Medical marijuana may ease some MS; Little evidence for other complementary or alternative therapies

March 24, 2014

Science Daily/American Academy of Neurology (AAN)

A new guideline from the American Academy of Neurology suggests that there is little evidence that most complementary or alternative medicine therapies (CAM) treat the symptoms of multiple sclerosis (MS). However, the guideline states the CAM therapies oral cannabis, or medical marijuana pills, and oral medical marijuana spray may ease patients' reported symptoms of spasticity, pain related to spasticity and frequent urination in multiple sclerosis (MS). The guideline, which is published in the March 25, 2014, print issue of Neurology®, the medical journal of the American Academy of Neurology, states that there is not enough evidence to show whether smoking marijuana is helpful in treating MS symptoms.

The guideline looked at CAM therapies, which are nonconventional therapies used in addition to or instead of doctor-recommended therapies. Examples include oral cannabis, or medical marijuana pills and oral medical marijuana spray, ginkgo biloba, magnetic therapy, bee sting therapy, omega-3 fatty acids and reflexology.

"Using different CAM therapies is common in 33 to 80 percent of people with MS, particularly those who are female, have higher education levels and report poorer health," said guideline lead author Vijayshree Yadav, MD, MCR, with Oregon Health & Science University in Portland and a member of the American Academy of Neurology. "People with MS should let their doctors know what types of these therapies they are taking, or thinking about taking."

For most CAM therapies, safety is unknown. There is not enough information to show if CAM therapies interact with prescription MS drugs. Most CAM therapies are not regulated by the Food and Drug Administration (FDA). Dronabinol and nabilone are synthetic forms of key ingredients in marijuana. The FDA approved both drugs as treatments for nausea and vomiting associated with cancer chemotherapy that do not respond to standard treatments. Dronabinol also is approved for loss of appetite associated with weight loss in patients with AIDS.

The guideline found that certain forms of medical marijuana, in pill or oral spray form only, may help reduce patients' reported spasticity symptoms, pain due to spasticity, and frequent urination but not loss of bladder control. The therapy may not help reduce tremor. Long-term safety of medical marijuana use in pill or oral spray is not known. Most of the studies are short, lasting six to 15 weeks. Medical marijuana in pill or oral spray form may cause side effects, some of which can be serious. Examples are seizures, dizziness, thinking and memory problems as well as psychological problems such as depression. This can be a concern given that some people with MS are at an increased risk for depression or suicide. Both doctors and patients must weigh the possible side effects that medical marijuana in pill or oral spray form can cause.

Among other CAM therapies studied for MS, ginkgo biloba might possibly help reduce tiredness but not thinking and memory problems. Magnetic therapy may also help reduce tiredness but not depression.

Reflexology might possibly help ease symptoms such tingling, numbness and other unusual skin sensations. Bee sting therapy, a low-fat diet with fish oil, and a therapy called the Cari Loder regimen all do not appear to help MS symptoms such as disability, depression and tiredness. Bee stings can cause a life-threatening allergic reaction and dangerous infections.

Moderate evidence shows that omega-3 fatty acids such as fish oil likely do not reduce relapses, disability, tiredness or MRI brain scan lesions, nor do they improve quality of life in people with MS.

https://www.sciencedaily.com/releases/2014/03/140324181258.htm

Marijuana's anxiety relief effects: Receptors found in emotional hub of brain

March 6, 2014

Science Daily/Vanderbilt University Medical Center

An international group led by Vanderbilt University researchers has found c, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

This is the first time cannabinoid receptors have been identified in the central nucleus of the amygdala in a mouse model, they report in the current issue of the journal Neuron.

The discovery may help explain why marijuana users say they take the drug mainly to reduce anxiety, said Sachin Patel, M.D., Ph.D., the paper's senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Led by first author Teniel Ramikie, a graduate student in Patel's lab, the researchers also showed for the first time how nerve cells in this part of the brain make and release their own natural "endocannabinoids."

The study "could be highly important for understanding how cannabis exerts its behavioral effects," Patel said. As the legalization of marijuana spreads across the country, more people -- and especially young people whose brains are still developing -- are being exposed to the drug.

Previous studies at Vanderbilt and elsewhere, Patel said, have suggested the following:

·     The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate.

·     Chronic stress or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their "buffering" effect, anxiety goes up.

·     While marijuana's "exogenous" cannabinoids also can reduce anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This can trigger "a vicious cycle" of increasing marijuana use that in some cases leads to addiction.

In the current study, the researchers used high-affinity antibodies to "label" the cannabinoid receptors so they could be seen using various microscopy techniques, including electron microscopy, which allowed very detailed visualization at individual synapses, or gaps between nerve cells.

"We know where the receptors are, we know their function, we know how these neurons make their own cannabinoids," Patel said. "Now can we see how that system is affected by … stress and chronic (marijuana) use? It might fundamentally change our understanding of cellular communication in the amygdala."

https://www.sciencedaily.com/releases/2014/03/140306142803.htm

Hempseed oil packed with health-promoting compounds

January 29, 2014

Science Daily/American Chemical Society

Long stigmatized because of its "high"-inducing cousins, hemp -- derived from low-hallucinogenic varieties of cannabis -- is making a comeback, not just as a source of fiber for textiles, but also as a crop packed with oils that have potential health benefits. A new study, which appears in ACS' Journal of Agricultural and Food Chemistry, details just how many healthful compounds hempseed oil contains.

Maria Angeles Fernández-Arche and colleagues note that for millennia, people around the world cultivated cannabis for textiles, medicine and food. Hemp has high levels of vitamins A, C and E and beta carotene, and it is rich in protein, carbohydrates, minerals and fiber. In the early 20th century, many countries banned cannabis because some varieties contain large amounts of the high-inducing compound THC. And although Colorado recently legalized recreational marijuana use -- and some states have passed medical marijuana laws -- the drug remains illegal according to U.S. federal law. But the European Union has legalized growing low-THC versions of hemp, and it's making its way back into fabrics and paper. With increasing interest in plant oils as a source of healthful compounds, Fernández-Arche's team wanted to investigate hempseed oil's potential.

They did a detailed analysis of a portion of hempseed oil. They found it has a variety of interesting substances, such as sterols, aliphatic alcohols and linolenic acids, that research suggests promote good health. For example, it contains α-linolenic acid, which is an omega-3 fatty acid that some studies suggest helps prevent coronary heart disease. The findings could have implications in the pharmaceutical, cosmetic, food and non-food industries, they state.

https://www.sciencedaily.com/releases/2014/01/140129115155.htm

Drugs related to cannabis have pain-relieving potential for osteoarthritis

January 7, 2014

Science Daily/University of Nottingham

Chemical compounds synthesized in the laboratory, similar to those found in cannabis, could be developed as potential drugs to reduce the pain of osteoarthritis.

These compounds could also reduce joint inflammation, according to new research carried out at the Arthritis Research UK Pain Centre at The University of Nottingham.

Cannabis contains a number of natural chemicals called cannabinoids and the brain has the ability to respond to such compounds. Cannabis and synthetically manufactured cannabinoid compounds can relieve pain in animal models of arthritis, but their use has been limited because of undesirable psychological side-effects.

Now a team of researchers led by Professor Victoria Chapman at the Arthritis Research UK Pain Centre at The University of Nottingham have shown that selectively targeting one of the molecules involved in the body's natural pain-sensing pathways, called cannabinoid receptor2 (CB2) can also reduce pain in animal models of osteoarthritis. This works in part through the central nervous system (spinal cord and brain). The compound used in this study, called JWH133, is a synthetic cannabinoid molecule manufactured in a laboratory and is not derived from the cannabis plant.

When the research was extended to humans, studies of the human spinal cord tissue showed for the first time the presence of this receptor and, interestingly, that the amount of receptor was related to the severity of the osteoarthritis. This provides evidence from patients that this drug target may have clinical relevance to osteoarthritis pain.

Cannabinoids are known to have anti-inflammatory effects, and the team have demonstrated that JWH133 reduced the levels of inflammation in their studies of osteoarthritis. Thus, cannabinoid CB2 targeted drugs may have a dual beneficial effect for people with osteoarthritis by providing pain relief as well as reducing inflammation in the joint.

Their findings are published online in the journal PLOS One.

Victoria Chapman, Professor of Neuropharmacology, said: "This finding is significant, as spinal and brain pain signalling pathways are known to make a major contribution to pain associated with osteoarthritis. These new data support the further evaluation of the selective cannabinoid-based interventions for the treatment of osteoarthritis pain."

Professor Alan Silman, medical director of Arthritis Research UK, added: "Millions of people are living with the severe, debilitating pain caused by osteoarthritis, and better pain relief is urgently needed. This research does not support the use of recreational cannabis use. What it does suggest is that there is potential to develop a synthetic drug that mimics the behavior of cannabinoid receptors without causing serious side effects."

Osteoarthritis affects eight million people the UK and occurs when the cartilage at the ends of bones wears away, causing joint pain and stiffness, and is a major cause of pain and disability. Current treatment is limited to pain relief, exercise, physiotherapy weight-loss and joint replacement. There are currently no drugs that slow down its progression, and more effective treatment is urgently needed.

https://www.sciencedaily.com/releases/2014/01/140107092825.htm

Molecule discovered that protects brain from cannabis intoxication

January 2, 2014

Science Daily/INSERM (Institut national de la santé et de la recherche médicale)

Two INSERM research teams recently discovered that pregnenolone, a molecule produced by the brain, acts as a natural defense mechanism against the harmful effects of cannabis in animals. Pregnenolone prevents THC, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC causes the intoxicating effects of cannabis. By identifying this mechanism, the INSERM teams are already developing new approaches for the treatment of cannabis addiction.

These results are to be published in Science on 3 January.

Over 20 million people around the world are addicted to cannabis, including a little more than a half million people in France. In the last few years, cannabis addiction has become one of the main reasons for seeking treatment in addiction clinics. Cannabis consumption is particularly high (30%) in individuals between 16 to 24 years old, a population that is especially susceptible to the harmful effects of the drug.

While cannabis consumers are seeking a state of relaxation, well-being and altered perception, there are many dangers associated to a regular consumption of cannabis. Two major behavioural problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation. Thus, in addition to being extremely dependent on the drug, regular users of cannabis show signs of memory loss and a lack of motivation that make quite hard their social insertion.

The main active ingredient in cannabis, THC, acts on the brain through CB1 cannabinoid receptors located in the neurons. THC binds to these receptors diverting them from their physiological roles, such as regulating food intake, metabolism, cognitive processes and pleasure. When THC overstimulates CB1 receptors, it triggers a reduction in memory abilities, motivation and gradually leads to dependence.

Increase of dopamine release

Developing an efficient treatment for cannabis addiction is becoming a priority of research in the fiend of drug addiction.

In this context, the INSERM teams led by Pier Vincenzo Piazza and Giovanni Marsicano have investigated the potential role of pregnenolone a brain produced steroid hormone. Up to now, pregnenolone was considered the inactive precursor used to synthesize all the other steroid hormones (progesterone, estrogens, testosterone, etc.). The INSERM researchers have now discovered that pregnenolone has quite an important functional role: it provide a natural defence mechanism that can protect the brain from the harmful effects of cannabis.

Essentially, when high doses of THC (well above those inhaled by regular users) activate the CB1 cannabinoid receptor they also trigger the synthesis of pregnenolone. Pregnenole then binds to a specific site on the same CB1 receptors and reducing the effects of THC.

The administration of pregnenolone at doses that increase the brain's level of this hormone even more, antagonize the behavioral effects of cannabis.

At the neurobiological level, pregnenolone greatly reduces the release of dopamine triggered by THC. This is an important effect, since the addictive effects of drugs involve an excessive release of dopamine.

This negative feedback mediated by pregnenolone (THC is what triggers the production of pregnenolone, which then inhibits the effects of THC) reveal a previously unknown endogenous mechanism that protects the brain from an over-activation of CB1 receptor.

A protective mechanism that opens the doors to a new therapeutic approach.

The role of pregnenolone was discovered when, rats were given equivalent doses of cocaine, morphine, nicotine, alcohol and cannabis and the levels of several brain steroids (pregnenolone, testosterone, allopregnenolone, DHEA etc..) were measured. It was then found that only one drug, THC, increased brain steroids and more specifically selectively one steroid, pregnenolone, that went up3000% for a period of two hours.

The effect of administering THC on the pregnenolone synthesis (PREG) and other brain steroids

This increase in pregnenolone is a built-in mechanism that moderates the effects of THC. Thus, the effects of THC increase when pregnenolone synthesis is blocked. Conversely, when pregnenolone is administered to rats or mice at doses (2-6 mg/kg) that induce even greater concentrations of the hormone in the brain, the negative behavioural effects of THC are blocked. For example, the animals that were given pregnenolone recover their normal memory abilities, are less sedated and less incline to self-administer cannabinoids.

Experiments conducted in cell cultures that express the human CB1 receptor confirm that pregnenolone can also counteract the molecular action of THC in humans.

Pier Vincenzo Piazza explains that pregnenolone itself cannot be used as a treatment "Pregnenolone cannot be used as a treatment because it is badly absorbed when administerd orally and once in the blood stream it is rapidly transformed in other steroids."

However, the researcher says that there is strong hope of seeing a new addiction therapy emerge from this discovery. "We have now developed derivatives of pregnenolone that are well absorbed and stable. They then present the characteristics of compounds that can be used as new class of therapeutic drugs. We should be able to begin clinical trials soon and verify whether we have indeed discovered the first pharmacological treatment for cannabis dependence."

https://www.sciencedaily.com/releases/2014/01/140102142012.htm

Scientists discover potential new way to treat anxiety

August 4, 2013

Science Daily/Vanderbilt University Medical Center

Chemically modified inhibitors of the COX-2 enzyme relieve anxiety behaviors in mice by activating natural "endocannabinoids" without gastrointestinal side effects, Vanderbilt University scientists will report next week.

Endocannabinoids are natural signaling molecules that activate cannabinoid receptors in the brain, the same receptors turned on by the active ingredient in marijuana.

These receptors are also found in the gastrointestinal system and elsewhere in the body, and there is evidence that they play a role in wide range of physiological and pathological processes, in addition to modulating stress and anxiety.

If the "substrate-selective" COX-2 inhibitors developed at Vanderbilt also work in humans without side effects, they could represent a new approach to treating mood and anxiety disorders, the researchers conclude in a paper to be posted online Sunday in the journal Nature Neuroscience.

Clinical trials of some of these potential drugs could begin in the next several years, said Lawrence Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology and the paper's co-senior author with Sachin Patel, M.D., Ph.D.

The Vanderbilt scientists are pursuing other potential applications of activating endocannabinoids by substrate-selective COX-2 inhibition, including relieving pain, treating movement disorders, and possibly preventing colon cancer.

"The door is really wide open," said Patel, assistant professor of Psychiatry and of Molecular Physiology & Biophysics. "We've just scratched the surface."

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) relieve pain and inflammation by blocking either or both of the cyclooxygenase (COX) enzymes, which produce pro-inflammatory prostaglandins.

It has been known for several years that COX-2 inhibition also activates endocannabinoids.

Because the "substrate selective" inhibitors developed at Vanderbilt increase endocannabinoid levels in the mouse without blocking prostaglandin production, "we think (they) will not have the gastrointestinal and possibly cardiovascular side effects that other NSAIDs do," said Marnett, University Professor and Mary Geddes Stahlman Professor of Cancer Research.

"We thought we knew everything there was to know about (COX-2 inhibitors) until about five years ago when we discovered the substrate selective inhibition," he added. The approach used by the Vanderbilt team "is a really powerful way to help design the next generation of drugs."

https://www.sciencedaily.com/releases/2013/08/130804144523.htm

Cannabis constituent has no effect on multiple sclerosis progression

July 23, 2013

Science Daily/University of Plymouth

The first large non-commercial clinical study to investigate whether the main active constituent of cannabis (tetrahydrocannabinol or THC) is effective in slowing the course of progressive multiple sclerosis (MS), shows that there is no evidence to suggest this; although benefits were noted for those at the lower end of the disability scale.

The study is published in The Lancet Neurology.

The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study was carried out by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry. The study was funded by the Medical Research Council (MRC), the Multiple Sclerosis Society and the Multiple Sclerosis Trust, and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

CUPID enrolled nearly 500 people with MS from 27 centres around the UK, and has taken eight years to complete. People with progressive MS were randomised to receive either THC capsules or identical placebo capsules for three years, and were carefully followed to see how their MS changed over this period. The two main outcomes of the trial were a disability scale administered by neurologists (the Expanded Disability Status Scale), and a patient report scale of the impact of MS on people with the condition (the Multiple Sclerosis Impact Scale 29).

Overall the study found no evidence to support an effect of THC on MS progression in either of the main outcomes. However, there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of enrolment but, as the benefit was only found in a small group of people rather than the whole population, further studies will be needed to assess the robustness of this finding.

One of the other findings of the trial was that MS in the study population as a whole progressed slowly, more slowly than expected. This makes it more challenging to find a treatment effect when the aim of the treatment is to slow progression.

As well as evaluating the potential neuroprotective effects and safety of THC over the long-term, one of the aims of the CUPID study was to improve the way that clinical trial research is done, by exploring newer methods of measuring MS and using the latest statistical methods to make the most of every piece of information collected. This analysis continued for several months and has provided important information about conducting further large scale clinical trials in MS.

Professor John Zajicek, Professor of Clinical Neuroscience at Plymouth University Peninsula Schools of Medicine and Dentistry, said: "To put this study into context: current treatments for MS are limited, either being targeted at the immune system in the early stages of the disease or aimed at easing specific symptoms such as muscle spasms, fatigue or bladder problems. At present there is no treatment available to slow MS when it becomes progressive. Progression of MS is thought to be due to death of nerve cells, and researchers around the world are desperately searching for treatments that may be 'neuroprotective'. Laboratory experiments have suggested that certain cannabis derivatives may be neuroprotective."

He added: "Overall our research has not supported laboratory based findings and shown that, although there is a suggestion of benefit to those at the lower end of the disability scale when they joined CUPID, there is little evidence to suggest that THC has a long term impact on the slowing of progressive MS."

https://www.sciencedaily.com/releases/2013/07/130723113703.htm

Brain makes its own version of Valium

May 30, 2013

Science Daily/Stanford University Medical Center

Researchers at the Stanford University School of Medicine have found that a naturally occurring protein secreted only in discrete areas of the mammalian brain may act as a Valium-like brake on certain types of epileptic seizures.

The protein is known as diazepam binding inhibitor, or DBI. It calms the rhythms of a key brain circuit and so could prove valuable in developing novel, less side-effect-prone therapies not only for epilepsy but possibly for anxiety and sleep disorders, too. The researchers' discoveries will be published May 30 in Neuron.

"This is one of the most exciting findings we have had in many years," said John Huguenard, PhD, professor of neurology and neurological sciences and the study's senior author. "Our results show for the first time that a nucleus deep in the middle of the brain generates a small protein product, or peptide, that acts just like benzodiazepines." This drug class includes not only the anti-anxiety compound Valium (generic name diazepam), first marketed in 1965, but its predecessor Librium, discovered in 1955, and the more recently developed sleep aid Halcyon.

Valium, which is notoriously addictive, prone to abuse and dangerous at high doses, was an early drug treatment for epilepsy, but it has fallen out of use for this purpose because its efficacy quickly wears off and because newer, better anti-epileptic drugs have come along.

For decades, DBI has also been known to researchers under a different name: ACBP. In fact, it is found in every cell of the body, where it is an intracellular transporter of a metabolite called acyl-CoA. "But in a very specific and very important brain circuit that we've been studying for many years, DBI not only leaves the cells that made it but is -- or undergoes further processing to become -- a natural anti-epileptic compound," Huguenard said. "In this circuit, DBI or one of its peptide fragments acts just like Valium biochemically and produces the same neurological effect."

Other endogenous (internally produced) substances have been shown to cause effects similar to psychoactive drugs. In 1974, endogenous proteins called endorphins, with biochemical activity and painkilling properties similar to that of opiates, were isolated. A more recently identified set of substances, the endocannabinoids, mimic the memory-, appetite- and analgesia-regulating actions of the psychoactive components of cannabis, or marijuana.

DBI binds to receptors that sit on nerve-cell surfaces and are responsive to a tiny but important chemical messenger, or neurotransmitter, called GABA. The roughly one-fifth of all nerve cells in the brain that are inhibitory mainly do their job by secreting GABA, which binds to receptors on nearby nerve cells, rendering those cells temporarily unable to fire any electrical signals of their own.

Benzodiazepine drugs enhance GABA-induced inhibition by binding to a different site on GABA receptors from the one GABA binds to. That changes the receptor's shape, making it hyper-responsive to GABA. These receptors come in many different types and subtypes, not all of which are responsive to benzodiazepines. DBI binds to the same spot to which benzodiazepines bind on benzodiazepine-responsive GABA receptors. But until now, exactly what this means has remained unclear.

Huguenard, along with postdoctoral scholar and lead author Catherine Christian, PhD, and several Stanford colleagues zeroed in on DBI's function in the thalamus, a deep-brain structure that serves as a relay station for sensory information, and which previous studies in the Huguenard lab have implicated on the initiation of seizures. The researchers used single-nerve-cell-recording techniques to show that within a GABA-secreting nerve-cell cluster called the thalamic reticular nucleus, DBI has the same inhibition-boosting effect on benzodiazepine-responsive GABA receptors as do benzodiazepines. Using bioengineered mice in which those receptors' benzodiazepine-binding site was defective, they showed that DBI lost its effect, which Huguenard and Christian suggested makes these mice seizure-prone.

In another seizure-prone mouse strain in which that site is intact but the gene for DBI is missing, the scientists saw diminished inhibitory activity on the part of benzodiazepine-responsive GABA receptors. Re-introducing the DBI gene to the brains of these mice via a sophisticated laboratory technique restored the strength of the GABA-induced inhibition. In normal mice, a compound known to block the benzodiazepine-binding site weakened these same receptors' inhibitory activity in the thalamic reticular nucleus, even in the absence of any administered benzodiazepines. This suggested that some naturally occurring benzodiazepine-like substance was being displaced from the benzodiazepine-binding site by the drug. In DBI-gene-lacking mice, the blocking agent had no effect at all.

Huguenard's team also showed that DBI has the same inhibition-enhancing effect on nerve cells in an adjacent thalamic region -- but also that, importantly, no DBI is naturally generated in or near this region; in the corticothalamic circuit, at least, DBI appears to be released only in the thalamic reticular nucleus. So, the actions of DBI on GABA receptors appear to be tightly controlled to occur only in specific brain areas.

Huguenard doesn't know yet whether it is DBI per se, or one of its peptide fragments (and if so which one), that is exerting the active inhibitory role. But, he said, by finding out exactly which cells are releasing DBI under what biochemical circumstances, it may someday be possible to develop agents that could jump-start and boost its activity in epileptic patients at the very onset of seizures, effectively nipping them in the bud.

https://www.sciencedaily.com/releases/2013/05/130530132429.htm

Marijuana users have better blood sugar control

May 15, 2013

Science Daily/Elsevier

Regular marijuana use is associated with favorable indices related to diabetic control, say investigators. They found that current marijuana users had significantly lower fasting insulin and were less likely to be insulin resistant, even after excluding patients with a diagnosis of diabetes mellitus. Their findings are reported in the current issue of The American Journal of Medicine.

Marijuana (Cannabis sativa) has been used for centuries to relieve pain, improve mood, and increase appetite. Outlawed in the United States in 1937, its social use continues to increase and public opinion is swinging in favor of the medicinal use of marijuana. There are an estimated 17.4 million current users of marijuana in the United States. Approximately 4.6 million of these users smoke marijuana daily or almost daily. A synthetic form of its active ingredient, tetrahydrocannabinol, commonly known as THC, has already been approved to treat side-effects of chemotherapy, AIDS-induced anorexia, nausea, and other medical conditions. With the recent legalization of recreational marijuana in two states and the legalization of medical marijuana in 19 states and the District of Columbia, physicians will increasingly encounter marijuana use among their patient populations.

A multicenter research team analyzed data obtained during the National Health and Nutrition Survey (NHANES) between 2005 and 2010. They studied data from 4,657 patients who completed a drug use questionnaire. Of these, 579 were current marijuana users, 1,975 had used marijuana in the past but were not current users, and 2,103 had never inhaled or ingested marijuana. Fasting insulin and glucose were measured via blood samples following a nine hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance.

Participants who reported using marijuana in the past month had lower levels of fasting insulin and HOMA-IR and higher levels of high-density lipoprotein cholesterol (HDL-C). These associations were weaker among those who reported using marijuana at least once, but not in the past thirty days, suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use. Current users had 16% lower fasting insulin levels than participants who reported never having used marijuana in their lifetimes.

Large waist circumference is linked to diabetes risk. In the current study there were also significant associations between marijuana use and smaller waist circumferences.

"Previous epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared to people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes, but ours is the first study to investigate the relationship between marijuana use and fasting insulin, glucose, and insulin resistance," says lead investigator Murray A. Mittleman, MD, DrPH, of the Cardiovascular Epidemiology Research Unit at the Beth Israel Deaconess Medical Center, Boston.

"It is possible that the inverse association in fasting insulin levels and insulin resistance seen among current marijuana users could be in part due to changes in usage patterns among those with a diagnosis of diabetes (i.e., those with diabetes may have been told to cease smoking). However, after we excluded those subjects with a diagnosis of diabetes mellitus, the associations between marijuana use and insulin levels, HOMA-IR, waist circumference, and HDL-C were similar and remained statistically significant," states Elizabeth Penner, MD, MPH, an author of the study.

Although people who smoke marijuana have higher average caloric intake levels than non-users, marijuana use has been associated with lower body-mass index (BMI) in two previous surveys. "The mechanisms underlying this paradox have not been determined and the impact of regular marijuana use on insulin resistance and cardiometabolic risk factors remains unknown," says coauthor Hannah Buettner.

The investigators acknowledge that data on marijuana use were self-reported and may be subject to underestimation or denial of illicit drug use. However, they point out, underestimation of drug use would likely yield results biased toward observing no association.

Editor-in-Chief Joseph S. Alpert, MD, Professor of Medicine at the University of Arizona College of Medicine, Tucson, comments, "These are indeed remarkable observations that are supported, as the authors note, by basic science experiments that came to similar conclusions.

"We desperately need a great deal more basic and clinical research into the short- and long-term effects of marijuana in a variety of clinical settings such as cancer, diabetes, and frailty of the elderly," continues Alpert." I would like to call on the NIH and the DEA to collaborate in developing policies to implement solid scientific investigations that would lead to information assisting physicians in the proper use and prescription of THC in its synthetic or herbal form."

https://www.sciencedaily.com/releases/2013/05/130515085208.htm

Brain-imaging study links cannabinoid receptors to post-traumatic stress disorder: First pharmaceutical treatment for PTSD within reach

May 14, 2013

Science Daily/NYU Langone Medical Center

In a first-of-its-kind effort to illuminate the biochemical impact of trauma, researchers at NYU Langone Medical Center have discovered a connection between the quantity of cannabinoid receptors in the human brain, known as CB1 receptors, and post-traumatic stress disorder, the chronic, disabling condition that can plague trauma victims with flashbacks, nightmares and emotional instability.

Their findings, which appear online today in the journal Molecular Psychiatry, will also be presented this week at the annual meeting of the Society of Biological Psychiatry in San Francisco.

CB1 receptors are part of the endocannabinoid system, a diffuse network of chemicals and signaling pathways in the body that plays a role in memory formation, appetite, pain tolerance and mood. Animal studies have shown that psychoactive chemicals such as cannabis, along with certain neurotransmitters produced naturally in the body, can impair memory and reduce anxiety when they activate CB1 receptors in the brain. Lead author Alexander Neumeister, MD, director of the molecular imaging program in the Departments of Psychiatry and Radiology at NYU School of Medicine, and colleagues are the first to demonstrate through brain imaging that people with PTSD have markedly lower concentrations of at least one of these neurotransmitters -- an endocannabinoid known as anandamide -- than people without PTSD. Their study, which was supported by three grants from the National Institutes of Health, illuminates an important biological fingerprint of PTSD that could help improve the accuracy of PTSD diagnoses, and points the way to medications designed specifically to treat trauma.

"There's not a single pharmacological treatment out there that has been developed specifically for PTSD," says Dr. Neumeister. "That's a problem. There's a consensus among clinicians that existing pharmaceutical treatments such as antidepressant simple do not work. In fact, we know very well that people with PTSD who use marijuana -- a potent cannabinoid -- often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications. Clearly, there's a very urgent need to develop novel evidence-based treatments for PTSD."

The study divided 60 participants into three groups: participants with PTSD; participants with a history of trauma but no PTSD; and participants with no history of trauma or PTSD. Participants in all three groups received a harmless radioactive tracer that illuminates CB1 receptors when exposed to positron emissions tomography (PET scans). Results showed that participants with PTSD, especially women, had more CB1 receptors in brain regions associated with fear and anxiety than volunteers without PTSD. The PTSD group also had lower levels of the neurotransmitter anandamide, an endocannabinoid that binds to CB1. If anandamide levels are too low, Dr. Neumeister explains, the brain compensates by increasing the number of CB1 receptors. "This helps the brain utilize the remaining endocannabinoids," he says.

Much is still unknown about the effects of anandamide in humans but in rats the chemical has been shown to impair memory. "What is PTSD? It's an illness where people cannot forget what they have experienced," Dr. Neumeister says. "Our findings offer a possible biological explanation for this phenomenon."

Current diagnostics for PTSD rely on subjective measures and patient recall, making it difficult to accurately diagnose the condition or discern its symptoms from those of depression and anxiety. Biological markers of PTSD, such as tests for CB1 receptors and anandamide levels, could dramatically improve diagnosis and treatment for trauma victims.

Among the 1.7 million men and women who have served in the wars in Iraq and Afghanistan, an estimated 20% have PTSD. But PTSD is not limited to soldiers. Trauma from sexual abuse, domestic violence, car accidents, natural disaster, violent assault or even a life-threatening medical diagnosis can lead to PTSD. The condition affects nearly 8 million Americans annually.

These findings were made possible through the collaborative efforts of researchers at NYU School of Medicine, Yale School of Medicine, Harvard Medical School, the Department of Veterans Affairs National Center for PTSD and the University of California at Irvine.

https://www.sciencedaily.com/releases/2013/05/130514085016.htm

Synthetic derivatives of THC may weaken HIV-1 infection to enhance antiviral therapies

April 30, 2013

Science Daily/Federation of American Societies for Experimental Biology

A new use for compounds related in composition to the active ingredient in marijuana may be on the horizon: a new research report published in the Journal of Leukocyte Biology shows that compounds that stimulate the cannabinoid type 2 (CB2) receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection. The CB2 receptor is the molecular link through which the pharmaceutical properties of cannabis are manifested. Diminishing HIV-1 infection in this manner might make current anti-viral therapies more effective and provide some protection against certain HIV-1 complications.

"The synthetic compounds we used in our study may show promise in helping the body fight HIV-1 infection,'" said Yuri Persidsky, M.D., Ph.D., a researcher involved in the work from the Department of Pathology and Laboratory Medicine at Temple University School of Medicine in Philadelphia, PA. "As compounds like these are improved further and made widely available, we will continue to explore their potential to fight other viral diseases that are notoriously difficult to treat."

To make this discovery, scientists used a cell culture model to infect human macrophages with HIV-1 and added synthetic compounds similar to the active ingredient in marijuana to activate the CB2 receptor. At different times during the infection, samples from the culture were taken to see if the replication of the HIV virus was decreased. The researchers observed diminished HIV growth and a possible protective effect from some HIV-1 complications.

"HIV/AIDS has posed one of the most significant health challenges in modern medicine," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "Recent high profile vaccine failures mean that all options need to be on the table to prevent or treat this devastating infection. Research on the role of cannabinoid type 2 receptors and viral infection may one day allow targeting these receptors to be part of combination therapies that use exploit multiple weaknesses of the virus simultaneously."

https://www.sciencedaily.com/releases/2013/04/130430131530.htm

Key shift in brain that creates drive to overeat identified

April 29, 2013

Science Daily/Indiana University

A team of American and Italian neuroscientists has identified a cellular change in the brain that accompanies obesity. The findings could explain the body's tendency to maintain undesirable weight levels, rather than an ideal weight, and identify possible targets for pharmacological efforts to address obesity.

The findings, published in the Proceedings of the National Academy of Sciences Early Edition this week, identify a switch that occurs in neurons within the hypothalamus. The switch involves receptors that trigger or inhibit the release of the orexin A peptide, which stimulates the appetite, among other behaviors. In normal-weight mice, activation of this receptor decreases orexin A release. In obese mice, activation of this receptor stimulates orexin A release.

"The striking finding is that you have a massive shift of receptors from one set of nerve endings impinging on these neurons to another set," said Ken Mackie, professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. "Before, activating this receptor inhibited the secretion of orexin; now it promotes it. This identifies potential targets where an intervention could influence obesity."

The work is part of a longstanding collaboration between Mackie's team at the Gill Center for Biomolecular Science at IU Bloomington and Vincenzo Di Marzo's team at the Institute of Biomolecular Chemistry in Pozzuoli, Italy. Both teams study the endocannabinoid system, which is composed of receptors and signaling chemicals that occur naturally in the brain and have similarities to the active ingredients in cannabis, or marijuana. This neurochemical system is involved in a variety of physiological processes, including appetite, pain, mood, stress responses and memory.

Food consumption is controlled in part by the hypothalamus, a portion of the brain that regulates many essential behaviors. Like other important body systems, food consumption is regulated by multiple neurochemical systems, including the endocannabinoid system, representing what Mackie describes as a "balance of a very fine web of regulatory networks."

An emerging idea, Mackie said, is that this network is reset during obesity so that food consumption matches maintenance of current weight, not a person's ideal weight. Thus, an obese individual who loses weight finds it difficult to keep the weight off, as the brain signals the body to eat more in an attempt to return to the heavier weight.

Using mice, this study found that in obesity, CB1 cannabinoid receptors become enriched on the nerve terminals that normally inhibit orexin neuron activity, and the orexin neurons produce more of the endocannabinoids to activate these receptors. Activating these CB1 receptors decreases inhibition of the orexin neurons, increasing orexin A release and food consumption.

"This study identifies a mechanism for the body's ongoing tendency to return to the heavier weight," Mackie said.

The researchers conducted several experiments with mice to understand how this change takes place. They uncovered a role of leptin, a key hormone made by fat cells that influences metabolism, hunger and food consumption. Obesity causes leptin levels to be chronically high, making brain cells less sensitive to its actions, which contributes to the molecular switch that leads to the overproduction of orexin.

https://www.sciencedaily.com/releases/2013/04/130429154214.htm

Mental illness linked to heavy cannabis use

April 2, 2013

Science Daily/Centre for Addiction and Mental Health

People with mental illnesses are more than seven times more likely to use cannabis weekly compared to people without a mental illness, according to researchers from the Centre for Addiction and Mental Health (CAMH) who studied U.S. data.

Cannabis is the most widely used illicit substance globally, with an estimated 203 million people reporting use. Although research has found links between cannabis use and mental illness, exact numbers and prevalence of problem cannabis use had not been investigated.

"We know that people with mental illness consume more cannabis, perhaps partially as a way to self- medicate psychiatric symptoms, but this data showed us the degree of the correlation between cannabis use, misuse, and mental illness," said Dr. Shaul Lev-ran, Adjunct Scientist at CAMH and Head of Addiction Medicine at the Sheba Medical Center, Israel.

"Based on the number of individuals reporting weekly use, we see that people with mental illness use cannabis at high rates. This can be of concern because it could worsen the symptoms of their mental illness," said Lev-ran, who conducted the research as a post-doctoral fellow with the Social Aetiology of Mental Illness (SAMI) Training Program at CAMH.

Researchers also found that individuals with mental illness were 10 times more likely to have a cannabis use disorder.

In this new study, published in the journal Comprehensive Psychiatry, CAMH researchers analyzed data from face-to-face interviews with over 43,000 respondents over the age of 18 from the National Epidemiologic Survey on Alcohol and Related Conditions. Using structured questionnaires, the researchers assessed cannabis use as well as various mental illnesses including depression, anxiety, drug and alcohol use disorders and personality disorders, based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).

Among those will mental illness reporting at least weekly cannabis use, rates of use were particularly elevated for those with bipolar disorder, personality disorders and other substance use disorders.

In total, 4.4 per cent of individuals with a mental illness in the past 12 months reported using cannabis weekly, compared to 0.6 per cent among individuals without any mental illness. Cannabis use disorders occurred among 4 per cent of those with mental illness versus 0.4 per cent among those without.

Researchers also noted that, although cannabis use is generally higher among younger people, the association between mental illness and cannabis use was pervasive across most age groups.

They emphasize the importance of screening for frequent and problem cannabis use among those with mental illness, so that targeted prevention and intervention may be employed.

This study was funded through the SAMI Training Program of the Canadian Institutes of Health Research (CIHR).

https://www.sciencedaily.com/releases/2013/04/130402124817.htm

How the brain suppresses pain during times of stress

March 6, 2013

Science Daily/National University of Ireland, Galway

New findings about how the brain functions to suppress pain have been published in the leading journal in the field Pain, by National University of Ireland Galway (NUI Galway) researchers. For the first time, it has been shown that suppression of pain during times of fear involves complex interplay between marijuana-like chemicals and other neurotransmitters in a brain region called the amygdala.

The work was carried out by Dr David Finn and his research team in Pharmacology and Therapeutics, Centre for Pain Research and Galway Neuroscience Centre at the National Centre for Biomedical Engineering Science, NUI Galway. The research builds on previous breakthrough findings from Dr Finn's research group on the role of marijuana-like chemicals in the brain's hippocampus in pain suppression during fear.

Pain is both a sensory and an emotional experience and is subject to modulation by a number of factors including fear and stress. During exposure to a high-stress environment or stimulus, pain transmission and perception can be potently suppressed. This important survival response can help us cope with or escape from potentially life-threatening situations. One brain region that is integral to the processing and expression of both emotional responses and pain is the amygdala.

Working with Dr Finn, first author Dr Kieran Rea was able to confirm the amygdala as a key brain region in the suppression of pain behaviour by fear (so-called fear-induced analgesia). Fear-induced analgesia was associated with increases in levels of marijuana-like substances known as endocannabinoids in the amygdala.

Furthermore, fear-induced analgesia was prevented by injecting a drug that blocked the receptor at which these endocannabinoids act into the amygdala. Further experimentation revealed that these effects involved an interaction between endocannabinoids and the classical neurotransmitters GABA (Gamma-amino butyric acid) and glutamate. An increased understanding of the biological mechanisms involved in fear-induced analgesia is important from a fundamental physiological perspective and may also advance the search for new therapeutic approaches to the treatment of pain.

Dr David Finn, Leader of the Galway Neuroscience Centre, Co-Director of the Centre for Pain Research at NUI Galway and study leader says: "The body can suppress pain when under extreme stress, in part through the action of marijuana-like substances produced in the brain. This research provides information on the complex interactions between multiple neurotransmitter systems including endocannabinoids, GABA and glutamate in times of stress and pain. This research which was funded by a grant from Science Foundation Ireland, advances our fundamental understanding of the neurobiology of pain and may facilitate the identification of new therapeutic targets for the treatment of pain and anxiety disorders."

https://www.sciencedaily.com/releases/2013/03/130306134014.htm

New study shows cannabis effects on driving skills

March 1, 2013

Science Daily/American Association for Clinical Chemistry (AACC)

New research appearing online today in Clinical Chemistry, the journal of AACC, shows that cannabis can be detected in the blood of daily smokers for a month after last intake. The scientific data in this paper by Bergamaschi et al. can provide real help in the public safety need for a drugged driving policy that reduces the number of drugged driving accidents on the road.

Cannabis is second only to alcohol for causing impaired driving and motor vehicle accidents. In 2009, 12.8% of young adults reported driving under the influence of illicit drugs and in the 2007 National Roadside Survey, more drivers tested positive for drugs than for alcohol. These cannabis smokers had a 10-fold increase in car crash injury compared with infrequent or nonusers after adjustment for blood alcohol concentration.

In this paper, 30 male chronic daily cannabis smokers resided on a secure research unit for up to 33 days, with daily blood collection. Twenty-seven of 30 participants were THC-positive on admission, with a median (range) concentration of 1.4 µg/L (0.3-6.3). THC decreased gradually with only 1 of 11 participants negative at 26 days; 2 of 5 remained THC-positive (0.3 µg/L) for 30 days.

These results demonstrate, for the first time, that cannabinoids can be detected in blood of chronic daily cannabis smokers during a month of sustained abstinence. This is consistent with the time course of persisting neurocognitive impairment reported in recent studies and suggests that establishment of 'per se' THC legislation might achieve a reduction in motor vehicle injuries and deaths. This same type of 'per se' alcohol legislation improved prosecution of drunk drivers and dramatically reduced alcohol-related deaths.

"These data have never been obtained previously due to the cost and difficulty of studying chronic daily cannabis smoking over an extended period," said Dr. Marylin Huestis of the National Institutes of Health and author on the paper. "These data add critical information to the debate about the toxicity of chronic daily cannabis smoking."

https://www.sciencedaily.com/releases/2013/03/130301122256.htm

Activation of cortical type 2 cannabinoid receptors ameliorates ischemic brain injury

February 21, 2013

Science Daily/Elsevier

A new study published in the March issue of The American Journal of Pathology suggests that cortical type 2 cannabinoid (CB2) receptors might serve as potential therapeutic targets for cerebral ischemia.

Researchers found that the cannabinoid trans-caryophyllene (TC) protected brain cells from the effects of ischemia in both in vivo and in vitro animal models. In rats, post-ischemic treatment with TC decreased cerebral infarct size and edema. In cell cultures composed of rat cortical neurons and glia exposed to oxygen-glucose deprivation and reoxygenation (OGD/R), TC decreased neuronal injury and mitochondrial depolarization, specifically through type 2 cannabinoid receptor (CB2R) pathways.

"To our knowledge, novel data presented in this study provide evidence for the first time supporting a previously unappreciated role of cortical CB2R, especially neuronal CB2Rs, in ischemia," says lead investigator Won-Ki Kim, PhD, of the Department of Neuroscience, College of Medicine, Korea University in Seoul. "This study suggests that further investigation is warranted to establish the clinical usefulness of TC as a preventative and therapeutic agent for treatment of stroke."

Results presented in the study shed light on the anatomy and mechanism of action of CB2R-mediated neuroprotection. In the in vivo study, which was performed in rats, the right middle cerebral artery was occluded for 1.5 hours to mimic an ischemic stroke; blood flow was allowed to return for the next 24 hours. Three hours after the occlusion began, the animals were treated with TC; some animals also received AM630, a CB2R antagonist. The next day, the brains were removed, and the volume of the infarct and extent of cerebral edema were measured.

Using immunocytochemistry, the investigators found evidence of CB2Rs in the cortex of both control and ischemic brains, mostly in cortical neurons but also to a lesser extent in some glial cells. This finding in itself is important because the question of whether CB2Rs are present in the cortex has long been a matter of debate, say the authors.

Post-ischemic treatment with TC reduced infarct size by 53.8% and reduced edema by 51.9%. However, co-administration of the CB2R antagonist AM630 completely blocked the protective effect of TC. Further analysis indicated that CB2R activation is involved in the ability of TC to induce cAMP responsive element-binding protein (CREB) phosphorylation and increase the expression of brain-derived neurotrophic factor (BDNF) in ischemic tissue.

Cell-culture studies of embryonic rat cortical neurons and glia exposed to OGD/R to simulate ischemic insult confirmed some of the findings of the in vivo studies and contributed to further understanding about cellular effects of ischemia and TC treatment. In the cultures, TC decreased neuronal injury, intracellular oxidative stress, and mitochondrial depolarization following OGD/R, and the effects were reversed by AM630 but not by a CB1R antagonist, AM251. Western blot analysis demonstrated that TC enhanced the phosphorylation of AMP protein kinase (AMPK) and CREB, while selective AMPK and CREB inhibitors blocked TC's neuroprotection. Other findings indicated that the anti-ischemic effect of TC was not mediated by NMDA receptor antagonism or antioxidant activity.

TC is a major cannabinoid derived from the essential oil of the flowering plant Cannabis sativa, but has a fundamentally different structure from classical cannabinoids. Unlike agents which activate CB1 receptors, selective CB2R receptor agonists do not have psychoactive side effects. TC appears to maintain CB2R agonist activity when administered orally and is a common ingredient found in many food additives and folk medicines. The intriguing results of the present study suggest that the anti-ischemic benefits of TC deserve further exploration.

https://www.sciencedaily.com/releases/2013/02/130221141140.htm

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

January 24, 2013

Science Daily/American Friends of Tel Aviv University

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

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

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

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

Cutting down on chronic medications

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

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

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

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

Connecting cannabis and swallowing

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

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

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

Brain imaging insight into cannabis as a pain killer

December 20, 2012

Science Daily/University of Oxford

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

December 12, 2012

Science Daily/BMJ-British Medical Journal

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Medical marijuana could help patients reduce pain with opiates

December 6, 2011

Science Daily/University of California - San Francisco

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Major Components of Cannabis

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

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

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

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

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