Making cannabis-based studies on MS easy: a review

As we start to delve into the experiments carried out about cannabis & MS, we soon notice that the publications released between 1980s and 1990s on cannabinoids and their efficacy on treating MS spasticity were mainly isolated studies, and only a small number of participants were engaged, so that little validity was attributed.

For an overview of previously published studies, see the work of Karst and colleagues and Correia de Sa and colleagues (1, 2)

In 2003 it was firstly published a larger study, which compared the effects of cannabis extract (2.5 mg THC + 1.25 mg CBD + 5% other cannabinoids daily, first 4 weeks the contents were tritated and doses were adjusted depending on side effects, up to a max of 25 mg of THC daily depending on body weight), THC only (Marinol, the route of administration was oral-capsules) and placebo in a large patient population of 630 patients with moderate to severe stages of Multiple Sclerosis. (3)

A change in spasticity was examined during the course of the 15 week study and evidences of beneficial effects of cannabinoids on pain and spasticity were noticed; however, accordingly with the Ashworth Scale, the estimated difference in mean reduction scores were low, differing from self evaluation tests, from which both active groups reported a highly significant improvement in spasticity, quality of sleep, depression and pain in comparison to those in the placebo groups.

Moreover, a significant amelioration in the timed 10 m walk only after long-term use of cannabis-based medicine was established.

To this study, it followed an extension for 12 months, from which 80% of the participants from the initial study participated, mainly those from the active groups. During the course of this follow up, the Rivermead Mobility Index (RMI) results showed a significant increase in scores, at contrary to the Ashworth Score, for which the improvement was only moderate for both cannabinoid-treated groups. (4)

Inconsistent results by the initial studies on the effects of cannabis-based medicines on MS (5), were mainly attributed to improper measurements parameters.

In 2006 Wade and colleagues published another study, investigating efficacy in the treatment of symptoms of MS with the use of a cannabis-based spray (Sativex), a mixture of THC and CBD (1:1), which was administered daily over 10 weeks to 137 patients. (6)

This time, the change in spasticity has been assessed exclusively with a visual scale and the effects on spasticity were extraordinary. Compared to placebo, the mean reduction in spasticity experienced by the patients of the Sativex group was of 54.6%. These results were confirmed from a 74 weeks follow up study, which proved that the progress lasted overtime.

These are not mere numbers, as 88% of patients voluntary re-started cannabis-based medications.

It appeared hence evident that the Ashworth Scale was not a reliable measurement for functional change in spasticity, and in 2007 a full ethical approval was granted to a numerical rating scale (NRS), ranging 0 to 10 and decided by the patients themselves.

The group of Collins and collegues used the above mentioned method to evaluate antispastic properties of Sativex for 189 MS patients (7).

For this study (lasting 6 weeks), the maximum dose per day allowed was up to 48 sprays, and delivered an impressive decrease in spasticity by NRS score for the active group. The NRS score in 6 weeks only was of 1.18 points for the Sativex group compared to the placebo group, meaning that 40% of the subjects achieved >30% of improvement of symptoms.

In 2010 the group of Wade and collegues (9) tested Sativex with 666 patients of MS and measured the outcomes with a Visual Analogue Scale, a Numerical Rating Scale as well as a Global Impression of Change, concluding that Sativex does reduce spasticity and is also well tolerated amongst patient population.

A different design was applied by the group of Novotna, which investigated the effects of Sativex during 12 weeks, only to the participants of a preliminary study which identified as “early responders” to the cannabis spray. (8)

The 4 week preliminary study aimed to filter those MS patients promptly responding to the cannabis-based medicine, which showed at least 20% of reduction in spasticity by the NRS scores, which proved to be 272 out of 572.

Despite the dose allowed per day of spray was significantly lower to that of Collins study (¼), the NRS scores was found to be decreased of 3.01 points (baseline =6.91 endpoint=3.9) for spasticity; the frequency of spasms and sleep problems were also attenuated by the use of Sativex.

This study was a phase III trial, the first one identifying clinically highly significant reduction in spasticity with the use of Sativex, a result that was expedited by the design of the study;

For the skeptics, a 5-week placebo-controlled, randomized withdrawal study in patients with ongoing benefit from nabiximols confirmed the long-term benefits of Sativex. (9)

As any substance we intake, either endogenous (which our own body produces) or exogenous (which we need to artificially create or extract from nature), this will come with any sort of advantages and risks. In pharmacology, a medicine is considered safe when the benefits of the chemicals are higher than their hazards, at a certain dose.

Obviously cannabis-derived medicines are not different; it is not a case that in most Countries recreational cannabis is banned due to its psychotropic effects. It is hence important to delve in the topic in order to examine the concerns related to its use.

Before you continue reading, tough, I would like to challenge you to open your medicines cabinet and pick any medicine; you will notice, for over-the-counter as well as prescribed medicines, a long leaflet. Scroll until the side effects reported, and start reading. None of it is desirable, is not it?

Keep that note next to you as you read along this article. And think how easily we are willing to put ourselves at risk or internal bleeding or amnesia for a common cold or insomnia.

As reported by several reports, the tolerance outcome of cannabis-based medicine was good, with sporadic adverse effects, ranging in the “nonserious” scale and mainly identified as dizziness, drowsiness, disorientation, impaired concentration, and impaired balance.

In order to address these issues, a large safety study carried out by Wade and collegues (9) examined 137 MS patients using up to 48 Sativex spray daily, from which was ruled out that cannabinoid therapy results in serious adverse effects in comparison to placebo groups.

Again, dizziness was the main side effect reported by the 17 participants whom decided to discontinue the study. Moreover, the use of cannabis-spray, seem to induce dryness of the mouth and in some cases even pain in the mouth.

In order to reduce to minimum the risk of side effects, it is advised to plan your dose slowly, adjusting it in the occurrence of unwanted adverse effects. Your physician will prepare an individual tritation phase for you as well as reviewing your doses periodically.

The main concern for patient with MS is their vulnerability to psychiatric symptoms, such as depression,cognitive impairment, and fatigue. Moreover, reduced information processing speed and impaired verbal memory are often associated with the progression of the disease.

A series of studies investigating neuropsychological effects of cannabis medicine on MS patients took place, showing that the treatment worsens verbal learning impairment compared with placebo.However, it has also been shown that medium to short-term use of cannabis-based medicinal extracts does not induce the cognitive decline that have been attributed to long-term heavy recreational use of cannabis (11)

For instance, the main deterrents to the use of cannabis extracts are euphoria/depression, tolerance, withdrawal, induction of psychosis or cognitive deficits; and yet from a meta-analysis on all published studies on Sativex, (12) euphoria was reported by 2.2% of patients, depression from 2.9% and tolerance and withdrawal symptoms did not occur, even when therapy was interrupted abruptly.

Amongst all studies participants, there were only 3 cases of psychoses and 10 hallucinations and remission of symptoms at therapy discontinuation.

It is important to assess the personality treats of the patients before embarking in this therapy; people with psychiatric illnesses or addictions are not indicated for the treatment.

1) Karst M., Wippermann S., Ahrens J. (2010) Role of cannabinoids in the treatment of pain and (painful) spasticity. Drugs 70: 2409–2438

2) Correia de Sa J., Airas L., Bartholome E., et al. (2011) Symptomatic therapy in multiple sclerosis – a review for a multimodal approach in clinical practice. Therap Adv Neurol Disord 4: 139–168.

3) Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A, UK MS Research Group: Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003, 362:1517-1526.

4) Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry

5) Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC,Staats PG, Gorter RW, Uitdehaag BM, Polman CH: Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002, 58:1404-1407

6) Wade D., Makela P., House H., Bateman C., Robson P. (2006) Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 12: 639–645.

7) Collins C., Davies P., Mutiboko I., Ratcliffe S. (2007) Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 14: 290–296

8) Novotna A., Mares J., Ratcliffe S., et al. (2011) A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R)) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 18: 1122–1131.

9) Wade D., Collin C., Stott C., Duncombe P. (2010) Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult Scler 16: 707–714.

10) Notcutt W., Langford R., Davies P., Ratcliffe S., Potts R. (2012) A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler 18: 219–228.

11) Papathanasopoulos P., Messinis L., Lyros E., Kastellakis A., Panagis G. (2008) Multiple sclerosis, cannabinoids, and cognition. J Neuropsychiat Clin Neurosci 20: 36–51

12) Robson P. (2011) Abuse potential and psychoactive effects of delta-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin Drug Saf 10: 675–685