Tag Archives: CB1

The endocannabinoid system as a target for the treatment of cannabis dependence

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“Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive downregulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling; and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.”

“Direct modulation of CB1receptors as a treatment for cannabis dependence”

“Even though, as we have seen above, direct activation of CB1 receptors may yield variable behavioral responses, low-dosage oral Δ9-THC has shown promise in the management of human cannabis withdrawal. The rationale for this approach is that controlled replacement of Δ9-THC for smoked cannabis may reduce the severity of withdrawal symptoms and allow a dependent individual to remain abstinent. Additionally, given that dependent subjects are experienced with cannabis, and Δ9-THC is administered at low doses, administration of the latter is unlikely to result in the anxiety responses observed with inexperienced users or high dosages. Consistent with this idea, two independent clinical studies have shown that low-dose oral Δ9-THC attenuates withdrawal symptom scores and is minimally intoxicating in non-treatment seeking daily cannabis users.””

“Several therapeutic modalities are currently being considered to treat cannabis dependence, including activation or deactivation of CB1receptors. While these stategies show promise in measures of cannabis withdrawal and abstinence, they may also create problems of abuse liability or adverse emotional effects. An additional approach might be to enhance endogenous anandamide signaling using agents that attenuate the deactivation of this endocannabinoid transmitter.”

“Increasing anandamide signaling with deactivation inhibitors, such as the FAAH blocker URB597, potentiates stress coping behaviors in animals, indicating a role for anandamide in physiopathological context of stress-related responses. Similarly, elevation of anandamide in specific brain regions opposes the anhedonic effects of stress and promotes normal positive responses to pleasurable stimuli in rodents. It is reasonable to hypothesize that these effects could act to blunt the negative affect and stress, which is common during cannabis withdrawal, thus allowing cannabis dependent individuals to successfully abstain from drug use.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647947/

Endocannabinoid involvement in endometriosis

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 “Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. Here, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments.”

“These findings implicate involvement of the endocannabinoid system in reproductive function and dysfunction. The endocannabinoid system plays a key role in pain mechanisms, and, previously, cannabinoids were long used by women to alleviate dysmenorrhea.”

“Together the findings suggest that the endocannabinoid system is involved in endometriosis and its associated pain via CB1 receptors and innervation of the ectopic growths. Using the rat model, we performed a combination of immunohistochemical and pharmacological studies to test this hypothesis and assess the endocannabinoid system’s potential as a target for new therapies.”

 Summary and conclusions

“These studies in a rat model of endometriosis provide evidence that endocannabinoids might regulate the innervation of the disease’s abnormal growths and that exogenous cannabinoid agents can be effective in reducing endometriosis symptoms. The fact that CB1 receptor expression is greater in the cysts than healthy uterus from the same rats suggests that treatments to activate CB1 receptors (either directly by CB1 agonists or indirectly by increasing relevant endocannabinoid levels) could be developed with minimal effects on uterine function. Although the rat model parallels many aspects of endometriosis in women, there are of course significant differences. However, when considered together with the past history of successful use of cannabinoids for alleviation of gynecological pains, and insofar as findings in rats can model mechanisms of endometriosis-related signs and symptoms, the present results suggest that approaches targeted at the endocannbinoid system represent a promising new direction for developing badly-needed new treatments for pain suffered by women with endometriosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972363/

Cannabinoids reduce symptoms of Tourette’s syndrome.

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Abstract

“Currently, the treatment of Tourette’s syndrome (TS) is unsatisfactory. Therefore, there is expanding interest in new therapeutical strategies. Anecdotal reports suggested that the use of cannabis might improve not only tics, but also behavioural problems in patients with TS. A single-dose, cross-over study in 12 patients, as well as a 6-week, randomised trial in 24 patients, demonstrated that Delta9-tetrahydrocannabinol (THC), the most psychoactive ingredient of cannabis, reduces tics in TS patients. No serious adverse effects occurred and no impairment on neuropsychological performance was observed. If well-established drugs either fail to improve tics or cause significant adverse effects, in adult patients, therapy with Delta9-THC should be tried. At present, it remains unclear whether herbal cannabis, different natural or synthetic cannabinoid CB1-receptor agonists or agents that interfere with the inactivation of endocannabinoids, may have the best adverse effect profile in TS.”

http://www.ncbi.nlm.nih.gov/pubmed/14521482

[Cannabis and cannabinoids as drugs].

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Abstract

“BACKGROUND:

Cannabis has been used throughout human history. Delta (9)-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. THC metabolises to 11-OH-THC and further to THC-acid, which is an inactive metabolite. We present an overview of the pharmacokinetics and pharmacodynamics of cannabinoids.

MATERIAL AND METHOD:

This article is based on selected literature with an emphasis on the pharmacodynamics of cannabinoids.

RESULTS AND INTERPRETATION:

It has been demonstrated that mammalian tissues express cannabinoid receptors (CB1, CB2 and most probably CB3) and endogenous ligands for these. Knowledge of these receptors has lead to the development of components that stimulate (CB-agonists) or block their function (CB-antagonists). This opens up for the study of any potential therapeutic effects of cannabinoids. Research on a possible therapeutic potential of cannabinoids should however not overshadow the well-documented negative effects of cannabis; i.e. impaired cognitive functions, intoxication and an increased risk for development of psychosis and psychotic symptoms.”

http://www.ncbi.nlm.nih.gov/pubmed/17332810

Therapeutic potential of cannabinoids in CNS disease.

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Abstract

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/12617697

Cannabinoid receptors and their ligands.

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Abstract

“There are at least two types of cannabinoid receptors, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors exist primarily on central and peripheral neurons, one of their functions being to modulate neurotransmitter release. CB(2) receptors are present mainly on immune cells. Their roles are proving more difficult to establish but seem to include the modulation of cytokine release. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether. Other endocannabinoids and cannabinoid receptor types may also exist. Although anandamide can act through CB(1) and CB(2) receptors, it is also a vanilloid receptor agonist and some of its metabolites may possess yet other important modes of action. The discovery of the system of cannabinoid receptors and endocannabinoids that constitutes the “endocannabinoid system” has prompted the development of CB(1)- and CB(2)-selective agonists and antagonists/inverse agonists. CB(1)/CB(2) agonists are already used clinically, as anti-emetics or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilation that accompanies advanced cirrhosis, and cancer. Following their release onto cannabinoid receptors, endocannabinoids are removed from the extracellular space by membrane transport and then degraded by intracellular enzymic hydrolysis. Inhibitors of both these processes have been developed. Such inhibitors have therapeutic potential as animal data suggest that released endocannabinoids mediate reductions both in inflammatory pain and in the spasticity and tremor of multiple sclerosis. So too have CB(1) receptor antagonists, for example for the suppression of appetite and the management of cognitive dysfunction or schizophrenia.”

http://www.ncbi.nlm.nih.gov/pubmed/12052030

The endocannabinoid system : a new target for the regulation of energy balance and metabolism.

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Abstract

“Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to “fix” the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.”

http://www.ncbi.nlm.nih.gov/pubmed/17667864

[The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans].

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Abstract

“The endocannabinoid system has been recently recognized as an important modulatory system in the function of brain, endocrine, and immune tissues. It appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and response to stress. The important elements of this system are: endocannabinoid receptors (types CB1 and CB2), their endogenous ligands (N-arachidonoylethanolamide, 2-arachidonoyl glycerol), enzymes involved in their synthesis and degradation, as well as cannabinoid antagonists. In humans this system also controls energy homeostasis and mainly influences the function of the food intake centers of the central nervous system and gastrointestinal tract activity. The endocannabinoid system regulates not only the central and peripheral mechanisms of food intake, but also lipids synthesis and turnover in the liver and adipose tissue as well as glucose metabolism in muscle cells. Rimonabant, a new and selective central and peripheral cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factor (metabolic syndrome) in obese patients by increasing HDL-cholesterol and adiponectin blood levels as well as decreasing LDL-cholesterol, leptin, and C-reactive protein (a proinflammatory marker) concentrations. It is therefore possible to speculate about a future clinical use of CB1 antagonists, as a means of improving gonadotrophin pulsatility and fertilization capacity as well as the prevention of cardiovasculary disease and type 2 diabetes mellitus. Drugs acting as agonists of CB1 receptors (Dronabinol, Dexanabinol) are currently proposed for evaluation as drugs to treat neurodegenerative disorders (Alzheimer’s and Parkinson’s diseases), epilepsy, anxiety, and stroke.”

http://www.ncbi.nlm.nih.gov/pubmed/17369778

[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

The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?

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Abstract

“The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. This mini-review summarizes the main findings that supported the clinical use of CB1 antagonists/inverse agonists, the clinical concerns that have emerged, and the possible future of cannabinoid-based therapy of obesity and related diseases. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes, liver, skeletal muscle and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways. Obese people seem to display an increased endocannabinoid tone, driving CB(1) receptor in a feed-forward dysfunction. Several CB(1) antagonists/inverse agonists have been developed for the treatment of obesity. Although these drugs were found to be efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors, they resulted in adverse psychiatric effects that limited their use and finally led to the end of the clinical use of systemic CB(1) ligands with significant inverse agonist activity for complicated obesity. However, the existence of alternatives such as CB(1) partial agonists, neutral antagonists, antagonists restricted to the periphery, allosteric modulators and other potential targets within the ECS indicate that a cannabinoid-based therapy for the management of obesity and its associated cardiometabolic sequelae should remain open for consideration.”

http://www.ncbi.nlm.nih.gov/pubmed/20347862