Research:Manipulating the Cannabinoid System

EpubPryce G , A Cabranes, Fernández-Ruiz J, Bisogno T, Di Marzo T, Long JZ, Cravatt BF, Giovannoni G, Baker D. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors Mult Scler 1352458513485982, doi:10.1177/1352458513485982

Background: It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects. 

Objective: We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects. 

Methods: Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge. 

Results: Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184. 

Conclusions: This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use.

We showed that if you smoke pot then it has the potential to alleviate limb stiffness (spasticity). We also showed that this could get you “stoned”. Importantly we showed that if you blocked the natural cannabis system , then we made things worse in beasties with spasticity from EAE. What this current study does is its shows that if you block the breakdown of the natural cannabis (you may have heard of endorphins these are the natural version of morphine in pain relief. Well anandamide is the natural version of cannabis) then it is good for controlling symptoms. The drugs work like SSRIs that block serotonin breakdown to treat depression, except that they blockbreakdown of the natural cannabis. Therefore, there is more around to treat symptoms, without causing the “high”
Whilst you can’t get your hands on Sativex, we have been devising new ways so that you don’t need to use a “drug of abuse”-honestly I never inhaled:-) . Pfizer the makers of the Pfizer riser (Viagra) have done a duff trial in the wrong sort of pain and have binned their drug. There are loads of other companies with drugs in this class ready to go. Sanofi (Genzyme) have about ten patents in this area.


COI. This work is from Team G, who are developing an alternative treatment for spasticity. This study is dedicated to Ana Cabranes a student from Madrid, Spain who spent a happy few months with the MDs  in London..who liked (favourite food) “soap” or was that “soup” had to be there..Unfortunately Ana lost her battle with Hodgkins Lymphoma.

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