Cannabis and cannabinoids
Effects of cannabis on cognition in patients with MS: A psychometric and MRI study.
OBJECTIVE: To determine functional and structural neuroimaging correlates of cognitive dysfunction associated with cannabis use in multiple sclerosis (MS).
METHODS: In a cross-sectional study, 20 subjects with MS who smoked cannabis and 19 noncannabis users with MS, matched on demographic and neurologic variables, underwent fMRI while completing a test of working memory, the N-Back. Resting-state fMRI and structural MRI data (lesion and normal-appearing brain tissue volumes, diffusion tensor imaging metrics) were also collected. Neuropsychological data pertaining to verbal (Selective Reminding Test Revised) and visual (10/36 Spatial Recall Test) memory, information processing speed (Paced Auditory Serial Addition Test [2- and 3-second versions] and Symbol Digit Modalities Test), and attention (Word List Generation) were obtained.
RESULTS: The cannabis group performed more poorly on the more demanding of the Paced Auditory Serial Addition Test tasks (i.e., 2-second version) (p < 0.02) and the 10/36 Spatial Recall Test (p < 0.03). Cannabis users had more diffuse cerebral activation across all N-Back trials and made more errors on the 2-Back task (p < 0.006), during which they displayed increased activation relative to nonusers in parietal (p < 0.007) and anterior cingulate (p < 0.001) regions implicated in working memory. No group differences in resting-state networks or structural MRI variables were found.
CONCLUSIONS: Patients with MS who smoke cannabis are more cognitively impaired than nonusers. Cannabis further compromises cerebral compensatory mechanisms, already faulty in MS. These imaging data boost the construct validity of the neuropsychological findings and act as a cautionary note to cannabis users and prescribers.
Pavisian B1, Macintosh BJ, Szilagyi G, Staines RW, O'Connor P, Feinstein A.
Sources: Neurology. 2014 Apr 30. [Epub ahead of print] & Pubmed PMID: 24789863 (06/05/14)
Cannabis may help with some MS symptoms(29/04/14)
Cannabis sprays and tablets can improve some symptoms of multiple sclerosis, a study shows. But the effect of cannabis on epilepsy and other brain conditions is less clear, and side effects are common.
What do we know already?
Cannabis (also called marijuana) contains around 60 chemicals that affect the brain. Some of these chemicals cause the ‘high’ that people get when they use cannabis as an illegal drug. But these chemicals can also have other effects, which may be helpful for conditions that affect the brain and nervous system, such as multiple sclerosis (MS), Parkinson’s disease, and epilepsy.
Some people smoke cannabis to help with these conditions. Researchers have also developed mouth sprays and tablets with cannabis extracts. Sprays and tablets don’t have some of the health risks associated with smoking cannabis, such as lung diseases.
However, it’s not clear how well any of these forms of cannabis work for people with these medical conditions, as studies have had different results.
How was the new study done?
Researchers searched for the best studies done so far on the effects of cannabis on several conditions affecting the brain and nervous system. These included multiple sclerosis, Huntington’s disease, Tourette’s syndrome, cervical dystonia (abnormal neck movements), and epilepsy. They also searched for studies on using cannabis to help with the movement problems (called dyskinesias) caused by treatment for Parkinson’s disease. They then summarised the studies’ results, to see what conclusions they might draw.
What does the new study say? The researchers found 34 studies in total. Several of these looked at using cannabis for multiple sclerosis. Overall, they found that cannabis sprays and tablets improved some symptoms, including twitching muscles (spasms) and some types of pain (such as pain related to spasms). Cannabis sprays also seemed to help with bladder problems causing people to urinate often. However, cannabis sprays and tablets did not help with tremors (this is when a part of the body shakes).
There wasn’t enough research to say whether cannabis treatments might help with Huntington’s disease, Tourette’s syndrome, cervical dystonia, and epilepsy. However, the research did suggest that cannabis tablets do not help with movement problems caused by treatment for Parkinson’s disease.
Most of the studies looked at taking cannabis by sprays or tablets. There were few useful studies looking at whether smoking cannabis in pipes or cigarettes helped with symptoms.
Many people had side effects when using cannabis. These included weakness, feeling sick, mood changes, dizziness, fatigue, thoughts of suicide, and hallucinations. Overall about 7 in every 100 people using cannabis stopped their treatment because of side effects, compared with 2 in every 100 people using a dummy (placebo) treatment.
Studies also suggested that people with multiple sclerosis were more likely to have a worsening of their thinking abilities (cognitive declines) if they used cannabis.
How reliable is the research?
This review of studies should provide an accurate summary of what the current research tells us. The findings on using cannabis tablets and sprays for multiple sclerosis should be reliable, as these were based on several good-quality studies.
However, we need much more research to know whether cannabis treatments are effective and safe for the other conditions. We also need studies that compare cannabis with other treatments for these conditions.
What does this mean for me?
If you have multiple sclerosis, these findings suggest that cannabis sprays and tablets may improve some of your symptoms. But you need to weigh these possible improvements against the chance of side effects. It is also illegal to possess most kinds of cannabis in the UK, although a cannabis spray called Sativex is available on prescription.
If you have epilepsy, Huntington’s disease, Tourette’s syndrome, or cervical dystonia, we don’t yet have enough research to know whether cannabis treatments are helpful or safe. However, if you have movement problems caused by treatment for Parkinson’s disease, studies do suggest that cannabis tablets are unlikely to help.
Source: WebMD ©2009-2014 WebMD UK Limited and Boots UK Limited (29/04/14)
AAN endorses cannabis for MS(27/03/14)
The American Academy of Neurology has issued new evidence-based complementary and alternative medicine guidelines for multiple sclerosis.
HealthDay News -- The American Academy of Neurology is recommending oral cannabis extract to help ease spasticity symptoms and pain in patients with multiple sclerosis, along with other therapies, in new evidence-based complementary and alternative medicine (CAM) recommendations.
Vijayshree Yadav, MD, of the Oregon Health & Science University in Portland, and other members of the AAN's Guideline Development Subcommittee, conducted a literature search to develop the recommendations, which are published online in Neurology.
Clinicians may offer oral cannabis extract (Level A) or tetrahydrocannabinol (Level B) for spasticity symptoms and pain (excluding central neuropathic pain), but should counsel patients that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term; Level C).
Sativex oromucosal cannabinoid spray (nabiximols) can be suggested for spasticity symptoms, pain and urinary frequency (Level B), but clinicians should counsel patients that these agents are probably ineffective for objective spasticity/urinary incontinence (Level B). Furthermore, the spray is not currently FDA-approved and is unavailable in the United States, the researchers noted.
"In the United States, caution should be exercised with regard to extrapolation of results of trials of standardized oral cannabis extracts (which are unavailable commercially) to other nonstandardized, nonregulated cannabis extracts (which may be commercially available in states with medical marijuana laws)," Yadav and colleagues wrote.
Magnetic therapy is probably effective for fatigue, but probably ineffective for depression (Level B). Among common supplements, clinicians can counsel patients that fish oil is probably ineffective for relapses, disability, fatigue, magnetic resonance imaging lesions, and quality of life (Level B). Ginkgo biloba is ineffective for cognition (Level A), but possibly effective for fatigue (Level C). Reflexology is possibly effective for paresthesia (Level C).
Possibly ineffective therapies (Level C) include Cari Loder for disability, depression and fatigue, and bee sting therapy for relapses, disability, fatigue and lesion burden/volume.
"Clinicians should exercise caution regarding standardized versus nonstandardized cannabis extracts and overall CAM quality control/nonregulation," the researchers wrote. "Safety/efficacy of other CAM/CAM interaction with MS disease-modifying therapies is unknown."
Reference 1.Yadav V et al. Neurology. 2014; 82(12): 1083-1092.
Source: Copyright © 2014 Haymarket Media, Inc. All Rights Reserved (27/03/14)
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)