotes smooth muscle cells proliferation, further favouring cardiovascular alterations. Neurohormonal activation plays a role in metabolic syndrome pathogenesis through adipokines such as leptin and adiponectin and through the activation of the renin angiotensin system. Leptin is an adipokine produced by adipose tissue and acts on hypothalamic receptors as a negative regulator of appetite control. Obesity increases leptin levels and higher leptin levels are directly correlated to increased cardiovascular risk. Adiponectin is an anti-inflammatory and antiatherogenic adipokine with effects opposed to those of high leptin levels. Adiponectin has been considered a protective factor against the development of diabetes, hypertension and acute myocardial infarction. Opposed to leptin, obesity reduces adiponectin production [61], [62]. Activation of the renin-angiotensin system also represents an important pathway contributing to the development of metabolic syndrome. Angiotensin II, formed as a result of angiotensin-converting enzyme activation, is also produced by adipose tissue. Angiotensin II, in turn, increases the reactive oxygen species (ROS) production with consequent LDL oxidation, endothelial injury, platelet aggregation, induction of NF-κB expression and expression of lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) on the endothelium and vascular smooth muscle cells. This systemic oxidative stress promotes inflammation, endothelial damage and fibroblast proliferation that contributes to the development of hypertension, dyslipidemia, diabetes, cardiac and CVD [63], [64]. Visceral obesity, insulin resistance and neuroendocrine activation induce a systemic inflammatory and pro-thrombotic state that represents the final common pathway leading to clinical manifestations of metabolic syndrome. Different inflammatory molecules are involved. Tumour necrosis factot-alpha (TNF-α) is secreted by adipose cell macrophages and in turn causes phosphorylation and inactivation of insulin receptor, leading to insulin resistance; furthermore, it induces lipolysis, increases free fatty acids and inhibits adiponectin production. Interleukin 6 (IL-6) is a cytokine produced by adipocytes and immune cells and its production increases with the increase in body fat and insulin resistance. It acts on the liver, bone marrow and endothelium, leading to increased production of acute phase proteins in the liver, including C-reactive protein (CRP). Several studies have demonstrated a correlation between high CRP levels and the development of metabolic syndrome, diabetes and cardiovascular disease. IL-6 also increases fibrinogen levels and promotes adhesion molecules expression by endothelial cells, resulting in a prothrombotic state [65], [66], [67].

Figure 3: Metabolic syndrome.
Figure 3:

Metabolic syndrome.

Early diagnosis of metabolic syndrome is fundamental to carry out lifestyle modification useful in preventing cardiovascular complications. One of the strategies adopted to combat obesity, a debilitating and highly onerous disease for the National Health Service of every industrialised country, consists of a hypocaloric diet associated with adequate physical activity [68]. Unfortunately, this strategy does not always restore the physiological parameters in obese subjects and the diet, often deprives the obese subject of “gratifying” food, thus making difficult to complete the diet [69]. Moreover, physical activity is not always free of side effects in subjects with a body mass index (BMI) above 30 kg/m2 [70]. Based on these assumptions, in the last 30 years, pharmacological research has developed compounds capable of regulating caloric intake and some biochemical parameters associated with metabolic syndrome. Among these compounds, it is worth remembering: (i) the amphetamine-like compounds (phentermine, sibutramine) used in the USA, but with strong cardiovascular side effects [71], [72]; (ii) pancreatic lipase inhibitors (Orlistat) able to block the absorption of lipids in the intestine, leading, however, to a malabsorption of fat-soluble vitamins [73], [74]; (iii) some studies reported that a treatment with erythropoietin, a glycoprotein cytokine secreted by the kidney, showed remarkable metabolic effects including protection against hyperlipidic and hypercarbohydrates diet associated with increased fat metabolism in the muscles [75]. This data is very important for all analytical investigations on biosimilar drugs [76].

Cannabinoids and metabolic syndrome

ECs regulate appetite and food intake in a local manner by modulating, via activation of CB1R, the activity of hypothalamic neurons and the release of orexigenic and anorexigenic neuropeptides, as well as the function of mesolimbic and brainstem neurons [77], [78]. Indeed, it is well accepted that CB1R activation stimulates feeding and EC levels significant increase within the hypothalamus and nucleus accumbens in response to fasting, returning to normal after refeeding, without changing in the brain areas not involved in feeding [79]. This action is mediated, at least in part, through the leptin and ghrelin pathways, which modulates EC levels within the hypothalamus and become deregulated during obesity, thus resulting in an elevated hypothalamic EC tone [15], [80]. Indeed, it is now known that obesity can be associated with a hyper-regulation of the EC system as it involves an increase in circulating/tissue levels of ECs and of the CB1R, which represents the EC receptor most involved in the pathophysiological relationship existing between the EC system and obesity [15]. The EC system interacts with the reward and reinforcement circuits by activating the mesolimbic system and by interacting with both the dopaminergic and opioidergic pathways, resulting in a preference for highly palatable foods [81], [82]. Indeed, endogenous or synthetic CB1R agonists increase sucrose-induced hedonic activity and dopamine release into the nucleus accumbens [83]. Furthermore, CB1R and μ-opioid antagonists reduce food intake and body weight in murine models [84]: indeed, both pharmacological CB1R antagonists and CB1R knockout mice are hypophagic models [85]. In healthy volunteers, consumption of palatable food, as compared to normal food, is accompanied by elevated plasma 2-AG levels, which correlate positively with plasma ghrelin levels [86]. Moreover, in diet-induced obesity (DIO) mice, the EC levels are upregulated within the hippocampus, a key centre of hedonic eating, indicating that very palatable foods might be more satisfying under these conditions, resulting in an inescapable road leading to obesity [87]. Also in the hypothalamus, 2-AG is upregulated after acute or chronic consumption of a high-fat diet and seems to lead to a preference for CB1R-mediated fat diet [88]. The upregulation of hypothalamic ECs, associated with impaired leptin signalling, might contribute in peripheral metabolic syndrome by causing insulin resistance in the mediobasal hypothalamus [88]. All these data highlight the key role of central ECs in the control of both central and peripheral energy homeostasis (Figure 4).

Figure 4: Effects of endocannabinoid system activation.
Figure 4:

Effects of endocannabinoid system activation.

Pharmacologic potential of cannabinoids in metabolic syndrome

Inverse cannabinoids, agonist/antagonist, both act on the hypothalamic centres, that regulate the sense of satiety and at the peripheral districts, which induce fat loss, thus counteracting the effects of e metabolic syndrome [89], [90], [91], [92]. Several clinical trials have tested the action of the rimonabant (the first CB1 antagonist in this class of drugs to be synthesised) in overweight or obese humans and all the studies have shown that the drug induces significant weight loss and improvement of metabolic alterations in the tested patients [93], [94], [95]. After Sanofi-Aventis placed rimonabant in the market, other pharmaceutical companies developed new drug CB1 antagonists, but unfortunately they were blocked for their serious side effects [96]. Indeed, despite the benefits of metabolic syndrome therapy, a careful analysis of rimonabant effects on a large scale of patients revealed a series of psychiatric adverse events related to the use of this drug, such as anxiety, depression and suicidal tendencies [93]. Consequently, rimonabant was withdrawn from the market (2007) because it was considered an unsafe drug and all the clinical trials aimed at testing the efficacy of other CB1 antagonist drugs were stopped [97]. Despite this, experimental evidence from recent years has shown that the peripheral components of the EC system can play an important role in regulating energy metabolism and the stimulation of hunger [98], [99]. In light of this evidence, a new anti-obesity pharmacological strategy has been proposed. In particular, several researchers characterised drugs that act exclusively by blocking the peripheral CB1 receptors with positive effects on the metabolism without modifying the CNS circuits responsible for psychiatric adverse reactions [100], [101], [102], [103], [104]. Several compounds CB1R selective antagonists for peripheral tissues were recently tested in animals and appeared to be particularly promising in regulating body weight and metabolic alterations generated by DIO [105], [106], [107]. In particular, chronic treatment with NESS038C6 (a CB1R antagonist) showed, in obese mice; a significant fat loss, an improvement of cardiovascular risk factors, an increase of metabolic enzymes expression levels in the liver and a normalisation of monoaminergic transporters and neurotrophic factors expression levels in the mesolimbic area [108]. Also, NESS06SM is a CB1R neutral antagonist, characterised by poor blood-brain barrier permeability, anti-obesity effects and a cardiovascular risk factor improvement in obese murine models [109], [110]. Moreover, a chronic administration of these drugs did not change the expression of both monoaminergic transporters and neurotrophins, highly related with anxiety and mood disorders, as noted instead with rimonabant treatment. Neutral antagonists of the CB1 receptor, such as NESS0327, or novel pyrazole derivatives should be added to these compounds, which improve energy homeostasis in obese mouse models by acting on food intake [111].


Neuroinflammation: definition and pathogenetic mechanisms

Neuroinflammation in a complex physiological process that normally initiates as a brain defence response, acting with a protective goal, but that can degenerate in a chronic immune system activation leading to a pathological state. Neuroinflammation is involved in the pathophysiology of several neurological diseases, such as ischaemia, neurodegenerative diseases (firstly in AD and PD) [112], psychiatric disorders (schizophrenia, major depressive disorders, bipolar disorders) [113], neurodevelopmental disorders (autism spectrum disorders, epilepsy) [114], [115], [116] and immune mediated disorders. Furthermore, it also emerged as a close link between psychosocial stressors and neuroinflammation [117]. Despite neuroinflammation being a common process to several CNS pathologies, different inflammatory states associated with varied immune cell phenotypes and diverse structural and functional state of the blood brain barrier represent important disease-specific features, crucial to determine the nature of the disease and its treatment [118].

Neuroinflammation involves different cell types: microglia, the resident immune cells of the CNS, mast cells, which regulate both innate and adaptive immunity; oligodendrocytes, which provide support and insulation to axons in the CNS but also interact with other immune cells in order to regulate inflammatory response; and astrocytes, the most abundant glial cells involved in neuroinflammation, a key component of the blood brain barrier and essential for brain repair.

Mast cells and microglia are the main neuro-immune sentinels in the brain and together with astrocytes represent important players in connecting peripheral immune signalling with the CNS during inflammation. All these cells are able to recognise harmful stimuli and to respond by producing inflammatory cytokines and chemokines; they have fundamental roles in several pathological processes [119]. With ageing, microglia and mast cells become more sensitive to environmental stressors and this may contribute to chronic low-grade non-resolving inflammation, leading to what has been called “inflammaging” [120], [121].

Microglia are the tissue-resident macrophages of the brain and they play a pivotal role in all inflammation-associated disorders. In the resting condition, microglia’s main role is to monitor and survey the parenchymal environment with their ramified and highly motile branches in order to detect extracellular signals and respond to them thus maintaining brain homeostasis [122]. When microglia, following the detection of a noxious stimulus, enter the “activated” state, they trigger an inflammatory response in order to protect the CNS and remove the pathogen or repair the damage. Uncontrolled and prolonged neuroinflammation is potentially harmful, generating a self-propagating inflammatory response that can result in cellular damage and tissue destruction [123]. Chronic neuroinflammation can lead to loss of synapses, impaired cognition and massive cells death, all events involved in neurodegenerative and other brain disorders pathogenesis [124]. Microglia can react in a classical activation (microglial M1 phenotype), that trigger the release of inflammatory cytokines (TNF-α, IL-6, IL-1β and others) and ROS, or in an alternative activation (microglial M2 phenotype), involved in wound repair, debris clearance and release of inflammation-inhibiting factors (such as IL-10 and YM1) with an anti-inflammatory function [125]. A failed M2 response may also be responsible for a lack of neuroprotective factors leading to chronic detrimental neuroinflammation. Recently, a key role for microglia in regulating neurodevelopment has also emerged; in particular, they play a key role during embryonic and later development acting together with the complement pathway as neuronal synaptic contact regulators to prune redundant non-functional connections, thus guiding learning-associated plasticity [126]. A dysregulation in the complement and microglia-dependent pruning activity is responsible for several brain diseases, ranging from neurodevelopmental and neurodegenerative disorders to chronic pain [127].

In particular, the brain of AD patients is characterised by the presence of conspicuous gliosis, due to the initial glial cells activation in the area surrounding plaques in order to phagocyte and remove protein aggregates, but that subsequently becomes a self-feeding pathological process with the excessive release of proinflammatory factors, the switch from M2 to M1 microglial phenotype, the loss of Aβ plaques removal and chronic neuroinflammation [123]. The inflammatory cascade hypothesis of AD states that Aβ deposition induces neuroinflammation, for the proinflammatory property of the peptide to activate microglia and astrocytes, and the inflammation itself can promote Aβ accumulation by inducing increased synthesis of the Aβ precursor protein (APP) and promoting the activity of its cleavage enzymes thus triggering a dangerous and noxious vicious cycle [128]. Astrocytes play a pivotal role in AD-associated neuroinflammation, being responsible, together with neurons, for Aβ peptide secretion and also the increase in the induction of all the Aβ cascade components [129].

Cannabinoids and neuroinflammation

ECs and CBs (both CB1R and CB2R) have been found to play important role in immunomodulation and inflammation [31], [130]. It has been demonstrated that pharmacological agents acting on different components of the EC system exert anti-inflammatory effects by blocking cytokine and chemokine production, inhibiting B and T cells proliferation and inducing T cells and dendritic cell apoptosis, thus inducing immunosoppression [131]. Furthermore, THC inhibits T helper cells activation by suppressing antigen presentation in macrophages [132]. Mecha and colleagues [133] demonstrated that ECs are able to induce the alternative M2 microglial phenotype with an anti-inflammatory effect.

CB1 receptors are expressed constitutively in microglial cells whereas cannabinoid receptor type 2 (CB2) receptors are not expressed in resting cells but only in activated cells [134]. During inflammation the EC system is highly upregulated in order to protect cells from damage and to counteract the toxic cytokine and inflammatory mediators massive release from microglia [135]. Indeed, the EC system also regulates the release by activated immune cells of anti-inflammatory mediators, such as interleukine-10 (IL-10) [136]. CB2 is mainly involved in immune system modulation; indeed, it is mostly localised in immune cells (including myeloid, macrophage, microglia, lymphoid and mast cells) [137] and its activation provokes cytokine production inhibition [138], antigen presentation reduction [139] and immune cell migration (chemotaxis) modulation [25]. Treatment with CB2 agonists on LPS-activated monocytes blocked TNF-α and IL-1β production [140]. Also the CB1 receptor is involved in inflammatory processes and immune system modulation. CB1 receptors, other than being expressed in microglial cells, are also localised in the neuronal presynaptic compartment [141], spinal cord [142] and dorsal root ganglia [143], [144]. Cannabinoids-mediated CB1 receptor stimulation promotes neuroprotection by several mechanisms, including the inhibition of pro-inflammatory mediators release, such as nitric oxide and TNF-α, during the acute phase of injury [145], and supplying on-demand protection against acute excitotoxicity [146]. A recent in vitro study on inflammatory processes implicated in neurodegeneration demonstrated a neuroprotective effect of arachidonyl-2’-chloroethylamide (ACEA), a selective CB1 receptor agonist, able to protect neurons from death and to reduce endoplasmic reticulum stress-related apoptosis [147]. Furthermore, also MAGL, the primary hydrolytic enzyme for endogenous cannabinoid ligand 2-AG, has a main role in inflammation. Indeed, it also acts as a rate-limiting enzyme in the production of free arachidonic acid in brain, liver and lung but not in the gut [148]. MAGL inhibitors induce both increased levels of 2-AG that bind and activates CBs, and decreased levels of arachidonic acid and its pro-inflammatory metabolites, thus acting as powerful anti-inflammatory agents.

Pharmacologic potential of cannabinoids in neuroinflammation

As previously mentioned, inflammation plays a major role in the pathogenesis of many diseases such as neurodegenerative disorders AD and PD, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), HIV encephalitis (HIVE), rheumatoid arthritis (RA) and colitis [149].

The cannabinoid system has been reported to have a neuroprotective role in several inflammation-mediated pathologies. In particular, cannabinoids were shown to be neuroprotective in AD by blocking microglial activation surrounding β-amyloid plaques [150]. Furthermore, both CP55940, a CB1/CB2 agonist, and JWH-015, a selective CB2 agonist, have been reported to protect and rescue peripheral blood lymphocytes from Aβ and H2O2-induced apoptosis [151].

MS is a chronic, inflammatory demyelinating disease of the human CNS characterised by T-cell mediated degeneration of the myelin that covers neuronal axons [152]. In human MS patients, significantly increased CB2-immunoreactive microglia/macrophages have been identified in the spinal cord compared to healthy subjects [153] and an overall disturbance of the EC system has been reported [136]. In a murine model of demyelination by encephalomyelitis virus, increased levels of AEA were able to downregulate microglial activation and to decrease pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and nitric oxide synthase-2 levels [154], [155]. AEA, the endogenous cannabinoid neurotransmitter, acts on both CB1 and CB2 receptors and protects neurons during inflammation by inducing mitogen activated protein kinase phosphatase-1 [156]. Furthermore, Δ9-THC has been reported to markedly inhibit neurodegeneration in the experimental autoimmune encephalomyelitis model and to reduce the associated induced elevated level of glutamate in cerebrospinal fluid [157].

Rheumatoid arthritis (RA) is a chronic autoimmune disorders characterised by highly activated inflammation particularly in joints and results in intense pain and marked joints swollen and finally deformation. Cannabinoids have also emerged as potential pharmacological agents in RA. Indeed, they elicit analgesic and anti-inflammatory effects. In fibroblast-like synoviocytes extracted from the synovial tissue of RA patients, cannabinoid agonists (both endogenous, such as AEA, and synthetic, such as CP55,940, WIN55,212, HU-308 and JWH133) were able to decrease pro-inflammatory cytokine (IL-6 and IL-8) levels and to inhibit matrix degrading enzymes matrix metalloproteinases-1, -3 and -9 [158], [159], [160], [161], [162].

Therefore, in light of the huge amount of data supporting a beneficial role of cannabinoids in inflammation (see Figure 4), high expectation is expected in new powerful anti-inflammatory agents deriving from cannabinoids. The goal of reducing inflammation, and often pain associated with inflammation, in chronic debilitating diseases with selective compounds, such as CB2 selective agonists avoid of psychoactive effects, is still matter of pharmacological study.

Expert opinion

Metabolic syndrome can be considered an inflammatory disease where the white fat tissue shows endocrine alterations with modifications in the hormones and cytokines release. In particular, the “theory of inflammatory state” is the mechanism that can explain how adipose tissue accumulation leads to insulin resistance, and consequently to metabolic syndrome. This inflammatory condition has been reported in different central and peripheral organs involved in the control of metabolic homeostasis and many brain functions. Indeed, numerous diseases of the CNS have an inflammatory genesis. Furthermore, the systemic inflammation and regulation of energy balance are strictly connected to the EC system. For these reasons, C. sativa has been used for many applications over past centuries. Indeed, numerous phytocannabinoids have shown several anti-inflammatory effects by modulating cannabinoids transmission. Unfortunately, CB1R and CB2R synthetic agonists or antagonists, which are capable of and useful in modulating inflammation, pain and metabolic processes, can have psychotropic central effects. Consequently, the new pharmacological strategy for CB1R compounds is to use molecules that do not cross the brain-blood barrier. Instead, CB2 agonist compounds seem to be an innovative way for peripheral and central anti-inflammatory therapy.


The EC system is a promising pathway for inflammatory, pain and metabolic therapies. For this reason, a fundamental starting point will be the identification of more selective compounds for the principal CBs. Indeed, together with the physical activity, innovative pharmacological therapies are very important, mostly in extreme obesity. In particular, in order to improve the metabolic profile of obese patients, CB1 receptor antagonists acting only on peripheral areas and that do not cross the blood-brain barrier should be used. Finally, inflammatory pathways are involved in many brain disorders, and current anti-inflammatory drugs have several side effects. Consequently, the use of CB2 agonists in the modulation of inflammation and pain will constitute a new therapeutic horizon.


  1. Sedative, antinociceptive, anti-inflammatory virtues of C. sativa were known more than 1000 years BC;

  2. metabolic syndrome, closely linked to obesity, originates from the breakdown of the hunger/satiety balance.

  3. chronic neuroinflammation, that involves microglia and astrocytes activation, leads to a loss of synapses and a massive neurons death with impaired cognitive functions;

  4. the activation of EC system blocks central and peripheral inflammation;

  5. in order to avoid side effects in the brain, the best anti-obesity therapies based on cannabinoids must act in peripheral districts;

  6. the use of highly selective CB2 agonist compounds could be considered a winning strategy to block many inflammatory-derived mental illnesses.

Author Statement

  1. Research funding: The authors state no funding involved.

  2. Conflict of interest: The authors declare no conflict of interest.

  3. Informed consent: Informed consent is not applicable.

  4. Ethical approval: The conducted research is not related to either human or animals use.


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Received: 2018-02-02
Accepted: 2018-03-02
Published Online: 2018-03-30

©2018 Walter de Gruyter GmbH, Berlin/Boston

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