Endocannabinoids and the gastrointestinal tract.

Posted on May 8, 2013 by David

“In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea.

Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor). While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish.

Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion.

For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn’s disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/16751708

The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract.

Posted on May 8, 2013 by David

“Numerous investigations have recently demonstrated the important roles of the endocannabinoid system in the gastrointestinal (GI) tract under physiological and pathophysiological conditions.

In the GI tract, cannabinoid type 1 (CB1) receptors are present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons, while cannabinoid type 2 receptors are located in immune cells. Activation of CB1 receptors was shown to modulate several functions in the GI tract, including gastric secretion, gastric emptying and intestinal motility.

Under pathophysiological conditions induced experimentally in rodents, the endocannabinoid system conveys protection to the GI tract (e.g. from inflammation and abnormally high gastric and enteric secretions).

Such protective activities are largely in agreement with anecdotal reports from folk medicine on the use of Cannabis sativa extracts by subjects suffering from various GI disorders.

Thus, the endocannabinoid system may serve as a potentially promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (e.g. Crohn’s disease), functional bowel diseases (e.g. irritable bowel syndrome) and secretion- and motility-related disorders.

As stimulation of this modulatory system by CB1 receptor agonists can lead to unwanted psychotropic side effects, an alternative and promising avenue for therapeutic applications resides in the treatment with CB1 receptor agonists that are unable to cross the blood-brain barrier, or with compounds that inhibit the degradation of endogenous ligands (endocannabinoids) of CB1 receptors, hence prolonging the activity of the endocannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/16133420

[Marihuana and cannabinoids as medicaments].

Posted on February 21, 2013 by David

“Biological activity of cannabinoids is caused by binding to two cannabinoid receptors CB1 and CB2. Psychoactive is not only tetrahydrocannabinol (THC) but also: cannabidiol, cannabigerol or cannabichromen. Formerly, the usefulness of hemp was assessed in the relation to temporary appeasement of the symptoms of some ailments as nausea or vomiting.

Present discoveries indicates that cannabis-based drugs has shown ability to alleviate of autoimmunological disorders such as: Multiple sclerosis (MS), Rheumatoid arthritis (RA) or inflammatory bowel disease. Another studies indicates that cannabinoids play role in treatment of neurological disorders like Alzheimer disease or Amyotrophic lateral sclerosis (ALS) or even can reduce spreading of tumor cells.

Cannabinoids stand out high safety profile considering acute toxicity, it is low possibility of deadly overdosing and side-effects are comprise in range of tolerated side-effects of other medications.

In some countries marinol and nabilone are used as anti vomiting and nausea drug. First cannabis-based drug containg naturally occurring cannabinoids is Sativex. Sativex is delivered in an mucosal spray for patients suffering from spasticity in MS, pain relevant with cancer and neuropathic pain of various origin. Despite the relatively low acute toxicity of cannabinoids they should be avoid in patients with psychotic disorders, pregnant or breastfeeding woman. Cannabinoids prolong a time of reaction and decrease power of concentration that’s why driving any vehicles is forbidden.

Cannabis side-effects varies and depend from several factors like administrated dose, rout of administration and present state of mind. After sudden break from long-lasting use, withdrawal symptoms can appear, although they entirely disappear after a week or two.”

http://www.ncbi.nlm.nih.gov/pubmed/23421098

Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease.

Posted on February 19, 2013 by David

“Inflammatory bowel disease (IBD) is an incurable disease which affects millions of people in industrialised countries. Anecdotal and scientific evidence suggest that Cannabis use may have a positive impact in IBD patients.

Here, we investigated the effect of cannabigerol (CBG), a non-psychotropic Cannabis-derived cannabinoid, in a murine model of colitis…

In conclusion, CBG attenuated murine colitis, reduced nitric oxide production in macrophages (effect being modulated by the CB(2) receptor) and reduced ROS formation in intestinal epithelial cells.

CBG could be considered for clinical experimentation in IBD patients.”

http://www.ncbi.nlm.nih.gov/pubmed/23415610

Latest advances in cannabinoid receptor agonists.

Posted on January 3, 2013 by David

“Since the discovery of cannabinoid receptors and their endogenous ligands in early 1990s, the endocannabinoid system has been shown to play a vital role in several pathophysiological processes. It has been targeted for the treatment of several diseases including neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and MS), cancer, obesity, inflammatory bowel disease, neuropathic and inflammatory pain. The last decade has witnessed remarkable advances in the development of cannabinergic ligands displaying high selectivity and potency towards two subtypes of cannabinoid receptors, namely CB1 and CB2.”

“…we highlight the latest advances made in the development of cannabinoid agonists and summarize recently disclosed, novel chemical scaffolds as CB-selective agonists…”

“CONCLUSIONS:

Our analysis reveals prolific patenting activity mainly in the CB2 selective agonist area. Limiting the BBB penetrability, thereby, leading to peripherally restricted CB1/CB2 agonists and enhancing CB2-selectivity emerge as likely prerequisites for avoidance of adverse central CB1 mediated side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/19939187

From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

Posted on November 20, 2012 by David

“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985

FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels.

Posted on November 14, 2012 by David

Abstract

“Apart from their widespread recreational abuse, the psychoactive preparations of the plant Cannabis sativa and its major psychotropic component, Delta9-tetrahydrocannabinol (THC), are also known for their medicinal properties. Following the identification of receptors for THC – the cannabinoid CB1 and CB2 receptors – in mammals, various pharmaceutical strategies have attempted to exploit the properties of the cannabinoid system while minimizing psychotropic side effects. The cloning of the cannabinoid CB1 and CB2 receptors enabled the discovery of the endogenous agonists of the receptors, the endocannabinoids, and eventually led to the identification of enzymes that catalyze endocannabinoid inactivation. Unlike exogenously administered THC and synthetic CB1 and CB2 agonists, the endocannabinoids that are produced endogenously following the onset of several pathologies may act in a site- and time-specific manner to minimize the consequences of such conditions. This observation has suggested the possibility of targeting endocannabinoid-degrading enzymes to prolong the precisely regulated pro-homeostatic action of endocannabinoids. Two major enzymes have been cloned and investigated thoroughly: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Inhibitors of these enzymes have demonstrated therapeutic benefit in animal models of several disorders, including neuropathic pain, anxiety and inflammatory bowel diseases, as well as against the proliferation and migration of cancer cells. This review describes the major biochemical properties of FAAH and MAGL, and the design and pharmacological properties of inhibitors of these enzymes.”

http://www.ncbi.nlm.nih.gov/pubmed/20047159

Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice

Posted on November 2, 2012 by David

“Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation.”

“Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB₁ receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.”

“The plant Cannabis sativa contains more than 60 terpenophenolic compounds, named phytocannabinoids. The best-studied phytocannabinoid is Δ⁹-tetrahydrocannabinol, which binds specific G-protein-coupled receptors, named cannabinoid (CB₁ and CB₂) receptors. The well-known psychotropic effects of Δ⁹-tetrahydrocannabinol, which are largely mediated by activation of brain cannabinoid CB₁ receptors, have always raised a number of clinical and ethical problems. Therefore, a valid therapeutic alternative may be the use of non-psychotropic phytocannabinoids, including cannabidiol (CBD). CBD, unlike Δ⁹-tetrahydrocannabinol, has very low affinity for both cannabinoid CB₁ and CB₂ receptors, although it has been proposed that CBD may modulate endocannabinoid function through its ability to inhibit the hydrolysis of anandamide and to act as a transient receptor potential vanilloid 1 agonist. CBD is a major component of Sativex, a preparation of cannabinoids, which has been approved by Health Canada for the treatment of neuropathic pain in multiple sclerosis.”

“The pharmacological profile of CBD has been recently reviewed. Briefly stated, CBD has been shown to exert (1) antioxidant, neuroprotective and antiproliferative actions in cultured cells and (2) anti-anxiety, hypnotic, anticonvulsant, neuroprotective, antinausea, anti-ischaemic, anticancer and notably anti-inflammatory effects in rodents in vivo. The anti-inflammatory effects of CBD have been demonstrated in both acute and chronic experimental models of inflammation, that is, paw oedema and arthritis.”

“In conclusion, we have shown that the marijuana component CBD normalize intestinal motility in an experimental model of ileitis. In vitro results showed antispasmodic actions of CBD on intestinal ileal segments. The inhibitory effect of CBD involves, at least in vivo, cannabinoid CB₁ receptors and FAAH. In view of its safety records in humans (an average daily dose of about 700mg/day for 6 weeks was found to be non-toxic, relative to placebo, in clinical trials; and because CBD reduced motility during inflammation and not in physiological conditions, CBD might be considered as a good candidate to be clinically evaluated for the treatment of hypermotility associated with inflammatory bowel disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2451037/

Cannabinoids for the treatment of inflammation.

Posted on November 1, 2012 by David

“Cannabinoids are effective at suppressing immune and inflammation functions in leukocytes in vitro, and in animal models of acute inflammation, such as the mouse hind paw, ear and air pouch models, as well as gastrointestinal, pulmonary, myocardial, vascular, periodontal, neural, hepatic, pancreatic and arthritic inflammation models.

The non-psychoactive cannabinoid receptor CB2 is emerging as a critical target for cannabinoid regulation of inflammation, and thus CB2-selective agonists are undergoing intense investigation and research. This review discusses the evidence for cannabinoid regulation of inflammation across a range of models and highlights the most promising drug candidates.”

http://www.ncbi.nlm.nih.gov/pubmed/17520866

Cannabinoid-based drugs as anti-inflammatory therapeutics.