Cannabinoid, CB1 agonists in cervical dystonia: Failure in a phase IIa randomized controlled trial
Introduction
Idiopathic cervical dystonia (CD) is the most common form of focal dystonia [1]. To date, oral pharmacological treatments have had limited efficacy and often poor tolerability in CD. The most effective therapy in current use is botulinum toxin, however, repeated injections are required every 3–4 months from an experienced clinician and there are subgroups of patients who do not respond or who may become secondary non responders due to the development of blocking antibodies to the toxin [2]. Thus, alternative therapeutic options are required.
The neural mechanisms underlying dystonia are not well understood but in keeping with findings in other hyperkinetic movement disorders, may involve underactivity of the output regions of the basal ganglia; the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNR) [3]. In support of this, electrophysiological recordings from patients with idiopathic dystonia undergoing surgery have demonstrated very low firing rates in GPi neurons [4]. A key abnormality responsible for underactivity of the GPi may be increased inhibitory GABAergic transmission from the external globus pallidus (GPe) [5], [6], [7]. Thus reducing GABAergic transmission in the GPe may reduce dystonia. One method of reducing GABAergic transmission may be via stimulation of cannabinoid receptors.
High levels of cannabinoid, CB1 receptors are found in the globus pallidus and SNR [8] and are located presynaptically on the GABA terminals of striatal projection neurons [9], [10]. Recent positron emission tomography studies have confirmed these findings in human subjects [11]. Cannabinoids function as neuromodulators and enhance GABA transmission in the GPe [12], possibly by reducing GABA reuptake [13], although the exact mechanism remains unclear [14], [15]. Furthermore, infusion of cannabinoids into the rodent globus pallidus results in a decrease in activity of pallidal neurons [16], [17]. Thus, cannabinoid receptor stimulation may reduce overactivity of the GPe and thereby reduce dystonic symptoms.
In support of this, the synthetic cannabinoid agonist, WIN 55–212, has been shown to enhance the antidystonic effects of benzodiazepines in a genetic rodent model of generalized dystonia [18]. There are currently no validated primate models of idiopathic dystonia but levodopa-induced dystonia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primate model of PD may model the neural mechanisms that underlie symptoms of idiopathic dystonia in man. In the MPTP-lesioned primate, levodopa induced dyskinesia, characterized by both dystonia and chorea, are reduced by systemic administration of the synthetic cannabinoid receptor agonist nabilone [19].
We have previously assessed the tolerability and efficacy of a single dose of the synthetic cannabinoid, nabilone in subjects with focal and generalized dystonia in a double blind randomised controlled study; this demonstrated tolerability but no significant effect on dystonia [20]. In a similar acute dose setting, nabilone was assessed in Parkinson’s disease patients, both off and on levodopa, with a significant improvement in levodopa-induced dyskinesia but of interest there was also an improvement in painful limb dystonia occurring prior to treatment with levodopa – so called ‘off-period’ dystonia in 2 subjects [21]. Therefore, we proposed to assess the benefit of another synthetic cannabinoid agonist, dronabinol, on dystonia over a 3 week treatment period. Dronabinol has been widely used in the treatment of anorexia and nausea in chemotherapy patients and has shown good safety and tolerability in that population [22], [23]. Due to the heterogeneity and variability in clinical severity of dystonia, we assessed dronabinol only in patients with idiopathic cervical dystonia (CD) using a double-blind, randomized, placebo controlled crossover design.
Section snippets
Methods
Male and female subjects, aged 18–75 yrs, with CD were recruited from the Toronto Western Hospital movement disorders center between January 2007 and May 2009. Exclusion criteria included secondary causes of dystonia, active or prior psychosis, history of substance abuse, use of any other cannabinoids in the preceding month, refusal to refrain from operating heavy machinery or driving during the trial. Subjects had to be at least 4 months since the time of their last botulinum toxin injection.
Results
Forty-one subjects were assessed for eligibility, but only nine were randomized. Due to difficulties with enrollment and loss of supply of active drug, the study was terminated after 2.5 years. Seventeen subjects were excluded; the reason in the majority was an inability to stop driving for the duration of the study. Two subjects dropped out during the study (1 due to adverse effects and 1 was lost to follow up after randomization), leaving 7 patients in the final analysis. Demographics and
Discussion
The cannabinoid CB1 receptor agonist, dronabinol, was ineffective in reducing CD symptoms over a 3 week treatment period. The drug was reasonably tolerated but this study suggests that cannabinoids may not be useful in the treatment of dystonia. A prior open label study reported that the cannabinoid, cannabidiol was effective in treating five patients with different forms of dystonia [27]. Cannabidiol is the non-psychometric component of cannabis sativa and the mechanism of action is poorly
Conclusions
Idiopathic dystonia remains poorly understood and inadequately treated. Cannabinoids have been suggested as a treatment for dystonia due to potential action on CB1 receptors within the basal ganglia. The synthetic cannabinoid, dronabinol, failed to show any effect in 9 subjects with cervical dystonia. However, due to difficulties with enrollment, the study was underpowered and therefore, results must be interpreted with caution. If further studies are attempted, a longer exposure to higher
Financial Disclosures of all authors
Dr. Zadikoff has received honoraria from Allergan, Teva Neurosciences, and Lundbeck.
Dr. R. Chen received consulting fees from Medtronic Inc, Teva, Novartis, Allergan and Biovail, honoraria from Merz, research grants from the Canadian Institutes of Health Research (CIHR), the Michael J. Fox Foundation for Parkinson’s Research and the Dystonia Medical Research Foundation, provided expert testimony and affidavit in welding related litigations. He holds the Catherine Manson Chair in Movement
Acknowledgements
This study was sponsored by a research grant from the Dystonia Medical Research Foundation. We are grateful to the staff from the Movement disorder clinic, TWH for referral of patients for this study. We would also like to thank Abena Asante for her assistance in preparing the manuscript.
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- 1
Present address: Northwestern University, Parkinson’s disease and Movement Disorders Center, 710 N Lake Shore Drive, Ste 1104 Chicago, IL 60611, USA.
- 2
Present address: Jaslok Hospital and Research Centre, 15, G Deshmukh Marg, Mumbai 400026, India.