The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”


“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases.

 ijms-logo“Endocannabinoid system consists of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. CB2, to a great extent, and CB1, to a lesser extent, are involved in regulating the immune response. They also regulate the inflammatory processes by inhibiting pro-inflammatory mediator release and immune cell proliferation. This review provides an overview on the role of the endocannabinoid system with a major focus on cannabinoid receptors in the pathogenesis and onset of inflammatory and autoimmune pediatric diseases, such as immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, obesity, neuroinflammatory diseases, and type 1 diabetes mellitus. These disorders have a high social impact and represent a burden for the healthcare system, hence the importance of individuating more innovative and effective treatments. The endocannabinoid system could address this need, representing a possible new diagnostic marker and therapeutic target.”

Cannabis May Cure Celiac Disease

Evidence suggests that there is a natural plant treatment that can mitigate or even cure celiac disease: cannabis.

“Celiac disease can be devastating to those who suffer from it, but evidence suggests that there is a natural plant treatment that can mitigate or even cure the ailment: cannabis.

People who have celiac suffer from autoimmune attacks on their small intestine after eating gluten, which can lead to pain and an inability to absorb nutrients, as well as diabetes, multiple sclerosis and cancer over the long term.

Gluten is ubiquitous in the Western diet and people who take pains to avoid eating it are still likely to consume some by accident on occasion, and even in small amounts gluten can lead to extremely painful and embarrassing episodes.

Fortunately, marijuana may be able to help.

A study published in the PLOS One journal in 2013 suggests that cannabis could play a key role in taming the ravages of celiac. The study, conducted by researchers at the University of Teramo in Italy, took intestinal biopsies from celiac patients and looked at the cannabinoid receptors in the gut, which play a role in controlling inflammation and dysfunction. The results showed significantly more receptors in people with an active disease than those who had been treating it with at least 12 months of a gluten-free diet, leading the scientists to suggest that the data “points to the therapeutic potential of targeting [cannabinoid receptors] in patients with celiac disease.”

Anecdotal reports corroborate the study’s findings. Some patients believe that marijuana has actually helped them cure celiac outright.”

“Altered Expression of Type-1 and Type-2 Cannabinoid Receptors in Celiac Disease”

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

The cannabinoid receptor type 2 Q63R variant increases the risk of celiac disease: implication for a novel molecular biomarker and future therapeutic intervention.

“Celiac disease (CD) is a chronic inflammatory disease of the small bowel that occurs with the ingestion of gluten, found in several grains products. Although HLA-DQ2 variant is required for the gluten-derived peptide gliadin presentation by antigen-presenting cells to T-cells, non-HLA genetic factors account for the majority of heritable risk. Several genome-wide association studies have identified susceptibility loci for CD on chromosome 1. Cells of the immune system express the cannabinoid receptor type 2 (CB2), a plasma-membrane receptor activated by both endogenous and exogenouscannabinoids. Consistent data evidence that CB2 is linked to a variety of immune functional events and that, in the course of an inflammatory process, an increased number of receptors becomes available for activation. The cannabinoid receptor type 2 gene (CNR2; GeneID1269) maps on 1p36.11. In order to investigate the possible involvement of CB2 in CD establishment, immunohistochemistry toward CB2 receptor and CD4+ cells in small bowel biopsies from celiac children and association analysis, through TaqMan assay, of a CNR2 common missense variant, rs35761398 (CAA/CGG), resulting in the aminoacidic substitution of Glutamine at codon 63 with Arginine (Q63R), in a cohort of 327 South Italian children have been performed. We observed in this study that CB2 is up-regulated in CD small bowel biopsies and CNR2 rs35761398 is significantly associated with CD (χ(2) = 37.064; d.f. 1; p = 1.14 × 10(-9)). Our findings suggest a role of CB2 in CD. The Q63R variant, increasing more than six-fold the risk for CD susceptibility, might eventually represent a novel molecular biomarker for CD risk stratification. Indeed, we provide here further evidence that CB2 receptor plays a critical role in autoimmunity susceptibility and indicates that it represents a molecular target to pharmacologically modulate the immune components in CD.”

Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-treated rats.

“The endocannabinoid system is upregulated in both human inflammatory bowel diseases and experimental models of colitis. In this study, we investigated whether this upregulation is a marker also of celiac disease-induced atrophy. The levels of the cannabinoid CB(1) receptor, of the endocannabinoids, anandamide, and 2-arachidonoyl-glycerol (2-AG), and of the anti-inflammatory mediator palmitoylethanolamide (PEA) were analyzed in bioptic samples from the duodenal mucosa of celiac patients at first diagnosis assessed by the determination of antiendomysial antibodies and histological examination. Samples were analyzed during the active phase of atrophy and after remission and compared to control samples from non-celiac patients. The levels of anandamide and PEA were significantly elevated (approx. 2- and 1.8-fold, respectively) in active celiac patients and so were those of CB(1) receptors. Anandamide levels returned to normal after remission with a gluten-free diet. We also analyzed endocannabinoid and PEA levels in the jejunum of rats 2, 3, and 7 days after treatment with methotrexate, which causes inflammatory features (assessed by histopathological analyses and myeloperoxidase activity) similar to those of celiac patients. In both muscle/serosa and mucosa layers, the levels of anandamide, 2-AG, and PEA peaked 3 days after treatment and returned to basal levels at remission, 7 days after treatment. Thus, intestinal endocannabinoid levels peak with atrophy and regress with remission in both celiac patients and methotrexate-treated rats. The latter might be used as a model to study the role of the endocannabinoid system in celiac disease.”

Abnormal anandamide metabolism in celiac disease.

“The endocannabinoid system has been extensively investigated in experimental colitis and inflammatory bowel disease, but not in celiac disease, where only a single study showed increased levels of the major endocannabinoid anandamide in the atrophic mucosa. On this basis, we aimed to investigate anandamide metabolism in celiac disease by analyzing transcript levels (through quantitative real-time reverse transcriptase-polymerase chain reaction), protein concentration (through immunoblotting) and activity (through radioassays) of enzymes responsible for anandamide synthesis (N-acylphosphatidyl-ethanolamine specific phospholipase D, NAPE-PLD) and degradation (fatty acid amide hydrolase, FAAH) in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also, treated celiac biopsies cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our in vivo experiments showed that mucosal NAPE-PLD expression and activity are higher in untreated celiac patients than treated celiac patients and controls, with no significant difference between the latter two groups. In keeping with the in vivo data, the ex vivo activity of NAPE-PLD was significantly enhanced by incubation of peptic-tryptic digest of gliadin with treated celiac biopsies. On the contrary, in vivo mucosal FAAH expression and activity did not change in the three groups of patients, and accordingly, mucosal FAAH activity was not influenced by treatment with peptic-tryptic digest of gliadin. In conclusion, our findings provide a possible pathophysiological explanation for the increased anandamide concentration previously shown in active celiac mucosa.”

Altered Expression of Type-1 and Type-2 Cannabinoid Receptors in Celiac Disease

“Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.

In conclusion, our findings together with those published in a previous study, suggest that an abnormal modulation of the endocannabinoid system, both at CBR and AEA levels, may be implicated in the pathogenesis of celiac disease. Further studies are needed to ascertain whether targeting these changes might have a therapeutic role, at least in those patients who are no longer responsive to gluten-free diet.”

More Evidence Pot Treats Auto-Immune Diseases

“Researchers at the University of South Carolina have another clue as to why patients with auto-immune diseases like multiple sclerosis, psoriasis, rheumatoid arthritisCrohn’s and celiac disease sometimes respond to medical marijuana therapies, according to Science World Reports.

The main active ingredient in pot, THC, regulates gene expression in immune cells, effectively switching off runaway inflammation at the DNA level.

The researchers used mice cells in vivo and the results suggest that “THC activates the expression of a subset of genes while suppressing the expression of another subset of genes.” The net result is less inflammatory response, which can severely damage and kill cells.

Autoimmune diseases involve an abnormal immune response of the body, causing immune cells to attack healthy cells instead of pathogens. Autoimmune diseases — a collection of about 80 diseases — are the 10th leading cause of death of women in all age groups up to 65 years old.

Despite the safety and efficacy of medical cannabis, providers remain under attack across America. California senators Barbara Boxer and Dianne Feinstein currently support the war on pot patients and providers. The Drug Policy Alliance has started a new campaign today to help citizens lobby Senators to defund the war on medical marijuana.”

The endocannabinoid system and its therapeutic exploitation.

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“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”