Multipal Sclerosis
The Indication by the Israeli Ministry of Health:
Multiple Sclerosis- Patients suffering from spasticity that aren’t responding to conventional treatment options. 
 
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Research

Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.

Zajicek JP, Sanders HP, Wight DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ.

J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1664-9.

Department of Mathematics and Statistics, University of Plymouth, Room N16, ITTC Building, Tamar Science Park, Plymouth, Devon PL6 8BX, UK. [email protected]

OBJECTIVE : To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study.

METHODS : In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here.

RESULTS : Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease.

CONCLUSIONS : These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

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Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.

Wade DT, Makela P, Robson P, House H, Bateman C.

Mult Scler. 2004 Aug;10(4):434-41.

Oxford Centre for Enablement, Windmill Road, Oxford OX3 7LD, UK. [email protected]

The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.

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Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

Conte A, Bettolo CM, Onesti E, Frasca V, Iacovelli E, Gilio F, Giacomelli E, Gabriele M, Aragona M, Tomassini V, Pantano P, Pozzilli C, Inghilleri M. Eur J Pain. 2009 May;13(5):472-7.

The study provides objective neurophysiological evidence that cannabinoids modulate the nociceptive system.

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.

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The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis

David Baker, Gareth Pryce, Samuel J. Jackson, Chris Bolton, Gavin Giovannoni

Department of Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom

Cannabis-based medicines have recently been approved for the treatment of pain and spasticity in multiple sclerosis (MS). This supports the original perceptions of people with MS, who were using illegal street cannabis for symptom control and pre-clinical testing in animal models of MS. This activity is supported both by the biology of the disease and the biology of the cannabis plant and the endocannabinoid system. MS results from disease that impairs neurotransmission and this is controlled by cannabinoid receptors and endogenous cannabinoid ligands. This can limit spasticity and may also influence the processes that drive the accumulation of progressive disability.

Role of cannabinoids in multiple sclerosis.

 
Zajicek JP, Apostu VI.
Clinical Neurology Research Group, Peninsula College of Medicine and Dentistry, Plymouth, UK. [email protected]
 
Abstract
Although extracts from the cannabis plant have been used medicinally for thousands of years, it is only within the last 2 decades that our understanding of cannabinoid physiology and the provision of evidence for therapeutic benefit of cannabinoids has begun to accumulate. This review provides a background to advances in our understanding of cannabinoid receptors and the endocannabinoid system, and then considers how cannabinoids may help in the management of multiple sclerosis (MS). The relative paucity of treatments for MS-related symptoms has led to experimentation by patients with MS in a number of areas including the use of cannabis extracts. An increasing amount of evidence is now emerging to confirm anecdotal reports of symptomatic improvement, particularly for muscle stiffness and spasms, neuropathic pain and sleep and bladder disturbance, in patients with MS treated with cannabinoids. Trials evaluating a role in treating other symptoms such as tremor and nystagmus have not demonstrated any beneficial effects of cannabinoids. Safety profiles of cannabinoids seem acceptable, although a slow prolonged period of titration improves tolerability. No serious safety concerns have emerged. Methodological issues in trial design and treatment delivery are now being addressed. In addition, recent experimental evidence is beginning to suggest an effect of cannabinoids on more fundamental processes important in MS, with evidence of anti-inflammation, encouragement of remyelination and neuroprotection. Trials are currently under way to test whether cannabinoids may have a longer term role in reducing disability and progression in MS, in addition to symptom amelioration, where indications are being established.
 
http://www.ncbi.nlm.nih.gov/pubmed/21323391
 
 
CANNABIDIOL INHIBITS PATHOGENIC T-CELLS, DECREASES SPINAL MICROGLIAL ACTIVATION AND AMELIORATES MULTIPLE SCLEROSIS-LIKE DISEASE IN C57BL/6 MICE.
 
Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, Ben-Nun A, Juknat A, Vogel Z.
The Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Physiology and Pharmacology Department, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Neurology Department, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Immunology Department, Histology Department, Neurobiology Department, Weizmann Institute of Science, Rehovot, Israel.
 
Abstract
Objective: Cannabis extracts and several cannabinoids, have been shown to exert broad anti-inflammatory activities including in experimental models of inflammatory CNS degenerative diseases. The clinical future of many cannabinoids is limited due to their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), void of psychoactive activity, have a potential to be safe and effective alternatives for alleviating neuroinflammation and neurodegeneration. Materials and methods: We studied the effects of CBD, in myelin oligodendrocyte glycoprotein (MOG)-induced EAE model of multiple sclerosis in C57BL/6 mice. Using immunocytochemistry and cell proliferation assays we evaluated the effects of CBD on microglial activation in MOG-immunized animals and CBD effect in MOG-specific T cell proliferation. Results: We observed that CBD administration during disease onset ameliorates the severity of EAE clinical signs. The alleviation of EAE severity by CBD was accompanied by diminished axonal damage and inflammation as well as microglial activation and T cell recruitment in the spinal cord of MOG-injected mice. Moreover, CBD inhibited MOG-induced T cell proliferation in vitro at both low and high concentrations of myelin antigen. This effect was not mediated via the known cannabinoid receptors, CB(1) and CB(2) . Conclusions: CBD, a non psychoactive cannabinoid, ameliorates clinical signs of MOG-immunized EAE mice. Suppression of microglial activity and T cell proliferation by CBD seems to contribute to these beneficial effects.
 
http://www.ncbi.nlm.nih.gov/pubmed/21449980