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Cannabinoids for the Treatment of Movement Disorders


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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.
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Cannabinoids for the Treatment of Movement Disorders - Springer[7/28/2015 4:25:00 PM]
Current Treatment Options in Neurology
DOI: 10.1007/s11940-015-0370-5
Movement Disorders (O Suchowersky and A Videnovic, Section
Cannabinoids for the Treatment of Movement
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
Juan Sanchez-Ramos (Corresponding author)
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.
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
Cannabinoids for the Treatment of Movement Disorders - Springer[7/28/2015 4:25:00 PM]
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
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” [2124]. 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 [3136]. Agents that block the CB1
receptors are more consistent in improving motor symptoms without increasing LID [3741]. 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 [4345]. 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 [5153]. 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 [6164]. 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
disorder Design Treatment Result Ref.
disease Randomized,
study (n=5)
Nabilone or placebo Significant reduction in levodopa-induced
dyskinesia and RMS [67]
CBD (75 mg/day or
300 mg/day) or placebo No change in UPDRS but improvement in
PDQ-39 (quality-of-life scale) [68•]
disease Randomized,
cross over
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
Tics Randomized,
cross over
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.
Table 2
Non-controlled clinical studies demonstrating beneficial effects of cannabinoids
disorder Design Treatment Result Ref.
disease Case
0.5 g of cannabis by
smoking:Thirty minutes later, the
motor and nonmotor battery was
Significant improvement in tremor and
bradykinesia as well as sleep [72]
Anonymous completion of
questionnaire about experience
with cannabis
Thirty-nine patients described mild or
substantial improvement of resting tremor
and levodopa-induced dyskinesia
CBD tabs (150 mg) gradually
titrated upwards over 4 weeks Decreased psychotic symptoms [73]
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CBD 75–300 mg day Improved REM-behavior sleep disorder [74]
Dystonia Case
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
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
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.
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
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
Cannabinoids for the Treatment of Movement Disorders - Springer[7/28/2015 4:25:00 PM]
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.
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Cannabinoids for the Treatment of Movement Disorders - Springer[7/28/2015 4:25:00 PM]
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Cannabinoids for the Treatment of Movement Disorders - Springer[7/28/2015 4:25:00 PM]
... However, most of these reviews focused on behavioral and neurochemical effects in preclinical models. Indeed, a systematic review on the efficacy and safety of medical cannabis in neurologic disorders from the Guideline Development Subcommittee of the American Academy of Neurology concluded, based on two randomized controlled trials (RCTs) [28,29] that "oral cannabis extract is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease" [24]. ...
... Thus, four RCTs with a total sample of 49 patients assessed the effects of CB 1 receptor agonists/antagonists in PD patients. These studies included 2 trials with the synthetic THC analogue and CB 1 receptor agonist nabilone [28,30], 1 trial with a cannabis standardized extract (2.5 mg THC/1.25 mg CBD) [29], and 1 trial with the synthetic CB 1 receptor antagonist rimonabant [31]. ...
... In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), oral administration of nabilone (single oral dose, 0.03 mg/kg) significantly reduced levodopa-induced dyskinesia in PD according to the Rush Dyskinesia Disability Scale [28]. Nabilone administration was safe. ...
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Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options. Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD. In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD. We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia). We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD. We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.
... A number of reviews have explored cannabinoid-based therapies for the treatment of chronic neurodegenerative diseases and movement disorders such as PD. 3,[17][18][19][20][21][22] While pre-clinical studies show promise, gaps remain in bridging these results to human trials with clinical applications. 23 We embarked on this review to expand our work into real-world observational data, looking specifically at efficacy for motor symptoms in PD and safety, and the applicability of these results in a Canadian context. ...
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Background: Recent changes to the legal status of cannabis across various countries have renewed interest in exploring its use in Parkinson's disease (PD). The use of cannabinoids for alleviation of motor symptoms has been extensively explored in pre-clinical studies. Objective: We aim to systematically review and meta-analyze literature on the use of medical cannabis or its derivatives (MC) in PD patients to determine its effect on motor function and its safety profile. Methods: We reviewed and analyzed original, full-text randomized controlled trials (RCTs) and observational studies. Primary outcomes were change in motor function and dyskinesia. Secondary outcomes included adverse events and side effects. All studies were analyzed for risk of bias. Results: Fifteen studies, including six RCTs, were analyzed. Of these, 12/15 (80%) mention concomitant treatment with antiparkinsonian medications, most commonly levodopa. Primary outcomes were most often measured using the Unified Parkinson Disease Rating Scale (UPDRS) among RCTs and patient self-report of symptom improvement was widely used among observational studies. Most of the observational data lacking appropriate controls had effect estimates favoring the intervention. However, the controlled studies demonstrated no significant motor symptom improvement overall. The meta-analysis of three RCTs, including a total of 83 patients, did not demonstrate a statistically significant improvement in UPDRS III score variation (MD -0.21, 95% CI -4.15 to 3.72; p = 0.92) with MC use. Only one study reported statistically significant improvement in dyskinesia (p < 0.05). The intervention was generally well tolerated. All RCTs had a high risk of bias. Conclusion: Although observational studies establish subjective symptom alleviation and interest in MC among PD patients, there is insufficient evidence to support its integration into clinical practice for motor symptom treatment. This is primarily due to lack of good quality data.
... Notably, phytocannabinoids, such as tetrahydrocannabinol (THC), can disrupt locomotor function via putative action in striatal circuits (Monory et al. 2007). Other groups have demonstrated striatal eCB signaling is important for movement (Catlow and Sanchez-Ramos 2015;Sañudo-Peña et al. 1999) as well as in the generation of movement disorders such as Huntington's and Parkinson's (Blázquez et al. 2011;Kreitzer and Malenka 2007;Mievis et al. 2011). Surprisingly, CB1R knockout from either D1 or A2a MSNs did not impact locomotor behavior (Fig. 1b, c). ...
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RationaleCannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain’s reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders.Objective and methodsWe sought to determine how cell type–specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes. We crossed conditional Cnr1fl/fl mice and striatal output pathway cre lines (Drd1a –cre; D1, Adora2a –cre; A2a) to generate cell type–specific CB1R knockout mice and assessed their performance in cocaine locomotor and associative behavioral assays.ResultsBoth knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1fl/fl mice did not display hyperlocomotion in response to acute cocaine dosing, and both knockout lines exhibited blunted locomotor activity across repeated cocaine doses. A2a-cre Cnr1fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task.Conclusions This study aids in mapping CB1R-dependent cocaine-induced behavioral adaptations onto distinct striatal neuron subtypes. A reduction of cocaine-induced locomotor activation in the D1- and A2a-Cnr1 knockout mice supports a role for CB1R function in the motor circuit. Furthermore, a lack of preference for cocaine-associated context in A2a-Cnr1 mice suggests that CB1Rs on A2a-neuron inhibitory terminals are necessary for either reward perception, memory consolidation, or recall. These results direct future investigations into CB1R-dependent adaptations underlying the development and persistence of substance use disorders.
... Over the past years cannabidiol (CBD) has been often considered as the leading cannabinoid with a wide range of pharmacological effects and the benefit of a non-intoxicating character, in contrast to Δ 9 -tetrahydrocannabinol (THC) [1][2][3][4]. CBD has a good safety profile, lacking drug abuse associated reinforcement, craving or compulsive consumption. These factors contribute to its elaborated research and pose a significant regulatory advantage [5][6][7][8]. ...
Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of many investigations. The reasons behind this popularity is the compound’s therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and characterized with a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid PK.
... On the other hand, Cannabis extract failed to improve parkinsonism or LID in a large double-blind, randomized placebo-controlled crossover trial (Carroll et al. 2004). As concluded in a systematic review conducted by Subcommittee on Developmental Guidelines by the American Academy of Neurology on the efficacy and safety of medical Cannabis in neurological disorders, using two controlled trials as reference, oral extract of Cannabis is probably ineffective for treating PD patients with LID (Gutierrez-Valdez et al. 2013;Catlow and Sanchez-Ramos 2015;Fernandez-Ruiz et al. 2015;Crippa et al. 2019). ...
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Parkinson’s disease (PD) and l-DOPA-induced dyskinesia (LID) are motor disorders with significant impact on the patient’s quality of life. Unfortunately, pharmacological treatments that improve these disorders without causing severe side effects are not yet available. Delay in initiating l-DOPA is no longer recommended as LID development is a function of disease duration rather than cumulative l-DOPA exposure. Manipulation of the endocannabinoid system could be a promising therapy to control PD and LID symptoms. In this way, phytocannabinoids and synthetic cannabinoids, such as cannabidiol (CBD), the principal non-psychotomimetic constituent of the Cannabis sativa plant, have received considerable attention in the last decade. In this review, we present clinical and preclinical evidence suggesting CBD and other cannabinoids have therapeutic effects in PD and LID. Here, we discuss CBD pharmacology, as well as its neuroprotective effects and those of other cannabinoids. Finally, we discuss the modulation of several pro- or anti-inflammatory factors as possible mechanisms responsible for the therapeutic/neuroprotective potential of Cannabis-derived/cannabinoid synthetic compounds in motor disorders.
... The benefits of cannabis administration on signs and symptoms of PD have reported by many studies [92]. In a recent open-label study in 22 PD patients examining the effects of smoking cannabis on motor and non-motor symptoms revealed significant improvement in sleep, bradykinesia, pain scores, rigidity and tremor during the analysis of specific motor symptoms [93]. ...
Neurodegenerative disorders (NDDs) like Alzheimer disease, Parkinson's disease and Huntington's disease are a heterogeneous group of disorders with the progressive and severe loss of neurons. There are no full proof cures for these diseases, and only medicines are available that can alleviate some of the symptoms. Developing effective treatments for the NDDs is a difficult but necessary task. Hence, the investigation of monoterpenoids which modulate targets applicable to many NDDs is highly relevant. Many monoterpenoids have demonstrated promising neuroprotective activity mediated by various systems. It can form the basis for elaboration of agents which will be useful both for the alleviation of symptoms of NDDs and for the treatment of diseases progression and also for prevention of neurodegeneration. The further developments including detections of monoterpenoids and their derivatives with high neuroprotective or neurotrophic activity as well as the results of qualified clinical trials are needed to draw solid conclusions regarding the efficacy of these agents.
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Pharmaceutical monotherapies against human malaria have proven effective, although ephemeral, owing to the inevitable evolution of resistant parasites. Resistance to two or more drugs delivered in combination will evolve more slowly; hence combination therapies have become the preferred norm in the fight against malaria. At the forefront of these efforts has been the promotion of Artemisinin Combination Therapy, but despite these efforts, resistance to artemisinin has begun to emerge. In 2012, we demonstrated the efficacy of the whole plant (WP)-not a tea, not an infusion-as a malaria therapy and found it to be more effective than a comparable dose of pure artemisinin in a rodent malaria model. Here we show that WP overcomes existing resistance to pure artemisinin in the rodent malaria Plasmodium yoelii. Moreover, in a long-term artificial selection for resistance in Plasmodium chabaudi, we tested resilience of WP against drug resistance in comparison with pure artemisinin (AN). Stable resistance to WP was achieved three times more slowly than stable resistance to AN. WP treatment proved even more resilient than the double dose of AN. The resilience of WP may be attributable to the evolutionary refinement of the plant's secondary metabolic products into a redundant, multicomponent defense system. Efficacy and resilience of WP treatment against rodent malaria provides compelling reasons to further explore the role of nonpharmaceutical forms of AN to treat human malaria.
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Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are Δ(9)-tetrahydrocannabinol, which possesses psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy, migraine and weight loss. Data are also limited in regards to adverse events and safety. Common nonspecific adverse events are similar to those of other CNS 'depressants' and include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even with recreational use. There is a concern about psychological dependence, but physical dependence is less well documented. 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 likely expand.
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Isolation and structure elucidation of most of the major cannabinoid constituents - including Δ(9)-tetrahydrocannabinol (Δ(9)-THC), which is the principal psychoactive molecule in Cannabis sativa - was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.
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Objective: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. Methods: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral D9-tetrahydrocannabinol (D9-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. Results: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (D9-THC mean reduction 1?82 (n=154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n=172, 95% CI 20.99 to 1.19), placebo 20.23 (n=176, 95% CI 21.41 to 0.94); p=0.04 unadjusted for ambulatory status and centre, p=0.01 adjusted). There was suggestive evidence for treatment effects of D9-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. Conclusions: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.
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Introduction: Parkinson's disease (PD) has a progressive course and is characterized by the degeneration of dopaminergic neurons. Although no neuroprotective treatments for PD have been found to date, the endocannabinoid system has emerged as a promising target. Methods: From a sample of 119 patients consecutively evaluated in a specialized movement disorders outpatient clinic, we selected 21 PD patients without dementia or comorbid psychiatric conditions. Participants were assigned to three groups of seven subjects each who were treated with placebo, cannabidiol (CBD) 75 mg/day or CBD 300 mg/day. One week before the trial and in the last week of treatment participants were assessed in respect to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and H(1)-MRS). Results: We found no statistically significant differences in UPDRS scores, plasma BDNF levels or H(1)-MRS measures. However, the groups treated with placebo and CBD 300 mg/day had significantly different mean total scores in the PDQ-39 (p = 0.05). Conclusions: Our findings point to a possible effect of CBD in improving quality of life measures in PD patients with no psychiatric comorbidities; however, studies with larger samples and specific objectives are required before definitive conclusions can be drawn.
Two subtypes of cannabinoid receptors have been identified to date, the CB, receptor, essentially located in the CNS, but also in peripheral tissues, and the CB2 receptor, found only at the periphery. The identification of Δ9-tetrahydrocannabinol (Δ9-THC) as the major active component of marijuana (Cannabis sativa), the recent emergence of potent synthetic ligands and the identification of anandamide and sn-2 arachidonylglycerol as putative endogenous ligands for cannabinoid receptors in the brain, have contributed to advancing cannabinoid pharmacology and approaching the neurobiological mechanisms involved in physiological and behavioral effects of cannabinoids. Most of the agonists exhibit nonselective affinity for CB1/CB2 receptors, and Δ9-THC and anandamide probably act as partial agonists. Some recently synthesized molecules are highly selective for CB2 receptors, whereas selective agonists for the CB1 receptors are not yet available. A small number of antagonists exist that display a high selectivity for either CB1 or CB2 receptors. Cannabinomimetics produce complex pharmacological and behavioral effects that probably involve numerous neuronal substrates. Interactions with dopamine, acetylcholine, opiate, and GABAergic systems have been demonstrated in several brain structures. In animals, cannabinoid agonists such as Δ9-THC, WIN 55,212-2, and CP 55,940 produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity, and catalepsy. They are reversed by the selective CB1 receptor antagonist, SR 141716, providing good evidence for the involvement of CB1-related mechanisms. Anandamide exhibits several differences, compared with other agonists. In particular, hypothermia, analgesia, and catalepsy induced by this endogenous ligand are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, inflammatory, and immune responses. Agonists may induce biphasic effects, for example, hyperactivity at low doses and severe motor deficits at larger doses. Intriguingly, although cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of Δ9-THC, WIN 55,212-2, and CP 55,940 is more readily obtained in a variety of tests. The selective blockade of CB1 receptors by SR 141716 impaired the perception of the appetitive value of positive reinforcers (food, cocaine, morphine) and reduced the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, by using SR 141716 as a tool, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. Some effects of SR 141716 also suggest that CB1-related mechanisms exert a tonic control on cognitive processes. Extensive basic research is still needed to elucidate the roles of cannabinoid systems, both in the brain and at the periphery, in normal physiology and in diseases. Additional compounds, such as selective CB1 receptor agonists, ligands that do not cross the blood brain barrier, drugs interfering with synthesis, degradation or uptake of endogenous ligand(s) of CB receptors, are especially needed to understand when and how cannabinoid systems are activated. In turn, new therapeutic strategies would likely to emerge.
Background: Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. Method: In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette- Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Results: Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p < .05) or a trend toward a significant difference (p < .05) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p < .05) between both groups. ANOVA as well demonstrated a significant difference (p = .037). No serious adverse effects occurred. Conclusion: Our results provide more evidence that THC is effective and safe in the treatment of tics. It, therefore, can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology.
There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and, particularly, for neurological 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 as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. 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 RLS. 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. © 2015 International Parkinson and Movement Disorder Society.