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

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

Marijuana Rivals Mainstream Drugs for Alleviating HIV/AIDS Symptoms

May 29, 2009

Science Daily/SAGE Publications

Those in the United States living with HIV/AIDS are more likely to use marijuana than those in Kenya, South Africa or Puerto Rica to alleviate their symptoms, according to a new study published in Clinical Nursing Research, published by SAGE. Those who did use marijuana rate it as effective as prescribed or over the counter (OTC) medicines for the majority of common symptoms, once again raising the issue that therapeutic marijuana use merits further study and consideration among policy makers.

A significant percentage of those with HIV/AIDS use marijuana as a symptom management approach for anxiety, depression, fatigue, diarrhoea, nausea, and peripheral neuropathy. Members of the University of California, San Francisco (UCSF) International HIV/AIDS Nursing Research Network examined symptom management and quality of life experiences among those with HIV/AIDS in the US, Africa, and Puerto Rico, to gain a fuller picture of marijuana’s effectiveness and use in this population.

With data from a longitudinal, multi-country, multi-site, randomised control clinical trial, the researchers used four different evaluation tools to survey demographics, self-care management strategies for six common symptoms experienced by those living with HIV/AIDS, quality of life instrument and reasons for non-adherence to medications.

Either marijuana use for symptom management is vastly higher in the US, or participants elsewhere chose not to disclose that they use it: nine tenths of study participants who said they used marijuana live in the US. No African participants said they used it, and the remaining ten percent were from Puerto Rico.

The researchers found no differences between marijuana users and nonusers in age, race, and education level, income adequacy, having an AIDS diagnosis, taking ARV medications, or years on ARV medications. But the two groups did differ in that marijuana users had been HIV positive longer, and were more likely to have other medical conditions. Transgender participants were also more likely to use marijuana.

Participants using marijuana as a management strategy were spread fairly consistent across all six symptoms, ranging from a low of 20% for fatigue to a high of 27% for nausea. Prescribed medications were used by 45% of those with fatigue, ranging down to almost 18% of those with neuropathy.

The findings contained nuances when comparing marijuana to other medications. Those who used marijuana rated their anxiety significantly lower than those who did not, and women who used marijuana had more intense nausea symptoms. For those who use both marijuana and medications for symptom management, antidepressants were considered more effective than marijuana for anxiety and depression, but marijuana was rated more highly than anti-anxiety medications. Immodium was better for diarrhoea than marijuana, as were prescribed medications for fatigue. However, marijuana was perceived to be more effective than either prescribed or OTC medications for nausea and neuropathy. However, the differenced in perceived efficacy in all these results were slight.

As found in previous studies, those who used marijuana were less likely to comply with their regime of ARV medications. But perhaps counter-intuitively of the many reasons given for skipping pills, ‘forgetfulness’ was no different in this group than among those who did not use marijuana. Marijuana use is known to contribute to patients’ lack of compliance with ARV drugs, however those who use marijuana to target a particular symptom are actually more likely to stick closely to their ARV regimen too. The researchers point out that of those who used marijuana for their symptoms, it is not known whether they also used the drug for recreation. Patterns of how marijuana use interferes with patients’ adherence to medication regimens, along with other drugs, warrant further study.

The 775 participants were recruited from Kenya, South Africa, two sites in Puerto Rico, and ten sites in the United States. They had on average been diagnosed for a decade - the majority (70%) were taking anti-retroviral (ARV) medications and more than half had other medical conditions alongside HIV/AIDS. It is hard to pinpoint the marijuana use targeted to alleviate symptoms of those other illnesses as distinct from those relating solely to HIV/AIDS.

Data suggest that marijuana is a trigger among those susceptible to psychosis, and is also associated with the risk of suicidal thoughts. However it is not linked to an increased risk of lung cancer (over and above risks associated with smoking it along with tobacco).

The question of the use of marijuana for symptom management when legal drugs are available remains a practice and policy issue.

“Given that marijuana may have other pleasant side effects and may be less costly than prescribed or OTC drugs, is there a reason to make it available?” asks study leader Inge Corless.  “These are the political ramifications of our findings. Our data indicate that the use of marijuana merits further inquiry.”

https://www.sciencedaily.com/releases/2009/05/090529081627.htm