Tag Archives: treatment

Why Cannabis Stems Inflammation

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“Cannabis has long been accredited with anti-inflammatory properties. ETH Zurich researchers, however, have now discovered that it is not only the familiar psychoactive substances that are responsible for this; a compound we take in every day in vegetable nutriment also plays a significant role.

People not only rate cannabis sativa L. highly because of its intoxicating effects; it has also long been used as a medicinal plant. Although the plant has been scrutinized for years, surprising new aspects keep cropping up. For example, researchers from ETH Zurich and Bonn University examined a component in the plant’s essential oil that until then had largely been ignored and found it to have remarkable phar- macological effects. The findings open up interesting perspectives, especially for the prevention and treatment of inflammations.

The hemp plant contains over 450 different substances, only three of which are responsible for its intoxicating effect. They activate the two receptors in the body CB1 and CB2. Whilst the CB1 receptor in the central nervous system influences perception, the CB2 receptor in the tissue plays a crucial role in inhibiting inflammation. If the receptor is activated, the cell releases fewer pro-inflammatory signal substances, or cytokines. The scientists have now discovered that the substance beta-carophyllene, which composes between 12 and 35 percent of the cannabis plant’s essential oil, activates the CB2 receptor selectively.”

http://www.sciencedaily.com/releases/2008/07/080720222549.htm

Cannabinoids and the immune system: potential for the treatment of inflammatory diseases?

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Abstract

“Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/16023222

Cannabinoids and the immune system: an overview.

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“Cannabinoids can influence the immune network. Data on the impact of exogenous cannabinoid ligands on immune function serve not only to understand how the endocannabinoid system modulates immune phenomena associated with infection or inflammation, but also to identify therapeutic targets for immune diseases.

Cannabinoids can modulate immune reactions in the periphery but also in the brain, influence T cell subset balance and cytokine expression and play a role in the balance between neuroinflammation and neurodegeneration. Immune cells can synthesize endocannabinoids and also be influenced by cannabinoid analogues.

Cannabinoid receptors show different expression on immune cells depending on activation status and stimuli. The complexity of relation between cannabinoid ligands of various classes and cannabinoid receptors brought the need to refine the simple conceptual frame of agonist-antagonists and offered potential implications for understanding interactions in pathological conditions.

The immune influence of cannabinoid ligands is not fully elucidated. However, aspects of their immunomodulatory effects provide the basis for a context-dependent targeted therapeutic approach, thus leading to the possibility for the use of cannabinoids in the treatment of inflammatory disease.”

[Endocannabinoid system and energy metabolism: physiology and pathophysiology].

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Abstract

“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 has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, therefore drugs interfering with this overactivation by blocking CB1 receptor are considered as valuable candidates for the treatment of obesity and related cardiometabolic risk factors.”

http://www.ncbi.nlm.nih.gov/pubmed/18773754

Expression of the cannabinoid system in muscle: effects of a high-fat diet and CB1 receptor blockade

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Abstract

“The ECS (endocannabinoid system) plays an important role in the onset of obesity and metabolic disorders, implicating central and peripheral mechanisms predominantly via CB1 (cannabinoid type 1) receptors. CB1 receptor antagonist/inverse agonist treatment improves cardiometabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. In the present study, we have identified the presence of the endocannabinoid signalling machinery in skeletal muscle and also investigated the impact of an HFD (high-fat diet) on lipid-metabolism-related genes and endocannabinoid-related proteins. Finally, we tested whether administration of the CB1 inverse agonist AM251 restored the alterations induced by the HFD. Rats were fed on either an STD (standard/low-fat diet) or an HFD for 10 weeks and then treated with AM251 (3 mg/kg of body weight per day) for 14 days. The accumulated caloric intake was progressively higher in rats fed on the HFD than the STD, resulting in a divergence in body weight gain. AM251 treatment reduced accumulated food/caloric intake and body weight gain, being more marked in rats fed on the HFD. CB2 (cannabinoid type 2) receptor and PPARα (peroxisome-proliferator-activated receptor α) gene expression was decreased in HFD-fed rats, whereas MAGL (monoglyceride lipase) gene expression was up-regulated. These data suggest an altered endocannabinoid signalling as a result of the HFD. AM251 treatment reduced CB2 receptor, PPARγ and AdipoR1 (adiponectin receptor 1) gene expression in STD-fed rats, but only partially normalized the CB2 receptor in HFD-fed rats. Protein levels corroborated gene expression results, but also showed a decrease in DAGL (diacylglycerol) β and DAGLα after AM251 treatment in STD- and HFD-fed rats respectively. In conclusion, the results of the present study indicate a diet-sensitive ECS in skeletal muscle, suggesting that blockade of C1 receptors could work towards restoration of the metabolic adaption imposed by diet.”

“In the present study, we focused on skeletal muscles, which are an important tissue for glucose and fat oxidation, being an important site for insulin action [27]. However, despite the fact that AEA can modify the pathways regulating fatty acid oxidation in the skeletal muscle, probably via CB1 receptors, suggesting that CB1 receptor antagonism would have an important role in oxidative metabolism and energy regulation [28,29], there is still a general lack of clarity regarding the physiological functions and molecular mechanism implicated. In fact, there are almost no studies demonstrating the presence of endocannabinoid signalling proteins and their sensitivity to HFDs (high-fat diets). Therefore, in the present study, we have (i) investigated the presence of the endocannabinoid signalling machinery in skeletal muscle, (ii) analysed the impact of an HFD on lipid and glucose metabolism and endocannabinoid-related genes, and (iii) monitored the effects of the CB1 receptor inverse agonist AM251 during an STD (standard/low-fat diet) and HFD on the endocannabinoid machinery and the genes related to lipid oxidative metabolism in skeletal muscle of rats. Among the many molecules involved in lipid metabolism of skeletal muscle, we evaluated changes in the gene and protein expression of relevant components of the ECS, such as the CB1 and CB2 receptors and some of the enzymes responsible for their synthesis.

The presence of the ECS in skeletal muscle

As a final note, the regulatory mechanisms may be different at rest and during exercise, may change as the exercise intensity increases, and this could be influential in endocannabinoid production [31,49]. It would be interesting to repeat this type of experiment combining exercise and diet in its original design. Regulation of skeletal muscle fat and glucose metabolism is clearly multifactorial, and different mechanisms may dominate in different conditions; besides, potential variations may exist between individuals in response to stimulating or blocking CB1 receptors. This could cause differences in response to treatment with CB1 receptor antagonists between different obese states. In conclusion, we have provided findings identifying important relevant players involved in the signalling pathways of CB1 receptor antagonism in skeletal muscle and determined the extent of changes in this system associated with either an HFD or CB1 receptor blockade.”

http://www.biochemj.org/bj/433/0175/bj4330175.htm

Obesity, the Endocannabinoid System, and Bias Arising from Pharmaceutical Sponsorship

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“Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees.

 This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.

CONCLUSIONS:

The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

In summary, financial conflicts permeate the system and are by no means limited to corporations referenced in this article, such as Merck, Parke-Davis, Pfizer, Sanofi-Aventis, and Wyeth-Ayerst. On balance, pharmaceutical corporations do good work and aid in humanitarian efforts. For example Sanofi-Aventis provides artemisinin at cost to malaria-endemic countries. Nevertheless, ghost authorship and the corrupting effects of covert financial support must cease. Only three of eight rimonabant review articles disclosed corporate sponsorship; two authors specifically denied conflicts. Lack of disclosure prevents readers from judging the credibility of an author. Medical journals should require stronger author disclosure procedures, and universities should discipline academics who sign ghostwritten articles. This behavior should be regarded as unethical misconduct. More broadly, researchers with conflicts of interest should not be allowed to sit on guideline committees and regulatory boards. Corporate funding of CME programs and review articles should be abolished.

While this paper was under review, Merck halted taranabant RCTs, and Sanofi-Aventis removed rimonabant from the European market. The FDA rejected rimonabant after data submitted by Sanofi-Aventis revealed adverse effects in RIO trials that went unreported in RIO publications [86], including one death in a rimonabant-treated subject (ruled a suicide by the FDA, [86]) that did not appear in the pertinent publication [7]. Although the risk-benefit ratio of cannabinoid receptor blockade may preclude its use for chronic conditions such as obesity and drug or alcohol dependence, cannabinoid receptor blockade could serve in the treatment of acute endocannabinoid dysregulation, such as hepatic cirrhosis, hemorrhagic or endotoxic shock, cardiac reperfusion injury, and doxorubicin-induced cardiotoxicity.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659447/

 

Rimonabant: a novel selective cannabinoid-1 receptor antagonist for treatment of obesity.

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Abstract

“PURPOSE:

The pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of rimonabant in the treatment of obesity and related metabolic factors are reviewed.

SUMMARY:

Discovery of the cannabinoid receptors has led to the development of rimonabant, a cannabinoid-1 (CB(1)) antagonist. Selective blockade of this receptor has been shown to lead to decreased appetite and food intake in animal models. Clinical studies have shown that rimonabant 20 mg once daily produces significant decreases in weight and waist circumference in obese human subjects and improves the lipid profile and glucose control. The frequency of metabolic syndrome also decreased significantly with rimonabant 20 mg daily. Limited data are available regarding the pharmacokinetics and pharmacodynamics of rimonabant. Preclinical data have demonstrated a long duration of action. As of yet, no drug-drug, drug-food, or drug-disease interactions have been identified with rimonabant. Adverse reactions occurred rarely, with nausea, dizziness, diarrhea, arthralgia, and back pain being the most common. Psychiatric disorders, including depression and anxiety, were the most common reasons for subjects to withdraw from rimonabant studies. Rimonabant has been shown to be safe for up to two years of treatment. Further research will clarify currently unknown areas, including pharmacokinetics, drug interactions, and the drug’s role in standard therapy.

CONCLUSION:

Rimonabant, a selective CB(1) antagonist, is a novel treatment option for obese and overweight individuals. Significant weight loss, decrease in waist circumference, and improvements in lipid profile and glucose control have been shown in clinical trials of rimonabant.”

http://www.ncbi.nlm.nih.gov/pubmed/17322160

Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity.

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Abstract

“Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti-smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA (Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress.”

http://www.ncbi.nlm.nih.gov/pubmed/19443932

The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism–or inverse agonism–as potential obesity treatment and other therapeutic use.

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Abstract

“There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/17489873

Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity.

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Abstract

“Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/23070073