Q In your experience in clinical practice are there many mulitple sclerosis patients who smoke or eat cannabinoids?
A Professor Haas: In the advanced stages of multiple sclerosis (MS) I believe there is no abuse or misuse of cannabis, but some of my patients with Expanded Disability Status Scale (EDSS) scores of seven or eight report that they enjoy using cannabis in the evening in the form of smoking or eating cookies. It is reasonably common in Berlin, although patients do have to obtain the cannabis illegally.
Q Can you please comment on the potential of cannabinoids for the treatment of chronic pain?
A Professor Haas: There are insufficient data to draw definitive conclusions about the use of cannabinoids to treat chronic pain at the present time.
Q Can you explain the anti-inflammatory mechanisms of cannabinoids?
A Professor Di Marzo: The anti-inflammatory mechanisms of cannabinoids are mediated mainly via CB2 receptors and consist primarily of inhibiting the release of proinflammatory cytokines, such as IL-6 or TNF-α, and in most cases at the level of MS, by stimulating the release of anti-inflammatory interleukins, such as IL-10. Given that tetrahydrocannabinol (THC) is more active at CB1 than at CB2 receptors, the anti-inflammatory effects of Sativex® are likely to be due mainly to the cannabidiol (CBD) component, which has a low affinity for both receptor types. As such we believe that, in animal models at least, there are other mechanisms by which Sativex may exert anti-inflammatory effects. As far as we know at present, the anti-spasticity activity of Sativex is not due to any anti-inflammatory effects but rather to its actions on neurons and, more specifically, on neuron excitability and perhaps also at the neuromuscular junction.
Q Why is it necessary to combine CBD with THC in order to treat spasticity?
A Professor Di Marzo: We do not yet fully understand the mechanism of action of Sativex and, in particular, of CBD with regard to the effects on spasticity. Based on our current level of understanding, the inclusion of CBD is necessary as it allows us to scale-up the THC dose without causing a concurrent increase in THC-related side effects. By indirectly antagonizing the psychotropic effects of THC, CBD provides a wider therapeutic window for THC. Personally, however, I am convinced that there is much more to CBD than meets the eye and we are going to discover several distinct functions for CBD perhaps with regard to spasticity and/or neuroprotection. For now, we must view Sativex as a mixture of two components; one component (THC) is the so-called ‘magic bullet’ at CB1 receptors but is too much of a good thing; the other component (CBD) tames some of the effects of THC and allows for a wider therapeutic window. But we are open to surprises in the future.
Q Are there any studies demonstrating the effect of Sativex on serum cytokines in MS patients?
A Professor Di Marzo: Preclinical studies with THC or CBD in animal models show a clear reduction of cytokine levels, but I am not aware that this has been shown as yet in any clinical trials of Sativex conducted in patients with MS.
Q In your opinion what are the potential advantages and disadvantages of Sativex compared with other anti-spasticity drugs?
A Professor Vermersch: This is an important question in terms of how Sativex is used in clinical practice. Although Sativex itself has anti-spasticity activity, it has been investigated as add-on therapy in key pivotal studies. In practice, baclofen or dantrolene are generally used as first-line treatment for spasticity, but many patients do not tolerate these drugs. Furthermore, many patients consider their spasticity to be moderate or severe and do not achieve an adequate response to baclofen or dantrolene. I believe that Sativex has a useful role as add-on therapy in these situations.
Q If there is no response to Sativex after 4 weeks of treatment should it be discontinued?
A Professor Vermersch: In the setting of a controlled clinical study, it is important that we have a design to select responders and nonresponders. We know that most patients who respond to Sativex will do so during an initial 4-week treatment period. In the clinical practice setting, it is also important to select a population of good responders, partial responders and nonresponders, especially considering that MS patients may be receiving a number of medications – not only disease-modifying treatments but also symptomatic treatments. It is often difficult to differentiate between good and partial responders because a partial response may be reported as ‘no positive response’ by patients. In such an instance, it might be useful to continue treatment with Sativex for some time before concluding definitively that a patient will not respond. I think we can possibly prolong the period of testing for a response to Sativex, but not for more than 2–3 months at maximum.
Q In the third pivotal clinical trial of Sativex why did responders in phase A who were treated with placebo in phase B not return to their baseline spasticity scores?
A Professor Vermersch: This a difficult question to answer and is likely to be combination of factors. I can offer three explanations. First, to some degree this reflects regression to the mean. Second, there is known to be a clear placebo effect with all symptomatic treatments. Third, this probably indicates a sustained effect with Sativex for a period of time in the group of patients who were switched to placebo during phase B of the study. Eventually, however, responders who discontinue Sativex will experience deterioration in their condition. In the study reported by Notcutt and colleagues, MS patients who had been receiving long-term treatment with Sativex (mean of 3.6 years) entered into a 5-week withdrawal period Citation[1]. Among patients who had placebo substituted for Sativex there was a significant worsening of their condition, as defined by early withdrawal from the trial, worsening of spasticity or an increase in the use of anti-spasticity/disease-modifying medications.
Financial & competing interests disclosure
For full financial and competing interests disclosure please see the Contents page.
Reference
- Notcutt W, Davies P, Langford R, Ratcliffe S. Results of a randomised withdrawal study of subjects with spasticity due to multiple sclerosis who were receiving long term Sativex®. Mult. Scler.15, S258 (2009).