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Marijuana and Multiple Sclerosis
Summary, References, and link to Full Text in PDF format

 
Douglas Goodin; The Lancet Neurology; 3(2); pages 79-80; 2004
[Identifier: http://www.doctordeluca.com/Library/Med/MedMJ/MjAndMs04.htm]
[Related resources: http://www.doctordeluca.com/Library/LibPages/WODjournalism-lib.htm]

 
See also:
[WAR ON PAIN SUFFERERS #3 - Medical Marijuana: 2000-2005]
 
[
Cannabinoids Show Long-Term Benefits for MS Patients, 1 year Follow-up Study Says]
 

[Full Text of this article in PDF format]

Marijuana—Cannabis sativa—has been used for centuries, both as a recreational drug and as a herbal medicine. It contains more than 450 substances, including at least 66 aromatic hydrocarbon compounds collectively referred to as cannabinoids.1 The main active cannabinoid in marijuana is Δ9-tetrahydrocannabinol (Δ9-THC), which is available in several countries as a prescription medication. Two endogenous cannabinoid receptors (CB1 and CB2), and a series of arachadonic acid-derived endogenous ligands (eg, anandamide and 2-arachidonylglycerol), have been identified.2 Only CB1 receptors are expressed in the brain, where they are localised to axons and nerve terminals-mainly in the frontal cortex, basal ganglia, cerebellum, hypothalamus, anterior cingulate cortex, and hippocampus2-but are absent from soma and dendrites. Δ9-THC and other cannabinoids are agonists of CB1 receptors and, presumably, modify synaptic function by inhibiting the release of monoamine and amino-acid neurotransmitters.2

Despite a long history of the medicinal use of marijuana, its therapeutic role remains both controversial and politically charged. Indeed, in the USA, a recent Federal Court decision (upheld by the US Supreme Court) effectively nullified a California state law specifically allowing medicinal use.3 Nevertheless, if the medical benefits of marijuana could be conclusively established, the nature of the debate would be fundamentally transformed.

In multiple sclerosis (MS), studies of the potential clinical value of marijuana have focused on the reduction of spasticity and pain. Several anecdotal reports and small randomised trials, from the late 1970s onwards, have suggested that marijuana reduces the severity of these symptoms in patients with MS.4, 5, 6, 7, 8 and 9 By contrast, the results of a small, randomised, placebo-controlled crossover trial of Δ9-THC and C sativa extract in 16 patients with MS showed that treatment was not beneficial for spasticity and was, in fact, associated with worsening of the patient's global impression score.10

Zajicek and colleagues11 recently reported the results of a large, randomised, placebo-controlled trial of marijuana for the treatment of spasticity in MS. 630 patients were randomly assigned to receive Δ9-THC (2.5 mg), C sativa extract (2.5 mg Δ9-THC, 1.25 mg cannabidiol, and <5% other cannabinoids), or matched placebo at 33 centres across the UK. Total daily dose was titrated (on the basis of body weight and dose tolerated) up to a maximum dose of 25 mg Δ9-THC per day. The primary outcome measure was a change in spasticity as measured on the Ashworth scale.12

In this trial, no significant clinical effect was seen on this primary outcome for treatment with either Δ9-THC or C sativa extract. However, the authors argue that the Ashworth scale may be too insensitive to detect a difference between the groups. Nevertheless, this study was powered (90%) to test specifically the hypothesis that marijuana was at least as effective as other spasticity treatments on the Ashworth scale. The fact that the results do not show an effect raises the question of how much additional benefit marijuana could provide relative to available treatments.

Numerous secondary outcomes—including irritability, pain, spasticity, fatigue, depression, tremor, sleep, and mobility—were also investigated. The authors report several positive findings that led them to conclude that there might be some beneficial effect of cannabinoids in MS. This benefit may, however, be wishful thinking. For example, improved mobility, assessed by the time taken to walk 10 m, was improved in the Δ9-THC group compared with the placebo group (p<0•05). By contrast, C sativa extract provided no such benefit. This suggests either that the original observation is spurious or that other cannabinoids inhibit the beneficial effect of Δ9-THC. The former explanation seems more plausible. Similarly, the subjective reports of reduced pain, decreased spasticity, improved sleep, and reduced spasms (all p<0•05) are suggestive but unconvincing, especially because of the unblinding of the treating physicians and the patients (p<0•001). Moreover, none of these findings would survive even a modest statistical adjustment for multiple comparisons. In addition, the fact that few patients reached their target dose because of side-effects also suggests that the therapeutic potential of either Δ9-THC or C sativa extract in the symptomatic management of MS is limited. Perhaps most intriguing, in light of the expression of CB2 receptors on the surfaces of immune system cells, is the observation that exacerbation rates were lower in both cannabinoid groups compared with placebo (p<0•05). Nevertheless, even this result requires replication before it can be considered reliable, because it relates only to undocumented attacks and is statistically marginal.

Despite these essentially negative results, Zajicek's study is unlikely to resolve or even substantially add to the heated political debate. Enthusiasts for the medicinal use of marijuana will be unconvinced by the negative result and will, no doubt, focus on the suggestive (but subjective) reports in favour of treatment. Conversely, opponents of the medicinal use of marijuana will readily accept the negative findings on the primary outcome measure and will dismiss the other findings as meaningless and not worthy of further study. Unfortunately, neither viewpoint represents a balanced assessment because both are tainted by preconceived biases. On the one hand, because cannabinoids activate specific receptor systems within the brain, it is possible, and indeed probable, that marijuana will ultimately prove to be medically valuable in some clinical settings; if not in MS, then in some other diseases. On the other hand, the medical community should demand solid evidence from carefully designed clinical trials in support of any particular use. The present study11 is an excellent example of such a study, which, as it turned out, did not substantiate a role for marijuana in the management of spasticity. Whether the subjective reports of benefit found by these authors are accurate or spurious will await further, and more focused, investigation, but the therapeutic potential of marijuana should not simply be dismissed.


References

1  SA Ross and MA Elsohly, Constituents of Cannabis sativa: a review of the natural constituents: 1980–1994, J Pharm Sci 4 (1995), pp. 1–10.

2  L Iverson, Cannabis and the brain, Brain 126 (2003), pp. 1252–1270.

3  USA v Rosenthal. Case #CR02-0053CRB; June 9, 2003; Federal Supplement, #266F. Supp. 2d 1091.

4  WA Check, Marijuana may lessen spasticity of MS, Am Medical Assoc J 241 (1979), p. 2476.

5  JT Ungerleiter, T Andyrsiak and L Fairbanks et al., Delta 9 THC in the treatment of spasticity associated with multiple sclerosis, Adv Alc Sub Abuse 7 (1987), pp. 39–50.

6  HM Meinck, PW Schonle and B Conrad, Effect of cannabinoids on spasticity and ataxia in multiple sclerosis, J Neurol 236 (1989), pp. 120–122.

7  PF Smith, Cannabinoids in the treatment of pain and spasticity in multiple sclerosis, Curr Opin Investig Drugs 3 (2002), pp. 859–864.

8  RG Pertwee, Cannabinoids and multiple sclerosis, Pharmacol Ther 95 (2002), pp. 165–174.

9  SA Page, MJ Verhoef and RA Strebbins et al., Cannabis use as described by people with multiple sclerosis, Can J Neurol Sci 30 (2003), pp. 181–182.

10  J Killestine, ELJ Hoogervorst and M Reif et al., Safety, tolerability, and efficacy of orally administered cannabinoids in MS, Neurology 58 (2002), pp. 1404–1407.

11  J Zajicek, P Fox and H Sanders et al., Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial, Lancet 362 (2003), pp. 1517–1526.

12  B Ashworth, Preliminary trial of carisoprodol in multiple sclerosis, Practitioner 192 (1964), pp. 540–542.   

[Full Text of this article in PDF format]
 

 

Dr. DeLuca's Addiction, Pain, and Public Health Website

Alexander DeLuca, M.D., MPH

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Originally posted: 2005-09-29

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