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ARTICLES: C. B. Carroll, P. G. Bain, L. Teare, X. Liu, C. Joint, C. Wroath, S. G. Parkin, P. Fox, D. Wright, J. Hobart, and J. P. Zajicek Cannabis for dyskinesia in Parkinson disease: A randomized double-blind crossover study Neurology 2004; 63: 1245-1250 [Abstract] [Full text] [PDF]

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Reply to Dr McSherry

Camille B Carroll, John Zajicek, Lara Teare, Peter Bain   (18 November 2004)

Cannabis for dyskinesia in Parkinson disease: A randomized double-blind crossover study

Joseph W McSherry   (18 November 2004)

Reply to Dr McSherry 18 November 2004
Camille B Carroll, Derriford Hospital, Plymouth Room N16, ITTC Building, Tamar Science Park, Plymouth, UK. PL6 8BX, John Zajicek, Lara Teare, Peter Bain Send Correspondence to journal: Re: Reply to Dr McSherry cbc{at}doctors.org.uk Camille B Carroll, et al.	Dear Sirs, We welcome JW McSherry’s positive and interesting comments on our double- blind randomised crossover trial (RCT) of cannabis for dyskinesia in Parkinson’s disease.1 We agree with his view that further studies are required to examine the effects of cannabis on other aspects of Parkinson’s disease and in particular cognition, as our trial was only powered to look at the effect of cannabis on dyskinesia. The improvement in the MMSE in our dose escalation study (treatment effect: 1.5 + 0.6, p<0.01) is intriguing. Although we ascribed this to a practice effect, this may not be the case and this issue certainly merits further examination using more subtle measures of cognitive indices. If this effect is real it is likely to be the result of cannabis having a reasonably rapid pro-cognitive action rather than a neuroprotective mechanism, as the observed improvement in the MMSE occurred within 4 weeks of initiating cannabis treatment. However, this does not exclude the possibility that cannabis may also have a neuroprotective role on cognition in Parkinson’s disease. Our finding in this study was that subjectively ‘patients did not feel better on cannabis extract’. However, we did not specifically examine the effect of cannabis on patients’ wellbeing or feelings other than their reflection in sub-scales of the PDQ-39, on which no differences were detected compared with placebo. The very complex question of whether or not the effects of cannabis depend on the route of administration cannot be answered by our study. Whilst oral administration results in lower peak concentrations than following inhalation, the maximum dose achievable by patients in our study was limited by side effects, implying that further dose titration would not have been possible. As cannabinoids are lipid soluble, it is possible that following prolonged administration the duration of action in the brain is longer than that implied by measurement of serum levels. Ultimately, similar RCTs need to be performed utilizing different modes of administration, for example intra-nasal or inhaled cannabis. Only then will definitive data be available to inform medical practice. We await the outcome of such studies with considerable interest. 1. Carroll C, Bain PG, Teare L et al. Cannabis for dyskinesia in Parkinson’s disease: a randomized double-blind crossover study. Neurology 2004; 63: 1245-1250.
Cannabis for dyskinesia in Parkinson disease: A randomized double-blind crossover study 18 November 2004
Joseph W McSherry, University of Vermont College of Medicine 111 Colchester Avenue, Burlington, VT 05401 Send Correspondence to journal: Re: Cannabis for dyskinesia in Parkinson disease: A randomized double-blind crossover study joe.mcsherry{at}vtmednet.org Joseph W McSherry	I read Carroll et al's article with interest. Although the outcome was negative, an unusual finding may warrant further studies and the outcome highlights the need to consider routes of administration. The improvement in MMSE in the pilot study could have been followed with a comparison of MMSE results after the various segments of the crossover trial, compensating for practice effects. Effects on cognition are very important as cannabis has been recommended for behavior in Alzheimer patients. [1] It is disappointing that patients report benefits from cannabis and the study found none. If cholera or anorexia is being treated [2], delivering the drug to the bowel makes sense. Patients using Marinol for nausea report variability in dose effect from toxicity in 45 minutes to nothing in two hours, presumably depending on other foods in the bowel and hepatic enzyme activity. The authors found peak blood levels of "0.25 ng/mL to 5.4 ng/mL, with no clear dose response." Future studies of systemic effects should use routes of administration that do not make a first pass through the liver. The effects of the mix of metabolites from the first pass differs from the effects of sublingual or vaporized cannabis is further illustrated by the observation that patients did not feel better on cannabis "(treatment effect -0.7, CI -1.5 to 0.2)" in contrast to the subjective response of some patients and other users. It is possible that only some patients respond favorably and perhaps only to certain cultivars. The study does illustrate the complexities of finding the basis of patients' observation of improvement and oral Cannador does not have a therapeutic role in the treatment of dyskinesia in this study group. References 1. Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease Int J Geriatr Psychiatry. 1997 Sep;12:913-9 2. Izzo AA, Capasso F, Costagliola A, et al. An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice Gastroenterology. 2003 Sep;125:765-74