Multiple sclerosis - randomised controlled trials and other studies

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29 August 2017
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Randomised controlled trials

Single-blind, parallel RCT
Grade 1- high

Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003; 362: 1517-26.

657 patients at 33 UK centres with stable multiple sclerosis and muscle spasticity with a mean age of 50 were enrolled in this trial; 630 were treated with either dronabinol, an oral cannabis extract containing THC:CBD (Cannador), or placebo over 15 weeks. The study cannabinoid was supplied by the Berlin Society for Oncological and Immunologic Research.

Double-blind, parallel RCT
Grade 2- moderate

Turcotte D, Doupe M, Torabi M, Gomori A, Ethans K, Esfahani F, et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Medicine 2015; 16: 149-59.

15 adults aged 18–65 with relapsing-remitting MS and MS-induced neuropathic pain recruited from a MS clinic in Winnipeg, Canada were randomised to receive gabapentin plus nabilone or gabapentin plus placebo with a 4 week titration phase followed by 5 weeks with 2 mg nabilone per day or placebo.

Double-blind, parallel RCT
Grade 2- moderate

Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of Neurology 2013; 260: 984-97.

339 patients at 33 sites in UK, Czech Republic, Canada, Spain and France with a mean age of 49 and central neuropathic pain due to MS were randomised to treatment with nabiximols (Sativex) spray (maximum dose 12 sprays per day or placebo) in combination with existing treatment over 14 weeks.

Double-blind, parallel RCT
Grade 2- moderate

Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. Journal of Neurology, Neurosurgery, and Psychiatry 2012; 83: 1125-32.

279 patients at 22 UK centres aged 18-64 with stable MS were randomised to receive an oral extract of Cannabis sativa standardised to 2.5 mg of THC per capsule (Cannador) or placebo. Study cannabinoid was provided by the Berlin Society for Oncological and Immunologic Research.

Double-blind, parallel RCT
Grade 2- moderate

Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurological Research 2010; 32: 451-9.

337 patients with a mean age of 47in the UK and Czech republic with MS spasticity not fully relieved with current anti-spasticity therapy were randomised to receive nabiximols (Sativex) THC:CBD spray (maximum dose 24 sprays per day) or placebo over 14 weeks.

Double-blind, parallel RCT
Grade 2- moderate

Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Multiple Sclerosis 2010; 16: 1349-59.

135 adults with a diagnosis of MS and symptoms of overactive bladder who had failed to respond adequately to first-line therapies (mean age 47) were randomised to nabiximols (Sativex) THC:CBD spray or placebo over 10 weeks.

Double-blind, parallel RCT
Grade 2- moderate

Collin C, Davies P, Mutiboko IK, Ratcliffe S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. European Journal of Neurology 2007; 14: 290-6.

189 adults aged 20-69 in the UK and Romania with definite MS diagnosis and spasticity were randomised to receive nabiximols (Sativex) THC:CBD spray (maximum dose of 48 sprays per day) or placebo over 6 weeks.

Double-blind, parallel RCT
Grade 2- moderate

Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65: 812-9.

66 adults in the UK aged 26-71 with MS spasticity and pain were randomised to nabiximols (Sativex) spray (maximum dose 48 sprays per day) or placebo over 5 weeks.

Double-blind, parallel RCT
Grade 2- moderate

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. Multiple Sclerosis 2004; 10: 434-41.

160 outpatients with MS aged 27-74 from 3 sites with at least one of five key symptoms (spasticity, spasms, bladder problems, tremor or pain) were randomised to receive nabiximols (Sativex) spray or placebo for a six week trial.

Double-blind, parallel RCT
Grade 3- low

Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, Domino EF. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clinical Pharmacology and Therapeutics 1994; 55: 324-8.

20 participants including 10 adults aged 21-55 with MS and 10 normal volunteers participated in this experiment to compare smoked cannabis to placebo cigarettes. In a double-blind trial over 3 consecutive days, on 2 of those days, each received active marijuana on one day and placebo on the other. A single marijuana (1.54% THC) or placebo cigarette was smoked and each subject was tested at expected time of peak plasma concentration of THC.

Double-blind, crossover RCT
Grade 3- low

Leocani L, Nuara A, Houdayer E, Del Carro U, Straffi L, Martinelli V, et al. Effect of THC-CBD oromucosal spray (Sativex) on measures of spasticity in multiple sclerosis: a double-blind, placebo-controlled, crossover study (abstract only of paper presented at the Joint Americas/European Committees for Treatment and Research in Multiple Sclerosis Meeting; Boston). Multiple Sclerosis 2014; 20: 498.

43 patients with progressive MS compared nabiximols (Sativex) THC:CBD spray with placebo over two 4 week periods with 2 weeks washout.

Double-blind, crossover RCT
Grade 3- low

Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ: Canadian Medical Association Journal 2012; 184: 1143-50.

37 adult patients in the USA with multiple sclerosis and spasticity and a mean age of 51 compared smoked cannabis (4% THC) with placebo cigarettes for 3 days each with an 11 day washout.

Double-blind, crossover RCT
Grade 3- low

Conte A, Bettolo CM, Onesti E, Frasca V, Iacovelli E, Gilio F, et al. Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. European Journal of Pain 2009; 13: 472-7.

18 adult patients aged 43-59 with secondary progressive MS compared nabiximols (Sativex) THC:CBD spray (maximum 48 sprays per day) with placebo in an 8 week trial of three week periods separated by 2 weeks washout.

Double-blind, crossover RCT
Grade 3- low

Wissel J, Haydn T, Muller J, Brenneis C, Berger T, Poewe W, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. Journal of Neurology 2006; 253: 1337-41.

13 adults aged 19-68 with chronic upper motor neuron syndrome suffering from disabling spasticity-related pain refractory to previous pain treatment compared nabilone to placebo over 9 weeks (two 4 week treatment periods separated by one week washouts) Dosage in the first week was 0.5 mg per day or placebo, followed by three weeks 1 mg per day or placebo.

Double-blind, crossover RCT
Grade 3- low

Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ Case Reports 2004; 329: 253.

24 patients aged between 23 and 55 years with multiple sclerosis and central pain compared dronabinol (maximum 10mg per day) with placebo over 9 weeks (two 3 week periods with a 3 week washout).

Double-blind, crossover RCT
Grade 3- low

Vaney C, Heinzel-Gutenbrunner M, Jobin P, Tschopp F, Gattlen B, Hagen U, et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Multiple Sclerosis 2004; 10: 417-24.

57 MS patients with poorly controlled spasticity at a Swiss rehabilitation centre compared oral cannabis extract (THC:CBD) in capsule form with placebo; starting with 6 capsules per day increasing to a maximum 12 capsules per day over 5 days. Study medication was provided by the Berlin Society for Oncological and Immunological Research.

Double-blind, crossover RCT
Grade 3- low

Fox P, Bain PG, Glickman S, Carroll C, Zajicek J. The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004; 62: 1105-9.

14 adult patients aged 35-56 with upper limb tremors due to MS compared an oral cannabis (THC: CBD) extract of Cannabis sativa standardised to 2.5 mg of THC per capsule (Cannador) with placebo. Study medication was provided by the Berlin Society for Oncological and Immunologic Research.

Double-blind, crossover RCT
Grade 3- low

Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC, Staats PG, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58: 1404-7.

16 patients in the Netherlands with MS and a mean age of 46 who presented with severe spasticity compared dronabinol (maximum dose of 10mg per day) with a cannabis extract with standardised THC content plus CBD (max 10mg per day) provided by the Society for Oncological and Immunologic Research and with placebo in identical appearing capsules in two 4 week study periods with 4 weeks washout.

Double-blind, crossover RCT
Grade 3- low

Petro DJ, Ellenberger C, Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. Journal of Clinical Pharmacology 1981; 21: 413S-16S.

9 patients with several types of spasticity compared synthetic THC with placebo. Study investigators tested muscle tone, reflexes, strength and performed EMGs before and after double-blinded oral administration of either 10 or 5 mg THC or placebo. The blinded examiner correctly identified the trials in which the patients received THC in seven of nine cases.

N of 1 x 34 /Crossover RCT
Grade 3- low

Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia 2004; 59: 440-52.

34 adults aged 26-66 (16 with MS) compared cannabis extracts as THC spray, CBD spray, THC:CBD spray and placebo. Each week for the first 4 weeks they randomly received a different formulation (THC, CBD, THC:CBD or placebo). Each CBME was then given again in random order over the next 4 weeks.

Crossover, N of 1 consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials
Grade 3- low

Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation 2003; 17: 21-9.

24 patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1) compared three cannabis extracts with each other and with placebo. After the first 2 week period using open-label known THC:CBD, patients entered an 8 week double-blind study phase with four 2 week stages using THC:CBD, or CBD alone, or THC alone, or placebo.

Crossover RCT single dose
Grade 3- low

Fox SH, Kellett M, Moore AP, Crossman AR, Brotchie JM. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Movement Disorders 2002; 17: 145-9.

15 adults aged 28-63 with a clinical diagnosis of primary dystonia recruited from a regional movement disorders clinic compared nabilone in oral capsule form with placebo. After a single dose assessments were performed 60, 120, and 180 minutes later; the assessments were repeated 2 weeks later in a crossover design.

Double-blind, crossover RCT
Grade 3- low

Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Advances in Alcohol and Substance Abuse 1987; 7: 39-50.

13 adult patients aged 26-64 with clinical multiple sclerosis and spasticity compared oral THC with placebo in escalating doses over 5 days of active treatment and 5 days of placebo in random order separated by 2 day washout.

Crossover RCT
Grade 4- very low

Martyn CN, Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis (letter to the editor). Lancet 1995; 345: 579.

A 45 year old man who asked to be prescribed nabilone compared this treatment to placebo in an "N of 1" study. The patient was given 1 mg of nabilone every second day or placebo for four successive periods lasting 4 weeks.

Other studies

Follow up from RCT
Grade 3- low

Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol /cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clinical Therapeutics 2007; 29: 2068-79.

63 adult patients with MS aged 27-71 years continued treatment with nabiximols (Sativex) THC:CBD spray while varying other analgesic treatment as required.

Prospective, open-label trial extension study; Follow up RCT open-label
Grade 3- low

Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple Sclerosis 2006; 12: 639-45.

137 adult MS patients aged 27-73 with symptoms not controlled satisfactorily using standard drugs were treated with nabiximols (Sativex) THC:CBD spray.

Substudy from parallel RCT (Zajicek 2003)
Grade 2- moderate

Freeman RM, Adekanmi O, Waterfield MR, Waterfield AE, Wright D, Zajicek J. The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). International Urogynecology Journal and Pelvic Floor Dysfunction 2006; 17: 636-41.

A secondary analysis of 522 patients from 33 neurology and rehabilitation centres in the UK who were randomised to receive dronabinol, THC:CBD extract or placebo in oral capsules.

Subset of single-blind, parallel RCT (Zajicek, et al. 2003)
Grade 3- low

Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. Journal of Neurology, Neurosurgery, and Psychiatry 2005; 76: 1664-9.

A substudy of 502 patients with stable MS muscle spasticity from 33 UK centres who were randomised to receive dronabinol, oral cannabis THC:CBD extract, or placebo.

Substudy of crossover RCT (Killestein 2002)
Grade 3- low

Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, et al. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. Journal of Neuroimmunology 2003; 137: 140-3.

A substudy of 16 MS patients treated with oral cannabinoids who compared dronabinol with a cannabis extract with standardised THC content plus CBD and with placebo in identical appearing capsules.

Case series; open-label
Grade 4- very low

Centonze D, Mori F, Koch G, Buttari F, Codeca C, Rossi S, et al. Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurological Sciences: Official Journal of the Italian Neurological Society and the Italian Society of Clinical Neurophysiology 2009; 30: 531-4.

20 adult MS patients aged 21-51 with chronic neuropathic pain refractory or intolerant to commonly prescribed medications were treated with nabiximols (Sativex) THC:CBD spray.

Case series; open-label pilot
Grade 4- very low

Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis 2004; 10: 425-33.

15 adult patients aged 18-65 with advanced MS and refractory lower urinary tract symptoms were treated with cannabis extract (THC:CBD) spray or THC only spray.

Case series; single blind
Grade 4- very low

Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Annals of Neurology 1983; 13: 669-71.

8 adult patients aged 21-49 with multiple sclerosis who were seriously disabled with tremor and ataxia compared oral THC with placebo.