Cannabis does not affect electrophysiological response in spasticity

Leocani L, Nuara A, Houdayer E, Schiavetti I, Del Carro U, Amadio S, Straffi L, Rossi P, Martinelli V, Vila C, Sormani MP, Comi G. Sativex® and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol. 2015 Aug. [Epub ahead of print]

Despite the proven efficacy of Sativex® (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms inmultiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our centre were randomized to 4 weeks’ treatment (including 2 weeks’ titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.

Spasticity is the limb stiffness that occurs in MS. It is measured by a visual scale called the Ashworth Scale.

In the original large trials of cannabis in MS, there was a failure to see any changes in the Ashworth Scale. This also happened in trials with baclofen and tizanidine too. This indicates that it is insensitive to small changes. However, the people in the trials felt that their spasticity was improving. Eventually the companies convinced the regulators to accept visual analogue scales where the people taking the drug rated the effect rather than the physician-rated Ashworth Scale. 

We have invented a scale to look at spasticity in rodents should we call it the Mashworth..mouse Ashworth? 🙂
One other way is to get physical measures of change and this could be via electrophysiology. You can stimulate a nerve and the electric signal from an electrode stimulator can stimulate the nerve to send a signal directly to the muscle, which can be measured. This is called the M wave. However, the electrode signal can travel the other way up the nerve into the spinal cord. The signal travels from the nerve and makes a synapses with the motor nerve that sends the signal down to the muscle and this is gives an electrical signal a few thousandth of a second later and this is called the H wave. In the mouse if you stimulate the sciatic nerve in the leg it takes about 2 milli seconds to make the M wave and an extra 7 milli-seconds to make the H wave. Its a bit like an echo of the M wave and in healthy people an animals the H wave is quite small. But when you have spasticity the inhibitory signals normally present in the spinal cord are reduced and so the H wave is exaggerated and is a measure of spasticity. 
In this study whilst surprisingly they could see an effect on the Ashworth Scale, when they looked they did not see any influence on the M/H ratio (if the drug had an effect on spasticity the H wave should have been reduced). This shows that this electrophysiology outcome is not always responsive to drug treatment. In a previous study they did not find any influence either.

Centonze D, Mori F, Koch G, Buttari F, Codecà C, Rossi S, Cencioni MT, Bari M, Fiore S, Bernardi G, Battistini L, Maccarrone M.
Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurol Sci. 2009;30(6):531-4.

For this reason we are not concentrating on electrophysiology in our ongoing clinical trial with an new anti-spastic tiral

Canbex – Phase II proof of concept trial VSN16R
Investigators: R Farrell (CI) UCLH, Dr Clarence Liu (Barts Health),

4 phases:
Screening and wash out
Daily single escalating dose – 5 days
Three weeks twice daily stable dosing
Washout and end of study review


Be between 18 and 70 years of age
Have MS
Able to walk 20 metres ( with aid as needed)
Have spasticity
Not on medication or willing to withdraw current medication

Please note you cannot self-refer for clinical trials you have to be referred via your neurologist, clinical nurse specialist or general practitioner.

CoI  I am founder, shareholder consultant to Canbex, which will compete with sativex. 

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  • Mouse, if your spasticity drug gets licensed, will you end up like Harry Enfield's Loadsamoney? I can't imagine you in a big mansion with a baby Bentley. I'm guessing when you're in the money Prof G might invite you round his place for one of his posh candlelit suppers. I'm guessing you'll ditch heavy metal for classical music. Will you trade in Mrs M for a Serbian supermodel (Bernie Ecclestonesque)? Feel sorry for socialist Welshman MD2. Can't imagine he'd feel comfortable at Claridges and when you're rolling in money you won't want to be seen with him in an east end pub.

  • Canbex sounds a really interesting drug! I have spms and my right leg often goes tense with spasticity. The only medicine offered by GP and neurologist (this is UK) is baclofen, which I turn down knowing there are side-effects. I've asked for sativex before but of course GP won't prescribe (too expensive and I haven't had the alternative). Would canbex be more available? (perhaps cheaper than the very expensive sativex?). Wishing you some well deserved success. ☺ Jill

  • I hope for success too but first we need to recruit, it needs to work and then phase III. However if you are near a centre and fit the eligibility criteria, the trial is recruiting now. It will not just be in London.

    As for expense…and cheap….. I doubt it very much as companies are out to make a buck. Thankfully that has nothing to do with me.

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