Medical cannabis provides dramatic relief for sufferers of chronic ailments, Israeli study finds

January 24, 2013

Science Daily/American Friends of Tel Aviv University

Though controversial, medical cannabis has been gaining ground as a valid therapy, offering relief to suffers of diseases such as cancer, Post-Traumatic Stress Disorder, ALS and more. The substance is known to soothe severe pain, increase the appetite, and ease insomnia where other common medications fail.

In 2009, Zach Klein, a graduate of Tel Aviv University's Department of Film and Television Studies, directed the documentary Prescribed Grass. Through the process, he developed an interest in the scientific research behind medical marijuana, and now, as a specialist in policy-making surrounding medical cannabis and an MA student at TAU's Porter School of Environmental Studies, he is conducting his own research into the benefits of medical cannabis.

Using marijuana from a farm called Tikkun Olam -- a reference to the Jewish concept of healing the world -- Klein and his fellow researchers tested the impact of the treatment on 19 residents of the Hadarim nursing home in Israel. The results, Klein says, have been outstanding. Not only did participants experience dramatic physical results, including healthy weight gain and the reduction of pain and tremors, but Hadarim staff saw an immediate improvement in the participants' moods and communication skills. The use of chronic medications was also significantly reduced, he reports.

Klein's research team includes Dr. Dror Avisar of TAU's Hydrochemistry Laboratory at the Department of Geography and Human Environment; Prof. Naama Friedmann and Rakefet Keider of TAU's Jaime and Joan Constantiner School of Education; Dr. Yehuda Baruch of TAU's Sackler Faculty of Medicine and director of the Abarbanel Mental Health Center; and Dr. Moshe Geitzen and Inbal Sikorin of Hadarim.

Cutting down on chronic medications

Israel is a world leader in medical cannabis research, Klein says. The active ingredient in marijuana, THC, was first discovered there by Profs. Raphael Mechoulam and Yechiel Gaoni. Prof. Mechoulam is also credited for having defined the endocannabinoid system, which mimics the effects of cannabis and plays a role in appetite, pain sensation, mood and memory.

In the Hadarim nursing home, 19 patients between the ages of 69 and 101 were treated with medical cannabis in the form of powder, oil, vapor, or smoke three times daily over the course of a year for conditions such as pain, lack of appetite, and muscle spasms and tremors. Researchers and nursing home staff monitored participants for signs of improvement, as well as improvement in overall life quality, such as mood and ease in completing daily living activities.

During the study, 17 patients achieved a healthy weight, gaining or losing pounds as needed. Muscle spasms, stiffness, tremors and pain reduced significantly. Almost all patients reported an increase in sleeping hours and a decrease in nightmares and PTSD-related flashbacks.

There was a notable decline in the amount of prescribed medications taken by patients, such as antipsychotics, Parkinson's treatment, mood stabilizers, and pain relievers, Klein found, noting that these drugs have severe side effects. By the end of the study, 72 percent of participants were able to reduce their drug intake by an average of 1.7 medications a day.

Connecting cannabis and swallowing

This year, Klein is beginning a new study at Israel's Reuth Medical Center with Drs. Jean-Jacques Vatine and Aviah Gvion, in which he hopes to establish a connection between medical cannabis and improved swallowing. One of the biggest concerns with chronically ill patients is food intake, says Klein. Dysphagia, or difficulty in swallowing, can lead to a decline in nutrition and even death. He believes that cannabis, which has been found to stimulate regions of the brain associated with swallowing reflexes, will have a positive impact.

Overall, Klein believes that the healing powers of cannabis are close to miraculous, and has long supported an overhaul in governmental policy surrounding the drug. Since his film was released in 2009, the number of permits for medical cannabis in Israel has increased from 400 to 11,000. His research is about improving the quality of life, he concludes, especially for those who have no other hope.

https://www.sciencedaily.com/releases/2013/01/130124123453.htm

Brain imaging insight into cannabis as a pain killer

December 20, 2012

Science Daily/University of Oxford

The pain relief offered by cannabis varies greatly between individuals, a brain imaging study carried out at the University of Oxford suggests.

The researchers found that an oral tablet of THC, the psychoactive ingredient in cannabis, tended to make the experience of pain more bearable, rather than actually reduce the intensity of the pain.

MRI brain imaging showed reduced activity in key areas of the brain that substantiated the pain relief the study participants experienced.

'We have revealed new information about the neural basis of cannabis-induced pain relief,' says Dr Michael Lee of Oxford University's Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB).

He adds: 'Our small-scale study, in a controlled setting, involved 12 healthy men and only one of many compounds that can be derived from cannabis. That's quite different from doing a study with patients. My view is the findings are of interest scientifically but it remains to see how they impact the debate about use of cannabis-based medicines. Understanding cannabis' effects on clinical outcomes, or the quality of life of those suffering chronic pain, would need research in patients over long time periods.'

The researchers report their findings in the journal Pain. The study was funded by the UK Medical Research Council and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre.

Long-term pain, often without clear cause, is a complex healthcare problem. Different approaches are often needed to help patient manage pain, and can include medications, physiotherapy and other forms of physical therapy, and psychological support. For a few patients, cannabis or cannabis-based medications remain effective when other drugs have failed to control pain, while others report very little effect of the drug on their pain but experience side-effects.

'We know little about cannabis and what aspects of pain it affects, or which people might see benefits over the side-effects or potential harms in the long term. We carried out this study to try and get at what is happening when someone experiences pain relief using cannabis,' says Dr Lee.

The Oxford research team carried out a series of MRI scans with each of the 12 volunteers at the FMRIB centre in Oxford.

Before a scan, participants were given either a 15mg tablet of THC or a placebo. THC, or delta-9-tetrahydrocannabinol, is the active psychotropic compound in cannabis -- the ingredient that's responsible for the high that drives recreational use of the drug.

To induce a certain level of pain, the volunteers also had a cream rubbed into the skin of one leg. This was either a dummy cream or a cream that contained 1% capsaicin, the ingredient of chillis that causes a hot, burning and painful sensation.

Each participant had four MRI tests to cover each combination of THC or placebo, and chilli pain-inducing cream or dummy cream.

'The participants were asked to report the intensity and unpleasantness of the pain: how much it burned and how much it bothered them,' says Dr Lee. 'We found that with THC, on average people didn't report any change in the burn, but the pain bothered them less.'

While this average effect was statistically significant, there was great variability among the participants in THC's effect on the pain they experienced. Only six out of the 12 reported a clear change in how much the pain bothered them, for example.

The brain imaging results substantiate the reports of the participants. The change in unpleasantness of pain was matched with a suppression of activity in the part of the brain called the anterior mid-cingulate cortex. This structure sits in a deep part of the brain and is involved in many functions, and has previously been implicated in the emotional aspects of pain.

There were also changes in activity of the right amygdala that correlated with the lessening in the unpleasantness of the pain with THC. It is already known that the right side of the amygdala can be 'primed' by pain.

Of most interest to the researchers, however, was the strength of the connection in individuals between their right amydala and a part of the cortex called the primary sensorimotor area. The strength of this connection in individual participants correlated well with THC's different effects on the pain that that volunteer experienced.

This is suggestive that there might be a way of predicting who would see benefits from taking cannabis for pain relief.

'We may in future be able to predict who will respond to cannabis, but we would need to do studies in patients with chronic pain over longer time periods,' says Dr Lee.

He adds: 'Cannabis does not seem to act like a conventional pain medicine. Some people respond really well, others not at all, or even poorly. Brain imaging shows little reduction in the brain regions that code for the sensation of pain, which is what we tend to see with drugs like opiates. Instead cannabis appears to mainly affect the emotional reaction to pain in a highly variable way.'

https://www.sciencedaily.com/releases/2012/12/121220195744.htm

No strong evidence to back use of cannabis extract in multiple sclerosis

December 12, 2012

Science Daily/BMJ-British Medical Journal

There is no strong evidence to back the use of cannabis extract in the treatment of Multiple Sclerosis (MS), concludes a review of the available evidence on the first licensed preparation, published in the December issue of Drug and Therapeutics Bulletin (DTB).

Sativex, in the form of a mouth spray, contains the principal extracts -- dronabinol and cannabidiol -- found in the leaf and flower of the cannabis plant. It is the first cannabinoid preparation to be licensed for use in the treatment of muscle spasms in MS.

MS is estimated to affect around 60,000 people in England and Wales, and around one in every 1000 people will develop the condition in the UK.

An increase in muscle tone, or spasticity is a common symptom of the condition, causing involuntary spasms, immobility, disturbed sleep, and pain.

Complex combinations of drugs are sometimes needed to manage spasticity, but they don't work that well and have a range of unpleasant side effects.

Sativex is intended for use as a second line treatment in patients in whom these other options have failed. But the DTB review found that the trial data on which the success of Sativex is based, are limited.

Overall, the trials, on which the drug's approval was based, did show a small difference in the numbers of patients who in whom symptoms abated compared with those taking a dummy (placebo) preparation.

But in many of these studies, Sativex was used for relatively short periods -- from six weeks to four months. And none included an active ingredient with which the effects of Sativex could be compared.

Two of the trials included doses that exceeded the 12 daily sprays for which the preparation is licensed. One trial did not have sufficient numbers of participants to validate the results.

A third trial, which was properly designed, and did have sufficient numbers of participants, did not find any significant difference in symptom relief between those who took Sativex and those who didn't.

The preparation is also expensive, notes DTB, and costs around 10 times as much as other drugs used for the secondary treatment of MS muscle spasms.

As yet, the body that advised the NHS on its use of treatments, the National Institute for Health and Clinical Excellence (NICE) has not offered any advice on the use of cannabis extract either, although it is set to do so.

But the DTB review says that the strength of the evidence is insufficient to warrant its routine use. "We believe that such limitations make it difficult to identify the place of this product in clinical practice," it concludes. Commenting on the review, GP and DTB editor, James Cave, said the findings of the review were "disappointing."

"MS is a serious and disabling condition, and it would be great to say that this drug could make a big difference, but the benefit is only modest," he said.

https://www.sciencedaily.com/releases/2012/12/121212205729.htm

Medical marijuana could help patients reduce pain with opiates

December 6, 2011

Science Daily/University of California - San Francisco

A UCSF study suggests patients with chronic pain may experience greater relief if their doctors add cannabinoids -- the main ingredient in cannabis or medical marijuana -- to an opiates-only treatment. The findings, from a small-scale study, also suggest that a combined therapy could result in reduced opiate dosages.

More than 76 million Americans suffer from chronic pain -- more people than diabetes, heart disease and cancer combined, according to the National Centers for Health Statistics.

"Pain is a big problem in America and chronic pain is a reason many people utilize the health care system," said the paper's lead author, Donald Abrams, MD, professor of clinical medicine at UCSF and chief of the Hematology-Oncology Division at San Francisco General Hospital and Trauma Center (SFGH). "And chronic pain is, unfortunately, one of the problems we're least capable of managing effectively."

In a paper published this month in Clinical Pharmacology & Therapeutics, researchers examined the interaction between cannabinoids and opiates in the first human study of its kind. They found the combination of the two components reduced pain more than using opiates alone, similar to results previously found in animal studies.

Researchers studied chronic pain patients who were being treated with long-acting morphine or long-acting oxycodone. Their treatment was supplemented with controlled amounts of cannabinoids, inhaled through a vaporizer. The original focus was on whether the opiates' effectiveness increased, not on whether the cannabinoids helped reduce pain.

"The goal of the study really was to determine if inhalation of cannabis changed the level of the opiates in the bloodstream," Abrams said. "The way drugs interact, adding cannabis to the chronic dose of opiates could be expected either to increase the plasma level of the opiates or to decrease the plasma level of the opiates or to have no effect. And while we were doing that, we also asked the patients what happened to their pain."

Abrams and his colleagues studied 21 chronic pain patients in the inpatient Clinical and Transitional Science Institute's Clinical Research Center at SFGH: 10 on sustained-release morphine and 11 on oxycodone. After obtaining opiate levels from patients at the start of the study, researchers exposed them to vaporized cannabis for four consecutive days. On the fifth day, they looked again at the level of opiate in the bloodstream. Because the level of morphine was slightly lower in the patients, and the level of oxycodone was virtually unchanged, "one would expect they would have less relief of pain and what we found that was interesting was that instead of having less pain relief, patients had more pain relief," Abrams said. "So that was a little surprising."

The morphine group came in with a pain score of about 35, and on the fifth day, it decreased to 24 -- a 33 percent reduction. The oxycodone group came in with an average pain score of about 44, and it reduced to 34 -- a drop of 20 percent. Overall, patients showed a significant decrease in their pain.

"This preliminary study seems to imply that people may be able to get away perhaps taking lower doses of the opiates for longer periods of time if taken in conjunction with cannabis," Abrams said.

Opiates are very strong powerful pain medicines that can be highly addictive. They also can be deadly since opiates sometimes suppress the respiratory system.

As a cancer doctor, Abrams was motivated to find safe and effective treatments for chronic pain. Patients in the cannabis-opiates study experienced no major side effects such as nausea, vomiting or loss of appetite.

"What we need to do now is look at pain as the primary endpoint of a larger trial," he said. "Particularly I would be interested in looking at the effect of different strains of cannabis."

For instance, Delta 9 THC is the main psychoactive component of cannabis but cannabis contains about 70 other similar compounds with different effects. One of those is cannabidiol, or CBD. It appears to be very effective against pain and inflammation without creating the "high" created by THC.

"I think it would be interesting to do a larger study comparing high THC versus high CBD cannabis strains in association with opiates in patients with chronic pain and perhaps even having a placebo as a control," Abrams said. "That would be the next step."

Abrams is the lead author of the paper; co-authors are Paul Couey, BA, and Mary Ellen Kelly, MPH, of the UCSF Division of Hematology-Oncology at SFGH; Starley Shade, PhD, of the UCSF Center for AIDS Prevention Studies; and Neal Benowitz, MD, of the UCSF Division of Clinical Pharmacology and Experimental Therapeutics.

The study was supported by funds from the National Institutes on Drug Abuse (NIDA), a subsidiary of the National Institutes of Health (NIH).

Major Components of Cannabis

·     Delta-9 Tetrahydrocannabinol (Delta-9 THC)-- It is the main psychoactive component of cannabis with mild to moderate painkilling effects. It also helps treat nausea associate with cancer chemotherapy and to stimulate appetite. It induces feelings of euphoria. Potential side effects include accelerated heartbeat, panic, confusion, anxiety and possible paranoia.

·     Cannabidiol (CBD)- It is a major, non-psychoactive component of cannabis that helps shrink inflammation and reduce pain without inducing the euphoria effects of THC. It has been used to treat rheumatoid arthritis, inflammatory bowel diseases, psychotic disorders and epilepsy. Larger amounts of CBD can relax the mind and body without causing negative side effects associated with THC.

·     Cannabinol (CBN)-- It is a secondary psychoactive component of cannabis. It is not associated with painkilling effects of THC or CBD. CBN is formed as THC ages. Unlike the euphoria effects of THC, CBN can induce headaches and a sense of lethargy.

·     Tetrahydrocannabivarin (THCV) -- It is found primarily in strains of African and Asian cannabis. THCV heightens the intensity of THC effects and the speed in which the component is delivered, but also causes the sense of euphoria to end sooner.

https://www.sciencedaily.com/releases/2011/12/111206151448.htm

Marijuana use may cause severe cyclic nausea, vomiting, a little-known, but costly effect

October 22, 2012

Science Daily/American College of Gastroenterology (ACG)

Marijuana use -- both natural and synthetic -- may cause cannabinoid hyperemesis (CH) a little-known but costly effect that researchers suggest is a serious burden to the health care system as it often leads to expensive diagnostic tests and ineffective treatments in an effort to find the cause of a patient's symptoms and provide relief, according to two separate case reports unveiled October 22 at the American College of Gastroenterology's (ACG) 77th Annual Scientific meeting in Las Vegas. Cannabinoid hyperemesis is characterized by a history of chronic cannabis use followed by a cyclic pattern of nausea, vomiting and colicky abdominal pain. Interestingly, compulsive hot baths or showers temporarily relieve symptoms, another characteristic which aids clinicians in diagnosis.

"Most healthcare providers are unaware of the link between marijuana use and these episodes of cyclic nausea and vomiting so they are not asking about natural or synthetic cannabinoid use when a patient comes to the emergency room or their doctor's office with these symptoms," said co-investigator Ana Maria Crissien-Martinez, M.D. of Scripps Green Hospital and Clinic in San Diego. She said CH was first described in a 2004 case series of 9 patients in Australia and since then, 14 case reports and 4 case series have been published, including a prospective series of 98 patients published by Mayo Clinic in February 2012.

"Patients who use cannabis whether natural or in synthetic form called 'Spice' also don't realize their unexplained episodes of cyclic nausea and vomiting may be a result of this use, with some increasing their cannabis use because they may think it will help alleviate their symptoms -- and it actually makes them worse," said Dr. Crissien-Martinez. "The only resolution is cannabis cessation."

Dr. Crissien-Martinez co-authored the case report, "Marijuana: Anti-Emetic or Pro-Emetic" which described a series of 9 patients with cannabinoid hyperemesis at Scripps Green Hospital with average age at diagnosis 30 years-old; 88 percent male; onset of cannabis use during teen years; 88 percent used cannabis daily; 56 percent compulsive bathing behavior; and 80 percent symptom resolution with cannabis cessation.

The other case report, "Spicing Up the Differential for Cyclic Vomiting: A Case of Synthetic-Cannabinoid Induced Hyperemesis Syndrome (CHS)," may be the first reported case of CH attributed to synthetic cannabinoid, according to Fong-Kuei Cheng, M.D. and his research team from Walter Reed Walter Reed National Military Medical Center/Uniformed Services University of the Health Sciences in Bethesda, MD.

"Legal synthetic cannabinoids became available in the United States by 2009 with widespread usage among military personnel due to its ability to elude standard drug testing. It is important to recognize that routine urine drug testing does not include JWH-018 and JWH 073, which are the primary components in synthetic cannabinoids," said Dr. Cheng.

The case report described a 22-year active duty military male who was admitted with a 10-month history of progressive, intermittent abdominal pain, nausea and vomiting, with episodes occurring every two months and lasting up to a week. He underwent several diagnostic tests before a urine synthetic cannabinoid test confirmed the diagnosis of cannabinoid hyperemesis syndrome (CHS). Since discontinuing these drugs, the patient has remained symptom-free, according to the case report.

"This case illustrates that CHS should be in the differential diagnosis of unexplained, episodic abdominal pain with nausea and vomiting, particularly if relieved with compulsive hot showers. Recognition of this syndrome is important to prevent unnecessary testing and to reduce health care expenditures," said Dr. Cheng. "We have also noted, particularly in the active duty population where drug testing for cannabis usage is done routinely, that there appears to be an increased usage instead of the synthetic cannabinoids, so we would advocate routine additional testing for them when the clinical suspicion is high."

Patients frequently have multiple hospital, clinic and emergency room visits with extensive negative work-up to include imaging studies, endoscopies, and laboratory testing before they are finally diagnosed with cannabinoid hyperemesis, according to the researchers of both case reports.

"We estimate $10,000 to be the minimum cost of one admission -- but on average our patients required admission to the hospital 2.8 times, a total of almost $30,000 for workup," said Dr. Crissien-Martinez, who added that that cost does not include the added costs of primary care physician and/or gastroenterologist and emergency room visits, which averaged 2.5 and 6 times respectively.

Dr. Crissien-Martinez said that 80 percent of the Scripps Green patients who stopped cannabis experienced symptom resolution; however, only one of them remained abstinent and consequently symptom-free.

"As health care providers, we must be aware of the potential side effects of chronic cannabis use and understand that cannabinoid hyperemesis is diagnosed clinically to avoid expensive diagnostic and therapeutic modalities," said Dr. Crissien-Martinez. "Instead the focus should be shifted towards counseling and resources allocated towards marijuana cessation."

https://www.sciencedaily.com/releases/2012/10/121022081353.htm

The new 'runner's high'? Some often mix weed, workouts

82% of cannabis users say they partake before, after exercise

May 1, 2019

Science Daily/University of Colorado at Boulder

Eight out of 10 marijuana users in states where cannabis is legal say they partake in the drug shortly before or after exercise, and most report that it motivates them to work out, helps them enjoy exercise more and improves their recovery, according to surprising new University of Colorado Boulder research.

The paper, published Tuesday in the journal Frontiers in Public Health, is among the first to explore the complicated intersection between cannabis use and physical activity.

While many assume the former impedes the later, the data suggest otherwise.

"There is a stereotype that cannabis use leads people to be lazy and couch-locked and not physically active, but these data suggest that this is not the case," said senior author Angela Bryan, a professor in the Department of Psychology and Neuroscience and the Institute for Cognitive Science.

She stresses that she is in no way recommending using cannabis as an adjunct to exercise.

"The evidence is not there yet," she said. "But I am also not convinced it is harmful."

Marijuana is now legal for recreational use in 10 states and medicinal use in dozens more. Yet, little is known about how rising acceptance could impact public health measures like physical activity and obesity.

Some have speculated that increased use could worsen the obesity epidemic by fueling a sedentary lifestyle. On the other hand, the authors note, the World Anti-Doping Agency prohibits cannabis use in sporting competitions due to its potential to improve performance.

Anecdotally, ultrarunners sometimes use marijuana to battle nausea and boredom on long runs. And epidemiological studies show cannabis-users tend to be leaner, less prone to diabetes and have healthier blood sugar levels.

"There are a lot of interesting data points and hypotheses out there but not a lot of them have been tested," says Bryan.

In a first step toward filling the research gap, she and her colleagues surveyed 600 adult marijuana users in California, Colorado, Nevada, Oregon and Washington, asking -- among other questions -- if they ever used cannabis within one hour before or four hours after exercise.

Eighty-two percent said 'yes.'

"We were stunned it was that high," says Bryan.

A follow-up question of 345 "co-users" (people who use cannabis with exercise) found they were more likely to use it after than before. But 67% said they did both.

Among those who co-used, 70% said it increased enjoyment of exercise, 78% said it boosted recovery, and 52% said it heightened motivation.

"Given that these are all recognized barriers to exercise, it is possible that cannabis might actually serve as a benefit to exercise engagement," the authors write.

Only 38% said it boosted performance, and in fact some small previous studies have suggested it may harm it.

Notably, those who co-used also got about 43 minutes more exercise per week than those who didn't.

How might cannabis, physiologically, impact physical activity?

"There is evidence to suggest that certain cannabinoids dampen pain perception, and we also know that the receptors cannabis binds to in the brain are very similar to the receptors that are activated naturally during the runners high," said co-author Arielle Gillman, a former PhD student in Bryan's lab who recently published a review paper on the subject. "Theoretically, you could imagine that if it could dampen pain and induce an artificial 'runner's high,' it could keep people motivated."

Cannabis is also anti-inflammatory, which could aid recovery.

The study did not look at which kind of cannabis (edibles, smoked flower, etc.) people use alongside exercise.

The authors note that the survey has limitations, in that it looked only at people who use cannabis regularly and focused on states which have already legalized it.

But more research is already in the works at CU Boulder, comparing the activity levels of older adults who use cannabis with those who do not.

Preliminary results of that separate study show that after embarking on a 16-week exercise program, the cannabis users exercised more than the non-users.

"As we get older, exercise starts to hurt, and that is one reason older adults don't exercise as much," Bryan said. "If cannabis could ease pain and inflammation, helping older adults to be more active that could be another benefit."

Graduate students Sophie York Williams (first author), Charleen Gust and Raeghan Mueller, Assistant Professor Cinnamon Bidwell and Professor Kent Hutchison contributed to this study.

https://www.sciencedaily.com/releases/2019/05/190501114629.htm

Insight into the proteins in the brain that detect cannabis

April 30, 2019

Science Daily/University of Bristol

Researchers at the University of Bristol have made new progress in understanding how cannabinoid receptors (CB1Rs), the proteins that detect the active components of marijuana, are controlled in the brain.

The brain contains about 100 billion nerve cells that are constantly communicating with one another at specialised junctions called synapses. Nerve cells possess extensions called axons, which send signals to synapses, and dendrites, which receive information from synapses.

At the synapse, the electrical 'firing' of a nerve cell causes the release of chemicals called neurotransmitters from the presynaptic terminals of its axon. These neurotransmitters cross the synapse and pass on the signal by binding to receptors at postsynaptic sites on the dendrites of the next nerve cell.

CB1Rs help control information flow in the brain by binding molecules made in the brain called endocannabinoids, which influence brain functions such as pain, appetite, mood and memory. Unusually, endocannabinoid signalling goes in the reverse direction compared to most other neurotransmitters. The 'receiving' CB1Rs are located at presynaptic sites on axons, whereas the release sites are at postsynaptic sites on dendrites.

This reverse or 'retrograde' signalling that activates presynaptic CB1Rs 'dampens down' presynaptic release of other neurotransmitters resulting in a slowing of brain activity. Moreover, the active components of cannabis bind to CB1Rs in a similar manner to endocannabinoids, resulting in the 'mellow' sensation caused by the recreational use of cannabis.

For CB1Rs to regulate brain function properly, it is essential that they are sent to the right place on the surface of the axon. However, very little is known about exactly how this occurs. The research published today [Tuesday 30 April] in eLife investigated how this process happens.

The Bristol group showed that a specific part of the CB1R protein plays a key role in the getting CB1R into axons. The research team tracked newly made CB1Rs in nerve cells grown in a dish and found that a short region of CB1R is crucial for sending CB1R to the axon and preventing it from going to the dendrites. They also discovered that this region stabilises CB1R at the surface of the axon, making it more available to receive signals from endocannabinoids.

Jeremy Henley, Professor of Molecular Neuroscience in Bristol's School of Biochemistry, said: "In recent years there has been tremendous interest in -- and controversy about -- activation of CB1R by medical marijuana. It is becoming increasingly apparent that activation of CB1Rs could be therapeutically useful for a wide range of diseases such as chronic pain, epilepsy, or multiple sclerosis. Understanding the fundamental properties of CB1R is an important basis for future studies exploring the efficacy and optimisation of these targeted approaches."

It is hoped that this increased understanding of how CB1Rs behave in nerve cells will pave the way for future studies aimed at examining the possible medical uses of marijuana, or other drugs that target CB1Rs, in treating a wide range of disorders.

https://www.sciencedaily.com/releases/2019/04/190430103457.htm

Cannabis-based medicine may reduce seizures for children with difficult-to-treat epilepsy

April 30, 2019

Science Daily/American Academy of Neurology

Taking a pharmaceutical formulation of cannabidiol, a cannabis-based medicine, cut seizures nearly in half for children with a rare and severe type of epilepsy called Dravet syndrome, according to a phase 3 study released today that will be presented at the American Academy of Neurology's 71st Annual Meeting in Philadelphia, May 4 to 10, 2019. Dravet syndrome, which starts in infancy, can lead to intellectual disability and frequent, prolonged seizures. Cannabidiol is derived from marijuana that does not include the psychoactive part of the plant that creates a "high."

"It's exciting to be able to offer another alternative for children with this debilitating form of epilepsy and their families," said study author Ian Miller, MD, of Nicklaus Children's Hospital, formerly Miami Children's Hospital, in Florida. "The children in this study had already tried an average of four epilepsy drugs with no success and at the time were taking an average of three additional drugs, so to have this measure of success with cannabidiol is a major victory."

The study involved 199 children with an average age of 9 who were divided into three groups. One group received 20 milligrams per kilogram (mg/kg) per day of cannabidiol, the second group received 10 mg/kg per day and the third group received a placebo.

Seizures were recorded for four weeks before the treatments were started to establish a baseline. Then the participants received the treatment for 14 weeks. By the end of the study, seizures with convulsions had decreased for those taking the high dose of the drug by 46 percent and by 49 percent for those taking the lower dose of the drug, compared to 27 percent for those taking the placebo.

Total seizures reduced by 47 percent for those in the high dose group, by 56 percent for those in the lower dose group and by 30 percent for those in the placebo group. In the high dose group, 49 percent of the participants had their seizures cut in half or more, compared to 44 percent in the low dose group and 26 percent in the placebo group.

All of the groups reported side effects, with 90 percent of the high dose group, 88 percent of the low dose group and 89 percent of the placebo group. The most common side effects were decreased appetite, diarrhea, sleepiness, fever and fatigue. About 25 percent of those in the high dose group had serious side effects, compared to 20 percent of those in the low dose group and 15 percent of those in the placebo group. Only participants in the high dose group stopped taking the drug due to side effects; that number was 7 percent.

"Based on these results, dose increases above 10 mg/kg per day should be carefully considered based on the effectiveness and safety for each individual," Miller said.

https://www.sciencedaily.com/releases/2019/04/190430164219.htm

One in 7 Washington State drivers with children in the car recently used marijuana

April 25, 2019

Science Daily/Journal of Studies on Alcohol and Drugs

According to a roadside survey conducted in Washington State, 14.1% of drivers with children in the car -- nearly one in seven -- tested positive for THC, the principal psychoactive compound in marijuana. The results are published in the latest issue of the Journal of Studies on Alcohol and Drugs.

Because detecting THC in blood or saliva does not correspond to impairment as does a positive alcohol test, it's unclear if these drivers were actively impaired by THC. Nonetheless, the study sheds light on the potential for increased impaired driving, and the risks for children, for states considering legalizing marijuana, and the need for better roadside testing for THC.

"Currently, there are a number of different tests being developed and validated to detect whether drugs are present, including saliva and even breath tests for THC," according to study coauthor Angela Eichelberger, Ph.D., from the Insurance Institute for Highway Safety. "However, there is still a need for reliable, valid measures of impairment."

For their research, the group, which was led by Eduardo Romano, Ph.D., of the Pacific Institute for Research and Evaluation, analyzed data from a roadside survey of more than 2,000 drivers age 21 and older conducted in Washington State in 2014 and 2015, after the legalization of recreational marijuana sales there.

During both daytime and nighttime hours, researchers asked drivers at stop lights and stop signs if they wanted to volunteer for the study. They obtained breath samples as well as blood and saliva samples from the volunteers and noted if children were present in the car, and surveyed the drivers about their attitudes regarding substance use.

Whether drivers had a child in the car seemed to affect their choice to drive while impaired by alcohol (that is, have a breath alcohol concentration over .08%).

"Encouragingly, we . . . found that among those with children [in the car], most did not drink and drive," the authors write. No study volunteers had breath alcohol concentrations above .08% if they had a child in the vehicle. But nearly 1% of those without children in the car were above this legal limit. Further, only 0.2% of drivers of children had any alcohol in their system compared with 4.5% of drivers with no children present.

However, having a child in the car did not affect whether drivers had THC in their system. More than 14% of drivers with a child in the car tested positive for THC, but so did 17.7% of drivers without a child in the car, not a statistically significant difference.

The authors also found that most of those surveyed said marijuana was "very likely" to affect driving. Still, some drivers did not recognize the risk of impairment, and those who thought marijuana was not likely to impair driving were more likely to test positive for THC than were other drivers. Among drivers with children who thought marijuana was not impairing, 40.6% tested positive for THC. Eichelberger notes that her previous research has shown that people tend to think that marijuana is less likely to impair driving than is alcohol.

"States need to consider multiple factors when legalizing marijuana," concludes coauthor Tara Kelley-Baker, Ph.D., of the AAA Foundation for Traffic Safety in Washington, DC. "Although there are legal age limits for purchasing and using, we know from previous research examining child endangerment issues that very young children are really vulnerable to driver impairment. States' policies protecting young children from alcohol-impaired drivers are ineffective. Now we are legalizing another drug which may further increase risk to the most vulnerable group."

https://www.sciencedaily.com/releases/2019/04/190425073640.htm

Boosting natural marijuana-like brain chemicals treats fragile X syndrome symptoms

September 25, 2012

Science Daily/University of California - Irvine

American and European scientists have found that increasing natural marijuana-like chemicals in the brain can help correct behavioral issues related to fragile X syndrome, the most common known genetic cause of autism.

The work indicates potential treatments for anxiety and cognitive defects in people with this condition. Results appear online in Nature Communications.

Daniele Piomelli of UC Irvine and Olivier Manzoni of INSERM, the French national research agency, led the study, which identified compounds that inhibit enzymes blocking endocannabinoid transmitters called 2-AG in the striatum and cortex regions of the brain.

These transmitters allow for the efficient transport of electrical signals at synapses, structures through which information passes between neurons. In fragile X syndrome, regional synapse communication is severely limited, giving rise to certain cognitive and behavioral problems.

Fragile X syndrome is caused by a mutation of the FMR1 gene on the X chromosome. People born with it are mentally disabled; generally experience crawling, walking and language delays; tend to avoid eye contact; may be hyperactive or impulsive; and have such notable physical characteristics as an elongated face, flat feet and large ears.

The researchers stress that their findings, while promising, do not point to a cure for the condition.

"What we hope is to one day increase the ability of people with fragile X syndrome to socialize and engage in normal cognitive functions," said Piomelli, a UCI professor of anatomy & neurobiology and the Louise Turner Arnold Chair in the Neurosciences.

The study involved mice genetically altered with FMR1 mutations that exhibited symptoms of fragile X syndrome. Treated with novel compounds that correct 2-AG protein signaling in brain cells, these mice showed dramatic behavioral improvements in maze tests measuring anxiety and open-space acceptance.

While other work has focused on pharmacological treatments for behavioral issues associated with fragile X syndrome, Piomelli noted that this is the first to identify the role endocannabinoids play in the neurobiology of the condition.

About endocannabinoids

Endocannabinoid compounds are created naturally in the body and share a similar chemical structure with THC, the primary psychoactive component of the marijuana plant, Cannabis. Endocannabinoids are distinctive because they link with protein molecule receptors -- called cannabinoid receptors -- on the surface of cells. For instance, when a person smokes marijuana, the cannabinoid THC activates these receptors. Because the body's natural cannabinoids control a variety of factors -- such as pain, mood and appetite -- they're attractive targets for drug discovery and development. Piomelli is one of the world's leading endocannabinoid researchers. His groundbreaking work is showing that this system can be exploited by new treatments to combat anxiety, pain, depression and obesity.

https://www.sciencedaily.com/releases/2012/09/120925121349.htm

Marijuana use implicated in pregnancy problems

September 12, 2012

Science Daily/Cincinnati Children's Hospital Medical Center

New research indicates marijuana-like compounds called endocannabinoids alter genes and biological signals critical to the formation of a normal placenta during pregnancy and may contribute to pregnancy complications like preeclampsia.

A study in the Sept. 14 edition of the Journal of Biological Chemistry offers new evidence that abnormal biological signaling by endocannabinoid lipid molecules produced by the body disrupts the movement of early embryonic cells important to a healthy pregnancy, in particular trophoblast cells that form the placenta. Abnormal placental function is common in preeclampsia -- a medical condition of unknown cause that is a danger to mother and child.

The research -- from scientists in the Division of Reproductive Sciences at Cincinnati Children's Hospital Medical Center -- analyzed mouse preimplantation embryos mutated to alter endocannabinoid signaling. They found that either silencing or enhancing endocannabinoid signaling adversely affects trophoblast stem cell migration.

"The findings or our investigation raise concerns that exposure to cannabis products may adversely affect early embryo development that is then perpetuated later in pregnancy," said Sudhansu K. Dey, PhD., principal investigator on the study and division director. "Also, given that endocannabinoid signaling plays a key role in the central nervous system, it would be interesting in future studies to examine whether affected cell migration-related genes in early embryos also participate in neuronal cell migration during brain development."

Along with co-first authors Huirong Xie and Xiaofei Sun, Dey and other members of the research team studied mouse embryos that had not yet implanted inside the uterus of the mother. Previous research by Dey's laboratory has shown the timing of critical events in early pregnancy, including when and how well an embryo implants in the uterus, is vital to a healthy pregnancy and birth.

In the current study, researchers conducted DNA microarray analyses to determine how the expression levels of genes important to healthy embryo development were affected in embryos with abnormal endocannabinoid signaling.

In one group of embryos endocannabinoid signaling was silenced by deleting the gene Cnr1, which activates endocannabinoid signaling processes. A second group of mice was mutated to produce elevated endocannabinoid levels similar to that observed in wild type mice treated with tetrahydrocannabinol (THC), the active psychotropic agent in cannabis. This was done by deleting the gene Faah, which breaks down molecules that activate endocannabinoid signaling.

In both groups, the expression of numerous genes known to be important to cell movement and embryo development was lower than in normal wild type mice. This included the development and migration of trophoblast stem cells. Trophoblast cells help anchor the conceptus with the uterus and also form much of the placenta, critical to establishment of maternal-fetal circulation and exchange of nutrients.

Researchers said mouse models developed for the current study (with silenced and elevated endocannabinoid signaling) may help advance more extensive studies on the causes of preeclampsia.

https://www.sciencedaily.com/releases/2012/09/120912101806.htm

Marijuana use may increase risk of testicular cancer

September 10, 2012

Science Daily/Wiley

A new study from the University of Southern California (USC) has found a link between recreational marijuana use and an increased risk of developing subtypes of testicular cancer that tend to carry a somewhat worse prognosis. Published early online in Cancer, a peer-reviewed journal of the American Cancer Society, the findings suggest that the potential cancer-causing effects of marijuana on testicular cells should be considered not only in personal decisions regarding recreational drug use, but also when marijuana and its derivatives are used for therapeutic purposes in young male patients.

Testicular cancer is the most common cancer diagnosed in young men ages 15 to 45 years. The malignancy is becoming more common, and researchers suspect this is due to increasing exposure to unrecognized environmental causes.

To see if recreational drug use might play a role, Victoria Cortessis, MSPH, PhD, assistant professor of preventive medicine at the Keck School of Medicine of USC in Los Angeles, and her colleagues looked at the self-reported history of recreational drug use in 163 young men diagnosed with testicular cancer and compared it with that of 292 healthy men of the same age and race/ethnicity.

The investigators found that men with a history of using marijuana were twice as likely to have subtypes of testicular cancer called non-seminoma and mixed germ cell tumors. These tumors usually occur in younger men and carry a somewhat worse prognosis than the seminoma subtype. The study's findings confirm those from two previous reports in CANCER on a potential link between marijuana use and testicular cancer.

"We do not know what marijuana triggers in the testis that may lead to carcinogenesis, although we speculate that it may be acting through the endocannabinoid system -- the cellular network that responds to the active ingredient in marijuana -- since this system has been shown to be important in the formation of sperm," said Cortessis.

The researchers also discovered that men with a history of using cocaine had a reduced risk of both subtypes of testicular cancer. This finding suggests that men with testicular cancer are not simply more willing to report a history of using recreational drugs. While it is unknown how cocaine may influence testicular cancer risk, the authors suspect that the drug may kill sperm-producing germ cells since it has this effect on experimental animals.

"If this is correct, then 'prevention' would come at a high price," Cortessis said. "Although germ cells can not develop cancer if they are first destroyed, fertility would also be impaired. Since this is the first study in which an association between cocaine use and lower testis cancer risk is noted, additional epidemiological studies are needed to validate the results."

https://www.sciencedaily.com/releases/2012/09/120910082534.htm

Potential drug for treatment of Alzheimer's disease investigated

August 31, 2012

Science Daily/Cleveland Clinic

A compound developed to treat neuropathic pain has shown potential as an innovative treatment for Alzheimer's disease, according to a study by researchers at Cleveland Clinic's Lerner Research Institute and Anesthesiology Institute.

"Cleveland Clinic dedicated two years of research into the examination of this compound and our findings show it could represent a novel therapeutic target in the treatment of Alzheimer's disease," said Mohamed Naguib, M.D., Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine. "Development of this compound as a potential drug for Alzheimer's would take many more years, but this is a promising finding worthy of further investigation."

In a study published online in the Neurobiology of Aging, the compound MDA7 induced beneficial immune responses that limited the development of Alzheimer's disease. Treatment with the compound restored cognition, memory and synaptic plasticity -- a key neurological foundation of learning and memory -- in an animal model.

Neuroinflammation is an important mechanism involved in the progression of Alzheimer's disease. The MDA7 compound has anti-inflammatory properties that act on the CB2 receptor -- one of the two cannabinoid receptors in the body -- but without the negative side effects normally seen with cannabinoid compounds.

Alzheimer's disease is an irreversible, fatal brain disease that slowly destroys memory and thinking skills. About 5 million people in the United States have Alzheimer's disease. With the aging of the population, and without successful treatment, there will be 16 million Americans and 106 million people worldwide with Alzheimer's by 2050, according to the 2011 Alzheimer's Disease Facts and Figures report from the Alzheimer's Association.

https://www.sciencedaily.com/releases/2012/08/120831123750.htm

Cannabis as painkiller

August 7, 2012

Science Daily/Deutsches Aerzteblatt International

Cannabis-based medications have been demonstrated to relieve pain. Cannabis medications can be used in patients whose symptoms are not adequately alleviated by conventional treatment. The indications are muscle spasms, nausea and vomiting as a result of chemotherapy, loss of appetite in HIV/Aids, and neuropathic pain.

This is the conclusion drawn by Franjo Grotenhermen and Kirsten Müller-Vahl in issue 29-30 of Deutsches Ärzteblatt International.

The clinical effect of the various cannabis-based medications rests primarily on activation of endogenous cannabinoid receptors. Consumption of therapeutic amounts by adults does not lead to irreversible cognitive impairment. The risk is much greater, however, in children and adolescents (particularly before puberty), even at therapeutic doses.

Over 100 controlled trials of the effects of cannabinoids in various indications have been carried out since 1975. The positive results have led to official licensing of cannabis-based medications in many countries. In Germany, a cannabis extract was approved in 2011 for treatment of spasticity in multiple sclerosis. In June 2012 the Federal Joint Committee (the highest decision-making body for the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany) pronounced that the cannabis extract showed a slight additional benefitfor this indication and granted a temporary license until 2015.

https://www.sciencedaily.com/releases/2012/08/120807101232.htm

Mothers' teen cannabinoid exposure may increase response of offspring to opiate drugs

Science Daily/June 5, 2012

Tufts University, Health Sciences Campus

Mothers who use marijuana as teens -- long before having children -- may put their future children at a higher risk of drug abuse, new research suggests.

Researchers in the Neuroscience and Reproductive Biology section at the Cummings School of Veterinary Medicine conducted a study to determine the transgenerational effects of cannabinoid exposure in adolescent female rats. For three days, adolescent rats were administered the cannabinoid receptor agonist WIN-55, 212-2, a drug that has similar effects in the brain as THC, the active ingredient in marijuana. After this brief exposure, they remained untreated until being mated in adulthood.

The male offspring of the female rats were then measured against a control group for a preference between chambers that were paired with either saline or morphine. The rats with mothers who had adolescent exposure to WIN-55,212-2 were significantly more likely to opt for the morphine-paired chamber than those with mothers who abstained. The results suggest that these animals had an increased preference for opiate drugs.

The study was published in the Journal of Psychopharmocology and funded by the National Institutes of Health.

"Our main interest lies in determining whether substances commonly used during adolescence can induce behavioral and neurochemical changes that may then influence the development of future generations," said Research Assistant Professor John J. Byrnes, the study's lead author, "We acknowledge that we are using rodent models, which may not fully translate to the human condition. Nevertheless, the results suggest that maternal drug use, even prior to pregnancy, can impact future offspring."

Byrnes added that much research is needed before a definitive connection is made between adolescent drug use and possible effects on future children.

The study builds on earlier findings by the Tufts group, most notably a study published last year in Behavioral Brain Research by Assistant Professor Elizabeth Byrnes that morphine use as adolescent rats induces changes similar to those observed in the present study.

Other investigators in the field have previously reported that cannabinoid exposure during pregnancy (in both rats and humans) can affect offspring development, including impairment of cognitive function, and increased risk of depression and anxiety.

https://www.sciencedaily.com/releases/2012/06/120605155944.htm

How cannabis use during adolescence affects brain regions associated with schizophrenia

May 8, 2012

Science Daily/Royal College of Surgeons in Ireland (RCSI)

New research from the Royal College of Surgeons in Ireland (RCSI) published in Nature's Neuropsychopharmacology has shown physical changes to exist in specific brain areas implicated in schizophrenia following the use of cannabis during adolescence. The research has shown how cannabis use during adolescence can interact with a gene, called the COMT gene, to cause physical changes in the brain.

The COMT gene provides instructions for making enzymes which breakdown a specific chemical messenger called dopamine. Dopamine is a neurotransmitter that helps conduct signals from one nerve cell to another, particularly in the brains reward and pleasure centres. Adolescent cannabis use and its interaction with particular forms of the COMT gene have been shown to cause physical changes in the brain as well as increasing the risk of developing schizophrenia.

Dr Áine Behan, Department of Physiology, RCSI and lead author on the study said 'This is the first study to show that the combined effects of the COMT gene with adolescent cannabis use cause physical changes in the brain regions associated with schizophrenia. It demonstrates how genetic, developmental and environmental factors interact to modulate brain function in schizophrenia and supports previous behavioural research which has shown the COMT gene to influence the effects of adolescent cannabis use on schizophrenia-related behaviours.

The three areas of the brain assessed in this study were found to show changes in cell size, density and protein levels.

'Increased knowledge on the effects of cannabis on the brain is critical to understanding youth mental health both in terms of psychological and psychiatric well-being,' Dr Behan continued.

The research was funded by the Health Research Board and Science Foundation Ireland.

Senior authors include Professor David Cotter and Professor Mary Cannon, Department of Psychiatry and Professor John Waddington, Department of Molecular and Cellular Therapeutics, RCSI. Additional authors in the study included Magdalena Hryniewiecka,

Department of Psychiatry, RCSI, Dr Colm O'Tuathaigh and Dr Anthony Kinsella, Department of Molecular and Cellular Therapeutics, RCSI as well as collaborators Professor Maria Karayiorgou and Professor Joseph Gogos from the Department of Neuroscience, Columbia University, New York.

https://www.sciencedaily.com/releases/2012/05/120508112748.htm

Marijuana-like chemicals inhibit human immunodeficiency virus (HIV) in late-state AIDS

March 20, 2012

Science Daily/Mount Sinai Medical Center

Mount Sinai School of Medicine researchers have discovered that marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, according to new findings published online in the journal PLoS ONE.

Medical marijuana is prescribed to treat pain, debilitating weight loss and appetite suppression, side effects that are common in advanced AIDS. This is the first study to reveal how the marijuana receptors found on immune cells -- called cannabinoid receptors CB1 and CB2 -- can influence the spread of the virus. Understanding the effect of these receptors on the virus could help scientists develop new drugs to slow the progression of AIDS.

"We knew that cannabinoid drugs like marijuana can have a therapeutic effect in AIDS patients, but did not understand how they influence the spread of the virus itself," said study author Cristina Costantino, PhD, Postdoctoral Fellow in the Department of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine. "We wanted to explore cannabinoid receptors as a target for pharmaceutical interventions that treat the symptoms of late-stage AIDS and prevent further progression of the disease without the undesirable side effects of medical marijuana."

HIV infects active immune cells that carry the viral receptor CD4, which makes these cells unable to fight off the infection. In order to spread, the virus requires that "resting" immune cells be activated. In advanced AIDS, HIV mutates so it can infect these resting cells, gaining entry into the cell by using a signaling receptor called CXCR4. By treating the cells with a cannabinoid agonist that triggers CB2, Dr. Costantino and the Mount Sinai team found that CB2 blocked the signaling process, and suppressed infection in resting immune cells.

Triggering CB1 causes the drug high associated with marijuana, making it undesirable for physicians to prescribe. The researchers wanted to explore therapies that would target CB2 only. The Mount Sinai team infected healthy immune cells with HIV, then treated them with a chemical that triggers CB2 called an agonist. They found that the drug reduced the infection of the remaining cells.

"Developing a drug that triggers only CB2 as an adjunctive treatment to standard antiviral medication may help alleviate the symptoms of late-stage AIDS and prevent the virus from spreading," said Dr. Costantino. Because HIV does not use CXCR4 to enhance immune cell infection in the early stages of infection, CB2 agonists appear to be an effective antiviral drug only in late-stage disease.

As a result of this discovery, the research team led by Benjamin Chen, MD, PhD, Associate Professor of Infectious Diseases, and Lakshmi Devi, PhD, Professor of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine, plans to develop a mouse model of late-stage AIDS in order to test the efficacy of a drug that triggers CB2 in vivo. In 2009 Dr. Chen was part of a team that captured on video for the first time the transfer of HIV from infected T-cells to uninfected T-cells.

Funding for this study was provided to Drs. Chen and Devi by the National Institutes of Health in Bethesda, Maryland. Dr. Costantino is supported by a National Institutes of Health Clinical and Translational Science Award grant awarded to Mount Sinai School of Medicine.

https://www.sciencedaily.com/releases/2012/03/120320195252.htm

How marijuana impairs memory

March 1, 2012

Science Daily/Cell Press

A major downside of the medical use of marijuana is the drug's ill effects on working memory, the ability to transiently hold and process information for reasoning, comprehension and learning. Researchers provide new insight into the source of those memory lapses. The answer comes as quite a surprise: Marijuana's major psychoactive ingredient (THC) impairs memory independently of its direct effects on neurons.

The findings offer important new insight into the brain and raise the possibility that marijuana's benefits for the treatment of pain, seizures and other ailments might some day be attained without hurting memory, the researchers say.

With these experiments in mice, "we have found that the starting point for this phenomenon -- the effect of marijuana on working memory -- is the astroglial cells," said Giovanni Marsicano of INSERM in France.

"This is the first direct evidence that astrocytes modulate working memory," added Xia Zhang of the University of Ottawa in Canada.

The new findings aren't the first to suggest astroglia had been given short shrift. Astroglial cells (also known as astrocytes) have been viewed as cells that support, protect and feed neurons for the last 100 to 150 years, Marsicano explained. Over the last decade, evidence has accumulated that these cells play a more active role in forging the connections from one neuron to another.

The researchers didn't set out to discover how marijuana causes its cognitive side effects. Rather, they wanted to learn why receptors that respond to both THC and signals naturally produced in the brain are found on astroglial cells. These cannabinoid type-1 (CB1R) receptors are very abundant in the brain, primarily on neurons of various types.

Zhang and Marsicano now show that mice lacking CB1Rs only on astroglial cells of the brain are protected from the impairments to spatial working memory that usually follow a dose of THC. In contrast, animals lacking CB1Rs in neurons still suffer the usual lapses. Given that different cell types express different variants of CB1Rs, there might be a way to therapeutically activate the receptors on neurons while leaving the astroglial cells out, Marsicano said.

"The study shows that one of the most common effects of cannabinoid intoxication is due to activation of astroglial CB1Rs," the researchers wrote.

The findings further suggest that astrocytes might be playing unexpected roles in other forms of memory in addition to spatial working memory, Zhang said.

The researchers hope to explore the activities of endogenous endocannabinoids, which naturally trigger CB1Rs, on astroglial and other cells. The endocannabinoid system is involved in appetite, pain, mood, memory and many other functions. "Just about any physiological function you can think of in the body, it's likely at some point endocannabinoids are involved," Marsicano said.

And that means an understanding of how those natural signaling molecules act on astroglial and other cells could have a real impact. For instance, Zhang said, "we may find a way to deal with working memory problems in Alzheimer's."

https://www.sciencedaily.com/releases/2012/03/120301143424.htm

Cannabis: The good, the evil, the ugly

February 28, 2012

Science Daily/Umeå University

Cannabis-like substances that are produced by the body have both therapeutic and harmful properties, besides their well-known intoxicating effects, and the body's cannabinoid system may be a target for new strategies in cancer treatment. This is what Sofia Gustafsson finds in the dissertation she recently defended at Umeå University in Sweden.

Abuse of cannabis and preparations containing synthetic cannabis-like substances (cannabinoids) is on the rise all over Europe. At the same time, cannabis-based drugs have been approved for certain medical purposes, and in Sweden a compound was approved for symptom alleviation in multiple sclerosis (MS) just the other day. Intensive research is underway about whether new substances that affect the body's own cannabinoids can be exploited for medical purposes, for instance, to relieve pain and to inhibit the growth of tumors. These are the reasons why Sofia Gustafsson studied the impact of cannabinoids on both the nervous system and tumor cells.

The body's own cannabinoids, so-called endocannabinoids, mediate a number of different functions in the central nervous system and in the immune system and are involved in motor movement, reward effects, and learning and memory processes. Cannabinoids from the plant kingdom and synthetically produced cannabinoids affect both of these functions, all of which are mediated via cannabinoid receptors.

Cannabinoids have moreover been shown to affect the fate of cells. Cannabinoids protect some brain cells, whereas cells in certain types of brain tumors, such as glioma, are stimulated to commit controlled cell suicide (apoptosis). Most research on the effects of cannaboids on the nervous system has focused on the adult, fully developed nervous system, while we have relatively little knowledge about the effects on a nervous system that is still developing.

In summary, the findings of Sofia Gustafsson's studies show that cannabinoids can be toxic for cancer cells as well as for nerve cells, and that they decrease emryonal survival. These findings are important for our knowledge both of the potential of the cannabinoid system as a target system for new strategies in cancer treatment and of the risks of new drugs, such as Spice, on nerve development.

https://www.sciencedaily.com/releases/2012/02/120228114159.htm

New way to boost potency of natural pain relief chemical in body

November 21, 2011

Science Daily/University of California - Irvine

UC Irvine and Italian researchers have discovered a new means of enhancing the effects of anandamide -- a natural, marijuana-like chemical in the body that provides pain relief.

Led by Daniele Piomelli, UCI's Louise Turner Arnold Chair in the Neurosciences, the team identified an "escort" protein in brain cells that transports anandamide to sites within the cell where enzymes break it down. They found that blocking this protein -- called FLAT -- increases anandamide's potency.

Previous work by the researchers indicates that compounds boosting anandamide's natural abilities 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 for new, safe drugs," said Piomelli, a professor of pharmacology. "Specific drug compounds we are creating that amplify the actions of natural, marijuana-like chemicals are showing great promise."

For the study, which appears in the Nov. 20 online version of Nature Neuroscience, he and his colleagues used computational methods to understand how FLAT binds with anandamide and escorts it to cell sites to be degraded by fatty acid amide hydrolase (FAAH) enzymes.

Anandamide has been dubbed "the bliss molecule" for its similarities to the active ingredient in marijuana. A neurotransmitter that's part of the body's endocannabinoid system, it's 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 several effects of anandamide without generating the "high" seen with marijuana.

Piomelli and his collaborators speculate that inhibiting FLAT (FAAH-like anandamide transporters) might be particularly useful in controlling certain forms of pain -- that caused by damage to the central nervous system, for example -- and curbing addiction to such drugs as nicotine and cocaine.

Researchers from UCI, Italy's University of Parma and University of Bologna, and the Italian Institute of Technology participated in the study, which was supported by grants from the U.S. National Institute on Drug Abuse, the U.S. National Institute on Alcohol Abuse & Alcoholism, and the U.S. National Institute of General Medical Sciences.

https://www.sciencedaily.com/releases/2011/11/111121142501.htm