Parkinson’s disease (PD) is one of the most common type of neurodegenerative disease, affecting approximately 60 000 Americans each year. While the main causes of PD are unknown, several genes and environmental factors have been identified as potential contributors. PD is a progressive movement disorder consisting of bradykinesia, rest tremor, rigid muscles, and impaired posture and balance as well as other non-motor features. The main pathological hallmarks of PD are the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta located in the midbrain and the accumulation of misfolded a-synuclein, found within Lewy bodies (LB). Although there is no cure, several pharmacological and non-pharmacological treatment options are available to attempt to slow the symptoms but are often associated with unwanted side effects. One alternative therapeutic agent to reduce PD associated symptoms is the use of medical cannabis. While animal studies, patient’s surveys and early clinical trials have shown some improvement in PD associated symptoms, additional work is needed to fully understand its effects. As such, an increase in the number of double-blind randomized, placebo-controlled studies with a large number of patients will shine more light onto the role of cannabis and other derivates in the treatment of PD.
Parkinson’s disease (PD) is one of the most common types of neurodegenerative disease, first described by James Parkinson at the beginning of the 19th century, in which he provides six examples of individuals with involuntary tremulous motion referring to the disease as “paralysis agitans” or “shaking palsy”.1 The condition was further characterized by Jean-Martin Charcot who named the disease after James Parkinson about 60 years later.2 According to the Parkinson’s Foundation, approximately 60 000 Americans are diagnosed with PD each year and more than 10 million individuals worldwide are living with PD.3 It is estimated that 1.2 millions of individuals in the US will be diagnosed with PD by 2030, raising direct and indirect costs including diagnostic tools and treatment. PD is usually uncommon among younger individuals, and the prevalence is increasing with age to approximately 0.5-1% among 65-69 years and peaking to 1-3% among persons of age 80 and older.4,5 Despite PD affecting men twice more often that women, women have a higher mortality rate and faster disease progression.6 While the main causes of PD are unknown, several genes and environmental factors have been identified as potential contributors.7,8
PD is a progressive movement disorder consisting of bradykinesia (slowed movement), rest tremor (or shaking, usually beginning in a limb such as hand or fingers), rigid muscles (which can be painful and limit range of motion), and impaired posture and balance as well as other non-motor features (e.g., olfactory dysfunction, cognitive impairment or fatigue).9 The main pathological hallmarks of PD are the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta located in the midbrain and the accumulation of misfolded a-synuclein, found within Lewy bodies (LB), which are sticky protein lumps disrupting normal brain function.10,11 Because of the effects on DA neurons loss, attempting to restore the dopaminergic tone in the striatum is one of the current pharmacological treatment approaches to treat PD. While there is no cure to treat the disease, the major objective of PD research is to develop therapeutics that may help to slow or stop the neurodegenerative process and reduce associated symptoms. Pharmacological interventions are broadly classified as dopaminergic supplementation, dopaminergic drugs and monoamine oxidase (MAO) B inhibitors. As such, one of the potent medications within the dopaminergic supplementation category is levodopa (L-dopa), dopamine precursor developed in the 1960s, aiming at increasing the levels of dopamine in the substantia nigra.12,13 However, long-term treatment can be unstable and may lead to levodopa-induced dyskinesia (abnormality or impairment in voluntary movement).14 Dopaminergic drugs are dopamine agonist compounds acting on the postsynaptic dopamine receptors to mimic the effects of dopamine, which have been found to be more effective than L-dopa in the treatment of late stage PD (e.g., apomophine and bromocriptine).15-17 Finally, MOA inhibitors which help prevent the breakdown of dopamine by inhibiting the brain enzyme MOA B, result in an increasing amount of dopamine in the neurons, which is necessary to attempt to treat PD pathology (e.g., selegiline and rasagiline).18,19 Non-pharmacological interventions include the use of deep brain stimulation (DBS) as an established treatment for PD to treat dopamine-dependent motor symptoms in patients who have unstable medication responses and involve the surgical implantation of electrodes to stimulate subcortical structures. 20,21 Despite these readily available options, these treatments provide some limited relief and are often associated with unwanted side effects. As such, there is a need to investigate other alternative approaches that not only will provide improvement in patients’ symptoms and prevent its progression but also reduce these adverse effects.
One exiting and novel research area is to determine whether medical cannabis may be used as a therapeutic agent to reduce PD associated symptoms and to ameliorate everyday activities for these patients. The endocannabinoid system (ECS) is one of the newly discovered system in the human body, known to regulate sleep, mood, appetite and maintain body homeostasis, a state of stability needed for survival.22,23 These tasks are mediated in part, by the interaction of the endogenous cannabinoids (cannabinoids found in the body) with the cannabinoid receptor 1 (CB1), mostly present in the CNS (cortex, hippocampus, and cerebellum) and cannabinoid receptor 2 (CB2), mainly located in the PNS and in the immune system.24-26 Medical cannabis consists of a wide array of molecules including phytocannabinoids (delta-9-tetrahydrocannabinol (D9-THC), delta-8-tetrahydrocannabinol (D8-THC), cannabidiol (CBD)) which are known to have euphoric-like effects and may play therapeutic roles in a wide range of complex diseases including cancer, glaucoma or multiple sclerosis. More particularly, THC, the main psychoactive molecule of the cannabis plant is a partial agonist at CB1 and CB2 receptors while CBD, the non-psychoactive analog has little binding affinity to either one but can antagonize them in the presence of THC. 27,28 Moreover, the presence in high abundance of CB1 and more recently CB2 receptors in the basal ganglia, one of the area of the brain impacted by PD, suggest that modulating their activities via pharmacological agents such as cannabis may represent an interesting avenue for treating PD symptoms.29-31
Animal studies have attempted to determine whether cannabis may be used as therapeutic agent to reduce L-dopa-induced dyskinesia in mouse models of PD. In Dos-Santos-Pereira et al., the authors treated mice with 6-hydroxydopamine (6-OHDA) neurotoxin to induce hallmarks of PD and these lesioned animals were treated with L-Dopa to induce dyskinesia. 32 While administration of CBD alone was not able to prevent dyskinesia, the combination of CBD and caspazepine, a transient receptor potential vanilloid-1(TRPV-1) receptor antagonist, led to reduction of dyskinesia.32 In Celorrio et al, the team investigated whether abnormal-cannabidiol (Abn-CBD), a synthetic CBD isomer and a G-protein-coupled receptor 55 (GPR55) agonist, highly expressed in the basal ganglia, may serve as a therapeutic agent in mouse models of PD.33 They found that administration of Abn-CBD improved motor behavior and produced morphological changes in the microglia, probably due to the anti-inflammatory response.33 Administration of THC improved both activity and hand-eye coordination in a mouse model of PD, suggesting it may have therapeutic values and could supplement existing therapies.34
Several surveys have been published in the past attempting to determine whether cannabis may be beneficial in alleviating PD associated symptoms. A study published in 2004 showed that cannabis administration led a general improvement of PD symptoms including resting tremor, relief from rigidity, and reduced bradykinesia in PD patients. 35 Similar findings were noted in a study performed at the Sackler Faculty of Medicine in Israel in which cannabis inhalation was responsible for an amelioration of both motor and non-motor symptoms as well as sleep and pain scores in PD patients.36 More recently, researchers at the University Medical Center Hamburg-Eppendorf in Germany found that more than 40% of PD patients who used medical cannabis either in the form of CBD or THC reported a beneficial clinical effect in terms of reduction of pain and muscle cramps.37 Moreover, symptoms improvement was more frequent in the THC compared to the CBD group, more specifically in terms of reducing akinesia (loss of ability to move muscles voluntary) and stiffness.37 While these studies may indicate some beneficial effects in relieving PD symptoms, it is difficult to provide substantial conclusions due to the missing information of the different amount of phytocannabinoids present and the specific routes of administration as well as the low sample size.
In 2009, Zuardi et al. evaluated for the first time the efficacy, tolerability and safety of CBD on patients with PD with psychotic symptoms in an open-label study with daily flexible dose over the course of four weeks and noted a decreased in psychotic symptoms without inducing any decrease in cognitive function with no adverse side effects. 38 It is important to note the low sample size (n=6) and the lack of placebo group in this study make it difficult to draw any potential conclusions. In addition, Chagas et al. designed an exploratory double-blind trial attempting to further investigate the potential role of CBD in alleviating PD symptoms and reported an increased in the well-being and the quality-of-life scores (PDQ-39) in PD patients (without lifetime psychiatric or dementia diagnoses) who received daily CBD intake for six weeks with no overall improvement in motor and general symptoms scores (UPDRS).39 The authors inferred this effect may be linked to CBD’s anxiolytic and antipsychotic properties. While this study included a placebo group and a higher sample size (n=21), studies involving larger samples with systematic assessment of specific PD symptoms are needed. In 2017, Shohet et al. performed an open label, uncontrolled, observational study including 18 PD patients and were evaluated before, 30 min after smoking cannabis and again long-term (10-14 weeks of continued cannabis use).40 The authors reported a significant improvement from baseline to 30 min after use in mean motor and pain scores while mean heat pain threshold decreased significantly in the more affected limb after long-term use in PD patients who smoked cannabis compared to control group. While this study indicated that cannabis improves motor function and lessens the subjective perception of pain in patients with PD, suggesting it may act on pain via peripheral and central pathways, further placebo-controlled studies to verify these findings are needed. More recently, a randomized, double-blinded, placebo-controlled study on 24 individuals with PD was performed to determine the effects of CBD on anxiety signs and tremors on a simulated public speaking test. 41 The findings showed that acute administration of CBD compared to placebo before the experimental sessions attenuated anxiety and decreased tremor amplitude in an anxiogenic situation, suggesting it may be an important agent to treat these PD-related symptoms. 41 The use of cannabis and derivates in an attempt to reduce levodopa-induced dyskinesia in PD was also investigated and results showed that nabilone, a CB1 and CB2 receptors agonist, was able to decrease dyskinesia duration and severity compared to the placebo group. 42 No such effects was noted in orally administrated cannabis extract (Cannador®, THC:CBD 2:1), which resulted in no objective or subjective improvement in dyskinesias or parkinsonism in patients with PD.43
As of today, there are eight active or completed clinical trials on clinicaltrials.gov attempting to determine the effects of cannabis and other derivates as a potential agent to reduce PD associated symptoms. Notably, an open-label extension study for participants of the randomized placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal NMS-Nab Study, assessing the long-term safety and efficacy of nabilone for non-motor symptoms in patients with PD is currently in a Phase 3 trial.44
As a conclusion, Parkinson’s disease is one of the most common type of neurodegenerative diseases, affecting dopaminergic neurons, resulting in motor and non-motor symptoms that develop slowly over the years. Although there is no cure, several pharmacological and non-pharmacological treatment options are available to attempt to slow the symptoms including the use of Levodopa, dopamine receptor agonists and the use of deep-brain stimulation. While these have shown some beneficial relief, they are often associated with unwanted side effects. As such, alternative therapeutic agents are being considered, one of which is the use of cannabis. While animal studies, patient’s surveys and early clinical trials have shown some improvement in PD associated symptoms, additional work is needed to fully understand its effects. The increase in the number of double-blind randomized, placebo-controlled studies with a large number of patients will shine more light onto the role of cannabis and other derivates in the treatment of PD. Understanding the effects will also help determine any potential unwanted adverse effects as well as short and long-term effects associated with cannabis use. Despite remaining a Schedule I substance with no definitive proof of medical use and a high potential of abuse, 33 US states have legalized its use for medical purposes, listing PD as one of the conditions.
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- Nabilone for Non-motor Symptoms in Parkinson’s Disease (NMS-Nab2) (NCT03773796). (https://www.clinicaltrials.gov/ct2/show/NCT03773796?term=Parkinson%27s+disease+cannabis&recrs=abdefm&phase=2&draw=2&rank=1).