The Therapeutic Potential of Cannabinoids for Movement Disorders

Background

There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and particularly for neurologic conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science, preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders.

Results

The pharmacology of cannabis is complex with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of Parkinson’s (PD) and Huntington’s disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia or ataxia and nonexistent for myoclonus or restless legs syndrome.

Conclusions

Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological and therapeutic effects of this class of drugs in movement disorders.

Introduction

Cannabis (marijuana) has long been used for medicinal purposes in many cultures as well as for spiritual and recreational purposes due to its psychoactive properties. Over 60 pharmacologically active compounds or phytocannabinoids have been isolated from cannabis including Δ9-tetrahydrocannabinol (THC), the primary psychotropic compound, and cannabidiol (CBD), a nonpsychoactive chemical with potential therapeutic properties.¹ Nearly all cannabis strains are derived from two cannabis species, sativa and indica. Sativa strains have higher THC concentrations and produce more euphoria, whereas indica strains have more CBD and have more sedating, anti-emetic, and analgesic properties.

Over the past three decades, cannabinoid receptors and endogenously produced cannabinoids (eCBs) have been discovered in a wide range of tissues including peripheral nerves and the central nervous system (CNS). The endocannabinoid system (ECS) has been implicated in a broad range of physiological functions, including cognition, mood, motor control, feeding behaviors, and pain.²–5 Consequently, cannabinoid-based therapies have been studied for a variety of illnesses.⁶ Cannabinoid-based medicines, such as nabilone, dronabinol, and Sativex^{, are now approved for clinical indications, including pain, anorexia, spasticity, and chemotherapy-induced nausea and Epidiolex recently obtained orphan drug status for Dravet syndrome. 6}, 7

Preclinical research suggests that cannabinoids have symptomatic and neuroprotective potential for a variety of neurologic conditions, including movement disorders. The American Academy of Neurology (AAN) Guideline Development Subcommittee systematically evaluated the published clinical evidence and concluded that oral cannabis extract is effective in treating multiple sclerosis (MS) related spasticity and central pain or painful spasms, and that cannabinoid-based therapies are probably ineffective in treating levodopa-induced dyskinesias (LID) in Parkinson’s disease (PD) or tremor and are of unknown efficacy for Huntington’s disease (HD), tics or dystonia.⁸ Our objective is to provide a more in-depth review of preclinical and clinical studies related to the therapeutic potential of cannabinoids for movement disorders.

PRECLINICAL RESEARCH

Endocannabinoids and the Basal Ganglia

The primary cannabinoid receptor subtypes are cannabinoid receptors type 1 (CB₁) and type 2 (CB₂). CB₁ receptors are highly expressed in the CNS, especially the basal ganglia, and also identified in almost all peripheral tissues and cell types.⁹ CB₂ receptors are expressed primarily in the immune system, where they modulate inflammation, but are also expressed in the CNS, particularly in neurons within the dorsal vagal motor nucleus, the nucleus ambiguous, the spinal trigeminal nucleus, and microglia.¹⁰, 11 Recently, CB₂ receptors were found in the basal ganglia and studies suggest that impairment of these receptors may be associated with dyskinesias ¹² While most actions of cannabinoids are related to CB₁ and CB₂ receptors, other receptor types have been described, including the transient receptor potential vanilloid type 1 (TRPV1) cation channel,¹³ the GTP-binding protein-coupled receptor GPR55,¹⁴ the abnormal-CBD receptor,¹⁵ and the peroxisome-proliferator-activated receptor (PPAR).¹⁶

eCBs are lipophilic compounds that demonstrate varying degrees of affinity for G-protein coupled cannabinoid receptors and include anandamide and 2-arachidonoglycerol (2-AG; see Table 1). eCBs primarily function through retrograde signaling, wherein post-synaptic activity leads to eCB production and release with backward transmission across the synapse to depress presynaptic neurotransmitter release.⁵ The ECS may also support synapse formation and neurogenesis.⁵ Within the basal ganglia, eCBs and CB₁ receptors tend to increase GABAergic and inhibit glutamatergic transmission.⁹ eCBs also tend to inhibit dopamine release through GABAergic mechanisms.¹⁷ eCBs are not stored and are quickly degraded after exerting a transient and localized effect. Removal of eCBs from the extracellular space occurs through cellular uptake and metabolism with anandamide degraded primarily by fatty acid amide hydrolysis (FAAH) and 2-AG degraded by monoacylglycerol lipase.¹⁸

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, 27 However, in one study, both a CB₁ agonist, THC, and a selective CB₁ antagonist, rimonabant, exacerbated malonate-induced striatal lesions.²⁸

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.²⁹–33 These 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.³⁹–44 Studies 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 CB₁ modulators may also exhibit functional selectivity for different G proteins or subpopulations of CB₁ receptors, a phenomenon referred to as biased agonism.⁵⁰, 51

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 CB₁ agonists⁵² 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.⁶⁷,28,126 Therapeutic 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

Dystonia and Tremor

It has been hypothesized that CB₁ agonists reduce overactivity of the globus pallidus interna (GPi) and improve dystonia by reducing GABA reuptake.⁷³ In support of this idea, the CB₁ and CB₂ agonist WIN55,212-2 produces antidystonic effects in a mutant hamster model of dystonia, increases the antidystonic efficacy of benzodiazepines and is reversed by rimonabant, a selective CB₁ antagonist.⁷⁴, 75 Animal models suggest that cannabinoids may reduce MS-related tremor, an effect that appears to be selectively mediated by CB₁ receptors.⁹²

CLINICAL RESEARCH

Parkinson’s Disease

Compared to control subject, humans with PD show elevated cerebrospinal fluid levels of anandamide and autopsied brains of PD patients show decreased CB₁ mRNA expression in the basal ganglia.³⁴, 36 It is not clear whether these discrepancies reflect medication effects, down-regulation from increased agonist activity or differences in disease severity. Regarding non-motor symptoms, one study reported CB₁ receptor gene (CNR1) polymorphisms may influence depression risk in PD.³⁷

Observational and uncontrolled studies suggest cannabinoids may improve PD motor symptoms.⁵⁶–58 In a survey of PD patients (N = 339) in the Czech Republic, 25% of respondents reported using cannabis and 46% of these described some benefit; 31% reported improvement of rest tremor, 45% of bradykinesia, and 14% of LID.⁵⁷ Notably, there was a 54% response rate to this survey suggesting a potential for respondent bias. A small (N=22) open-label study assessing motor exam 30 minutes after smoking cannabis also reported improvements in tremor, rigidity, bradykinesia, pain and sleep.⁵⁸ Regarding nonmotor symptoms, a small (N=6) 4-week open-label study of CBD for psychosis in PD found improvements on the Brief Psychiatric Rating Scale and Parkinson Psychosis Questionnaire and another case series (N=4) reported benefits for rapid eye movement sleep behavior disorder.⁵⁶,139 However, a case series of 5 patients found no benefit for tremor following a single administration of smoked cannabis.¹³⁸

In contrast, 4 controlled clinical studies of cannabinoids reported no benefit for motor symptoms, mixed results regarding LID and quality of life.⁵⁹–61, 140 (Table 4) A small (N=5) randomized, double-blind, placebo-controlled crossover trial, assessed the efficacy of 0.03 mg/kg nabilone, a CB₁ and CB₂ agonist for LID given in a split dose 12 and 1 hour prior to a levodopa challenge.⁶¹ They found a significant reduction in LID versus placebo on the Rush Dyskinesia Disability Scale and total LID time. Nabilone did not diminish the antiparkinsonian actions of levodopa or improve parkinsonian symptoms although 2 patients reported improvements in painful off-period dystonia. A larger (N=17) 4-week randomized double-blind crossover study of twice daily Cannador, an oral cannabis extract containing 1.25 mg CBD and 2.5 mg THC, titrated Cannador up to 0.25 mg/kg THC for LID.⁵⁹ Although the blinding seemed to be compromised (71% correct identification of treatment), Cannador failed to improve LID on multiple outcomes, including a non-significant worsening on their primary outcome (UPDRS dyskinesia items) and the Rush Dyskinesia scale. There were no significant changes for other secondary outcomes including motor symptoms (Part 3 UPDRS), quality of life (PDQ-39) or sleep. Another small (N=8) 16-day randomized placebo-controlled trial assessing the efficacy of 20 mg daily oral rimonabant (CB₁ antagonist) showed no effect on parkinsonian motor symptoms or LID as measured by the UPDRS and a standardized videotape procedure.⁶⁰ Examination of data suggested a trend towards worsening in motor scores but the small sample size and other methodological issues prevent any meaningful conclusions. Most recently, 21 PD patients were randomized to placebo, CBD 75mg/day or CBD 300 mg/day for a 6-week trial.¹⁴⁰ No significant changes were found for the total UPDRS or any subscales or measures of neuroprotection (serum brain derived neurotrophic factor levels or putamen magnetic resonance spectroscopy). Improvements were noted for the total PDQ-39 score and stigma and activities of daily living subscores for the CBD 300 mg/day group. Despite the low sample size and quality of these studies, the data suggest cannabinoid agonists and antagonists are probably ineffective for both LID and motor symptoms although further study using different doses, formulations or target symptoms (e.g. dystonia, psychosis, sleep) may be justified. While there were no serious adverse events reported, side effects included hypotension, vertigo, visual hallucinations, dizziness and somnolence.

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: {"type":"clinical-trial","attrs":{"text":"NCT01502046","term_id":"NCT01502046"}}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)⁸⁵ suggest 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

Discussion and Directions for Future Research

Although the number of preclinical studies of cannabinoids for movement disorders has rapidly increased in the last three decades, there are marked gaps in our knowledge about their effects on motor pathways. There are also marked discrepancies and conflicting results in preclinical studies including the precise effects of cannabinoids on neurotransmission and cellular mechanisms of neuroprotection. Furthermore, the paradox of how both CB₁ agonists and antagonists exert similar effects on LID and other hyperkinetic movement disorders needs to be explained. Future studies should address not only motor and behavioral effects of cannabinoids but, because of their proven effects on the sensory system, also explore their effects on sensory-motor integration, a disorder which is increasingly recognized as an aspect of movement disorders.¹¹⁴

Several factors may help explain conflicting preclinical results. Given that cannabinoids interact with a wide range of pharmacological targets, discrepancies in data obtained from preclinical studies may partly reflect the multiplicity of cannabinoid actions.¹¹⁵ The complex localization of cannabinoid receptors at different sites in basal ganglia circuits and the broad array of formulations and doses used in preclinical and clinical studies may also help explain contradictory results.⁸, 50

A change in classification from Schedule I to Schedule IV or V would not only improve access to medical marijuana but could facilitate development and conduct of clinical trials for cannabinoids.¹¹⁶ Future clinical trials should be adequately powered, employ appropriate methodology and outcome measures for the specific movement disorder studied and assess blinding adequacy.¹¹⁷ Improved knowledge of cannabinoids and their pharmacology may help identify specific cannabinoids or combinations that provide therapeutic or neuroprotective benefits in patients with movement disorders.

Acknowledgments