Reflection & Reaction

Cannabinoids on trial for multiple sclerosis

Extracts from the plant Cannabis sativa have been used therapeutically for thousands of years, although there has been a decline in use since the early 20th century, largely based on perceived lack of effect. After the discovery of the endocannabinoid systemcomposed of endogenous cannabinoid receptors and ligands such as 2-arachidonylglycerol and anandamidethere has been a considerable renewal of interest in the therapeutic potential of the cannabinoid family of chemicals. Although extracts have been used to treat a wide variety of disordersincluding epilepsy, pain, dyskinesia and other movement disorders, appetite, bladder disturbance, and spasticitythere is comparatively little valid experimental evidence in published work upon which to base therapeutic decisions. One of the biggest patient groups to use cannabis is those individuals with multiple sclerosis (MS), who have reported anecdotal benefit (eg, for muscle spasms and spasticity). Until recently, however, there were only about 40 published cases, with the largest study comprising only 13 patients.1 This makes sensible scientific debate very difficult. A recent paper by Killestein and co-workers2 has made a significant contribution to the number of published cases; it describes a double-blind randomised placebocontrolled crossover study in 16 people with chronic MS. Researchers encounter a number of difficulties in designing studies that use cannabinoids. First, it can be difficult to control for the mood-enhancing effects of cannabis; this potentially introduces bias by the lack of appropriate placebo. However, some studies have reported hallucinations in the placebo group of cannabis studies, highlighting the potential power of the placebo effect. One way to overcome this is to ensure that assessment of the primary outcome measure, such as spasticity, is done by an assessing individual who is blinded to any medication side-effects, and different to the treating physician who may adjust dose and monitor side-effects. In their recent study, Killestein and colleagues2 used similar methods, and also assessed the degree of blinding at the end of the study. A second difficulty is the dose and route of administration. The active component of cannabis is thought to be tetrahydrocannabinol (THC), which can be synthesised and is commercially available in the form of dronabinol. However, cannabinoids are very lipid soluble and subject to some benefit in terms of quality of life measures, a visual analogue score of subjects global impression showed significant detriment after the use of cannabinoids by comparison with placebo. There was one incident of psychosis following the use of the plant extract and a number of other milder side-effects which were more common in the active treatment groups. One problem with the recent study is that there is no mention of any power calculations or the size of effect sought in any of the outcome measures. The overall occurrence of spasticity in the group appears to have been modest, and so it may have been difficult to demonstrate an effect based on 16 patients. The UK national study of cannabinoids in MS (CAMS) has almost recruited the target number of 660 patients,3 and is using the same treatment groups as the recentlypublished study.2 The CAMS study has a target population of 220 patients randomised to each therapeutic group in order to provide 90% power to detect a moderate effect in the Ashworth score with a two-tailed 5% significance level. Clearly there is a huge difference in patient numbers between these studies, which possibly illustrates the large numbers needed to identify an effect on the basis of very little previous information. Although the recent paper by Killestein and colleagues has produced some interesting information, we await the results from the CAMS study, which will hopefully provide definitive answers to the uncertainty associated with the therapeutic benefits of cannabinoids.
Conflict of interest
ZJ is one of the principal investigators in the MRCsponsored CAMS study.

Cannabis sativa

considerable first-pass metabolism in the liver, leading to great interindividual variation. Smoking cannabis can result in high plasma concentrations of THC within a few minutes, but has the disadvantage of potential carcinogenicity. Solutions to these problems include the development of alternative routes of administration, or to accept that variation between individuals exists, and then to introduce a titration phase into the study to obtain the correct dose for that particular person. The design of the recent study by Killesteins group was a doublecrossover type in which patients received three treatments: oral THC (dronabinol), cannabis plant extract, and placebo. Each treatment period lasted 4 weeks with a 4-week washout period between treatments. They chose a particular dose equivalent of THC and doubled the dose after 2 weeks if the previous dose had been well tolerated. Patients were assessed at baseline and after 4 weeks for each treatment group. No significant effect was found in spasticity scores in any treatment group by use of the Ashworth spasticity scale. Although the researchers found

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John Zajicek Peninsula Medical School, Derriford Hospital, Plymouth, Devon, PL 8DH, UK
References
1 Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 1987; 7: 3950. Killestein J, Hoogervorst ELJ, Reif M, et al. Safety, tolerability and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58: 140407. Fox P, Zajicek J. A multicentre randomized controlled trial of cannabinoids in multiple sclerosis. J Neurol Sci 2001; 187 (suppl 1): S453.

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THE LANCET Neurology Vol 1 July 2002

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