The evaluation of the effects of Sativex (1:1; THC BDS:CBD BDS) on the inhibition of spasticity in an experimental model of multiple sclerosis

Annie Patel1, Colin Stott1, Stephen Wright1, Geoffrey Guy1, Gareth Pryce2, Sarah Al-Izki2, David Baker2, Chris Bolton2, Gavin Giovannoni2. 1GW Pharma Ltd, London, United Kingdom, 2Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom.

Introduction/Aim: Spasticity is a common, painful symptom that develops during multiple sclerosis (MS) and spinal cord injury, where damage to the nervous system results in uncontrolled limb motor function. Current therapy is often associated with dose-limiting adverse side-effects, which in turn has led to patient self-medication providing reports of perceived benefits following cannabis use. It is known that the cannabinoid system regulates neurotransmission and it may therefore be anticipated that cannabinoids may control spasticity, which is a product of uncontrolled nervous signalling. Sativex (Nabiximols) (1:1 THC BDS:CBD BDS) has been used for the treatment of spasticity in MS, therefore the aim of this study was to investigate the anti-spastic potential of nabiximols in animals with severe spasticity and to therefore provide supportive evidence for the use of nabiximols in the treatment of spasticity in MS and other neurological diseases.

Method: 20-25g Adult (6-8 week) Biozzi ABH mice were injected on days 0 and 7 to induce a relapsing-remitting paralytic disease and animals accumulated increasing neurological deficit. 7-8 months post-disease injection, animals exhibited visual evidence of spasticity.

Vehicle, nabiximols and baclofen (an anti-spastic agent used in the treatment of human spasticity) were injected intravenously in the tail vein at a volume of 0.1ml. the ‘stiffness’ of limbs was then measured using a strain gauge and assessed by the resistance force (in Newtons (N)) against hind limb flexion. The measurement of the left then right hindlimbs was repeated typically 5 times per time point. Analogue signals were then digitized and data was calculated to represent a mean score for each limb at each time point. Each group contained at least 5 animals and results expressed as the mean ± SEM change in hindlimb stiffness (%) followed by repeated measures analysis of variance (RM ANVOA) with Student-Newman-Keuls post-hoc test.

Results: Vehicle administration failed to induce a significant change in the degree of spasticity over a 2 hour observation period. Baclofen administration (5 mg/kg, i.v.) induced approximately a 40% peak reduction in spasticity. Nabiximols dose-dependently reduced spasticity, where administration of a dose of 5 mg/kg THC + 5 mg/kg CBD (i.v.) induced, approximately, a 20% peak reduction, whereas the higher nabiximols dose of 10 mg/kg THC + 10 mg/kg CBD approximately produced a 40% peak reduction in hindlimb stiffness (spasticity). Additionally, on a mg per mg basis, nabiximols was better tolerated compared to baclofen, where mice treated with nabiximols were more mobile as assessed by observations of in cage mouse movement.

Conclusion: It is evident that compounds within nabiximols have the potential to dose-dependently inhibit spasticity in an experimental mouse model of multiple sclerosis. Baclofen also inhibited spasticity and served as a positive control. Yet results indicate nabiximols (10 mg/kg) to be just as effective as the anti-spastic treatment baclofen, currently used in human spasticity. This study therefore provides supportive evidence for the use of nabiximols in the treatment of spasticity in MS and other neurological diseases.

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