Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain.

“Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest.

Sativex(®) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-δ-tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-δ-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression.

 Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events.

Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents.”

http://www.ncbi.nlm.nih.gov/pubmed/23369054

The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis

“The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS) and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19–43 years), 25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS.

 Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxic action in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not.

Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.”

http://brain.oxfordjournals.org/content/130/10/2543.abstract

Medical cannabis relieves sufferers of chronic ailments

“Treatment can improve appetite, ease chronic pain, and more, say TAU researchers. Though controversial, medical cannabis has been gaining ground as a valid therapy, offering relief to suffers of diseases such as cancer, Post-Traumatic Stress Disorder, ALS and more. The substance is known to soothe severe pain, increase the appetite, and ease insomnia where other common medications fail.”

More: http://www.virtualmedicalcentre.com/news/medical-cannabis-relieves-sufferers-of-chronic-ailments/18330

Cannabis and Δ(9)-tetrahydrocannabinol (THC) for weight loss?

“Obesity is one of the highest preventable causes of morbidity and mortality in the developed world. It has been well known for a long time that exposure to cannabis produces an increase of appetite (a phenomenon referred to as the ‘munchies’).

This phenomenon led to an exploration of the role of the endocannabinoid system in the regulation of obesity and associated metabolic syndrome. This effort subsequently led to the development of a successful therapeutic approach for obesity that consisted of blocking the cannabinoid CB(1) receptors using ligands such as Rimonabant in order to produce weight loss and improve metabolic profile. Despite being efficacious, Rimonabant was associated with increased rates of depression and anxiety and therefore removed from the market.

We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age.

 Here, we propose that this effect is directly related to exposure to the Δ(9)-tetrahydrocannabinol (THC) present in cannabis smoke. We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.”

http://www.ncbi.nlm.nih.gov/pubmed/23410498

Role of cannabinoid and vanilloid receptors in invasion of human breast carcinoma cells.

“It is known that the diversified effects of cannabinoid on the fate of carcinoma cells are mediated predominantly through receptors. However, little is known about the effects of the individual activities of cannabinoid and noncannabinoid receptors. Here we investigate the role of cannabinoid receptor (CB) 1, CB2, and transient receptor potential vanilloid type 1 in cell proliferation and invasion patterns in the MDA-MB-231 cell line.

Our results showed that activation of CB1 and vanilloid receptors by methanandamide, a nonselective agonist, and arachidonyl-2′-choloroethylamide (ACEA) and N-oleoyldopamine, selective agonists, reduced invasion of MDA-MB-231 cells at pharmacological concentrations. Accordingly, CB1 activation resulted in decreased expression of matrix metalloproteinase (MMP) 2. On the other hand, administration of a CB2 agonist (CB65) increased cell invasion and expression of MMP2. The data obtained from MTT assay did not show any correlation between reduced invasion and cytotoxic effects of drugs. In addition, the level of vascular endothelial growth factor was significantly reduced in treatment with (R)-(+)-methanandamide, ACEA, CB65, and AM251 (a potent agonist for GPR55 and selective antagonist of CB1) compared with control. Elevated expression of cyclooxygenase-2 was observed in all of the MDA-MB-231 cells treated with agonists.

These results underline the influence of cannabinoid and vanilloid receptors on the invasiveness of MDA-MB-231 human breast carcinoma cells.”

http://www.ncbi.nlm.nih.gov/pubmed/23394450

Cannabis compound can help cells

“Cannabis has been used recreationally and for medicinal purposes for centuries, yet its 60 plus active components are only partly understood. Now scientists have discovered how a compound in cannabis can help cells to function in our bodies, and aid recovery after a damaging event.

In a paper published in the Journal of Neuroscience, the researchers report on their studies into cannabidiol – a naturally occurring molecule found in cannabis.

Also known as CBD, it is not the constituent that gives the high – that compound is called tetrahydrocannabinol or THC – and so may be more acceptable as a drug treatment.

Both compounds are currently used in a pharmaceutical medicine to help patients relieve pain and other symptoms of Multiple Sclerosis.

Now researchers have discovered how CBD actually works within brain cells.

By interacting with mitochondria – which are the power generators of all cells – it can help maintain normal levels of calcium allowing cells to function properly and providing a greater resistance to damage.

Disturbance of calcium levels has long been associated with a number of brain disorders. So the finding could have implications for the development of new treatments for disorders related to malfunctioning mitochondria.

Dr Bettina Platt, from the University’s School of Medical Sciences, said: “Scientists have known for a long time that cannabidiol can help with pain relief but we never really knew how it worked.

“However we have discovered what it actually does at the cellular level.

“We are hoping that our findings can instruct the development of cannabidiol based treatments for disorders related to mitochondrial dysfunction such as Parkinson’s disease or Huntington’s disease.”

More: http://phys.org/news154280470.html

The pharmacologic and clinical effects of medical cannabis.

“Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals.

Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB(1) and CB(2) ) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ(9) -tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended.

Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use.”

http://www.ncbi.nlm.nih.gov/pubmed/23386598

Targeting the endocannabinoid system to limit myocardial and cerebral ischemic and reperfusion injury.

“Coronary and carotid arterial occlusion due to thrombosis after atherosclerotic plaque rupture is the major cause of myocardial and cerebral infarction. Together these acute events represent the leading cause of death worldwide. Early reperfusion is the best method to salvage the ischemic organ; however, it leads to additional damage known as reperfusion injury. A large number of experimental studies has been performed in the past aimed at targeting individual mediators of reperfusion injury such as treatment with anti-oxidants or anti-inflammatory agents. Although many agents proved beneficial in animal models of myocardial or cerebral ischemia/reperfusion, the attempts to translate these protective effects into clinical practice were mostly disappointing. Elucidating the complex cellular and molecular mechanisms involved in ischemic cell death is crucial for the development of more efficient drugs in order to improve current treatment strategies. The aim of this review is to discuss cannabinoid and endocannabinoid-mediated effects in the pathogenesis of myocardial infarction and reperfusion injury, post-myocardial infarction remodeling, as well as ischemic stroke and reperfusion injury.

 We report experimental evidence suggesting that targeting the endocannabinoid system might evolve as a novel therapeutic concept to limit the devastating consequences of these acute vascular events through a wide variety of mechanisms, including lowering inflammation, oxidative stress, fibrosis, and excitotoxicity, and enhanced blood flow.”

http://www.ncbi.nlm.nih.gov/pubmed/21470162

Modulation of Cannabinoid Receptor Activation as a Neuroprotective Strategy for EAE and Stroke

“These results provide evidence that alteration of the activation patterns of the various cannabinoid receptors warrant consideration for future therapeutic strategies.

Interest in the medicinal use of Cannabis sativa (marijuana) has a long historical record, extending back thousands of years. In comparison to the extensive history for medicinal applications of marijuana, the existence of an “endocannabinoid system”, with important homeostatic and pathologic functions, has only recently gained appreciation. The endocannabinoid system consists of endogenously produced cannabinoids, their receptors, and the enzymes responsible for their synthesis and degradation…

Although used in ancient Greece, Rome, and China for therapeutic purposes, concern about the use of cannabinoids as a drug of abuse has dampened interest in developing the potential therapeutic benefits of these compounds. However, a better understanding of the biologic effects has led recently to an upsurge in interest for the development of therapeutic drugs through modification of the endocannabinoid system. An additional incentive was provided by the development of synthetic cannabinoid analogs and specific inhibitors of cannabinoid receptors. Several excellent reviews cover the therapeutic potential of cannabinoids….

The present review is focused on the effects of CB2 receptor activation in models of multiple sclerosis (experimental autoimmune encephalomyelitis) and stroke (middle cerebral occlusion/reperfusion).

In summary, selective CB2 receptor agonists and CB1 receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855650/

Endocannabinoid regulation of matrix metalloproteinases: implications in ischemic stroke.

“Stroke is a major cause of morbidity and mortality and follows heart disease and cancer as the third leading cause of death in Western societies. Despite many advances in stroke research and pharmacotherapy, clinical treatment of this debilitating disorder is still inadequate.

Recent findings from several laboratories have identified the endocannabinoid signaling pathway, comprised of the endocannabinoid agonist anandamide and its pharmacological targets, CB1 and CB2 cannabinoid receptors and associated anandamide receptors, as a physiological system with capacity to mitigate cardiovascular and cerebrovascular disorders through neuronal and endothelial actions. Variability in experimental stroke models and modes of outcome evaluation, however, have provoked controversy regarding the precise roles of endocannabinoid signals in mediating neural and/or vascular protection versus neurovascular damage.

Clinical trials of the CB1 antagonist rimonabant demonstrate that modulation of endocannabinoid signaling during metabolic regulation of vascular disorders can significantly impact clinical outcomes, thus providing strong argument for therapeutic utility of endocannabinoids and/or cannabinoid receptors as targets for therapeutic intervention in cases of stroke and associated vascular disorders.

The purpose of this review is to provide updated information from basic science and clinical perspectives on endocannabinoid ligands and their effects in the pathophysiologic genesis of stroke. Particular emphasis will be placed on the endocannabinoids anandamide and 2-arachidonylglycerol and CB1 receptor-mediated mechanisms in the neurovascular unit during stroke pathogenesis. Deficiencies in our knowledge of endocannabinoids in the etiology and pathogenesis of stroke, caveats and limitations of existing studies, and future directions for investigation will be addressed.”

http://www.ncbi.nlm.nih.gov/pubmed/17979695