Key words
Parkinson’s disease - THC - cannabinoids
Introduction
At the latest since the resolution of the German parliament on January 19, 2017 to
ament the German Narcotic Drugs Act (Betäubungsmittelgesetz, BtMG ) with regard to
the treatment of severely ill patients with high-quality cannabis medications (documents
18/8965 and 18/10902 of the German parliament), there has been growing public interest
in the therapeutic properties of cannabis. Until then, an exemption of the Federal
Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte,
BfArM) was required to allow for treating patients with cannabis products. Until 2016,
such exemptions had been issued for about 1000 patients (www.bundestag.de). While so far patients had to pay for this treatment themselves, the new amendment
now regulates the covering of treatment costs by health insurance companies.
Besides the change of the legal status, scientific interest in the potential therapeutic
properties of cannabis has been growing, driven by advances in the understanding of
the endocannabinoid system.
The isolation of cannabinoid receptors and endogenous cannabinoids in the nervous
system by Raphael Mechoulam [1] and other groups and the discovery that the endocannabinoid system is capable of
modulating numerous physiological processes, such as pain, eating behavior, memory,
and mood [2]
[3] have paved the way for systematic research into the effects of cannabis on a variety
of chronic diseases [4]
[5]
[6]
[7]. Data from clinical studies supported a role of cannabis and endocannabinoids in
the treatment of specific symptoms, such as spasticity and central or spasticity-associated
pain in patients with multiple sclerosis, chemotherapy-induced nausea, and anorexia
[7]. Until recently, the only medicines of this class approved in Germany were the combination
drug Sativex® as an add-on therapy for adult multiple-sclerosis patients with moderate
to severe spasticity, and the synthetically manufactured tetrahydrocannabinol analogue
nabilone (Canemes®) for the treatment of adult cancer patients suffering from chemotherapy-induced
nausea. Since March 10, 2017 cannabis flowers and their extracts can be prescribed
on a narcotic drug prescription form without limitation to specific indications [8].
The discovery of high concentrations of cannabinoid receptors in the basal ganglia
triggered an increasing interest in the therapeutic potential of cannabinoids for
the treatment of Parkinson’s disease (PD) and other movement disorders. Public awareness
of this topic was raised by anecdotal reports of considerable improvement of PD symptoms
after cannabis consumption that were shared via social networks and published in the
general press. For example, Larry Smith, a US-American PD patient claiming improvement
of his dyskinesia with cannabis consumption, attracted broader public attention via
YouTubeTM [9]. In Germany, cannabis consumption to alleviate PD symptoms gained attention when
the topic was raised in the German TV drama series “Lindenstrasse” (the German equivalent
to the British TV drama series “Coronation Street”) [10].
Cannabis and the Endocannabinoid System
Cannabis and the Endocannabinoid System
Cannabis is a mixture of more than 60 substances, referred to as phytocannabinoids
due to their plant origin (as opposed to endocannabinoids produced by the human body).
The main active constituents of cannabis are the psychotropic cannabinoid delta9-tetrahydrocannabinol
(THC) and the non-psychotropic cannabinoid cannabidiol (CBD). These substances were
isolated in the 1960s and proven to be active components of cannabis [1]
[11]. In the 1990s, the two most important receptors — the cannabinoid receptor 1 (CB-1R)
[12] and the cannabinoid receptor 2 (CB-2R) [13] — and their endogenous ligands, such as anandamide and 2-arachidonylglycerol (2-AG),
and hence the endocannabinoid system (ECS) were discovered.
CB-1R is primarily located in the nervous system (except for the thalamus and brain
stem), with high concentrations in the hippocampus, the association cortex, cerebellum,
basal ganglia, and spinal cord (here with high concentration in the dorsal roots),
and peripheral nerves [7]. CB-2R is expressed in the gastrointestinal tract, in lymphatic tissue and peripheral
nervous system. However, in 2014 it was shown that CB-2R is also expressed in the
CNS, primarily in neurons of the dorsal nucleus of the vagus nerve, the nucleus ambiguus,
in the spinal trigeminal nucleus, and on microglia [14]
[15]
[16].
CB-1R and CB-2R are G protein-coupled receptors and via the G0/Gi unit inhibit the activity of the adenyl cyclase, thereby influencing the release
of excitatory neurotransmitters, such as glutamate, dopamine and acetylcholine. In
addition, other transmitter systems, such as the NMDA (N-methyl-D-aspartate) and the
serotonin, the opioid and GABA (γ-aminobutyric acid) systems are also modulated via
indirect mechanisms [7]. Furthermore, the mitogen-activated protein kinase/extracellular signal–regulated
kinase (MAPK/ERK) pathway is activated via the Gβγ complex [17]
[18]
[19], a pathway that has regulatory properties regarding cell development, cell differentiation
and apoptosis [20].
The structural analysis of cannabinoid receptors ultimately paved the way for the
development of synthetic cannabinoids. Today, several cannabinoid-based preparations
are available for medicinal use ([Table 1]).
Table 1 Overview on the case series and randomized controlled trials evaluating the effects
of cannabinoids or cannabinoid antagonists on symptoms of Parkinson’s disease.
|
Author [reference]
|
Year
|
Study design
|
Sample size
|
Active substance evaluated
|
Results
|
|
Venderová et al. [40]
|
2004
|
open anonymous survey
|
85
|
asked about type of cannabis consumption: 84 patients with 1/2 teaspoon cannabis orally;
1 patient inhaled, 52.9% daily.
|
improvement of cardinal PD symptoms in 45.9% and LID in 14.1%
|
|
Lotan et al. [41]
|
2014
|
case series
|
22
|
after baseline screening using motor and non-motor tests, smoked 0.5 g cannabis. After
30 min, testing repeated
|
improvement of tremor and bradykinesia
|
|
Frankel et al. [42]
|
1990
|
case series
|
5
|
1 g cannabis (with 2.9% THC) smoked once
|
no improvement of tremor
|
|
Chagas et al. [43]
|
2014
|
randomized, double-blind, placebo-controlled
|
21
|
randomized to receive 75 mg, 300 mg daily dose of CBD or placebo for 6 weeks
|
improvement of PDQ-39 with 300 mg CBD; UPDRS unchanged
|
|
Sieradzan et al. [44]
|
2001
|
randomized, double-blind, placebo-controlled crossover design
|
7
|
randomized to receive single exposure to 0.03 mg/kg nabilone or placebo; half of dose
administered 12 h and 1 h, respectively, before acute levodopa challenge test; crossover
after 2 weeks
|
reduction in LID severity and duration
|
|
Carroll et al. [45]
|
2004
|
randomized, double-blind, placebo-controlled crossover design
|
17
|
randomized to receive standardized daily dose of Cannador (2.5 mg THC+1.25 mg CBD)
for 4 weeks, crossover after 2-week wash-out period
|
no improvement in LID severity duration, motor symptoms quality of life or sleep
|
|
Mesnage et al. [46]
|
2004
|
randomized, double-blind, placebo-controlled
|
4
|
randomized to receive daily dose of 20 mg rimonabant (CB-1R antagonist) or placebo
for 16 days
|
no change in motor impairment or LID in neither On- nor Off-state
|
Parkinson’s Disease and Neuroprotection in Experimental Studies
Parkinson’s Disease and Neuroprotection in Experimental Studies
In the late 1960s and early 1970s, early animal studies demonstrated an effect of
cannabinoids on the catecholaminergic and dopaminergic systems [21]
[22]. CB-1R and the endocannabinoid ligands anandamide and 2-AG occur in high concentrations
in the dopaminergic system, including the striatum [23], where they modulate dopaminergic transmission as a retrograde feedback system on
presynaptic glutamatergic and GABAergic nerve endings. In-vitro studies in the late
1970s generated conflicting evidence, demonstrating both an increase [24] and a dose-dependent decrease of dopamine synthesis [25] and release [22]. In-vivo studies showed an increase in dopamine release in the prefrontal cortex,
striatum, but also in the nucleus accumbens. Thus, an increased firing rate of dopaminergic
neurons after acute THC exposure can be assumed, resulting in augmented dopamine synthesis
and release. Interestingly, acute and chronic THC exposure seems to result in different
effects on neuronal firing rate, transmitter synthesis, transmitter release and reuptake
within the dopaminergic system [26].
An increase in ECS activity was detected both in a PD animal model and in human tissue
analyses from PD patients [27], including an upregulation of cannabinoid receptors [28]
[29]
[29], an accumulation of cannabinoid receptor agonists [30]
[31] and a reduction in their degradation [32]. This adaptation of the ECS was reversed by chronic levodopa substitution in an
animal model [33].
With regards to the effect of CB-1R on motor function, experimental studies yielded
heterogeneous and partially conflicting results. Direct activation of CB-1R reduced
dopamine release and resulted in an increase in bradykinesia, shown in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
animal model of PD [34]. Others reported improvement of motor impairment with cannabinoid receptor agonists,
possibly due to receptor-independent mechanism of action [35]
[36]. Furthermore, alleviation of levodopa-induced dyskinesia has been reported for cannabinoid
receptor agonists and antagonists [31]
[37].
In addition, ECS activation may confer neuroprotective such as direct receptor-independent
mechanisms [38], activation of anti-inflammatory cascades in glial cells via CB-2R [39]
[40], and anti-glutamatergic and thus anti-excitotoxic properties [41].
Clinical Research
Numerous case series and single case reports concluded that cannabinoids might have
potential beneficial effects on PD symptoms.
In a large survey with 339 Czech PD patients, about 25% of the respondents stated
to regularly consume cannabis as an add-on therapy. Of these 85 patients, 39 (46%)
reported general improvement of their PD symptoms. 26 patients (31%) reported a reduction
of resting tremor, 38 patients (45%) an improvement of bradykinesia, 32 patients (38%)
a decrease in muscle rigidity, and 12 patients (14%) reduction of levodopa-induced
dyskinesia [42].
An observational study from Israel involving 22 PD patients showed a reduction of
the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score of 30% thirty minutes
after patients smoked cannabis. In addition, pain and sleep quality improved under
long-term therapy with cannabis [43]. A very early and small case series from London with 5 PD patients evaluated the
effect of cannabis smoking on resting tremor but found no improvement [44].
In contrast to the clearly positive effects described in single case reports and case
series, data from randomized placebo-controlled trials (RCTs) on effects on PD motor
symptoms are less encouraging. So far, 4 RCTs evaluating the effects of cannabinoids
on altogether 49 PD patients have been published.
In a study by Chagas et al., PD patients were randomized to receive CBD daily in doses
of either 75 mg, 300 mg, or placebo, with 7 patients randomized into each group. After
6 weeks, motor function (UPDRS motor score) and quality of life (Parkinson’s Disease
Questionnaire - PDQ-39) were assessed and compared to baseline. The improvement in
PDQ-39 sum score was significantly higher in patients treated with 300 mg/day of CBD,
while UPDRS scores did not differ between groups [45].
A study from Manchester evaluated the effect of nabilone, a CB-1R and CB-2R agonist,
on levodopa-induced dyskinesia in 7 patients in a crossover design. A total dose of
0.03 mg/kg body weight was administered with half the dose 12 h before the remainder
1 h before an acute levodopa challenge, which then was repeated 14 days later when
groups had been crossed over. Dyskinesia duration and severity were significantly
reduced in the nabilone group. However, no change in the severity of PD symptoms and
no difference in motor improvement after the acute levodopa challenge were observed.
In the nabilone group, 5 of 7 patients experienced mild sedation, dizziness, hyperacusis,
disorientation, and scenic visual hallucinations [46].
Caroll et al. studied the effect of Cannador®, a whole-plant extract with defined
THC content and a THC to CBD ratio of about 2:1, on 17 PD patients. Over a period
of 4 weeks, increasing doses of Cannador®, were administered b.i.d., up to a maximum
THC daily dose of 0.25 mg/kg. Despite the double-blind design, 71% of patients correctly
identified their respective treatment arm. Neither levodopa-induced dyskinesia (assessed
with UPDRS dyskinesia score and Rush Dyskinesia Rating Scale) nor UPDRS motor scores,
PDQ-39 or sleep quality improved. In contrast, a (non-significant) trend towards an
increase of dyskinesia severity with Cannador® treatment was observed [47].
In 2004, Mesnage et al. studied the CB-1R antagonist rimonabant, among others, and
its effect on PD symptoms. Over a period of 16 days, 4 patients received 20 mg/day
of rimonabant. At the end of period, neither UPDRS motor scores nor UPDRS dyskinesia
scores changed significantly [48].
To date, only one other study investigating the effect of CBD on PD tremor has been
registered (NCT02818777), aiming at recruiting 60 patients.
Psychotropic and Cardiovascular Side Effects
Psychotropic and Cardiovascular Side Effects
Considering the increased prevalence of psychotic symptoms in patients with idiopathic
Parkinson’s disease, psychotropic effects of cannabis and cannabinoids are of special
interest (Chang and Fox 2016). In a study by Sieradzan and colleagues, 5 of 7 PD patients
treated with the THC analog nabilone experienced psychotropic side effects such as
scenic visual hallucinations [46]. In the study of Lotan et al., 6 of the initially included 28 patients (21%) with
an average age of 65 years dropped out due to psychotic symptoms following cannabis
consumption [43].
The primary active component responsible for the psychotropic effect of cannabis is
THC. In clinical studies investigating the effects of CBD, no psychotic side effects
were observed [45]. In an open-label study, 6 PD patients with psychiatric plus symptoms, such as illusions
and hallucinations, and minus symptoms, such as withdrawal and depression, received
CBD over a period of 4 weeks. Treatment was started with an initial daily dose of
150 mg and gradually increase over a period of 1 month up to a maximum daily dose
of 400 mg [49]. The authors reported a significant reduction in psychotic symptoms, as measured
with the Parkinson Psychosis Questionnaire (PPQ) and the Brief Psychiatric Rating
Scale (BPRS).
Apart from psychotropic effects, cannabinoids are associated with adverse cardiovascular
events. Non-motor PD symptoms include orthostatic hypotension caused by sympathetic
cardiac denervation, among others [50]. Similarly, cannabis consumption can also lead to an orthostatic drop in blood pressure
and even orthostatic syncope [51]. Due to sympathetic cardiac denervation, the ability to counteract a drop in blood
pressure by increasing the heart rate is limited in PD patients. This, in turn, may
intensify the impact of cannabinoids on orthostatic dysregulation. The study of Sieradzan
et al. detected an orthostatic drop in systolic blood pressure in all patients. One
patient in the nabilone group was unable to continue the study due to symptomatic
orthostatic hypotension [46]. Furthermore, the increased sympathetic activity with cannabis consumption results
in an increased myocardial oxygen demand. In patients with preexisting angina pectoris,
exercise symptoms of myocardial hypoxia occur earlier with cannabis consumption [52]
[53]. In addition, the risk of myocardial infarction is increased by 1 to 4.8 fold in
cannabis users [54]
[55]. With the possibility of cardiac comorbidities in PD patients, these adverse events
should receive additional attention.
Conclusion
In summary, the positive effects of cannabinoid consumption on motor symptoms in patients
with Parkinson’s disease described in single case reports and case series have not
been confirmed by the few placebo-controlled studies available as yet. Results of
studies on cannabinoids for the treatment levodopa-induced dyskinesia have been inconsistent.
The postulated beneficial effects of cannabinoids are opposed by potential side effects,
such as hallucinations and orthostatic hypotension, which require special attention
in PD patients.
Therefore, the clinical use of cannabinoids in patients with Parkinson’s disease should
be preceded by careful individual risk-benefit assessments. Currently, it should be
limited to symptoms for which positive effects can be expected from other indications
for cannabinoids, such as refractory pain or sleep disorders. In view of the extended
approval of cannabinoids, further controlled studies are urgently needed to provide
data that support evidence-based treatment recommendations, and to increase confidence
in the safety of prescribing cannabinoid therapies.
