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Biological bases for a possible effect of cannabidiol in Parkinson’s disease

Abstract

Current pharmacotherapy of Parkinson’s disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients’ quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson’s animal models; Parkinson’s history; Parkinson’s and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.

Cannabidiol; CBD; Parkinson; neurodegeneration; neuroprotection


Pathophysiology of Parkinson’s disease

In “An essay on the shaking palsy” (1817), James Parkinson first described a condition of insidious onset with a progressive and disabling course characterized by resting tremor, flexed posture, and festinating gait.11. Parkinson J. An essay on the shaking palsy. London: Whittingham and Rowland Sherwood, Neely and Jones; 1817. Martin Charcot later added extensive details to Parkinson’s observations, identifying bradykinesia and rigidity as key symptoms of the disease.22. Charcot JM. Lectures on the diseases of the nervous system, delivered at la salpetriere. London: New Sydenham Society; 1877. In 1895, Brissaud hypothesized that the substantia nigra (SN) was the main brain nucleus affected in Parkinson's disease (PD),33. Parent M, Parent A. Substantia nigra and Parkinson's disease: a brief history of their long and intimate relationship. Can J Neurol Sci. 2010;37:313-9. and Friedrich Heinrich Lewy described protein aggregates in brain areas of PD patients, including the globus pallidus, the dorsal nucleus of the vagus, and the locus coeruleus.44. Holdorff B, Rodrigues e Silva AM, Dodel R. Centenary of Lewy bodies (1912-2012). J Neural Transm (Vienna). 2013;120:509-16. Shortly thereafter, in 1919, Tretiakoff validated Lewy’s hypothesis by describing the protein aggregates observed in postmortem brain tissue of PD patients, which he called Lewy bodies.55. Tretiakoff C. Contribution à l’étude de l’anatomie pathologique du locus niger de Soemmering avec quelques deductions relatives à la pathologie des troubles musculaires et de la maladie de Parkinson. These de Paris, n° 231919.

Pathologically, PD is characterized by early death of dopaminergic neurons in the SN pars compacta (SNpc), leading to dopamine deficiency within the basal ganglia and a movement disorder consisting of the classic parkinsonian motor symptoms. However, PD is also associated with multiple non-motor symptoms, some of which precede motor dysfunction by more than a decade. The mainstay of PD management is symptomatic treatment with drugs that increase brain dopamine concentrations or directly stimulate dopamine receptors.

As noted above, PD begins years before clinical diagnosis, involves multiple brain regions, and entails motor and non-motor symptoms. It is a slow, progressive neurodegenerative disorder of multifactorial etiology, resulting from a combination of genetic and environmental factors. For instance, although still controversial, smokers are twice as likely to develop PD,66. Allam MF, Campbell MJ, Hofman A, Del Castillo AS, Fernandez-Crehuet Navajas R. Smoking and Parkinson's disease: systematic review of prospective studies. Mov Disord. 2004;19:614-21. caffeine consumers have a lower incidence of the disease,77. Ascherio A, Chen H, Schwarzschild MA, Zhang SM, Colditz GA, Speizer FE. Caffeine, postmenopausal estrogen, and risk of Parkinson's disease. Neurology. 2003;60:790-5. and association between obesity and herbicide exposure seems to be a risk factor for dopaminergic neurodegeneration.88. Elbaz A, Tranchant C. Epidemiologic studies of environmental exposures in Parkinson's disease. J Neurol Sci. 2007;262:37-44. From the genetic standpoint, studies have shown that mutations in different genes – such as Parkin, PINK1, DJ-1, LRRK2, GBA, and ATP13A2 – are implicated in several types of parkinsonism as well as in PD.99. Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet. 2009;373:2055-66.

10. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.
-1111. Michel PP, Hirsch EC, Hunot S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron. 2016;90:675-91. Hereditary PD is classified as either dominant or recessive; the majority of genetically associated cases feature early (rarely, even juvenile) onset.1111. Michel PP, Hirsch EC, Hunot S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron. 2016;90:675-91.,1212. Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol. 2006;5:355-63.

In the literature, the genetic factors associated with PD have often been related to causal mechanisms such as oxidative stress, glutamate excitotoxicity, mitochondrial dysfunction, neuroinflammation, apoptosis, and increased susceptibility of the dopaminergic neurons of the SNpc to neurotoxins.99. Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet. 2009;373:2055-66.,1010. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. An important hypothesis proposes that oxidative stress generates free radicals, such as dopamine quinone, that can react with the cytoplasmic protein α-synuclein, producing protofibrils that cannot be degraded by the ubiquitin-proteasome system. These protofibrils accumulate and generate eosinophilic cytoplasmic inclusions (Lewy bodies), causing the death of dopaminergic neurons in the nigrostriatal pathway.1010. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.,1111. Michel PP, Hirsch EC, Hunot S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron. 2016;90:675-91.,1313. Fahn S. Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci. 2003;991:1-14.

Although the understanding of the pathophysiology of PD has improved markedly since its initial characterization, an effective pharmacological treatment to prevent or slow the progression of dopaminergic neuronal degeneration has yet to be developed. The pharmacotherapy of PD continues to be palliative, aiming to restore reduced dopamine levels in the striatum.1414. LeWitt PA. Levodopa therapy for Parkinson's disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30:64-72.,1515. Liss B, Striessnig J. The potential of l-type calcium channels as a drug target for neuroprotective therapy in Parkinson's disease. Annu Rev Pharmacol Toxicol. 2019;59:263-89. The standard treatment is based on (S)-2 amino-3-(3,4-dihydroxyphenyl)propionic acid, also known as levodopa (L-DOPA).1414. LeWitt PA. Levodopa therapy for Parkinson's disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30:64-72.,1515. Liss B, Striessnig J. The potential of l-type calcium channels as a drug target for neuroprotective therapy in Parkinson's disease. Annu Rev Pharmacol Toxicol. 2019;59:263-89. L-DOPA is considered a safe and effective drug for reducing the motor symptoms of PD, with only mild side effects, such as nausea, vomiting, and postural hypotension.1414. LeWitt PA. Levodopa therapy for Parkinson's disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30:64-72.,1515. Liss B, Striessnig J. The potential of l-type calcium channels as a drug target for neuroprotective therapy in Parkinson's disease. Annu Rev Pharmacol Toxicol. 2019;59:263-89. However, the long-term efficacy of L-DOPA is limited by the development of disabling motor complications such as L-DOPA-induced dyskinesia, a set of abnormal involuntary movements that include chorea, hemiballismus, and athetosis.1616. Schaeffer E, Pilotto A, Berg D. Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease. CNS Drugs. 2014;28:1155-84.

In this context, the search for more effective and tolerable treatments is imperative. Preclinical research provides opportunities for the discovery of new PD drugs, and animal models that mimic some aspects of PD have been used in an attempt to describe promising candidate agents. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson’s animal models; Parkinson’s history; Parkinson’s and cannabidiol.

Animal models for the study of Parkinson’s disease

Toxin-based models

Neurotoxin-based models are useful to understand the mechanisms underlying the neurobiology of PD and the dopaminergic neuronal loss observed in PD, through the use of neurotoxins such as dopamine analogs (e.g., 6-hydroxydopamine [6-OHDA]), contaminants of synthetic heroin (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]), herbicides (e.g., rotenone), heavy metals (e.g., manganese and iron), and lipopolysaccharide (LPS).

The first substance reported to cause lesions in the nigrostriatal pathway in rats was 6-OHDA.1717. Ungerstedt U. 6-hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol. 1968;5:107-10. This toxin accumulates in the cytosol of neurons and promotes the formation of hydrogen peroxide, other reactive oxygen species, and quinines by auto-oxidation.1818. Simola N, Morelli M, Carta AR. The 6-hydroxydopamine model of Parkinson's disease. Neurotox Res. 2007;11:151-67. 6-OHDA is a hydrophilic compound and cannot cross the blood-brain barrier. It is administered by direct injection into the SNpc, medial forebrain bundle, or striatum, depending on the objective of the researcher (rate and extent of injury).1919. Jeon BS, Jackson-Lewis V, Burke RE. 6-hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration. 1995;4:131-7. Even though 6-OHDA has been the most common model in preclinical research, it is non-selective for dopamine transporters, and is commonly co-administered with selective noradrenaline uptake blockers to prevent loss of noradrenergic neurons.2020. Luthman J, Fredriksson A, Sundstrom E, Jonsson G, Archer T. Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res. 1989;33:267-77. Another disadvantage of 6-OHDA use relies on its inability to produce Lewy body-like inclusions.2121. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003;39:889-909.

MPTP is a neurotoxin that is converted into an intermediate metabolite by the action of monoamine oxidase B in glial cells, and then oxidized to 1-methyl-4-phenylpyridinium (MPP+).2222. Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson's disease. Nat Protoc. 2007;2:141-51. MPP+ has high affinity for the dopamine transporter, but lower affinity for norepinephrine and serotonin transporters.2323. Javitch JA, D'Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A. 1985;82:2173-7. Within dopaminergic neurons, MPP+ is sequestrated into synaptic vesicles or concentrated within the mitochondria, where it blocks the electron transport chain.2424. Varastet M, Riche D, Maziere M, Hantraye P. Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease. Neuroscience. 1994;63:47-56. In monkeys, MPTP administration produces Lewy body-like inclusions, and the susceptibility to MPTP-induced lesions increases with age.2525. Ovadia A, Zhang Z, Gash DM. Increased susceptibility to MPTP toxicity in middle-aged rhesus monkeys. Neurobiol Aging. 1995;16:931-7.

Rotenone is a pesticide that acts by blocking the mitochondrial electron transport chain, mitosis, and cell proliferation.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503. Chronic systemic exposure to rotenone in rats causes many features of PD, including nigrostriatal degeneration and Lewy body-like inclusions, but this model is difficult to replicate due to the high mortality of animals.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503.,2727. Fleming SM, Zhu C, Fernagut PO, Mehta A, DiCarlo CD, Seaman RL, et al. Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp Neurol. 2004;187:418-29. Another pesticide used to study PD is paraquat, one of the most widely used herbicides in agriculture.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503. It shares structural similarity to MPP+.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503. Paraquat generates Lewy body-like inclusions,2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503. but it has low specificity for dopaminergic neurons and causes variable cell death.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503.,2828. Miller GW. Paraquat: the red herring of Parkinson's disease research. Toxicol Sci. 2007;100:1-2.

Paraquat has been used in conjunction with manganese ethylene-bis-dithiocarbamate (maneb), a fungicide which has been shown to potentiate the toxic effects of paraquat and of MPTP.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503. Results have shown that maneb may, on its own, decrease locomotor activity and produce loss of neurons in the substantia nigra.2929. Thrash B, Uthayathas S, Karuppagounder SS, Suppiramaniam V, Dhanasekaran M. Paraquat and maneb induced neurotoxicity. Proc West Pharmacol Soc. 2007;50:31-42. Chronic exposure to maneb produces signs of manganese intoxication,3030. Ferraz HB, Bertolucci PH, Pereira JS, Lima JG, Andrade LA. Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology. 1988;38:550-3. followed by a neurological syndrome with cognitive, psychiatric, and movement abnormalities that resemble some clinical features of PD.3131. Guilarte TR. Manganese and Parkinson's disease: a critical review and new findings. Environ Health Perspect. 2010;118:1071-80. Maneb appears to cross the blood-brain barrier and inhibit mitochondrial complex III.3232. Zhang J, Fitsanakis VA, Gu G, Jing D, Ao M, Amarnath V, et al. Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. J Neurochem. 2003;84:336-46.,3333. Cicchetti F, Drouin-Ouellet J, Gross RE. Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci. 2009;30:475-83. The paraquat/maneb model can induce behavioral and motor impairments, significant dopamine-related degeneration, and altered responsiveness to dopamine therapy. Conversely, multiple variants of this animal model have been reported to evoke neither formation of Lewy bodies nor non-motor symptoms.3333. Cicchetti F, Drouin-Ouellet J, Gross RE. Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci. 2009;30:475-83. Moreover, some nonspecific and undesirable peripheral effects are reported, mainly in the lungs (respiratory distress), which limits utilization of these toxins.3333. Cicchetti F, Drouin-Ouellet J, Gross RE. Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci. 2009;30:475-83.

Genetic models

A large genome-analysis study has implicated 28 independent variants across 24 loci in the pathogenesis of familial PD.3131. Guilarte TR. Manganese and Parkinson's disease: a critical review and new findings. Environ Health Perspect. 2010;118:1071-80. Five genes associated with familial PD have been extensively studied and used as genetic models of PD in rodents: α-synuclein, PINK1, Parkin, DJ-1, and LRKK2.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503.,3434. Giraldez-Perez R, Antolin-Vallespin M, Munoz M, Sanchez-Capelo A. Models of alpha-synuclein aggregation in Parkinson's disease. Acta Neuropathol Commun. 2014;2:176.,3535. Asakawa T, Fang H, Sugiyama K, Nozaki T, Hong Z, Yang Y, et al. Animal behavioral assessments in current research of Parkinson's disease. Neurosci Biobehav Rev. 2016;65:63-94. Considering that the more prevalent forms of PD involve several genes and alterations in many gene functions,2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503.,3636. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46:989-93. monogenic models of PD would be expected to be less successful than toxin-induced models to evoke loss in the dopaminergic nigrostriatal pathway. However, genetic models are interesting tools to help to recognize whether a mutant gene is associated with the progression of PD in humans, verify the involvement of unknown genes in the disease, and understand the more common genetic mechanisms of PD.2626. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's Disease. Front Neurosci. 2015;9:503.

Several studies have demonstrated the contribution of genetic factors to PD development. A meta-analysis evaluated the interaction between the diagnosis of PD and risk factors. The strongest association with later diagnosis of PD was found for patients having a first-degree or any relative with PD, suggesting an increased risk of PD diagnosis in patients with a family history of PD.3737. Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol. 2012;72:893-901. Further convincing evidence for the contribution of genetic factors to PD was provided by the discovery of monogenic forms of the disease. The SNCA gene, which encodes α-synuclein, was the first to be associated with inherited PD.3838. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997;276:2045-7. Mutations in the LRRK2 and Parkin genes have been associated with dominantly and recessively inherited PD, respectively.3939. Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol Rev. 2011;91:1161-218.,4040. Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386:896-912. Currently, the most significant genetic risk factor for developing PD appears to be a mutation in the GBA gene, which encodes β-glucocerebrosidase.4040. Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386:896-912.,4141. Sidransky E, Lopez G. The link between the GBA gene and parkinsonism. Lancet Neurol. 2012;11:986-98.

Endocannabinoids and basal ganglia

Preclinical studies have suggested that endocannabinoid signaling plays an important role in basal ganglia circuitry.4242. Hermann H, Marsicano G, Lutz B. Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience. 2002;109:451-60.

43. Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature. 2007;445:643-7.

44. Papa SM. The cannabinoid system in Parkinson's disease: multiple targets to motor effects. Exp Neurol. 2008;211:334-8.
-4545. Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM. Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology. 2017;124:52-61. Endocannabinoids are neurotransmitters derived from membrane phospholipids produced on demand by enzymes expressed throughout the central nervous system (CNS).4646. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,4747. Lu HC, Mackie K. An introduction to the endogenous Cannabinoid system. Biol Psychiatry. 2016;79:516-25. The main endogenous ligands are anandamide (AEA) and 2-arachidonoylglycerol (2-AG).4646. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,4747. Lu HC, Mackie K. An introduction to the endogenous Cannabinoid system. Biol Psychiatry. 2016;79:516-25. Endocannabinoids bind both to subtype 1 (CB1) and 2 (CB2) cannabinoid receptors4646. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,4747. Lu HC, Mackie K. An introduction to the endogenous Cannabinoid system. Biol Psychiatry. 2016;79:516-25. AEA is synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and degraded by fatty acid amide hydrolase (FAAH),4646. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,4747. Lu HC, Mackie K. An introduction to the endogenous Cannabinoid system. Biol Psychiatry. 2016;79:516-25. while 2-AG is synthesized by diacylglycerol lipase (DGL) and degraded by monoacylglycerol lipase.4646. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,4747. Lu HC, Mackie K. An introduction to the endogenous Cannabinoid system. Biol Psychiatry. 2016;79:516-25.

In the striatum, CB1 is expressed at low levels in glutamatergic terminals and at high levels in GABAergic neurons in both D1 (substance P) and D2 (enkephalin) spiny projection neurons.4848. Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J Neurosci. 2007;27:3663-76. The co-localization of CB1 and GABAergic interneurons is controversial. Double-labeling in situ hybridization revealed that neither somatostatinergic nor cholinergic interneurons expressed CB1 receptors,4949. Hohmann AG, Herkenham M. Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience. 1999;90:923-31. while GABAergic immunohistochemistry showed high CB1 immunoreactivity in the perikarya and axons of parvalbuminergic interneurons, and low levels in nitric oxide synthase (NOS)/somatostatin-positive interneurons.4848. Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J Neurosci. 2007;27:3663-76. On the other hand, another study showed that the highest expression of CB1 occurs in calbindin interneurons, with less expression in parvalbumin-positive neurons.5050. Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci. 1999;11:4213-25. No CB1 immunostaining was found in calretinin or cholecystokinin neurons.4848. Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J Neurosci. 2007;27:3663-76.

AEA synthesized in striatal postsynaptic GABAergic neurons can act on glutamatergic presynaptic terminals,5151. Gerdeman G, Lovinger DM. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol. 2001;85:468-71. decreasing glutamate release from cortical areas.5252. Brotchie JM. CB1 cannabinoid receptor signalling in Parkinson's disease. Curr Opin Pharmacol. 2003;3:54-61. Striatal CB1 receptor stimulation is critical for long-term depression (LTD) in corticostriatal synapses,5252. Brotchie JM. CB1 cannabinoid receptor signalling in Parkinson's disease. Curr Opin Pharmacol. 2003;3:54-61.,5353. Gerdeman GL, Ronesi J, Lovinger DM. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci. 2002;5:446-51. thus reducing glutamatergic synaptic effectiveness. Dopaminergic neurons do not express CB1 receptors,5454. Fitzgerald ML, Shobin E, Pickel VM. Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:21-9. but the endocannabinoid system can interact indirectly with dopaminergic neurotransmission in the striatum, interfering with the control of voluntary movements.5555. Pisani V, Madeo G, Tassone A, Sciamanna G, Maccarrone M, Stanzione P, et al. Homeostatic changes of the endocannabinoid system in Parkinson's disease. Mov Disord. 2011;26:216-22.,5656. Fernandez-Ruiz J, Gonzales S. Cannabinoid control of motor function at the basal ganglia. Handb Exp Pharmacol. 2005;(168):479-507. Application of cannabinoid agonists to striatal slices produces either no effect or a decrease in electrical stimulation-evoked dopamine release,5757. Cadogan AK, Alexander SP, Boyd EA, Kendall DA. Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum. J Neurochem. 1997;69:1131-7.,5858. Kofalvi A, Rodrigues RJ, Ledent C, Mackie K, Vizi ES, Cunha RA, et al. Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci. 2005;25:2874-84. while systemic administration of a CB1 agonist leads to inhibition of dopamine release evoked by pulse-train stimulation of the medial forebrain bundle.5959. Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM. Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci. 2004;24:4393-400.

CB1 receptors in the striatum mediate motor deficits induced by cannabinoids.6060. Sanudo-Pena MC, Tsou K, Walker JM. Motor actions of cannabinoids in the basal ganglia output nuclei. Life Sci. 1999;65:703-13. The main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), exerts its effects in the CNS via activation of CB1 receptors.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. Consistent with effects on basal-ganglia function, CB1 activation by THC (or other cannabinoid agonists) alters motor performance in a dose-dependent manner, fluctuating from increased mobility6262. Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav. 1998;59:347-52.,6363. Sanudo-Pena MC, Romero J, Seale GE, Fernandez-Ruiz JJ, Walker JM. Activational role of cannabinoids on movement. Eur J Pharmacol. 2000;391:269-74. to inhibition of spontaneous activity,6464. Navarro M, Fernandez-Ruiz JJ, de Miguel R, Hernandez ML, Cebeira M, Ramos JA. An acute dose of delta 9-tetrahydrocannabinol affects behavioral and neurochemical indices of mesolimbic dopaminergic activity. Behav Brain Res. 1993;57:37-46.,6565. Shi LH, Luo F, Woodward DJ, Chang JY. Dose and behavioral context dependent inhibition of movement and basal ganglia neural activity by Delta-9-tetrahydrocannabinol during spontaneous and treadmill locomotion tasks in rats. Synapse. 2005;55:1-16. irregular locomotion, or even immobility (catalepsy).6262. Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav. 1998;59:347-52.,6666. Gough AL, Olley JE. Catalepsy induced by intrastriatal injections of delta9-THC and 11-OH-delta9-THC in the rat. Neuropharmacology. 1978;17:137-44.,6767. Onaivi ES, Chakrabarti A, Gwebu ET, Chaudhuri G. Neurobehavioral effects of delta 9-THC and cannabinoid (CB1) receptor gene expression in mice. Behav Brain Res. 1995;72:115-25.

On the other hand, CB1 receptor activation dampens amphetamine-induced hyperlocomotion, as well as the rise in dopamine and glutamate release in the striatum.6868. Polissidis A, Chouliara O, Galanopoulos A, Naxakis G, Papahatjis D, Papadopoulou-Daifoti Z, et al. Cannabinoids negatively modulate striatal glutamate and dopamine release and behavioural output of acute D-amphetamine. Behav Brain Res. 2014;270:261-9. Striatal CB1 receptors also decrease GABAergic input to dopaminergic neurons of the SNpc, thus modulating the firing activity of these neurons.6969. Lovinger DM. Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum. Neuropharmacology. 2010;58:951-61. Accordingly, it has been accepted that the endocannabinoid system modifies striatal functioning and interferes with motor control.

Cannabidiol and neuroprotection

Unlike THC, which elicits subjective effects by binding at CB1 receptors, cannabidiol (CBD), the main non-psychotomimetic component of Cannabis sp., has low affinity to cannabinoid receptors.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,7070. Bloomfield MA, Ashok AH, Volkow ND, Howes OD. The effects of Delta(9)-tetrahydrocannabinol on the dopamine system. Nature. 2016;539:369-77. CBD was isolated by Adams et al. in 19407171. Adams R, Madison H, Clark JH. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. J Am Chem Soc. 1940;62:196-200. and its structure was identified 23 years later by Mechoulam & Shvo.7272. Mechoulam R, Shvo Y. Hashish. I. The structure of cannabidiol. Tetrahedron. 1963;19:2073-8. The concentration of CBD in cannabis is highly variable, depending on plant phenotype, cultivation conditions, and which part of the plant is used to obtain the extract.7373. Fischedick JT, Hazekamp A, Erkelens T, Choi YH, Verpoorte R. Metabolic fingerprinting of cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry. 2010;71:2058-73.

CBD exerts a variety of effects in laboratory animals and humans, including sedative/hypnotic,7474. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl). 1982;76:245-50.,7575. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Braz J Psychiatry. 2008;30:271-80. anticonvulsant,7676. Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981;21:417S-27S.,7777. Verrotti A, Striano P, Iapadre G, Zagaroli L, Bonanni P, Coppola G, et al. The pharmacological management of Lennox-Gastaut syndrome and critical literature review. Seizure. 2018;63:17-25. neuroprotective,7878. Peres FF, Lima AC, Hallak JE, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol. 2018;9:482.,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology. 2019;146:1-11. cardiovascular,8080. McQueen DS, Bond SM, Smith PJ, Balali-Mood K, Smart D. Cannabidiol lacks the vanilloid VR1-mediated vasorespiratory effects of capsaicin and anandamide in anaesthetised rats. Eur J Pharmacol. 2004;491:181-9.,8181. Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A. 1999;96:14136-41. and anti-inflammatory.7878. Peres FF, Lima AC, Hallak JE, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol. 2018;9:482.,8282. Rajesh M, Mukhopadhyay P, Batkai S, Patel V, Saito K, Matsumoto S, et al. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 2010;56:2115-25. These actions do not seem to be dependent on cannabinoid receptors.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. Moreover, it is not completely understood whether these effects are related to CBD or to other organic compounds present in Cannabis extracts, such as myrcene and other terpenoids.8383. Russo EB. Cannabidiol claims and misconceptions. Trends Pharmacol Sci. 2017;38:198-201. Therefore, more studies using pure CBD are needed to confirm the effects of CBD in animals and humans.

CBD binds to cannabinoid receptors only at micromolar concentrations (≥ 10 µM),6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. acting as a low-potency agonist, inverse agonist, antagonist, or even as an allosteric modulator of the cannabinoid CB1 receptor.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8484. Howlett AC, Fleming RM. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol. 1984;26:532-8.,8585. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172:4790-805. Some CBD effects are antagonized by CB1 receptor inverse agonists,6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. suggesting this drug may exert “indirect agonism” at CB1 receptors. Studies show that CBD can increase AEA concentration by blocking the AEA membrane transporter (AMT) or the FAAH enzyme, which catalyzes AEA hydrolysis.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8686. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845-52.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. CBD also enhances membrane fluidity,8888. Howlett AC, Scott DK, Wilken GH. Regulation of adenylate cyclase by cannabinoid drugs. Insights based on thermodynamic studies. Biochem Pharmacol. 1989;38:3297-304. increases 2-AG levels,8989. Maione S, Piscitelli F, Gatta L, Vita D, De Petrocellis L, Palazzo E, et al. Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol. 2011;162:584-96. and upregulates CB1 receptor expression.9090. Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernandez-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. J Neurosci Res. 2011;89:1509-18.

Several studies have demonstrated the neuroprotective properties of the CBD in different conditions, such as newborn hypoxic-ischemic encephalopathy,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology. 2019;146:1-11. chronic cerebral hypoperfusion,9191. Santiago AN, Mori MA, Guimaraes FS, Milani H, Weffort de Oliveira RM. Effects of cannabidiol on diabetes outcomes and chronic cerebral hypoperfusion comorbidities in middle-aged rats. Neurotox Res. 2019;35:463-74. neonatal iron overload,9292. da Silva VK, de Freitas BS, Garcia RC, Monteiro RT, Hallak JE, Zuardi AW, et al. Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload. Transl Psychiatry. 2018;8:176. and kainic acid-induced seizures.9393. Friedman LK, Wongvravit JP. Anticonvulsant and neuroprotective effects of cannabidiol during the juvenile period. J Neuropathol Exp Neurol. 2018;77:904-19. The neuroprotective properties of CBD do not appear to depend on direct activation of CB1 receptors,9494. Fernandez-Ruiz J, Sagredo O, Pazos MR, Garcia C, Pertwee R, Mechoulam R, et al. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol. 2013;75:323-33. but can be related to a reduction in glutamate excitotoxicity and oxidative stress,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology. 2019;146:1-11. neuroinflammation decrease,9191. Santiago AN, Mori MA, Guimaraes FS, Milani H, Weffort de Oliveira RM. Effects of cannabidiol on diabetes outcomes and chronic cerebral hypoperfusion comorbidities in middle-aged rats. Neurotox Res. 2019;35:463-74. anti-apoptotic action,9292. da Silva VK, de Freitas BS, Garcia RC, Monteiro RT, Hallak JE, Zuardi AW, et al. Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload. Transl Psychiatry. 2018;8:176. or modulation/polarization of glial cells.9393. Friedman LK, Wongvravit JP. Anticonvulsant and neuroprotective effects of cannabidiol during the juvenile period. J Neuropathol Exp Neurol. 2018;77:904-19.

In spite of the involvement of CB2 receptors in the neuroprotective effect of CBD in a model of hypoxic-ischemic in newborn mice,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology. 2019;146:1-11. the possibility of its direct action at these receptors remains controversial.8686. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845-52.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. CBD also interacts with several other targets.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. One of them is a family of ionotropic receptors permeable to monovalent cations and calcium named transient receptor potential vanilloid (TRPV).8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215.,9595. Harteneck C, Plant TD, Schultz G. From worm to man: three subfamilies of TRP channels. Trends Neurosci. 2000;23:159-66. At low concentrations (sub-micromolar scale), CBD binds to equilibrative nucleoside transporter (ENT), transient receptor potential melastatin type 8 (TRPM8), serotonin 1A receptor (5-HT1A), glycine receptors A1 and A3, and transient receptor potential ankyrin type-1 (TRPA1).4646. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-84.,6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. On the other hand, at high concentrations (micromolar scale), CBD activates TRPV2, TRPV3, and TRPV4 receptors and peroxisome proliferator-activated receptor-γ (PPAR-γ).6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. CBD is also an antagonist of the orphan receptor GPR559696. Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092-101. and it may also increase intracellular calcium in physiological conditions but decrease it under high neuronal excitability conditions.6161. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215.

Cannabidiol and Parkinson’s disease

Preclinical studies

Several in vitro experiments have demonstrated promising neuroprotective effects of CBD in PD models. In one of these models, using PC12 and SH-SY5Y cells treated with MPP+, CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. These neuroprotective effects depended on the activation of tropomyosin receptor kinase A (TrkA) receptors.9797. Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, Queiroz RH, et al. The neuroprotection of cannabidiol against MPP(+)-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease. Toxicol In Vitro. 2015;30:231-40. CBD also protected SH-SY5Y cells against LPS- and β-amyloid-induced decreases in cell viability, while increasing the viability of SH-SY5Y cells incubated with conditioned media derived from microglia previously activated with LPS.9898. Janefjord E, Maag JL, Harvey BS, Smid SD. Cannabinoid effects on beta amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell Mol Neurobiol. 2014;34:31-42. In another study, CBD blunted ATP-induced increases in intracellular calcium and LPS-evoked nitrite generation in both N13 microglial cells and rat primary microglia. The authors suggested that the reduction of microglial cell activation promoted by CBD depends on both cannabinoid and adenosine receptors.9999. Martin-Moreno AM, Reigada D, Ramirez BG, Mechoulam R, Innamorato N, Cuadrado A, et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol. 2011;79:964-73.

In vivo studies, however, have produced conflicting results. A neurotoxic model of PD using MPTP demonstrated that administration of CBD (5 mg/kg) for 5 weeks did not reduce motor deficits or dopaminergic neuronal loss in the nigrostriatal pathway.100100. Celorrio M, Fernandez-Suarez D, Rojo-Bustamante E, Echeverry-Alzate V, Ramirez MJ, Hillard CJ, et al. Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson's disease. Brain Behav Immun. 2016;57:94-105. On the other hand, daily administration of CBD (3 mg/kg) for 14 days decreased both dopamine depletion and tyrosine hydroxylase expression within the striatum of rats that received 6-OHDA.101101. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease. Neurobiol Dis. 2005;19:96-107. These neuroprotective effects were associated with an upregulation of mRNA levels of Cu2+/Zn superoxide dismutase, a key enzyme necessary for the endogenous control of oxidative stress.102102. Garcia-Arencibia M, Gonzalez S, de Lago E, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res. 2007;1134:162-70.

Beyond these neuroprotective effects, one study suggested a putative antidyskinetic effect of CBD in hemiparkinsonian mice chronically treated with L-DOPA. Of note, although CBD administration does not reduce L-DOPA-induced dyskinesia, when combined with the TRPV1 receptor antagonist capsazepine, a significant antidyskinetic effect was observed (capsazepine alone also failed to decrease dyskinesia).103103. Dos-Santos-Pereira M, da-Silva CA, Guimaraes FS, Del-Bel E. Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: possible mechanism of action. Neurobiol Dis. 2016;94:179-95. CBD also prevented cataleptic behavior induced by repeated administration of reserpine9191. Santiago AN, Mori MA, Guimaraes FS, Milani H, Weffort de Oliveira RM. Effects of cannabidiol on diabetes outcomes and chronic cerebral hypoperfusion comorbidities in middle-aged rats. Neurotox Res. 2019;35:463-74. or haloperidol. In the latter case, CBD also produced a reduction in c-Fos protein expression in the dorsal striatum via activation of 5-HT1A serotonin receptors.104104. Sonego AB, Gomes FV, Del Bel EA, Guimaraes FS. Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice. Behav Brain Res. 2016;309:22-8.,105105. Gomes FV, Del Bel EA, Guimaraes FS. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:43-7.

Clinical studies

An open-label pilot study conducted in PD patients showed that oral doses of CBD ranging from 150-400 mg/day, combined with classic antiparkinsonian agents, reduced psychotic symptoms evaluated by different scales (the Brief Psychiatric Rating Scale [BPRS] and the Parkinson Psychosis Questionnaire [PPQ]) with no influence on cognitive and motor signs and no severe side effects.106106. Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH, Rodrigues GG, et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol. 2009;23:979-83. In a case series with four patients, CBD reduced the frequency of events related to REM sleep behavior disorder.107107. Chagas MH, Eckeli AL, Zuardi AW, Pena-Pereira MA, Sobreira-Neto MA, Sobreira ET, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J Clin Pharm Ther. 2014;39:564-6.

In a subsequent clinical trial, 300 mg/day of CBD improved mobility, emotional well-being, cognition, communication, and body discomfort compared to placebo. The authors suggest that this effect might be related to the anxiolytic, antidepressant, and antipsychotic properties of CBD.108108. Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, et al. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28:1088-98. Since CBD is well tolerated in humans, these positive effects suggest it could be a promising alternative for PD pharmacotherapy.

Therefore, double-blind, placebo-controlled, randomized trials with larger samples of patients with PD are needed to elucidate the possible effectiveness and mechanisms involved in the therapeutic potential of CBD in this movement disorder. This will also include the putative effects of CBD in preventing L-DOPA-induced severe side effects and preventing PD progression. Additionally, studies conducted specifically to evaluate the safety profile of CBD in patients with PD (including long-term safety), possible interactions with other antiparkinsonian drugs, and possible side effects, as well as the therapeutic window for motor and non-motor PD symptoms are also required.

Acknowledgements

This study was supported in part by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grant 2015/05551-0 awarded to ACC); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Fundação de Apoio ao Ensino, Pesquisa e Assistência (FAEPA), Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP); Núcleo de Apoio à Pesquisa em Neurociência Aplicada (NAPNA), USP; and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM; CNPq/FAPESP).

FSG, JAC, and AWZ are recipients of CNPq 1A productivity fellowships. ACC is recipient of CNPq 2 productivity fellowship. ED-B is recipient of CNPq productivity fellowship. JAC has received travel support from and is medical advisor of SCBD Centre; and has received a grant from University Global Partnership Network (UGPN) – “Global priorities in cannabinoid research excellence.” JAC is member of the international advisory board of The Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), funded by the National Health and Medical Research Council through the Centre of Research Excellence).

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Publication Dates

  • Publication in this collection
    15 July 2019
  • Date of issue
    Mar-Apr 2020

History

  • Received
    20 Feb 2019
  • Accepted
    8 Apr 2019
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