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Cannabinoids for the Treatment of Movement Disorders - Springer
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(1)
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Current Treatment Options in Neurology
2015
17:39
DOI: 10.1007/s11940-015-0370-5
Movement Disorders (O Suchowersky and A Videnovic, Section
Editors)
Cannabinoids for the Treatment of Movement
Disorders
Briony Catlow1 and Juan Sanchez-Ramos2
Lieber Institute for Brain Development, Baltimore, MD, USA
Department of Neurology, University of South Florida, 13320 Laurel Dr, Tampa, FL 33612, USA
Briony Catlow
Email: briony.catlow@libd.org
Juan Sanchez-Ramos (Corresponding author)
Email: jsramos@health.usf.edu
Published online: 25 July 2015
© Springer Science+Business Media New York 2015
Opinion statement
Use of cannabinoids as medications has a long history. Unfortunately, the prohibition of cannabis and its classification
in 1970 as a schedule 1 drug has been a major obstacle in studying these agents in a systematic, controlled manner.
The number of class 1 studies (randomized, double-blind, placebo-controlled) in patients with movement disorders is
limited. Hence, it is not possible to make recommendations on the use of these cannabinoids as primary treatments for
any of the movement disorders at this time. Fortunately, there is an expanding body of research in animal models of
age-dependent and disease-related changes in the endocannabinoid system that is providing new targets for drug
development. Moreover, there is growing evidence of a “cannabinoid entourage effect” in which a combination of
cannabinoids derived from the plant are more effective than any single cannabinoid for a number of conditions.
Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this
point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic
application of cannabinoids will expand.
Keywords
Cannabinoids – Cannabis – Schedule 1 drug – THC – CBD – Movement disorders – Endocannabinoid system –
Cannabis preparations – Compassionate use – Therapeutic application
This article is part of the Topical Collection on Movement Disorders
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Introduction
Preparations of the cannabis plant have been used to treat a wide range of medical conditions by many cultures for
thousands of years. The first written records of therapeutic use of cannabis were found in Egyptian medical papyri
dating from approximately 1700 BC. An excellent historical review of the medicinal use of cannabis has recently been
published [1]. The first description of cannabis to specifically treat muscle spasms was in the writings of Al-Kindi in the
ninth century AD. Almost 1000 years later, cannabis extracts were used to increase survival from tetanus in India, and
the use of cannabis preparations as muscle relaxants and anti-spasmodics became prevalent in Britain and the North
America [1]. A supply of cannabis herbal material (in the form of “Squire’s Extract”, a tincture of Indian hemp) was
brought to England from Calcutta by a British physician who provided this to other practitioners in the British Isles. The
use of tincture of Indian hemp to treat the tremor of Parkinson’s disease was first described by Sir William Gowers in
his landmark textbook of Neurology published in the late nineteenth century [2].
"In one case tremor had commenced in the right arm and leg an hour after a railway accident and
extended, three months later into the left arm. Two years subsequently there was a constant lateral
movement at the wrist joints, but no tremor the fingers. A great improvement occurred on Indian hemp
and a year later the tremor had almost ceased, being occasional only."
Here, we will review the rationale for using cannabinoid drugs and their potential role for the treatment of a range of
movement disorders. An excellent review of this topic has recently been published that covers much of the clinical
material in this chapter, but that report has much more detail on the pre-clinical research in animal models [3••].
Plant cannabinoids, endocannabinoids, and cannabinoid
receptors in the brain
The cannabis plant is notable for its morphological variability and versatility as a foodstuff (seeds), fiber (stalks), and
pharmaceutical (unfertilized flowering tops) [1]. There are many strains of cannabis derived from two primary species,
Cannabis sativa and Cannabis indica. Cannabis is known to contain over 100 related molecules, the
phytocannabinoids and greater than 200 terpenoids [4]. What purpose these molecules serve for the plant itself is not
really understood. Phytocannabinoids are seen by some researchers as by-products of intermediary metabolism with
no specific function in the plant. However, some phytocannabinoids are mildly anti-fungal and others may serve to
repel destructive insects and to attract others (e.g., to lure bees for cross-pollination). Some cannabinoids may
possess physiological properties involved in the regulation of plant growth and sexual development [4].
In contrast to the paucity of information regarding the function of cannabinoids in plants, the actions of
phytocannabinoids in the human brain are much better understood. ∆9-Tetrahydrocannabinol (THC) was isolated in
1963 and its metabolism in rodents and humans was elucidated, including its hydroxylation to an active metabolite and
further oxidation to an inactive acid which then binds to a sugar molecule [5]. The acid-derived metabolites are stored
in lipid-rich tissues and are slowly released. Hence, the major final THC metabolite can be detected in human urine for
several weeks after cannabis use. Administration of Δ9-THC (orally, intravenously or inhaled in smoke), results in
psychological changes similar to those reportedly experienced in response to recreationally consumed plant material
[6]. A synthetic analog of Δ9-THC, nabilone (Cesamet: Valeant Pharm North America) was approved by FDA in 1981
to suppress nausea and vomiting associated with chemotherapy [5]. Synthetic Δ9-THC dronabinol (Marinol; Solvay
Pharmaceuticals, Inc) was approved as an anti-emetic in 1985 and subsequently as an appetite enhancer in 1992.
Identification of brain receptors that interact with natural or synthetic cannabinoids in the 1980s stimulated the quest for
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the brain’s endogenous cannabis-like molecule [5]. From the abundance of cannabinoid (CB) receptors, it was inferred
that there must be an endogenous ligand that activates those receptors. Following many years of research, the elusive
endogenous CB was identified as arachidonolyl ethanolamide and named anandamide [5]. The molecule is found in
nearly all tissues in many animals. Anandamide binds to both types of CB receptors, the CB1 receptor found in the
central nervous system and the CB2 receptors distributed in peripheral tissues, immune cells, but also is found in
some neurons of the brain stem (dorsal motor nucleus of the vagus, spinal trigeminal nucleus and nucleus
ambiguous). Anandamide is derived from fatty acid metabolism and serves as a “lipid messenger” that activates the
CB receptors on nearby cells. Although its pharmacological properties are similar to THC, its chemical structure is very
different.
Distribution of cannabinoid receptors and their alterations in disorders of the
basal ganglia
The CB receptor CB1 has been shown to be heavily distributed in the basal ganglia of the rodent and human brain [7,
8]. The basal ganglia is a term that refers to a set of interconnected deep grey structures in brain (substantia nigra,
sub-thalamic nucleus, putamen, caudate, globus pallidus) responsible for the automatic execution of learned motor
programs. Dysfunction of one or more components, or disruption of the neural circuitry of the basal ganglia results in
diseases characterized by involuntary movements or difficulties in initiating or terminating movement. A prototype of a
basal ganglia disorder is Parkinson’s disease (PD), characterized clinically by slowness of movement, rigidity of
muscles, tremors and loss of balance. Another example is Huntington’s disease (HD), a hereditary neurodegenerative
disease known by its involuntary movements known as chorea. In both of these disease states, the endocannabinoid
system changes with disease progression [9]. Early pre-symptomatic phases in both disorders are associated with
down-regulation or desensitization of CB1 receptors (Fig. 1). Since activation of CB1 receptors inhibits glutamate
release, it follows that the downregulation or desensitization of these receptors observed in both disorders is
associated with enhanced glutamate levels and excitotoxicity. Hence the decreased expression of CB1 receptor likely
plays an instrumental role in disease progression. In intermediate and advanced stages of disease, when neuronal
death is occurring, the changes in the CB1 receptors are characterized by opposite changes in both disorders. In the
case of HD there is a loss of CB1 receptor associated with the death of striatal neurons which express CB1 receptors.
These changes correlate with the choreic movements typical of HD. The loss of CB1 receptors has been documented
in humans with HD by in vivo imaging of CB1 ligand binding [10]. In contrast, there is significant upregulation of CB1
receptors in PD, consistent with the bradykinetic feature of the disease [11]. However, some studies have described
reductions in expression of CB1 mRNA in post-mortem PD brains [12] or reduction in CB1 receptor in striatum of a rat
model of PD [13]. CB2 receptors, typically abundant in the immune tissues of the periphery have been found in a few
neuronal subpopulations [14] but most of the brain’s CB2 receptors are expressed in glial cells [15]. Activated
astrocytes and microglia in HD and PD are associated with up-regulatory responses of CB2 receptors. Hence, CB2
receptors provide a potential target for cannabinoid agents to confer neuroprotection by reducing microglia-dependent
toxic influences and promoting beneficial effects of activated astrocytes [15].
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Fig. 1
CB1 and CB2 changes in experimental models of Huntington’s and Parkinson’s disease in progression from early pre-
symptomatic to symptomatic stages. Figure adapted from review article by [9].
Both CB1 and CB2 receptors and other elements of the endogenous cannabinoid signaling system provide attractive
targets for novel pharmacotherapies useful in PD and HD and other basal ganglia disorders. Patients may benefit from
symptom-alleviating actions of cannabinoid medications but perhaps more importantly, cannabinoids can serve as
neuro-protective agents to mitigate progression of disease.
Cannabinoids modulate neurotransmission
The CB1 receptor is often localized in axon terminals, and its activation leads to inhibition of transmitter release. The
consequence is inhibition of neurotransmission by a presynaptic mechanism. The modulation of glutamatergic,
GABAergic, glycinergic, cholinergic, noradrenergic and serotonergic neurotransmission has been observed in many
regions of the central nervous system including the basal ganglia [16]. Dopamine (DA) is the major neurotransmitter
produced by neurons located in the substantia nigra (SN) a key node in the basal ganglia network. These neurons
project their fibers to the corpus striatum. Striatal neurons that bear DA receptors are components of a system of
neuronal feedback loops critical for the normal execution of motor programs. Gradual loss of DA neurons of the SN
results in decreased concentrations of the neurotransmitter DA in the striatum. The loss of DA is responsible for the
gradual manifestation and progression of slowness, rigidly, and tremor, the signs and symptoms of PD. Drugs that
block the actions of DA at dopamine D2 receptors in the striatum (e.g., neuroleptic drugs, major tranquilizers) produce
sedation as well as a parkinson-like syndrome. Stimulation of dopamine D2 receptors located in striatal neurons
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triggers the release of anandamide [17]. In turn, the released endocannabinoid inhibits the facilitatory role on
movement derived from DA D2 receptor stimulation. The majority of the striatal CB1 receptors are located
presynaptically on inhibitory GABAergic terminals, in a position to modulate neurotransmitter release and influence the
activity of nigro-striatal dopaminergic neurons [17]. Activation of the CB1 receptor with a CB agonist inhibits DA
release, and therefore results in less activity at the D1 and D2 receptors. This effect correlates with the decrease in
locomotor activity and sedation noted in animals given cannabinoids systemically. However, activation of the CB1
receptor inhibits DA re-uptake thereby potentiating the effects of DA. Drugs that specifically inhibit DA re-uptake
(dopamine transporter blockers like cocaine) increase locomotor activity and can produce anxiety. The capacity of
anandamide and CB1 agonists to both inhibit and stimulate nigro-striatal dopaminergic activity reflects its function as a
modulator of DA neuro-transmission.
GABA is the major inhibitory neurotransmitter in the nervous system. In the basal ganglia, GABA plays a major role as
a “brake” in the network of feedback loops involved in the control of movement. Activation of CB1 receptors in
terminals of striato-pallidal axons modulates GABAergic synaptic transmission between these axons and globus
pallidus neurons [18]. Cannabinoids microinjected into the globus pallidus or systemically cause catalepsy [19]. GABA-
like drugs and cannabinoids appear to act synergistically. In rats the combination results in catalepsy, a profound state
of immobility during which the limbs remain in whatever position they are placed, but this is not typically seen in
humans and dogs.
Glutamate is the primary excitatory transmitter in basal ganglia. Neurons of the sub-thalamic nucleus (an important
relay station in the neural networks of the basal ganglia) employ glutamate as their transmitter. In PD, there is
overactivity of glutamatergic transmission in sub-thalamic nucleus to globus pallidus pathway. An overactive glutamate
system may contribute to progression of neuronal degeneration (excitotoxicity). In addition, many of the motor
manifestations of PD and the involuntary movements that development after long-term use of DA replacement
medications (levodopa) can be attributed to over activation of this glutamate-mediated pathway. Cannabinoids inhibit
glutamatergic neurotransmission in the subthalamo-pallidal projection [20]. By modulating glutamate
neurotransmission with cannabinoids, some symptoms of PD can be alleviated and in addition, may serve to slow
progression of disease.
Effects of cannabinoids in animal models of disease
Given the abundance of CB receptors in the basal ganglia, it is not surprising that cannabinoids have significant effects
on the control of movement, both in health and disease. Since the development of synthetic cannabinoids that interact
with the CB receptors, many studies have reported effects of these agents on motor activity in animals. CB agonists
tend to initially increase locomotor activity followed by a late phase of motor depression or “catalepsy” [21–24]. Other
actions reported included the inhibition of psychomotor stimulant-induced behavior, inhibition of exploratory behavior
and production of anxiety-like behavior [25]. Drugs that inhibit anandamide hydrolysis by blocking fatty acid amide
hydrolase (FAAH) tend to potentiate the actions of the endogenous ligand, but the effects on locomotor activity are
more modest than those elicited by CB1 agonists [26]. FAAH inhibitors also elicit anxiolytic-like, antidepressant and
analgesic effects [27, 28]. The effects of specific CB receptor antagonists, drugs which bind and block the receptors,
depend on species of animal and on whether the animals are drug naïve [26, 29].
In animal models of PD, cannabinoids have been reported to improve motor symptoms of slowness and akinesia. They
also may be beneficial in treating a complication of levodopa treatment known as levodopa-induced-dyskinesia (LID).
However the results are mixed. CB1 agonists inhibit nigro-striatal DA release so it should be expected that these
agents would not be effective in alleviating PD motor symptoms. Indeed, CB1 agonists have been reported to worsen
slowness of movement (bradykinesia) in MPTP-lesioned primates [30]. In contrast, CB1 agonists have also been
reported to improve motor deficits, perhaps by non-dopaminergic mechanisms [31–36]. Agents that block the CB1
receptors are more consistent in improving motor symptoms without increasing LID [37–41]. These effects also appear
to involve non-dopaminergic mechanisms, including enhanced striatal glutamate release [37, 38, 42]. There are many
possible explanations for the therapeutic variability of cannabinoids, including variations in lesion severity, trial design,
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animal species studied dose and formulation of the CB, and gender [37, 39, 40]. CB-based therapies may improve LID
without worsening motor control. These beneficial effects are reported for both CB1 agonists [37, 39, 40] and
antagonists [41]. The beneficial effects were not observed in all studies perhaps because higher doses of CB1
agonists may impair motor function. This would suggest that CB1 agonist effects on LID are related to inhibition of
locomotor activity overall [43–45]. Other CB receptors may also be involved in LID. Administration of a drug that
increases anandamide levels by inhibiting the enzyme fatty acid amide hydrolase (FAAH) did not improve LID when
used as monotherapy. When this drug was co-administered with an antagonist of a non-CB receptor (TRPV1), there
was improvement in LID [44].
Experimental animal models of HD reveal early and widespread reductions in the endocannabinoid system, particularly
CB1 receptors in the striatum [46, 47]. 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 [48•, 49, 50]. Caution is warranted given that several studies using
identical cannabinoids and models showed no benefit or even exacerbation of neurotoxicity [51–53]. Therapeutic
studies of cannabinoid-based agents in HD animal models suggest that CB1 and endovanilloid receptor agonists [54]
and anandamide reuptake inhibitors [51] are capable of alleviating hyperkinesia. This therapeutic potential is likely to
be realized in early phases of HD because of progressive loss of CB1 receptors in advanced stages.
It has been hypothesized that CB1 agonists reduce overactivity of the globus pallidus interna and improve dystonia by
reducing GABA reuptake [55]. 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 [56, 57].
Cannabinoids are neuroprotective and mitigate neurodegeneration in several animal models. Research demonstrating
anti-oxidant and neuroprotective effects of cannabinoids possessed led to the award of U.S. Patent 6630507 to
researchers at the US National Institute of Health (NIH), which lists the use of cannabinoids found within the C. sativa
plant as useful in certain neurodegenerative diseases, such as PD, Alzheimer’s disease, and dementia caused by
human immunodeficiency virus [58]. Cannabinoids provide neuroprotective effects through both receptor- and non-
receptor mediated mechanisms. Cannabinoids are effective scavengers of reactive oxygen species and enhance
endogenous antioxidant systems [59]. This property appears to be independent of CB1 and CB2 receptor modulation
and restricted to certain cannabinoids, including cannabidiol (CBD), THC, cannabinol, CP55,940, and the anandamide
analog, AM404.2 [60, 61]. CB2 agonists exert anti-inflammatory effects by inhibiting reactive microglia and cytokine
release [61–64]. CB1 agonists reduce excitotoxicity by suppressing glutamatergic activity, subsequent calcium ion
influx, and nitric oxide production [58, 65].
Cannabinoids for patients with Parkinson’s disease
PD is a progressive neurodegenerative disease characterized by slowness of movement, rigidity of muscles, tremor at
rest and loss of postural reflexes [66]. This disease is associated with the gradual loss of nigro-striatal dopaminergic
neurons and the accumulation of intracellular inclusions (Lewy Bodies). As mentioned in the beginning, tincture of C.
indica was prescribed for PD in the nineteenth century, along with belladonna alkaloids. These latter drugs are
represented by the anti-cholinergic drugs trihexyphenidyl and benztropine both of which continue to be occasionally
prescribed in PD. Cannabis was rarely recommended for treatment of PD in the twentieth century primarily because of
societal and legal restrictions. Consequently, there are many observational and anecdotal reports, but few controlled
clinical trials on the usefulness of cannabis preparations for treatment of symptoms of PD and for alleviation of the
involuntary movements dyskinesias that often plague patients who take levodopa for treatment of PD (see Tables 1
and 2).
Table 1
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Controlled clinical studies demonstrating beneficial effects of cannabinoids
Movement
disorder Design Treatment Result Ref.
Parkinson’s
disease Randomized,
double-
blind,
placebo-
controlled,
crossover
study (n = 5)
Nabilone or placebo Significant reduction in levodopa-induced
dyskinesia and RMS [67]
Double-blind,
placebo
controlled
(n = 21)
CBD (75 mg/day or
300 mg/day) or placebo No change in UPDRS but improvement in
PDQ-39 (quality-of-life scale) [68•]
Huntington’s
disease Randomized,
double-
blind,
placebo-
controlled,
cross over
(n = 37)
Nabilone (1 and 2 mg)
versus placebo. For the
last 10 days of each
treatment block, patients
were taking nabilone 1 or
2 mg/day.
Significantly improved motor coordination
and chorea. Measures: UHDRS: motor
scale; cognitive assessment; and behavioral
assessment.
[69]
Tics Randomized,
double-
blind,
placebo-
controlled,
cross over
(n = 24)
THC (up to 10 mg/day for
6 weeks) Scores on Global Clinical Impression Scale,
Shapiro Tourette-Syndrome Severity Scale,
Yale Global Tic Severity Scale, and Tourette
Syndrome Symptom List revealed dose-
dependent improvement in tics.
[70,
71]
Table 2
Non-controlled clinical studies demonstrating beneficial effects of cannabinoids
Movement
disorder Design Treatment Result Ref.
Parkinson’s
disease Case
series
(n = 22)
0.5 g of cannabis by
smoking:Thirty minutes later, the
motor and nonmotor battery was
administered
Significant improvement in tremor and
bradykinesia as well as sleep [72]
Cross-
sectional
survey
(n = 84)
Anonymous completion of
questionnaire about experience
with cannabis
Thirty-nine patients described mild or
substantial improvement of resting tremor
and levodopa-induced dyskinesia
[66]
Open-
label
(n = 4)
CBD tabs (150 mg) gradually
titrated upwards over 4 weeks Decreased psychotic symptoms [73]
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Open-
label
(n = 4)
CBD 75–300 mg day Improved REM-behavior sleep disorder [74]
Dystonia Case
series
(n = 5)
Oral doses of cannabidiol rising
from 100to 600 mg/day over a 6-
week period
Dose-related improvement in dystonia.
Cannabidiol at doses over 300 mg/day
exacerbated the hypokinesia and resting
tremor.
[75]
The frequency of self-medication with cannabis in the USA is not known, but a survey of PD patients in a European
country revealed a significant proportion of respondents to a mailed questionnaire were using marijuana for treatment
of PD [72]. The survey was undertaken in response to reports in the media describing marijuana as potentially helpful
in PD. Out of 630 questionnaires sent by mail, 339 (53.8 %) were returned. The responders’ mean age was 65.7 years
and the patients had carried the diagnosis of PD for an average of 8.5 years. Cannabis use was reported by 85
patients (25 % of returned questionnaires; 55 men, 29 women). Most of them used approximately half a teaspoon of
fresh or dried leaves orally; only 1 patient smoked the cannabis. There was no major difference in age and duration of
PD between the sub-group of patients who used cannabis and those who had never tried it. Patients usually ingested
the marijuana with meals. Interestingly, none of the patients had any experience with recreational use of cannabis and
none had been advised to use the medication by a doctor. Most decided to give it a try based on information given in
the media (newspapers and television). All of them continued using the antiparkinsonian medications prescribed by
their neurologist. After starting to use cannabis, 39 patients (45.9 %) reported mild or substantial alleviation of their PD
symptoms in general, 26 (30.6 %) improvement of tremor, 38 (44.7 %) alleviation of bradykinesia, 32 (37.7 %)
alleviation of muscle rigidity, and 12 (14.1 %) improvement of LID. Four patients (4.7 %) claimed that cannabis actually
worsened their symptoms. Based on the information obtained from the patients, alleviation of symptoms was noted
within an average of 1.7 months of use. Patients that used cannabis for at least 3 months reported significantly more
often a mild or substantial alleviation of symptoms in general. Only 2 patients used cannabis for purposes other than
alleviation of PD symptoms. One patient used it to relieve depression and the other to have more energy. In a small
analytical component of this study, a cannabinoid assay was done in the donated urine samples from 7 patients who
had taken cannabis regularly for more than 1 year and a single patient who had only taken it 1 day before analysis. In
the group of 7 patients with chronic use of cannabis, there was a relationship between the level of the major metabolite
of THC in the urine and the improvement of symptoms. In those that had high levels (>50 ng/mL), there was a reported
improvement in bradykinesia or rigidity. In those patients where the THC metabolite was <50 ng/mL, there was no
reported improvement in either slowness or rigidity. Clearly, self-medication of PD with cannabis appeared to be
beneficial in a significant proportion of patients. Although questionnaires have many limitations and cannot be
conclusive, they can serve as a stimulus for conducting more definitive studies.
Several small studies have reported benefits of cannabis administration on signs and symptoms of PD. A recent open-
label study in 22 PD patients examined the effects of smoking cannabis on motor and non-motor symptoms [68•]. Mean
total score on the motor Unified Parkinson Disease Rating Scale (UPDRS) score improved significantly from 33.1
(SD = 13.8) at baseline to 23.2 (SD = 10.5) 30 min after smoking 0.5 g of cannabis. Analysis of specific motor
symptoms revealed significant improvement after treatment in tremor, rigidity (P = 0.004), and bradykinesia. In addition,
the authors reported significant improvement of sleep and pain scores and no significant adverse effects of the drug
were observed.
A double-blind, placebo-controlled trial investigated the effects of the non-psychotropic CBD in 21 PD patients without
dementia or comorbid psychiatric conditions [73]. Participants were assigned to three groups of 7 subjects each who
were treated with placebo, CBD 75 mg/day or CBD 300 mg/day. One week before the trial and in the last week of
treatment, participants were scored using the UPDRS as well as the well-being and quality-of-life scale (PDQ-39). The
researchers did not find statistically significant differences in UPDRS motor scores, but reported that the CBD
300 mg/day group scored significantly better in PDQ-39 than the placebo group. These findings suggest CBD
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administration can increase quality-of-life measures in PD patients with no psychiatric comorbidities [73]. Interestingly,
a small open-label study in 6 PD patients with psychosis reported beneficial effects following treatment with CBD for
4 weeks. Scores on the Brief Psychiatric Rating Scale and the Parkinson psychosis questionnaire were significantly
improved after treatment [74]. A study of the effects of CBD on 4 PD patients with RBD (REM behavior sleep disorder)
reported prompt and substantial reduction in the frequency of RBD-related events without side effects [67].
Scientific evidence documenting the merits of cannabis for treating LID is spotty. Dyskinesia refers to the involuntary
choreiform or dystonic movements that are associated with levodopa therapy in moderate to advanced disease. While
laboratory work provides promising results, studies with actual patients are less conclusive. In a pilot study published
in 2001, researchers enrolled seven PD patients with stable, LID occupying 25–50 % of the day [76]. All individuals
received a total dose of 0.03 mg/kg nabilone, a cannabinoid agonist that interacts with both CB1 and CB2 receptors, or
placebo in addition to daily levodopa. The active drug dosage was split, half given 12 hours prior to examination, the
second dose given an hour prior to testing. Subjects underwent two sessions of experimental treatment; one involved
the placebo, and the other involved the active compound nabilone. Two weeks divided the treatment sessions.
Compared to placebo, nabilone significantly reduced total dyskinesias evident on the dyskinesia disability scale,
without an increase in parkinsonian disability. The active treatment averaged a 22.2 % reduction in on-time
dyskinesias compared to the average on-time reduction in treatment with placebo. No significant differences were
apparent in duration of the on-period, on-period dyskinesias, best on-scores or times until on-periods began, and
nabilone had no evident antiparkinsonian effect when assessed during off- time. However, with only seven subjects
and a single trial of the active compound, no true conclusions can be made from the data, other than more testing with
a larger population is warranted.
In another study, researchers implemented a 4-week dose escalation study assessing the safety and tolerability of
cannabis in six PD patients with LIDs. Subsequently, the team conducted a larger randomized placebo-controlled
crossover study (RCT) that failed to demonstrate cannabis has a beneficial effect on dyskinesia in PD [70]. In this
study, 19 patients ages 18 to 78 received Cannador, an alcohol-based extract from C. sativa, followed by placebo or
vice versa. The active drug capsules contained 2.5 mg of THC and 1.25 mg of CBD; the placebo pills were identical in
appearance. Dosages depended on subject body weight, with a maximum of 0.25 mg of THC/kg of body weight each
day. Subjects increased their intake of Cannador over a period of four weeks, attaining a stable dose for a minimum of
4 days prior to testing. Assessments occurred three times- at baseline, after treatment with placebo and after treatment
with the active drug. However 11 of 17 or 65 % of subjects failed to reach their target amount of Cannador, averaging
instead 0.146 mg per kg of body weight/day with a range of 0.034 to 0.25 mg. Dosages split into morning and evening
portions, were to be increased every three days until the target weight- adjusted quantity was reached, but subjects
commonly developed intolerable side effects and dropped back to a former tolerated dose. The most common side
effect was dry mouth, though subjects also reported constipation, nausea, lethargy, detachment, vivid dreams or
nightmares, and poor concentration. Each treatment phase lasted 4 weeks with an intervening 2-week washout period
between placebo and active treatment phases. The primary outcome measure was a change in UPDRS (items 32 to
34) dyskinesia score. Secondary outcomes assessed how cannabis affected functioning with dyskinesia, precursors to
and duration of dyskinesia, quality of life, sleep, pain related to PD, and general parkinsonism. Seventeen of 19
patients completed the study. Cannabis was well tolerated and had no pro- or antiparkinsonian action at the doses
provided. There was no evidence for a treatment effect on LID as assessed by the UPDRS or any of the secondary
outcome measures. Researchers were left to conclude orally administered cannabis extract resulted in no objective or
subjective improvement in dyskinesias or parkinsonism.
Cannabinoids for Tourette’s syndrome
Past studies provided evidence that C. sativa and its major psychoactive compound THC were beneficial for the
treatment of tics and behavioral problems seen in Tourette’s syndrome [69, 71]. Human and animal studies suggest
the central CB receptor, CB1, is involved in regulating attention, memory, and other cognitive functions. As concerns
exist about the effects of the drug on acute and long-term cognition, investigators conducted a randomized, double-
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blind, placebo-controlled study of up to 10 mg THC provided over a span of 6 weeks, on the neuropsychological
performance of 24 patients with Tourette’s syndrome [69]. Subjects varied in age from 18 to 68 years, averaging
33 years of age. Of the 24 subjects, 17 had never used marijuana, 4 reported occasional use, and 3 regularly smoked
the herb, using it twice or more weekly. All were asked to suspend use 6 weeks prior to entering the study, and
investigators conducted urine and blood analysis to confirm THC and its metabolites were absent before the
investigation began. Subjects in the active treatment phase began taking 2.5 mg/day, increasing the dosage by
2.5 mg/day over 4 days to reach 10 mg/day. If individuals found they could not tolerate the maximum dose, they were
allowed to adjust the amount taken until they achieved a maximal yet tolerable level. Treatment was to be taken with
breakfast, once daily. Four subjects withdrew from the study. One dropped out due to feelings of anxiety and
restlessness, two were dropped for noncompliance, and one for questionable results on a blood test. Of the nine
subjects who received the active drug, six achieved the maximal dosage of 10 mg/day, two patients took 7.5 mg/day,
and one took 2.5 mg/day. Three tests were used to assess changes in function: the VLMT, the German version of the
auditory verbal learning test, the Benton visual retention test (BVRT), and the divided attention test (TAP).
Researchers performed the multiple choice vocabulary test (Mehrfachwahl-Wortschatztest MWT-B) measuring verbal
intelligence once at the first visit, and data were used to compare results from the BVRT. Data demonstrated no
significant deterioration in cognitive function during the 6-week investigation. In fact, the authors found a trend toward
significance in the group given THC in the parameter concerning immediate memory span. Withdrawal from
medication provided no impact on neuropsychological function. THC is beneficial for the control of tics and appears to
be well tolerated with no significant negative influence on neuropsychological function. However, according to a recent
Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials
including a larger number of patients are missing [77]. Notwithstanding this appraisal, THC is recommended for the
treatment of TS in adult patients, when first-line treatments failed to improve the tics. In treatment-resistant adult
patients, therefore, treatment with THC should be taken into consideration [78••].
Cannabinoids for dystonia
Dystonia refers to neurological conditions characterized by abnormal twisting and turning movements that may result in
abnormal postures due to sustained contractions of muscles. Dystonia can be focal, as in spasmodic torticollis
(cervical dystonia), or generalized. Focal dystonias of the eyes or neck may respond well to injections of botulinum
toxin. Generalized dystonia, however, is very difficult to treat either with medications or injections. Deep brain
stimulation may be helpful in well-selected patients (see article “DBS in Dystonia and Other Movement Disorders” in
this issue). Cannabinoids have been administered very rarely for treatment of dystonia, as documented in several case
reports. A single patient with dystonia associated with Wilson’s disease (a disorder of copper metabolism) who smoked
3 to 4 g of marijuana was reported to experience marked improvement of the dystonia [75]. CBD, a nonpsychoactive
cannabinoid of cannabis, was given to five patients with dystonic movement disorders in an open-label pilot study [79].
Oral doses of CBD from 100 to 600 mg/day over a 6-week period were administered along with standard medication.
Dose-related improvement in dystonia was observed in all patients and ranged from 20 to 50 %. Side effects of CBD
were mild and included hypotension, dry mouth, psychomotor slowing, lightheadedness, and sedation. In 2 patients
with coexisting Parkinsonian features, CBD at doses over 300 mg/day exacerbated the hypokinesia and resting
tremor. In a double-blind, placebo-controlled study, 15 patients with regional or generalized dystonia received a single
dose of placebo or nabilone (a synthetic THC used for glaucoma), followed by the other treatment within 2 weeks [80].
Two patients withdrew due to postural hypotension or sedation. No difference between the treatments was seen in
mean total dystonic movements as assessed by a dystonia rating scale (Burke-Fahn-Marsden scale). Another
randomized, double-blind placebo-controlled study of dronabinol (a synthetic THC) or placebo daily for 3 weeks failed
to find improvement in tics [81]. The usefulness of cannabinoids for dystonia will clearly depend on the correct
formulation of the cannabinoid. The CB1 agonist dronabinol appeared not to be effective whereas smoked cannabis or
CBD appeared to be beneficial. The ability to gradually titrate the dose to a tolerable and effective one will be important
when choosing the formulation and dosage regimen in future studies.
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Cannabinoids for Huntington’s disease
HD is an autosomal dominant slowly progressive neurodegenerative disease that affects mood, cognition, and results
in involuntary movements. The average age of onset is between the late 30s to early 50s; occasionally, onset in
childhood or up to the seventh decade can be seen. Treatment is symptomatic, and medications are available to treat
the chorea (such as neuroleptics or dopamine depleting agents), depression, and behavioral issues. There are many
anecdotal reports of HD patients, who tend to be relatively young, who smoke marijuana to relieve their chorea.
However, controlled clinical trials of cannabinoids for HD are rare and have not used THC or variations of it. There is a
single study of CBD for treatment of HD in 15 patients and it failed to produce significant benefit [82]. There is a need
to do more studies with various preparations of cannabis or synthetic cannabinoids in this patient population.
Adverse effects
No direct fatalities (overdoses) have been attributed to cannabis, even in recreational users of increasingly potent
strains of the plant, possibly because of the lack of endocannabinoid receptors in the brainstem [83]. Of course, the
sedative effects of some cannabis preparations can indirectly endanger patients who perform dangerous tasks such as
driving and operating heavy machinery. In addition, smoking and, possibly, even the use of vaporized preparations
expose users to carbon monoxide and other respiratory toxins. A review of 25 studies on the safety and efficacy of
CBD reported that administration did not induce side effects across a wide range of dosages, including acute and
chronic dose regimens, using various modes of administration [84]. Oral administration of 10 mg CBD daily for 21 days
did not induce any changes in neurological (including EEG), clinical (including ECG), psychiatric, blood, or urine
examinations. Oral CBD in epileptic patients (200–300 mg daily for 135 days) was well tolerated and no signs of
toxicity or serious side effects were detected on neurological and physical examinations, blood and urine analysis, and
repeated ECGs and EEGs [85]. The only mild adverse effect was initial somnolence that resolved in most subjects.
Exacerbation of psychosis in pre-existing schizophrenia is commonly reported as a potential adverse effect of
cannabis. However, several studies demonstrate that cannabis use does not cause or increase the likelihood of
schizophrenia [86, 87]. In one study, the frequency of cannabis use increased substantially in the UK over a period
from 1996 to 2005 in a cohort of 600,000 subjects per year (aged 16–44), while the incidence and prevalence of
schizophrenia declined or remained stable. More recently, another study [87] found that an increased familial morbid
risk for schizophrenia is the most likely underlying basis for schizophrenia in cannabis users and not cannabis use by
itself. However, cannabis use may precipitate disorders in persons who are vulnerable to developing psychosis or
exacerbate the disorder in those who have already developed schizophrenia [88]. In a review of 29 clinical studies on
the use of medical cannabis preparations for selected neurologic disorders, the frequency of adverse effects was
somewhat higher in the cannabis arm compared to placebo [83]. Of 1619 patients treated with cannabinoids for less
than 6 months, 6.9 % stopped the medication because of adverse effects. Of the 1118 who received placebo, 2.2 %
stopped because of adverse effects. Symptoms that caused medication withdrawal were not recorded in some studies,
but symptoms that appeared in at least two studies in patients treated with cannabinoids included the following:
nausea, increased weakness, behavioral or mood changes, suicidal ideation or hallucinations, dizziness or vasovagal
symptoms, fatigue, and feelings of intoxication. With preparations containing higher doses of THC, psychosis,
dysphoria, and anxiety were more likely to be reported. Higher THC concentrations, however, were not typical for the
clinical studies reviewed. A recent review of adverse effects of short-term use included impaired short-term memory,
motor incoordination, altered judgment and in high doses, paranoia, and psychosis [88]. One study of chronic medical
cannabis for a duration of 1 year revealed 31 of 207 patients treated with cannabis extract (15 %) stopped medication,
as did 28 of 197 treated with THC (14 %) and 10 of 207 given placebo (5 %) [89]. However, adverse effects were not
necessarily the reason medication was stopped. For example, cannabinoids inhibit many enzymes of the cytochrome
P450 system, which will cause interactions with other medications being taken concurrently, especially opiates for
pain.
Cannabis use has been reported to result in adverse effects on the cardiovascular system, including tachycardia,
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palpitations, and fluctuations in blood pressure. These effects are uncommon in controlled clinical trials, but several
case reports have described atrial fibrillation, myocardial infarction, and TIA associated with cannabis use [90, 91].
When it is smoked, marijuana carries a risk of pulmonary complications. Cannabis contains a similar number of
carcinogenic compounds to cigarette smoke. Some formulations may even contain higher concentrations of these
detrimental components. This puts patients at risk for cancers such as lung or head and neck cancer [90, 92]. In
addition, cannabis use has been associated with overall decreased pulmonary function, chronic obstructive pulmonary
diseases, and pulmonary infections. There are also reports that failed to find significant pulmonary pathology in long-
term cannabis smokers, especially if they were light smokers, two to three times per month [93]. In a federally
sponsored “Compassionate Investigational New Drug program of the FDA,” mild changes in pulmonary function were
found in patients who smoked marijuana daily for at least a decade (averaging ten marijuana cigarettes daily) [94].
“Entourage” effect of cannabinoid mixtures
Most physicians are not aware of the fact that monotherapy with pure THC is not effective for many conditions for which
cannabis preparations containing combinations of THC and CBD have been shown to be beneficial. These therapeutic
effects were documented in class I studies (randomized double-blind, placebo-controlled studies) in multiple sclerosis
(MS) patients with spasticity, patients with chronic neuropathic pain, cancer pain, bladder hyperactivity, and urge
incontinence [83, 95••]. The cannabis preparations were taken orally as whole cannabis extracts, smoked or vaporized,
or by oral-mucosal spray (Sativex TM) of an extract of the plant containing ∆9 THC and CBD in a 1:1 ratio. There are
several explanations for why THC alone does not seem to be effective for these neurologic conditions [96]. Orally
administered THC has very long latency of onset and cannot be easily titrated to a therapeutic dose without eliciting
adverse effects in some patients. A more important explanation relates to the synergistic effects achieved when THC is
administered along with an entourage of phytocannabinoids found in the plant, especially CBD and terpenes. The
entourage effect was first brought up in relation to the endocannabinoid system, with its combination of active and
inactive synergists [97]. The concept was refined and qualified by Mechoulam: “this type of synergism may play a role
in the widely held view that in some cases, plants are better drugs than the natural products isolated from them” [98]. A
recent review of the phytocannabinoids supports the entourage concept: combinations of cannabinoids can in certain
circumstances be more effective than THC or CBD alone [4]. The entourage effect is not unique to the
phytocannabinoids. Pharmaceutical monotherapies against human malaria are effective, but ephemeral, because of
the inevitable evolution of resistant parasites. Dried whole-plant Artemesia annua has been reported to be more
effective in slowing the evolution of malaria drug resistance than artemisinin, the pure drug isolated from the plant [99].
A critical area of future research will be the study of the interaction of combinations of cannabinoids with the
endocannabinoid system in health and disease.
Summary
Preparations of the cannabis plant contain cannabinoids that interact with central nervous system receptors to
produce biological effects and, in some cases, may improve symptoms of disease in a range of movement
disorders.
Most of the evidence for beneficial effects of cannabis is from observation and open-label studies, but there are
some high-quality clinical trials of cannabinoids using gold standard designs (double-blind, placebo-controlled
studies) that report its therapeutic effects.
Adverse effects reported in the literature are most often benign, though there are deleterious effects that depend on
dose and route of administration.
There is a need for more research, both basic and clinical. Pharmaceutical companies would do well to research
cannabinoid molecules or agents that selectively benefit specific symptoms or conditions. The critical variables are
the respective proportions of specific compounds, routes of administration and dosing.
It is possible that combinations of cannabinoids are necessary to produce clinical benefits, so that quality control
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1.
2.
3.••
4.
5.
6.
7.
8.
9.
measurements of the principal bioactive components of the preparation will be helpful when conducting future
clinical studies.
Compliance with Ethics Guidelines
Conflict of Interest
The authors declare that they have no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the authors.
References and Recommended Reading
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Cannabinoids for the Treatment of Movement Disorders - Springer
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