Cannabis And Cannabinoids
Multiple sclerosis is an inflammatory disease in which the immune system attacks the nervous system. The result can be a wide range of debilitating motor, physical and mental problems. No one knows why people get the disease or how to treat it.
In a new study published in the Journal of Neuroimmune Pharmacology, Ewa Kozela, Ana Juknat, Neta Rimmerman and Zvi Vogel of Tel Aviv Univ.'s Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases and Sackler Faculty of Medicine demonstrate that some chemical compounds found in marijuana can help treat MS-like diseases in mice by preventing inflammation in the brain and spinal cord.
"Inflammation is part of the body's natural immune response, but in cases like MS it gets out of hand," says Kozela. "Our study looks at how compounds isolated from marijuana can be used to regulate inflammation to protect the nervous system and its functions." Researchers from the Weizmann Institute of Science co-authored the study.
Israel has a strong tradition of marijuana research. Israeli scientists Raphael Mechoulam and Yechiel Gaoni discovered THC, or tetrahydrocannabinol, in 1964, kick-starting the scientific study of the plant and its chemical constituents around the world. Since then, scientists have identified about 70 compounds — called cannabinoids — that are unique to cannabis and have interesting biological effects. In the 1990s, Prof. Vogel was among the first researchers to describe endocannabinoids, molecules that act like THC in the body.
Besides THC, the most plentiful and potent cannabinoid in marijuana is cannabidiol, or CBD. The TAU researchers are particularly interested in CBD, because it offers medicinal benefits without the controversial mind-altering effects of THC.
In a 2011 study, they showed that CBD helps treat MS-like symptoms in mice by preventing immune cells in their bodies from transforming and attacking the insulating covers of nerve cells in the spinal cord. After inducing an MS-like condition in mice — partially paralyzing their limbs — the researchers injected them with CBD. The mice responded by regaining movement, first twitching their tails and then beginning to walk without a limp. The researchers noted that the mice treated with CBD had much less inflammation in the spinal cord than their untreated counterparts.
High hopes for humans
In the latest study, the researchers set out to see if the known anti-inflammatory properties of CBD and THC could also be applied to the treatment of inflammation associated with MS — and if so, how. This time they turned to the immune system.
The researchers took immune cells isolated from paralyzed mice that specifically target and harm the brain and spinal cord, and treated them with either CBD or THC. In both cases, the immune cells produced fewer inflammatory molecules, particularly one called interleukin 17, or IL-17, which is strongly associated with MS and very harmful to nerve cells and their insulating covers. The researchers concluded that the presence of CBD or THC restrains the immune cells from triggering the production of inflammatory molecules and limits the molecules' ability to reach and damage the brain and spinal cord.
Further research is needed to prove the effectiveness of cannabinoids in treating MS in humans, but there are reasons for hope, the researchers say. In many countries, CBD and THC are already prescribed for the treatment of MS symptoms, including pain and muscle stiffness.
"When used wisely, cannabis has huge potential," says Kozela, who previously studied opiates like morphine, derived from the poppy plant. "We're just beginning to understand how it works."
Source: Advantage Business Media © Copyright 2013 Advantage Business Media (09/10/13)
Therapeutic Potential of a Novel Cannabinoid Agent CB52 in the Mouse Model ofExperimental Autoimmune Encephalomyelitis.
Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS.
The protective mechanisms of cannabinoids are thought to be mediated by activation of cannabinoid receptor 1 (CB1) and 2 (CB2) expressed primarily in neurons and immune cells, respectively. However, the molecular mechanisms and the contribution of each receptor in ameliorating disease progression are still debatable.
Although CB1 and CB2 are expressed in oligodendrocytes, the myelin producing cells in the central nervous system, the role of cannabinoids in oligodendrocyte survival has not been well investigated. Using primary cultures of mature oligodendrocytes, we tested the effect of a novel synthetic cannabinoid CB-52 on oligodendrocyte toxicity induced by peroxynitrite, the primary toxic species released by microglia.
Interestingly, we found that CB-52 is more potent than a number of broad and selective CB1 and CB2 agonists in protecting oligodendrocytes against peroxynitrite-induced toxicity. The protection provided by CB-52 is likely due to its reduction of ERK1/2 phosphorylation and ROS generation in these cells. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found that CB-52 reduces microglia activation, nitrotyrosine formation, T cell infiltration, oligodendrocyte toxicity, myelin loss and axonal damage in the mouse spinal cord white matter and alleviates the clinical scores when given either before or after disease onset.
These effects are reversed by the CB1 receptor antagonist, but not by the CB2 receptor antagonist, suggesting that activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS.
Ribeiro R, Yu F, Wen J, Vana A, Zhang Y.
Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
Source: Neuroscience. 2013 Sep 11. pii: S0306-4522(13)00775-6. doi: 10.1016/j.neuroscience.2013.09.005. [Epub ahead of print] Copyright © 2013 Elsevier Ltd & Pubmed PMID: 24036373 (23/09/13)
Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ9-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis.
In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18—65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0—5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668).
Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68—1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol—placebo) of −0·9 points (95% CI −2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group).
Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change.
UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.
Prof John Zajicek PhD, Susan Ball MSc, Prof David Wright PhD, Jane Vickery MSc, Prof Andrew Nunn MSc, Prof David Miller FMedSci, Mayam Gomez Cano PhD, David McManus MSc, Sharukh Mallik MSc, Prof Jeremy Hobart PhD, on behalf of the CUPID investigator group.
Source: The Lancet Neurology Copyright © 2013 Elsevier Limited (19/07/13)
Echo Pharmaceuticals announced that Namisol® has completed successfully a Phase II trial with 24 patients suffering from spasticity and pain due to multiple sclerosis (MS). The trial has been conducted by the Centre for Human Drug Research (CHDR) in the VU University Medical Center Amsterdam and it was led by Dr. G.J. Groeneveld, Research Director Neurology & Pain, CHDR. The clinical trial was a double blind, placebo-controlled study of Namisol® to determine safety, tolerability and efficacy in MS patients. The outcome of this trial showed efficacy and consistent results on both spasticity and pain.
Simultaneously, The Sage Group has been appointed by Echo Pharmaceuticals to assist the company in its search for a strategic partner for commercialisation of its lead Namisol® program.
Dr. Vanesa Fernandez, CEO of Echo Pharmaceuticals, said "We are very pleased that The Sage Group has been selected by our Company to assist in the commercialisation phase of Namisol®. The successful Phase 2 trial in MS patients is a major milestone for Echo and we believe there will be strong global interest in working with us to take the product to market. The Sage Group are very experienced in developing such partnerships and will add a valuable business development activity to our drug development capability."
Dr. Bill Mason and Wayne Pambianchi of The Sage Group based in Europe and the USA said "We are delighted to be selected as managers for this exciting program and we look forward to working with Echo and key interested parties in the pharma industry to develop strong partnerships for global commercialisation of Namisol®."
About Namisol® Namisol® is the world's first oral tablet that contains pure (≥98,0%), natural Δ9-tetrahydrocannabinol (THC or dronabinol) in fixed dosages with high, predictable bioavailability (due to Echo's innovative drug delivery technology AlitraTM) and a long, stable shelf life at room temperature. Namisol®'s current clinical program includes, in addition to the MS indication, a number of phase II clinical trials for the indications behavioral disturbances in patients with Alzheimer's Disease, and Chronic Pain.
Source: heraldonline.com © Rock Hill Herald Online 2013 (12/07/13)
Aphios USA and VivaCell Spain to develop novel class of compounds for MS and CNS disorders(12/06/13)
Aphios Corporation, today announced that it has entered into joint Research Collaboration and Commercialisation Agreements with VivaCell Biotechnology España S.L., Cordoba, Spain to develop therapeutics for multiple sclerosis and other neurodegenerative diseases of the central nervous system (CNS).
Multiple sclerosis (MS), a neurodegenerative disease of the CNS, is one of the main causes of irreversible neurologic disability in young adults. MS is notoriously heterogeneous in terms of clinical manifestations and evolution. The disease affects more than 2 million people worldwide, of which an estimated 400,000 are in the US and 500,000 in Europe. According to the Cleveland Clinic, MS-related health care costs are estimated to be over $10 billion per year in the United States. While progress has been made on developing therapeutics for this debilitating disease, there is still a high unmet need for safe and cost-effective therapeutics that can efficiently cross the blood brain barrier.
Recently, researchers at the University of Córdoba and Cajal Institute (Spain) in collaboration with VivaCell Biotechnology, a Spanish-based biotech company, discovered a novel class of non-psychotropic cannabinoids that has multiple activities on key molecular targets involved in neuroinflammatory and neurodegenerative diseases, with very positive in vitro and in vivo data (US and International Patents Pending). Dr. Eduardo Muñoz, Chief Scientific Officer of VivaCell states, “In vitro experiments have demonstrated that these compounds activate the PPARy pathway and bind to CB2 receptor showing both anti-inflammatory and neuroprotective activities. In vivo experiments have shown that they cross the blood brain barrier and inhibit neuroinflammation in well-defined animal models of multiple sclerosis and Huntington’s disease.”
Aphios and VivaCell have executed research and commercialisation agreements to develop these drug candidates through preclinical studies, clinical development and commercialization in the United States and Europe. According to Dr. Trevor P. Castor, President & CEO, Aphios Corporation, “We are jointly developing this novel class of non-psychotropic cannabinoids that could have a significant impact on multiple sclerosis and other neurodegenerative diseases such as Huntington’s, Parkinson’s and Alzheimer’s disease. We will apply our enabling technology platforms to enhance the oral bioavailability of these first in class compounds, bypass first round metabolism in the liver, improve safety and increase therapeutic efficacy.”
Source: Fort Mill Times © Copyright 2013, Fort Mill Times (12/06/13)
The consumption of legal hemp seed nutritional oil, in conjunction with the intake of evening primrose oils and a restricted diet high in Hot-natured foods (such as pepper) and low in saturated fats and sugars, is associated with “significant improvement” in symptom management and immunological characteristics in subjects with multiple sclerosis, according to clinical trial data published this month in the scientific journal BioImpacts.
Researchers at Tabriz University of Medical Sciences in Iran assessed the impact of hemp seed oil, evening primrose oils, and a restricted diet for a period of six months in 23 patients diagnosed with relapsing remitting MS. Researchers reported that participants at the study’s completion “were healthier in comparison to baseline,” concluding that “clinical and immunological parameters showed improvement in the patients after the intervention.” They noted that hemp seed oil possesses potent antioxidative properties and also likely acts on specific signaling pathways that regulate inflammatory responses — two characteristics that would presumably make it beneficial in the treatment of MS.
Authors concluded: “After 6 months, significant improvements in extended disability status score were found. … Our study demonstrates for the first time in the literature a decrease in both clinical and pro- inflammatory disease activity in MS patients during periods of dietary intervention. Our data demonstrated that co-supplemented hemp seed and evening primrose oils with Hot-natured diet intervention may decrease the risk of developing MS.”
Previously published clinical trials assessing the impact of inhaled cannabis and extracted organic cannabinoids in patients with MS have demonstrated that plant cannabinoids can alleviate disease symptoms — such as involuntary spasticity, neuropathy, and bladder dysfunction — and, in some subjects, may actually moderate disease progression. Nonetheless, the National MS Society shares little enthusiasm for cannabis or cannabis-derived products as a therapeutic option for MS patients, stating on its website: “[B]ased on the studies to date — and the fact that long-term use of marijuana may be associated with significant, serious side effects — it is the opinion of the National Multiple Sclerosis Society’s Medical Advisory Board that there are currently insufficient data to recommend marijuana or its derivatives as a treatment for MS symptoms.”
Source: Hawaii News Daily Copyright © 2013 Prohibition News (28/05/13)
Where numerous other treatments have failed to safely relieve stiffness in patients with multiple sclerosis, cannabis extract proved twice as effective as a placebo. It also helped with pain, spasms, and sleep.
PROBLEM: Muscle stiffness, often painful, affects up to 90 percent of patients with multiple sclerosis (MS), yet no reliable treatment has been found. Drugs that have undergone clinical trials have been proven to be either ineffective or, in the case of baclofen, to further weaken those with the disease. This phase-III trial considers the clinical effectiveness of cannabis, already turned to as an alternative treatment by patients.
METHODOLOGY: At different sites across the UK, adult MS patients were randomly assigned to 12 weeks of treatment: 144 received cannabis extract in the form of a pill, while 135 others were treated with a placebo. A rating scale was used to evaluate improvements in muscle stiffness, its associated pain, muscle spasms, and sleep quality.
RESULTS: Just under 30 percent of subjects treated with cannabis extract experienced relief from muscle stiffness, making their success rate almost double that of the placebo group. Pain, spasms, and sleep quality were also improved in the treatment group to about the same extent. At the end of the twelve weeks only one in four patients were taking the maximum daily dose of 25 mg of cannabis. None of the side effects experienced by those in the treatment group were particularly severe. Most occurred during the first two weeks of the trial (when they were allowed to increase their dosage) and were therefore probably attributable to the rapid dose escalation.
CONCLUSION: Cannabis extract was confirmed as a viable treatment option, and an effective form of pain relief, for those experiencing muscle problems associated with MS.
Full study, "Multiple Sclerosis and Extract of Cannabis: results of the MUSEC trial"
Source: The Atlantic COPYRIGHT © 2012 BY THE ATLANTIC MONTHLY GROUP (09/10/12)
The oral administration of cannabis extracts significantly reduces muscle stiffness in patients with multiple sclerosis (MS), according to just published clinical trial data published in the Journal of Neurology, Neurosurgery & Psychiatry.
Investigators at the University of Plymouth, Clinical Neurology Research Group, in the United Kingdom assessed the use of cannabinoids versus placebo in 279 subjects with MS over a twelve-week period. Cannabis extracts in the study contained standardized doses of THC and cannabidiol (CBD), a non-psychoactive constituent in cannabis, contained in a soft, gelatin capsule.
Investigators reported that oral cannabis extracts were “superior” over placebo in the treatment of MS-associated muscle stiffness and pain.
Authors concluded: “Treatment with standardised oral extract of cannabis sativa relieved muscle stiffness. The proportion of participants experiencing relief was almost twice as large in the cannabis extract group as in the placebo group. … Effective pain relief is also achieved by cannabis extracts, especially in patients with a high baseline pain score. Our findings suggest that standardised cannabis extracts can be clinically useful in treating the highly complex phenomenon of spasticity in MS.”
In May, clinical trial data published in the Journal of the Canadian Medical Association reported that cannabis inhalation significantly mitigates spasticity and pain in patients with treatment-resistant multiple sclerosis.
Separate clinical trials assessing the administration of oral cannabis extracts on patients with MS have indicated that cannabinoids can alleviate symptoms of the disease long-term and may also act in ways to mitigate MS progression. Sativex, an oral spray containing plant cannabis extracts, is presently legal by prescription to treat MS-related symptoms in over a dozen countries, including Canada, Germany, Great Britain, New Zealand, and Spain. Nonetheless, the National MS Society of the United States shares little enthusiasm for cannabis as a potential treatment for multiple sclerosis, stating, “Studies completed thus far have not provided convincing evidence that marijuana or its derivatives provide substantiated benefits for symptoms of MS.”
Full text of the study, “Multiple Sclerosis and Extract of Cannabis: results of the MUSEC trial,” appears in the Journal of Neurology, Neurosurgery & Psychiatry.
Source: The Weed Blog.com (25/07/12)
Cannabis capsules failed to slow the progression of multiple sclerosis in a large British study, dealing a blow to hopes that it could provide long-term benefits.
Despite promising signs in earlier, shorter studies, researchers found patients who took capsules containing tetrahydrocannabinol (THC), a key active ingredient in cannabis, fared no better than those given a placebo.
The finding is a disappointment for researchers who thought cannabis might provide a viable therapy in the disease's secondary progressive stage, when patients have few treatment options.
Multiple sclerosis (MS) patients were assessed in the trial known as CUPID (cannabinoid use in progressive inflammatory brain disease) on both a disability scale administered by neurologists and another based on their own reporting.
"Overall the study found no evidence to support an effect of THC on MS progression in either of the main outcomes," write researchers led by John Zajicek of the Peninsula College of Medicine and Dentistry, Plymouth University.
Results from the study, which was funded by Britain's Medical Research Council, will be presented at the Association of British Neurologists' annual meeting in Brighton this week.
Cannabis contains more than 60 different cannabinoids, of which THC is thought to be the most active, and many MS patients have long said the drug helps them cope with the effects of the disease.
Questions still remain
Professor David Nutt, of Imperial College London, who was not involved in the latest research, says the study's failure did not mean cannabis had no role in helping MS patients.
"It would be wrong to interpret these preliminary findings to mean that cannabis does not achieve its licensed use. Cannabis is not licensed for limiting disease progression, it is licensed for dealing with spasticity and pain," he says.
Zajicek's study did find some evidence to suggest a beneficial effect in less disabled patients but because this was seen in only a small group of people it was unclear how strong the effect was.
The overall study population also experienced slower disease progression than had been expected, making it more challenging to detect any treatment effect, the research team adds.
MS is a disease in which immune system cells destroy the myelin sheath that protects the nerve cells in the brain and spinal cord.
The most common type is relapsing-remitting MS, affecting around 85 per cent of patients at the time of diagnosis. Several drugs are available to treat this stage of the disease, including injections of beta-interferons and a new pill called Gilenya.
Secondary progressive MS comes later and involves a sustained build up of disability.
Source: ABC Science © 2012 ABC (29/05/12)