The therapeutic potential of cannabinoids for movement disorders.

Neuroprotective Potential of Cannabinoids

Several studies in animal models of both PD and HD suggest that cannabinoid-based therapies may attenuate neurodegeneration (Table 2). Indeed, on October 7, 2003, U.S. Health and Human Services was granted U.S. Patent 6630507, which lists the use of cannabinoids found within the cannabis sativa plant as useful in certain neurodegenerative diseases such as PD, Alzheimer’s disease and dementia caused by human immunodeficiency virus.141 Cannabinoids may offer neuroprotection through both receptor-mediated and receptor-independent mechanisms. Cannabinoids are capable of reducing oxidative damage by acting as scavengers of reactive oxygen species (ROS) and enhancing endogenous antioxidant defenses.19 This property appears to be independent of CB1 and CB2 receptor modulation and restricted to certain cannabinoids, including CBD, THC, cannabinol, CP55,940, and the anandamide analogue AM404.20–22 CB2 agonists exert anti-inflammatory effects by inhibiting reactive microglia and cytokine release.20, 23–25 Lastly, CB1 agonists reduce excitotoxicity by suppressing glutamatergic activity, subsequent calcium ion influx, and nitric oxide production.26, 27However, in one study, both a CB1 agonist, THC, and a selective CB1 antagonist, rimonabant, exacerbated malonate-induced striatal lesions.28

Table 2

Preclinical Neuroprotective Studies of Cannabinoids

Parkinson’s disease

Experimental models of PD show increased ECS activity in the basal ganglia, including increased CB1 mRNA levels, CB1 activity, anandamide levels, and decreased cannabinoid clearance.29–33These changes appear to be associated with movement suppression and may be reversed by chronic levodopa treatment.29, 35 Importantly, many cannabinoids demonstrate neuroprotective effects in several models of PD (Table 2). These effects appear to be mediated by both CB receptor dependent and independent mechanisms including antioxidant effects, reduced microglia activation, and modulation of glial-neuron interactions.20,24,67,121

Animal studies further suggest that cannabinoids may improve motor symptoms of PD and LID, but results are variable (Table 3). CB1 agonists inhibit basal ganglia dopamine release and are there for expected to be ineffective in alleviating PD motor symptoms. Indeed, CB1 agonists have been shown to exacerbate bradykinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates.38 However, CB1 agonists have also been reported to improve motor impairments, possibly through nondopaminergic mechanisms including interactions with adenosine A2A receptors.39–44Studies of CB1 antagonists are more consistent in improving motor symptoms without increasing dyskinesias.45–49 These effects appear to involve nondopaminergic mechanisms including enhanced striatal glutamate release and may be greater in animals with more severe striatonigral degeneration.29, 46, 47 Potential explanations for the therapeutic variability of CB-based compounds include differences in lesion severity, trial design, dose, and gender.46, 48, 49 Different CB1modulators may also exhibit functional selectivity for different G proteins or subpopulations of CB1receptors, a phenomenon referred to as biased agonism.50, 51

Table 3

Preclinical studies assessing therapeutic symptomatic efficacy of cannabinoids for movement disorders

While CB1 and CB2 receptors are decreased in the basal ganglia of dyskinetic animals, it is not known whether this is compensatory or causal.12 Animal studies suggest cannabinoid-based therapies may improve LID without worsening motor control. Interestingly, these effects are reported for both CB1agonists52 and antagonists45, although these effects are not seen in all studies and higher doses of CB1 agonists may impair motor function suggesting that CB1 agonist effects on LID are related to general motor suppressant effects.53–55 Other CB receptors may also be involved in LID as URB597 (a FAAH inhibitor which increases anandamide levels) did not affect LID as monotherapy but did improve LID when co-administered with a TRPV1 antagonist, suggesting that TRPV1 and CB1 may have opposing effects.54

Huntington’s Disease

Experimental animal models indicate that HD is associated with early and widespread reductions in the ECS, particularly CB1 receptors in the striatum.62,63 CB1 receptors mediate brain-derived neurotrophic factor expression and CB1 receptor loss is associated with exacerbation of symptoms, neuropathology, and molecular pathology in the striatum. Moreover, cannabinoid-based therapies generally show neuroprotection in several animal models through both CB receptor mediated and independent effects (Table 2).145,124,127 Caution is warranted as several studies using identical cannabinoids and models showed no benefit or even exacerbation of neurotoxicity.67,28,126Therapeutic studies of cannabinoid-based agents in HD animal models suggest that CB1 and endovanilloid receptor agonists28, 66 and anandamide reuptake inhibitors67 are capable of alleviating hyperkinesia (Table 3). This therapeutic potential is likely to be realized in early phases of HD because of progressive loss of CB1 receptors in advanced stages.68

Huntington’s Disease

Post-mortem human studies and PET imaging studies using a CB1 ligand support experimental HD models in demonstrating early and marked decreases in both subcortical and cortical CB1 receptors.64,65 Clinical research of cannabinoids for HD symptoms are inconclusive. (Table 4) Case reports using nabilone, a CB1 agonist, reported worsening of chorea severity in one patient and benefits for chorea and irritability in another.69, 70 A small (N=15) randomized double-blind placebo-controlled crossover trial assessed CBD capsules (10 mg/kg divided in twice daily doses) given for 6-weeks for chorea as measured by the Marsden and Quinn chorea severity scale.71 This study found small and statistically insignificant differences between groups on primary and secondary outcomes, including patient global impressions. A larger (N=37) 5-week double-blind placebo-controlled randomized cross-over trial assessed nabilone titrated to 1 or 2 mg given twice daily for 5 weeks on the total motor score of the Unified Huntington’s disease rating scale (UHDRS).72 Change in total UHDRS did not differ between groups. However, statistically significant improvements were noted for the UHDRS chorea scale and the neuropsychiatric inventory with a trend for improvement on the UHDRS behavior score. There were no statistical differences reported between the 1 and 2 mg. Notably, one patient withdrew due to severe sedation. These results are encouraging and suggest a need for larger controlled trials. A phase II (N=25) double-blind placebo-controlled randomized clinical trial is examining the safety and neuroprotective efficacy of nabiximols, a combination of CBD and THC, using clinical and biomarker (cerebrospinal brain-derived neurotrophic factor) outcomes, but results are not yet available (NCT Identifier: NCT01502046).

Dystonia

While case reports of smoked cannabis for generalized dystonia in Wilson’s disease,76 idiopathic hemidystonia,77 and a case series of 5 patients with dystonia secondary to diverse causes treated with oral CBD (100–600 mg daily)78 suggest cannabinoids may alleviate dystonia, 2 small randomized placebo-controlled clinical trials for dystonia showed no effect (Table 4). Notably, the case series reported exacerbated hypokinesia and tremor in 2 patients and other mild side effects including hypotension, dry mouth, psychomotor slowing, lightheadedness, and sedation.78 A small (N=13) randomized double-blind placebo-controlled cross-over trial tested a single dose of 0.03 mg/kg nabilone or placebo on patients with medication refractory focal or generalized dystonia using the Burke-Fahn-Marsden dystonia scale.73 They reported no significant differences between groups at 60, 120 or 180 minutes, including when separating generalized from segmental patients. 4 patients reported a subjective improvement lasting 3 days after nabilone and 2 patients withdrew secondary to hypotension and sedation. A second small (N=7) randomized placebo-controlled crossover trial assessed 7.5 mg dronabinol, a CB1 and CB2 agonist, given twice daily for 2 weeks in patients with cervical dystonia using the Toronto Western Hospital Spasmodic Torticollis Rating Scale (TWSTRS).79 There were no significant differences noted on TWSTRS (total or subscales) or subjective ratings. One subject withdrew secondary to insomnia and sensation of heart racing, and all but one subject reported mild side effects including lightheadedness, hypotension, vertigo and dry mouth.

Tics and Tourette Syndrome

Case reports of smoked cannabis,80 oral THC,81–84 and case series of smoked cannabis (N = 3)85suggest that cannabinoids may be beneficial for tics in patients with Tourette syndrome (TS). Similarly, a survey of 64 TS patients found that 17 (27%) had tried marijuana and 14 of them (82%) found it helpful for tics and behavioral disturbances.86 Although only 2 controlled trials have assessed the efficacy of cannabinoids for tics, the results support these uncontrolled clinical reports. A small (N=12) randomized double-blind placebo-controlled single-dose crossover trial assessed a single dose of 5–10 mg oral THC (dose based on body weight and prior marijuana use) for tics in TS using the Tourette Syndrome Symptom List (TSSL).87 Tics and obsessive compulsive behavior significantly improved on the TSSL with statistically significant improvements or trends towards improvement in other secondary outcomes including the Yale Global Tic Severity Scale. Mild side effects noted by 5 patients included headache, dizziness, nausea and cognitive changes. Another small (N=17) 6-week randomized placebo-controlled parallel group trial of 6-weeks 10 mg daily orally-administered THC assessed tic reduction in TS patients using the Tourette Syndrome Clinical Global Impression scale (TS-CGI).88 This study also found significant improvements in the primary and most secondary outcomes. A related study from the same cohort reported no significant change in neuropsychological performance with THC treatment.89 Limitations of these studies include small sample size, short treatment period, multiple comparisons, fixed or single dose approach, potential blinding issues and possible selection bias. Given these limitations, AAN evidence-based systematic review, as well as a recent Cochran review on the efficacy of cannabinoids in TS, state that there is presently “insufficient evidence to support or refute the clinical use of THC, nabilone, or cannabis for tics”.8, 90 However, in treatment resistant adult patients, THC may have therapeutic effects and is recommended by some experts.91 Positive results of preliminary studies warrant validation of the efficacy and safety of THC for tics in larger randomized clinical trials.

Multiple Sclerosis-related Tremor

A small (N=8) case series of 5–15 mg oral THC given 4 times a day reported objective improvement in tremor in 2 patients and subjective improvement in 5.93 However, subsequent clinical trials assessing the efficacy of cannabinoids for MS-related tremor failed to show benefit. A small (N=13) 6-week randomized double-blind placebo-controlled trial assessed Cannador dosed up to 0.125 mg/kg THC twice daily for patients with MS-related tremor.94 There were no statistically significant effects as measured by a tremor index, the Nine-Hole Peg Test of manual dexterity, spiral drawings or other objective measures although 5 patients reported subjective benefits. Notably, 9 of 13 patients correctly guessed their treatment group and 10 reported mild adverse effects including cognitive changes, drowsiness, lightheadedness and dry mouth. A large (N=337) 8-week double-blind, randomized placebo-controlled trial of up to 24 actuations per day of oral nabiximols spray (65 mg THC, 60 mg CBD), evaluated tremor as a secondary outcome with an index score and patient global impression of change and reported no effect on tremor.95 Another large (N=391) 15-week randomized placebo-controlled trial assessing the efficacy of oral THC (marinol) versus oral cannabis extract (both dosed up to 12.5 mg given twice daily) versus placebo showed no difference in patient ratings of tremor as a secondary outcome.96 Given the consistent lack of response to cannabinoids in patients suffering from MS-related tremor, AAN evidence-based guidelines state THC and oral cannabis extract are probably ineffective for reducing MS-related tremor and nabiximols are possibly ineffective.8 To our knowledge there have been no studies of CB-based treatments for essential tremor or other tremor types.

Other Movement Disorders

There have been no published clinical trials of cannabinoids for ataxia, myoclonus or restless legs syndrome. Two case reports suggest ataxia (in combination with spasticity) in MS may improve following smoked cannabis or oral THC and a survey of 112 MS patients reported some individuals noting improvement in balance.93, 97, 98 Marijuana may be effective for psychogenic symptoms as illustrated by a report by Sanjay Gupta, called “Weed”, which featured a 19 year old young man who after 7 minutes of “convulsing” with “myoclonus – diaphragmatic flutter”, resembling psychogenic tic or tremor, had a sudden resolution of the movement, respiratory and speech disorder within seconds of smoking marijuana.99,142

Adverse Effects and Risk of Addiction

While cannabinoids appear to be well tolerated when used in moderation, AEs are clearly a major concern. In the systematic review of CB studies conducted by the AAN 6.9% (95% CI 5.7%–8.2%) of participants stopped their medication due to AEs.8 AEs include ataxia, nausea, impaired short-term memory, stroke, cognitive impairment, dry mouth, suicidal ideation, hallucinations, dizziness, fatigue, behavioral or mood changes, impaired motor skills, increased weakness, heart rate and appetite.8, 100, 101 Marijuana use is also associated with an increased risk of chronic anxiety, depression and psychosis, though causality has not been established.102 Except for ataxia, there have been no documented cases of movement disorders induced by cannabis use. However, there has been one case report of propriospinal myoclonus possibly induced by cannabis,103 but this form of myoclonus is often of psychogenic origin.104

It is important to note that side effects, as well as therapeutic effects, vary depending on the CB(s), concentration of CB(s), or ratio of CBs in formulations.105 Smoking cannabis has been associated with lung cancer risk so future trials should focus on other methods of ingestion, although oral administration is also problematic due to deposition of cannabinoids into fatty tissue, from which they are released slowly, causing variability in plasma concentrations.106, 107

There is also an important risk of abuse with marijuana and cannabis-based drugs.108 Studies of marijuana outside of the medical context estimate 9% of persons using cannabis may become addicted and experience symptoms of withdrawal after quitting the drug.109 The mechanism of abuse in marijuana users is not well understood but may involve blunted dopamine reactivity. This is supported by the observation that marijuana abusers, compared to healthy controls, showed markedly blunted dopamine responses when challenged with methylphenidate and that PET scans using [11C] raclopride, a D2 ligand, show dopamine in ventral striatum of marijuana abusers was inversely correlated with addiction severity and craving.110 It is likely that patients using medical formulations may be at lower risk, due to lower doses, use related to a specific indication, and formulations with a lower concentration of THC, the key component responsible for the dependence potential of cannabis.111 Cannabis is generally safe in overdose although illicit synthetic cannabinoids have been associated with severe medical and psychiatric complications.112, 113 Finally, epidimiological studies suggest that cannabis may be a “gateway drug” as its use is associated with later use of other illicit substances.143 While the causal role and mechanisms of the gateway idea are still debated, it is prudent for future clinical trials to monitor for current and subsequent use of other illicit substances.144

Funding sources: This work was not funded.

Dr. Jankovic acknowledges the support of his Centers of Excellence by the National Parkinson Foundation and the Huntington Disease Society of America.