Tag Archives: marijuana

‘Cannabis’ receptor discovery may help understanding of obesity and pain

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“Aberdeen scientists believe that the findings—published in the —might help our understanding of these conditions and also be a step towards the development of personalised therapies to help treat them.

The team from the University’s Kosterlitz Centre for Therapeutics studied around the gene CNR1. This gene produces what are known as cannabinoid receptors, which are found in the brain, and which activate parts of the brain involved in memory, mood, appetite and pain.

activate these areas of the brain when they are triggered by chemicals produced naturally in our bodies called .

Chemicals found in the drug cannabis mimic the action of these endocannabinoids and there is growing evidence that cannabis has pain relieving and anti-inflammatory properties which can help treat diseases such as and arthritis. 

In order to understand more about these side effects and the which determine how people respond, the scientists studied genetic differences around the CNR1 gene.

Dr Alasdair MacKenzie, who helped lead the team, said: “We chose to look at one specific genetic difference in CNR1 because we know it is linked to and addiction. What we found was a mutation that caused a change in the genetic switch for the gene itself—a switch that is very ancient and has remained relatively unchanged in overthree hundred million years of evolution, since before the time of the dinosaurs.”

http://phys.org/news/2012-08-cannabis-receptor-discovery-obesity-pain.html

Fight obesity… with marijuana?

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“What did the study find?
Dr. Yann Le Strat, a psychiatrist at France’s Louis-Mourier Hospital, looked at data from two studies of U.S. adults from the early 2000s and noted the weight differences between those who used cannabis and those who didn’t. In both studies, cannabis users had relatively low rates of obesity: 14.3 and 17.2 percent. American adults who didn’t use cannabis had obesity rates of 22 and 25.3 percent.

Is this what researchers expected?
Nope. “Cannabis is supposed to increase appetite,” says Le Strat. “So we hypothesized that cannabis users would be more likely to have higher weight than non-users and be more likely to be obese.” Marijuana activist Michelle Aldrich isn’t all that surprised. “It’s true,” she says. “I don’t know too many fat marijuana smokers.”

What’s causing this phenomenon?
“There could be many other reasons why pot smokers have less obesity,” says dietitian Andrea Giancoli. “Maybe they’re inclined to exercise more, be outdoors more, eat more fruits and vegetables.” Aldrich thinks it could be related to the body’s endocannabinoid system — a group of receptors, primarily in the brain, that respond to compounds in marijuana. But the bottom line is that the exact mechanism responsible for this correlation remains a mystery — for now.”

http://news.yahoo.com/fight-obesity-marijuana-114000508.html

Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome.

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Abstract

“Endogenous signaling lipids (“endocannabinoids”) functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems including type-2 diabetes, atherothrombosis, inflammation, and immune disorders. Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.”

http://www.ncbi.nlm.nih.gov/pubmed/18155257

Neurobiology and systems physiology of the endocannabinoid system.

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Abstract

“Endocannabinoids are synthesised from lipid precursors, are released from postsynaptic neurons in an activity-dependent way, and act as retrograde signalling messengers on specific G (i)-protein-coupled cannabinoid (CB (1)) receptors on presynaptic terminals. Hence, endocannabinoids are in a strategic position to regulate transmitter release. CB (1)-receptors are abundant on GABAergic, glutamatergic and dopaminergic synapses and play an essential role in a variety of cognitive processes and in the control of behaviour. The endocannabinoid system is not only the target of the psychoactive components of the hemp plant (tetrahydrocannabinol from hashish and marijuana) but has also been exploited for drugs acting as agonists (e.g. dronabinol) or antagonists (e.g. rimonabant) of the CB (1)-receptor. The former drugs exert orexigenic effects and can be used for the mitigation of anorexia e.g. in cancer patients, but have also been used for the treatment of multiple sclerosis. The latter have been used to treat adipositas. The role of the endocannabinoid system in the development of drug dependence has been discussed controversially, but recent evidence suggests that chronic stimulation of the endocannabinoid system may facilitate drug dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/19434559

Endocannabinoid chemical biology: a tool for the development of novel therapies.

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Abstract

“The identification of the major psychoactive constituent of Cannabis and marijuana, Delta(9)-tetrahydrocannabinol, opened the way first to the cloning of the G-protein-coupled cannabinoid CB(1) and CB(2) receptors, and then to the isolation and characterisation of their endogenous agonists, the endocannabinoids. Considerable progress has been made in the characterisation of pathways and enzymes for the biosynthesis and degradation of anandamide and 2-arachidonoylglycerol, the two best-known endocannabinoids, as well as of endocannabinoid-related molecules, such as the N-acylethanolamines, which, as in the case of N-palmitoylethanolamine and N-oleoylethanolamine, may interact with other receptor types. However, it is still not fully understood how other plant cannabinoids, of which cannabidiol is the most studied representative, exert their pharmacological effects. Together with these issues, this first review article on the endocannabinoids describes the synthetic pharmacological tools that have been designed so far to interact with the proteins of the ‘endocannabinoid system’ and that can potentially be used as templates for the development of new therapies.”

http://www.ncbi.nlm.nih.gov/pubmed/19457702

The endocannabinoid system: a general view and latest additions

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Abstract

“After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana’s psychoactive principle Delta(9)-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest ‘additions’ to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids.”

Introduction

“The discovery in the early 1990s of specific membrane receptors of marijuana’s psychoactive component (-)-Δ9-tetrahydrocannabinol (THC) opened the way to the revelation of a whole endogenous signaling system now known as the endocannabinoid system. Apart from the cannabinoid CB1 and CB2 receptors (Pertwee, 1997), this system comprises also their endogenous ligands (the endocannabinoids) and the proteins for their synthesis and inactivation, as well as other molecular targets for the endocannabinoids. However, as new findings on the regulation of the levels and action of the endocannabinoids, and new data on their possible physiological and pathological role, are reported every day in the literature, it is easy to understand that the story of the endocannabinoid system is far from set. For example, while until the end of the 20th century only two endocannabinoids, anandamide (N-arachidonoyl-ethanolamine, AEA) and 2-arachidonoyl-glycerol (2-AG) had been discovered (Devane et al., 1992; Mechoulam et al., 1995; Sugiura et al., 1995), in just a couple of years, three more candidates to the role of cannabinoid receptor agonists have been proposed: 2-arachidonyl-glyceryl ether (noladin, 2-AGE), O-arachidonoyl-ethanolamine (virhodamine) and N-arachidonoyl-dopamine (NADA) (Bisogno et al., 2000; Huang et al., 2002; Porter et al., 2002). These findings not only suggest that the endocannabinoid family is larger than initially thought but also enlarge our view on the possible molecular mechanisms for the biosynthesis, action and inactivation of these lipid mediators. This brief article aims at giving a picture as much updated as possible on the ‘old’ and ‘new’ components of the endocannabinoid system, while highlighting the latest and most important findings in this field.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574255/

 

The endocannabinoid system: a drug discovery perspective.

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Abstract

“The endocannabinoids are lipid messengers that engage the same cell surface receptors targeted by delta9-tetrahydrocannabinol, the active component of marijuana. They are produced by cells in the brain and other tissues and combine with two subtypes of G protein-coupled cannabinoid receptors, CB1 and CB2. Their ability to modulate a variety of pathophysiological processes, including appetite, pain and mood, provides unique opportunities for drug discovery. Three such opportunities are discussed here: reduction of body weight through blockade of CB1 receptors, alleviation of pain through activation of extracerebral cannabinoid receptors, and modulation of pain and anxiety through inhibition of endocannabinoid degradation.”

http://www.ncbi.nlm.nih.gov/pubmed/16044662

Marijuana takes on colon cancer

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“The chemicals in marijuana could put the brakes on colon cancer, according to new research. That doesn’t mean smoking a joint will help, though, as the chemicals only form part of the process.

Raymond DuBois and colleagues at the University of Texas in Houston discovered that a key receptor for cannabinoids, which are found in marijuana, is turned off in most types of human colon cancer.

Without this receptor, a protein called survivin, which stops cells from dying, increases unchecked and causes tumour growth.

To better understand the role that the receptor, called CB1, plays in cancer progression, the researchers manipulated its expression in mice that had been genetically engineered to spontaneously develop colon tumours.

“When we knocked out the receptor, the number of tumors went up dramatically,” says DuBois. Alternatively, when mice with normal CB1 receptors were treated with a cannabinoid compound, their tumours shrank.

Dual attack

The findings suggest a two-step treatment plan for colon cancer, as well as for other cancers that might be linked to this receptor.

First, turn the CB1 receptor back on, and then activate it with drugs currently in development that mimic marijuana. But how to turn it on?

The researchers found that in human colon cancer cells, the gene that makes the receptor is blocked by a process called methylation, in which a small chemical group is added to the DNA.

Treating the cells with decitibine – a demethylating drug already approved for use in humans – removed the chemical group and the gene began making the receptor. Drugs that mimic marijuana might then activate the receptor, although DuBois did not test this.”

 

http://www.newscientist.com/article/dn14451-marijuana-takes-on-colon-cancer.html

Cluster attacks responsive to recreational cannabis and dronabinol.

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Abstract

“Pharmacological preparations of cannabinoid compounds have a variety of therapeutic uses in medicine, including different pain syndromes, but have not been previously reported as beneficial for cluster headache. We present a patient with cluster headache who was refractory to multiple acute and preventive medications but successfully aborted his attacks with recreational marijuana use; subsequent use of dronabinol provided equally effective pain relief. The beneficial effect may be related to the high concentration of cannabinoid receptors in the hypothalamus, which has been implicated as a site of dysfunction in neuroimaging studies of patients with cluster headache.”

http://www.ncbi.nlm.nih.gov/pubmed/19220500

Cannabis for migraine treatment: the once and future prescription? An historical and scientific review.

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Abstract

“Cannabis, or Marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was highly esteemed as a headache remedy by the most prominent physicians of the age between 1874 and 1942, remaining part of the Western pharmacopoeia for this indication even into the mid-twentieth century. Current ethnobotanical and anecdotal references continue to refer to its efficacy for this malady, while biochemical studies of THC and anandamide have provided a scientific basis for such treatment. The author believes that controlled clinical trials of Cannabis in acute migraine treatment are warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/9696453