Marijuana cuts lung cancer tumor growth in half

April 17, 2007

Science Daily/American Association for Cancer Research

The active ingredient in marijuana cuts tumor growth in common lung cancer in half and significantly reduces the ability of the cancer to spread, say researchers at Harvard University who tested the chemical in both lab and mouse studies.

They say this is the first set of experiments to show that the compound, Delta-tetrahydrocannabinol (THC), inhibits EGF-induced growth and migration in epidermal growth factor receptor (EGFR) expressing non-small cell lung cancer cell lines. Lung cancers that over-express EGFR are usually highly aggressive and resistant to chemotherapy.

THC that targets cannabinoid receptors CB1 and CB2 is similar in function to endocannabinoids, which are cannabinoids that are naturally produced in the body and activate these receptors. The researchers suggest that THC or other designer agents that activate these receptors might be used in a targeted fashion to treat lung cancer.

"The beauty of this study is that we are showing that a substance of abuse, if used prudently, may offer a new road to therapy against lung cancer," said Anju Preet, Ph.D., a researcher in the Division of Experimental Medicine.

Acting through cannabinoid receptors CB1 and CB2, endocannabinoids (as well as THC) are thought to play a role in variety of biological functions, including pain and anxiety control, and inflammation. Although a medical derivative of THC, known as Marinol, has been approved for use as an appetite stimulant for cancer patients, and a small number of U.S. states allow use of medical marijuana to treat the same side effect, few studies have shown that THC might have anti-tumor activity, Preet says. The only clinical trial testing THC as a treatment against cancer growth was a recently completed British pilot study in human glioblastoma.

In the present study, the researchers first demonstrated that two different lung cancer cell lines as well as patient lung tumor samples express CB1 and CB2, and that non-toxic doses of THC inhibited growth and spread in the cell lines. "When the cells are pretreated with THC, they have less EGFR stimulated invasion as measured by various in-vitro assays," Preet said.

Then, for three weeks, researchers injected standard doses of THC into mice that had been implanted with human lung cancer cells, and found that tumors were reduced in size and weight by about 50 percent in treated animals compared to a control group. There was also about a 60 percent reduction in cancer lesions on the lungs in these mice as well as a significant reduction in protein markers associated with cancer progression, Preet says.

Although the researchers do not know why THC inhibits tumor growth, they say the substance could be activating molecules that arrest the cell cycle. They speculate that THC may also interfere with angiogenesis and vascularization, which promotes cancer growth.

Preet says much work is needed to clarify the pathway by which THC functions, and cautions that some animal studies have shown that THC can stimulate some cancers. "THC offers some promise, but we have a long way to go before we know what its potential is," she said.

The research was presented at the 2007 meeting of the American Association for Cancer Research, held Apr 14-18, 2007 in Los Angeles, CA.

https://www.sciencedaily.com/releases/2007/04/070417193338.htm

Cannabis-related schizophrenia set to rise

March 26, 2007

Science Daily/Bristol University

If cannabis causes schizophrenia - and that remains in question - then by 2010 up to 25 per cent of new cases of schizophrenia in the UK may be due to cannabis, according to a new study by Dr Matthew Hickman of the University of Bristol and colleagues, published in Addiction journal.

Substantial increases in both prevalence and incidence of the disease are forecast by the end of the decade, with increases in schizophrenia starting earlier among young men in particular.

The research study matches historic trends in cannabis use and exposure from a national population survey against estimates of new occurrences of schizophrenia in three English cities (Nottingham, Bristol and the London Borough of Southwark). 

The researchers assess what might happen to schizophrenia cases if we assume a causal link between cannabis use and onset of psychotic symptoms, an association widely recognised by some psychiatrists and researchers and considered recently by the Advisory Council on the Misuse of Drugs.

Exposure to cannabis grew fourfold over the thirty years to 2002, and its use among under-18s by 18-fold, say the researchers. If cannabis use causes schizophrenia, these increases in its use would lead to increases in overall schizophrenia incidence and prevalence of 29 per cent and 12 per cent respectively, between 1990 and 2010.  (Incidence is defined as the frequency of new occurrences; and prevalence is the percentage of the population affected by the disease.)

Model projections suggest that if the association is confined to heavy cannabis users only, then approximately 10 per cent of schizophrenia cases may be due to cannabis by 2010.  However, assuming an association between onset of the disease and both light and heavy users, then approximately one-quarter of new cases could be due to cannabis. 

John Macleod, co-author and academic GP, said: “We need to remember that our study does not address the question whether cannabis causes schizophrenia: this remains unclear.”

Matthew Hickman, lead author of the study, added: “The challenge now is to improve our data on schizophrenia occurrence to see whether the projected increase occurs.  This will tell us more about how important cannabis is as a cause of schizophrenia.”

Reference: Matthew Hickman, Peter Vickerman, John Macleod, James Kirkbride, Peter B. Jones.  Cannabis and schizophrenia: model projections of the impact of the rise in cannabis use on historical and future trends in schizophrenia in England and Wales (2007).  Addiction 102 (4), 597-606.

https://www.sciencedaily.com/releases/2007/03/070324132832.htm

Smoked Cannabis Reduces Foot Pain Associated with HIV in Placebo Trial

February 13, 2007

Science Daily/University of California - San Francisco

In a randomized placebo-controlled trial, patients smoking cannabis experienced a 34 percent reduction in intense foot pain associated with HIV--twice the rate experienced by patients who smoked placebo.

"This placebo-controlled clinical trial showed that people with HIV who smoked cannabis had substantially greater pain reduction than those who did not smoke the cannabis," said study lead author Donald I. Abrams, MD, UCSF professor of clinical medicine. "These results provide evidence that there is a measurable medical benefit to smoking cannabis for these patients."

The study, published in the February 13 issue of the journal "Neurology," looked at 50 HIV patients with HIV-associated sensory neuropathy, a painful and often debilitating condition that is the most common peripheral nerve disorder that occurs as a complication of HIV infection. Occurring usually in the feet and characterized at times by tingling, numbness, the sensation of pins and needles, burning, and sharp intense pain, severe peripheral neuropathy can make walking or standing difficult.

Patients participating in the study were randomized into two equal groups--one assigned to smoke cannabis and the other assigned to smoke identical placebo cigarettes with the cannabinoids extracted. The patients smoked the study cigarettes three times a day for five days under supervision as inpatients in the General Clinical Research Center at San Francisco General Hospital Medical Center.

"Even though antiretroviral treatments have reduced the prevalence and severity of many HIV-related neurological complications, neuropathy continues to affect up to one of every three patients," said co-author Cheryl A. Jay, MD, UCSF professor of clinical neurology. "There are no FDA-approved treatments for HIV-related neuropathy. This study suggests new avenues to manage neuropathic pain in this setting."

The study also incorporated a pain model developed at UCSF that provided a standardized reference point. This model allowed researchers to compare relief of chronic HIV-associated neuropathic pain simultaneously with patient response to pain and skin sensitivity induced by heating and capsaicin application.

"The beauty of this study is the use of the pain model as a neutral and physiological anchor for pain measurement. Patients' eyes were averted during the measurements and were uninfluenced by expectations. Smoked cannabis was shown to work on the pain system by shrinking the area of painfully sensitive skin created by the model. The response was comparable to strong pain relievers we have studied, such as morphine," said co-author Karin L. Petersen, MD, UCSF assistant adjunct professor of neurology.

This study is the first to be completed of several clinical trials of medicinal cannabis being conducted under the auspices of the University of California's Center for Medicinal Cannabis Research.

"It has been many years since clinical trials with cannabis have been conducted in the United States," said Igor Grant, MD, professor of psychiatry at the UC San Diego School of Medicine and director of the CMCR. "As a result there has been insufficient light shed on the possible therapeutic value of cannabis. The results of this first study indicate that cannabis may indeed be useful in the amelioration of a very distressing, disabling, and difficult to treat complication of HIV. We look forward to the results of several additional CMCR studies nearing completion to continue clarifying cannabis' possible role as a therapeutic agent."

Co-authors include Starley B. Shade, MPH; Hector Vizoso, RN; and Mary Ellen Kelly, MPH, from the UCSF Positive Health Program at San Francisco General Hospital Medical Center, and Michael C. Rowbotham, MD; Haatem Reda, BA; and Scott Press, BS, from the UCSF Pain Clinical Research Center.

The General Clinical Research Center at SFGH is funded by NIH.

https://www.sciencedaily.com/releases/2007/02/070212185335.htm

Enhancing Activity of Marijuana-like Chemicals in Brain Helps Treat Parkinson's Symptoms in Mice

February 8, 2007

Science Daily/Stanford University Medical Center

Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson's disease. In a study to be published in the Feb. 8 issue of Nature, researchers from the Stanford University School of Medicine report that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson's.

"This study points to a potentially new kind of therapy for Parkinson's disease," said senior author Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "Of course, it is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease."

Malenka and postdoctoral scholar Anatol Kreitzer, PhD, the study's lead author, combined a drug already used to treat Parkinson's disease with an experimental compound that can boost the level of endocannabinoids in the brain. When they used the combination in mice with a condition like Parkinson's, the mice went from being frozen in place to moving around freely in 15 minutes. "They were basically normal," Kreitzer said.

But Kreitzer and Malenka cautioned that their findings don't mean smoking marijuana could be therapeutic for Parkinson's disease.

"It turns out the receptors for cannabinoids are all over the brain, but they are not always activated by the naturally occurring endocannabinoids," said Malenka. The treatment used on the mice involves enhancing the activity of the chemicals where they occur naturally in the brain. "That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

The researchers began their study by focusing on a region of the brain known as the striatum. They were interested in that region because it has been implicated in a range of brain disorders, including Parkinson's, depression, obsessive-compulsive disorder and addiction.

The activity of neurons in the striatum relies on the chemical dopamine. A shortage of dopamine in the striatum can lead to Parkinson's disease, in which a person loses the ability to execute smooth motions, progressing to muscle rigidity, tremors and sometimes complete loss of movement. The condition affects 1.5 million Americans, according to the National Parkinson Foundation.

"It turns out that the striatum is much more complicated than imagined," said Malenka. The striatum consists of several different cell types that are virtually indistinguishable under the microscope. To uncover the individual contributions of the cell types, Malenka and Kreitzer used genetically modified mice in which the various cell types were labeled with a fluorescent protein that glows vivid green under a microscope. Having an unequivocal way to identify the cells allowed them to tease apart the functions of the different cell types.

Malenka's lab has long studied how the communication between different neurons is modified by experience and disease. In their examination of two types of mouse striatum cells, Kreitzer and Malenka found that a particular form of adaptation occurs in one cell type but not in the other.

Malenka said this discovery was exciting because no one had determined whether there were functional differences between the various cell types. Their study indicated that the two types of cells formed complementary circuits in the brain.

One of the circuits is thought to be involved in activating motion, while the other is thought to be involved in restraining unwanted movement. "These two circuits are critically involved in a push-pull to select the appropriate movement to perform and to inhibit the other," said Kreitzer.

Dopamine appears to modulate these two circuits in opposite ways. When dopamine is depleted, it is thought that the pathway responsible for inhibiting movement becomes overly activated - leading to the difficulty of initiating motion, the hallmark of Parkinson's disease.

Current treatment for Parkinson's includes drugs that stimulate or mimic dopamine. It turns out that the neurons Kreitzer identified as inhibiting motion had a type of dopamine receptor on them that the other cells didn't. The researchers tested a drug called quinpirole, which mimics dopamine, in mice with a condition similar to human Parkinson's disease, resulting in a small improvement in the mice.

"That was sort of expected," said Malenka. "The cool new finding came when we thought to use drugs that boost the activity of endocannabinoids." Based on prior knowledge of endocannabinoids and dopamine, they speculated that the two chemicals were working in concert to keep the inhibitory pathway in check.

When they added a drug that slows the enzymatic breakdown of endocannabinoids in the brain - URB597, being developed by Kadmus Pharmaceuticals in Irvine, Calif. - the results were striking.

"The dopamine drug alone did a little bit but it wasn't great, and the drug that targeted the enzyme that degrades endocannabinoids basically did nothing alone," Kreitzer said. "But when we gave the two together, the animals really improved dramatically."

This work was supported by a Ruth L. Kirchenstein Fellowship, the National Institutes of Health and the National Parkinson Foundation. Neither researcher has financial ties to Kadmus Pharmaceuticals.

https://www.sciencedaily.com/releases/2007/02/070207171915.htm

Enzyme Builds Neurotransmitters Via Newly Discovered Pathway

September 22, 2006

Science Daily/Scripps Research Institute

Scientists at the Scripps Research Institute have uncovered a previously unknown function of an enzyme that appears to play a primary role in the biosynthesis of a large class of lipids that help modulate diverse physiological processes, including anxiety, inflammation, learning and memory and appetite.

The study, which was directed by Scripps Research Professor Benjamin Cravatt, Ph.D., is being published in the September 8 issue of The Journal of Biological Chemistry.

The new study describes a pathway-different than the one previously suggested-for the biosynthesis of neurotransmitter lipids, N-acyl ethanolamines (NAEs), which include the endogenous cannabinoid ("endocannabinoid") anandamide. The high activity of the enzyme a/b hydrolase4 (Abh4) in areas such as the central nervous system suggests that the pathway makes a "potentially major contribution" to endocannabinoid signaling.

Endocannabinoids are naturally produced substances similar to the active ingredient D9-tetrahydrocannabinol (THC) in marijuana. Cannabinoid receptors were first discovered in 1988; the first endocannabinoid, anandamide, which shares some of the pharmacologic properties of THC, was identified in 1992.

Other research has shown that the endogenous cannabinoid system helps control food intake, among other critical processes, by acting on cannabinoid receptors in the central nervous system. The system drives consumption of fat and calorie-rich foods and the amount of fat stored or expended and plays a significant role in energy homeostasis.

"At least one cannabinoid receptor antagonist is on the verge of approval for the treatment of obesity-metabolic disorders," said Cravatt. "Enzymes involved in endocannabinoid biosynthesis, such as the one highlighted in our study, can be viewed as complementary drug targets. One potential advantage of this approach is that it may prove more selective than a receptor antagonist. By inhibiting enzymes such as Abh4, we may be able to disrupt the activity of a single class of endocannabinoids, rather than all of them."

In the new study, the researchers provide biochemical evidence of an alternative pathway for NAE biosynthesis in vivo and demonstrate that these new routes are especially important for the creation of a number of NAEs, including anandamide. The researchers also isolated and identified the enzyme Abh4 by combining traditional protein purification and functional proteomic technologies, concluding that Abh4 "displayed multiple properties" that would be expected of an enzyme involved in NAE biosynthesis.

However, the authors of the study noted, the unique contribution that this Abh4-mediated route makes to the production of NAEs in vivo is yet to be determined and will require "the generation of genetic or pharmacological tools that selectively [interrupt] this pathway."

"The continued pursuit of additional enzymes involved in NAE biosynthesis should further enrich our understanding of the complex metabolic network that supports the endocannabinoid/NAE system in vivo," Cravatt said. "From a therapeutic perspective, any of these enzymes could represent an attractive drug target for a range of human disorders in which disruption of endocannabinoid signaling by cannabinoid receptor antagonists has proven beneficial."

Gabriel Simon of Scripps Research was the other author of the study, titled "Endocannabinoid biosynthesis proceeding through Glycerophospho-N-Acyl ethanolamine and a role for a/b hydrolase 4 in this pathway."

The research was supported by the National Institutes of Health, the Skaggs Institute for Chemical Biology, and the Helen L. Dorris Institute for the Study of Neurological and Psychiatric Disorders of Children and Adolescents.

https://www.sciencedaily.com/releases/2006/09/060915203730.htm

Brain's Cannabinoid System 'Mellows' Seizures

August 17, 2006

Science Daily/Cell Press

The same brain machinery that responds to the active substance in marijuana provides a central "on-demand" protection against seizures, researchers have found. They said their discoveries suggest that the "endocannabinoid" system might constitute a prime target for drugs against seizures of epilepsy and other neurodegenerative diseases.

The findings were published by Beat Lutz and Giovanni Marsicano, of Max Planck Institute of Psychiatry and Johannes Gutenberg University in Mainz, and colleagues in the August 17, 2006, issue of the journal Neuron, published by Cell Press.

The endocannabinoid system--which includes the receptors, the natural cannabinoid compounds that trigger them, as well as the machinery for regulating the process--was already known to modulate the excitation of neuronal transmission, noted the researchers. However, it had not been established that such modulation might affect neurons in the hippocampus responsible for the "excitotoxicity" that underlies the uncontrolled activity of seizures.

Thus, Lutz, Marsicano, and his colleagues used genetic techniques to pinpoint the role of the endocannabinoid system on these neurons and on seizure activity. They used mice as their animal model and induced seizures in these mice with the chemical kainic acid (KA).

In particular, they wanted to explore the role played by the endocannabinoid system in hippocampal neurons that are responsive to the neurotransmitter glutamine. These neurons are known to play a central role in seizure activity. The endocannabinoid regulatory system is also active in another type of neuron triggered by the neurotransmitter gamma-aminobutyric acid (GABA).

Thus, the researchers conducted experiments in which they genetically knocked out the endocannabinoid receptor CB1 and analyzed the effects on seizure sensitivity. They found that, indeed, when they knocked out CB1 in glutamatergic, but not GABAergic neurons, the chemically induced seizures increased in the mice. In fact, their experiments all but ruled out the role of GABAergic neurons in the seizure-protection function, they concluded.

"Altogether, these results confirm that physiological endocannabinoid-dependent control of GABAergic transmission depends on intact CB1 signaling in GABAergic interneurons and suggest that the endocannabinoid system does not influence GABAergic transmission during the development of KA-induced seizures," they concluded. "Therefore, direct modulation of glutamatergic transmission by CB1 receptors expressed on cortical glutamatergic neurons appears to be the major mechanism of endocannabinoid-mediated protection against KA-induced seizures."

Furthermore, the researchers' experiments established that endocannabinoid receptors were also present in the same glutamatergic neurons in areas of the hippocampus known to be central to seizure generation. The researchers wrote that this finding "represents a novel step in understanding the progression of acute excitotoxic seizures and the development of epileptic states."

And significantly, when the researchers used a targeted virus to knock out the CB1 gene for the endocannabinoid receptor specifically in the glutamatergic neurons of the hippocampus, the mice also showed strong worsening of chemically induced seizures in comparison to mice still expressing CB1.

"Altogether, these observations support a hypothetical scenario in which acute KA-induced excitotoxic seizures would activate the endocannabinoid system in respect to its ability to inhibit only 'harmful' glutamatergic transmission, but not 'protective' GABAergic release," concluded Lutz, Marsicano, and colleagues.

"In conclusion, our study reveals a mechanism through which the endocannabinoid system is able to provide on-demand protection against acute behavioral seizures. CB1 expression on hippocampal glutamatergic circuits accounts for this protection and might represent a suitable target for the treatment of neurological disorders associated with excessive neuronal excitation," they wrote.

https://www.sciencedaily.com/releases/2006/08/060817103710.htm

Brain's receptors sensitive to pot may 'open door' in treating drug dependence, brain disorders

June 7, 2006

Science Daily/Society of Nuclear Medicine

A team of Johns Hopkins researchers developed a new radiotracer—a radioactive substance that can be traced in the body—to visualize and quantify the brain’s cannabinoid receptors by positron emission tomography (PET), opening a door to the development of new medications to treat drug dependence, obesity, depression, schizophrenia, Parkinson’s disease and Tourette syndrome.

Discovery of the [11C]JHU75528 radioligand, a radioactive biochemical substance that is used to study the receptor systems of the brain, “opens an avenue for noninvasive study of central cannabinoid (CB1) receptors in the human and animal brain,” explained Andrew Horti, assistant professor of radiology at Johns Hopkins Medicine, Baltimore, Md. He explained that there is evidence that CB1 receptors play an essential role in many disorders including schizophrenia, depression and motor function disorders. “Quantitative imaging of the central CB1 using PET could provide a great opportunity for the development of cannabinergic medications and for studying the role of CB1 in these disorders,” added the co-author of “PET Imaging of Cerebral Cannabinoid CB1 Receptors with [11C]JHU75528.”

Cannabinoid receptors are proteins on the surface of brain cells; they are most dense in brain regions involved with thinking and memory, attention and control of movement. The effects of tetrahydrocannabinol (THC), the primary psychoactive compound in marijuana, are due to its binding to specific cannabinoid receptors located on the surface of brain cells. “Blocking CB1 receptors presents the possibility of developing new, emerging medications for treatment of obesity and drug dependence including alcoholism, tobacco and marijuana smoking,” said Horti.

The usefulness of in vivo (in the body) radioligands for studying cerebral receptors by PET depends on the image quality, and a good PET radiotracer must display a high level of specific receptor binding and low non-specific binding (binding with other proteins, cell membranes, etc.), said Horti. “If the non-specific binding is too high and specific binding is too low, the PET images become too ‘noisy’ for quantitative measurements,” he noted. “We developed a PET radiotracer with a unique combination of good CB1 binding affinity and relatively low non-specific binding in mice and baboon brains,” he added. “Previously developed PET radioligands for imaging of CB1 receptors were not suitable for quantitative imaging due to the high level of image ‘noise,’” he added.

“Even though PET methodology was developed 30 years ago, its application for studying cerebral receptors is limited due to the lack of suitable radioligands,” said Horti. “Development of [11C]JHU75528 will allow noninvasive research of CB1 receptor,” he added, indicating that Johns Hopkins researchers need to complete various safety studies and obtain Food and Drug Administration approval before [11C]JHU75528 can be used for PET imaging in people.

“This discovery would not have been possible without involvement of many highly qualified researchers, including the teams of Robert Dannals and Dean Wong and support of Richard Wahl, director of the nuclear medicine department,” said Horti.

https://www.sciencedaily.com/releases/2006/06/060607082641.htm

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