Movement Disorders
Movement disorders are a group of neurological conditions caused by abnormalities in the basal ganglia and their subcortical connections through the thalamus with cortical motor areas. The abundance of CB1 receptors in basal ganglia and reports of animal studies showing the involvement of cannabinoids in the control of movement suggest that cannabinoids would be useful in treating movement disorders in humans. The movement disorders most often considered for marijuana or cannabinoid therapy are dystonia, Huntington's disease, Parkinson's disease, and Tourette's syndrome. Movement disorders are often transiently exacerbated by stress and activity and improved by factors that reduce stress. This is of particular interest because for many people marijuana reduces anxiety.
Dystonia
Dystonia can be a sign of other basal ganglion disorders, such as Huntington's disease and tardive dyskinesia (irreversible development of involuntary dyskinetic movements) and can be a primary basal ganglion disorder. Dystonia can cause mild to severe disability and sometimes pain secondary to muscle aching or arthritis. Some dystonias are genetic; others are caused by drugs. The specific neuropathological changes in these diseases have not been determined.
No controlled study of marijuana in dystonic patients has been published, and the only study of cannabinoids was a preliminary open trial of cannabidiol (CBD) that suggested modest dose-related improvements in the five dystonic patients studied.(30) In mutant dystonic hamsters, however, the cannabinoid receptor agonist, WIN 55,212-2, can produce antidystonic effects.(153)
30. Consroe P, Sandyk R, Snider SR. 1986. Open label evaluation of cannabidiol in dystonic movement disorders. International Journal of Neuroscience 30:277-282.
153. Richter A, Loscher W. 1994. (+)-WIN55,212-2 A novel cannabinoid receptor agonist, exerts antidystonic effects in mutant dystonic hamsters. European Journal of Pharmacology 264:371-377.
Huntington's Disease
Huntington's disease is an inherited degenerative disease that usually appears in middle age and results in atrophy or loss of neurons in the caudate nucleus, putamen, and cerebral cortex. It is characterized by arrhythmic, rapid muscular contractions (chorea), emotional disturbance, and dementia (impairment in intellectual and social ability). Animal studies suggest that cannabinoids have antichoreic activity, presumably because of stimulation of CB1 receptors in the basal ganglia.(129,168)
On the basis of positive results in one of four Huntington's disease patients, CBD and a placebo were tested in a double-blind crossover study of 15 Huntington's disease patients who were not taking any antipsychotic drugs. Their symptoms neither improved nor worsened with CBD treatment. (27,164)
The effects of other cannabinoids on patients with Huntington's disease are largely unknown. THC and other CB1 agonists are more likely candidates than CBD, which does not bind to the CB1 receptor. Those receptors are densely distributed on the very neurons that perish in Huntington's disease.(152) Thus far there is little evidence to encourage clinical studies of cannabinoids in Huntington's disease.
27. Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K. 1991. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacology, Biochemistry and Behavior (New York) 40:701-708.
129. Miller AS, Walker JM. 1995. Effects of a cannabinoid on spontaneous and evoked neuronal activity in the substantia nigra pars reticulata. European Journal of Pharmacology 279:179-185.
152. Richfield EK, Herkenham M. 1994. Selective vulnerability in Huntington's disease: Preferential loss of cannabinoid receptors in lateral globus pallidus. Annals of Neurology 36:577-584.
164. Sandyk R, Consroe P, Stern P, Biklen D. 1988. Preliminary trial of cannabidiol in Huntington's disease. Chesher G, Consroe P, Musty R., Editors, Marijuana: An International Research Report. Canberra: Australian Government Publishing Service.
168. Sanudo-Pena MC, Walker JM. 1997. Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat. Journal of Neurophysiology 77:1635-1638.
Parkinson's Disease
Parkinson's disease, a degenerative disease, affects about 1 million Americans over the age of 50. It is characterized by bradykinesia (slowness in movement), akinesia (abrupt stoppage of movement), resting tremor, muscular rigidity, and postural instability.
Theoretically, cannabinoids could be useful for treating Parkinson's disease patients because cannabinoid agonists specifically inhibit the pathways between the subthalamic nucleus and substantia nigra and probably also the pathways between the subthalamic nucleus and globus pallidus (these structures shown in Figure 2.6).(165,169) The latter effect was not directly tested but is consistent with what is known about these neural pathways. Hyperactivity of the subthalamic neurons, observed in both Parkinson's patients and animal models of Parkinson's disease, is hypothesized to be a major factor in the debilitating bradykinesia associated with the disease.(36) Furthermore, although cannabinoids oppose the actions of dopamine in intact rats, they augment dopamine activation of movement in an animal model of Parkinson's disease. This suggests the potential for adjunctive therapy with cannabinoid agonists.(165-167,169)
At the time of this writing, we could find only one published clinical trial of marijuana involving five cases of idiopathic Parkinson's disease.(48) That trial was prompted by a patient's report that smoking marijuana reduced tremor, but the investigators found no improvement in tremor after the five patients smoked marijuana--whereas all subjects benefited from the administration of standard medications for Parkinson's disease (levodopa and apomorphine).(48) Although new animal data might someday indicate a use for cannabinoids in treating Parkinson's disease, current data do not recommend clinical trials of cannabinoids in patients with Parkinson's disease.
36. DeLong MR, Georgopoulos AP, Crutcher MD, Mitchell S J, Richardson RT, Alexander GE. 1984. Functional organization of the basal ganglia: Contributions of single-cell recording studies. CIBA Foundation Symposium 107:64-82.
48. Frankel JP, Hughes A, Lees AJ, Stern GM. 1990. Marijuana for Parkinsonian tremor. Journal of Neurology, Neurosurgery and Psychiatry 53:436.
165. Sanudo-Pena MC, Patrick SL, Patrick RL, Walker JM. 1996. Effects of intranigral cannabinoids on rotational behavior in rats: Interactions with the dopaminergic system. Neuroscience Letters 206:21-24.
166. Sanudo-Pena MC, Tsou K, and Walker JM. Cannabinoid dopamine interactions in the basal ganglia in an animal model of Parkinson disease. (in preparation).
167. Sanudo-Pena MC, Tsou K, and Walker JM. Superior colliculus and turning: Dopamine and cannabinoids. (in preparation).
169. Sanudo-Pena MC, Walker JM. 1998. Effects of intrastriatal cannabinoids on rotational behavior in rats: Interactions with the dopaminergic system. Synapse 30:221-226.
Tourette's Syndrome
Tourette's syndrome usually begins in childhood and is characterized by motor and vocal tics (involuntary rapid repetitive movements or vocalizations). It has been suggested that the symptoms might be mediated by a reduction in the activity of limbic-basal ganglia-thalamocortical circuits (shown in Figure 2.4). These circuits, while not well understood, appear to be responsible for translating a person's intentions to move into actual movements. Damage to these structures leads to either involuntary increases in movement (as in Huntington's disease) or the inability to make voluntary movements (as in Parkinson's disease). The nature of the deficit in Tourette's syndrome is unknown.
No clear link has been established between symptoms of Tourette's syndrome and cannabinoid sites or mechanism of action. Pimozide and haloperidol, two widely used treatments for Tourette's syndrome, inhibit effects mediated by the neurotransmitter dopamine, whereas cannabinoids can increase dopamine release.(154,181) The physiological relevance, if any, of these two observations has not been established.
Clinical reports consist of four case histories indicating that marijuana use can reduce tics in Tourette's patients.(75,163) In three of the four cases the investigators suggest that beneficial effects of marijuana might have been due to anxiety-reducing properties of marijuana rather than to a specific antitic effect.(163)
75. Hemming M, Yellowlees PM. 1993. Effective treatment of Tourette's syndrome with marijuana. Journal of Psychopharmacology 7:389-391.
154. Rodriguez de Fonseca F, Carrera MRA, Navarro M, Koob G, Weiss F. 1997. Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal [see comments Science 1997., 276:1967-1968]. Science 276:2050-2054.
163. Sandyk R, Awerbuch G. 1988. Marijuana and Tourette's syndrome. Journal of Clinical Psychopharmacology 8:444-445.
181. Tanda G, Pontieri FE, Di Chiara G. 1997. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common µ1 opioid receptor mechanism. Science 276:2048-2049.
