Advertisement

Is cannabidiol the ideal drug to treat non-motor Parkinson’s disease symptoms?

  • José Alexandre S. CrippaEmail author
  • Jaime E. C. Hallak
  • Antônio W. Zuardi
  • Francisco S. Guimarães
  • Vitor Tumas
  • Rafael G. dos Santos
Invited Review

Abstract

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options. Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD. In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD. We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia). We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD. We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.

Keywords

Parkinson’s disease Non-motor symptoms Cannabinoids Cannabidiol 

Notes

Acknowledgements

The authors are thankful to Dr. José Diogo de Souza and Mr. Luíz Avanzo for the preparation of the Figure. JAC, JEH, AWZ, and FSG are recipients of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) 1A productivity fellowships. Research was supported in part by Grants from (1) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); (2) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); (3) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); (4) Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA, Brazil); (5) Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil (NAPNA); and (6) National Institute for Translational Medicine (INCT-TM; CNPq/FAPESP, Brazil).

Compliance with ethical standards

Conflict of interest

JAC, JH, FSG, and AWZ are co-inventors (Mechoulam R, Crippa JA, Guimaraes FS, Zuardi A, Hallak, JE, and Breuer A) of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023” Def. US no. Reg. 62193296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders”. JAC and JEH have received travel support from and are medical advisors of BSPG-Pharm. JAC has a Grant from University Global Partnership Network (UGPN)—Global priorities in cannabinoid research excellence. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. 1.
    World Health Organization (WHO) (2006) Neurological disorders: public health challenges. WHO Press, GenevaGoogle Scholar
  2. 2.
    Giacoppo S, Mandolino G, Galuppo M et al (2014) Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 19:18781–18816CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stampanoni Bassi M, Sancesario A, Morace R et al (2017) Cannabinoids in Parkinson’s disease. Cannabis Cannabinoid Res 2:21–29CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Di Marzo V, Hill MP, Bisogno T et al (2000) Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson’s disease. FASEB J 14:1432–1438PubMedGoogle Scholar
  5. 5.
    Lastres-Becker I, Cebeira M, de Ceballos ML et al (2001) Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson’s syndrome and of MPTP-treated marmosets. Eur J Neurosci 14:1827–1832CrossRefPubMedGoogle Scholar
  6. 6.
    Silverdale MA, McGuire S, McInnes A et al (2001) Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson’s disease. Exp Neurol 169:400–406CrossRefPubMedGoogle Scholar
  7. 7.
    Brotchie JM (2003) CB1 cannabinoid receptor signalling in Parkinson’s disease. Curr Opin Pharmacol 3:54–61CrossRefPubMedGoogle Scholar
  8. 8.
    Farkas S, Nagy K, Jia Z et al (2012) The decrease of dopamine D2/D3 receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB1 cannabinoid receptors in Parkinson’s disease: a preliminary autoradiographic study with the selective dopamine D2/D3 antagonist [3H]raclopride and the novel CB1 inverse agonist [125I]SD7015. Brain Res Bull 87:504–510CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gómez-Gálvez Y, Palomo-Garo C, Fernández-Ruiz J et al (2016) Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 64:200–208CrossRefPubMedGoogle Scholar
  10. 10.
    Maneuf YP, Crossman AR, Brotchie JM (1997) The cannabinoid receptor agonist WIN 55,212-2 reduces D2, but not D1, dopamine receptor-mediated alleviation of akinesia in the reserpine-treated rat model of Parkinson’s disease. Exp Neurol 148:265–270CrossRefPubMedGoogle Scholar
  11. 11.
    Fox SH, Henry B, Hill M et al (2002) Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson’s disease. Mov Disord 17:1180–1187CrossRefPubMedGoogle Scholar
  12. 12.
    González S, Mena MA, Lastres-Becker I et al (2005) Cannabinoid CB(1) receptors in the basal ganglia and motor response to activation or blockade of these receptors in parkin-null mice. Brain Res 1046:195–206CrossRefPubMedGoogle Scholar
  13. 13.
    Lastres-Becker I, Molina-Holgado F, Ramos J et al (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19:96–107CrossRefPubMedGoogle Scholar
  14. 14.
    Cao X, Liang L, Hadcock JR et al (2007) Blockade of cannabinoid type 1 receptors augments the antiparkinsonian action of levodopa without affecting dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys. J Pharmacol Exp Ther 323:318–326CrossRefPubMedGoogle Scholar
  15. 15.
    Morgese MG, Cassano T, Cuomo V et al (2007) Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson’s disease: role of CB(1) and TRPV1 receptors. Exp Neurol 208:110–119CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    García-Arencibia M, Ferraro L, Tanganelli S et al (2008) Enhanced striatal glutamate release after the administration of rimonabant to 6-hydroxydopamine-lesioned rats. Neurosci Lett 438:10–13CrossRefPubMedGoogle Scholar
  17. 17.
    van Vliet SA, Vanwersch RA, Jongsma MJ et al (2008) Therapeutic effects of Delta9-THC and modafinil in a marmoset Parkinson model. Eur Neuropsychopharmacol 18:383–389CrossRefGoogle Scholar
  18. 18.
    Price DA, Martinez AA, Seillier A et al (2009) WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur J Neurosci 29:2177–2186CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Walsh S, Gorman AM, Finn DP et al (2010) The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats. Brain Res 1363:40–48CrossRefPubMedGoogle Scholar
  20. 20.
    Chung YC, Bok E, Huh SH et al (2011) Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation. J Immunol 187:6508–6517CrossRefPubMedGoogle Scholar
  21. 21.
    García C, Palomo-Garo C, García-Arencibia M et al (2011) Symptom-relieving and neuroprotective effects of the phytocannabinoid ∆9-THCV in animal models of Parkinson’s disease. Br J Pharmacol 163:1495–1506CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Carroll CB, Zeissler ML, Hanemann CO et al (2012) ∆9-tetrahydrocannabinol (∆9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol Appl Neurobiol 38:535–547CrossRefPubMedGoogle Scholar
  23. 23.
    Martinez A, Macheda T, Morgese MG et al (2012) The cannabinoid agonist WIN55212-2 decreases L-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats. Neurosci Res 72:236–242CrossRefPubMedGoogle Scholar
  24. 24.
    Gutiérrez-Valdez AL, García-Ruiz R, Anaya-Martínez V et al (2013) The combination of oral L-DOPA/rimonabant for effective dyskinesia treatment and cytological preservation in a rat model of Parkinson’s disease and L-DOPA-induced dyskinesia. Behav Pharmacol 24:640–652CrossRefPubMedGoogle Scholar
  25. 25.
    Benbadis SR, Sanchez-Ramos J, Bozorg A et al (2014) Medical marijuana in neurology. Expert Rev Neurother 14:1453–1465CrossRefPubMedGoogle Scholar
  26. 26.
    Koppel BS, Brust JC, Fife T et al (2014) Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82:1556–1563CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Arjmand S, Vaziri Z, Behzadi M et al (2015) Cannabinoids and tremor induced by motor-related disorders: friend or foe? Neurotherapeutics 12:778–787CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Catlow B, Sanchez-Ramos J (2015) Cannabinoids for the treatment of movement disorders. Curr Treat Options Neurol 17:370CrossRefPubMedGoogle Scholar
  29. 29.
    Fernández-Ruiz J, Romero J, Ramos J (2015) Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, and others. Handb Exp Pharmacol 231:233–259CrossRefPubMedGoogle Scholar
  30. 30.
    Sieradzan KA, Fox SH, Hill M et al (2001) Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 57:2108–2111CrossRefPubMedGoogle Scholar
  31. 31.
    Fox SH, Kellett M, Moore AP et al (2002) Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Mov Disord 17:145–149CrossRefPubMedGoogle Scholar
  32. 32.
    Carroll CB, Bain PG, Teare L et al (2004) Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology 63:1245–1250CrossRefPubMedGoogle Scholar
  33. 33.
    Mesnage V, Houeto JL, Bonnet AM et al (2004) Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson disease. Clin Neuropharmacol 27:108–110CrossRefPubMedGoogle Scholar
  34. 34.
    Venderová K, Růzicka E, Vorísek V et al (2004) Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms. Mov Disord 19:1102–1106CrossRefPubMedGoogle Scholar
  35. 35.
    Finseth TA, Hedeman JL, Brown RP 2nd et al (2015) Self-reported efficacy of cannabis and other complementary medicine modalities by Parkinson’s disease patients in Colorado. Evid Based Complement Altern Med 874849:6Google Scholar
  36. 36.
    Balash Y, Bar-Lev Schleider L, Korczyn AD et al (2017) Medical cannabis in Parkinson disease: real-life patients’ experience. Clin Neuropharmacol 40:268–272CrossRefPubMedGoogle Scholar
  37. 37.
    Lotan I, Treves TA, Roditi Y et al (2014) Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol 37:41–44CrossRefPubMedGoogle Scholar
  38. 38.
    García-Arencibia M, González S, de Lago E et al (2007) 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 1134:162–170CrossRefPubMedGoogle Scholar
  39. 39.
    Casarejos MJ, Perucho J, Gomez A et al (2013) Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J Alzheimers Dis 35:525–539CrossRefPubMedGoogle Scholar
  40. 40.
    Gomes FV, Del Bel EA, Guimaraes FS (2013) Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Prog Neuropsychopharmacol Biol Psychiatry 46:43–47CrossRefPubMedGoogle Scholar
  41. 41.
    dos-Santos-Pereira M, da-Silva CA, Guimarães FS et al (2016) Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: possible mechanism of action. Neurobiol Dis 94:179–195CrossRefGoogle Scholar
  42. 42.
    Peres FF, Levin R, Suiama MA et al (2016) Cannabidiol prevents motor and cognitive impairments induced by reserpine in rats. Front Pharmacol 7:343PubMedPubMedCentralGoogle Scholar
  43. 43.
    Zuardi AW, Crippa JA, Hallak JE et al (2009) Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol 23:979–983CrossRefPubMedGoogle Scholar
  44. 44.
    Chagas MH, Zuardi AW, Tumas V et al (2014) Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol 28:1088–1098CrossRefPubMedGoogle Scholar
  45. 45.
    Chagas MH, Eckeli AL, Zuardi AW et al (2014) 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 39:564–566CrossRefPubMedGoogle Scholar
  46. 46.
    Vanle B, Olcott W, Jimenez J et al (2018) NMDA antagonists for treating the non-motor symptoms in Parkinson’s disease. Transl Psychiatry 8:117CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zuardi AW, Crippa JA, Hallak JE et al (2012) A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr Pharm Des 18:5131–5140CrossRefGoogle Scholar
  48. 48.
    Schubart CD, Sommer IE, Fusar-Poli P et al (2014) Cannabidiol as a potential treatment for psychosis. Eur Neuropsychopharmacol 24:51–64CrossRefPubMedGoogle Scholar
  49. 49.
    Iseger TA, Bossong MG (2015) A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr Res 162:153–161CrossRefPubMedGoogle Scholar
  50. 50.
    Fakhoury M (2016) Could cannabidiol be used as an alternative to antipsychotics? J Psychiatr Res 80:14–21CrossRefPubMedGoogle Scholar
  51. 51.
    Gururajan A, Malone DT (2016) Does cannabidiol have a role in the treatment of schizophrenia? Schizophr Res 176:281–290CrossRefPubMedGoogle Scholar
  52. 52.
    Guimarães VM, Zuardi AW, Del Bel EA et al (2004) Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum. Life Sci 75:633–638CrossRefPubMedGoogle Scholar
  53. 53.
    Leweke FM, Piomelli D, Pahlisch F et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    McGuire P, Robson P, Cubala WJ et al (2018) Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry 175:225–231CrossRefPubMedGoogle Scholar
  55. 55.
    Schier AR, Ribeiro NP, Silva AC et al (2012) Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Rev Bras Psiquiatr 34:S104–S110CrossRefPubMedGoogle Scholar
  56. 56.
    Blessing EM, Steenkamp MM, Manzanares J et al (2015) Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12:825–836CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zlebnik NE, Cheer JF (2016) Beyond the CB1 receptor: is cannabidiol the answer for disorders of motivation? Annu Rev Neurosci 39:1–17CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Soares VP, Campos AC (2017) Evidences for the anti-panic actions of cannabidiol. Curr Neuropharmacol 15:291–299CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Zuardi AW, Cosme RA, Graeff FG et al (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 7:82–88CrossRefPubMedGoogle Scholar
  60. 60.
    Crippa JA, Zuardi AW, Garrido GE et al (2004) Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 29:417–426CrossRefPubMedGoogle Scholar
  61. 61.
    Bhattacharyya S, Morrison PD, Fusar-Poli P et al (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774CrossRefGoogle Scholar
  62. 62.
    Zuardi AW, Rodrigues NP, Silva AL et al (2017) Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol 8:259CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Bergamaschi MM, Queiroz RH, Chagas MH et al (2011) Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 36:1219–1226CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Crippa JA, Derenusson GN, Ferrari TB et al (2011) Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol 25:121–130CrossRefPubMedGoogle Scholar
  65. 65.
    Mandolini GM, Lazzaretti M, Pigoni A et al (2018) Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview. Epidemiol Psychiatr Sci 27:327–335CrossRefPubMedGoogle Scholar
  66. 66.
    Chagas MH, Crippa JA, Zuardi AW et al (2013) Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. J Psychopharmacol 27:312–316CrossRefPubMedGoogle Scholar
  67. 67.
    Gates PJ, Albertella L, Copeland J (2014) The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev 18:477–487CrossRefGoogle Scholar
  68. 68.
    Murillo-Rodríguez E, Sánchez D, Tejeda-Padrón A et al (2014) Potential effects of cannabidiol as a wake-promoting agent. Curr Neuropharmacol 12:269–272CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Babson KA, Sottile J, Morabito D (2017) Cannabis, cannabinoids, and sleep: a review of the literature. Curr Psychiatry Rep 19:23CrossRefPubMedGoogle Scholar
  70. 70.
    Linares IMP, Crippa JAS, Chagas MHN (2017) Beneficial effects of cannabis and related compounds on sleep. In: Preedy V (ed) Handbook of cannabis and related pathologies: biology, pharmacology, diagnosis, and treatment, 1st edn. Academic Press, London, pp 877–882CrossRefGoogle Scholar
  71. 71.
    Carlini EA, Cunha JM (1981) Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol 21:S417–S427CrossRefGoogle Scholar
  72. 72.
    Linares IMP, Guimaraes FS, Eckeli A et al (2018) No acute effects of cannabidiol on the sleep-wake cycle of healthy subjects: a randomized, double-blind, placebo-controlled, crossover study. Front Pharmacol 9:315CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Nicholson AN, Turner C, Stone BM et al (2004) Effect of delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol 24:305–313CrossRefPubMedGoogle Scholar
  74. 74.
    Peres FF, Lima AC, Hallak JEC et al (2018) Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol 9:482CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Campos AC, Fogaça MV, Scarante FF et al (2017) Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol 8:269CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Little JP, Villanueva EB, Klegeris A (2011) Therapeutic potential of cannabinoids in the treatment of neuroinflammation associated with Parkinson’s disease. Mini Rev Med Chem 11:582–590CrossRefPubMedGoogle Scholar
  77. 77.
    Bergamaschi M, Queiroz RH, Zuardi AW et al (2011) Safety and side effects of cannabidiol, a Cannabis sativa. Curr Drug Saf 6:237–249CrossRefGoogle Scholar
  78. 78.
    Kerstin I, Grotenhermen F (2017) An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res 2:139–154CrossRefGoogle Scholar
  79. 79.
    Solowij N, Broyd SJ, Beale C et al (2018) Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: a pragmatic open-label clinical trial. Cannabis Cannabinoid Res 3:21–34CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Beiske AG, Loge JH, Ronningen A et al (2009) Pain in Parkinson’s disease: prevalence and characteristics. Pain 141:173–177CrossRefPubMedGoogle Scholar
  81. 81.
    Nègre-Pagès L, Regragui W, Bouhassira D et al (2008) Chronic pain in Parkinson’s disease: the cross-sectional French DoPaMiP survey. Mov Disord 23:1361–1369CrossRefPubMedGoogle Scholar
  82. 82.
    Politis M, Wu K, Molloy S et al (2010) Parkinson’s disease symptoms: the patient’s perspective. Mov Disord 25:1646–1651CrossRefPubMedGoogle Scholar
  83. 83.
    Silverdale MA, Kobylecki C, Kass-Iliyya L et al (2018) A detailed clinical study of pain in 1957 participants with early/moderate Parkinson’s disease. Parkinsonism Relat Disord.  https://doi.org/10.1016/j.parkreldis.2018.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Costa B, Trovato AE, Comelli F et al (2007) The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol 556:75–83CrossRefPubMedGoogle Scholar
  85. 85.
    Ward SJ, Ramirez MD, Neelakantan H et al (2011) Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female c57bl6 mice. Anesth Analg 113:947–950CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Genaro K, Fabris D, Arantes ALF et al (2017) Cannabidiol is a potential therapeutic for the affective-motivational dimension of incision pain in rats. Front Pharmacol 8:391CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Mücke M, Phillips T, Radbruch L et al (2018) Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 3:CD012182Google Scholar
  88. 88.
    Cuñetti L, Manzo L, Peyraube R et al (2018) Chronic pain treatment with cannabidiol in kidney transplant patients in Uruguay. Transplant Proc 50:461–464CrossRefPubMedGoogle Scholar
  89. 89.
    Howick J, Chalmers I, Glasziou P et al (2011) The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed 31 July 2018
  90. 90.
    Wise J (2018) FDA approves its first cannabis based medicine. BMJ 361:k2827CrossRefPubMedGoogle Scholar
  91. 91.
    Corroon J, Philips JA (2018) A cross-sectional study of cannabidiol users. Cannabis Cannabinoid Res 3:152–161CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Horth RZ, Crouch B, Horowitz BZ et al (2018) Notes from the field: acute poisonings from a synthetic cannabinoid sold as cannabidiol—Utah, 2017–2018. MMWR Morb Mortal Wkly Rep 67:587–588CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurosciences and BehaviorRibeirão Preto Medical School, University of São PauloRibeirão PretoBrazil
  2. 2.National Institute of Science and Technology-Translational MedicineRibeirão PretoBrazil
  3. 3.Department of PharmacologyRibeirão Preto Medical School, University of São PauloRibeirão PretoBrazil
  4. 4.Hospital das ClínicasRibeirão PretoBrazil

Personalised recommendations