Medical Marijuana Effects in Movement Disorders, Focus on Huntington Disease; A Literature Review.

PURPOSE
 We aimed to comprehensively evaluate the effects of medical marijuana on symptoms that are relevant to movement disorders with a focus on Huntington disease (HD).


METHODS
 A systematic review by literature search through PubMed and EBSCO electronic databases was conducted for relevant studies reported after 2002 on the effects of medical marijuana or cannabis use on tremor, spasm, spasticity, chorea, sleep quality and HD-specific rating scales. Study selection, quality assessment and data extraction was performed by three reviewers. Outcome measures were changes in psychomotor, and sleep related symptoms. The methodological quality of the included studies was evaluated. Results: A total of 22 studies were reviewed. There was strong evidence for significant improvement in the neurologic symptoms of spasms, tremors, spasticity, chorea, and quality of sleep following treatment with medical marijuana. Analysis of specific motor symptoms revealed significant improvement after treatment in tremors and rigidity. Furthermore, all pretreatment and post-treatment measures indicated a significant increase in average number of hours slept.


CONCLUSION
 Larger scale studies are warranted to test the benefits of medical marijuana in HD patients.  In the meanwhile, clinicians may consider prescribing medical marijuana as part of their strategy for better symptomatic treatment of patients with HD.


INTRODUCTION
Neurodegenerative diseases are characterized by a loss of neurons and neuropathological lesions distributed in particular regions of the central nervous system. Huntington disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by an elongated CAG repeat (36 repeats or more) in the huntingtin gene on the short arm of chromosome 4p16.3 (1,2). In HD, there is neuronal loss in the neostriatum, most markedly in the caudate nucleus, and progressing through the putamen (1). Clinically, HD is characterized by worsening involuntary choreic movements, behavioral and psychiatric disturbances, and dementia (2). Psychomotor processes become severely retarded as patients experience psychiatric symptoms and cognitive decline (2). The prevalence of HD in the Caucasian population is estimated at 1/10,000-1/20,000 with mean age of onset at 30-50 years (2).
Cannabidiol (CBD) is regarded as a compound with therapeutic potential against neurodegenerative and hyperkinetic disorders in view of its neuroprotective effects (3). The endocannabinoid system has been implicated in a broad range of physiological functions such as cognition, mood, motor control, feeding behaviors, and pain (4). The clinical manifestation of movement disorders includes motor symptoms such as resting tremors, rigidity (cogwheel…), akinesia, bradykinesia, loss of righting reflex, chorea, gait disturbances (shuffling gait…), spasticity, and loss of automatic movement, retrocollis, impaired eye movement (downward gaze), pseudobulbar palsy; as well as autonomic dysfunction, cognitive impairment, and depression (1). Preclinical research suggests that cannabinoids have symptomatic and neuroprotective potential for a variety of neurologic conditions-including movement disorders (3,4). Marijuana contains around 60 pharmacologically active compounds known as "cannabinoids" (5).
Studies have shown that nonpsychoactive cannabidiol is well tolerated and safe in humans even at high doses (6). Cannabis strains high in CBD content have been used for treatment of patients with intractable seizures, and to relieve symptoms in patients with chronic pain, arthritis, tremors, dementia, post-traumatic stress disorder, and in patients undergoing chemotherapy (6,7). The medical properties of CBD that have been demonstrated in animal studies include antiemetic, anticonvulsant, antipsychotic, anti-inflammatory, antioxidant, anti-cancer, anxiolytic, and anti-depressant effects (7). As of July 2019, 33 states and the District of Columbia in the United States of America have enacted laws allowing marijuana use to treat certain medical conditions (8).
The most common cause of death in HD is pneumonia, followed by suicide (2). In this study, we focus on the effects of medical marijuana on the symptoms of HD including emotional turmoil (depression, apathy, irritability, anxiety, obsessive behavior), cognitive loss (inability to focus, plan, recall or make decisions; impaired insight), and physical deterioration (weight loss, involuntary movements, diminished coordination, difficulty walking, talking, and swallowing) (9).

METHODS
A systematic review was conducted by literature search through PubMed and EBSCO electronic databases.
The inclusion criteria were the following: 1) must be a scholarly or peer-reviewed source, 2) a relevant article published after 2002, and 3) articles published in the English language only. Exclusion criteria were the following: 1) publications potentially used for marketing purposes, 2) articles in foreign languages, 3) articles dated prior to 2002.
Outcome measures included any changes in symptoms such as choreic movements, chorea, rigidity, tremors, psychomotor decline, cognitive impairment, and depression. The quality of evidence was assessed by scoring the articles according to the following rating scheme: (1) properly conducted randomized clinical trial, (2) well-designed controlled trial without randomization or prospective comparative cohort study, (3) case-control study or retrospective cohort study, (4) cross-sectional study or case series, (5) case reports or opinion of respected authorities.

RESULTS
All together 50 relevant reports were identified, 43 through direct and 7 by indirect searches. After cutting the redundancies, 27 full-text articles were assessed, from which 22 were found eligible for inclusion.
The outcomes data were extracted from studies conducted on populations with several conditions including multiple sclerosis (MS), parkinson disease (PD), fibromyalgia, posttraumatic stress disorder (PTSD) and HD. Effects of cannabis use or medical marijuana treatments were tabulated by signs and symptoms of relevance to HD including spasm and spasticity (Table 1), tremor (Table 2), sleep quality (Tables 1 and 3), chorea, motor and dystonia subscales on the Unified Huntington's Disease Rating Scale (UHDRS) which assesses motor function, cognitive function, behavioral abnormalities, and functional capacity (Table 4), and biochemical markers in animal models (Tables 5 and 6).      (23). Expression of the endocannabinoid-deactivating enzyme fatty acid amide hydrolase (FAAH) is higher in symptomatic (8-to 12-week-old) R6/2 mice than in their wild-type littermates (23).

2017
R6/2 and wild-type mice were housed in rooms with controlled photoperiod with free access to standard food and water. Sativex®-like combination of phytocannabinoids treatment completely reversed the reduction in NAA/Cho (p<0.005) (24).
∆9-THCand CBD-enriched botanical extracts combined in a Sativex®-like ratio 1:1 (4.5 mg/kg equivalent to 3 mg/kg of pure CBD + ∆9-THC) Studies have demonstrated that Fatty acid amide hydrolase (FAAH), an anandamidedegrading enzyme that deactivates endocannabinoids, is upregulated in striatal brain tissue from symptomatic Huntington disease-like R6/2 mice, as well as in Huntington disease patients (23). NAA/Cho (N-acetyl-aspartate/Choline) levels were shown to be reduced in Huntington disease-like mice, possibly reflecting neuronal and mitochondrial dysfunction/damage (24). Treatment with either a broad-spectrum cannabinoid, or combinations of cannabinoids with complementary profiles, have been found to delay progression in an experimental Huntington disease model, and to preserve the integrity of striatal neurons demonstrating that a Sativex®like combination of phytocannabinoids treatment completely reversed the reduction in NAA/Cho (p=<0.005) (24).

DISCUSSION
A systematic review was conducted to evaluate the strength of evidence for the efficacy of medical marijuana in alleviating the symptoms that manifest in movement disorders that are particularly relevant in Huntington disease. The eligible studies included 5 randomized placebocontrolled clinical trials, 2 case-control studies, 2 cross-sectional studies, 2 cohort studies, 2 experimental observational studies, 1 open-label pilot study, and 1 case report. The studies of highest quality were the 5 randomized placebo/controlled trials which included a sum total of 1,329 human subjects. The human studies reviewed demonstrated therapeutic effects for medical marijuana in the management of movement disorder symptomatology including the use of Sativex®, which is an oral spray that contains a combination of tetrahydrocannabinol and cannabidiol, and Nabilone, which is a synthetic cannabinoid capsule that is a selective agonist for CB1 and CB2 receptors (4,25). It is assumed that the effects demonstrated by data extracted from the studies which utilized standardized pharmaceutical formulations would be more clinically reliable than those from survey studies which collected self-reported accounts of cannabis use. Furthermore, since pain is also prevalent in Huntington disease patients, the use of medical marijuana could be helpful for them in light of evidence that cannabinoid-based pharmacotherapies might be effective for management of chronic pain (26). It would be expected that any benefits experienced by patients would have been longer lasting after ingestion as compared to inhalation. Although the majority of studies showed statistically significant results favoring the use of medical marijuana, especially for improving motor symptoms and quality of sleep, the number of Huntington disease patients who were available to participate in these studies was a sum total of 78, and it was necessary to examine the effects seen in patients diagnosed with other diseases in which the same type of symptoms exist. As such, the findings of decreased spasticity were demonstrated primarily by measurements in patients with the autoimmune demyelinative disease multiple sclerosis ( Table  1). The findings of reduced tremor were demonstrated primarily by assessements in patients with the nigrostriatal neurodegenerative parkinson disease ( Table 2). The findings of improved sleep quality were derived from populations of respondents with either the chronic pain disorder fibromyalgia, or the anxiety disorder PTSD, or miscellaneous conditions for which they sought treatment at a cannabis clinic ( Table 3). The findings that were shown in patients with the basal ganglial neurodegenerative Huntington disease were improvements in chorea, improvements in the neuropsychiatric index, and trends for improvements in the Unified Huntington's Disease Rating Scale motor score, the dystonia subscore and behavior score ( Table 4).
The animal studies reviewed included experimental observations following activation of CB1 receptors by THC that demonstrate a protective role of the endocannabinoid system against the development and progression of symptoms in R6/2 murine models for Huntington-like disease (22,23).

CONCLUSION
The observed or reported improvements in the symptoms of movement disorders are consistent with the principal pharmacological effects of THC and CBD. Alleviation of spasticity, tremors, chorea and dystonia might be attributed to the muscle relaxant and analgesic effects of both THC and CBD. Improvements in sleep quality, behavioral and neuropsychiatric indices could be attributable to the anxiolytic, neuroprotective, anti-oxidant, anticonvulsant, and anti-psychotic activities of CBD. Large scale, randomized, clinical trials, perhaps international collaborative efforts, are warranted to test the use of medical marijuana more widely in HD patient populations, and who may be at various stages of disease progression. Acknowledging the need for determining that the therapeutic benefits shall outweigh any long term risks, we nevertheless recommend that physicians consider prescribing medical marijuana as adjunctive treatment for symptomatic relief to slow the progression or reverse spasms, tremor, spasticity, chorea, dystonia, behavioral, neuropsychiatric and sleep disturbances in patients with Huntington disease.