The Endocannabinoid (EC) system is a physiologic system, acts centrally as well as peripherally, and plays a key role in regulating body weight and metabolic processes. The EC System also plays a role in tobacco dependence.

Endocannabinoids (ECBs), are the chemical messengers of the EC System, which bind and activate the cannabinoid (CB) receptors. There are currently two known subtypes of cannabinoid receptors namely, CB1 and CB2.

CB1 is expressed in the brain, adipose tissue, liver, muscle and GI tract and CB2 is mainly expressed in the immune system. CB1 receptors are found in the brain as well as in some peripheral tissues of the body such as adipocytes (or "fat cells"), are associated with lipid and glucose metabolism.

EC System through both central and peripheral activity helps to regulate food intake and energy expenditure.

CB1 receptor on a cell membrane being activated by an ECB

CB1-receptors in the CNS, are necessary to kick-start food intake after a short period of food deprivation. When activated, they also preferentially stimulate the ingestion of palatable food. Studies using a variety of behavioural paradigms indicate that ECBs may play a very specific role in appetite control. This is achieved by modulating the expression and release of appetite suppressing and appetite stimulating chemical messengers in the hypothalamus region of the brain.

CB1 receptor activation is also apparent in an area of the brain called the nucleus accumbens shell, a small subcortical area that is believed to be important in motivational processes that mediate the incentive value of food, and which is also important in the process by which tobacco dependence is acquired and maintained.

EC System: Peripheral Activity

The EC System functions in many levels of the energy balance system including the gastrointestinal tract and adipocyte. At the peripheral level the activation of the CB1 receptor has been shown to stimulate lipogenesis in adipocytes that results in fat accumulation and modulation of the expression of adiponectin, a hormone that regulates the metabolism of lipids and glucose. Through its effects on the multiple components of the energy balance system, the EC System helps regulate the physiologicalnee d to eat and the energy storage state.

EC System: Over-activation in obesity and metabolic disorders

Overweight and obesity are some of the biggest challenges facing modern medicine today Obesity has reached global epidemic proportions with more than 1.6 billion adults overweight and at least 400 million of them recognized as clinically obese (BMI >30 kg/m2).

Obesity is usually defined by measure of the body mass index (BMI) (weight/ (kg)/height (m²). The World Health Organization (WHO) defines overweight as a BMI of 25.0-29.9 and obesity as a BMI >30. Obesity is widely recognised as a major contributor to the global burden of chronic disease and disability and appears on the WHO list of Top 10 global health risks.

Food storage and adjustment to environmental changes are critical to all living organisms. There is interplay between multiple mechanisms in our body and brain that signal hunger and satiety in an extremely precise fashion. Signals from stored and available fuel are integrated and help determine food intake and energy expenditure. The EC System plays a major role within this complex interplay of mechanisms, helping to maintain energy balance by regulating what and how much we eat and how much fat we store or use. This energy balance system can be disturbed externally by environmental factors or internally by genetic factors.

The explosive worldwide growth of obesity is due to alteration in our nutritional habits and sedentary lifestyle. Furthermore, the modern high-fat, high-carbohydrate diet has also contributed to the increase in the incidence of obesity. The combination of a sedentary lifestyle and a calorie-dense diet can disrupt the energy balance system, leading to obesity and chronic over-stimulation of the EC System.

Long-lasting over-stimulation of ECB synthesis (or under-stimulation of their breakdown), by some chronic pathologic states such as obesity results in permanent over-activation of CB1 receptors, which may then contribute to the symptoms of these disorders.

The EC System is operating out of its normal range in obesity and receives aberrant signals from the malfunctioning weight control system. Its activity is up regulated and it is converted from a system that is intermittently transiently activated, to one that is chronically overactivated. This overactivity not only promotes fat storage in the adipocytes, but can also be associated with insulin resistance, glucose intolerance, elevated triglycerides and low HDL cholesterol levels, all of which are risk factors for cardiovascular disease. Therefore, regulating the EC System is important in the control of food/energy storage and release in the body.

Blockade CB1 receptor modulates overactivity of the EC System resulting in the restoration of balance. Blocking the CB1 receptor eliminates the part of obesity that is controlled by the EC System such as increased appetite, excessive hunger and food intake. It also increases adiponectin levels, which is thought to result in increased fat metabolism and an improvement in glucose metabolism. This may result in reducing cardiovascular risk factors through weight loss and an improvement in metabolic risk factor profile.

EC System Over-activation in nicotine dependence

Smoking tobacco, remains the leading preventable cause of death in the world. Nicotine is the chemical within tobacco smoke that causes addiction. It is difficult to explain why some people become dependent on nicotine, while others develop a pattern of occasional use or abstain from it completely.

It has been demonstrated that chronic nicotine consumption results in persistent over-stimulation of the EC System in animals. Dopamine release into the nucleus accumbens is one of the neurochemical substrates underlying the motivation to consume nicotine. The chronic consumption of nicotine permanently over-stimulates the EC System in the nucleus accumbens shell, with subsequent reinforcement of dopamine release and nicotine abuse.

Blockade of CB1, possibly by impairing the release of dopamine in the nucleus accumbens shell, reduces motivation to self-administer nicotine.

The discovery of the first selective CB1 blocker, rimonabant, has helped to characterize and increase the understanding of the many facets of the EC System and opened the door for the development of novel pharmacotherapies

It is well documented that the EC System exerts significant influence on a number of risk factors for cardiovascular disease. Overeating and increased fat storage due to dysregulation of endocannabinoid signalling can contribute to obesity and other hallmarks of the metabolic syndrome, such as dyslipidemia and type 2 diabetes. Additionally, dysregulated endocannabinoid signalling can reinforce tobacco dependence. Thus, using a selective CB1 blocker to regulate endocannabinoid signalling represents a potential therapeutic strategy in managing cardiovascular risk factors.

Rimonabant promises a new approach to address cardiovascular risk factor management, specifically in the areas of obesity, metabolic disorders, and tobacco dependence. By selectively blocking the CB1 receptor, rimonabant modulates over-activity of the EC System, which is thought to result in weight loss and improvement of metabolic risk factors (i.e. HDL, triglycerides and insulin resistance) in obesity.

In chronic tobacco use, rimonabant similarly balances the activity of the EC System, which is thought to result in reduced dependence on tobacco, which in turn helps to achieve smoking cessation without associated post-cessation weight gain.

Data from the Rimonabant In Obesity - Europe (RIO-Europe) trial shows that patients treated for one year with rimonabant 20mg/day lost an average of 8.6kg (about 19 lbs) (p < 0.001 vs placebo) compared to 4.8kg (about 11 lbs) for patients on rimonabant 5mg/day (p=0.038 vs placebo) and 3.6kg (about 8 lbs) for those on placebo. Moreover, 39 percent (p < 0.001 vs placebo) of patients on rimonabant 20mg/day lost more than 10 percent of their initial body weight compared 12.4 percent of those on placebo. People taking rimonabant 20mg also had a significant reduction in waist circumference and improvements in lipid and glycemic profiles. Data from other studies (RIO- Lipid and RIO- North America) also show consistent weight changes

Available data from the STudies with Rimonabant And Tobacco USe-US (STRATUS-US) trial shows that, at ten weeks of follow-up, treatment with rimonabant 20mg/day doubled the odds of quitting smoking versus placebo and significantly reduced post-cessation weight gain.

Both the RIO studies and STRATUS-US studies also indicated a favourable safety profile of rimonabant. In the RIO studies side effects were mainly mild and transient and most frequently involved nausea (4.3 percent, 5.1 percent and 12.9 percent for placebo, rimonabant 5mg and rimonabant 20 mg respectively), diarrhoea (3.0 percent, 6.0 percent and 7.2 percent for placebo, rimonabant 5mg and rimonabant 20 mg respectively) and dizziness (4.9 percent, 7.0 percent and 8.7 percent for placebo, rimonabant 5mg and rimonabant 20 mg respectively). Only in a very small number of cases did these side effects lead to discontinuation of drug use. Data from STRATUS-US study also show similar safety and tolerability profile of rimonabant.

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