Cannabinoids May Inhibit Cancer Cell Invasion

December 27, 2007

Science Daily/Journal of the National Cancer Institute

Cannabinoids may suppress tumor invasion in highly invasive cancers, according to a study published online December 25 in the Journal of the National Cancer Institute.

Cannabinoids, the active components in marijuana, are used to reduce the side effects of cancer treatment, such as pain, weight loss, and vomiting, but there is increasing evidence that they may also inhibit tumor cell growth. However, the cellular mechanisms behind this are unknown.

Robert Ramer, Ph.D., and Burkhard Hinz, Ph.D., of the University of Rostock in Germany investigated whether and by what mechanism cannabinoids inhibit tumor cell invasion.

Cannabinoids did suppress tumor cell invasion and stimulated the expression of TIMP-1, an inhibitor of a group of enzymes that are involved in tumor cell invasion.

“To our knowledge, this is the first report of TIMP-1-dependent anti-invasive effects of cannabinoids. This signaling pathway may play an important role in the antimetastatic action of cannabinoids, whose potential therapeutic benefit in the treatment of highly invasive cancers

Separating the Therapeutic Benefits of Cannabis from its Mood-altering Side-effects

November 30, 2007

Science Daily/Queen Mary, University of London

Scientists from Queen Mary, University of London, have discovered a new way to separate the therapeutic benefits of cannabis from its mood-altering side-effects.

Cannabis contains a chemical called THC, which binds to, and activates, proteins in the brain known as ‘CB1 cannabinoid receptors’. Activating these receptors can relieve pain and prevent epileptic seizures; but it also causes the mood-altering effect experienced by people who use cannabis as a recreational drug.

Now, Professor Maurice Elphick and Dr Michaela Egertová from Queen Mary’s School of Biological and Chemical Sciences may have found a way of separating out the effects of cannabis – a discovery which could lead to the development of new medicines to treat conditions such as epilepsy, obesity and chronic pain. The research is described in the December issue of the journal Molecular Pharmacology.

Working in collaboration with scientists based in the USA*, they have identified a protein that binds to the CB1 receptors in the brain. But unlike THC, this ‘Cannabinoid Receptor Interacting Protein’ or CRIP1a, suppresses the activity of CB1 receptors.

Professor Elphick explains: “Because CRIP1a inhibits the activity of the brain’s cannabinoid receptors, it may be possible to develop drugs that block this interaction, and in turn enhance CB1 activity. This may give patients the pain relief associated with CB1 activity, without the ‘high’ that cannabis users experience.”

Leslie Iversen FRS, Professor of Pharmacology at the University of Oxford and author of The Science of Marijuana, commented on the new findings: “This interesting discovery provides a completely new insight into the regulation of the cannabinoid system in the brain - and could offer a new approach to the discovery of cannabis-based medicines in the future.”

“CB1 Cannabinoid Receptor Activity Is Modulated by the Cannabinoid Receptor Interacting Protein CRIP1a” is published online in the December issue of Molecular Pharmacology.

The Elphick laboratory in the School of Biological & Chemical Sciences at Queen Mary is supported by grants from UK research councils (BBSRC, MRC) and the Wellcome Trust.

https://www.sciencedaily.com/releases/2007/11/071129151109.htm

Marijuana Compound Shows Promise in Fighting Breast Cancer

November 26, 2007

Science Daily/California Pacific Medical Center

A compound found in cannabis may prove to be effective at helping stop the spread of breast cancer cells throughout the body. The study is raising hope that CBD, a compound found in Cannabis sativa, could be the first non-toxic agent to show promise in treating metastatic forms of breast cancer.

The study, by scientists at the California Pacific Medical Center Research Institute, is raising hope that CBD, a compound found in Cannabis sativa, could be the first non-toxic agent to show promise in treating metastatic forms of breast cancer.

“Right now we have a limited range of options in treating aggressive forms of cancer,” says Sean D. McAllister, Ph.D., a cancer researcher at CPMCRI and the lead author of the study. “Those treatments, such as chemotherapy, can be effective but they can also be extremely toxic and difficult for patients. This compound offers the hope of a non-toxic therapy that could achieve the same results without any of the painful side effects.”

The researchers used CBD to inhibit the activity of a gene called Id-1, which is believed to be responsible for the aggressive spread of cancer cells throughout the body, away from the original tumor site.

“We know that Id-1 is a key regulator of the spread of breast cancer,” says Pierre-Yves Desprez, Ph.D., a cancer researcher at CPMCRI and the senior author of the study. “We also know that Id-1 has also been found at higher levels in other forms of cancer. So what is exciting about this study is that if CBD can inhibit Id-1 in breast cancer cells, then it may also prove effective at stopping the spread of cancer cells in other forms of the disease, such as colon and brain or prostate cancer.”

However, the researchers point out that while their findings are promising they are not a recommendation for people with breast cancer to smoke marijuana. They say it is highly unlikely that effective concentrations of CBD could be reached by smoking cannabis. And while CBD is not psychoactive it is still considered a Schedule 1 drug.

This study was recently published in the journal Molecular Cancer Therapeutics.

The study was primarily funded by the California Breast Cancer Research Program.

https://www.sciencedaily.com/releases/2007/11/071123211703.htm

Marijuana-like Brain Chemicals Work as Antidepressant

November 7, 2007

Science Daily/University of California - Irvine

American and Italian researchers have found that boosting the amounts of a marijuana-like brain transmitter called anandamide produces antidepressant effects in test rats.

Led by Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at the University of California, Irvine, the researchers used a drug they created, called URB597, which blocks anandamide degradation in the brain, thereby increasing the levels of this chemical.

“These findings raise the hope that the mood-elevating properties of marijuana can be harnessed to treat depression,” Piomelli said. “Marijuana itself has shown no clinical use for depression. However, specific drugs that amplify the actions of natural marijuana-like transmitters in the brain are showing great promise.”

The researchers administered URB597 to chronically stressed rats which showed behaviors similar to those seen in depressed human patients. After five weeks of treatment, the stressed rats treated with the drug were behaving similarly to a comparison group of unstressed animals. 

URB597 works by inhibiting FAAH, an enzyme in the body that breaks down anandamide.  Dubbed “the bliss molecule” for its similarities to the active ingredient in marijuana, anandamide is a neurotransmitter that is part of the brain’s endocannabinoid system and it has been shown in studies by Piomelli and others to play analgesic, anti-anxiety and antidepressant roles. It also is involved in regulating feeding and obesity. Blocking FAAH activity boosts the effects of anandamide without producing the “high” seen with marijuana.

Piomelli and colleagues at the Universities of Urbino and Parma in Italy created URB597. A patent was issued in 2007. The European pharmaceutical company Organon holds the license to the patent and will begin clinical studies on the drug in 2008, according to Piomelli.

Marco Bortolato, Regina Mangieri, Jin Fu, Janet Kim and Oliver Arguello of UC Irvine; Andrea Duranti, Andrea Tontini and Giorgio Tarzia of the University of Urbino; and Marco Mor of the University of Parma also participated in the study. It was supported by the National Institute on Drug Abuse, the University of California Discovery Program and the National Alliance for Research on Schizophrenia and Depression.

https://www.sciencedaily.com/releases/2007/11/071105120556.htm

Cannabis: Potent Anti-depressant In Low Doses, Worsens Depression at High Doses

October 24, 2007

Science Daily/McGill University

A new neurobiological study has found that a synthetic form of THC, the active ingredient in cannabis, is an effective anti-depressant at low doses. However, at higher doses, the effect reverses itself and can actually worsen depression and other psychiatric conditions like psychosis.

It has been known for many years that depletion of the neurotransmitter serotonin in the brain leads to depression, so SSRI-class anti-depressants like Prozac and Celexa work by enhancing the available concentration of serotonin in the brain. However, this study offers the first evidence that cannabis can also increase serotonin, at least at lower doses.

Laboratory animals were injected with the synthetic cannabinoid WIN55,212-2 and then tested with the Forced Swim test -- a test to measure "depression" in animals; the researchers observed an antidepressant effect of cannabinoids paralleled by an increased activity in the neurons that produce serotonin. However, increasing the cannabinoid dose beyond a set point completely undid the benefits, said Dr. Gabriella Gobbi of McGill University.

"Low doses had a potent anti-depressant effect, but when we increased the dose, the serotonin in the rats' brains actually dropped below the level of those in the control group. So we actually demonstrated a double effect: At low doses it increases serotonin, but at higher doses the effect is devastating, completely reversed."

The anti-depressant and intoxicating effects of cannabis are due to its chemical similarity to natural substances in the brain known as "endo-cannabinoids," which are released under conditions of high stress or pain, explained Dr. Gobbi. They interact with the brain through structures called cannabinoid CB1 receptors. This study demonstrates for the first time that these receptors have a direct effect on the cells producing serotonin, which is a neurotransmitter that regulates the mood.

Dr. Gobbi and her colleagues were prompted to explore cannabis' potential as an anti-depressant through anecdotal clinical evidence, she said. "As a psychiatrist, I noticed that several of my patients suffering from depression used to smoke cannabis. And in the scientific literature, we had some evidence that people treated with cannabis for multiple sclerosis or AIDS showed a big improvement in mood disorders. But there were no laboratory studies demonstrating the anti-depressant mechanism of action of cannabis."

Because controlling the dosage of natural cannabis is difficult -- particularly when it is smoked in the form of marijuana joints -- there are perils associated with using it directly as an anti-depressant.

"Excessive cannabis use in people with depression poses high risk of psychosis," said Dr. Gobbi. Instead, she and her colleagues are focusing their research on a new class of drugs which enhance the effects of the brain's natural endo-cannabinoids.

"We know that it's entirely possible to produce drugs which will enhance endo-cannabinoids for the treatment of pain, depression and anxiety," she said.

The study, published in the October 24 issue of The Journal of Neuroscience, was led by Dr. Gabriella Gobbi of McGill University and Le Centre de Recherche Fernand Seguin of Hôpital Louis-H. Lafontaine, affiliated with l'Université de Montréal. First author is Dr. Gobbi's McGill PhD student Francis Bambico, along with Noam Katz and the late Dr. Guy Debonnel* of McGill's Department of Psychiatry.

https://www.sciencedaily.com/releases/2007/10/071023183937.htm

Cannabis Use, Effect and Potential Therapy for Alzheimer's, MS and Parkinson's

October 15, 2007

Science Daily/European College of Neuropsychopharmacology

Cannabis (marijuana) is the most widely produced plant-based illicit drug worldwide and the illegal drug most frequently used in Europe. Its use increased in almost all EU countries during the 1990s, in particular among young people, including school students. Cannabis use is highest among 15- to 24-year-olds, with lifetime prevalence ranging for most countries from 20--40% (EMCDDA 2006).

Recently there has been a new surge in the level of concern about potential social and health outcomes of cannabis use, although the available evidence still does not provide a clear-cut understanding of the issues. Intensive cannabis use is correlated with non-drug-specific mental problems, but the question of co-morbidity is intertwined with the questions of cause and effect (EMCDDA 2006). Prevention is of importance in adolescents, which is underlined by evidence that early-onset cannabis-users (pre- to mid-adolescence) have a significantly higher risk of developing drug problems, including dependence (Von Sydow et al., 2002; Chen et al., 2005).

The illegal status and wide-spread use of cannabis made basic and clinical cannabis research difficult in the past decades; on the other hand, it has stimulated efforts to identify the psychoactive constituents of cannabis. As a consequence, the endocannabinoid system was discovered, which was shown to be involved in most physiological systems -- the nervous, the cardiovascular, the reproductive, the immune system, to mention a few.

One of the main roles of endocannabinoids is neuroprotection, but over the last decade they have been found to affect a long list of processes, from anxiety, depression, cancer development, vasodilatation to bone formation and even pregnancy (Panikashvili et al., 2001; Pachter et al., 2006).

Cannabinoids and endocannabinoids are supposed to represent a medicinal treasure trove which waits to be discovered.

Raphael Mechoulam will tell the discovery story of the endocannabinoid system. His research has not only helped us to advance our understanding of cannabis use and its effects, but has also made key contributions with regard to understanding "neuroprotection," and has opened the door for the development of new drugs.

Endocannabinoid system

In the 1960s the constituent of the cannabis plant was discovered -- named tetrahydrocannabinol, or THC -- which causes the 'high' produced by it (Gaoni & Mechoulam, 1964). Thousands of publications have since appeared on THC. Today it is even used as a therapeutic drug against nausea and for enhancing appetite, and, surprisingly, has not become an illicit drug -- apparently cannabis users prefer the plant-based marijuana and hashish.

Two decades later it was found that THC binds to specific receptors in the brain and the periphery and this interaction initiates a cascade of biological processes leading to the well known marijuana effects. It was assumed that a cannabinoid receptor is not formed for the sake of a plant constituent (that by a strange quirk of nature binds to it), but for endogenous brain constituents and that these putative 'signaling' constituents together with the cannabinoid receptors are part of a new biochemical system in the human body, which may affect various physiological actions. 

In trying to identify these unknown putative signaling molecules, our research group in the 1990s was successful in isolating 2 such endogenous 'cannabinoid' components -- one from the brain, named anandamide (from the word ´ananda, meaning ´supreme joy´ in Sanscrit), and another one from the intestines named 2-arachidonoyl glycerol (2-AG) (Devane et al., 1992; Mechoulam et al., 1995).

Neuroprotection

The major endocannabinoid (2-AG) has been identified both in the central nervous system and in the periphery. Stressful stimuli -- traumatic brain injury (TBI) for example -- enhance brain 2-AG levels in mice. 2-AG, both of endogenous and exogenous origin, has been shown to be neuroprotective in closed head injury, ischemia and excitotoxicity in mice. These effects may derive from the ability of cannabinoids to act through a variety of biochemical mechanisms. 2-AG also helps repair the blood brain barrier after TBI. 

The endocannabinoids act via specific cannabinoid receptors, of which the CB1 receptors are most abundant in the central nervous system. Mice whose CB1 receptors are knocked out display slower functional recovery after TBI and do not respond to treatment with 2-AG. Over the last few years several groups have noted that CB2 receptors are also formed in the brain, particularly as a reaction to numerous neurological diseases, and are apparently activated by the endocannabinoids as a protective mechanism.

Through evolution the mammalian body has developed various systems to guard against damage that may be caused by external attacks. Thus, it has an immune system, whose main role is to protect against protein attacks (microbes, parasites for example) and to reduce the damage caused by them. Analogous biological protective systems have also been developed against non-protein attacks, although they are much less well known than the immune system. Over the last few years the research group of Esther Shohami in collaboration with our group showed that the endocannabinoid system, through various biological routes, lowers the damage caused by brain trauma. Thus, it helps to attenuate the brain edema and the neurological injuries caused by it (Panikashvili et al., 2001; Panikashvili et al., 2006).

Clinical importance

Furthermore it is assumed that the endocannabinoid system may be involved in the pathogenesis of hepatic encephalopathy, a neuropsychiatric syndrome induced by fulminant hepatic failure. Indeed in an animal model the brain levels of 2-AG were found to be elevated. Administration of 2-AG improved a neurological score, activity and cognitive function (Avraham et al., 2006). Activation of the CB2 receptor by a selective agonist also improved the neurological score. The authors concluded that the endocannabinoid system may play an important role in the pathogenesis of hepatic encephalopathy. 

Modulation of this system either by exogenous agonists specific for the CB2 receptors or possibly also by antagonists to the CB1 receptors may have therapeutic potential. The endocannabinoid system generally is involved in the protective reaction of the mammalian body to a long list of neurological diseases such as multiple sclerosis, Alzheimer's and Parkinson's disease. Thus, there is hope for novel therapeutic opportunities.

Numerous additional endocannabinoids -- especially various fatty acid ethanolamides and glycerol esters -- are known today and regarded as members of a large ´endocannabinoid family´. Endogenous cannabinoids, the cannabinoid receptors and various enzymes that are involved in their syntheses and degradations comprise the endocannabinoid system.

The endocannabinoid system acts as a guardian against various attacks on the mammalian body.

Conclusion

The above described research concerning the endocannabinoid-system is of importance in both basic science and in therapeutics:

·     The discovery of the cannabis plant active constituent has helped advance our understanding of cannabis use and its effects.

·     The discovery of the endocannabinoids has been of central importance in establishing the existence of a new biochemical system and its physiological roles -- in particular in neuroprotection.

·     These discoveries have opened the door for the development of novel types of drugs, such as THC for the treatment of nausea and for enhancing appetite in cachectic patients.

·     The endocannabinoid system is involved in the protective reaction of the mammalian body to a long list of neurological diseases such as multiple sclerosis, Alzheimer's and Parkinson's disease which raises hope for novel therapeutic opportunities for these diseases.

References

Avraham Y, Israeli E, Gabbay E, et al. Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice. Neurobiology of Disease 2006;21:237-245

Chen CY, O´Brien MS, Anthony JC. Who becomes cannabis dependent soon after onset of use" Epidemiological evidence from the United States: 2000-2001. Drug and alcohol dependence 2005;79:11-22

Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946-1949

[EMCDDA 2006] European Monitoring Centre for Drugs and Drug Addiction. The state of the drugs problem in Europe. Annual Report 2006 (http://www.emcdda.europa.eu)

Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Amer Chem Soc 1964;86:1646-1647

Journal Interview 85: Conversation with Raphael Mechoulam. Addiction 2007;102:887-893

Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995;50:83-90

Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury. Trends Mol Med 2002;8:58-61

Pachter P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006;58:389-462

Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 2001;413:527-531

Panikashvili D, Shein NA, Mechoulam R, et al. The endocannabinoid 2-AG protects the blood brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Disease 2006;22:257-264

Von Sydow K, Lieb R, Pfister H, et al. What predicts incident use of cannabis and progression to abuse and dependence" A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Drug and alcohol dependence 2002;68:49-64

https://www.sciencedaily.com/releases/2007/10/071014163644.htm

Cannabis May Help Alleviate Allergic Skin Disease

August 17, 2007

Science Daily/The Hebrew University of Jerusalem

Administering a substance found in the cannabis plant can help the body's natural protective system alleviate an allergic skin disease (allergic contact dermatitis), an international group of researchers from Germany, Israel, Italy, Switzerland and the U.S. has found.

Allergic contact dermatitis is caused by reaction to something that directly contacts the skin. Many different substances (allergens) can cause allergic contact dermatitis. Usually these substances cause no trouble for most people, but if the skin is sensitive or allergic to the substance, any exposure will produce a rash, which may become very severe. Allergic contact dermatitis affects about 5 percent of men and 11percent of women in industrialized countries and is one of the leading causes for occupational diseases.

An article describing the work of the international research group, led by Dr Andreas Zimmer from the University of Bonn, was published recently in the journal Science. The article deals with alleviating allergic skin disease through what is called the endocannabinoid system. Among the members of the group is Prof. Raphael Mechoulam of the Hebrew University of Jerusalem School of Pharmacy.

In earlier work, Prof.Mechoulam's research group at the Hebrew University isolated two naturally occurring cannabinoid (cannabis-like) components -- one from the brain, named anandamide (from the word ananda, meaning supreme joy in Sanskrit), and another from the intestines named 2-AG. These two cannabinoids, plus their receptors and various enzymes that are involved in the cannnabinoids' syntheses and degradations, comprise the endocannabinoid system. These materials have similar effects to those of the active components in hashish and marijuana, produced from the cannabis plant.

Research by groups throughout the world has since shown that the endocannabinoid system is involved in many physiological processes, including the protective reaction of the mammalian body to a long list of neurological diseases, such as multiple sclerosis, Alzheimer's and Parkinson's.

In the article in Science, the researchers detail how the endocannabinoid system serves as a major regulator of cutaneous (skin) contact hypersensitivity (CHS) in a mouse model. In this model, they showed, for example, that mice lacking cannabinoid receptors display exacerbated inflammatory skin responses to an allergen.

Because the data indicate that enhanced activation of the endocannabinoid system may function to dampen the CHS response, the researchers administered cannabinoids such as tetrahydrocannabinol (THC), a constituent derived from the cannabis plant, to the experimental animals. They findings showed that the THC significantly decreased the allergic reaction in comparison to untreated mice.

In order to better understand the molecular mechanism that may contribute to the increased CHS in cannabinoid-receptor deficient mice, the researchers performed a series of experiments which showed that mouse skin cells produce a specific chemical (a chemokine) which is involved in the annoying disease reaction. Activation of the endocannabinoid system in the skin upon exposure to a contact allergen lowers the allergic responses through modulating the production of this chemokine.

The results thus clearly show a protective role for the endocannabinoid system in contact allergy in the skin and suggest that development of cannabinoid compounds based on elements produced from the cannabis plant could enhance therapeutic treatment for humans.

https://www.sciencedaily.com/releases/2007/08/070816094649.htm

Marijuana Component Opens the Door for Virus that Causes Kaposi's Sarcoma

August 2, 2007

Science Daily/American Association for Cancer Research

The major active component of marijuana could enhance the ability of the virus that causes Kaposi's sarcoma to infect cells and multiply, according to a team of researchers at Harvard Medical School. According to the researchers, low doses of Ä-9 tetrahydrocannabinol (THC), equivalent to that in the bloodstream of an average marijuana smoker, could be enough to facilitate infection of skin cells and could even coax these cells into malignancy.

While most people are not at risk from Kaposi's sarcoma herpes virus (KSHV), researchers say those with lowered immune systems, such as AIDS patients or transplant recipients, are more susceptible to developing the sarcoma as a result of infection. Their findings, reported in the August 1 issue of Cancer Research, a journal of the American Association for Cancer Research, offer cautionary evidence that those with weakened immune systems should speak with their doctors before using marijuana medicinally or recreationally.

"These findings raise some serious questions about using marijuana, in any form, if you have a weakened immune system," said lead study author Jerome E. Groopman, M.D., professor of medicine at Harvard Medical School. "While THC is best known as the main psychotropic part of marijuana, an analog of THC is the active ingredient of marinol, a drug frequently given to AIDS patients, among others, for increasing appetite and limiting chemotherapy-induced nausea and vomiting."

While previous studies indicated that marijuana smoking was associated with Kaposi's sarcoma, this is the first to demonstrate that THC itself can assist the virus in entering endothelial cells, which comprise skin and related tissue.

According to Dr. Groopman, the study illustrates the complicated role marijuana and other cannabinoids play in human health. Numerous types of cells display cannabinoid receptors on their outer surfaces, which act as switches that control cellular processes. Dr. Groopman's laboratory had previously demonstrated that THC could have a protective effect against a certain form of invasive, drug-resistant lung cancer.

To study the combined effect of THC and KSHV, the researchers examined a culture of human skin cells, which are susceptible to infection and could provide a model of Kaposi's sarcoma. These culture cells display many copies of two prominent cannabinoid receptors. Dr. Groopman and his colleagues found that by bonding to these receptors, low doses of THC activate two proteins responsible for maintaining a cell's internal framework, or cytoskeleton.

By altering the cytoskeleton, THC effectively opens the door for KSHV, allowing the virus to more easily enter and infect the cell. "We can take away that effect by using antagonists that block the two cannabinoid receptors, which adds evidence that THC is the culprit," Dr. Groopman said.

Once a cell is infected, the presence of THC may also promote the cellular events that turn it cancerous, the researchers say. They found that THC also promotes the production of a viral receptor similar to one that attracts a cell-signaling protein called interleukin-8. Previous studies have noted that this receptor could trigger the cell to reproduce, causing Kaposi's sarcoma-like lesions in mice. Indeed, the researchers saw that THC induced the infected cells to reproduce and form colonies in culture.

"Here we see both infection and malignancy going on in the presence of THC, offering some serious concerns about the safety of THC among those at risk," Dr. Groopman said. "Of course, we still do not know the exact molecular events that are occurring here, but these results are just the first part of our ongoing research."

The study was funded by the National Institutes of Health.

https://www.sciencedaily.com/releases/2007/08/070801112156.htm

Constituents of hashish and marijuana may help to fight inflammation and allergies

June 8, 2007

Science Daily/University of Bonn

Endocannabinoids seem to play an important role in regulating inflammation processes. Scientists have discovered this in experiments on mice. The study may also have implications for therapy. In animal experiments, a solution with an important component made from cannabis reduced allergic reactions of the skin.

Extracts of the hemp plant cannabis are traditionally used as a popular remedy against inflammation. At the beginning of the last century this natural remedy was even available at every chemist's. But due to the intoxicating effect of the component THC (tetrahydrocannabinol) the plant was taken off the chemist's shelves in the 1930s.

THC acts on the cannabinoid receptors, of which there are two types, CB1 and CB2. Both receptors are made such that THC can attach itself to them. In the brain this causes the intoxicating effect of hashish, cannabis and marijuana. But why does the body have CB1 and CB2 anyway" For two decades it has been known that the human body also produces its own cannabinoids. Like THC they can attach themselves to the receptors. The brain scientist Professor Andreas Zimmer from the Bonn Institute of Molecular Psychiatry is investigating what the function of this endocannabinoid system is. 'Mice without CB1 receptors show psychological abnormalities,' he explains. 'By contrast, CB2 regulates the growth of bones, for example.'

Coincidence

However, according to these most recent results, endocannabinoids also seem to play an important part in regulating inflammation processes. As is often the case with important discoveries, coincidence was involved. In scientific experiments mice are given an ear clip, so that researchers can tell them apart.' In most cases the mice can handle this without problems,' Dr. Meliha Karsak, a member of Professor Zimmer's team, explains. 'With our mice this was different. The skin around the ear clips became inflamed.' There are genetically modified strains of mice in which both cannabinoid receptors are dysfunctional.' And it was in precisely these strains that the inflammation occurred,' she explains.

Together with the Bonn dermatologists Dr. Evelyn Gaffal and Professor Thomas Tüting the researchers investigated these findings. Skin rash can be caused by allergens in laboratory mice. 'However, normally these rashes are only minor,' Dr. Gaffal emphasises. 'However, strains of mice in which the cannabinoid receptors are missing react much more intensely. We observed something similar when we blocked the receptors with medication.'

Step on the brakes

When inflammation occurs the endocannabinoids act like someone stepping on the brakes. They prevent the body from doing too much of a good thing and the immune reaction from getting out of control. This is consistent with the fact that at the beginning of the infection the endocannabinoid concentration increased in the mice. 'Apart from that there are strains of mice in which the breakdown of these active substances produced by the body is malfunction-ing,' Evelyn Gaffal says. 'They have an increased endocannabinoid concen-tration in their skin. In our experiments these animals also showed a less marked allergic reaction.'

The results open up new options for the treatment of skin allergies and inflammation. Firstly, drugs which prevent the breakdown of endocannabin-oids look promising. But the old household remedy cannabis could also make a comeback as an ointment. In the experiment on mice this approach has already been successful. 'If we dabbed THC solution on to the animals' skin shortly before and after applying the allergen, a lot less swelling occurred than normal,' Professor Thomas Tüting explains. 'THC attaches itself to cannabin-oid receptors and activates them. In this way the active substance reduces the allergic reaction.' Incidentally, ointment like this would probably not have an intoxicating effect, for this the amount of THC contained would be much too small.

https://www.sciencedaily.com/releases/2007/06/070607171120.htm

Marijuana vaporizer provides same level of THC, fewer toxins

May 16, 2007

Science Daily/University of California - San Francisco

A smokeless cannabis-vaporizing device delivers the same level of active therapeutic chemical and produces the same biological effect as smoking cannabis, but without the harmful toxins, according to University of California San Francisco researchers.

Results of a UCSF study, which focuses on delivery of the active ingredient delta-9-tertrahydrocannibinol, or THC, are reported in the online issue of the journal "Clinical Pharmacology and Therapeutics."

"We showed in a recent paper in the journal 'Neurology' that smoked cannabis can alleviate the chronic pain caused by HIV-related neuropathy, but a concern was expressed that smoking cannabis was not safe. This study demonstrates an alternative method that gives patients the same effects and allows controlled dosing but without inhalation of the toxic products in smoke," said study lead author Donald I. Abrams, MD, UCSF professor of clinical medicine.

The research team looked at the effectiveness of a device that heats cannabis to a temperature between 180 and 200 degrees C, just short of combustion, which occurs at 230 degrees C. Eighteen individuals were enrolled as inpatients for six days under supervision in the General Clinical Research Center at San Francisco General Hospital Medical Center.

Under the study protocol, the participants received on different days three different strengths of cannabis by two delivery methods--smoking or vaporization--three times a day.

Plasma concentrations of THC were measured along with the exhaled levels of carbon monoxide, or CO. A toxic gas, CO served as a marker for the many other combustion-generated toxins inhaled when smoking. The plasma concentrations of THC were comparable at all strengths of cannabis between smoking and vaporization. Smoking increased CO levels as expected, but there was little or no increase in CO levels after inhaling from the vaporizer, according to Abrams.

"Using CO as an indicator, there was virtually no exposure to harmful combustion products using the vaporizing device. Since it replicates smoking's efficiency at producing the desired THC effect using smaller amounts of the active ingredient as opposed to pill forms, this device has great potential for improving the therapeutic utility of THC," said study co-author Neal L. Benowitz, MD, UCSF professor of medicine, psychiatry and biopharmaceutical sciences. He added that pills tend to provide patients with more THC than they need for optimal therapeutic effect and increase side effects.

Patients rated the "high" they experienced from both smoking and vaporization and there was no difference between the two methods by patient self-report of the effect, according to study findings. In addition, patients were asked which method they preferred.

"By a significant majority, patients preferred vaporization to smoking, choosing the route of delivery with the fewest side effects and greatest efficiency," said Benowitz.

Co-authors include Cheryl A. Jay, MD, UCSF neurology; and Starley B. Shade, MPH; Hector Vizoso, RN; and Mary Ellen Kelly, MPH, UCSF Positive Health Program at San Francisco General Hospital Medical Center.

The study was funded by the University of California's Center for Medicinal Cannabis Research.

https://www.sciencedaily.com/releases/2007/05/070515151145.htm