1) Zajicek JP, Sanders HP, Wight DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1664-9.
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.
2) Wade DT, Makela P, Robson P, House H, Bateman C. 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. Mult Scler. 2004 Aug;10(4):434-41.
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.
3) 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. Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. Eur J Pain. 2009 May;13(5):472-7.
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.
4) David Baker, Gareth Pryce, Samuel J. Jackson, Chris Bolton, Gavin Giovannoni. The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis. Mult Scler Relat Disord. 2012 Apr;1(2):64-75.
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.
5) Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs. 2011 Mar;25(3):187-201.
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