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
system—composed of endogenous
cannabinoid receptors and ligands
such as 2-arachidonylglycerol and
anandamide—there has been a
considerable renewal of interest in the
therapeutic potential of the cannabi-
noid family of chemicals. Although
extracts have been used to treat a
wide variety of disorders—including
epilepsy, pain, dyskinesia and other
movement disorders, appetite, bladder
disturbance, and spasticity—there 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 placebo-
controlled 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
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For personal use. Only reproduce with permission from The Lancet Publishing Group.
colleagues2 used similar methods, and some benefit in terms of quality of life
also assessed the degree of blinding at measures, a visual analogue score of
the end of the study. “subject’s global impression” showed
A second difficulty is the dose and significant detriment after the use of
route of administration. The active cannabinoids by comparison with
component of cannabis is thought placebo. There was one incident of
to be tetrahydrocannabinol (THC), psychosis following the use of the plant
which can be synthesised and is extract and a number of other milder
commercially available in the form of side-effects which were more common
dronabinol. However, cannabinoids in the active treatment groups.
are very lipid soluble and subject to 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
Rights were not measures. The overall occurrence of
spasticity in the group appears to have
granted to include this been modest, and so it may have been
© Robert Harding/Digital Vision
image in electronic difficult to demonstrate an effect
media. Please refer to based on 16 patients.
The UK national study of
the printed journal. cannabinoids in MS (CAMS) has
almost recruited the target number of
660 patients,3 and is using the same
Cannabis sativa treatment groups as the recently-
published study.2 The CAMS study has
considerable first-pass metabolism in a target population of 220 patients
the liver, leading to great inter- randomised to each therapeutic group
individual variation. Smoking cannabis in order to provide 90% power to
can result in high plasma concen- detect a “moderate” effect in the
trations of THC within a few minutes, Ashworth score with a two-tailed 5%
but has the disadvantage of potential significance level. Clearly there is a
carcinogenicity. Solutions to these huge difference in patient numbers
problems include the development of between these studies, which possibly
alternative routes of administration, or illustrates the large numbers needed to
to accept that variation between identify an effect on the basis of very
individuals exists, and then to little previous information. Although
introduce a titration phase into the the recent paper by Killestein and
study to obtain the correct dose for colleagues has produced some
that particular person. interesting information, we await the
The design of the recent study by results from the CAMS study, which
Killestein’s group was a double- will hopefully provide definitive
crossover type in which patients answers to the uncertainty associated
received three treatments: oral THC with the therapeutic benefits of
(dronabinol), cannabis plant extract, cannabinoids.
and placebo. Each treatment period Conflict of interest
lasted 4 weeks with a 4-week washout ZJ is one of the principal investigators in the MRC-
sponsored CAMS study.
period between treatments. They chose
a particular dose equivalent of THC John Zajicek
and doubled the dose after 2 weeks if Peninsula Medical School, Derriford
Hospital, Plymouth, Devon, PL 8DH, UK
the previous dose had been well
tolerated. Patients were assessed at References
baseline and after 4 weeks for each 1 Ungerleider JT, Andyrsiak T, Fairbanks L,
Ellison GW, Myers LW. Delta-9-THC in the
treatment group. treatment of spasticity associated with multiple
sclerosis. Adv Alcohol Subst Abuse 1987; 7: 39–50.
No significant effect was found in 2 Killestein J, Hoogervorst ELJ, Reif M, et al. Safety,
tolerability and efficacy of orally administered
spasticity scores in any treatment cannabinoids in MS. Neurology 2002; 58: 1404–07.
group by use of the Ashworth spasticity 3 Fox P, Zajicek J. A multicentre randomized
controlled trial of cannabinoids in multiple sclerosis.
scale. Although the researchers found J Neurol Sci 2001; 187 (suppl 1): S453.
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