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

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

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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,...

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... 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]. ...

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... The development of metabolic syndrome and metabolic pathologic disorders can be attributed to lifestyle, environmental, and genetic factors. A sedentary lifestyle and an unhealthy diet are the most obvious reasons [1][2][3][4][5][6][7][8]. ...
... Among their multiple roles, ECS and cannabinoid receptor signaling also play a regulatory role in food intake and energy metabolism. Activation of the cannabinoid type 1 receptor (CB 1 R) signaling pathway may upregulate food uptake, while inhibition of ECS signaling may depress food uptake mechanisms to develop weight loss [6,12,13]. Other studies have demonstrated a significant role of the ECS in lipid homeostasis [14][15][16]. ...
... Metabolic syndrome, as a complex disorder, involves the disturbance of glucose metabolism, dyslipidemias, central obesity, and elevated blood pressure, promoting further cardiovascular morbidities such as atherosclerosis [2][3][4][5][6][7][8][17][18][19][20]. An earlier term has also been used, "syndrome X" or IR syndrome with hyperinsulinemia [6,17,21]. ...
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Metabolic syndrome is a complex disease state, which appears mostly as a consequence of an unhealthy, sedentary lifestyle. Metabolic complications include insulin resistance (IR), diabetes, dyslipidemia, hypertension, and atherosclerosis, impairing life standards and reducing life expectancy. The endocannabinoid system (ECS) has an important role in signalization processes, not only in the central nervous system, but also in the peripheral tissues. Several physiological functions are affected, and overexpression or downregulation contributes to several diseases. A better understanding of the functions of cannabinoid (CB) receptors may propose potential therapeutic effects by influencing receptor signaling and enzymes involved in downstream pathways. In this review, we summarize recent information regarding the roles of the ECS and the CB1 receptor signaling in the physiology and pathophysiology of energy and metabolic homeostasis, in the development of obesity by enhancing food intake, upregulating energy balance and fat accumulation, increasing lipogenesis and glucose production, and impairing insulin sensitivity and secretion. By analyzing the roles of the ECS in physiological and pathophysiological mechanisms, we introduce some recently identified signaling pathways in the mechanism of the pathogenesis of metabolic syndrome. Our review emphasizes that the presence of such recently identified ECS signaling steps raises new therapeutic potential in the treatment of complex metabolic diseases such as diabetes, insulin resistance, obesity, and hypertension.
... Ghrelin levels are increased in negative energy balance, such as in fasting, and decrease in positive energy balance, as in obesity and MetS (López-Lopez et al., 2018). Given the complexity of MetS, complete treatment requires changes to the diet, physical exercise, and polypharmacological intervention, including hypoglycemic agents for diabetes, hypolipidemics for dyslipidemia, antithrombotics (aspirin), antihypertensives, and antiobesity agents (Mastinu et al., 2018). Besides, MetS links well with alterations associated to psychological factors, neuroendocrine functioning, and immunological response. ...
... CB2 agonists have also shown anti-inflammatory effects in cell culture models involving human astrocytes pre-stimulated with IL-1β, human endothelial cells prestimulated with TNF-α, human T-lymphocytes, and neutrophils (Scharf, 2017). CB2 agonists regulate the pathogenesis and progression of various inflammationand immune-related diseases by increasing the recruitment, migration, and adhesion of leukocytes, and by modulating the release of chemokines and cytokines (increased production of anti-inflammatory IL-10 and reduced TNF-α, IL-2, IL-12, and IFN-γ expression) in in vivo and in vitro models of chronic diseases, including atherosclerosis, multiple sclerosis, and metabolic disorders (Hu, Tao, Hu, 2019;Mastinu et al., 2018;Vecera et al., 2020). In contrast, antagonism with selective CB2 ligands such as SR144528 blocks the anti-inflammatory effects elicited by the activation of this receptor. ...
... Although the potential utility of CB1 antagonists or CB2 agonists in the treatment obesity, diabetes, and MetS, including diabetic complications among other diseases, has been shown in clinical and experimental studies, further studies yet are required. These should assess various aspects such as the simultaneous evaluation of CB1 antagonists and CB2 agonists, determination of the clinical implications of polymorphisms in CB1 and CB2, the assessment of new CB1 antagonists that do not cross the brain-blood barrier or more selective CB2 agonists, and studying the therapeutic potential of other natural cannabinoids (Horvát et al., 2012;Gruden et al., 2016;Mastinu et al., 2018). One of the fundamental aspects that should be investigated is associated with the assessment of CB1 antagonists, in particular rimonabant, with potential for the treatment of disorders related to glucose homeostasis (Borowska et al., 2018). ...
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Abstract Metabolic syndrome (MetS), an epidemic defined as a group of interconnected physiological, biochemistry, clinical, and metabolic factors, directly increases the risk of cardiovascular disease, atherosclerosis, type 2 diabetes, and death. MetS therapy includes diet, physical exercise, and a poly-pharmacological intervention. Cannabis is mainly recognized for its recreational uses and has several medical applications for neurological diseases, due to its hypnotic, anxiolytic, antinociceptive, anti-inflammatory, and anticonvulsant activities. Although several clinical observations in Cannabis smokers suggest metabolic effects, its utility in metabolic disorders is unclear. This review aims to determine under what conditions Cannabis might be useful in the treatment of MetS. Cannabis contains 120 phytocannabinoids, of which Δ9-THC mediates its psychoactive effects. Cannabinoids exert biological effects through interactions with the endocannabinoid system, which modulates several physiologic and metabolic pathways through cannabinoid receptors (CB1/CB2). Signaling through both receptors inhibits neurotransmitter release. In general, endocannabinoid system stimulation in Cannabis smokers and Δ9-THC signaling through CB1 have been implicated in MetS development, obesity, and type 2 diabetes. In contrast, CB1 antagonists and non-psychotropic phytocannabinoids like cannabidiol reduce these effects through interactions with both cannabinoid and non-cannabinoid receptors. These pharmacological approaches represent a source of new therapeutic agents for MetS. However, more studies are necessary to support the therapeutic potential of Cannabis and cannabinoids in metabolic abnormalities.
... In relation to eating behavior, emerging evidence points to an important role of cannabinoids in regulating appetite, and consequently food intake. Additionally, cannabinoids are also an important player in the reward circuitries [13][14][15][16]. Thus, we found it timely to conduct a review in order to better clarify the potential impact of CBD on appetite and body weight in humans. ...
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Background and objective: Cannabidiol, one of the main components of the Cannabis sativa plant, is a non-psychotropic cannabinoid that has recently drawn the attention of researchers and clinicians for its potential therapeutic applications. In this systematic review, we aim to describe the possible effects of cannabidiol in appetite and body weight. Methods: Both authors independently ran a thorough search in both PubMed and Cochrane databases up to 31 July, 2022 and included every peer-reviewed, original randomized controlled clinical trial that reported data on either of the said outcomes. Risk of assessment bias was performed with Cochrane's risk of bias tool and results were summarized in tables. Results: A total of 11 trials were included in this review. Of these, the majority reported on cannabidiol reducing appetite and/or body weight whilst some have found no significant changes and one trial described an increase in appetite. Conclusions: This systematic review suggests that cannabidiol has an anorexigenic effect, correlated with a decrease in body weight. However, most of the studies included in the present review raised some concerns in terms of risk of bias. We believe further research is needed in order to clarify potential mechanisms involved in the effect of cannabidiol on feeding/appetite.
... Several neurodegenerative disorders display alterations in components of the endocannabinoid system (ECS), and a cannabinoid-based approach has proven efficacious in the reversal of certain neurodegenerative events in pre-clinical models of neuroinflammation, oxidative stress, and neuronal loss, among others (Basavarajappa et al., 2009;Di Marzo 2009;Aymerich et al., 2018;Mastinu et al., 2018). The ECS is a complex signaling system consisting of cannabinoid receptors, their endogenous ligands (known as "endocannabinoids"), and the enzymes responsible for endocannabinoid biosynthesis, cellular uptake and catabolism (Bisogno et al., 2005). ...
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It is well known that G protein–coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units. This approach proved to be very promising showing several advantages over monovalent targeting strategies, including an increased affinity or selectivity, a bias in signaling pathway activation, reduced off-target activity and therapeutic resistance. Our study focused on the cannabinoid receptor type 2 (CB2R), considered a clinically promising target for the control of brain damage in neurodegenerative disorders. Indeed, CB2R was found highly expressed in microglial cells, astrocytes, and even in some neuron subpopulations. Here, we describe the design, synthesis, and biological evaluation of two new classes of potential dualsteric (bitopic) CB2R ligands. The new compounds were obtained by connecting, through different linkers, the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both developed in our laboratories. A preliminary screening enabled us to identify compound JR64a as the most promising of the series. Indeed, functional examination highlighted a signaling ‘bias’ in favor of G protein activation over βarrestin2 recruitment, combined with high affinity for CB2R and the ability to efficiently prevent inflammation in human microglial cells (HMC3) exposed to LPS/TNFα stimulation, thus demonstrating great promise for the treatment of neurodegenerative diseases.
... This active ingredient binds to key brain receptors involved in the metabolic and neuroinflammatory pathologies and a variety of brain functions including the type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) (Kumar et al. 2019). The metabolic syndromes are thought to be linked to a change in systemic inflammation, with CBD playing a major role in the mitigation (Mastinu et al. 2018). Patients who want to use cannabis for medical purposes must first get a prescription from a practitioner, dentist, or a registered Thai-traditional medical professional. ...
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The current revision to Thailand's Narcotics Act (B.E. 2563) permits Thai corporations to produce cannabis (ganja) for therapeutic purposes, as well as conduct beneficial research and development in science and agriculture. While ganja possession, distribution, and use are still illegal in Thailand, the law removes certain elements of Cannabis sativa (including hemp) from the narcotic lists as of December 2020 and Thailand's narcotics board plans to remove them totally from the lists before the last quarter of 2022. The Thai Food and Drug Administration (Thai FDA) board maintains the exclusive licensing authority to assess applications and provide authorization due to the complexity of the registration process. In this view, we analyzed the guidelines for obtaining cannabis production license, and it was apparent that the announced law was in-line with regulations set-out by many countries in terms of security and prevention of misuse. The other criteria however fall merely onto the government gains, rather than public interests. To avoid the claimed state monopoly, several types of licensing should be issued in the future, depending on the genuine purpose of the farmers. The complete regulation process and conditions for obtaining a ganja growing license in Thailand are highlighted and discussed in this review.
... Depression was assessed with The Calgary Depression Scale for Schizophrenia (CDSS) (Addington, Addington, & Schissel, 1990) and social function with the self-report Social Function Scale (SFS) (Birchwood, Smith, Cochrane, Wetton, & Copestake, 1990) and observer-rated Global Assessment of Functioning (GAF) scale. Lifetime cannabis use was assessed using a self-report measure and current BMI was calculated as both can effect inflammatory measures (Mastinu et al., 2018;Visser, Bouter, McQuillan, Wener, & Harris, 1999). ...
... For the imaging analysis, sex, age and scan site were controlled for when comparing groups. BMI and lifetime cannabis use were controlled for as potential confounders in the analysis of inflammation markers (Mastinu et al., 2018;Visser et al., 1999) Raw p-values are reported for ANOVAs. To control for multiple testing, main effects were adjusted for false discovery rate (FDR) using the Benjamini-Hochberg method (Benjamini & Hochberg, 1995). ...
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Background Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation. Method 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF- α . Results Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ ( F (2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ ( F (2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls. Conclusions The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).
... Following CB 1 activation, AEA is enzymatically degraded post-synaptically by FAAH, and 2-AG is degraded by MAGL pre-synaptically and by ABHD6 post-synaptically. Adapted from "Cannabinoids in health and disease: Pharmacological potential in metabolic syndrome and neuroinflammation" by Mastinu et al. (2018) and Murataeva et al. (2014). membranes, where the production is initiated by a rising level of calcium ions (Hartsel et al., 2019). ...
Article
Recent advances in cannabidiol (CBD) use in canines and felines for anxiety management, pain management, and anti-inflammatory effects were reviewed using a literature search conducted with the following keywords: CBD, anxiety, inflammation, pain, dogs, cats, and companion animals. For decades, research on CBD has been hindered due to the status of cannabis (C. sativa L.) as an illicit drug. Limited safety data show that CBD is well-tolerated in dogs, with insufficient information on the safety profile of CBD in cats. Upon oral supplementation of CBD, elevation in liver enzymes was observed for both dogs and cats, and pharmacokinetics of CBD are different in the two species. There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management. There is evidence that chronic osteoarthritic pain in dogs can be reduced by supplementation with CBD. Furthermore, experiments are required to better understand whether CBD has an influence on noise-induced fear and anxiolytic response. Preliminary evidence exists to support the analgesic properties of CBD in treating chronic canine osteoarthritis; however, there are inter- and intra-species differences in pharmacokinetics, tolerance, dosage, and safety of CBD. Therefore, to validate the anxiety management, pain management, and anti-inflammatory efficacy of CBD, it is essential to conduct systematic, randomized, and controlled trials. Further, the safety and efficacious dose of CBD in companion animals warrants investigation.
... After the 1930s, medical use of cannabis significantly decreased as it was considered to be an illegal substance, and its use in psychiatry was limited. However, after the identification of the main components of cannabis and the discovery that the endocannabinoid system (ECS) is able to modulate different processes in pain medicine and psychiatric disorders, interest in the use of cannabinoids has been renewed [10,12,13,18,26]. The medical use of cannabis extracts was approved in June 2010 by ten European countries [7]. ...
Article
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Over the past two decades, numerous tools have been developed to study the endocannabinoid system. Studies show the potential effectiveness of endocannabinoids for the relief of pain and neurological disorders. However, global targeting of the endocannabinoid system has also been associated with unwanted outcomes, including deleterious effects on cognitive and emotional functions, the development of tolerance and dependence, and withdrawal symptoms after drug cessation in humans. The main objective of the present study was to determine whether male mice develop tolerance to delta-9-tetrahydro-cannabinol (THC) and cannabinolic acid (CBNA)-induced antinociception with long-term treatment. Using behavioral tests of mechanical and thermal nociception, we found that systemic (intraperitoneal, i.p.) administration of THC and CBNA resulted in strong antinociception on the first day of the experiment. However, over the next four days, the behavior indices of antinociception to mechanical and thermal stimuli gradually decreased, indicating the development of tolerance following systemic administration of these drugs. Thus, the two main components of cannabis, THC and CBNA, are characterized by the development of tolerance in mice as a result of their repeated i.p. administration.
... MAGL and FAAH might implement therapeutic effects without causing unpleasant side effects correlated with direct CB1 receptor stimulation by THC (Egmond et al., 2021). Palmitoyl and oleoyl ethanolamide are some of the many fatty acid amides on which FAAH has a catabolic effect (Mastinu et al., 2018). Therefore, natural or many synthetic molecules that inhibit FAAH can generate biological responses that are not limited to ECS (Kumar, et al., 2019). ...
Article
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To combat the coronaviruses and their novel variants, therapeutic drugs and the development of vaccines that are to be effective throughout human life are urgently needed. The endocannabinoid system (ECS) acts as a modulator in the activation of the microcirculation, immune system, and autonomic nervous system, along with controlling pharmacological functions such as emotional responses, homeostasis, motor functions, cognition, and motivation. The ECS contains endogenous cannabinoids, cannabinoid receptor (CBRs), and enzymes that regulate their biosynthesis, transport, and degradation. Moreover, phytocannabinoids and synthetic cannabinoids that mimic the action of endocannabinoids also play an essential role in the modulation of the ECS. Cannabinoids, the main constituents of cannabis (Cannabis sativa L.), are therapeutic compounds that have received international attention in the health field due to their therapeutic properties. Recently, they have been tested for the treatment of COVID-19 due to their antiviral properties. Indeed, cannabinoid-type compounds, and in particular cannabidiol (CBD), isolated from glandular trichomes found in the calyx of cannabis flowers with reported antiviral properties is hypothesized to be a therapeutic option in the ministration of SARS-CoV-2 consorted with COVID-19 disease. The relevant articles were determined from the database search published mainly in Web of Science, Google scholar, PubMed, Crossref, and ClinicalTrials.gov database during the pandemic period. The articles were evaluated for the therapeutic potentials, mechanisms of action of cannabinoids, the roles of the ECS in the immune system, impact of cannabinoids in SARS-CoV-2 septic, especially if they address the application of cannabinoids as drugs for the curability and management of SARSCoV-2 and its novel variants. Although the evidence needed to be considered using cannabinoids in the control and treatment of viral diseases is currently in its infancy, they already offer an opportunity for clinicians due to their effects in relieving pain, improving appetite, and improving childhood epilepsy, especially in cancer and human immunodeficiency virus (HIV/AIDS) patients. In addition to these, the most recent scientific evidence emphasizes their use in the treatment of the coronavirus infected patients. In brief, all preclinic and clinic studies that have been reported show that, through the cannabinoid system, cannabinoids, particularly CBD, have many mechanisms that are effective in the treatment of patients infected by SARS-CoV-2. Thus, more extensive studies are necessary in this area to fully identify the effects of cannabinoids on SARS-CoV-2.
... Adult neurogenesis has been shown to be a solid instance of brain plasticity, modulated by the endocannabinoid system. In recent years, numerous studies have reported the expression of the endocannabinoid system in neural stem cells (Mastinu et al. 2018). The non-psychoactive cannabidiol (CBD) has become an interesting research subject in clinical and preclinical areas to treat substance abuse disorders (Wenzel and Cheer 2018). ...
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Chronic methamphetamine (meth) abuse can lead to certain deficits in the hippocampal function by affecting the hippocampal neurogenesis and plasticity. To determine whether cannabidiol (CBD) can promote proliferation and maturation of neuronal progenitor cells, this study investigated the CBD effect on neurogenesis in the hippocampal dentate gyrus (DG) following chronic exposure to meth in rats. The rats received 2 mg/kg of meth twice a day for ten days. Next, immunofluorescence was performed to evaluate the effect of intracerebroventricular (ICV) administration of CBD (50 μg/5 μL) over an abstinence period (ten days) on the expression levels of neurogenesis markers, such as Ki67, NeuN, and doublecortin (DCX). Moreover, neuronal degeneration in the hippocampus was assessed using Nissl staining. According to our findings, repeated ICV administration of CBD improved cell proliferation and neurogenesis and increased the number of Ki-67 and DCX-positive cells in the abstinence period. Meanwhile, meth treatment subjects caused a significant decrease in the number of neurogenesis makers, as compared to the control group. The neurogenesis markers (Ki-67 and DCX) could be somewhat reversed, while NeuN did not show any significant increase in the CBD group. Our findings demonstrated that CBD can induce neuroprotective effects by modulating neurogenesis. Therefore, it can provide a promising therapeutic approach to improve cognitive performance following chronic exposure to psychostimulant drugs, including meth.