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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
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PMID:Therapeutic potential of cannabinoids in CNS disease. 1261 97

The ability of Cannabis sativa (marijuana) to increase hunger has been noticed for centuries, although intensive research on its molecular mode of action started only after the characterization of its main psychoactive component Delta(9)-tetrahydrocannabinol in the late 1960s. Despite the public concern related to the abuse of marijuana and its derivatives, scientific studies have pointed to the therapeutic potentials of cannabinoid compounds and have highlighted their ability to stimulate appetite, especially for sweet and palatable food. Later, the discovery of specific receptors and their endogenous ligands (endocannabinoids) suggested the existence of an endogenous cannabinoid system, providing a physiological basis for biological effects induced by marijuana and other cannabinoids. Epidemiological reports describing the appetite-stimulating properties of cannabinoids and the recent insights into the molecular mechanisms underlying cannabinoid action have proposed a central role of the cannabinoid system in obesity. The aim of this review is to provide an extensive overview on the role of this neuromodulatory system in feeding behavior by summarizing the most relevant data obtained from human and animal studies and by elucidating the interactions of the cannabinoid system with the most important neuronal networks and metabolic pathways involved in the control of food intake. Finally, a critical evaluation of future potential therapeutical applications of cannabinoid antagonists in the therapy of obesity and eating disorders will be discussed.
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PMID:Endogenous cannabinoid system as a modulator of food intake. 1262 55

Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.
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PMID:Cannabinoids and the regulation of ingestive behaviour. 1577 91

The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein-coupled family receptors and they were discovered while investigating the mode of action of ?(9)-tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long-lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up-regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors.
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PMID:The endocannabinoid system and the treatment of obesity. 1601 25

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.
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PMID:The emerging role of the endocannabinoid system in endocrine regulation and energy balance. 1630 85

The promising results obtained by clinical trials using Rimonabant to tackle visceral obesity and related disorders recently promoted a remarkable impulse to carry out detailed investigations into the mechanisms of action of endocannabinoids in regulating food intake and energy metabolism. The endocannabinoid system has been known for many years to play an important role in the modulation of the neuronal pathways mediating the rewarding properties of food. However, in the last few years, with the advanced understanding of the crucial role of the hypothalamic neuronal network in the regulation of appetite, several studies have also directed attention to the orexigenic role of the endocannabinoid system, substantiating the well known appetite stimulating properties of derivatives of Cannabis sativa. Furthermore, the last 2 years have seen a number of relevant publications emphasizing the role of endocannabinoids as significant players in various peripheral metabolic processes. To date, the roles of the endocannabinoid system in influencing energy metabolism have proved to be more complex than was formerly believed. However, the diverse ability to modulate both central and peripheral processes highlights the pivotal involvement of the endocannabinoid system in the control of metabolic processes. This review describes the roles of endocannabinoids and the cannabinoid type 1 receptor (CB1) in the control of energy balance.
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PMID:How many sites of action for endocannabinoids to control energy metabolism? 1657 Jan 4

The dramatic increase in the prevalence of obesity worldwide represents one of the most important challenges of modern medicine, owing to its myriad related complications-in particular cardiovascular disease, the leading cause of death worldwide. Originating from early studies with Cannabis sativa, the active compound of marijuana, there has been an impressive progress in the knowledge about the endocannabinoid network, leading to the identification of specific pathways that modulate feeding behavior. The effects of endocannabinoids are not limited to the central nervous system, but also include peripheral tissues. Experimental and clinic trials have demonstrated the efficacy of endocannabinoid antagonists in the management of obesity and the cardiometabolic syndrome. Better understanding of the mechanisms underlying obesity will lead to development of more active and specific agents, which surely will enlarge the role of this efficacious alternative for management of obesity.
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PMID:The endocannabinoid network: insight into the regulation of the neuroendocrine and metabolic systems. 1768 53

The CB1 and CB2 cannabinoid receptors have been described as two prime sites of action for endocannabinoids. Both the localization and pharmacology of these two G-protein-coupled receptors are well-described, and numerous selective ligands have been characterized. The physiological effects of Cannabis sativa (cannabis) and a throughout study of the endocannabinoid system allowed for the identification of several pathophysiological conditions--including obesity, dyslipidemia, addictions, inflammation, and allergies--in which blocking the cannabinoid receptors might be beneficial. Many CB1 receptor antagonists are now in clinical trials, and the results of several studies involving the CB1 antagonist lead compound rimonabant (SR141716A) are now available. This review describes the pharmacological tools that are currently available and the animal studies supporting the therapeutic use of cannabinoid receptor antagonists and inverse agonists. The data available from the clinical trials are also discussed.
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PMID:Blocking the cannabinoid receptors: drug candidates and therapeutic promises. 1771 20

Endogenous signaling lipids ("endocannabinoids") functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems including type-2 diabetes, atherothrombosis, inflammation, and immune disorders. Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.
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PMID:Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome. 1815 57

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.
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PMID:Cannabinoids in health and disease. 1828 1


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