Do deficits in brain cannabinoids contribute to eating disorders?

October 31, 2011

Science Daily/Elsevier

A new report in Biological Psychiatry suggests that deficits in endocannabinoid function may contribute to anorexia nervosa and bulimia. Endocannabinoids are substances made by the brain that affect brain function and chemistry in ways that resemble the effects of cannabis derivatives, including marijuana and hashish. These commonly abused drugs are well known to increase appetite, i.e. to cause the "munchies." Thus, it makes sense that deficits in this brain system would be associated with reduced appetite.

Researchers measured the status of the endocannabinoid system indirectly by determining whether there was an increase or decrease in the density of endocannabinoid receptors, called the CB1 receptor, in several brain regions using positron emission tomography, or PET, imaging. They compared these densities in women with anorexia or bulimia with those of healthy women.

They found global increases in ligand binding to CB1 receptors in the brains of women with anorexia nervosa. This finding is consistent with a compensatory process engaged by deficits in endocannabinoid levels or reduced CB1 receptor function.

CB1R availability was also increased in the insula in both anorexia and bulimia patients. The insula "is a region that integrates body perception, gustatory information, reward and emotion, functions known to be disturbed in these patients," explained Dr. Koen Van Laere, the study's lead author.

"The role of endocannabinoids in appetite control is clearly important. These new data point to important connections between this system and eating disorders," added Dr. John Krystal, Editor of Biological Psychiatry.

Additional research is now needed to establish whether the observed changes are caused by the disease or whether these are neurochemical alterations that serve as risk factors for developing an eating disorder.

Furthermore, since very few effective treatments exist for these disorders, these data indicate that the endocannabinoid system may be a potential new target for developing drugs to treat eating disorders. Such new therapies are currently being investigated in animal models.

https://www.sciencedaily.com/releases/2011/10/111031115226.htm

How cannabis causes 'cognitive chaos' in the brain

October 28, 2011

Science Daily/University of Bristol

Cannabis use is associated with disturbances in concentration and memory. New research by neuroscientists at the University of Bristol, published in the Journal of Neuroscience, has found that brain activity becomes uncoordinated and inaccurate during these altered states of mind, leading to neurophysiological and behavioural impairments reminiscent of those seen in schizophrenia.

The collaborative study, led by Dr Matt Jones from the University's School of Physiology and Pharmacology, tested whether the detrimental effects of cannabis on memory and cognition could be the result of 'disorchestrated' brain networks.

Brain activity can be compared to performance of a philharmonic orchestra in which string, brass, woodwind and percussion sections are coupled together in rhythms dictated by the conductor. Similarly, specific structures in the brain tune in to one another at defined frequencies: their rhythmic activity gives rise to brain waves, and the tuning of these brain waves normally allows processing of information used to guide our behaviour.

Using state-of-the-art technology, the researchers measured electrical activity from hundreds of neurons in rats that were given a drug that mimics the psychoactive ingredient of marijuana. While the effects of the drug on individual brain regions were subtle, the drug completely disrupted co-ordinated brain waves across the hippocampus and prefrontal cortex, as though two sections of the orchestra were playing out of synch. Both these brain structures are essential for memory and decision-making and heavily implicated in the pathology of schizophrenia.

The results from the study show that as a consequence of this decoupling of hippocampus and prefrontal cortex, the rats became unable to make accurate decisions when navigating around a maze.

Dr Jones, lead author and MRC Senior Non-clinical Fellow at the University, said: "Marijuana abuse is common among sufferers of schizophrenia and recent studies have shown that the psychoactive ingredient of marijuana can induce some symptoms of schizophrenia in healthy volunteers. These findings are therefore important for our understanding of psychiatric diseases, which may arise as a consequence of 'disorchestrated brains' and could be treated by re-tuning brain activity."

Michal Kucewicz, first author on the study, added: "These results are an important step forward in our understanding of how rhythmic activity in the brain underlies thought processes in health and disease."

The research is part of a Medical Research Council (MRC)-supported collaboration between the University and the Eli Lilly & Co. Centre for Cognitive Neuroscience that aims to develop new tools and targets for treatment of brain diseases like schizophrenia and Alzheimer's disease.

https://www.sciencedaily.com/releases/2011/10/111025172633.htm

The cannabis genome: How hemp got high

October 20, 2011

Science Daily/BioMed Central

Throughout history, Cannabis sativa has been exploited by humanity. Hemp seed oil is rich in omega 6, an essential fatty acid, and its fibre is used in the production of fabrics. Marijuana is known for its mind-altering properties and has been used medicinally for over 2700 years. The changes to the genome that led to drug-producing plants is a mystery of cannabis evolution, but one that has now been solved, thanks to an article published in BioMed Central's open access journal Genome Biology.

A team of researchers led by Drs Jon Page and Tim Hughes from Canada sequenced DNA from the potent Purple Kush (PK) marijuana strain, which is widely used for medicinal purposes. The PK genome and transcriptome (genes that are switched on) were then compared to those of 'Finola' hemp, and scanned for differences which might explain why marijuana produces tetrahydrocannabinolic acid (THCA), the active ingredient of cannabis, while hemp strains lack THCA but contain the non-psychoactive cannabinoid, cannabidiolic acid (CBDA).

The transcriptome held the clues to solving this genomic puzzle. Dr Page explained, "The transcriptome analysis showed that the THCA synthase gene, an essential enzyme in THCA production, is turned on in marijuana, but switched off in hemp." Dr Hughes continued, "Detailed analysis of the two genomes suggests that domestication, cultivation, and breeding of marijuana strains has caused the loss of the enzyme (CBDA synthase) which would otherwise compete for the metabolites used as starting material in THCA production."

Dr Page added: "Plants continue to be a major source of medicines, both as herbal drugs and as pharmaceutical compounds. Although more than twenty plant genomes have been published, ranging from major food crops such as rice and corn, to laboratory models like Arabidopsis, this is the first genome of a medicinal plant. Decoding the cannabis genome will help answer basic questions about the biology of Cannabis sativa and further the development of its myriad applications including strains for pharmaceutical production, and hemp plants with improved productivity and fatty acid profiles."

https://www.sciencedaily.com/releases/2011/10/111020024443.htm

How hemp got high: Cannabis genome mapped

October 24, 2011

Science Daily/University of Saskatchewan

A team of Canadian researchers has sequenced the genome of Cannabis sativa, the plant that produces both industrial hemp and marijuana, and in the process revealed the genetic changes that led to the plant's drug-producing properties.

Jon Page is a plant biochemist and adjunct professor of biology at the University of Saskatchewan. He explains that a simple genetic switch is likely responsible for the production of THCA, or tetrahydrocannabinolic acid, the precursor of the active ingredient in marijuana.

"The transcriptome analysis showed that the THCA synthase gene, an essential enzyme in THCA production, is turned on in marijuana, but switched off in hemp," Page says.

Tim Hughes, co-leader of the project, is a professor at the Terrence Donnelly Centre for Cellular and Biomolecular Research and the Department of Molecular Genetics at the University of Toronto. He explains the team compared the potent Purple Kush marijuana variety with 'Finola' hemp, which is grown for seed production. Hemp lacks THCA, but does contain another, non-psychoactive substance called CBDA, or cannabidiolic acid.

"Detailed analysis of the two genomes suggests that domestication, cultivation, and breeding of marijuana strains has caused the loss of the enzyme (CBDA synthase), which would otherwise compete for the metabolites used as starting material in THCA production," Hughes says.

Essentially, this means that over thousands of years of cultivation, hemp farmers selectively bred Cannabis sativa into two distinct strains -- one for fibre and seed, and one for medicine. Marijuana has been used medicinally for more than 2,700 years, and continues to be explored for its pharmaceutical potential.

"Plants continue to be a major source of medicines, both as herbal drugs and as pharmaceutical compounds," Page says. "Although more than 20 plant genomes have been published, ranging from major food crops such as rice and corn, to laboratory models like Arabidopsis, this is the first genome of a medicinal plant."

The researchers expect that sequencing the Cannabis sativa genome will help answer basic questions about the biology of the plant as well as furthering development of its myriad applications. These include strains for pharmaceutical production, high-producing industrial hemp plants, and hemp seed varieties to produce high-quality edible oil. Hemp seed oil is rich in omega 6, an essential fatty acid, and its fibre is used in the production of textiles.

According to the Canadian Hemp Trade Alliance, about 25,000 acres of the crop were sown in Canada in 2010, much of this in Manitoba. Due to hemp's association with marijuana, farmers need to be licensed through Health Canada to grow the crop. Canadian medicinal marijuana is currently produced under Health Canada contract with Prairie Plant Systems, a biotechnology company based in Saskatoon.

https://www.sciencedaily.com/releases/2011/10/111020025752.htm

How the brain’s own marijuana-like chemicals suppress pain

October 12, 2011

Science Daily/National University of Ireland, Galway

New findings about how the brain functions to suppress pain have been published in the journal Pain, by NUI Galway researchers. For the first time, it has been shown that the hippocampus of the brain, which is usually associated with memory, has an active role to play in suppressing pain during times of stress.

The work was carried out by researchers in Pharmacology and Therapeutics, and the Centre for Pain Research at the National Centre for Biomedical Engineering Science, NUI Galway.

In times of immense stress or fear, pain transmission and perception can be suppressed potently in humans and other animals. This important survival response can help us cope with, or escape from, potentially life-threatening situations. An increased understanding of the biological mechanisms involved in this so-called fear-induced analgesia is important from a fundamental physiological perspective and may also advance the search for new therapeutic approaches to the treatment of pain.

Dr David Finn, Co-Director of the Centre for Pain Research at NUI Galway, and study leader, says: "The body can suppress pain when under extreme stress, in part through the action of marijuana-like substances produced in the brain. What we have now identified for the first time, is that the brain's hippocampus is an important site of action of these endocannabinoids during the potent suppression of pain by fear. This research, which was funded by a grant from Science Foundation Ireland, advances our fundamental understanding of the neurobiology of pain and may facilitate the identification of new therapeutic targets for the treatment of pain and anxiety disorders."

Working with Dr Finn, first author Dr Gemma Ford was able to demonstrate that inhibition of the enzyme that breaks down one of these endogenous marijuana-like substances in the hippocampus, had the effect of enhancing stress-induced pain suppression. Further experimentation revealed that these effects were mediated by the cannabinoid CB1 receptor and were likely to be mediated by stress-induced increases in levels of endocannabinoids in the hippocampus.

https://www.sciencedaily.com/releases/2011/10/111012083619.htm

Marijuana component could ease pain from chemotherapy drugs

October 6, 2011

Science Daily/Temple University

A chemical component of the marijuana plant could prevent the onset of pain associated with drugs used in chemo therapy, particularly in breast cancer patients, according to researchers at Temple University's School of Pharmacy.

The researchers published their findings in the journal Anesthesia and Analgesia.

The researchers developed animal models and tested the ability of the compound cannabidiol, which is the second most abundant chemical found in the marijuana plant, to relieve chemo-induced neuropathic pain, said Sara Jane Ward, research assistant professor of pharmaceutical sciences in Temple's School of Pharmacy and the study's lead author.

"We found that cannabidiol completely prevented the onset of the neuropathic, or nerve pain caused by the chemo drug Paclitaxel, which is used to treat breast cancer," said Ward, who is also a research associate professor in Temple's Center for Substance Abuse Research.

Ward said that one of cannabidiol's major benefits is that, unlike other chemicals found in marijuana such as THC, it does not produce psycho-active effects such as euphoria, increased appetite or cognitive deficits. "Cannabidiol has the therapeutic qualities of marijuana but not the side effects," she said.

Ward's research has long focused on systems in the brain that are impacted by marijuana and whether those systems could be targeted in the treatment of various disorders. "Marijuana binds to the cannabinoid receptors in the body and researchers have long been interested in whether there is therapeutic potential for targeting this receptor system," she said.

Ward became interested in this current study after attending a conference in which she learned about a pain state that is induced by chemo-therapeutic agents, especially those used to treat breast cancer, which can produce really debilitating neuropathic pain.

Cannabidiol has also demonstrated the ability to decrease tumor activity in animal models, said Ward, which could make it an effective therapeutic for breast cancer, especially if you "combined it with a chemo agent like Paclitaxel, which we already know works well."

According to Ward, there are currently about 10 clinical trials underway in the United States for cannabidiol on a range of different disorders, including cannabis dependence, eating disorders and schizophrenia. Because of this, she believes it will be easier to establish a clinical trial for cannabidiol as a therapeutic against neuropathic pain associated with chemo drugs.

In addition to Ward, Temple researchers involved in the study included Michael David Ramirez, Harshini Neelakantan and Ellen Ann Walker. The study was supported by grants from the National Institutes of Health and the Peter F. McManus Charitable Trust.

https://www.sciencedaily.com/releases/2011/10/111006125418.htm

Bodyguard for the brain: Researchers identify mechanism that seems to protect brain from aging

July 13, 2011

Science Daily/University of Bonn

Researchers from the Universities of Bonn and Mainz have discovered a mechanism that seems to protect the brain from aging. In experiments with mice, they switched off the cannabinoid-1 receptor. As a consequence, the animals showed signs of degeneration -- as seen in people with dementia -- much faster.

The research results are presented in a current issue of the Proceedings of the National Academy of Sciences (PNAS).

Humans are getting older and older, and the number of people with dementia is increasing. The factors controlling degeneration of the brain are still mostly unknown. However, researchers assume that factors such as stress, accumulation of toxic waste products as well as inflammation accelerate aging. But, vice versa, there are also mechanisms that can -- like a bodyguard -- protect the brain from degenerating, or repair defective structures.

Researchers from the Universities of Bonn and Mainz have now discovered a hitherto unknown function of the cannabinoid-1 receptor (CB1). A receptor is a protein that can bind to other substances, triggering a chain of signals. Cannabinoids such as THC -- the active agent in cannabis sativa -- and endocannabinoids formed by the body bind to the CB1 receptors. The existence of this receptor is also the reason for the intoxicating effect of hashish and marijuana.

Not only does the CB1 receptor have an addictive potential, but it also plays a role in the degeneration of the brain. "If we switch off the receptor using gene technology, mouse brains age much faster," said Önder Albayram, principal author of the publication and a doctoral student on the team of Professor Dr. Andreas Zimmer from the Institut für Molekulare Psychiatrie at the University of Bonn. "This means that the CB1 signal system has a protective effect for nerve cells."

Mice prove their brain power in a pool

The researchers studied mice in different age categories -- young six week old animals, middle-aged ones at five months, and those of an advanced age at 12 months. The animals had to master various tasks -- first, they had to find a submerged platform in the pool. Once the mice knew its location, the platform was moved, and the animals had to find it again. This was how the researchers tested how well the rodents learned and remembered.

The animals in which the CB1 receptor had been switched off (the knock-out mice) clearly differed from their kind. "The knock-out mice showed clearly diminished learning and memory capacity," said Privatdozent Dr. Andras Bilkei-Gorzo from Professor Zimmer's team, who led the study. So, animals that did not have the receptor were less successful in their search for the platform. "In addition, they showed a clear loss of nerve cells in the hippocampus," he explained further. This part of the brain is the central area for forming and storing information. In addition, the researchers found inflammation processes in the brain. As the mice advanced in age, the degenerative processes became increasingly noticeable.

Amazing parallels with the human brain

The animals with the intact CB1 receptor, to the contrary, did clearly better with regard to their learning and memory capabilities, as well as the health of their nerve cells. "The root cause of aging is one of the secrets of life," commented Albayram. This study has begun to open the door to solving this enigma. The processes in the mouse brains have a surprising number of parallels with age-related changes in human brains. So, the endocannabinoid system may also present a protective mechanism in the aging of the human brain.

The principal author cautioned, "This will require additional research." The scientists would like to better understand the mechanism by which CB1 receptors protect the brain from inflammation processes. And based on these signal chains, it might then be possible to develop substances for new therapies.

https://www.sciencedaily.com/releases/2011/07/110712093856.htm

Chronic marijuana smoking affects brain chemistry, molecular imaging shows

June 13, 2011

Science Daily/Society of Nuclear Medicine

Definitive proof of an adverse effect of chronic marijuana use revealed at SNM's 58th Annual Meeting could lead to potential drug treatments and aid other research involved in cannabinoid receptors, a neurotransmission system receiving a lot of attention. Scientists used molecular imaging to visualize changes in the brains of heavy marijuana smokers versus non-smokers and found that abuse of the drug led to a decreased number of cannabinoid CB1 receptors, which are involved in not just pleasure, appetite and pain tolerance but a host of other psychological and physiological functions of the body.

"Addictions are a major medical and socioeconomic problem," says Jussi Hirvonen, MD, PhD, lead author of the collaborative study between the National Institute of Mental Health and National Institute on Drug Abuse, Bethesda, Md. "Unfortunately, we do not fully understand the neurobiological mechanisms involved in addiction. With this study, we were able to show for the first time that people who abuse cannabis have abnormalities of the cannabinoid receptors in the brain. This information may prove critical for the development of novel treatments for cannabis abuse. Furthermore, this research shows that the decreased receptors in people who abuse cannabis return to normal when they stop smoking the drug."

According to the National Institute on Drug Abuse, marijuana is the number-one illicit drug of choice in America. The psychoactive chemical in marijuana, or cannabis, is delta-9-tetrahydrocannabinol (THC), which binds to numerous cannabinoid receptors in the brain and throughout the body when smoked or ingested, producing a distinctive high. Cannabinoid receptors in the brain influence a range of mental states and actions, including pleasure, concentration, perception of time and memory, sensory perception, and coordination of movement. There are also cannabinoid receptors throughout the body involved in a wide range of functions of the digestive, cardiovascular, respiratory and other systems of the body. Currently two subtypes of cannabinoid receptors are known, CB1 and CB2, the former being involved mostly in functions of the central nervous system and the latter more in functions of the immune system and in stem cells of the circulatory system.

For this study, researchers recruited 30 chronic daily cannabis smokers who were then monitored at a closed inpatient facility for approximately four weeks. The subjects were imaged using positron emission tomography (PET), which provides information about physiological processes in the body. Subjects were injected with a radioligand, 18F-FMPEP-d2, which is a combination of a radioactive fluorine isotope and a neurotransmitter analog that binds with CB1 brain receptors.

Results of the study show that receptor number was decreased about 20 percent in brains of cannabis smokers when compared to healthy control subjects with limited exposure to cannabis during their lifetime. These changes were found to have a correlation with the number of years subjects had smoked. Of the original 30 cannabis smokers, 14 of the subjects underwent a second PET scan after about a month of abstinence. There was a marked increase in receptor activity in those areas that had been decreased at the outset of the study, an indication that while chronic cannabis smoking causes downregulation of CB1 receptors, the damage is reversible with abstinence.

Information gleaned from this and future studies may help other research exploring the role of PET imaging of CB1 receptors -- not just for drug use, but also for a range of human diseases, including metabolic disease and cancer.

https://www.sciencedaily.com/releases/2011/06/110606131705.htm

How marijuana affects the way the brain processes emotional information

April 11, 2011

Science Daily/University of Western Ontario

Drugs like marijuana act on naturally occurring receptors in the brain called cannabinoid receptors. However, the mechanisms by which these drugs produce their sensory and mood altering effects within the brain are largely unknown. Research led by Steven Laviolette at The University of Western Ontario has now identified a critical brain pathway responsible for the effects of cannabinoid drugs on how the brain processes emotional information.

The findings, published in The Journal of Neuroscience, also help to explain the possible link between marijuana use and schizophrenia.

Laviolette and his team at the Schulich School of Medicine & Dentistry discovered that activating cannabinoid receptors directly in a region of the brain called the amygdala, can strongly influence the significance of emotional information and memory processes. It also dramatically increased the activity patterns of neurons in a connected region of the brain called the prefrontal cortex, controlling both how the brain perceived the emotional significance of incoming sensory information, and the strength of memories associated with these emotional experiences.

"These findings are of great clinical relevance given recent evidence suggesting that exposure to marijuana during adolescence can increase the likelihood of developing schizophrenia later in life," says Laviolette, an associate professor in the Department of Anatomy and Cell Biology. "We know there are abnormalities in both the amygdala and prefrontal cortex in patients who have schizophrenia, and we now know these same brain areas are critical to the effects of marijuana and other cannabinoid drugs on emotional processing."

Furthermore, the findings by Laviolette's laboratory identify a novel new brain pathway by which drugs acting on the cannabinoid system can distort the emotional relevance of incoming sensory information which in turn may lead to psychotic side-effects, such as paranoia, associated with heavy marijuana use. Developing pharmacological compounds, and there already are some, that block or modify this pathway could help control psychotic episodes. It could also be used to help patients with Post Traumatic Stress Disorder who have difficulty controlling the resurgence of highly emotional events into their memory.

Laviolette's research was funded by the Ontario Mental Health Foundation and the Natural Sciences and Engineering Research Council of Canada (NSERC).

https://www.sciencedaily.com/releases/2011/04/110405174833.htm

Cannabis ingredient can help cancer patients regain their appetites and sense of taste

February 25, 2011

Science Daily/Oxford University Press (OUP)

The active ingredient in cannabis can improve the appetites and sense of taste in cancer patients, according to a new study published online in the cancer journal, Annals of Oncology.

Loss of appetite is common among cancer patients, either because the cancer itself or its treatment affects the sense of taste and smell, leading to decreased enjoyment of food. This, in turn, can lead to weight loss, anorexia, a worse quality of life and decreased survival; therefore, finding effective ways of helping patients to maintain a good diet and consume enough calories is an important aspect of their treatment.

Researchers in Canada ran a small pilot study from May 2006 to December 2008in 21 adult patients with any advanced cancer (except brain cancer) who had been eating less as a result of their illness for two weeks or more. All were either being treated with chemotherapy or had been in the past. The patients were randomly assigned to receive medication from a pharmacist in a double-blind manner, which meant that neither the patients nor the doctors knew which treatment they were receiving. Eleven patients received oral capsules containing delta-9-tetrahydrocannabinol (THC) -- the main psychoactive ingredient in cannabis -- and eight patients were assigned to the control group to receive placebo capsules. The active capsules contained 2.5mg of THC and the patients took them once a day for the first three days, twice a day thereafter, and they had the option to increase their dose up to a maximum of 20mg a day if they wished; however, most followed the dosing protocol, with three patients in both groups increasing their dose to three times a day. The treatment ran for 18 days.

From patient answers to questionnaires conducted before, during and at the end of the trial, the researchers found that the majority (73%) of THC-treated patients reported an increased overall appreciation of food compared with patients receiving placebo (30%) and more often stated that study medication "made food taste better" (55%) compared with placebo (10%).

The majority of THC-treated patients (64%) had increased appetite, three patients (27%) showed no change, and one patient's data was incomplete. No THC-treated patients showed a decrease in appetite. By contrast, the majority of patients receiving placebo had either decreased appetite (50%) or showed no change (20%).

Although there was no difference in the total number of calories consumed by both groups, the THC-treated patients tended to increase the proportion of protein that they ate, and 55% reported that savoury foods tasted better, whereas no patients in the placebo group reported an increased liking for these foods. (Cancer patients often find that meat smells and tastes unpleasant and, therefore, they eat less of it).

In addition, THC-treated patients reported better quality of sleep and relaxation than in the placebo group.

Dr Wendy Wismer (PhD), associate professor at the University of Alberta (Edmonton, Canada), who led the study, said: "This is the first randomised controlled trial to show that THC makes food taste better and improves appetites for patients with advanced cancer, as well as helping them to sleep and to relax better. Our findings are important, as there is no accepted treatment for chemosensory alterations experienced by cancer patients. We are excited about the possibilities that THC could be used to improve patients' enjoyment of food.

"Decreased appetite and chemosensory alterations can be caused by both cancer and its treatment; untreated tumours cause loss of appetite, and by itself, chemotherapy also causes loss of appetite. In any individual patient, some part of both of these effects is usually present.

"It's very important to address these problems as both appetite loss and alterations to taste and smell lead to involuntary weight loss and reduce an individual's ability to tolerate treatment and to stay healthy in general. Additionally, the social enjoyment of eating is greatly reduced and quality of life is affected. For a long time everyone has thought that nothing could be done about this. Indeed, cancer patients are often told to 'cope' with chemosensory problems by eating bland, cold and odourless food. This may well have the result of reducing food intake and food enjoyment."

The researchers say that larger, phase II trials should test their findings further, but, in the meantime Dr Wismer thinks that doctors could consider THC treatment for cancer patients. "It could be investigated for any stage of cancer where taste and smell dysfunction and appetite loss has been indicated by the patient," she said. In addition, treatment would not necessarily have to be limited to the 18 days of the study. "Long term therapy with cannabinoids is possible, however, in each case this would be up to the patient's physician to determine."

Although the study was unable to show that THC treatment could increase total calorie intake, Dr Wismer said this was unsurprising. "In the healthy adult population, we know from personal experience that we usually eat more of something if it tastes better. However, in this advanced cancer population, there is a real struggle with appetite; normal appetitive pathways do not seem to be functioning. We know from our earlier work that individuals with advanced cancer have diminished appetite and have to make a big conscious effort to eat; they are motivated to eat simply to survive. So, although THC did not significantly increase total calorie intake, the fact that it improved appetite and protein intake is important."

This work was supported by the Canadian Institutes of Health Research, the Alberta Cancer Board, Alberta Heritage Foundation for Medical Research, and the Natural Sciences and Engineering Research Council of Canada.

https://www.sciencedaily.com/releases/2011/02/110222192830.htm

How cannabis suppresses immune functions: Cannabis compounds found to trigger unique immune cells which promote cancer growth

November 26, 2010

Science Daily/Wiley-Blackwell

An international team of immunologists studying the effects of cannabis have discovered how smoking marijuana can trigger a suppression of the body's immune functions. The research, published in the European Journal of Immunology, reveals why cannabis users are more susceptible to certain types of cancers and infections.

The team, led by Dr Prakash Nagarkatti from the University of South Carolina, focused their research on cannabinoids, a group of compounds found inside the cannabis plant, including THC (delta-9 tetahydrocannabinol) which is already used for medical purposes such as pain relief.

"Cannabis is one of the most widely used drugs of abuse worldwide and it is already believed to suppress immune functions making the user more susceptible to infections and some types of cancer," said Dr Nagarkatti. "We believe the key to this suppression is a unique type of immune cell, which has only recently been identified by immunologists, called myeloid-derived suppressor cells, MDSCs."

While most immune cells fight against infections and cancers to protect the host, MDSCs actively suppress the immune system. The presence of these cells is known to increase in cancer patients and it is believed that MDSCs may suppress the immune system against cancer therapy, actually promoting cancer growth.

Dr Nagarkatti's team demonstrated that cannabinoids can trigger a massive number of MDSCs through activation of cannabinoid receptors. This research reveals, for the first time, that marijuana cannabinoids may suppress the immune system by activating these unique cells.

"These results raise interesting questions on whether increased susceptibility to certain types of cancers or infections caused from smoking marijuana results from induction of MDSCs," said Nagarkatti. "MDSCs seem to be unique and important cells that may be triggered by inappropriate production of certain growth factors by cancer cells or other chemical agents such as cannabinoids, which lead to a suppression of the immune system's response."

In a related study, also published in the European journal of Immunology, Dr Christian Vosshenrich from the Institut Pasteur in Paris, reveals that when cancer cells grow they produce a molecule called interleukin-1 β (IL-1β), which also triggers MDSCs. This study identifies how MDSCs produced during cancer growth also weaken the ability of immune cells to kill cancer cells.

"Marijuana cannabinoids present us with a double edged sword," concluded Dr Nagarkatti. "On one hand, due to their immunosuppressive nature, they can cause increased susceptibility to cancer and infections. However, further research of these compounds could provide opportunities to treat a large number of clinical disorders where suppressing the immune response is actually beneficial."

https://www.sciencedaily.com/releases/2010/11/101124214728.htm

Compound boosts marijuana-like chemical in the body to relieve pain at injury site

September 21, 2010

Science Daily/University of California -- Irvine

American and Italian researchers have found that a novel drug allows anandamide -- a marijuana-like chemical in the body -- to effectively control pain at the site of an injury.

Led by Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at UC Irvine, the study suggests that such compounds could form the basis of pain medications that don't produce sedation, addiction or other central nervous system side effects common with existing painkillers, such as opiates.

"These findings raise hope that the analgesic properties of marijuana can be harnessed to curb pain," Piomelli said. "Marijuana itself is sometimes used in clinical settings for pain relief but causes many unwanted effects. However, specific drugs that amplify the actions of natural, marijuana-like chemicals are showing great promise."

For the study, which appears in the Sept. 19 online version of Nature Neuroscience, rats and mice were given a drug created by Piomelli and colleagues at the Italian universities of Urbino and Parma. The researchers discovered that the compound, URB937, did not enter the central nervous system but simply boosted the levels of anandamide in peripheral tissues. Still, it produced a profound analgesic effect for both acute and chronic pain. This was surprising, since anandamide had been thought to only work in the brain.

The synthetic drug inhibits FAAH, an enzyme in the body that breaks down anandamide, dubbed "the bliss molecule" for its similarities to the active ingredient in marijuana. A neurotransmitter that's part of the endocannabinoid system, anandamide has been shown in studies by Piomelli and others to play analgesic, antianxiety and antidepressant roles. It's also important in regulating food consumption. Blocking FAAH activity enhances the effects of anandamide without generating the "high" seen with marijuana.

Piomelli and his team are now collaborating with drug discovery specialists at the Italian Institute of Technology, in Genoa, to develop the new compound -- which is protected by a patent application -- into a clinically useful medication.

Researchers from UCI, the University of Georgia, the University of Naples, the University of Parma, the University of Urbino and the Italian Institute of Technology participated in the study, which was supported by the National Institute on Drug Abuse and the Italian Ministry of Public Education.

https://www.sciencedaily.com/releases/2010/09/100920131140.htm

Painkilling system in brain: Too much of a good thing?

August 25, 2010

Science Daily/Scripps Research Institute

Repeatedly boosting brain levels of one natural painkiller soon shuts down the brain cell receptors that respond to it, so that the painkilling effect is lost, according to a surprising new study led by Scripps Research Institute and Virginia Commonwealth University scientists. The study has important implications for drug development.

The natural painkiller, 2-AG, is one of the two major "endocannabinoid" neurotransmitters. The other, anandamide, can be kept at high levels in the brain without losing its therapeutic effects, and researchers had hoped that the same would be true for 2-AG.

"One implication is that maximally elevating 2-AG levels in the brain might not provide a straightforward path to new pain drugs," says Benjamin F. Cravatt III, PhD, professor and chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Biology at Scripps Research in La Jolla, California, who led the study with Aron Lichtman, PhD, a professor of pharmacology and toxicology at Virginia Commonwealth University in Richmond, Virginia. "But we remain optimistic that more modest elevations in 2-AG could produce sustained pain relief. Perhaps more importantly, on a basic science level, we've been able to tease apart a key difference between the two major endocannabinoid signaling pathways, since one can maximally elevate anandamide without observing tolerance."

The report appears in the August 22, 2010 issue of Nature Neuroscience.

A Better Chill Pill

Like the opioid system, the endocannabinoid system was discovered as a result of humans identifying a plant -- in this case marijuana (cannabis sativa) -- that artificially boosts its activity. Marijuana's main active ingredient, THC, typically reduces pain and anxiety. Researchers have sought to develop drugs that reproduce such therapeutic effects while leaving out THC's unwanted side effects -- which include memory impairment, locomotor dysfunction, and possibly addiction.

Cannabinoid research received a boost in 1990 with the description of the main cannabinoid receptor in the brain, CB1, and a few years later with the discoveries of the body's own (endo-) cannabinoids, anandamide and 2-AG, which exert most of their effects by binding to CB1. Cannabinoid receptors are now known to be widely distributed in the brain, and when activated by anandamide or 2-AG, tend to calm the activity of the neurons where they reside. However, researchers so far have been unable to develop artificial cannabinoids that bind to CB1 without producing unwelcome THC-like side effects.

An alternative strategy has been to boost levels of the body's own cannabinoids by inhibiting the enzymes that normally break them down. And so far this has worked for anandamide. Inhibitors of its breakdown enzyme, fatty acid amide hydrolase (FAAH), have been shown to boost anandamide levels and reduce pain and inflammation without adverse side effects in animal tests and early clinical trials.

A similar strategy for boosting 2-AG may be promising, too, especially since 2-AG levels in the brain are naturally higher than anandamide's. Two years ago, the Cravatt and Lichtman laboratories jointly reported the development of an inhibitor of 2-AG's breakdown enzyme, monoacylglycerol lipase (MAGL). When administered to mice, it boosted their brain levels of 2-AG on average by a factor of eight, and produced a pain-killing effect comparable to that of FAAH inhibitors.

Diminishing Returns

Now the two labs report that 2-AG's pain-killing effect disappears after six days of treatment. "When you continually stimulate the endocannabinoid system by maximally raising 2-AG levels, you effectively desensitize the system," says Cravatt.

In one experiment, an injection of the MAGL inhibitor into mice showed evidence of pain relief on standard tests, but after six consecutive daily injections the drug could no longer achieve this effect. These chronically treated mice also lost much of their sensitivity to THC and to a synthetic CB1-binding compound, and showed a classic sign of drug dependency�when abruptly withdrawn from 2-AG's influence by having their CB1 receptors blocked, they developed paw flutters -- a murine version of the shakes.

"When we investigated at the molecular level, we found that the number of CB1 receptors in the mouse brains had been reduced," says Jacqueline Blankman, a graduate student at the Scripps Research Kellogg School of Science and Technology who was co-first-author on the paper with Joel Schlosburg of the Lichtman lab. This receptor "downregulation" occurred in some brain areas but not others

To confirm this effect, the researchers utilized another experimental mouse model where the gene for MAGL was inactivated. This lifelong genetic disruption of MAGL also resulted in high 2-AG levels as well as a reduced and desensitized CB1 system.

"Because we're seeing downregulation of the whole cannabinoid system and tolerance to the anti-pain effects, it does raise some concern about whether MAGL would be a suitable pain target," says Blankman.

"If you are going to inhibit MAGL, you probably wouldn't want to produce a complete inactivation of the enzyme," Cravatt adds.

By contrast with the 2-AG experiments, chronically boosting anandamide had none of these effects on the CB1 system. Cravatt doesn't yet know why these two molecules have such different impacts when delivered chronically. He notes, however, that anandamide may be produced selectively under stress conditions, and perhaps for that reason is less likely to trigger a brain-wide CB1 downregulation.

"The question of why anandamide and 2-AG have such different effects when given chronically is certainly going to be motivating us from now on," says Cravatt. "But already with this finding and the development of these models we've taken a significant step forward in understanding and being able to manipulate this important neurotransmitter system."

This study was supported by the National Institutes of Health.

https://www.sciencedaily.com/releases/2010/08/100824151036.htm

Study overturns decade-old findings in neurobiology: Research suggests potential target for drugs to combat alcohol addiction

May 13, 2010

Science Daily/Scripps Research Institute

In findings that should finally put to rest a decade of controversy in the field of neurobiology, a team at The Scripps Research Institute has found decisive evidence that a specific neurotransmitter system -- the endocannabinoid system -- is active in a brain region known to play a key role in the processing of memory, emotional reactions, and addiction formation. The new study also shows that this system can dampen the effects of alcohol, suggesting an avenue for the development of drugs to combat alcohol addiction.

The research was published in the journal Neuropsychopharmacology on May 12.

"This study will change a lot in the field," said Scripps Research Associate Professor Marisa Roberto, who was first author of the paper. "I'm confident it will have a big impact."

"This is very new," said Paul Schweitzer, associate professor of the neurobiology of addiction at Scripps Research and corresponding author of the paper. "It is the first time a study has shown a direct cellular interaction between endocannabinoids and alcohol in the brain."

The Missing Link?

The new research overturns the conclusions of a paper published by a European group in the Journal of Neuroscience in 2001. This paper claimed that endocannabinoid receptors, in particular the most common type called CB1, did not exist in the brain region called the central amygdala.

"Yet CB1 receptors are very abundant," said Schweitzer. "They are almost everywhere in the brain and there are lots of them. The endocannabinoid system acts on appetite, mood, memory -- and addiction. Addiction is why we started to study it in the central amygdala."

The Scripps Research scientists began to suspect that the 2001 study, whose conclusions had been widely accepted in the field, might have missed the CB1 receptors in the brain's central amygdala. Indirect evidence from a number of subsequent studies -- including one by Scripps Research Associate Professor Loren "Larry" Parsons -- had suggested that the endocannabinoid system (and by implication its receptors) were indeed active in this brain region.

The Scripps Research team decided to take a fresh look at the whole question, and set out to conduct a new physiological study specifically looking for signs of the missing CB1 receptors in the central amygdala.

"There wasn't much physiology done before this," said Roberto. "There were a lot of behavioral studies, but very few on physiology and, aside from the 2001 study, none on the physiology in the central amygdala -- this brain region that is so important for drugs of abuse."

Back on Track

Using electrophysiological techniques in brain slices to test the response of brain cells from the rat central amygdala, the scientists indeed found compelling evidence that CB1 receptors were active there.

The cells responded to a substance (agonist) mimicking the action of endocannabinoids in the brain. Up to a point, the more of the agonist the scientists applied, the bigger the effect. An inhibitor (antagonist) reversed this response.

"We saw a big and consistent physiological effect," said Roberto. "It was beautiful. The receptor had to be there or otherwise it wouldn't have worked."

With this major milestone achieved, the researchers extended their investigation to their primary area of interest -- the brain's response to alcohol. Alcohol abuse can lead to devastating consequences for individuals and families. It is also associated with direct and indirect public health costs estimated to be in the hundreds of billions of dollars yearly in the United States alone.

To learn more about the effect of alcohol on the biology of the brain, the scientists focused on the transmission of one particular neurotransmitter called gamma amino butyric acid (GABA). GABA is the main inhibitory neurotransmitter in the brain, and neurons in every brain region use GABA to fine-tune signaling throughout the nervous system. Previous studies by the Scripps Research scientists indicated that GABA plays a critical role in alcohol dependence and other addictions.

"We knew ethanol in these neurons increase GABA transmission, and that cannabinoids decrease GABA transmission," said Roberto. "So the question was what happens if we activate the cannabinoid system and we put ethanol on it."

When the scientists first applied the CB1 agonist on cells from the central amygdala, it decreased GABA transmission; when the scientists proceeded to put ethanol on top, the effect of ethanol was abolished. When the team reversed the order of application, GABA transmission first went up with the application of ethanol, then down with the application of the CB1 agonist.

"Alcohol and CB1 agonists have opposing effects on GABA," summarized Schweitzer. "Our feeling is that since the CB1 system is so widely expressed, there's a big role there in dampening the effect of alcohol."

While the team's research points to the endocannibinoid system as a potential target in the development of drugs to treat alcoholism, Schweitzer notes there are still many questions to be answered: Do CB1 agonists work the same way in brains that have become addicted to alcohol? What is the mechanism for this action? Can the effects of CB1 on alcohol metabolism be separated from its many other effects on mood, appetite, and memory?

Schweitzer also cautions against equating CB1 agonists and cannabis in interpreting the study's results. "This study does not have to do with marijuana, but the endocannabinoid system," he said. "On this level of analysis, the two don't have much in common."

The work was supported by National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health.

https://www.sciencedaily.com/releases/2010/05/100512151549.htm

Enhanced sweet taste: Endocannabinoids act directly on tongue taste receptors

December 23, 2009

Science Daily/Monell Chemical Senses Center

New findings from the Monell Center and Kyushu University in Japan report that endocannabinoids act directly on taste receptors on the tongue to enhance sweet taste.

"Our taste cells may be more involved in regulating our appetites than we had previously known," said study author Robert Margolskee, M.D., Ph.D., a Monell molecular biologist. "Better understanding of the driving forces for eating and overeating could lead to interventions to stem the burgeoning rise in obesity and related diseases."

Endocannabinoids are substances similar to THC, the active ingredient in marijuana. Produced in the brain and body, they bind with cannabinoid receptors to help regulate appetite and many other processes involved in health and disease.

"Endocannabinoids both act in the brain to increase appetite and also modulate taste receptors on the tongue to increase the response to sweets," said study senior author Yuzo Ninomiya, Ph.D., Professor of Oral Neuroscience in the Graduate School of Dental Sciences at Kyushu University in Japan.

In the study, published online in the Proceedings of the National Academy of Sciences, the researchers conducted a series of experiments in mice to determine the behavioral, neural and cellular responses to sweet taste stimuli before and after the administration of endocannabinoids.

Sweet taste responses were enhanced by endocannabinoids in every case. The effect was specific for sweet taste, as endocannibinoids had no effect on responses to sour, salty, bitter or umami taste stimuli.

The effects were abolished when the experiments were repeated using knockout mice lacking the CB1 cannabinoid receptor. Additional studies revealed that the CB1 receptor and the T1R3 sweet taste receptor are present in the same taste cells.

Together, the experiments demonstrate that endocannabinoids selectively enhance sweet taste by acting on tongue taste cells and that the effect is mediated by the endocannabinoid receptor.

"Modulation of sweet taste responses may be an important component of the endocannabinoid system's role in regulating feeding behavior," said Margolskee. He parenthetically noted that the well-known "marijuana munchies" may depend at least in part on endocannabinoid stimulation of tongue taste cells.

Sweet taste receptors also are found in the intestine and pancreas, where they help regulate nutrient absorption, insulin secretion and energy metabolism. If endocannibinoids also modulate the responses of pancreatic and intestinal sweet receptors, the findings may open doors to the development of novel therapeutic compounds to combat metabolic diseases such as obesity and diabetes.

Also contributing to the study were Ryusuke Yoshida, Tadahiro Ohkuri, Masafumi Jyotaki, Toshiaki Yasuo, Nao Horio, Keiko Yasumatsu, Keisuke Sanematsu, Noriatsu Shigemura, Yuzo Ninomiya from Kyushu University and Tsuneyuki Yamamoto from Nagasaki International University.

The research was funded by grants from the Japan Society for the Promotion of Science and the National Institute on Deafness and Other Communication Disorders, National Institutes of Health.

https://www.sciencedaily.com/releases/2009/12/091222104920.htm

Cannabis hope for inflammatory bowel disease

December 21, 2009

Science Daily/British Pharmacological Society

Chemicals found in cannabis could prove an effective treatment for the inflammatory bowel diseases Ulcerative Colitis and Crohn's Disease, say scientists.

Laboratory tests have shown that two compounds found in the cannabis plant -- the cannabinoids THC and cannabidiol -- interact with the body's system that controls gut function.

Crohn's Disease and Ulcerative Colitis, which affect about one in every 250 people in Northern Europe, are caused by both genetic and environmental factors. The researchers believe that a genetic susceptibility coupled with other triggers, such as diet, stress or bacterial imbalance, leads to a defective immune response.

Dr Karen Wright, Peel Trust Lecturer in Biomedicine at Lancaster University, presented her soon-to-be published work at The British Pharmacological Society's Winter Meeting in London.

She said: "The lining of the intestines provides a barrier against the contents of the gut but in people with Crohn's Disease this barrier leaks and bacteria can escape into the intestinal tissue leading to an inappropriate immune response.

"If we could find a way to restore barrier integrity in patients we may be able to curb the inflammatory immune response that causes these chronic conditions."

Dr Wright, working with colleagues at the School of Graduate Entry Medicine and Health in Derby, has shown that cells that react to cannabinoid compounds play an important role in normal gut function as well as the immune system's inflammatory response.

"The body produces its own cannabinoid molecules, called endocannabinoids, which we have shown increase the permeability of the epithelium during inflammation, implying that overproduction may be detrimental," said Dr Wright.

"However, we were able to reverse this process using plant-derived cannabinoids, which appeared to allow the epithelial cells to form tighter bonds with each other and restore the membrane barrier."

The research was carried out using cell cultures in a dish but, interestingly, when the team attempted to mimic the conditions of the gut by reducing the amount of oxygen in the cells' environment, much lower concentrations of cannabinoid were needed to produce the same effect.

Dr Wright added: "What is also encouraging is that while THC has psychoactive properties and is responsible for the 'high' people experience when using cannabis, cannabidiol, which has also proved effective in restoring membrane integrity, does not possess such properties."

https://www.sciencedaily.com/releases/2009/12/091220175502.htm

Cannabis damages young brains more than originally thought

December 20, 2009

Science Daily/McGill University Health Centre

Canadian teenagers are among the largest consumers of cannabis worldwide. The damaging effects of this illicit drug on young brains are worse than originally thought, according to new research by Dr. Gabriella Gobbi, a psychiatric researcher from the Research Institute of the McGill University Health Centre. The new study, published in Neurobiology of Disease, suggests that daily consumption of cannabis in teens can cause depression and anxiety, and have an irreversible long-term effect on the brain.

"We wanted to know what happens in the brains of teenagers when they use cannabis and whether they are more susceptible to its neurological effects than adults," explained Dr. Gobbi, who is also a professor at McGill University. Her study points to an apparent action of cannabis on two important compounds in the brain -- serotonin and norepinephrine -- which are involved in the regulation of neurological functions such as mood control and anxiety.

"Teenagers who are exposed to cannabis have decreased serotonin transmission, which leads to mood disorders, as well as increased norepinephrine transmission, which leads to greater long-term susceptibility to stress," Dr. Gobbi stated.

Previous epidemiological studies have shown how cannabis consumption can affect behaviour in some teenagers. "Our study is one of the first to focus on the neurobiological mechanisms at the root of this influence of cannabis on depression and anxiety in adolescents," confirmed Dr. Gobbi. It is also the first study to demonstrate that cannabis consumption causes more serious damage during adolescence than adulthood.

Dr. Gabriella Gobbi is a researcher at the neuroscience axis of the Research Institute of the McGill University Health Centre and also a psychiatrist and associate professor at the Department of Psychiatry, McGill University.

This study was funded by a grant from The Canadian Psychiatric Research Foundation (CPRF)

https://www.sciencedaily.com/releases/2009/12/091217115834.htm

Hemp and Marijuana: Genes Producing THC, Active Ingredient in Cannabis Plant, Identified

September 15, 2009

Science Daily/University of Minnesota

In a first step toward engineering a drug-free Cannabis plant for hemp fiber and oil, University of Minnesota researchers have identified genes producing tetrahydrocannabinol (THC), the psychoactive substance in marijuana. Studying the genes could also lead to new and better drugs for pain, nausea and other conditions.

The finding is published in the September issue of the Journal of Experimental Botany. Lead author is David Marks, a professor of plant biology in the College of Biological Sciences.

The study revealed that the genes are active in tiny hairs covering the flowers of Cannabis plants. In marijuana, the hairs accumulate high amounts of THC, whereas in hemp the hairs have little. Hemp and marijuana are difficult to distinguish apart from differences in THC.

With the genes identified, finding a way to silence them—and thus produce a drug-free plant — comes a step closer to reality. Another desirable step is to make drug-free plants visually recognizable. Since the hairs can be seen with a magnifying glass, this could be accomplished by engineering a hairless Cannabis plant.

The researchers are currently using the methods of the latest study to identify genes that lead to hair growth in hopes of silencing them.

"We are beginning to understand which genes control hair growth in other plants, and the resources created in our study will allow us to look for similar genes in Cannabis sativa," said Marks.

"Cannabis genetics can contribute to better agriculture, medicine, and drug enforcement," said George Weiblen, an associate professor of plant biology and a co-author of the study.

As with Dobermans and Dachshunds, marijuana and hemp are different breeds of the same species (Cannabis sativa), but marijuana contains much more THC than hemp, which is a source of industrial fiber and nutritious oil.

Hemp was raised for its fiber — which is similar to cotton but more durable — in the United States until legislation outlawed all Cannabis plants because they contain THC. Today, marijuana contains as much as 25 percent THC, whereas hemp plants contain less than 0.3 percent.

Hemp was once a popular crop in the upper Midwest because it tolerates a cool climate and marginal soils that won't support other crops but, after drug legislation, hemp fiber was replaced by plastic and other alternatives. Recent popular demand for hemp products has led some states to consider the economic and environmental benefits of hemp. North Dakota legislation aims to reintroduce it as a crop, and Minnesota is considering similar legislation. At the same time, California and other states permit the medicinal use of marijuana.

"I can't think of a plant so regarded as a menace by some and a miracle by others," says Weiblen, who is one of the few researchers in the United States permitted to study Cannabis genetics. In 2006, Weiblen and colleagues developed a DNA "fingerprinting" technique capable of distinguishing among Cannabis plants in criminal investigations.

https://www.sciencedaily.com/releases/2009/09/090915113538.htm

Endocannabinoids, Closely Related to Active Ingredients in Cannabis Plant, Can Promote Pain

https://www.sciencedaily.com/images/2009/09/090911212404_1_540x360.jpg

September 14, 2009

Science Daily/ETH Zurich

The endocannabinoids occurring naturally in the human body are closely related to the active ingredients of the cannabis plant. Cannabis has been used for thousands of years, for example to treat chronic pain. However, the fact that the endocannabinoids produced by the body itself can also be involved in the origin of pain is the astonishing result of studies by a Zurich research team.

The first mention of cannabis as a medicinal plant was in the Chinese book of medicinal plants “Shennong bencao jing”, which is almost 5000 years old. The Chinese emperor Shennong is said to have recommended cannabis resin as a remedy for various illnesses. After the use of its active ingredients for thousands of years to alleviate chronic pain, a study by the research group led by Hanns Ulrich Zeilhofer, Professor at the Institute of Pharmaceutical Sciences at ETH Zurich and the Institute of Pharmacology and Toxicology at the University of Zurich now shows that the endocannabinoids produced by the body itself can lead to pain sensitisation in certain types of pain. Their study was recently published in the scientific journal Science.

Short-circuit in the spinal cord

Pain and touch are conducted to the brain through the spinal cord via two different systems. This enables the brain to distinguish between pain and simple touch. However, because the two systems are interconnected via nerve fibres in the spinal cord, simple touches can also be perceived as pain, for example as a result of a “short circuit”. Such faulty circuits can occur if inhibitory chemical messengers (neurotransmitters) in the spinal cord are absent or blocked. Zeilhofer says, “This happens in various illnesses and can even be triggered by intense pain stimuli themselves.”

The body’s own endocannabinoids play a considerable part in the biochemical processes taking place in this, as the study by Zeilhofer and his team shows. In particular, the release of endocannabinoids in the spinal cord seems to be responsible for the fact that, after an initial pain stimulus, pain sensitivity spreads beyond the area originally stimulated. Even slight touch in this area is then perceived as painful. The endocannabinoids thus cause a “short circuit” between the touch signals and pain.

The scientists tested the theory that endocannabinoids released in the spinal cord during intense pain stimuli are responsible for this short-circuit. It actually became apparent that activating the endocannabinoid receptors on isolated spinal cord reduced the release of pain-inhibiting neurotransmitters. Animals that had developed the expected oversensitivity to slight touching after a pain stimulus behaved normally again after their cannabinoid receptors in the spinal cord were blocked.

Endocannabinoid inhibitors relieve pain

The fact that these processes also occur in humans was shown by experiments on healthy volunteers carried out in the Anaesthesiology Department at the University of Erlangen. Pain receptors in the volunteers’ skin were locally stimulated with an electric current, after which the size of the area hypersensitive to pain was determined. In the next step, half of the volunteers received a placebo for ten days, while the others were given Rimonabant, a substance that blocks certain cannabinoid receptors. The experiment was then repeated. Zeilhofer says, “The painful area formed in the test subjects whose endocannabinoid receptors had been blocked was about fifty percent smaller than in those who had taken the placebo.”

Helpful to the pharmaceutical industry

However, further experiments also showed that other forms of pain, e.g. those occurring as a result of nerve injuries, developed normally in mice that lacked endocannabinoid receptors. The endocannabinoids seem to play no major pain promoting role in this case. Zeilhofer says, “In the next step we want to find out which pain patients might possibly benefit from blocking the cannabinoid receptors. At any rate our findings should be of great interest to drug companies who are working with this pain model to develop new analgesics.”

https://www.sciencedaily.com/releases/2009/09/090911212404.htm

Impact of Cannabis on Bones Changes with Age

August 16, 2009

Science Daily/University of Edinburgh

Scientists investigating the effects of cannabis on bone health have found that its impact varies dramatically with age.

The study has found that although cannabis could reduce bone strength in young people, it may protect against osteoporosis, a weakening of the bones, in later life.

The team at the University of Edinburgh has shown that a molecule found naturally in the body, which can be activated by cannabis – called the type 1 cannabinoid receptor (CB1) – is key to the development of osteoporosis.

It is known that when CB1 comes into contact with cannabis it has an impact on bone regeneration, but until now it was not clear whether the drug had a positive or negative effect.

Researchers, funded by the Arthritis Research Campaign, investigated this by studying mice that lacked the CB1 receptor. The scientists then used compounds – similar to those in cannabis – that activated the CB1 receptor. They found that compounds increased the rate at which bone tissue was destroyed in the young.

The study also showed, however, that the same compounds decreased bone loss in older mice and prevented the accumulation of fat in the bones, which is known to occur in humans with osteoporosis. The results are published in Cell Metabolism.

Osteoporosis affects up to 30 per cent of women and 12 per cent of men at some point in life.

Stuart Ralston, the Arthritis Research Campaign Professor of Rheumatology at the University of Edinburgh, who led the study, said: "This is an exciting step forward, but we must recognise that these are early results and more tests are needed on the effects of cannabis in humans to determine how the effects differ with age in people.

"We plan to conduct further trials soon and hope the results will help to deliver new treatments that will be of value in the fight against osteoporosis."

https://www.sciencedaily.com/releases/2009/08/090813142341.htm

How Marijuana Causes Memory Deficits

August 4, 2009

Science Daily/Nature Medicine

Memory loss associated with marijuana use is caused by the drug’s interference with the brain’s natural protein synthesis machinery, according to a study published in Nature Neuroscience.

Though it has been documented that marijuana impairs memory, the precise mechanism for this memory impairment was previously unknown. Andrés Ozaita, of the Universitat Pompeu Fabra in Spain, along with colleagues in France and Germany, focused on THC, the main psychoactive chemical compound in marijuana, which acts on a specific class of receptors known as cannabinoid receptors. These receptors are known to affect the connection strength between neurons.

The scientists found that THC increases the activity of a pathway that promotes protein synthesis in the mouse brain. This transient increase of protein synthesis was mediated specifically by cannabinoid receptors expressed on the brain’s inhibitory neurons, and correlated with long-term memory deficits in mice. Interestingly, the authors also found that inhibition of this signaling pathway by rapamycin, an immunosuppressant drug used to prevent organ rejection following transplantation, prevents THC-induced amnesia in mice.

https://www.sciencedaily.com/releases/2009/08/090803123240.htm