Active Component of Marijuana Has Anti-cancer Effects

April 9, 2009

Science Daily/Journal of Clinical Investigation

Guillermo Velasco and colleagues, at Complutense University, Spain, have provided evidence that suggests that cannabinoids such as the main active component of marijuana (THC) have anticancer effects on human brain cancer cells.

In the study, THC was found to induce the death of various human brain cancer cell lines and primary cultured human brain cancer cells by a process known as autophagy.

Consistent with the in vitro data, administration of THC to mice with human tumors decreased tumor growth and induced the tumor cells to undergo autophagy. As analysis of tumors from two patients with recurrent glioblastoma multiforme (a highly aggressive brain tumor) receiving intracranial THC administration showed signs of autophagy, the authors suggest that cannabinoid administration may provide a new approach to targeting human cancers.

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells

https://www.sciencedaily.com/releases/2009/04/090401181217.htm

Discovery of Mechanism that Processes 'THC' Type Brain Compound May Lead to New Medicines for Pain, Addiction

March 31, 2009

Science Daily/Stony Brook University Medical Center

Dale Deutsch, Ph.D., Professor of Biochemistry and Cell Biology at Stony Brook University and colleagues discovered a new molecular mechanism for the processing of endocannabinoids, brain compounds similar to THC, the active ingredient in marijuana, and essential in physiological processes such as pain, appetite, and memory.

Reported online this week in the Proceedings of the National Academy of Sciences (PNAS), the finding could pave the way for new medicines for pain, addiction, appetite control and other disorders.

Dr. Deutsch and colleagues in the Departments of Biochemistry and Cell Biology (Martin Kaczocha) and Neurobiology and Behavior (Sherrye Glaser, Ph.D.) are the first to successfully identify two known fatty acid binding proteins (FABPs) that carry the endocannabinoid anandamide (AEA), a neurotransmitter, from the cell membrane to interior of the cell where it is destroyed. This identification enabled the research team to inhibit FABPs in various laboratory experiments and thereby reduce AEA breakdown inside cells. In their study, “Identification of intracellular carriers for the endocannabinoid anandamide,” the researchers report that they decreased the breakdown of AEA in some instances by approximately 50 percent.

“Inhibiting FABPs could potentially raise the levels of AEA in the brain’s synapses,” says Dr. Deutsch. “Naturally occurring AEA levels have been shown to curb pain without the negative side effects, such as motor coordination problems, from molecules like THC. Therefore, it makes sense to target AEA for therapeutic purposes.”

He emphasizes that their groundbreaking discovery of the role of FABPs in transporting this class of neurotransmitters may prove to be a crucial step in developing novel drug targets for endocannabinoids by way of inhibiting FABPs. In support of the research, The State University of New York (SUNY) Stony Brook Office of Technology Licensing and Industry Relations (OTLIR) has filed U.S. Patent applications comprising the discovery.

The OTLIR manages all intellectual property matters for the SUNY Research Foundation. In actively marketing this unlicensed technology created by Dr. Deutsch, the Stony Brook OTLIR welcomes commercial entities interested in partnering with the University. The licensing agent for the project is Adam DeRosa of the OTLIR.

The breakdown of AEA requires two factors. First, there needs to be a mechanism for transporting AEA to the location where it is inactivated because AEA is a fatty compound and thus unable to move inside the watery cellular environment. Second, the cell must express an enzyme called FAAH, which controls the breakdown and inactivation of AEA. In the laboratory, the researchers coaxed a nonneuronal cell type (COS-7) to express FAAH. These FAAH-expressing COS-7 cells were able to break down AED efficiently, indicating that the intracellular AEA transport mechanism was already present and operation in these cells. The researchers identified these carriers as two separate FABPs.

Dr. Deutsch believes that because a transporter for the AEA class of neurotrasmitters had never been discovered until the Stony Brook findings, continued research may explain many unanswered questions about AEA. Future research may uncover more knowledge about AEA transport, as well as the entire role these neurotransmitters play in pain, inflammation, appetite control, addiction, and perhaps other physiological processes related to many human disorders.

The research was funded by the National Institute on Drug Abuse, part of the National Institutes of Health.

https://www.sciencedaily.com/releases/2009/03/090325190342.htm

Marijuana Use Linked to Increased Risk of Testicular Cancer

February 13, 2009

Science Daily/Fred Hutchinson Cancer Research Center

Frequent and/or long-term marijuana use may significantly increase a man's risk of developing the most aggressive type of testicular cancer, according to a study by researchers at Fred Hutchinson Cancer Research Center. The study results were published online Feb. 9 in the journal Cancer.

The researchers found that being a marijuana smoker at the time of diagnosis was associated with a 70 percent increased risk of testicular cancer. The risk was particularly elevated (about twice that of those who never smoked marijuana) for those who used marijuana at least weekly and/or who had long-term exposure to the substance beginning in adolescence.

The results also suggested that the association with marijuana use might be limited to nonseminoma, a fast-growing testicular malignancy that tends to strike early, between ages 20 and 35, and accounts for about 40 percent of all testicular-cancer cases.

Since the 1950s, the incidence of the two main cellular subtypes of testicular cancer, nonseminoma and seminoma – the more common, slower growing kind that strikes men in their 30s and 40s – has increased by 3 percent to 6 percent per year in the U.S., Canada, Europe, Australia and New Zealand. During the same time period, marijuana use in North America, Europe and Australia has risen accordingly, which is one of several factors that led the researchers to hypothesize a potential association.

"Our study is not the first to suggest that some aspect of a man's lifestyle or environment is a risk factor for testicular cancer, but it is the first that has looked at marijuana use," said author Stephen M. Schwartz, M.P.H., Ph.D., an epidemiologist and member of the Public Health Sciences Division at the Hutchinson Center.

Established risk factors for testicular cancer include a family history of the disease, undescended testes and abnormal testicular development. The disease is thought to begin in the womb, when some fetal germ cells (those that eventually make sperm in adulthood) fail to develop properly and become vulnerable to malignancy. Later, during adolescence and adulthood, it is thought that exposure to male sex hormones coaxes these cells to become cancerous.

"Just as the changing hormonal environment of adolescence and adulthood can trigger undifferentiated fetal germ cells to become cancerous, it has been suggested that puberty is a 'window of opportunity' during which lifestyle or environmental factors also can increase the risk of testicular cancer," said senior author Janet R. Daling, Ph.D., an epidemiologist who is also a member of the Center's Public Health Sciences Division. "This is consistent with the study's findings that the elevated risk of nonseminoma-type testicular cancer in particular was associated with marijuana use prior to age 18."

Chronic marijuana exposure has multiple adverse effects on the endocrine and reproductive systems, primarily decreased sperm quality. Other possible effects include decreased testosterone and male impotency. Because male infertility and poor semen quality also have been linked to an increased risk of testicular cancer, this further reinforced the researchers' hypothesis that marijuana use may be a risk factor for the disease.

Daling first got the idea to explore a possible association between marijuana use and testicular cancer about eight years ago, when she attended a talk by a physician at the University of Washington who presented findings that only two organs, the brain and the testes, had receptors for tetrahydrocannabinol, or THC, the main psychoactive component of marijuana. Since then, a number of other sites have been found to contain THC receptors, including the heart, uterus, spleen and immune-system cells.

The male reproductive system also naturally produces a cannabinoid-like chemical that is thought to have a protective effect against cancer. The authors speculate that marijuana use may disrupt this anti-tumor effect, which could be another explanation for the possible link between marijuana and increased risk of testicular cancer.

For the population-based, case-control study, Daling, Schwartz and colleagues interviewed 369 Seattle-Puget Sound-area men, ages 18 to 44, who had been diagnosed with testicular cancer about their history of marijuana use. For comparison purposes they also assessed marijuana use among 979 randomly selected age- and geography-matched healthy controls. (More than 90 percent of the cases and 80 percent of the controls in the study were Hispanic or non-Hispanic white men, due to the fact that testicular cancer is very rare in African-Americans, and because the Seattle-Puget Sound region has a relatively small African-American population.)

Study participants were also asked about other habits that may be correlated with marijuana use, including smoking and alcohol consumption. Even after statistically controlling for these lifestyle factors, as well as other risk factors, such as first-degree family history of testicular cancer and a history of undescended testes, marijuana use emerged as a significant, independent risk factor for testicular cancer.

The researchers emphasize that their results are not definitive, but rather open a door to more research questions.

"Our study is the first inkling that marijuana use may be associated with testicular cancer, and we still have a lot of unanswered questions," Schwartz said, such as why marijuana appears to be associated with only one type of testicular cancer. "We need to conduct additional research to see whether the association can be observed in other populations, and whether measurement of molecular markers connected to the pathways through which marijuana could influence testicular cancer development helps clarify any association that exists," he said.

In future studies the researchers plan to measure the expression of cannabinoid receptors in both seminomatous and nonseminomatous tumor tissue from the cases in the study, and to see whether variation in the genes for the receptors and other molecules involved in cannabinoid signaling influences the risk of testicular cancer.

In the meantime, Schwartz said, "What young men should know is that first, we know very little about the long-term health consequences of marijuana smoking, especially heavy marijuana smoking; and second, our study provides some evidence that testicular cancer could be one adverse consequence," he said. "So, in the absence of more certain information, a decision to smoke marijuana recreationally means that one is taking a chance on one's future health."

The National Cancer Institute, the National Institute on Drug Abuse and funds from the Hutchinson Center supported this research, which also involved researchers from the University of Washington, Vanderbilt University and Cincinnati Children's Research Foundation.

https://www.sciencedaily.com/releases/2009/02/090209075631.htm

Marijuana-inspired Painkiller? New Chemical Pathway Discovered

November 27, 2008

Science Daily/Scripps Research Institute

Marijuana can be an effective painkiller, but social issues and unhealthy smoke inhalation complicate its use. As a result, researchers have focused great attention on understanding the biochemical system involved so they might manipulate it by other means. Toward that end, scientists have definitively identified a chemical pathway that, in mice, imitates marijuana's painkilling effect. The work could enable the development of new pain treatments.

Marijuana kills pain by activating a set of proteins known as cannabinoid receptors, which can also regulate appetite, inflammation, and memory. The body also has chemicals known as endocannabinoids that naturally activate these same receptors, namely N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG).

These natural components of the cannabinoid system remain the focus of intense efforts to develop new treatments not only for chronic pain, but also for obesity, anxiety, and depression. However, until the new paper (citation below) specific methods to study 2-AG signaling have been lacking.

AEA's activity has been well understood for years. In past research, Cravatt and his team identified an enzyme called fatty acid amide hydrolase, or FAAH, that breaks down AEA, effectively reducing its pain killing activity. A number of compounds are now in clinical development that target and breakdown FAAH, allowing AEA to build up, reducing pain. However, FAAH does not control 2-AG metabolism in vivo, and therefore, the potential biological functions and therapeutic potential of this second endocannabinoid have remained largely unknown.

Teasing out 2-AG's specific impacts have proven challenging. Comparable to FAAH, an enzyme called monoacylglycerol lipase (MAGL) breaks down 2-AG. But, despite numerous attempts, no group had been able to develop a chemical that inhibits MAGL specifically.

"The tools—selective and efficacious MAGL inhibitors—just weren't there, " says Jonathan Long, a graduate student of the Scripps Research Kellogg School of Science and Technology who is a member of the Cravatt lab and a first author of the new paper.

But now, a MAGL-specific inhibitor is finally available, thanks to the lab's new work. Key to this success was Activity-Based Protein Profiling, a unique chemical technique the group devised and has used fruitfully in other inhibitor hunts. This system enables the rapid engineering and testing of chemical compounds against many members of enzyme families, in hope of finding effective and selective inhibitors.

For this project, the group developed about 200 compounds and found that one was a highly effective block for MAGL. The scientists dubbed the compound JZL184, named after Long's initials and the order in the series of potential inhibitors tested. JZL184 effectively blocks only MAGL among more than 40 related brain enzymes, which opened the door for the first definitive study of 2-AG's activity.

A New View of 2-AG

Unlike increased AEA, which causes only reduced pain sensation, the team found that MAGL inhibition using JZL184, and the resulting increase in 2-AG concentration, not only reduced pain in mice, but also induced other effects associated with the cannabinoid receptors, namely hypothermia and decreased movement.

"This really does suggest a sort of segregation of labor, if you will," says Cravatt of the differential effects of elevating AEA versus 2-AG as part of the overall function of the cannabinoid system. "That, I think, is a truly unique result."

While treatments based on inhibiting FAAH show great promise for controlling pain, manipulating MAGL levels could also be a boon for treatment development, especially if 2-AG's other effects, such as hypothermia, can be managed.

"There are so many different types of pain," Cravatt says, "that it's possible some types could be more effectively treated with one treatment than another."

This research was supported by the National Institutes of Health, the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute, and the Skaggs Institute for Chemical Biology.

https://www.sciencedaily.com/releases/2008/11/081123150249.htm

Could Marijuana Substance Help Prevent or Delay Memory Impairment in the Aging Brain?

November 23, 2008

Science Daily/Ohio State University

Ohio State University scientists are finding that specific elements of marijuana can be good for the aging brain by reducing inflammation there and possibly even stimulating the formation of new brain cells.

Their research suggests that the development of a legal drug that contains certain properties similar to those in marijuana might help prevent or delay the onset of Alzheimer’s disease. Though the exact cause of Alzheimer’s remains unknown, chronic inflammation in the brain is believed to contribute to memory impairment.

Any new drug’s properties would resemble those of tetrahydrocannabinol, or THC, the main psychoactive substance in the cannabis plant, but would not share its high-producing effects. THC joins nicotine, alcohol and caffeine as agents that, in moderation, have shown some protection against inflammation in the brain that might translate to better memory late in life.

“It’s not that everything immoral is good for the brain. It’s just that there are some substances that millions of people for thousands of years have used in billions of doses, and we’re noticing there’s a little signal above all the noise,” said Gary Wenk, professor of psychology at Ohio State and principal investigator on the research.

Wenk’s work has already shown that a THC-like synthetic drug can improve memory in animals. Now his team is trying to find out exactly how it works in the brain.

The most recent research on rats indicates that at least three receptors in the brain are activated by the synthetic drug, which is similar to marijuana. These receptors are proteins within the brain’s endocannabinoid system, which is involved in memory as well as physiological processes associated with appetite, mood and pain response.

This research is also showing that receptors in this system can influence brain inflammation and the production of new neurons, or brain cells.

“When we’re young, we reproduce neurons and our memory works fine. When we age, the process slows down, so we have a decrease in new cell formation in normal aging. You need those cells to come back and help form new memories, and we found that this THC-like agent can influence creation of those cells,” said Yannick Marchalant, a study coauthor and research assistant professor of psychology at Ohio State.

Marchalant described the research in a poster presentation November 19 at the Society for Neuroscience meeting in Washington, D.C.

Knowing exactly how any of these compounds work in the brain can make it easier for drug designers to target specific systems with agents that will offer the most effective anti-aging benefits, said Wenk, who is also a professor of neuroscience and molecular virology, immunology and medical genetics.

“Could people smoke marijuana to prevent Alzheimer’s disease if the disease is in their family? We’re not saying that, but it might actually work. What we are saying is it appears that a safe, legal substance that mimics those important properties of marijuana can work on receptors in the brain to prevent memory impairments in aging. So that’s really hopeful,” Wenk said.

One thing is clear from the studies: Once memory impairment is evident, the treatment is not effective. Reducing inflammation and preserving or generating neurons must occur before the memory loss is obvious, Wenk said.

Marchalant led a study on old rats using the synthetic drug, called WIN-55212-2 (WIN), which is not used in humans because of its high potency to induce psychoactive effects.

The researchers used a pump under the skin to give the rats a constant dose of WIN for three weeks – a dose low enough to induce no psychoactive effects on the animals. A control group of rats received no intervention. In follow-up memory tests, in which rats were placed in a small swimming pool to determine how well they use visual cues to find a platform hidden under the surface of the water, the treated rats did better than the control rats in learning and remembering how to find the hidden platform.

“Old rats are not very good at that task. They can learn, but it takes them more time to find the platform. When we gave them the drug, it made them a little better at that task,” Marchalant said.

In some rats, Marchalant combined the WIN with compounds that are known to block specific receptors, which then offers hints at which receptors WIN is activating. The results indicated the WIN lowered the rats’ brain inflammation in the hippocampus by acting on what is called the TRPV1 receptor. The hippocampus is responsible for short-term memory.

With the same intervention technique, the researchers also determined that WIN acts on receptors known as CB1 and CB2, leading to the generation of new brain cells – a process known as neurogenesis. Those results led the scientists to speculate that the combination of lowered inflammation and neurogenesis is the reason the rats’ memory improved after treatment with WIN.

The researchers are continuing to study the endocannabinoid system’s role in regulating inflammation and neuron development. They are trying to zero in on the receptors that must be activated to produce the most benefits from any newly developed drug.

What they already know is THC alone isn’t the answer.

“The end goal is not to recommend the use of THC in humans to reduce Alzheimer’s,” Marchalant said. “We need to find exactly which receptors are most crucial, and ideally lead to the development of drugs that specifically activate those receptors. We hope a compound can be found that can target both inflammation and neurogenesis, which would be the most efficient way to produce the best effects.”

The National Institutes of Health supported this work.

https://www.sciencedaily.com/releases/2008/11/081119120141.htm

Use of non-psychoactive cannabinoids in the treatment of neurodegenerative diseases

September 19, 2008

Science Daily/Complutense University of Madrid

Scientists at the Complutense University of Madrid (UCM) have studied the effects of a drug that reduces the progression of a disease similar to multiple sclerosis in animals. This discovery represents another step in the standing fight against the disease.

The research, published in the Journal of Biological Chemistry, aimed to study in depth the already known effects of lessening the symptoms and stopping the advance of multiple sclerosis that cannabinoids have, while developing a drug that would not have the psychoactive effects of the marijuana plant (Cannabis sativa). To achieve this, the scientists have focused their study on the role of the cannabinoids receptor CB2, present both in the immune system as well as in the defence-cells of the nervous system (microglial cells).

Multiple sclerosis is a neurodegenerative disease whose causes are not yet fully understood. It is known that the disease is produced by an autoimmune response where the defence-cells in the organism attack and destroy the nerve cells of the organism generating symptoms such as stiffness, twitching, progressive paralysis, etc.

The researchers managed by Professor Ismael Galve from the UCM, founded their conclusions on the role of the cannabinoids receptors in Experimental autoimmune encephalomyelitis, a disease that reproduces some of the processes and symptoms of multiple sclerosis. In the study it has been tested that administering a drug that activates receptor CB2 (but not CB1, responsible for the psychactive effects), the symptoms of the disease lessen and a reduction of 50% in nerve cell loss was perceived.

This research has introduced yet another novelty: The stimulation of the CB2 receptor not only reduces the excessive activation of brain cells in charge of the defence of the central nervous system, but it also reduces the supply of new defence-cells that travelling throughout the blood stream from bone marrow, would act as reinforcements for the defence-cells of the central nervous system.

According to Ismael Galve, the results are important because the drug is capable of acting in an already sick animal, reducing the symptoms and the brain cell loss. The obtained results, along with other predecessors confirm the role of endogenous cannabinoids in the origin of experimental autoimmune encephalomyelitis and its possible application to multiple sclerosis. Therefore the role of the CB2 receptor in the regulation and neuro-immune response supports the research currently being carried out on the possible use of cannabinoid drugs in the treatment of neurodegenerative diseases.

The research has been carried out by the department of biochemistry and molecular biology of the Complutense University of Madrid, in collaboration with the Neuroscience research Institute of Lyon in France and the pharmaceutical company Pharmos.

https://www.sciencedaily.com/releases/2008/09/080916154721.htm

Turned-off Cannabinoid Receptor Turns on Colorectal Tumor Growth

August 4, 2008

Science Daily/University of Texas M. D. Anderson Cancer Center

New preclinical research shows that cannabinoid cell surface receptor CB1 plays a tumor-suppressing role in human colorectal cancer, scientists report in the Aug. 1 edition of the journal Cancer Research.

CB1 is well-established for relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. It now may serve as a new path for cancer prevention or treatment.

"We've found that CB1 expression is lost in most colorectal cancers, and when that happens a cancer-promoting protein is free to inhibit cell death," said senior author Raymond DuBois, M.D., Ph.D., provost and executive vice president of The University of Texas M. D. Anderson Cancer Center.

DuBois and collaborators from Vanderbilt-Ingram Cancer Center also show that CB1 expression can be restored with an existing drug, decitabine. They found that mice prone to developing intestinal tumors that also have functioning CB1 receptors develop fewer and smaller tumors when treated with a drug that mimics a cannabinoid receptor ligand. Ligands are molecules that function by binding to specific receptors. Agonists are synthetic molecules that mimic the action of a natural molecule.

"Potential application of cannabinoids as anti-tumor drugs is an exciting prospect, because cannabinoid agonists are being evaluated now to treat the side-effects of chemotherapy and radiation therapy," DuBois said. "Turning CB1 back on and then treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention."

Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the body internally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, most famously the active ingredient in marijuana (THC).

Receptor shutdown by methylation

Endocannabinoid signaling is important to the normal functioning of the digestive system and has been shown to protect the colon against inflammation. Since chronic inflammation is a known risk factor for colorectal cancer, the researchers decided to look into the role of cannabinoid receptors in a mouse model of colon cancer.

"People have looked at cannabinoids in cancer earlier, mainly in cell culture experiments," DuBois said. "The molecular mechanisms for loss of the receptor and its effect on cancer have not been previously shown."

First, the team found that CB1 was largely absent in 18 of 19 human tumor specimens and in 9 of 10 colorectal cancer cell lines. Further experimentation showed that the gene that encodes the CB1 protein was not damaged, but shut down chemically by the attachment of methyl groups - a carbon atom surrounded by three hydrogen atoms - to the gene encoding CB1.

Treating cell lines with decitabine, a demethylating agent approved for some types of leukemia, removed the methyl groups, restoring gene expression in 7 of 8 cell lines and full expression of CB1 protein in three lines.

Next, the group found that deletion of the CB1 gene in a strain of mice that spontaneously develops precancerous polyps resulted in a 2.5-to-3.8-fold increase in the number of polyps and a 10-fold increase in the number of large growths, those most likely to develop into cancer.

Treating mice that had the CB1 receptor with an endocannabinoid agonist resulted in a decline in polyps ranging from 16.7 percent to 50 percent. The reduction was greater for larger polyps.

CB1 thwarts survivin, a protein that protects cancer

Cannabinoids previously had been shown to kill cancer cells in lab experiments by inducing apoptosis - programmed cell death. The team confirmed the role of CB1 in apoptosis, showing that tumor cells with high CB1 expression were sensitive to apoptosis when treated by a cannabinoid agonist. Cell lines with silenced CB1 resisted cell death.

A series of experiments showed that CB1 increases cancer cell death by stifling a protein called survivin. Survivin is overexpressed in nearly every human tumor but is barely detectable in normal tissue, DuBois noted. Overexpression of survivin is associated with poor outcome and reduced apoptosis in colorectal cancer patients. The researchers pinpointed a cell signaling pathway by which activated CB1 cuts down survivin.

"Just increasing the levels of cannabinoids to treat colorectal cancer won't work if the CB1 receptor is not present," DuBois said. This suggests that treating first with a demethylating agent, such as decitabine, to reactivate CB1 in the tumor and following up with a cannabinoid might be an effective attack on colorectal cancer.

Scarcity of CB1 also is associated with Huntington's disease, Alzheimer's disease and multiple sclerosis. Further investigation, the researchers note, is needed to define its role in those diseases and other types of cancer. The team also analyzed the other main cannabinoid receptor, CB2, and found no role for it in colorectal cancer.

They also treated the mice with a CB1 antagonist, a compound that binds to the receptor but does not activate it. Mice with CB1 blocked in this manner also showed an increase in the number and size of polyps. A CB1 antagonist called rimonabant is currently marketed overseas for weight loss. The researchers note that a patient's risk for colorectal cancer should be assessed when use of such drugs is being considered.

The study was funded by grants from the National Cancer Institute and the National Colorectal Cancer Research Alliance.

https://www.sciencedaily.com/releases/2008/08/080801074056.htm

Can Cannabis Compounds Slow the Progression of Multiple Sclerosis?

July 21, 2008

Science Daily/The Peninsula College of Medicine and Dentistry

The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study at the Peninsula Medical School in Plymouth has reached an important milestone with the news that the full cohort of 493 people with multiple sclerosis (MS) has been recruited to the study.

CUPID is a clinical trial which will evaluate whether tetrahydrocannabinol (THC), one of many compounds found in the in the cannabis plant (and the main active ingredient) is able to slow the progression of MS.

This is an important study for people with MS because current treatments either target the immune system in the early stages of MS, or are aimed at easing specific symptoms such as muscle spasms or bladder problems. At present there is no treatment which slows progression of the disease.

The CUPID trial follows an earlier study -- Cannabinoids and Multiple Sclerosis (CAMS) -- which suggested a link between THC and the slowing of MS. The CAMS trial saw participants take THC for a year -- the CUPID trial will last for longer and aims to assess the effect of THC on progressive MS.

It has taken two years to recruit the 493 participants who will each take part in the trial for three years, and in some cases three and a half years. After data cleaning and analysis the results should be available by spring/early summer 2012.

Professor John Zajicek from the Peninsula Medical School, who heads the team carrying out the CUPID study, said: "We are delighted to have achieved the correct number of patient participants for this trial. Patients have been recruited from 27 sites across the UK. If we are able to prove beyond reasonable doubt the link between THC and the slowing down of progressive MS, we will be able to develop an effective therapy for the many thousands of MS sufferers around the world."

The CUPID trial is funded by the Medical Research Council, the Multiple Sclerosis Society and the Multiple Sclerosis Trust.

Chris Jones, chief executive of the MS Trust, commented: "The MS Trust is delighted to be supporting this study on behalf of people with MS. The ability to halt progression in MS is what we dream of - the Holy Grail for those whose condition deteriorates year on year. This study should give us the definitive answer as to whether cannabinoids will prove to be such an agent."

Dr Laura Bell, research communications officer for the MS Society, said: "People affected by MS are keen to know whether there's any truth in the suggestion that elements of the cannabis plant can help ease the symptoms and slow down progression of the condition.

"The MS Society is supportive of safe clinical trials investigating the medicinal properties of cannabis and it's great news that this trial is going ahead. We look forward to the results of this exciting study."

https://www.sciencedaily.com/releases/2008/07/080721114608.htm

Weeding Out the Highs of Medical Marijuana

July 15, 2008

Science Daily/University of Manchester

Research exploring new ways of exploiting the full medicinal uses of cannabis while avoiding unwanted side-effects will be presented to pharmacologists on July 15 by scientists attending the Federation of European Pharmacological Societies Congress, EPHAR 2008.

Cannabis is a source of compounds known as cannabinoids, one of which, THC -- the main chemical responsible for the 'high' -- has long been licensed as a medicine for suppressing nausea produced by chemotherapy and for stimulating appetite, for instance, in AIDS patients.

More recently, the cannabis-based medicine Sativex was licensed both for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. Sativex contains approximately equal amounts of THC and the non-psychoactive plant cannabinoid, cannabidiol.

"THC works by targeting molecules in our bodies called cannabinoid receptors" said Roger Pertwee, Professor of Neuropharmacology at the University of Aberdeen, who is co-chairing the cannabis symposium.

"So some current research is focused on designing drugs that only target cannabinoid receptors in the part of the body relevant to the disease in question and not the receptors in the central nervous system involved in the unwanted effects of cannabis."

A further approach to avoiding the psychoactivity caused by THC involves harnessing the body's own cannabis, called 'endocannabinoids'.

"We don't have cannabinoid receptors just in case we come into contact with plant-derived chemicals that activate them but rather because we have our own molecules that do this," said Christopher Fowler, Professor of Pharmacology at Umea University, in Sweden, and co-chair of the meeting.

"The neat thing about endocannabinoids is that they are often produced only when we need them, such as when our bodies are damaged in some way; pain, for example, leads to a release of endocannabinoids in a region of the brain that is involved with pain control.

"The problem with this natural protective 'endocannabinoid system' is that it is too short-lived to be of great benefit -- enzymes in our bodies quickly breakdown or metabolise the endocannabinoids negating their effect. It's a bit like a bathtub without a plug -- the water is turned on but rapidly disappears down the plughole. This suggests an immediate target: block the plughole and the water will stay longer.

"Since the release of endocannabinoids is local, levels in other parts of the brain, stay low. This approach is under intense investigation and programmes for the development of new drugs targeting pain and possibly other disorders such as anxiety and depression are currently underway."

Speakers will report on promising studies that show improved strategies for targeting the endocannabinoid system, not only for pain relief, but also for treating other conditions, including stroke, liver diseases and, ironically, nicotine addiction and obesity.

Thus, as the conference will hear, there are some disorders in which endocannabinoid release appears to be detrimental to our health, one example being obesity, which can be treated with Acomplia*, a licensed synthetic medicine that acts by blocking cannabinoid receptors.

Professor Pertwee added: "THC in cannabis is of course well known for its ability to induce 'the munchies' and, as mentioned, is used in clinics to boost appetite. But my research group has discovered that another constituent of cannabis, THCV, acts in a similar way to Acomplia, blocking one of the cannabinoid receptors, so providing an alternative -- and potentially better -- treatment route in the fight against obesity.

"The conference will hear about some of the possible advantages THVC has over current obesity treatments, as well as data on the potential of cannabinoids to treat other conditions, including neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's disease."

*Acomplia has been a licensed medicine for obesity in the UK and Europe for about two years and was accepted by the National Institute for Clinical Excellence (NICE) on June 28, 2008.

https://www.sciencedaily.com/releases/2008/07/080714192555.htm

Body's Own 'Cannabis (Marijuana)' is Good for the Skin

Science Daily/July 3, 2008

Federation of American Societies for Experimental Biology

Scientists from Hungary, Germany and the U.K. have discovered that our own body not only makes chemical compounds similar to the active ingredient in marijuana (THC), but these play an important part in maintaining healthy skin.

This finding on "endocannabinoids" just published online in, and scheduled for the October 2008 print issue of, The FASEB Journal could lead to new drugs that treat skin conditions ranging from acne to dry skin, and even skin-related tumors.

"Our preclinical data encourage one to explore whether endocannabinoid system-acting agents can be exploited in the management of common skin disorders," said Tamás Biró, MD, PhD, a senior scientist involved in the research. "It is also suggested that these agents can be efficiently applied locally to the skin in the form of a cream."

Biró and colleagues came to this conclusion by treating cell cultures from human sebaceous glands (the glands that make the oil on our skin) with various concentrations of endocannabinoids (substances produced by the body that are similar to the active ingredient in marijuana).

Then they measured the production of lipids (fat cells, such as those in skin oil), cell survival and death, and changes in gene expression and compared these outcomes to those in an untreated control group.

"This research shows that we may have something in common with the marijuana plant," said Gerald Weissmann, MD. "Just as THC is believed to protect the marijuana plants from pathogens, our own cannabinoids may be necessary for us to maintain healthy skin and to protect us from pathogens ."

https://www.sciencedaily.com/releases/2008/07/080702160944.htm

Opioids and Cannabinoids Influence Mobility of Spermatozoids

June 24, 2008

Science Daily/Basque Research

A PhD thesis from the University of the Basque Country has concluded that there are opioid and cannabinoid receptors in human sperm and that these influence the mobility of spermatozoid. The research by Mr Ekaitz Agirregoitia opens the door to more effective treatment of fertility problems.

Freshly released spermatozoids cannot achieve fertilisation, they must undergo some changes for this to occur. Amongst other, such changes take place due to receptors situated in the plasmatic membrane (the layer covering the cells) and opioid and cannabinoid receptors are two of these. On coming into contact with these, physiological reactions are generated in the body which are similar to, for example, sedation, analgesia and low blood pressure. Moreover, according to the research undertaken to date, both substances have an influence on the process of fertilisation.

It is known that the consumption of external opiates (heroin, methadone) reduces the mobility of spermatozoids and that external cannabinoids (hachis) causes changes in the reproductive process. Also, the body itself generates internal opioids and cannabinoids, secreted to enable us withstand pain or stress situations, and it is also known that this phenomenon affects the reproduction process.

Despite all this being previously known, there has been no thorough study of the opioid and cannabinoid receptors in the human sperm such as this one, carried out by Mr Ekaitz Agirregoitia Marcos for his PhD thesis, defended at the Faculty of Medicine and Odontology of the University of the Basque Country (UPV/EHU) and entitled in Basque, Opioide-hartzaileak eta kannabinoide-hartzaileak giza espermatozoideetan espresatzen dira eta haien mugikortasunean eragiten dute (Opioid receptors and cannabinoid receptors are expressed in human spermatozoids and influence their mobility).

The aim was to define this expression and the location of three opioid receptors and two cannabinoid receptors, as well as to analyse the influence of their activity in the mobility of spermatozoids. Mr Agirregoitia has a degree in Biology, specialising in Health Sciences. He is currently working as a substitute lecturer in the Department of Physiology, giving classes in Medical Biophysics and General Physiology. His PhD work was led by Dr. Jon Irazusta Astiazaran from the same Department and was undertaken in collaboration with Dr. Carmen Ochoa of the Euskalduna Clinic and Dr. Manolo Guzmán from the Complutense University in Madrid.

Pinpointing the receptors

This PhD has shown, for the first time, that all the types of opioid and cannabinoid receptors are found in human sperm. To date, only the MU opioid receptor has been found in equine sperm, and the presence in human sperm of the CB1 cannabinoid receptor was only discovered this year. Dr. Agirregoitia has used a number of techniques to find three opioid receptors (DELTA, KAPPA and MU) and two cannabinoid receptors (CB1 and CB2) in the human sperm. According to his research, all these are found at the head, the middle and the tail of the spermatozoids.

How is mobility influenced?

After defining the expression and location of the opioid and cannabinoid receptors, Dr. Agirregoitia initiated an analysis of their influence on the mobility of the spermatozoids. These receptors act like a kind of lock catch mechanism to which the opioids and cannabinoids attach themselves. Some of these substances (agonists) are capable of activating the cells, just like a key opening a lock. Others (antagonists), although fitting perfectly into the “locks”, are not capable of opening them and have the effect of blocking the receptor. Mr Agirregoitia studied both processes, incubating human sperm with agonist and antagonist synthetic substances to this end.

From this PhD thesis, presented at the UPV/EHU, it was concluded that, for the movement of the spermatozoids to be maintained, a minimum number of DELTA receptors must remain active. On the other hand, it is pointed out that the activation of the MU opioid receptor inhibits the mobility of the spermatozoids, i.e. it causes them to slow down. Finally, the PhD concludes that the KAPPA opioid receptor participates in another process which has nothing to do with mobility.

As regards the cannabinoid system, the activation of the CB1 y CB2 receptors causes the percentage of spermatozoids with rapid and progressive mobility to be reduced. Even so, as a consequence of the activation of the CB1 receptor, the number of slow spermatozoids rises, while the activation of CB2 increases the number of spermatozoids with progressive but slow movement.

The most effective diagnoses and treatments

It is known that opiods and cannabinoids regulate the function of reproduction through the central nervous system and, according to this PhD thesis, they are also able to control the process through the receptors located in the spermatozoids themselves. Thus, the type and concentration of internal opioids and cannabinoids found in the spermatozoid on its way to the egg will condition its mobility.

This work opens the door – in the medium to long term – to the diagnosis and treatment of numerous pathologies. For example, an analysis of the components of the system of opioid and cannabinoid receptors would enable us to better understand fertility problems due to currently unknown causes, exhibited by both spermatozoids as well as the female reproductive organ. Also, when designing treatment aimed at fomenting the mobility of spermatozoids, it will enable the prescribing of treatment that activates or inhibits the appropriate receptor in order to benefit the process of fertilisation.

https://www.sciencedaily.com/releases/2008/06/080620115953.htm

Burning Incense is Psychoactive: New Class of Antidepressants Might be Right Under Our Noses

May 20, 2008

Science Daily/Federation of American Societies for Experimental Biology

Religious leaders have contended for millennia that burning incense is good for the soul. Now, biologists have learned that it is good for our brains too. An international team of scientists, including researchers from Johns Hopkins University and the Hebrew University in Jerusalem, describe how burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression. This suggests that an entirely new class of depression and anxiety drugs might be right under our noses.

"In spite of information stemming from ancient texts, constituents of Bosweilla had not been investigated for psychoactivity," said Raphael Mechoulam, one of the research study's co-authors. "We found that incensole acetate, a Boswellia resin constituent, when tested in mice lowers anxiety and causes antidepressive-like behavior. Apparently, most present day worshipers assume that incense burning has only a symbolic meaning."

To determine incense's psychoactive effects, the researchers administered incensole acetate to mice. They found that the compound significantly affected areas in brain areas known to be involved in emotions as well as in nerve circuits that are affected by current anxiety and depression drugs. Specifically, incensole acetate activated a protein called TRPV3, which is present in mammalian brains and also known to play a role in the perception of warmth of the skin. When mice bred without this protein were exposed to incensole acetate, the compound had no effect on their brains.

"Perhaps Marx wasn't too wrong when he called religion the opium of the people: morphine comes from poppies, cannabinoids from marijuana, and LSD from mushrooms; each of these has been used in one or another religious ceremony." said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Studies of how those psychoactive drugs work have helped us understand modern neurobiology. The discovery of how incensole acetate, purified from frankincense, works on specific targets in the brain should also help us understand diseases of the nervous system. This study also provides a biological explanation for millennia-old spiritual practices that have persisted across time, distance, culture, language, and religion--burning incense really does make you feel warm and tingly all over!"

According to the National Institutes of Health, major depressive disorder is the leading cause of disability in the United States for people ages 15--44, affecting approximately 14.8 million American adults. A less severe form of depression, dysthymic disorder, affects approximately 3.3 million American adults. Anxiety disorders affect 40 million American adults, and frequently co-occur with depressive disorders.

https://www.sciencedaily.com/releases/2008/05/080520110415.htm

Starting Point of Sun-induced Skin Cancer Discovered: Molecular 'Hooks' Also Pull Compounds from Marijuana from Bloodstream

May 16, 2008

Science Daily/University of Minnesota

According to a new study from the University of Minnesota, the earliest event in the development of sun-induced skin cancer may have been identified. The researchers found that the point of entry for skin cancer in response to sun exposure is in receptor molecules, molecular "hooks" on the outer surface of cells that also pull cannabinoid compounds found in marijuana out of the bloodstream.

"The question at the core of this research was, 'Why does ultraviolet light induce skin cancer?'" said lead researcher Zigang Dong, a professor of cellular and molecular biology and director of the university's Hormel Institute, which supported the study. "The idea is to find an agent that can prevent skin cancers after exposure to the sun."

The receptor molecules are protein structures that are components of cells's outer membranes. Acting like receiving docks, their function is to catch specific compounds from the blood and enable the cells to engulf or otherwise interact with the compounds. Receptors have been identified for many substances, including hormones and other chemical signals that regulate what cells do.

The researchers found that two receptors for cannabinoids also responded to UV light. They made the discovery during a search for the initial interaction between UV light and human skin cells.

The researchers began their search with plant cells because plants must interact with UV light in order to harness its energy for photosynthesis. They concluded that the UV receptors in plants ought to be similar to any found in humans, and, therefore, the genes for the plant and human receptors must also be similar. When they compared plant genes for UV receptors to human genetic material, they found that the human genes for cannabinoid receptors matched.

If cannabinoid receptors are important in the initiation of skin cancer by UV light, then animals that lack the receptors should be relatively protected from the ravages of the light. Working with mouse embryos, the researchers removed the genes for the cannabinoid receptors. They found that the skin of the resulting adult mice, which lacked the receptors, was resistant to the development of UV-induced inflammation and skin tumors called papillomas.

Also, when they exposed cannabinoid receptors to UV light, the receptors changed from an inactive to an active state, indicating they had absorbed and responded to the light.

Why should evolution have produced receptors that respond to both UV light and cannabinoids?

"That we don't know," said Dong.

 The research appears in the May 15 issue of Cancer Research.

The Hormel Institute is a collaborative research unit of the University of Minnesota and Mayo Clinic. The work was supported by the Hormel Foundation and the National Institutes of Health.

https://www.sciencedaily.com/releases/2008/05/080515072642.htm

Marijuana, Genes, Medicines and Brain Scans Help Scientists Find Better Anxiety Treatments

April 22, 2008

Science Daily/University of Michigan Health System

Right now, about half of all people who take medicine for an anxiety disorder don't get much help from it. And doctors have no definitive way to predict who will, and who won't, benefit from each anti-anxiety prescription they write.

But a University of Michigan Medical School researcher and his team are working to bring more certainty to how doctors and patients choose anxiety treatments, by probing the connection between brain activity, genetics and medication.

K. Luan Phan, M.D., and his former University of Chicago colleagues recently reported intriguing findings from a brain imaging study in occasional, non-dependent, marijuana users in the Journal of Neuroscience.

In a placebo-controlled design, they made the findings after giving the volunteers delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana, and exposing them to photographs of emotional faces, which served as signals of social communication. The study results, which showed that THC reduces the response to threat in a brain region called the amygdala, allowed the researchers to zero in on an area of the brain that might serve as a good target for new anti-anxiety drugs.

Now, with a new clinical trial that is currently seeking participants, Phan is searching for more clues as to how anxiety treatment could be tailored to the individual patient, to give the best chance that a treatment will work for him or her.

The new study will test a generic form of the drug Zoloft (sertraline), a selective serotonin reuptake inhibitor (SSRI) approved by the U.S. Food and Drug Administration for social anxiety disorder and other anxiety disorders. Both people with social anxiety disorder and a comparison group of people without anxiety are needed for brain scanning and genetic testing.

The idea is to see whether variations in the genes for certain brain receptors and transporters are linked with variations in how a person's brain reacts to pictures of emotional faces, and variations in how they respond to the anti-anxiety drug. This information could lead to an individualized or personalized approach to medical care.

"These two studies are trying to get to the same goal: to find better treatments for anxiety disorders that affect millions of Americans and seriously interfere with their functioning," says Phan, an assistant professor of psychiatry at U-M and the VA Ann Arbor Healthcare System. "The cannabis study highlights a new avenue that we need to explore further as we try to develop novel medications, while the sertraline study will try to find out if we can tell which patients might or might not respond well, and by what mechanism, to an already existing medication known to have some efficacy in treating anxiety disorders."

Phan led the cannabis study at the University of Chicago, collaborating with Harriet deWit, Ph.D., the director of the Human Behavioral Pharmacology Laboratory in the Department of Psychiatry there. Their results are based on brain scans of 16 recreational marijuana users who agreed to undergo functional magnetic resonance imaging, or fMRI.

The researchers chose fMRI because it allows them to see in real time which areas of the brain are most active while a volunteer is performing a certain task -- for example, viewing a picture of a human face that is expressing anger or fear, or performing a decision-making exercise.

That same approach will be used in the new sertraline study, with two different scans before and after anxiety patients are prescribed the medication. The healthy volunteers in the study will also have fMRI scans, though they will not receive the drug. All study participants must between 18 and 55 years old, and those with anxiety disorders must not be taking any other medication that could be affecting the brain in order to qualify to enter the study.

The cannabis study used THC, and a placebo caplet that looked exactly like the THC caplet. The researchers found that when the marijuana users received THC, their brain's response to "threatening" faces was less than it was when they received a placebo.

The difference in response was seen in an area of the brain called the amygdala, which is a hub for the brain's ability to process signs of danger or warning, and to decide how to respond. But there were no differences between THC and placebo in the areas of the brain that process non-emotional visual signals or govern body movement -- suggesting that THC had a specific effect on a specific brain region and on a specific task of processing fear. Other researchers have shown this to be a region that's rich in a receptor called CB1, part of the brain's "cannabinoid" system.

The human brain produces compounds called endocannabinoids that act on these receptors, and are involved in anxiety and fear-learning, or the learning of which threats to be afraid of. But little has been known about the effect of THC, an exogenous cannabinoid, on the brain's own system.

For ethical reasons, the researchers did not give THC to non-marijuana users, and the study was small. But the findings in the study volunteers suggest that THC and other compounds that act on the CB1 receptors in the amygdala could be fruitful targets for new anti-anxiety medicines. Phan notes that rimonabant, a smoking-cessation and weight-loss drug not yet available in the United States for clinical use, also acts on the CB1 receptor.

Understanding how drugs such as marijuana affect the brain may also help reveal more about why people become addicted to illicit drugs or abuse certain prescription drugs, Phan notes. Some individuals may be using illicit drugs and misusing prescribed drugs to alleviate their anxiety. He hopes to investigate this issue further by studying people who have used prescription pain drugs recreationally (such as oxycodone), using new funding from the National Institutes of Health.

The THC study links three key domains of human behavior: a specific region of the brain, the function of that area, and a neurochemical agent (THC) that appears to act on them. The new sertraline study will take it one step further, by looking at genetics too. Specifically, Phan and his colleagues will look for variations ("functional polymorphisms") among several genes in individual subjects. Key among them is the gene (5-HTTLPR) that encodes the serotonin transporter protein that transports the neurotransmitter serotonin in and out of brain cells. Serotonin has long been known to be involved in depression and anxiety, and indeed most modern antidepressant and anti-anxiety drugs (such as SSRIs) work on this transporter.

https://www.sciencedaily.com/releases/2008/04/080418154959.htm

Sexual Activity and Marijuana Use Associated with HPV-Positive Head and Neck Cancer

March 13, 2008

Science Daily/Johns Hopkins Medical Institutions

Researchers at the Johns Hopkins Kimmel Cancer Center have teased out two distinct sets of risk factors for head and neck cancers, suggesting that there are two completely different kinds of the disease.

In the Johns Hopkins study, head and neck tumors caused by the human papillomavirus (HPV), a common sexually transmitted virus, were most often linked to certain sexual behaviors and marijuana use, rather than tobacco and alcohol. The Johns Hopkins scientists also found that people with the viral-linked cancer were younger, more likely to be white, married, college-educated and have an annual income of $50,000 or higher. By contrast, those not caused by HPV, were associated with tobacco smoking, alcohol use and poor oral hygiene, which are the behaviors most often linked to head and neck cancer.

"Our results indicate that HPV-positive and HPV-negative head and neck cancers have different risk-factor profiles and should be considered two distinct diseases," says Maura L. Gillison, M.D., Ph.D., an associate professor of oncology and epidemiology at Hopkins. "They just happen to occur in the same place."

The findings are to be published in the March 12 issue of the Journal of the National Cancer Institute.

Gillison and her colleagues first reported in 2000 that HPV infection is associated with the development of some head and neck cancers, particularly in the upper throat and back of the tongue (oropharynx), where it has been observed in up to 72 percent of patients. In related work, Gillison and colleagues recently reported that HPV-linked cancer has nearly doubled in incidence over the past 30 years in the United States.  They also found that head and neck cancer patients with HPV-positive tumors tend to survive longer and are more responsive to treatment, compared with patients with HPV-negative tumors. That research was published online Feb. 12 also in the Journal of the National Cancer Institute. According to Gillison, the American Joint Committee on Cancer is now considering incorporating HPV status in its guidelines for determining clinical stages of head and neck cancer.

For the current study, Gillison and her team studied 240 patients diagnosed with head and neck squamous cell carcinomas at the Johns Hopkins Hospital between 2000 and 2006, and determined whether their tumors were positive or negative for HPV. They formed a control group by matching up to two people without cancer to each patient by similar age and sex. All study participants completed a computerized interview that asked questions about their risk factors.

Overall, the researchers detected HPV16 in 92 cancer patients. They found that HPV-positive cancers were associated with several measures of sexual behavior and exposure to marijuana but not with tobacco or alcohol use, or with poor oral hygiene. These associations became stronger with increasing numbers of oral sex partners, and with longer or more intense use of marijuana. In fact, among nonsmokers of tobacco, participants who smoked marijuana for at least five years were 11 times more likely to develop HPV-positive cancers.

Gillison says that her study is one of the first to connect marijuana use with the development of HPV-linked head and neck cancers. "It's possible that other behaviors linked with marijuana use could be the real culprit, and our results will need to be confirmed," she says. Some reports show that chemicals in marijuana called cannabinoids could affect the immune system's ability to clear a viral infection, according to Gillison.

Sexual behaviors associated with HPV-positive cancers included increasing numbers of lifetime vaginal or oral sex partners, participating in casual sex at least once, infrequent use of barriers during vaginal or oral sex, and having had at least one sexually transmitted disease. HPV-negative cancers were found to be associated with tobacco or alcohol use and with poor oral hygiene but not with any measure of sexual behavior or marijuana use. Poor oral hygiene, tobacco and alcohol use are well-known risk factors for non-HPV related head and neck cancer. Those who had heavily used tobacco and alcohol were nearly five times more likely to develop HPV-negative head and neck cancers. Participants who brushed their teeth less than once a day were four times more likely to develop HPV-negative tumors.

Head and neck cancers occur in more than 35,000 Americans each year, and the Johns Hopkins investigators believe that the rise in the HPV variety could be due to changing sexual behaviors.

This research was supported by the Damon Runyon Cancer Research Foundation, the State of Maryland Cigarette Restitution Fund, and the National Institute of Dental and Craniofacial Research.

https://www.sciencedaily.com/releases/2008/03/080311165905.htm

Curing Addiction with Cannabis Medicines?

March 10, 2008

Science Daily/University of Nottingham

Smokers trying to quit in the future could do it with the help of cannabis based medicines, according to research from The University of Nottingham.

Teams of pharmacologists, studying the cannabis-like compounds which exist naturally in our bodies (endocannabinoids), are exploring the potential for medical treatment. This includes treating conditions as diverse as obesity, diabetes, depression and addiction to substances like nicotine.

Scientists have known about endocannabinoids since the mid-1990s. This led to an explosion in the number of researchers looking into the future medical uses of cannabinoids and cannabis compounds.

Dr Steve Alexander, Associate Professor in the School of Biomedical Sciences, has looked at a number of these projects. Dr Alexander said: “It is clear that there is very realistic potential for cannabinoids as medicines. Scientists are looking at a range of possible applications.”

One of these researchers is Professor David Kendall, a cellular pharmacologist at the University: “The brain is full of cannabinoid receptors.  And so, not surprisingly with diseases like depression and anxiety, there's a great deal of interest in exploiting these receptors and in doing so, developing anti-depressant compounds.”

Addiction is a real target — researchers like Professor Kendall believe the endocannabinoids could be a crucial link to addictive behaviour: “We know that the endocannabinoid system is intimately involved in reward pathways and drug seeking behaviour. So this tends to indicate that that if the link involving endocannabinoids and the reward pathway, using inhibitors, can be interrupted, it could turn down the drive to seek addictive agents like nicotine.”

Because cannabinoids have also been shown to bring down blood pressure, it is hoped that related compounds can be used in patients with conditions like hypertension.

Dr Michael Randall, a cardiovascular pharmacologist at the University has looked at how endocannabinoids cause blood vessels to relax. “This could have many implications,” Dr Randall said. “The endocannabinoids appear to lower blood pressure under certain conditions; states of shock for example. If the endocannabinoids are of physiological importance, this could have real therapeutic possibilities.”

“In terms of getting better medicines the endocannabinoid system has a lot to offer,” said Dr Alexander. “The range of cannabis-related medicines is currently limited, but by increasing our knowledge in this area we can increase our stock.”

https://www.sciencedaily.com/releases/2008/03/080307110348.htm

Cannabinoid-blocking Weight-loss Drug Might Fight Alcoholic Fatty Liver

March 6, 2008

Science Daily/Cell Press

The cannabinoid receptors best known for delivering the psychological effects of marijuana also explain the connection between chronic alcohol use and a buildup of fat in the liver, according to a report in the March issue of Cell Metabolism. Alcoholic fatty liver can progress to more serious disease, and alcoholism is a leading cause of liver disease in Western societies.

The researchers also found that mice treated with rimonabant, a drug designed to block cannabinoid receptors, become resistant to alcohol's fat-building effects in the liver. Rimonabant is now in use for weight loss in several European countries but has not received FDA approval for use in the United States.

"What makes these findings particularly interesting from our perspective is that they may have practical implications," said George Kunos of the National Institute on Alcohol Abuse and Alcoholism. "Treatment of animals with a [cannabinoid receptor] antagonist largely prevented alcohol's effect. It suggests that the development of fatty liver in those who use alcohol could be interfered with, or perhaps reversed, with such treatment."

In addition to alcoholism, obesity can also lead to the development of fatty liver disease. Scientists have shown that natural cannabinoids, so-called endocannabinoids, and CB1 cannabinoid receptors in the livers of mice are increased when animals are fed a high-fat diet. Studies have also shown that mice lacking CB1 receptors and mice treated with drugs that block these receptors are protected from obesity and fatty liver.

"Similar to high-fat diet, chronic ethanol exposure can increase endocannabinoid levels, at least in the brain," the researchers said. The apparent similarities between diet- and ethanol-induced changes in fat metabolism and endocannabinoid activity in the liver suggested that endocannabinoids might also be a culprit in ethanol-induced fatty liver.

Kunos's team now shows that mice fed a low-fat diet and ethanol show an increase in the gene encoding the CB1 receptor and in liver levels of one endocannabinoid, 2-arachidonoylglycerol (2-AG). These mice also developed fatty livers. In contrast, the livers of mice fed the ethanol diet plus rimonabant did not differ in fat content from those of mice fed a control diet. Similarly, mice lacking CB1 receptors, either throughout the body or only in the liver, gained protection from alcoholic fatty liver.

"Although alcoholic fatty liver is reversible in its early stages by cessation of drinking, this is often not feasible," the researchers concluded. "The present findings suggest that treatment with a CB1 antagonist may slow the development of fatty liver and thus prevent or delay its progression to more severe and irreversible forms of liver disease."

Drugs designed to selectively act on CB1 receptors found outside of the brain might fight fatty liver with less risk of adverse side effects, including anxiety and depression, they added. "Rimonabant has recently been introduced in Europe for the treatment of visceral obesity and the metabolic syndrome, which themselves are known risk factors for [liver disease]. Clinical trials testing the effectiveness of CB1 receptor blockers in the treatment of both alcoholic and nonalcoholic fatty liver and their more severe sequelae may be warranted."

https://www.sciencedaily.com/releases/2008/03/080304124345.htm

Marijuana-based Drug Reduces Fibromyalgia Pain

February 18, 2008

Science Daily/American Pain Society

Patients with fibromyalgia treated with a synthetic form of marijuana, nabilone, showed significant reductions in pain and anxiety in a first-of-its-kind study, published in The Journal of Pain.

Fibromyalgia syndrome has no cure, is difficult to diagnose, and effective pain management strategies are a must to help patients cope with the disease. An estimated 12 million Americans have fibromyalgia, which is characterized by widespread muscle and joint pain and myriad other symptoms. The condition is far more prevalent in women and the incidence increases with age, reaching 7 percent among women 65 years and older.

Forty subjects were selected for the nabilone trial, conducted by researchers at the University of Manitoba Rehabilitation Hospital. They were divided into nabilone and placebo groups and were treated for four weeks. The authors noted this was the first randomized, controlled-access trial to evaluate nabilone for pain reduction and quality-of-life improvement in fibromyalgia patients. Nabilone is one of two oral marijuana-based compounds, known as cannabinoids, available in Canada and is approved for treatment of nausea and vomiting during chemotherapy.

Results of the Manitoba study showed the nabilone group had significant reductions in pain and anxiety, measured by comparisons with baseline scores on the visual analogue scale for pain, the Fibromyalgia Impact Questionnaire (FIQ) and the FIQ anxiety score. From the data, the study concluded nabilone has significant benefits for pain relief and functional improvement in fibromyalgia patients. Although the improvement was significant, none of the nabilone-treated subjects had complete relief of their fibromyalgia symptoms.

The drug was well tolerated by treated patients, which the authors characterized as reassuring since fibromyalgia patients are sensitive to most medications and have difficulty tolerating side effects. The downside, however, is cost. In Canada, nabilone would cost about $4,000 for a year's supply.

https://www.sciencedaily.com/releases/2008/02/080217214547.htm

Smoking Marijuana Impairs Cognitive Function in MS Patients

February 14, 2008

Science Daily/American Academy of Neurology

People with multiple sclerosis (MS) who smoke marijuana are more likely to have emotional and memory problems, according to new research.

"This is the first study to show that smoking marijuana can have a harmful effect on the cognitive skills of people with MS," said study author Anthony Feinstein, MPhil, PhD, of the University of Toronto. "This is important information because a significant minority of people with MS smoke marijuana as a treatment for the disease, even though there are no scientific studies demonstrating that it is an effective treatment for emotional difficulties."

Feinstein noted that MS itself can cause cognitive problems. "In addition, cognitive problems can greatly affect the quality of life for both patients and their caregivers," he said.

For the study, researchers interviewed 140 Canadian people with MS. Of those, 10 people had smoked marijuana within the last month and were defined as current marijuana users. The marijuana users were then each matched by age, sex, the length of time they had MS, and other factors to four people with MS who did not smoke marijuana.

The researchers then evaluated the participants for emotional problems such as depression, anxiety and other psychiatric disorders. They also tested the participants' thinking skills, speed at processing information, and memory.

The study found marijuana smokers performed 50 percent slower on tests of information processing speed compared to MS patients who did not smoke marijuana. There was also a significant association between smoking marijuana and emotional problems such as depression and anxiety.

People with MS have higher rates of depression and suicide compared to the general population. "Since marijuana can induce psychosis and anxiety in healthy people, we felt it was especially important to look at its effects on people with MS," Feinstein said.

This research was published February 13, 2008, in the online edition of Neurology®, the medical journal of the American Academy of Neurology. The study was supported by a grant from the Canadian Institutes for Health Research.

https://www.sciencedaily.com/releases/2008/02/080213160851.htm

Regular Marijuana Use Increases Risk of Hepatitis C-related Liver Damage

January 29, 2008

Science Daily/American Gastroenterological Association

Patients with chronic hepatitis C (HCV) infection should not use marijuana (cannabis) daily, according to a study published in Clinical Gastroenterology and Hepatology, the official journal of the American Gastroenterological Association (AGA) Institute. Researchers found that HCV patients who used cannabis daily were at significantly higher risk of moderate to severe liver fibrosis, or tissue scarring. Additionally, patients with moderate to heavy alcohol use combined with regular cannabis use experienced an even greater risk of liver fibrosis. The recommendation to avoid cannabis is especially important in patients who are coinfected with HCV/HIV since the progression of fibrosis is already greater in these patients.

"Hepatitis C is a major public health concern and the number of patients developing complications of chronic disease is on the rise," according to Norah Terrault, MD, MPH, from the University of California, San Francisco and lead investigator of the study. "It is essential that we identify risk factors that can be modified to prevent and/or lessen the progression of HCV to fibrosis, cirrhosis and even liver cancer. These complications of chronic HCV infection will significantly contribute to the overall burden of liver disease in the U.S. and will continue to increase in the next decade."

This is the first study that evaluates the relationship between alcohol and cannabis use in patients with HCV and those coinfected with HCV/HIV. It is of great importance to disease management that physicians understand the factors influencing HCV disease severity, especially those that are potentially modifiable. The use and abuse of both alcohol and marijuana together is not an uncommon behavior. Also, individuals who are moderate and heavy users of alcohol may use cannabis as a substitute to reduce their alcohol intake, especially after receiving a diagnosis like HCV, which affects their liver.

Researchers found a significant association between daily versus non-daily cannabis use and moderate to severe fibrosis when reviewing this factor alone. Other factors contributing to increased fibrosis included age at enrollment, lifetime duration of alcohol use, lifetime duration of moderate to heavy alcohol use and necroinflammatory score (stage of fibrosis). In reviewing combined factors, there was a strong (nearly 7-fold higher risk) and independent relationship between daily cannabis use and moderate to severe fibrosis. Gender, race, body mass index, HCV viral load and genotype, HIV coinfection, source of HCV infection, and biopsy length were not significantly associated with moderate to severe fibrosis.

Of the 328 patients screened for the study, 204 patients were included in the analysis. The baseline characteristics of those included in the study were similar to those excluded with the exception of daily cannabis use (13.7 percent of those studied used cannabis daily versus 6.45 percent of those not included). Patients who used cannabis daily had a significantly lower body mass index than non-daily users (25.2 versus 26.4), were more likely to be using medically prescribed cannabis (57.1 percent versus 8.79 percent), and more likely to have HIV coinfection (39.3 percent versus 18.2 percent).

The prevalence of cannabis use amongst adults in the U.S. is estimated to be almost 4 percent. Regular use has increased in certain population subgroups, including those aged 18 to 29.

Hepatitis is an inflammation of the liver. Hepatitis C is the most common form of hepatitis and infects nearly 4 million people in the U.S., with an estimated 150,000 new cases diagnosed each year. While it can be spread through blood transfusions and contaminated needles, for a substantial number of patients, the cause is unknown. This form of viral hepatitis may lead to cirrhosis, or scarring, of the liver. Coinfection of hepatitis C in patients who are HIV positive is common; about one quarter of patients infected with HIV are infected with hepatitis C. The majority of these patients, 50 to 90 percent, were infected through injection drug use. Hepatitis C ranks with alcohol abuse as the most common cause of chronic liver disease and leads to about 1,000 liver transplants yearly in the U.S.

https://www.sciencedaily.com/releases/2008/01/080128140840.htm