Study Finds No Link Between Marijuana Use and Lung Cancer

May 26, 2006

Science Daily/American Thoracic Society

People who smoke marijuana--even heavy, long-term marijuana users--do not appear to be at increased risk of developing lung cancer, according to a study to be presented at the American Thoracic Society International Conference on May 23rd.

Marijuana smoking also did not appear to increase the risk of head and neck cancers, such as cancer of the tongue, mouth, throat, or esophagus, the study found.

The findings were a surprise to the researchers. "We expected that we would find that a history of heavy marijuana use--more than 500-1,000 uses--would increase the risk of cancer from several years to decades after exposure to marijuana," said the senior researcher, Donald Tashkin, M.D., Professor of Medicine at the David Geffen School of Medicine at UCLA in Los Angeles.

The study looked at 611 people in Los Angeles County who developed lung cancer, 601 who developed cancer of the head or neck regions, and 1,040 people without cancer who were matched on age, gender and neighborhood. The researchers used the University of Southern California Tumor Registry, which is notified as soon as a patient in Los Angeles County receives a diagnosis of cancer.

They limited the study to people under age 60. "If you were born prior to 1940, you were unlikely to be exposed to marijuana use during your teens and 20s--the time of peak marijuana use," Dr. Tashkin said. People who were exposed to marijuana use in their youth are just now getting to the age when cancer typically starts to develop, he added.

Subjects were asked about lifetime use of marijuana, tobacco and alcohol, as well as other drugs, their diet, occupation, family history of cancer and socioeconomic status. The subjects' reported use of marijuana was similar to that found in other surveys, Dr. Tashkin noted.

The heaviest smokers in the study had smoked more than 22,000 marijuana cigarettes, or joints, while moderately heavy smokers had smoked between 11,000 to 22,000 joints. Even these smokers did not have an increased risk of developing cancer. People who smoked more marijuana were not at any increased risk compared with those who smoked less marijuana or none at all.

The study found that 80% of lung cancer patients and 70% of patients with head and neck cancer had smoked tobacco, while only about half of patients with both types of cancer smoked marijuana.

There was a clear association between smoking tobacco and cancer. The study found a 20-fold increased risk of lung cancer in people who smoked two or more packs of cigarettes a day. The more tobacco a person smoked, the greater the risk of developing both lung cancer and head and neck cancers, findings that were consistent with many previous studies.

The new findings are surprising for several reasons, Dr. Tashkin said. Previous studies have shown that marijuana tar contains about 50% higher concentrations of chemicals linked to lung cancer, compared with tobacco tar, he noted. Smoking a marijuana cigarette deposits four times more tar in the lungs than smoking an equivalent amount of tobacco. "Marijuana is packed more loosely than tobacco, so there's less filtration through the rod of the cigarette, so more particles will be inhaled," Dr. Tashkin said. "And marijuana smokers typically smoke differently than tobacco smokers--they hold their breath about four times longer, allowing more time for extra fine particles to deposit in the lung."

One possible explanation for the new findings, he said, is that THC, a chemical in marijuana smoke, may encourage aging cells to die earlier and therefore be less likely to undergo cancerous transformation.

The next step, Dr. Tashkin says, is to study the DNA samples of the subjects, to see whether there are some heavy marijuana users who may be at increased risk of developing cancer if they have a genetic susceptibility for cancer.

https://www.sciencedaily.com/releases/2006/05/060526083353.htm

Marijuana-like Compounds Suppress the Immune Response

April 26, 2006

Science Daily/American Society for Biochemistry and Molecular Biology

A group of Japanese scientists has discovered that cannabinoids can cause some white blood cells to lose their ability to migrate to the sites of infection and inflammation. These findings, which appear in the May 5 issue of the Journal of Biological Chemistry, could have potential use in the development of novel anti-inflammatory drugs.

The cannabinoids are a group of chemicals that include marijuana. These compounds bind to and activate the body's cannabinoid receptors. There are two types of cannabinoid receptor: the peripheral cannabinoid receptor (CB2) which is predominantly found in immune cells, and the central cannabinoid receptor (CB1) which occurs in the central nervous system.

Recent studies have suggested that CB2 may be involved in a wide range of physiologic phenomena related to immunity, although research on this function is still at an early stage. Among the possible immunological roles for CB2 is an involvement in the initiation of white blood cell migration to sites of infection and inflammation.

In the Journal of Biological Chemistry study, which was featured as a "Paper of the Week", Yumi Tohyama and colleagues used an in vitro model of blood cell migration to study the involvement of CB2 in the recruitment white blood cells. They found that treating the blood cells with compounds that bind to CB2 suppresses the migration of the cells. When they examined the cells, they discovered that they had lost their ability to develop a front/rear polarity, which is something they need to effectively migrate to sites of infection and inflammation.

Because cannabinoids seem to suppress activated white blood cells, Tohyama believes they could have a potential use in the treatment of inflammatory diseases.

The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at www.jbc.org.

The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, the Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings.

https://www.sciencedaily.com/releases/2006/04/060426174508.htm  

Marijuana Compound May Help Stop Diabetic Retinopathy

February 27, 2006

Science Daily/Medical College of Georgia

A compound found in marijuana won’t make you high but it may help keep your eyes healthy if you’re a diabetic, researchers say.

Early studies indicate cannabidiol works as a consummate multi-tasker to protect the eye from growing a plethora of leaky blood vessels, the hallmark of diabetic retinopathy, says Dr. Gregory I. Liou, molecular biologist at the Medical College of Georgia.

“We are studying the role of cannabinoid receptors in our body and trying to modulate them so we can defend against diabetic retinopathy,” Dr. Liou says. Diabetic retinopathy is the leading cause of blindness in working-age adults and affects nearly 16 million Americans.

High glucose levels resulting from unmanaged diabetes set in motion a cascade ultimately causing the oxygen-deprived retina to grow more blood vessels. Ironically, the leaky surplus of vessels can ultimately destroy vision.

Dr. Liou, who recently received a $300,000 grant from the American Diabetes Association, wants to intervene earlier in the process, as healthy relationships inside the retina first start to go bad.

Cannabinoid receptors are found throughout the body and endogenous cannabinoids are produced to act on them. “Their function is very different from organ to organ but in the central nervous system, cannabinoid receptors are responsible for the neutralization process that should occur after a nerve impulse is finished,” says Dr. Liou.

Nerves come together at a point of communication called a synapse. Glutamate is a neurotransmitter that excites these nerves to action at their point of communication. “There are also inhibitory neurotransmitters such as GABA,” Dr. Liou says. Endogenous cannabinoids help balance the excitation and inhibition, at least until oxygen gets scarce.

In the face of inadequate oxygen, or ischemia – another hallmark of diabetes – nerve endings start producing even more glutamate, setting in motion an unhealthy chain of events. Pumps that keep the right substances inside or outside of cells start to malfunction. Excess nitric oxide and superoxides are produced, which are toxic to the cells. Another irony is the heightened activity increases the retina’s need for oxygen. “We are talking about nerve cell death,” Dr. Liou says. “In the retina, if a lot of our nerve cells die, our vision is directly affected.”

And that’s not all that goes wrong in the nerve-packed retina. Glial cells, which support nerve cells by supplying nutrients and oxygen, are closely attuned to their charges. When they sense something is amiss, microglia, one type of glial cells, start eating the dying nerve cells.

“Microglial cells become voracious. They eat dying nerve cells, making the whole thing irreversibly bad,” says Dr. Liou. Interestingly, the body start producing more endogenous cannabinoids to stop the role reversal, then produces an enzyme to destroy the cannabinoids because of concern there are too many of them. The same thing happens in the brain after a stroke. “Long before all these blood vessels start growing, the partnership between glial cells and nerve cells starts breaking down,” says Dr. Liou.

That’s why cannabidiol, an antioxidant, may help save the retina. Test-tube studies by others, as well as Dr. Liou’s pilot studies in diabetic animal models show cannabidiol works to interrupt essentially all these destructive points of action.

“What we believe cannabidiol does is go in here as an antioxidant to neutralize the toxic superoxides. Number two, it inhibits the self-destructive system and allows the self-produced endogenous cannabinoids to stay there longer by inhibiting the enzyme that destroys them.” Cannabidiol also helps keep microglial cells from turning on nerve cells by inhibiting cannabinoid receptors on microglial cells that are at least partially responsible for their ability to destroy rather than support the cells.

“Cannabinoids are trying to ease the situation on both sides. They help save the neuron and, at the same time, make sure the microglial cells stay in microglial form. How good do you want a drug to be?” Dr. Liou says.

His earliest studies in animal models, published in the January issue of the American Journal of Pathology, indicate it may be very good.

Co-authors on the study include Dr. Azza B. El-Remessy, MCG Department of Pharmacology and Toxicology; Drs. Mohamed Al-Shabrawey, Nai-Tse Tsai and Ruth B. Caldwell, MCG Vascular Biology Center; and Dr. Yousuf Khalifa, MCG Department of Ophthalmology.

“We are very pleased,” he says of studies in which cannabidiol is injected into the stomachs of diabetic rats and mice.

He hopes the compound in marijuana may one day be given along with insulin to stop the early changes that set the stage for damaged or destroyed vision.

https://www.sciencedaily.com/releases/2006/02/060227184647.htm

New Antidepressant Drug Increases 'Brain's Own Cannabis'

December 13, 2005

Science Daily/McGill University

Researchers have discovered a new drug that raises the level of endocannabinoids -- the 'brain's own cannabis' -- providing anti-depressant effects. The new research published in this week's Proceedings of the National Academy of Sciences (PNAS), suggests the new drug, called URB597, could represent a safer alternative to cannabis for the treatment of pain and depression, and open the door to new and improved treatments for clinical depression--a condition that affects around 20% of Canadians.

In preclinical laboratory tests researchers found that URB597 increased the production of endocannabinoids by blocking their degradation, resulting in measurable antidepressant effects. "This is the first time it has been shown that a drug that increases endocannabinoids in the brain can improve your mood," says the lead investigator Dr. Gabriella Gobbi, an MUHC and Université de Montréal researcher.

Endocannabinoids are chemicals released by the brain under certain conditions, like exercise; they stimulate specific brain receptors that can trigger feelings of well-being. The researchers, which included scientists from the University of California at Irvine, were able to measure serotonin and noradrenaline activity as a result of the increased endocannabinoids, and also conducted standard experiments to gauge the 'mood' of their subjects and confirm their findings.

"The results were similar to the effect we might expect from the use of commonly prescribed antidepressants, which are effective on only around 30% of the population," explains Dr. Gobbi. "Our discovery strengthens the case for URB597 as a safer, non-addictive, non-psychotropic alternative to cannabis for the treatment of pain and depression and provides hope for the development of an alternate line of antidepressants, with a wider range of effectiveness."

Cannabis has been known for its anti-depressant and pain-relief effects for many years, but the addictive nature and general health concerns of cannabis use make this drug far from ideal as a medical treatment. The active ingredient in cannabis--THC (Tetrahydrocannabinol)--stimulates cannabinoid receptors.

Funding for this study was provided by the Fonds de la Recherche en Santé du Québec (FRSQ), the Canadian Psychiatric Research Foundation (CPRF), the National Institute on Drug Abuse (NIDA) and an MUHC fellowship.

https://www.sciencedaily.com/releases/2005/12/051213172852.htm

University of Saskatchewan Research Suggests Marijuana Analogue Stimulates Brain Cell Growth

October 16, 2005

Science Daily/University of Saskatchewan

A synthetic substance similar to ones found in marijuana stimulates cell growth in regions of the brain associated with anxiety and depression, pointing the way for new treatments for these diseases, according to University of Saskatchewan medical research published today in The Journal of Clinical Investigation.

Xia Zhang, an associate professor in the U of S neuropsychiatry research unit, led the team that tested the effects of HU-210, a potent synthetic cannabinoid similar to a group of compounds found in marijuana. The synthetic version is about 100 times as powerful as THC, the compound responsible for the high experienced by recreational users.

The team found that rats treated with HU-210 on a regular basis showed neurogenesis – the growth of new brain cells in the hippocampus. This region of the brain is associated with learning and memory, as well as anxiety and depression.

The effect is the opposite of most legal and illicit drugs such as alcohol, nicotine, heroin, and cocaine.

“Most ‘drugs of abuse’ suppress neurogenesis,” Zhang says. “Only marijuana promotes neurogenesis.”

Current theory states that depression may be sparked when too few new brain cells are grown in the hippocampus. It is unclear whether anxiety is part of this process, but if true, HU-210 could offer a treatment for both mood disorders by stimulating the growth of new brain cells.

But Zhang cautions that HU-210 is only one of many cannabinoids. His previous work with marijuana shows that while the plant may contain medicinal compounds, they come in the same package as those that cause symptoms such as acute memory impairment, addiction, and withdrawal. Also, the HU-210 used in the study is highly purified.

“This is a very potent cannabinoid oil,” Zhang says. “It’s not something that would be available on the street.”

Marijuana has been used for recreational and medicinal purposes for centuries, evoking public interest and controversy along the way. As a medicine, the plant is used to ease pain in multiple sclerosis patients, combat nausea in cancer patients, and stimulate appetite in people afflicted with AIDS. It has also been used to treat epilepsy and stroke.

Zhang’s work is the latest product of the U of S Neural Systems and Plasticity Research Group (http://www.usask.ca/neuralsystems/group.htm), a multidisciplinary effort by researchers from the Colleges of Arts and Science, Engineering, Kinesiology, Medicine, Pharmacy and Nutrition, and Veterinary Medicine. The group collaborates to study the function of neural systems, from nerves to brain, in living organisms. In particular, they look at how these systems change over time with experience.

Zhang’s research is supported by a grant from the Canadian Institutes of Health Research (CIHR), as well as a CIHR New Investigator Award. The Saskatchewan Health Research Foundation provided funding support to establish the Neural Systems and Plasticity Research Group, as well as post-doctoral fellowship awards to research team members Wen Jiang and Shao-Ping Ji.

https://www.sciencedaily.com/releases/2005/10/051016083817.htm

Role of Cannabinoid Receptors in Alcohol Abuse Examined

September 11, 2005

Science Daily/Brookhaven National Laboratory

A new set of experiments in mice confirms that a brain receptor associated with the reinforcing effects of marijuana also helps to stimulate the rewarding and pleasurable effects of alcohol.

The research, which was conducted at the U.S. Department of Energy’s Brookhaven National Laboratory and was published online September 2, 2005 by the journal Behavioural Brain Research, confirms a genetic basis for susceptibility to alcohol abuse and also suggests that drugs designed to block these receptors could be useful in treatment.

“These findings build on our understanding of how various receptors in the brain’s reward circuits contribute to alcohol abuse, help us understand the role of genetic susceptibility, and move us farther along the path toward successful treatments,” said Brookhaven’s Panayotis (Peter) Thanos, lead author of this study and many others on “reward” receptors and drinking.

Earlier studies in animals and humans have suggested that so-called cannabinoid receptors known as CB1 — which are directly involved in triggering the reinforcing properties of marijuana — might also stimulate reward pathways in response to drinking alcohol. Thanos’ group investigated this association in two experiments.

In the first experiment, they measured alcohol preference and intake in mice with different levels of CB1 receptors: wild type mice with normal levels of CB1; heterozygous mice with approximately 50 percent levels; and so-called knockout (KO) mice that lack the gene for CB1 and therefore have no CB1 receptors. All mice were given a choice of two drinking bottles, one with pure water and one with a 10 percent alcohol solution — approximately equivalent to the alcohol content of wine. Mice with the normal levels of CB1 receptors had a stronger preference for alcohol and drank more than the other two groups, with the CB1-deficient mice showing the lowest alcohol consumption.

After establishing each group’s level of drinking, the scientists treated animals with a drug known to block CB1 receptors (SR141716A) and tested them again. (These animals were also compared with animals injected with plain saline to control for the effect of the injection.) In response to the CB1 receptor-blocking drug, mice with normal and intermediate levels of receptors drank significantly less alcohol compared to their pre-treatment levels, while KO mice showed no change in drinking in response to the treatment.

In the second experiment, the scientists compared the tendency of wild type and KO mice to seek out an environment in which they had previously been given alcohol. Known as “conditioned place preference,” this is an established technique for determining an animal’s preference for a drug.

Animals were first conditioned to “expect” alcohol in a given portion of a three-chambered cage while being given an injection of saline in the opposite end, and then monitored for how much time they spent in the alcohol chamber “seeking” the drug. Wild type animals, with normal levels of CB1, spent more time in the alcohol-associated chamber than the saline chamber, showing a decided preference, while KO mice (with no CB1 receptors) showed no significant preference for one chamber over the other.

“These results support our belief that the cannabinoid system and CB1 receptors play a critical role in mediating the rewarding and pleasurable properties of alcohol, contributing to alcohol dependency and abuse,” Thanos said.

In addition, the fact that the mice with intermediate levels of CB1 exhibited alcohol preference and intake midway between those with high levels of receptors and those with none suggests that the genetic difference between strains quantitatively influences the preference for and the amount of alcohol consumed. “These results provide further evidence for a genetic component to alcohol abuse that includes the CB1 gene — the same gene that is important for the behavioral effects of marijuana,” Thanos said.

While it remains unclear exactly how CB1 triggers the rewarding effects of alcohol, one possibility is that activation of the CB1 receptor somehow blocks the brain’s normal “stop” signals for the production of dopamine, another brain chemical known to play a role in addiction. Without the stop signal, more dopamine is released to produce a pleasure/reward response.

Since blockade of the CB1 receptor with SR141716A appears to effectively reduce alcohol intake and preference, this study also suggests that such CB1 receptor-blocking drugs might play an important role in the future treatment of alcohol abuse.

This study was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy’s (DOE) Office of Science; by the National Institute on Drug Abuse and the Intramural Research Program of the NIH, [National Institute on Alcohol Abuse and Alcoholism]. The DOE has a long-standing interest in research on addiction that builds, as this study does, on the knowledge of brain receptors gained through brain-imaging studies. Brain-imaging techniques such as MRI and PET are a direct outgrowth of DOE’s support of basic physics research.

https://www.sciencedaily.com/releases/2005/09/050908084256.htm

Endocannabinoids -- The Brain's Cannabis -- Demonstrate Novel Modes of Action to Stress

July 20, 2005

Science Daily/American Physiological Society

Three separate research team reports -- one from Louisiana, one from Japan and one from Scotland -- are presenting independent research results pointing to involvement of endocannabinoids as a novel neural messenger in various stress-related situations with possible applications in eating, disease treatment and social behavior.

Tulane, LSU team on stress-related shutdown

The team from Tulane and Louisiana State Universities, led by Shi Di, found that in both physiological and psychological stress situations, stress hormones act on the brain to stimulate the release of endogenous cannabinoids from neurons in the hypothalamus, which act as a local messenger within the hypothalamus to shut down the neuroendocrine stress response.

One explanation for this hormone feedback regulation of the stress response might be to prepare the brain to mount another response in case of the onset of another possible stressor. The endogenous cannabinoids may serve to link the stress response with other neuroendocrine functions controlled by the hypothalamus, such as feeding.

Di says that the "actions of the endocannabinoids on the synaptic circuits that control the activity of the hypothalamic neurons serve to rapidly inhibit hormone secretion from the pituitary gland, providing a rapid negative feedback mechanism for the regulation of neuroendocrine function during stress."

Japanese team finds inhibition of excitatory and inhibitory synaptic transmission

In an in vitro study, a multi-center Japanese team led by Atsushi Soya focused on the supraoptic nucleus (SON) where vasopressin and oxytocin are synthesized. They found that a synthesized cannbinoid (CP55,940) inhibited both excitatory and inhibitory synaptic transmission and that a balanced input can produce sustained changes in neuronal activity without damage to neuronal homeostasis.

"Our next step is to investigate cannabinoids' effects in various stress conditions," Soya said. "Endocannabinoids may have possible involvement in stress-induced responses such as the changes of autonomic, endocrine and immune function."

Furthermore, Soya added, "cannabinoids are relevant to potential relief in such disease situations in the brain as multiple sclerosis and epilepsy, or feeding disorders. In these, their effects are similar to marijuana, except for the possible dangers of accidentally using the natural products at higher dosages."

Scottish team seeks social behavior answers

Nancy Sabatier of the University of Edinburgh, noted that "cannabis, or marijuana, is a drug that is widely abused because of the effects it can have on our mood and our social behavior. Cannabis works this way because it acts like substances that are produced inside our brains that are messengers between brain cells. Our work involves trying to understand what these substances, endocannabinoids, are for."

She said they are particularly interested in how endocannabinoids influence oxytocin cells in the brain, because because OT within the brain is involved in social behavior. "We have found that oxytocin cells produce endocannabinoids, and can release these to switch off other inputs to the oxytocin cells themselves. We are looking at what stimuli will cause oxytocin cells to release endocannabinoids to understand why this system might be important."

Sabatier noted that most related experiments are carried out in rats, "but we think that the basic ways in which these circuits work is very similar in all mammals. These brain circuits are very old in evolutionary terms, and they govern behaviors that are of fundamental importance to most species."

https://www.sciencedaily.com/releases/2005/07/050720065810.htm

Marijuana Ingredient May Stall Decline from Alzheimer's

March 4, 2005

Science Daily/Society for Neuroscience

New research shows that a synthetic analogue of the active component of marijuana may reduce the inflammation and prevent the mental decline associated with Alzheimer's disease.

"This research is not only a major step in our understanding [of] how the brain reacts to Alzheimer's disease, but may also help open a route to novel anti-Alzheimer's drugs," says Raphael Mechoulam, professor emeritus of medicinal chemistry at Hebrew University in Jerusalem and discoverer of marijuana's active component.

To show the preventive effects of cannabinoids on Alzheimer's disease, researchers at the Cajal Institute and Complutense University in Madrid, led by Maria de Ceballos, conducted studies using human brain tissue, as well as experiments with rats. The study appears in the February 23, 2005, issue of The Journal of Neuroscience.

The team first compared the brain tissue of patients who died from Alzheimer's disease with that of healthy people who had died at a similar age. They looked closely at cannabinoid receptors CB1 and CB2– proteins to which cannabinoids bind, allowing their effects to be felt – and at microglia, which activate the brain's immune response. Micro- glia collect near plaques and, when active, cause inflammation. The researchers found a dramatically reduced functioning of cannabinoid receptors in diseased brain tissue, meaning that patients had lost the capacity to experience cannabinoids' protective effects.

In addition, the researchers showed that cannabinoids prevented cognitive decline through rat experiments. They injected either amyloid (which leads to cognitive decline) that had been allowed to aggregate or control proteins into the brains of rats for one week. Other rats were injected with a cannabinoid and either amyloid or a control protein.

After two months, the researchers trained the rats over five days to find a platform hidden underwater. Rats treated with the control protein – with or without cannabinoids – and those treated with the amyloid protein and cannabinoid were able to find the platform. Rats treated with amyloid protein alone did not learn how to find the platform.

The researchers found that the presence of amyloid protein in the rats' brains activated immune cells. Rats that received the control protein alone or cannabinoid and a control protein did not show activation of microglia. Using cell cultures, the investigators confirmed that cannabinoids counteracted the activation of microglia and thus reduced inflammation.

"These findings that cannabinoids work both to prevent inflammation and to protect the brain may set the stage for their use as a therapeutic approach for [Alzheimer's disease]," de Ceballos says. The scientists will now focus their efforts on targeting one of the two main cannabinoid receptors that is not involved in producing the psychotropic effects, or high, from marijuana.

https://www.sciencedaily.com/releases/2005/02/050224111638.htm

Marijuana-Like Compounds May Aid Array of Debiliatiing Conditions Ranging from Parkinson's Disease to Pain

October 27, 2004

Science Daily/Society for Neuroscience

No longer a pipe dream, new animal research now indicates that marijuana-like compounds can aid a bevy of debilitating conditions, ranging from brain disorders such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease, to pain and obesity.

In past studies, researchers determined that the main active chemicals in the drug marijuana produce a variety of effects by connecting to specific sites on nerve cells, called cannabinoid receptors. Researchers also discovered that these receptors normally bind to natural internal chemicals, dubbed cannabinoids.

“Understanding how marijuana and the brain's own natural cannabinoid system works is helping researchers design new medicines,” says cannabinoid expert Daniele Piomelli, PhD, of the University of California in Irvine. “It's believed that the controlled therapies that come out of this research might provide select benefits to patients while avoiding some of the unwanted effects seen with the drug.”

Research from California Pacific Medical Center in San Francisco points to the promise of marijuana-like treatments for those with the fatal brain disorder ALS, also known as Lou Gehrig's disease.

“Our research indicates that select marijuana compounds, including THC, significantly slow the disease process and extend the life of mice with ALS,” says study author Mary Abood, PhD.

The study extends earlier work from Abood's group that found that THC also can alleviate some ALS symptoms, like muscle spasms, in patients.

ALS wreaks its havoc by harming nerve cells that control muscles. As a consequence of the damage, an estimated 5,000 Americans afflicted annually experience progressive muscle weakness that can hinder movement, speech, even swallowing and breathing. New treatments for ALS are desperately needed.

“The only FDA approved drug for ALS, riluzole, extends life on average by about two months,” says Abood. “Evidence from our study suggests that a marijuana-based therapy could create a much greater effect, perhaps extending life by three years or more.”

In the study, ALS mouse models were given either the marijuana compound THC, the marijuana compound cannabidiol, cannabidiol plus THC, or a placebo daily following the onset of disease signs. The researchers measured disease progression by testing how long the mice could stand on a slowly rotating rod. The more severe their nerve cell degeneration, the less time the mice can balance on the rod. In addition, two conditions of ALS, the loss of movement ability and survival time, were analyzed using a mathematical model.

“We found that treatment with THC delayed disease progression by seven days and extended survival by six days in the mouse model,” says Abood. “This corresponds to three years in human terms.”

Results also indicate that the combination of THC and cannabidiol further delays disease progression. Treatment with cannabidiol alone, however, had no effect.

Another part of the study determined that the marijuana compounds create their benefits by reducing two molecular processes, known as oxidative stress and glutamate excitotoxicity. These processes have been implicated in ALS and are thought to harm nerve cells.

As a next step, the researchers will further decipher the mechanisms of action of THC and cannabidiol.

Another animal study also indicates that a marijuana-like compound can protect brain cells from the damage produced by the disorder Parkinson's disease.

“For the first time, our research shows the neuroprotective value of marijuana-like compounds in a well-established animal model of Parkinson's disease,” says study author Andrea Giuffrida, PhD, of the University of Texas Health Science Center in San Antonio.

Parkinson's afflicts some 1 million Americans. Symptoms include slowness of movement, muscle stiffness, and shaky tremors, which can harm a person's ability to walk, talk, write, and eat. This havoc results from the death or injury of brain cells that produce the chemical dopamine.

“There are therapies that can help replenish depleted levels of dopamine and provide symptomatic relief, but none can reverse, prevent, or delay the progression of Parkinson's disease,” says Giuffrida. “Our research shows that marijuana-like compounds may be able to answer this need.”

In the study, researchers examined whether a marijuana-like compound designed to activate cannabinoid receptors, WIN 55212-2, could protect brain cells from degenerating in a Parkinson's mouse model, known as MPTP-treated mouse. These animals are given an injection of the toxin MPTP, which kills dopamine brain cells and induces symptoms seen in Parkinson's disease. The mice received a single injection of WIN 55212-2 30 minutes before the MPTP injection.

“We found that the brains of mice treated with the marijuana-like compound were almost indistinguishable from the brains of healthy mice,” says Giuffrida.

As a next step, the researchers are testing whether the marijuana-like compounds have neuroprotective value when brain cell damage is already present and whether they can prevent the progression of brain cell loss. “Learning more about the mechanisms by which marijuana-like compounds may slow down or prevent neurodegeneration in Parkinson's disease may translate into new pharmacological treatments that could fight this disorder in its earliest stages,” adds Giuffrida.

Another new animal study finds that drugs often prescribed for mild pain, like the pain from a tooth extraction, create greater pain relief when combined with a marijuana-like compound. If confirmed in humans, the combination strategy could be a boon to those with persistent pain conditions.

Persistent pain is notoriously difficult to treat. An estimated 50 million Americans endure some type of persistent pain that lasts for months, even years, including back pain, headaches, arthritis pain, and cancer pain.

“We found that the combination of a marijuana-like compound with either the mild pain medication ibuprofen or rofecoxib provides more pain relief than each of them given alone,” says study author Pierre Beaulieu, MD, PhD, of the University of Montreal in Canada .

The marijuana-like compound that researchers tested in the study is called anandamide, a natural internal chemical that activates the same system as marijuana. Nonsteroidal anti-inflammatory drugs such as ibuprofen and rofecoxib inhibit a specific enzyme that prevents the degradation of anandamide. This led researchers to suspect that supplements of anandamide could create even greater pain relief effects.

In the study, researchers injected the drugs into the back paw of rats. Then 15 minutes later, researchers injected the compound formalin into the same paw, which creates a persistent inflammatory pain condition locally.

“We found that compared to a separate administration of drugs, anandamide combined with either ibuprofen or rofecoxib doubled the animals' pain relief,” says Beaulieu. “Also since the compounds were injected locally, into the paw, we believe that the treatment would avoid some of the deleterious psychoactive effects seen with marijuana.”

Marijuana and marijuana-like compounds can act on receptors in the brain and the periphery, but only the brain ones contribute to the psychoactive effects.

As a next step, the researchers are testing the treatment strategy in animals that model a particularly hard-to-treat, persistent pain condition that can result from nerve injury, termed neuropathic pain.

Another new animal study supports the development of treatments that target the cannabinoid system for those with obesity. “We found that a compound that blocks activity in the cannabinoid system can significantly reduce food intake in animals by triggering activity in another system that is known to regulate appetite and body weight,” says study author Michael Cowley, PhD, of Oregon Health and Science University.

Obesity has risen at an epidemic rate during the past 20 years, according to the Centers for Disease Control and Prevention. More than 60 percent of adult Americans are overweight or obese. These people face an increased risk for a range of physical ailments, including high blood pressure, diabetes, and stroke.

“For many years anecdotal reports have described how marijuana use can increase appetite,” says Cowley. “Some users describe these cravings as the munchies.”

This and other work has prompted the development of drugs that combat appetite by blocking the cannabinoid receptors, which are activated by marijuana. “Some of these drugs are in late stage clinical trials,” says Cowley. “How they are able to control eating, however, has been a mystery.”

To shed some light on how they might work, Cowley and his colleagues gave mice a cannabinoid receptor blocker, termed AM251. “We found that the treated animals significantly reduced their food intake, as has been known for many years,” says Cowley. “We also found evidence that the activity of brain cells involved in the melanocortin system, which is known to control food intake and energy balance, increased.”

Several molecular measures signaled that there was increased activity in melanocortin brain cells. Included was the discovery that in treated animals there was a fourfold increase in the number of melanocortin brain cells that contained c-fos, a marker of cellular activation.

“These data show that cannabinoid receptor blockers can regulate the melanocortin pathways in animals and support the further development of cannabinoid blockers to help combat obesity in humans,” says Cowley.

https://www.sciencedaily.com/releases/2004/10/041027102621.htm

Cannabis May Help Combat Cancer-causing Herpes Viruses

September 24, 2004

Science Daily/University of South Florida Health Sciences Center

The compound in marijuana that produces a high, delta-9 tetrahydrocannbinol or THC, may block the spread of several forms of cancer causing herpes viruses, University of South Florida College of Medicine scientists report.

The findings, published Sept. 15 in the online journal BMC Medicine, could lead to the creation of antiviral drugs based on nonpsychoactive derivatives of THC.

The gamma herpes viruses include Kaposi's Sarcoma Associated Herpes virus, which is associated with an increased risk of cancer that is particularly prevalent in AIDS sufferers. Another is Epstein-Barr virus, which predisposes infected individuals to cancers such as Burkitt's lymphoma and Hodgkin's disease.

Once a person is infected, these viruses can remain dormant for long periods within white blood cells before they burst out and begin replicating. This reactivation of the virus boosts the number of cells infected thereby increasing the chances that the cells will become cancerous.

The USF team, led by virologist Peter Medveczky, MD, found that this sudden reactivation was prevented if infected cells were grown in the presence of THC. While cells infected with a mouse gamma herpes virus normally died when the virus was reactivated, these same cells survived when cultured in the laboratory along with the cannabinoid compound – further evidence that THC prevents viral reactivation.

Furthermore, the researchers showed that THC acts specifically on gamma herpes viruses. The chemical had no effect on another related virus, herpes simplex-1, which causes cold sores and genital herpes.

Small concentrations of THC were more potent and selective against gamma herpes viruses than the commonly used antiviral drugs acyclovir, gancicyclovir and foscamet, said Dr. Medveczky, a professor in the Department of Medical Microbiology and Immunology.

The USF researchers suggest that THC selectively inhibits the spread of gamma herpes viruses by targeting a gene these viruses all share called ORF50.

Dr. Medveczky emphasized that more studies are needed. "We have not evaluated the effect of THC in an animal model yet so we do not recommend people start using pot to prevent or treat cancers."

In fact, Dr. Meveczky said, THC has also been shown to suppress the immune system so smoking marijuana could "do more harm than good" to patients whose immune systems are often already weakened.

https://www.sciencedaily.com/releases/2004/09/040923092627.htm

Marijuana Ingredient Inhibits VEGF Pathway Required for Brain Tumor Blood Vessels

August 16, 2004

Science Daily/American Association for Cancer Research

Cannabinoids, the active ingredients in marijuana, restrict the sprouting of blood vessels to brain tumors by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).

According to a new study published in the August 15, 2004 issue of the journal Cancer Research, administration of cannabinoids significantly lowered VEGF activity in laboratory mice and two patients with late-stage glioblastoma.

"Blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available," said Manuel Guzmán, professor of biochemistry and molecular biology, with the Complutense University in Madrid, Spain, and the study's principal investigator.

"The present findings provide a novel pharmacological target for cannabinoid-based therapies."

Glioblastoma multiforme, the most aggressive form of glioma, strikes more than 7,000 Americans each year and is considered one of the most malignant and deadliest forms of cancer, generally resulting in death within one to two years following diagnosis.

The disease is usually treated with surgery, followed by conventional radiation alone or in combination with chemotherapy. However, the main tumor often evades total destruction, surviving and growing again, eventually killing the patient. For this reason, researchers are actively seeking other therapeutic strategies, some of which might be considered novel.

In this study, the investigators chose to work with cannabinoids which, in previous studies, have been shown to inhibit the growth of blood vessels, or angiogenesis, in laboratory mice. However, little was known about the specific mechanisms by which cannabinoids impair angiogenesis, or whether the chemical might do the same in human tumors.

To answer the first part of the question, the scientists induced gliomas in mice, which were subsequently inoculated with cannabinoids. Using DNA array analysis, the team examined 267 genes associated with the growth of blood vessels in tumors and found that cannabinoids lowered the expression of several genes related to the VEGF pathway, critical for angiogenesis.

The researchers also discovered that cannabinoids apparently worked by increasing the activity of ceramide, a lipid mediator of apoptosis, resulting in the functional inhibition of cells needed for VEGF production. The ability of cannabinoids to alter VEGF production was significantly stifled following the introduction of a ceramide inhibitor.

"As far as we know, this is the first report showing that ceramide depresses VEGF pathway by interfering with VEGF production," according to Guzmán.

To answer the second part of the question relating to clinical tests, the scientists obtained tumor biopsies from two patients with glioblastomas who had failed standard therapy, including surgery, radiotherapy and chemotherapy. The biopsied tissue was analyzed before and after local injection of a cannabinoid.

"In both patients, VEGF levels in tumor extracts were lower after cannabinoid inoculation," said Guzmán.

The results, he added, suggest a potential new approach toward the treatment of these otherwise intractable brain tumors.

"It is essential to develop new therapeutic strategies for the management of glioblastoma multiforme," the scientists wrote, "which will most likely require a combination of therapies to obtain significant clinical results."

Also participating in the study were Cristina Blázquez and Amador Haro, from Complutense University; Luis González-Feria, from University Hospital, Tenerife, Spain; Luis Álvarez, from La Paz University Hospital in Madrid; and M. Llanos Casanova, from the Project on Cellular and Molecular Biology and Gene Therapy, CIEMAT, also in Madrid.

https://www.sciencedaily.com/releases/2004/08/040816085401.htm

Cannabis Triggers Transient Schizophrenia-like Symptoms

June 15, 2004

Science Daily/Yale University

The principal active ingredient in marijuana causes transient schizophrenia-like symptoms ranging from suspiciousness and delusions to impairments in memory and attention, according to a Yale research study.

Lead author D. Cyril D'Souza, M.D., associate professor of psychiatry at Yale School of Medicine, said the study was an attempt to clarify a long known association between cannabis and psychosis in the hopes of finding another clue about the pathophysiology of schizophrenia.

"Just as studies with amphetamines and ketamine advanced the notion that brain systems utilizing the chemical messengers dopamine and NMDA receptors may be involved in the pathophysiology in schizophrenia, this study provides some tantalizing support for the hypotheses that the brain receptor system that cannabis acts on may be involved in the pathophysiology of schizophrenia," he said. "Clearly, further work is needed to test this hypothesis."

D'Souza and his co-researchers administered various doses of delta-9-THC, the main active ingredient in cannabis, to subjects who were screened for any vulnerability to schizophrenia. Some subjects developed symptoms resembling those of schizophrenia that lasted approximately one half hour to one hour. These symptoms included suspiciousness, unusual thoughts, paranoia, thought disorder, blunted affect, reduced spontaneity, reduced interaction with the interviewer, and problems with memory and attention. THC also induced euphoria and increased levels of the stress hormone cortisol. There were no side effects in the study participants one, three and six months after the study.

The findings of this study go along with several other lines of evidence that suggest a contribution of cannabis and/or abnormalities in the brain cannabinoid receptor system to the pathophysiology of schizophrenia.

https://www.sciencedaily.com/releases/2004/06/040615075809.htm#

Researchers Identify Clues About Marijuana Effects

March 9, 2004

Science Daily/Temple University

Scientists have been studying cannabinoids, substances that are chemically related to the ingredients found in marijuana, for more than two decades, hoping to learn more about how the drug produces its effects--both therapeutic and harmful. Marijuana has been reported effective in the treatment of multiple sclerosis, glaucoma, nausea caused by chemotherapy and wasting caused by AIDS. However, like all drugs, it also causes numerous unwanted side effects, including hypothermia, sedation, memory impairment, motor impairment and anxiety. Research on cannabinoids could someday yield new, more effective drugs or drug combinations.

At Temple University's School of Pharmacy and Center for Substance Abuse Research (CSAR), one of only a few centers in the nation focused on the basic science of substance abuse, several researchers are investigating how cannabinoids produce pharmacological effects in rats.

One such study, "L-NAME, a nitric oxide synthase inhibitor, and WIN 55212-2, a cannabinoid agonist, interact to evoke synergistic hypothermia," published in the February issue of the Journal of Pharmacology and Experimental Therapeutics, reveals how cannabinoids produce one of the drug's most robust actions, hypothermia, or decreased body temperature.

According to lead author Scott Rawls, Ph.D., assistant professor of pharmacodynamics at Temple's School of Pharmacy, "To operate at maximum efficiency, the body needs to maintain a stable, normal temperature. When the body's temperature is altered, as in hypothermia, normal body functions, such as blood pressure and circulation, are impaired."

Marijuana operates via two receptors in the body. One receptor, called CB1, is located in the brain and produces the drug's psychoactive effects, including euphoria and dizziness. The other receptor, CB2, is found throughout the body and impacts the immune system. Substances in marijuana bind to one of these receptors and set off a chemical process that leads to an effect, such as hypothermia. Scientists have focused on this chemical process at the molecular level to pinpoint the exact molecules involved.

Knowing that the molecule nitric oxide (NO) plays an important role in the regulation of body temperature, the Temple researchers set out to determine what role it might play in cannabinoid-induced hypothermia. By combining a cannabinoid with a substance that blocked NO synthesis, they found that cannabinoid-induced hypothermia increased more than two-fold.

"This demonstrates the possibility that NO plays a part in regulating the impact of cannabinoids on body temperature and other cannabinoid-mediated actions," said Rawls. "These findings could be helpful in determining the mechanisms that underlie some of the pharmacological actions of marijuana," he added.

Rawls' research team is currently investigating the impact of cannabinoids on other physiological systems, such as analgesia and movement, and the brain neurotransmitters that mediate those systems.

https://www.sciencedaily.com/releases/2004/03/040309071927.htm

Synthetic Marijuana Compound Reduces Agitation, Improves Appetite in Alzheimer's Patients

August 21, 2003

Science Daily/Meridian Health System

Study results suggest dronabinol, a synthetic version of THC, the active ingredient in Cannabis sativa L (marijuana), may reduce agitation and lead to weight gain in patients with Alzheimer's disease, according to data presented today at the annual meeting of the International Psychogeriatric Association.

"Our research suggests dronabinol may reduce agitation and improve appetite in patients with Alzheimer's disease, when traditional therapies are not successful," said Joshua Shua-Haim, M.D., lead investigator in the study and medical director of the Meridian Institute for Aging, a continuum of senior health programs and services in Central New Jersey affiliated with Meridian Health System. "In the study, dronabinol appeared to be safe and effective for these patients. The results point to a promising direction for future research."

Dronabinol, marketed under the trade name Marinol, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-THC also is a naturally occurring component of Cannabis sativa L (marijuana). Dronabinol is the only cannabinoid approved by the U.S. Food and Drug Administration (FDA) and is indicated for the treatment of anorexia in patients with HIV/AIDS and for the treatment of nausea and vomiting associated with cancer chemotherapy.

An estimated four million Americans have Alzheimer's disease and the number will grow to 14 million by 2050, according to the Alzheimer's Association. In addition to memory loss, patients often experience agitation, loss of body weight, depression and restlessness.

Agitation is the most frequently encountered type of behavioral disturbance associated with Alzheimer's disease and affects an estimated 75 percent of people with the disease. Weight loss, a common problem in patients with Alzheimer's disease, is a predictive factor of mortality. Weight loss may derive from the deterioration of patients' cognitive abilities, resulting in an inability to recognize hunger and thirst.

"It's important to look at all the aspects of Alzheimer's disease that contribute to quality of life for patients, family members and caregivers," said Dr. Shua-Haim. "Agitation and weight loss are upsetting and stressful as the patient's needs become ever more demanding."

The study was a retrospective review and examined 48 patients (mean age = 77) residing in a dementia unit of an assisted living facility or a nursing home. All patients met the DSM-IV and NINCDS-ADRDA criteria for possible Alzheimer's disease and, according to their family or caregivers, had unsatisfactory control of their agitation. The mini mental status examination (MMSE), a test used to measure a person's basic cognitive skills, and an assessment of activities of daily living were used to evaluate patients prior to treatment with dronabinol and at one month. Patients initially received 5 mg/day of dronabinol in two doses. The treatment was titrated up to a maximum of 10 mg/day. In addition, all patients were treated with atypical neuroleptics and at least four medications to control behavior.

The evaluation by caregivers following one month of treatment found 31 patients (66 percent) experienced a significant improvement in agitation. Functional improvement was observed in 33 (69 percent) of the patients. Prior to the study, all patients experienced weight loss and had been diagnosed with anorexia. After treatment with dronabinol, all patients (100 percent) had gained weight. No adverse events, such as falls, syncope, seizures or exacerbation of agitation or depression, were reported as a result of treatment.

Meridian Health System is comprised of Jersey Shore Medical Center in Neptune, Medical Center of Ocean County in Brick, and Riverview Medical Center in Red Bank, in addition to long-term care and assisted living facilities, a home care agency, ambulatory care sites, ambulance services, and other related health services and affiliations throughout Monmouth and Ocean counties in New Jersey.

https://www.sciencedaily.com/releases/2003/08/030821072622.htm

Mouse Model Links Alcohol Intake to Marijuana-like Brain Compounds

January 21, 2003

Science Daily/NIH/National Institute On Alcohol Abuse And Alcoholism

Brain molecules similar to the active compound in marijuana help to regulate alcohol consumption, according to new reports by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, and a separate NIAAA-supported group at several New York state research institutions.

In studies conducted with a strain of mice known to have a high preference for alcohol, the scientists found greatly reduced alcohol intake in mice specially bred to lack CB1, the brain receptor for innate marijuana-like substances known as endocannabinoids. The effect was age dependent, the Bethesda group found. The New York scientists showed that the endocannabinoid system activates a brain region known as the nucleus accumbens, which plays a major role in mediating the rewarding effects of alcohol. Both groups had shown that alcohol intake among normal mice of the same alcohol-preferring strain could be reduced by treating the animals with a drug that blocks CB1 receptors in the brain.

The new reports appear in the early online versions of the Proceedings of the National Academy of Sciences, Volume 20, Number 3, at www.pnas.org and the Journal of Neurochemistry, Volume 24, Number 4, at www.blackwell-synergy.com/servlet/useragent?func=showIssues&code=jnc in the week beginning January 20, 2003 (specific dates to be determined).

"These are important findings," notes NIAAA Director Ting-Kai Li, M.D. "Implicating yet another neurochemical mechanism in alcohol consumption opens another potential avenue for the development of new pharmacologic agents to prevent and treat alcohol problems."

The brain's multiple communication pathways employ a wide variety of signaling molecules known as neurotransmitters to relay messages from one brain cell to another. Researchers have found that alcohol affects numerous neurotransmitters and that a variety of brain pathways are involved in alcohol abuse and dependence. Determining precisely how alcohol interacts with brain cells and affects brain chemistry is an ongoing focus of research. Knowledge gained through this research helps scientists develop drugs to diminish the desire to consume alcohol and to counteract alcohol's effects.

Since their discovery in the early 1990's, endocannabinoids and endocannabinoid receptors have been studied intensely by alcohol and drug abuse researchers. Recent animal studies have suggested that the so-called "endocannabinoid system" is involved in some of the pharmacologic effects of alcohol and in drinking behavior.

In one of the current studies, researchers led by George Kunos, M.D., Ph.D., Scientific Director of NIAAA's Division of Intramural Biological and Clinical Research, found that, among the normal, alcohol-preferring mice–that is, those with intact CB1 receptors–the animals' appetite for both alcohol and food decreased with age. This occurred even though levels of endocannabinoids and the density of CB1 receptors were found to be similar in the brains of young and old mice.

"Although unexpected," says Dr. Kunos, "the observed age-dependent decline in alcohol preference in mice parallels observations in humans, in that only some teenage binge drinkers become alcoholics as adults, and that the onset of alcoholism declines with age."

The researchers found a possible explanation for this phenomenon by comparing the efficiency of the signal sent by the CB1 receptors in different regions of the brain in young and old mice. In old mice, they found diminished CB1 signaling in an area known as the limbic forebrain. The part of the limbic forebrain known as the nucleus accumbens plays a major role in mediating the rewarding properties of alcohol and cannabinoids and also is thought to help regulate appetite. The nucleus accumbens exerts its effects through the release of the neurotransmitter dopamine. Alcohol ingestion typically elicits a robust release of dopamine from the nucleus accumbens.

The second report by NIAAA-supported scientists led by Basalingappa L. Hungund, Ph.D., of the New York State Psychiatric Institute and Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, complements the findings of the Kunos research team. Dr. Hungund and colleagues found that, in addition to showing a dramatic reduction in alcohol intake, alcohol-preferring mice that lack CB1 receptors release no dopamine from the nucleus accumbens after they drink alcohol. In mice with intact CB1 receptors, the researchers were able to abolish alcohol-induced release of dopamine from the nucleus accumbens by treating the animals with a drug that blocks CB1 receptors.

"Our results," says coauthor Balapal Basavarajappa, Ph.D., "clearly suggest that the CB1 receptor system is involved in ethanol-induced dopamine release in the nucleus accumbens and indicate that activation of the limbic dopamine system is required for the reinforcing effects of alcohol. They further suggest an interaction between the cannabinoidergic and dopaminergic systems in the reinforcing properties of drugs of abuse, including alcohol."

"Taken together," adds Dr. Kunos, "these findings provide unequivocal evidence for the role of endocannabinoids and CB1 in alcohol drinking behavior in rodents, and suggest that the CB1 receptor may be a promising pharmacotherapy target."

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA disseminates research findings to scientists, practitioners, policy makers, and the general public.

https://www.sciencedaily.com/releases/2003/01/030121080758.htm

Marijuana's Distant Relative May Be The Next Prozac; Chemical Reduces Anxiety Using Novel Nerve System In Body

December 2, 2002

University of California - Irvine

Man-made chemicals that are distant relatives of marijuana may eventually become new drugs to combat anxiety and depression, according to a UC Irvine College of Medicine study. The study is the first to show how anxiety is controlled by the body's anandamide system, a network of natural compounds known for their roles in governing pain, mood and other psychological functions.

While marijuana relieves anxiety by working on the same system, laboratory rats given the new drugs don't seem to suffer the side effects produced by THC, marijuana's active ingredient. The study appears on Nature Medicine's Web site and will be published in the January 2003 issue.

After designing and testing a number of different chemicals, pharmacology professor Daniele Piomelli and his team found two, called URB532 and URB597, which relieved anxiety and worked in ways far gentler than THC.

"THC reduces anxiety by binding directly to receptors in the brain and resulting in its familiar 'high' sensation," Piomelli said. "This reaction is too strong, creating marijuana's side effects."

URB532 and URB597, on the other hand, inhibit the activity of an enzyme that breaks apart natural anandamide, leaving more of the neurotransmitter to help reduce anxiety and depression. This is similar to the way Prozac works on serotonin, another natural anti-depressant neurotransmitter. With this gentler biochemical approach, URB532 and URB597 were able to keep brain anandamide levels high for many hours after a single dose without producing visible side effects.

"While the study's results are promising, the road from laboratory discovery to available medication is years long, often winding, and definitely expensive," Piomelli said. "In fact, most drugs never make it beyond the discovery stage, for a number of scientific and commercial reasons. But nearly all drugs on the market today saw their start at the laboratory discovery phase."

https://www.sciencedaily.com/releases/2002/12/021202071928.htm

How Do You Solve Relief -- Structure Of Pain-Modulating Enzyme Described By Scripps Scientists

Science Daily/November 29, 2002

The Scripps Research Institute

A group of researchers from The Scripps Research Institute (TSRI) have solved the structure of an enzyme that modulates central nervous system (CNS) functions such as pain perception, cognition, feeding, sleep, and locomotor activity.

The enzyme, described in the latest issue of the journal Science, is called fatty acid amide hydrolase (FAAH), and it breaks down certain fatty signaling molecules that reside in the lipid membranes of CNS cells. The TSRI group reports that FAAH modulates the action of these fatty signaling molecules through an unusual mechanism of action whereby it scoops them out of the cell membranes and chews them up.

"I envision that if someone could make a specific inhibitor to FAAH, you could, in principal, get pain relief without any of the side effects," says Benjamin Cravatt, one of the paper’s lead authors and an investigator in TSRI's Department of Cell Biology, Department of Chemistry, and The Skaggs Institute for Chemical Biology.

"As soon as we had the view of the active site, we knew FAAH could be used to make lead clinical candidates," adds Raymond Stevens, who is a professor in the Department of Molecular Biology and Chemistry at TSRI and the other lead author on the paper. "The deep pocket with well-defined cavities provides the guidance to take the currently available tight binding inhibitors and improve on their specificity and pharmakokinetic properties."

Pain Management and FAAH

Easing pain is practically synonymous with practicing medicine, and since before the days of Hippocrates, doctors have sought the best ways of doing this--looking for compounds that not only ease pain, but do so as fast, effectively, and lastingly as possible--and without any unwanted side effects.

Every analgesic, from opiates to hypnotism to electroshocks to balms, have side effects, and therein lies the rub: whether relieving the pain or the side effects is more pressing.

One compound that has been hotly debated in the last 10 years is delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana. The reason THC works is that it mimics the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to "CB-1" receptors on cells on the rostral ventromedial medulla, a pain-modulating center of the brain, decreasing sensitivity to pain.

Unfortunately, the receptors that THC bind to are also widely expressed in other parts of the brain, such as in the memory and information-processing centers of the hippocampus. Binding to nerve cells of the hippocampus and other cells elsewhere in the body, THC creates a range of side effects as it activates CB-1 mediated signaling--including distorted perception, difficulty in problem-solving, loss of coordination, and increased heart rate and blood pressure, anxiety, and panic attacks.

The challenge posed by THC and other cannabinoids is to find a way to use them to produce effective, long-lasting relief from pain without the deleterious side effects. Now Cravatt and Stevens think they know just how to do that.

The solution, as they see it, is to increase the efficacy of the natural, endogenous cannabinoids ("endocannabinoids") the body produces to modulate pain sensations.

"When you feel pain, you release endocannabinoids [which provide some natural pain relief]," says Cravatt. "Then the amplitude and duration of their activity are regulated by how fast they are broken down."

In particular, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." When the body senses pain, anandamide binds to CB-1 and nullifies pain by blocking the signaling. However, this effect is weak and short-lived as FAAH quickly metabolizes the anandamide--the compound has a half-life of only a few minutes in vivo.

In some ways, THC is superior to anandamide as a pain reliever because it is not as readily metabolized by FAAH. But THC goes on to suppress cannabinoid receptor activity all over the body. This, coupled with the fact that it is a controlled substance, makes THC an unattractive target for developing therapeutics.

FAAH is much more attractive target for pain therapy because by inhibiting FAAH, you would increase the longevity of anandamide molecules--preventing their breakdown and allowing them to continue providing some natural pain relief.

The structure that Cravatt, Stevens, and their TSRI colleagues solved should form a template for designing specific inhibitors that control the action of FAAH when the body is sensing pain and releasing anandamide.

The research article, "Structural Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling" is authored by Michael H. Bracey, Michael A. Hanson, Kim R. Masuda, Raymond C. Stevens, and Benjamin F. Cravatt, and appears in the November 29, 2002 issue of the journal Science.

The research was funded by the National Institute on Drug Abuse, the Searle Scholars Program, The Skaggs Institute for Chemical Biology, a National Research Service Award, and a Jabinson graduate fellowship.

https://www.sciencedaily.com/releases/2002/11/021127072047.htm

Smoking Pot Alters More Than Mood — Human Immune System Affected

August 28, 2002

Science Daily/University Of South Florida Health Sciences Center

Marijuana may alter immune function in people -- but the jury is still out on whether it hurts or helps the body's ability to fight infection or other diseases, report researchers at the University of South Florida College of Medicine and the UCLA School of Medicine in Los Angeles. "The bottom line is you cannot routinely smoke marijuana without it affecting your immune system," said Thomas Klein, PhD, professor of medical microbiology and immunology at USF. "However, because of the complexity of the immune system, we can't say yet whether the effect we've observed in humans is good or bad."

A study by USF and UCLA is the first to show that healthy humans who smoke marijuana appear to alter the expression of marijuana receptors, or molecules, on immune cells in their blood. The findings were reported in the June issue of the Journal of Neuroimmunology.

Pot's influence on the immune system continues to be hotly debated. While more human studies are needed, overwhelming evidence from animal studies indicates that marijuana and its psychoactive compounds, known as cannabinoids, suppress immune function and inflammation.

"This suggests marijuana or cannabinoids might benefit someone with chronic inflammatory disease, but not someone who has a chronic infectious disease such as HIV infection," said Dr. Klein, lead investigator of the study.

The USF/UCLA group is one of few in the world conducting studies to define the role of cannabinoid receptors in regulating immunity in both drug abusers and nonusers.

If the results in animals hold true in humans, their work might lead to the development of safe and effective cannabinoid drugs for certain diseases, Dr. Klein said. "If the cannabinoids in marijuana are effective immune suppressors, this property might be harnessed to treat patients with overly aggressive immune responses or inflammatory diseases like multiple sclerosis and rheumatoid arthritis."

Receptors that react to delta-9 tetrahydrocannabinol or THC, the compound in marijuana that produces a high, have been found in tissues throughout the body and in the brain. A naturally circulating THC-like substance called anandamide also binds to and activates these marijuana, or cannabinoid, receptors, indicating that the body's own cannabinoid system plays a physiological role in normal immunity as well as defining moods, Dr. Klein said.

In the USF/UCLA study, researchers analyzed blood samples from 56 healthy volunteers -- including 10 chronic marijuana smokers, ages 22 to 46, participating in lung and immune function studies at UCLA. The marijuana smokers denied use of any other drugs, and the nonsmokers denied all illegal drug use. Because no accurate way yet exists to directly study the expression of cannabinoid receptors on immune cells, the researchers looked at the genetic material (messenger RNA) that is the direct predecessor, or precursor, of the receptor.

They found that the baseline genetic expression of precursor RNA was consistent across all age, gender and ethnic groups. But, the peripheral blood cells from the marijuana users expressed significantly higher levels of cannabinoid receptor messenger RNA than blood cells from non-users. The levels increased regardless of the amount of marijuana use, although all users in the study had a history of smoking pot several times or more a week.

https://www.sciencedaily.com/releases/2002/08/020828062229.htm

An Internal Cannabinoid-Signaling System Regulates Human Sperm, Fertilization Potential; Abusing Marijuana May Overload System, Inhibit Fertility

December 12, 2000

Science Daily/University at Buffalo

SAN FRANCISCO -- A cellular signaling system that responds to THC, the active substance in marijuana, as well as to anandamide, a cannabinoid-like molecule normally produced in the body, may regulate sperm functions required for fertilization in humans, a study headed by scientists from the University at Buffalo has found.

In addition, the findings suggest that men and women who abuse marijuana could jeopardize fertility by overloading this natural cannabinoid signaling system that regulates sperm structure, vigor and fertility.

Herbert Schuel, Ph.D., UB professor of anatomy and cell biology and lead author on the study, presented results of the research here today (Dec. 12, 2000) at the annual meeting of the American Society for Cell Biology.

Collaborating on the research were Lani Burkman, Ph.D., and Jack Lippes, M.D., of UB, and colleagues from the University of Connecticut, Eastern Virginia Medical School and University of California at Irvine.

The study presents the first evidence that anandamide exists in human seminal plasma, mid-cycle oviductal fluid and follicular fluid, and can regulate directly the human sperm's ability to fertilize an egg.

"These findings suggest that defects in the cannabinoid receptor-signaling system could account for certain types of infertility," Schuel said. "A better understanding of these mechanisms might lead to the development of novel drugs useful in reproductive medicine. For heavy marijuana users, the study results raise the possibility they are jeopardizing fertility by overloading this signaling system."

A receptor for cannabinoids was found in the human brain in the late 1980s. This finding suggested that the body must produce its own chemical version of THC to activate these receptors, and a substance called anandamide was found to be that chemical. Schuel and collaborators were the first to report cannabinoid receptors in sperm, using sea urchins as a model, and that anandamide also activated those receptors.

The regulatory mechanisms that prepare sperm to fertilize eggs within human reproductive tracts remain, for the most part, a scientific mystery. Human sperm are bathed in male reproductive-tract secretions when they are ejaculated into the female's vagina, and are not immediately capable of fertilizing eggs. However, once removed from the seminal plasma and exposed for several hours to secretions within the female reproductive tract, sperm become "capacitated" and can fertilize eggs.

Capacitated sperm exhibit a characteristic pattern of vigorous swimming called hyperactivated motility. When they bind to a specific protein in the egg's surface coat, sperm can be stimulated to secrete digestive enzymes that enable them to penetrate the egg coat during fertilization, a secretory process called the acrosome reaction.

"We know that sperm capacitation and fertilizing potential are tightly regulated within the female reproductive tract," Schuel said. "We also know that the cannabinoid receptor found in the human brain is expressed in the human testis, and that anandamide is produced in the testis and uterus of mammals. Within the uterus, anandamide regulates early development of the fertilized egg, and determines where the embryo will implant to initiate pregnancy. Cannabinoids also affect this process," he noted.

Now, Schuel and collaborators have the first evidence that anandamide can directly regulate human sperm's ability to fertilize an egg. Using a synthetic equivalent of natural anandamide called AM-356 and THC, the substance responsible for the "high" produced by marijuana smoke, the researchers showed that both chemicals regulate in vitro capacitation and fertilizing potential of human sperm in three ways:

• AM-356 produces opposite effects on hyperactivated sperm swimming, depending on the amount. Too much (a concentration of 2.5 nano Moles) inhibits hyperactivated motility, while at a 10-fold lower concentration, it stimulates hyperactivated swimming. Because anandamide is present in human-reproductive fluids and human sperm contain cannabinoid receptors, it is possible that localized differences in anandamide concentration may regulate sperm swimming patterns within the female-reproductive tract.

• Both AM-356 and THC inhibit structural changes over the acrosome. The structural integrity of the acrosome during capacitation is known to be a critical factor in sperm's ability to fertilize eggs.

• AM-356 significantly inhibits sperm binding to the zona, or egg coat. This observation provides the first evidence that anandamide (which AM-356 mimics) can regulate directly sperm fertilizing potential in humans.

"Defects in endocannabinoid signaling may be responsible for certain currently unexplained types of infertility," Schuel said. "Conversely, endocannabinoid signaling in human-reproductive tracts may provide potential targets for the future development of new drugs for use in reproductive medicine.

"In addition, the increased load of cannabinoids in people who abuse marijuana could flood natural endocannabinoid-signal systems in reproductive organs and adversely impact fertility," he said. "This possibility may explain observations made over the past 30-40 years that marijuana smoke drastically reduces sperm production in males."

Alexandros Makriyannis, Ph.D., and Robert Picone of the University of Connecticut; Mary C. Mahony, Ph.D., of Eastern Virginia Medical School, and Andrea Giuffrida, Ph.D., and Daniele Piomelli, Ph.D., of the University of California at Irvine, collaborated on this research.

https://www.sciencedaily.com/releases/2000/12/001212065509.htm

Center for Medicinal Cannabis Research Established at University of California

September 5, 2000

Science Daily/University of California, San Diego

A statewide, state-funded initiative to rigorously study the safety and efficacy of medicinal cannabis to treat certain diseases is being established at the University of California. The Center for Medicinal Cannabis Research (CMCR), headquartered at UCSD, will be a collaboration between UCSD and UCSF, two of the UC system's leading biomedical research campuses.

The CMCR will administer $3 million in first-year funding to support and coordinate scientific research at universities and research centers throughout California, assessing the use of cannabis as an alternative for treating specific medical conditions.

Funding of the CMCR is the result of SB847 (Vasconcellos), passed by the State Legislature and signed into law by Governor Gray Davis in October 1999. The legislation calls for a three-year program overseeing objective, high quality medical research that will "...enhance understanding of the efficacy and adverse effects of marijuana as a pharmacological agent," stressing that the project "should not be construed as encouraging or sanctioning the social or recreational use of marijuana."

Data from these studies will be used to develop guidelines for appropriate pharmaceutical use of medicinal cannabis. California voters approved such use in 1996, but exactly what role the substance should play in patient care, and how it should be administered as a pharmaceutical agent, is ambiguous because of the lack of definitive research, said Igor Grant, M.D., professor of psychiatry at UCSD and director of the CMCR. Grant is also executive vice chair of the department of psychiatry and director of UCSD's HIV Neurobehavioral Research Center.

Co-directors of the CMCR are Donald Abrams, M.D., professor of medicine at UCSF; and J. Hampton Atkinson, M.D., professor of psychiatry, and Andrew Mattison, Ph.D., associate clinical professor of psychiatry and family and preventive medicine, both of UCSD.

The CMCR plans to solicit applications this fall, to be reviewed by an independent Scientific Review Board of national experts. Funding will be awarded to support research focusing on diseases and conditions as defined in a report by the National Academy of Sciences/Institute of Medicine, and by a National Institutes of Health expert panel, according to Grant.

"The politics of medical marijuana are behind us as we begin the important work of researching the safety and efficacy of medical marijuana," said Senator John Vasconcellos (D-Santa Clara). "The National Institutes of Health and the Institute of Medicine of the National Academy of Sciences have independently called for further studies. Now, because of the vision of the Legislature, the Governor and the University of California, the issue of medical marijuana is properly in the hands of physicians and researchers."

The symptoms and conditions for which cannabis might be a useful treatment option include:

* Severe appetite suppression, weight loss and cachexia due to HIV infection and other medical conditions;

* Chronic pain resulting from certain types of injuries and diseases such as AIDS;

* Nausea associated with cancer and its treatment; and

* Severe muscle spasticity caused by diseases such as multiple sclerosis.

"This is an important opportunity to continue to evaluate the therapeutic potential of cannabis," said Abrams, a UCSF oncologist and AIDS expert who has just completed the first clinical trial of inhaled marijuana in patients with HIV infection. "The findings from our initial safety trial suggest that studies of the possible effectiveness of marijuana should be launched now. This state funding will allow that to happen quickly so that we may finally get some needed answers."

Support will be awarded on a competitive basis to those studies determined to be of the highest scientific quality, with studies anticipated to begin as early as January 2001. Most of the studies are anticipated to be patient trials, said Grant, though there is also interest in funding some basic research that has direct relevance to understanding safety, efficacy, and mechanisms of action of cannabis chemicals for the conditions in question.

The cannabis to be used in the studies will be obtained from the National Institute on Drug Abuse in accordance with procedures developed by the Public Health Service. Studies may also utilize alternative, non-smoked preparations of cannabis, as these become available through pharmaceutical research and are approved for clinical trials by the appropriate regulatory bodies.

In addition to the Scientific Review Board that will provide independent review of research proposals, the CMCR leadership is appointing an Advisory Board to provide input on how the CMCR can meet its objectives in the most scientifically sound, responsible and timely manner.

https://www.sciencedaily.com/releases/2000/09/000904122146.htm