Data from preclinical animal studies, (eg. mouse model of ALS), have implicated the endocannabinoid system in the pathophysiology of ALS. Exogenous cannabinoids have also been shown to slow down disease progression in ALS mice, likely via anti-oxidant, anti-inflammatory and neuroprotective effects (1). Large scale clinical trials designed to evaluate the efficacy of medicinal cannabis as a symptomatic treatment for ALS are lacking. Anecdotal reports and a few small-scale studies have reported cannabis use to moderately affect spasticity, pain, depression, appetite loss, and drooling (2). In a pilot study (n = 19), to investigate the safety and tolerability of THC in ALS patients, dronabinol (synthetic THC), was reported to be very well tolerated with symptomatic benefits seen in insomnia and appetite (3). In a small randomised, placebo-controlled, crossover trial, 5mg of oral THC bd was found to be well tolerated however, did not affect cramp frequency or intensity (4). Many limitations exist in these studies including short trial duration, small sample sizes and modest effect sizes.
Much of the more robust evidence for the anti-spasticity/cramping and analgesic effects of medicinal cannabis can be gleaned from clinical trials investigating the safety and efficacy of Sativex (a THC:CBD 1:1 ratio blend) for spasticity and pain symptoms in multiple sclerosis (MS). Sativex is currently approved in Canada and some European countries for muscle spasticity and neuropathic pain in MS.
The American Academy of Neurology recommends that clinicians may offer THC:CBD to reduce the symptoms of spasticity and pain, but should inform patients that it may not be effective for improving objective spasticity measures (5).
**(The term spasticity can be used to refer to the totality of the abnormal movement control caused by a motor neurone lesion, and spasticity may be considered more as a collection of motor programme disturbances rather than a single pathophysiological entity (6)).**
A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Novotna et al 2011 (7).
Cohort: Phase A; n = 538 completed 4 weeks of Sativex treatment. Phase B; n = 272 achieved a ³ 20% improvement in Phase A and progressed to 12-week placebo controlled Phase B. Completed Phase B; Sativex n = 109, placebo n = 115).
Results: The number of responders in the treatment group was significantly higher than in the placebo group (74% vs. 51%, P = 0.0003). Sativex significantly improved spasm frequency (P = 0.005) and sleep disruption (P < 0.0001). Modified Ashworth Score for spasticity: Sativex -0.1; Placebo +1.8 ; Adjusted Difference -1.75 (95% CI -3.80, 0.30) Spasm frequency (per day): Sativex -0.05; Placebo +2.41 Adjusted Difference -2.53 (95% CI -4.27, -0.79) Sleep disruption by spasticity: Sativex -0.25; Placebo +0.59 ; (0 to 10 NRS) Adjusted Difference -0.88 (95% CI -1.25, -0.51).
Safety: Sativex was found to be safe and well tolerated. The overall adverse event (AE) rate was similar to placebo. Two treatment-related serious AEs occurred, however, both resolved upon cessation of treatment.
MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial Zajicek et al 2012 (8).
Cohort: MS patients completed cannabis extract (CE) treatment n = 109, MS patients completed placebo treatment n = 115.
Results: Self-reported relief: 29.4% in CE group, 15.7% in placebo group. Self-reported relief from muscle stiffness, muscle spasms, body pain and sleep disturbance was significantly higher in CE group vs placebo at 4, 8 and 12 weeks.
Safety: Treatment was well tolerated. Over 95% of AE’s were mild to moderate. Rates of AE’s were higher in CE group during titration period and decreased over the course of the study.
Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain. A double-blind placebo-controlled cross-over trial. Wissel et al 2006 (9).
Cohort: Completed trial n = 11. Group 1 received Nabilone for 4 weeks, 1 week wash out period, and then placebo for 4 weeks. Group 2 received placebo for 4 weeks, 1 week wash out period, and then nabilone for 4 weeks.
Results: Spasticity related pain (measured by the 11-Point-Box-Test) decreased by a median 2 points with Nabilone compared with placebo treatment (p < 0.05).
Safety: Nabilone found to be safe and well tolerated.