Parkinson’s disease (PD), a neurodegenerative disorder, is the second most common neurological illness in United States. Neurologically, it is characterized by the selective degeneration of a unique population of cells, the nigrostriatal dopamine neurons. The current treatment is symptomatic and mainly involves replacement of dopamine deficiency. This therapy improves only motor symptoms of Parkinson’s disease and is associated with a number of adverse effects including dyskinesia. Therefore, there is unmet need for more comprehensive approach in the management of PD. Cannabis and related compounds have created significant research interest as a promising therapy in neurodegenerative and movement disorders. In this review we examine the potential benefits of medical marijuana and related compounds in the treatment of both motor and nonmotor symptoms as well as in slowing the progression of the disease. The potential for cannabis to enhance the quality of life of Parkinson’s patients is explored.
Marijuana, the crude product (dried flowers, stems, seeds, and leaves) derived from the cannabis sativa plant, consists of more than 85 phytocannabinoids [
Despite the placement of marijuana in the schedule 1 category under the US Federal Controlled Substance Act [
Although recent studies have provided strong evidence for the therapeutic benefit of medical marijuana [
The target of medical marijuana and its constituents is the endocannabinoid system, which is involved in the modulation of a number of physiological functions. The endocannabinoid system includes the endocannabinoids, the cannabinoid receptors, and the enzymes involved in the biosynthesis and inactivation of the endocannabinoids [
Parkinson’s disease (PD) is the second most common neurodegenerative disorder following Alzheimer’s disease and the 14th leading cause of death in all age groups in the United States [
Current therapy involves treatment of motor symptoms of PD through replacement of dopamine deficiency [
However these drugs treat only motor symptoms of Parkinson’s disease and are associated with a number of adverse effects. Long-term use of levodopa, the mainstay therapy for PD, is associated with motor fluctuations [
Medical marijuana has been demonstrated to improve motor symptoms including tremor, rigidity, and bradykinesia as well as nonmotor symptoms such as pain and sleep disorders of PD in observational studies [
In this review we seek to investigate any scientific evidence that indicates the potential use of marijuana and/or its components for the treatment of Parkinson’s disease. The review aims to (i) examine briefly current treatment and the unmet need of PD therapy, (ii) assess the role of the cannabinoid system in the modulation of movement and neuroprotection, (iii) look at the mechanism of action of marihuana constituents in the modulation of movement and PD-associated disorders, (iv) assess other beneficial effects of marihuana that contribute to the amelioration of PD, and (v) gather scientific evidence on the clinical benefit of marijuana and/or its constituents in PD patients.
Cannabis has been used to treat disease since ancient times. Marijuana is derived from the
Some cannabinoids (endocannabinoids or ECBs) are found in the body. Initially, ECBs were discovered in the brain and subsequently in the periphery in humans and animals. Endocannabinoids are produced by cultured neurons [
The major identified ECBs are arachidonoyl ethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), O-arachidonoyl ethanolamine (virodhamine), and 2-arachidonoyl glyceryl ether (noladin ether) [
Marijuana compound THC is CB1 and CB2 receptor partial agonist [
Unlike THC, CBD has little affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists. While this should cause CBD to reduce the effects of THC, it may potentiate THC’s effects by increasing CB1 receptor density or through another CB1-related mechanism [
Other cannabinoids can also contribute to the cannabis medicinal effects. Studies in experimental models and humans have suggested anti-inflammatory, neuroprotective, anxiolytic, and antipsychotic properties of chemicals extracted from marijuana [
Recent data from several studies indicate the important role of the endocannabinoid system in Parkinson’s disease. The components of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia, which is part of a complex neuronal system. This neuronal system coordinates activities from different cortical regions that directly or indirectly participate in the control of movement [
The cannabinoid signaling system mentioned above experiences a biphasic pattern of changes during the progression of PD [
In the brain, CB1 receptors are expressed by GABAergic neurons innervating the external and internal segments of the globus pallidus and the substantia nigra [
Endocannabinoid signaling is also bidirectionally linked to dopaminergic signaling within the basal ganglia [
Another receptor involved in control of movement is transient receptor potential vanilloid type 1 (TRPV1), which is expressed in sensory neurons and basal ganglia circuitry of dopaminergic neurons [
The association of cannabinoids with regulation of motor functions is well established [
Research with cannabinoid agonists and antagonists demonstrates that the cannabinoids can modulate motor activity and produce alterations in corresponding molecular correlates [
Administration of WIN 55,212-2 increased stimulation of
Cannabinoid agonist anandamide (AEA) and its synthetic analog methanandamide increased the extracellular dopamine levels in the nucleus accumbens shell of rats by the activation of the mesolimbic dopaminergic system [
Tissue concentrations of endocannabinoids are important for producing motor effects. Levels and activities of AEA and 2-AG can be manipulated by inhibition of FAAH enzyme, the action of which is reduced in experimental models of PD [
Overall, these results indicate that endogenous or exogenous cannabinoid agonists activate the dopaminergic system and play a very important role in modulation of motor behavior [
The CB1 receptor antagonists can also influence movement syndromes of Parkinson’s disease suggesting that modulation of the CB1 signaling system might be valuable in treatment of motor disorders. In a study with PD rats rimonabant (SR141716A), a selective antagonist of CB1 receptors has shown the potential to act as an antihypokinetic agent by enhancing glutamate release from excitatory afferents to the striatum [
Another CB1 receptor antagonist AM251 and SR141716A produced antiparkinsonian effects in rats with very severe nigral degeneration (>95% cell loss) [
The activation of CB2 receptors might also contribute to some extent to the potential of cannabinoids in PD [
The cannabinoid pharmacologic manipulation represents a promising therapy to alleviate movement disorders and levodopa-induced dyskinesias. Thus, CB1 antagonists appear to have antiparkinsonian effects, while cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson’s disease.
Cannabis and related compounds have created significant research interest as a promising therapy in neurodegenerative and movement disorders. The successful use of tincture of
A study with smoked cannabis queried 339 PD patients indicated that marijuana produced significant improvement of general PD symptoms in 46% of the patients; 31 % of them reported improvement in resting tremor, 38% reported relief from rigidity, 45% defined reduced bradykinesia, and 14% of the patients reported alleviated dyskinesias [
Few studies have evaluated the effects of CBD on PD symptoms. In a pilot study CBD lowered total UPDRS scores and significantly reduced psychotic symptoms in 6 PD patients with psychosis [
Clinical studies have been conducted to evaluate the effect of a synthetic cannabinoid nabilone. Oral nabilone significantly reduced dyskinesia without aggravating parkinsonism in seven PD patients with severe L-DOPA-induced dyskinesia [
Several clinical studies have been performed to evaluate the effect of marijuana on dystonia. Inhaled cannabis has provided a marked reduction in dystonia and complete pain relief in patients with right hemiplegic painful dystonia. Moreover, the patients have been able to completely discontinue opioid use [
Studies have looked at the potential benefits of medical marijuana and cannabinoids for the treatment of Huntington’s disease (HD). Nabilone versus placebo showed a treatment difference of 0.86 for total motor score; 1.68 for chorea; 3.57 for Unified Huntington’s Disease Rating Scale (UHDRS) cognition; 4.01 for UHDRS behavior; and 6.43 for the neuropsychiatric inventory in HD patients [
Few studies have indicated that marijuana and THC can reduce tics and associated behavioral disorders in patients with Tourette’s syndrome (TS) [
Considering the relevance of these data, the need for alternative treatments for PD motor and nonmotor symptoms, medical marijuana, or related compounds may provide a new approach to the treatment of Parkinson’s disease.
Cannabinoids have been shown to have neuroprotective effect due to their antioxidative, anti-inflammatory actions and their ability to suppress exitotoxicity. Plant-derived cannabinoids such as THC and CBD can provide neuroprotection against the in vivo and in vitro toxicity of 6-hydroxydopamine and this was thought to be due to their antioxidative property or modulation of glial cell function or a combination of both [
Inflammation has been shown to be a crucial pathological factor responsible for the demise of dopaminergic neurons in PD [
Marijuana may prevent brain damage by protecting against neuronal injury. There are a few mechanisms by which cannabinoids provide neuroprotection. One of the mechanisms involves an induction/upregulation of cannabinoid CB2 receptors, mainly in reactive microglia, and regulates the influence of these glial cells on homeostasis of surrounding neurons [
Pain is a relevant and often underestimated nonmotor symptom of PD [
Several clinical studies have been performed to investigate the effect of marijuana or cannabinoids on pain. Smoked cannabis significantly reduced neuropathic pain intensity as well as significantly improved mood disturbance, physical disability, and quality of life in HIV-patients [
These findings are consistent with other discoveries supporting the efficacy of cannabis in relieving pain. The analgesic effect of cannabinoids has been reviewed [
Depression is one of the common nonmotor symptoms of PD and the estimated rate varies widely, with an average prevalence of up to 50%. [
Sleep disorders are common in PD patients and negatively affect the quality of life. The reported prevalence ranges from 25% to 98% and this wide variation could be due to differences in study design and diagnostic tools used [
Cannabis and related compounds have recently been studied as promising therapeutic agents in treatment of neurodegenerative and movement disorders including Parkinson’s disease. In this review we have examined the potential benefits of medical marijuana and cannabinoids in the treatment of both motor and nonmotor symptoms as well as in slowing the progression of the disease. We have looked into any scientific evidence that indicates the potential use of marijuana and/or related compounds for the treatment of PD. Current treatments of PD provide only relief of motor symptoms and are associated with adverse effects such as dyskinesia. In addition, these therapies do not slow the progression of the disease. Therefore, there is an urgent need for safer drugs that can treat both motor and nonmotor symptoms of PD as well as drugs that slow the progression of the disease.
In spite of the placement of marijuana in schedule 1 category under the US Federal Controlled Substance Act, 24 states and Washington DC have enacted laws allowing the use of marijuana to treat a range of medical conditions. Parkinson’s disease has been listed as one of the disease conditions for which medical marijuana is allowed in a number of states. Research studies have provided evidence for the potential effectiveness of medical marijuana and its components in the treatment of PD as cannabinoids act on the same neurological pathway that is disrupted in Parkinson’s disease. Involvement of the endocannabinoid system in the regulation of motor behavior, the localization of the cannabinoid receptors in areas that control movement, and the effect of cannabinoids on motor activity indicate that cannabinoids can be potentially used in the treatment of movement disorders. Cannabinoid agonists and antagonists have been shown to modulate the endocannabinoid system and modify motor activity. Cannabinoid receptor antagonists appear to produce antiparkinsonian effects while cannabinoid receptor agonists exert a powerful motor inhibition and may be useful in the treatment of motor complications. In addition, we have assessed the role of the cannabinoid system and marijuana constituents in neuroprotection as well as considered other beneficial effects of marijuana. Marijuana has been shown to improve nonmotor symptoms of PD such as depression, pain, sleep, and anxiety. Moreover, components of cannabis have been demonstrated to have neuroprotective effect due to their anti-inflammatory, antioxidative, and antiexcitotoxic properties. Due to combination of the above mentioned beneficial effects, cannabis may provide a viable alternative or addition to the current treatment of Parkinson’s disease. However, there are concerns regarding the use of medical marijuana including lack of standardization and regulation, imprecise dosing, possible adverse effects, and medication interactions. Further studies are needed to provide more data on efficacy, safety, pharmacokinetics, and interactions of cannabinoids.
The authors declare that there is no conflict of interests regarding the publication of this paper.