Cannabinoids as neuroprotectants

#MSreseach. Treatment of progressive MS. Lost opportunity

Gareth Pryce, Dieter R. Riddall, David L. Selwood, Gavin Giovannoni, David BakerNeuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. Journal of Neuroimmune PharmacologyDecember 2014

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.
The biology of the cannabinoid system indicates that it should exert a neuroprotective effect and this can be seen in many, many experimental models. We have been looking at symptom control and we could find evidence for THC within cannabis and the CB1 cannabinoid receptor mediated effects. We have also found that these two components can mediate a neuroprotective effect and they can do this by many different mechanisms.

However, until now we have not found any use for cannabidiol, which is major non-phycoactive compound within some strains of cannabis.  In this study we find that cannabidiol can protect nerves from inflammatory damage in experimental animal models of MS, possibly via blocking ion channel activity.

Likewise, so could tetrahydrocannabinol (THC). However, the mixture (as in sativex) of cannabidiol and tetrahydrocnnabinol  was not additive and appeared worse than the individual compounds. 

It has been argued that cannabidiol blocks the psychoactive effects of THC maybe it does and maybe it blocks the beneficial effects of can't have it both ways.

But what happened in MS, The trial of THC (CUPID) in progressive MS as a neuroprotectant was considered a failure. Thus binning years of basic science work.

The placebo group did not progress as expected..maybe the placebo effect of being on a trial. However many people in the trail were using walking aids but it is those people less affected that progress the quickest and when planned subgroup analysis was done there was indeed a significant neuroprotective effect of THC. We got the trial data and can confirm this

So here you have another potential treatment that works in progressive MS....Now what?.....Sadly nothing.

This trial involved over 600 MSers and took 6-7 years to do. There is no enthusiasm to do it again. Likewise who is going to pay for another study. I suspect no one 

The original CAMS trial in 2003 for symptom control of cannabis failed, but they adapted their trial protocol and in 2012 the MUSEC study succeeded.  Throughout out history of MS pioneering trails have failed, such that neuros learn and are more likely to finding something that works next time.

To repeat a symptom control trial lasting a few weeks is different for a trial taking years to do. Sadly the CUPID did not attempt to repeat the CAMS extension data that also showed a treatment effect of THC so we will never know if these results were real or a fluke. Likewise, sadly we will not know if the positive data in the CUPID study was real or a fluke.

In the USA, medical marijuana is becoming increasingly available...and this study will no doubt help justify the claims from the suppliers for some benefit. "Hey they don't need real proof of benefit because they know it does everything...too much sampling of their own wares I suspect :-)".  However, will a study be done I doubt it. With access to pot for a few dollars, no-one is going to want to pay hundred for sativex, even if it did become available in USA . Likewise who would want to take a placebo in a trial when they could get the real thing . 

So the history books will simply state that cannabinoids are no good for neuroprotection.....sadly this one that got away. 

CoI. TeamG did this work