Advertisement

CNS Drugs

, Volume 32, Issue 8, pp 697–712 | Cite as

Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System

  • Patrícia Schonhofen
  • Ivi Juliana Bristot
  • José Alexandre Crippa
  • Jaime Eduardo Cecílio Hallak
  • Antônio Waldo Zuardi
  • Richard B. Parsons
  • Fábio Klamt
Current Opinion

Abstract

The endocannabinoid retrograde signaling pathway is widely expressed in the central nervous system, where it plays major roles in regulating synaptic plasticity (excitatory and inhibitory) through long-term potentiation and long-term depression. The endocannabinoid system (ECS) components—cannabinoid receptors, endocannabinoids and synthesis/degradation enzymes—are expressed and are functional from early developmental stages and throughout adolescent cortical development, regulating progenitor cell fate, neural differentiation, migration and survival. This may potentially confer increased vulnerability to adverse outcomes from early cannabinoid exposure. Cannabidiol (CBD) is one of the most studied exogenous cannabinoids, and CBD-enriched Cannabis extracts have been widely (and successfully) used as adjuvants to treat children with refractory epilepsy, and there is even a Food and Drug Administration (FDA)-approved drug with purified CBD derived from Cannabis. However, there is insufficient information on possible long-term changes in the central nervous system caused by cannabinoid treatments during early childhood. Like the majority of cannabinoids, CBD is able to exert its effects directly and indirectly through the ECS, which can perturb the regulatory processes mediated by this system. In addition, CBD has a large number of non-endocannabinoid targets, which can explain CBD’s effects. Here, we review the current knowledge about CBD-based therapies—pure and CBD-enriched Cannabis extracts—in studies with pediatric patients, their side effects, and their mechanisms of action regarding the central nervous system and neurodevelopment aspects. Since Cannabis extracts contain Δ9-tetrahydrocannabinol (Δ9-THC), we consider that pure CBD is possibly safer for young patients. Nevertheless, CBD, as well as other natural and/or synthetic cannabinoids, should be studied in more detail as a therapeutic alternative to CBD-enriched Cannabis extracts for young patients.

Notes

Acknowledgements

AWZ, JECH, FK and JAC are recipients of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil). This review was supported by the Brazilian funds CNPq/MS/SCTIE/DECIT Pesquisas Sobre Doenças Neurodegenerativas (466989/2014-8), CNPq/MS/SCTIE/DECIT No 26/2014 – Pesquisas sobre Distúrbios Neuropsiquiátricos (466805/2014-4) and INCT-TM/CNPq/FAPESP (465458/2014-9). PS wishes to acknowledge Marco Antonio de Bastiani, MSc for helpful comments made during the preparation of the manuscript.

Compliance with Ethical Standards

Funding

This review was supported by the Brazilian funds CNPq/MS/SCTIE/DECIT Pesquisas Sobre Doenças Neurodegenerativas (466989/2014-8), CNPq/MS/SCTIE/DECIT N 26/2014 – Pesquisas sobre Distúrbios Neuropsiquiátricos (466805/2014-4) and INCT-TM/CNPq/FAPESP (465458/2014-9). AWZ, JECH, FK and JAC are recipients of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil).

Conflict of interest

AWZ, JECH and JAC are co-inventors 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.” JECH and JAC have received travel support from and are medical advisors of BSPG-Pharm. AWZ is medical advisor of BSPG-Pharm. PS, FK, IJB, RBP declare no conflics of interest.

Supplementary material

40263_2018_550_MOESM1_ESM.pdf (147 kb)
Supplementary material 1 (PDF 147 kb)

References

  1. 1.
    Cassol-jr OJ, Comim CM, Silva BR, Hermani F V, Constantino LS, Felisberto F, et al. Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture. Brain Res [Internet]. 2010;1348:128–38. 10.1016/j.brainres.2010.06.023.Google Scholar
  2. 2.
    Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9—tetrahydrocannabinol in man. Eur J Pharmacol [Internet]. 1974;28:172–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Grlic L. A comparative study on some chemical and biological characteristics of various samples of cannabis resin. Bull Narcot. 1976;14:37–46.Google Scholar
  4. 4.
    Gaoni Y, Mechoulam R. Isolation and structure of Δ+ -tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc. 1971;93:217–24.CrossRefPubMedGoogle Scholar
  5. 5.
    Howlett AC, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. 2010;17:1382–93.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Luchicchi A, Pistis M. Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol. 2012;46:374–92.CrossRefPubMedGoogle Scholar
  7. 7.
    Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick MR, International Union of Basic and Clinical Pharmacology, et al. LXXIX. Cannabinoid receptors and their ligands: beyond CB 1 and CB 2. Pharmacol Rev. 2010;62:588–631.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc B Biol Sci. 2012;367:3353–63.CrossRefGoogle Scholar
  9. 9.
    Di Marzo V, De Petrocellis L. Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc B Biol Sci. 2012;367:3216–28.CrossRefGoogle Scholar
  10. 10.
    Lu HC, MacKie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Ibeas Bih C, Chen T, Nunn AVW, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders [Internet]. Neurotherapeutics. 2015.  https://doi.org/10.1007/s13311-015-0377-3.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2017;2:139–54.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wong SS, Wilens TE. Medical cannabinoids in children and adolescents: a systematic review. Pediatr Am Acad Pediatr. 2017;140:e20171818.Google Scholar
  14. 14.
    Health Reform and State Health Legislative Initiatives. State medical marijuana laws. 2018. http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx#. Accessed 18 Jan 2018.
  15. 15.
    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol [Internet]. 2015;15:270–8.  https://doi.org/10.1016/S1474-4422(15)00379-8.CrossRefPubMedGoogle Scholar
  16. 16.
    Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology [Internet]. 2018;90:e1204–11.Google Scholar
  17. 17.
    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol [Internet]. 2016;15:270–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy. Seizure [Internet]. 2016;35:41–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Hussain SA, Zhou R, Jacobson C, Weng J, Cheng E, Lay J, et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: a potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav [Internet]. 2015;47:138–41.  https://doi.org/10.1016/j.yebeh.2015.04.009.CrossRefPubMedGoogle Scholar
  20. 20.
    Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav [Internet]. 2015;45:49–52.CrossRefPubMedGoogle Scholar
  21. 21.
    O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav. 2017;70:341–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med [Internet]. 2017;376:2011–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21–47.CrossRefPubMedGoogle Scholar
  24. 24.
    Dow-Edwards D, Silva L. Endocannabinoids in brain plasticity: cortical maturation, HPA axis function and behavior. Brain Res [Internet]. 2017;1654:157–64.CrossRefPubMedGoogle Scholar
  25. 25.
    Definitions of weights of evidence. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. 2017. http://nationalacademies.org/hmd/~/media/Files/Report%20Files/2017/Cannabis-Health-Effects/Cannabis-conclusions.pdf. Accessed 12 June 2018.
  26. 26.
    Morales P, Hurst DP, Reggio PH. Molecular targets of the phytocannabinoids: a complex picture. Prog Chem Org Nat Prod. 2017;103:103–31.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Meyer HC, Lee FS, Gee DG. The role of the endocannabinoid system and genetic variation in adolescent brain development. Neuropsychopharmacology. 2017;43:21–33.CrossRefPubMedGoogle Scholar
  28. 28.
    Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol [Internet]. 2002;68:247–86.CrossRefPubMedGoogle Scholar
  29. 29.
    Velasco G, Sánchez C, Guzmán M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer [Internet]. 2012;12:436–44.CrossRefPubMedGoogle Scholar
  30. 30.
    Fowler CJ. Transport of endocannabinoids across the plasma membrane and within the cell. FEBS J. 2013;280:1895–904.CrossRefPubMedGoogle Scholar
  31. 31.
    Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci [Internet]. 2004;5:173–83.  https://doi.org/10.1038/nrn1346.CrossRefPubMedGoogle Scholar
  32. 32.
    Silva-Cruz A, Carlström M, Ribeiro JA, Sebastião AM. Dual influence of endocannabinoids on long-term potentiation of synaptic transmission. Front Pharmacol [Internet]. 2017;8:921.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005;168:299–325.CrossRefGoogle Scholar
  34. 34.
    Djeungoue-Petga M-A, Hebert-Chatelain E. Linking mitochondria and synaptic transmission: the CB1 receptor. BioEssays [Internet]. 2017;39:1700126.CrossRefGoogle Scholar
  35. 35.
    Harkany T, Guzmán M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci [Internet]. 2007;28:83–92.CrossRefPubMedGoogle Scholar
  36. 36.
    Díaz-Alonso J, Aguado T, Wu C-S, Palazuelos J, Hofmann C, Garcez P, et al. The CB(1) cannabinoid receptor drives corticospinal motor neuron differentiation through the Ctip2/Satb2 transcriptional regulation axis. J Neurosci [Internet]. 2012;32:16651–65.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Habayeb OMH, Taylor AH, Bell SC, Taylor DJ, Konje JC. Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology. 2008;149:5052–60.CrossRefPubMedGoogle Scholar
  38. 38.
    Galve-Roperh I, Chiurchiù V, Díaz-Alonso J, Bari M, Guzmán M, Maccarrone M. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res [Internet]. 2013;52:633–50.  https://doi.org/10.1016/j.plipres.2013.05.004.CrossRefPubMedGoogle Scholar
  39. 39.
    de Salas-Quiroga A, Díaz-Alonso J, García-Rincón D, Remmers F, Vega D, Gómez-Cañas M, et al. Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB 1 receptors on developing cortical neurons. Proc Natl Acad Sci [Internet]. 2015;201514962. https://doi.org/10.1073/pnas.1514962112.Google Scholar
  40. 40.
    Lovelace JW, Corches A, Vieira PA, Hiroto AS, Mackie K, Korzus E. An animal model of female adolescent cannabinoid exposure elicits a long-lasting deficit in presynaptic long-term plasticity. Neuropharmacology [Internet]. 2015;99:242–55.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70:313–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Blair RE, Deshpande LS, DeLorenzo RJ. Cannabinoids: is there a potential treatment role in epilepsy? Expert Opin Pharmacother. 2015;16:1911–4.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Braakman HMH, van Oostenbrugge RJ, van Kranen-Mastenbroek VHJM, de Krom MCTFM. Rimonabant induces partial seizures in a patient with a history of generalized epilepsy. Epilepsia. 2009;50:2171–2.Google Scholar
  44. 44.
    Silveira MM, Adams WK, Morena M, Hill MN, Winstanley CA. Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats. J Psychiatry Neurosci [Internet]. 2017;42:131–8.Google Scholar
  45. 45.
    Kaur R, Ambwani SR, Singh S. Endocannabinoid system: a multi-facet therapeutic target. Curr Clin Pharmacol. 2016;11:110–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Fernández-Ruiz J, Sagredo O, Pazos MR, García 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.CrossRefPubMedGoogle Scholar
  47. 47.
    Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J Pharmacol. 2011;163:1411–22.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Massi P, Solinas M, Cinquina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol. 2013;75:303–12.CrossRefPubMedGoogle Scholar
  49. 49.
    Crippa JAS, Zuardi AW, Hallak JEC. Therapeutical use of the cannabinoids in psychiatry. Rev Bras Psiquiatr. 2010;32(Suppl 1):S56–66.CrossRefPubMedGoogle Scholar
  50. 50.
    Campbell CT, Phillips MS, Manasco K. Cannabinoids in pediatrics. J Pediatr Pharmacol Ther. 2017;22:176–85.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Rock EM, Bolognini D, Limebeer CL, Cascio MG, Anavi-Goffer S, Fletcher PJ, et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol [Internet]. 2012;165:2620–34.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gonca E, Darıcı F. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias. J Cardiovasc Pharmacol Ther. 2015;20:76–83.CrossRefPubMedGoogle Scholar
  53. 53.
    Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia. 2014;55:787–90.CrossRefPubMedGoogle Scholar
  54. 54.
    Hind WH, England TJ, O’Sullivan SE. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors. Br J Pharmacol. 2016;173:815–25.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Xiong W, Cui T, Cheng K, Yang F, Chen S-R, Willenbring D, et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med. 2012;209:1121–34.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017;119:358–70.CrossRefPubMedGoogle Scholar
  57. 57.
    De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol [Internet]. 2011;163:1479–94.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Pucci M, Rapino C, Di Francesco A, Dainese E, D’Addario C, Maccarrone M. Epigenetic control of skin differentiation genes by phytocannabinoids. Br J Pharmacol. 2013;170:581–91.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737–53.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol [Internet]. 2007;150:613–23.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernández-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. J Neurosci Res. 2011;89:1509–18.CrossRefPubMedGoogle Scholar
  62. 62.
    Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172:4790–805.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature [Internet]. 2017;547:468–71.  https://doi.org/10.1038/nature23272.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Fernández Ó. THC:CBD in daily practice: available data from UK, Germany and Spain. Eur Neurol [Internet]. 2016;75:1–3.CrossRefPubMedGoogle Scholar
  65. 65.
    Romero K, Pavisian B, Staines WR, Feinstein A. Multiple sclerosis, cannabis, and cognition: a structural MRI study. NeuroImage Clin [Internet]. 2015;8:140–7.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Weinstein A, Livny A, Weizman A. Brain imaging studies on the cognitive, pharmacological and neurobiological effects of Cannabis in humans: evidence from studies of adult users. Curr Pharm Des [Internet]. 2017;22:6366–79.CrossRefGoogle Scholar
  67. 67.
    Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96.CrossRefPubMedGoogle Scholar
  68. 68.
    Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med [Internet]. 2018;378:1888–97.  https://doi.org/10.1056/NEJMoa1714631.CrossRefPubMedGoogle Scholar
  69. 69.
    Huizink AC. Prenatal cannabis exposure and infant outcomes: overview of studies. Prog Neuropsychopharmacol Biol Psychiatry. 2014;52:45–52.CrossRefPubMedGoogle Scholar
  70. 70.
    Ranganathan M, D’Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl) [Internet]. 2006;188:425–44.Google Scholar
  71. 71.
    Bossong MG, Niesink RJM. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol [Internet]. 2010;92:370–85.CrossRefPubMedGoogle Scholar
  72. 72.
    Bourque J, Afzali MH, Conrod PJ. Association of Cannabis use with adolescent psychotic symptoms. JAMA Psychiatry [Internet]. 2018. https://doi.org/10.1001/jamapsychiatry.2018.1330.Google Scholar
  73. 73.
    Niesink RJM, van Laar MW. Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry [Internet]. 2013;4:130.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Crippa JAS, Crippa ACS, Hallak JEC, Martín-Santos R, Zuardi AW. Δ9-THC intoxication by cannabidiol-enriched Cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol. Front Pharmacol [Internet]. 2016;7:359.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav [Internet]. 2013;29:574–7.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Rosemergy I, Adler J, Psirides A. Cannabidiol oil in the treatment of super refractory status epilepticus. A case report. Seizure [Internet]. 2016;35:56–8.Google Scholar
  77. 77.
    Seizures TCA, Results S, Available NR, States U, Specialists N, States U. ClinicalTrials.gov Search Results 06/15/2018; 2018. P. 7–8.Google Scholar
  78. 78.
    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia [Internet]. 2015;56:1246–51.  https://doi.org/10.1111/epi.13060.CrossRefPubMedGoogle Scholar
  79. 79.
    Gotfried J, Kataria R, Schey R. Review: the role of cannabinoids on esophageal function-what we know thus far. Cannabis Cannabinoid Res [Internet]. 2017;2:252–8.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Prospéro-García O, Amancio-Belmont O, Becerril Meléndez AL, Ruiz-Contreras AE, Méndez-Díaz M. Endocannabinoids and sleep. Neurosci Biobehav Rev [Internet]. 2016;71:671–9.CrossRefPubMedGoogle Scholar
  81. 81.
    Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci [Internet]. 2017;114:11229–34.CrossRefPubMedCentralGoogle Scholar
  82. 82.
    Alvarez FJ, Lafuente H, Rey-Santano MC, Mielgo VE, Gastiasoro E, Rueda M, et al. Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res [Internet]. 2008;64:653–8.CrossRefPubMedGoogle Scholar
  83. 83.
    Lafuente H, Alvarez FJ, Pazos MR, Alvarez A, Rey-Santano MC, Mielgo V, et al. Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr Res [Internet]. 2011;70:272–7.CrossRefPubMedGoogle Scholar
  84. 84.
    Pazos MR, Cinquina V, Gómez A, Layunta R, Santos M, Fernández-ruiz J, et al. Neuropharmacology cannabidiol administration after hypoxia e ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. 2012;63:776–83.Google Scholar
  85. 85.
    Perez M, Benitez SU, Cartarozzi LP, Del Bel E, Guimarães FS, Oliveira ALR. Neuroprotection and reduction of glial reaction by cannabidiol treatment after sciatic nerve transection in neonatal rats. Eur J Neurosci [Internet]. 2013;38:3424–34.CrossRefPubMedGoogle Scholar
  86. 86.
    Carty DR, Thornton C, Gledhill JH, Willett KL. Developmental effects of cannabidiol and Δ9-tetrahydrocannabinol in zebrafish. Toxicol Sci [Internet]. 2017;162:137–45.CrossRefGoogle Scholar
  87. 87.
    Valim Brigante TA, Abe FR, Zuardi AW, Hallak JEC, Crippa JAS, de Oliveira DP. Cannabidiol did not induce teratogenicity or neurotoxicity in exposed zebrafish embryos. Chem Biol Interact [Internet]. 2018;291:81–6.CrossRefPubMedGoogle Scholar
  88. 88.
    Paria BC, Das SK, Dey SK. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. Dev Biol [Internet]. 1995;92:9460–4.PubMedCentralGoogle Scholar
  89. 89.
    Bergamaschi MM, Queiroz RHC, Zuardi AW, Crippa JAS. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf [Internet]. 2011;6:237–49.CrossRefPubMedGoogle Scholar
  90. 90.
    Schönhofen P, de Medeiros LM, Bristot IJ, Lopes FM, De Bastiani MA, Kapczinski F, et al. Cannabidiol exposure during neuronal differentiation sensitizes cells against redox-active neurotoxins. Mol Neurobiol. 2015;52:26–37.CrossRefPubMedGoogle Scholar
  91. 91.
    Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JEC, Guimarães FS, et al. Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol [Internet]. 2017;8:259.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Genaro K, Fabris D, Arantes ALF, Zuardi AW, Crippa JAS, Prado WA. Cannabidiol is a potential therapeutic for the affective-motivational dimension of incision pain in rats. Front Pharmacol [Internet]. 2017;8:391.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Morales P, Reggio PH, Jagerovic N. An overview on medicinal chemistry of synthetic and natural derivatives of cannabidiol. Front Pharmacol [Internet]. 2017;8:422.  https://doi.org/10.3389/fphar.2017.00422/full.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Nahler G, Grotenhermen F, Zuardi AW, Crippa JAS. A conversion of oral cannabidiol to Delta9-tetrahydrocannabinol seems not to occur in humans. Cannabis Cannabinoid Res [Internet]. 2017;2:81–6.  https://doi.org/10.1089/can.2017.0009.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Haj CG, Sumariwalla PF, Hanu L, Kogan NM, Yektin Z, Mechoulam R, et al. HU-444, a novel, potent anti-inflammatory, nonpsychotropic cannabinoid. J Pharmacol Exp Ther [Internet]. 2015;355:66–75.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    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 [Internet]. 2001;134:845–52.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Juknat A, Pietr M, Kozela E, Rimmerman N, Levy R, Coppola G, et al. Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells. Br J Pharmacol. 2012;165:2512–28.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Fride E, Ponde D, Breuer A, Hanus L. Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors. Neuropharmacology [Internet]. 2005;48:1117–29.CrossRefPubMedGoogle Scholar
  99. 99.
    Pertwee RG, Thomas A, Stevenson LA, Maor Y, Mechoulam R. Evidence that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol activates a non-CB(1), non-CB(2), non-TRPV1 target in the mouse vas deferens. Neuropharmacology [Internet]. 2005;48:1139–46.CrossRefPubMedGoogle Scholar
  100. 100.
    CBD-OS for the treatment of Lennox-Gastaut syndrome and Dravet syndrome FDA advisory committee meeting briefing document. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm604738.pdf. Accessed 11 July 2018.
  101. 101.
    Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32:35–40.CrossRefPubMedGoogle Scholar
  102. 102.
    Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in sturge-weber syndrome. Pediatr Neurol. 2017;71:18–23.e2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Patrícia Schonhofen
    • 1
    • 2
    • 3
  • Ivi Juliana Bristot
    • 1
    • 2
    • 3
  • José Alexandre Crippa
    • 3
    • 4
  • Jaime Eduardo Cecílio Hallak
    • 3
    • 4
  • Antônio Waldo Zuardi
    • 3
    • 4
  • Richard B. Parsons
    • 5
  • Fábio Klamt
    • 1
    • 2
    • 3
  1. 1.Laboratory of Cellular Biochemistry, Department of BiochemistryICBS/UFRGSPorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Ciências Biológicas: BioquímicaICBS/UFRGSPorto AlegreBrazil
  3. 3.National Institutes of Science and Technology-Translational Medicine (INCT-TM)Porto AlegreBrazil
  4. 4.Neuroscience and Behavior DepartmentFaculty of Medicine of Ribeirão PretoRibeirão PretoBrazil
  5. 5.Institute of Pharmaceutical ScienceKing’s College London (KCL)LondonUK

Personalised recommendations