Cannabidiol and Cannabis Use Disorder

  • María S. García-Gutiérrez
  • Francisco Navarrete
  • Adrián Viudez-Martínez
  • Ani Gasparyan
  • Esther Caparrós
  • Jorge ManzanaresEmail author


Cannabis use disorders (CUD) represent a serious public health problem in occidental societies. Despite their devastating social, health, and economic impact, to date no pharmacological treatment has been approved for the clinical management of cannabis dependence.

Cannabidiol (CBD), one of the main compounds—together with Δ9-THC—present in the plant Cannabis sativa, has been reported to possess anxiolytic, antidepressant, and antipsychotic-like effects and neuroprotective properties. And, contrary to Δ9-THC, CBD does not appear to have addictive properties. Taken together, these results point to CBD as a promising candidate for the treatment of psychiatric and drug use disorders, including CUD.

In this respect, recent animal and human studies, carried out by our group and others, have provided the first evidence supporting the potential therapeutic use of CBD in the treatment of cannabis dependence. The administration of CBD reduced the behavioral disturbances associated with the CP-55,940-induced spontaneous cannabinoid withdrawal in mice. Despite controversial results obtained in humans, CBD showed a rapid decrease in withdrawal symptoms in patients with CUD.

Taken together, these preliminary results represent a starting point for further preclinical and large-scale clinical trials.


Cannabidiol Cannabis use disorders Mice Clinical studies Pharmacological treatment Anxiolytic 


  1. 1.
    Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219–27. Epub 2014/06/05.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Danovitch I, Gorelick DA. State of the art treatments for cannabis dependence. Psychiatr Clin North Am. 2012;35(2):309–26. Epub 2012/05/30PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Crime UNOoDa. World drug report 2017. 2017;1.Google Scholar
  4. 4.
    Quality. UDoHaHSSAaMHSACfBHSa. National survey on drug use and health: summary of national findings; 2014.Google Scholar
  5. 5.
    Degenhardt L, Ferrari AJ, Calabria B, Hall WD, Norman RE, McGrath J, et al. The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: results from the GBD 2010 study. PLoS One. 2013;8(10):e76635. Epub 2013/11/10PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Labonte B, Yerko V, Gross J, Mechawar N, Meaney MJ, Szyf M, et al. Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biol Psychiatry. 2012;72(1):41–8. Epub 2012/03/27.PubMedCrossRefGoogle Scholar
  7. 7.
    Jokinen J, Ouda J, Nordstrom P. Noradrenergic function and HPA axis dysregulation in suicidal behaviour. Psychoneuroendocrinology. 2010;35(10):1536–42. Epub 2010/06/26.PubMedCrossRefGoogle Scholar
  8. 8.
    Oquendo MA, Sullivan GM, Sudol K, Baca-Garcia E, Stanley BH, Sublette ME, et al. Toward a biosignature for suicide. Am J Psychiatry. 2014;171(12):1259–77. Epub 2014/09/30.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. J Addict Med. 2011;5(1):1–8. Epub 2011/02/16.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Di Forti M, Sallis H, Allegri F, Trotta A, Ferraro L, Stilo SA, et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophr Bull. 2014;40(6):1509–17. Epub 2013/12/19.PubMedCrossRefGoogle Scholar
  11. 11.
    Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, et al. Mutation screening of the Homer gene family and association analysis in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2003;120B(1):18–21. Epub 2003/06/20.PubMedCrossRefGoogle Scholar
  12. 12.
    Lynskey M, Hall W. The effects of adolescent cannabis use on educational attainment: a review. Addiction. 2000;95(11):1621–30. Epub 2001/02/24.PubMedCrossRefGoogle Scholar
  13. 13.
    Macleod J, Oakes R, Copello A, Crome I, Egger M, Hickman M, et al. Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. Lancet. 2004;363(9421):1579–88. Epub 2004/05/18.PubMedCrossRefGoogle Scholar
  14. 14.
    Fergusson DM, Boden JM. Cannabis use and adult ADHD symptoms. Drug Alcohol Depend. 2008;95(1–2):90–6. Epub 2008/02/05.PubMedCrossRefGoogle Scholar
  15. 15.
    McCaffrey DF, Pacula RL, Han B, Ellickson P. Marijuana use and high school dropout: the influence of unobservables. Health Econ. 2010;19(11):1281–99. Epub 2009/11/26.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Spellmann I, Rujescu D, Musil R, Mayr A, Giegling I, Genius J, et al. Homer-1 polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients. J Psychiatr Res. 2011;45(2):234–41. Epub 2010/07/06.PubMedCrossRefGoogle Scholar
  17. 17.
    Gladkevich A, Kauffman HF, Korf J. Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;28(3):559–76. Epub 2004/04/20.CrossRefGoogle Scholar
  18. 18.
    Levin KH, Copersino ML, Heishman SJ, Liu F, Kelly DL, Boggs DL, et al. Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers. Drug Alcohol Depend. 2010;111(1–2):120–7. Epub 2010/06/01.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, et al. Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology. 2004;29(1):158–70. Epub 2003/10/16.CrossRefGoogle Scholar
  20. 20.
    Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend. 2007;86(1):22–9. Epub 2006/06/14.PubMedCrossRefGoogle Scholar
  21. 21.
    Levin FR, Kleber HD. Use of dronabinol for cannabis dependence: two case reports and review. Am J Addict. 2008;17(2):161–4. Epub 2008/04/09.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2011;116(1–3):142–50. Epub 2011/02/12.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bowen R, McIlwrick J, Baetz M, Zhang X. Lithium and marijuana withdrawal. Can J Psychiatry. 2005;50(4):240–1. Epub 2005/05/19.PubMedCrossRefGoogle Scholar
  24. 24.
    Winstock AR, Lea T, Copeland J. Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study. J Psychopharmacol. 2009;23(1):84–93. Epub 2008/06/03.PubMedCrossRefGoogle Scholar
  25. 25.
    Sudol K, Mann JJ. Biomarkers of suicide attempt behavior: towards a biological model of risk. Curr Psychiatry Rep. 2017;19(6):31. Epub 2017/05/05.PubMedCrossRefGoogle Scholar
  26. 26.
    Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW. Bupropion SR worsens mood during marijuana withdrawal in humans. Psychopharmacology. 2001;155(2):171–9. Epub 2001/06/13.CrossRefGoogle Scholar
  27. 27.
    Haney M, Hart CL, Ward AS, Foltin RW. Nefazodone decreases anxiety during marijuana withdrawal in humans. Psychopharmacology. 2003;165(2):157–65. Epub 2002/11/20.CrossRefGoogle Scholar
  28. 28.
    Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology. 2008;197(1):157–68. Epub 2007/12/28.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vann RE, Warner JA, Bushell K, Huffman JW, Martin BR, Wiley JL. Discriminative stimulus properties of delta9-tetrahydrocannabinol (THC) in C57Bl/6J mice. Eur J Pharmacol. 2009;615(1–3):102–7. Epub 2009/05/28.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Stephens RR, A. The Nature, Consequences and Treatment of Cannabis Dependence: Implications for Future Research and Policy, in Cannabis Dependence; Its Nature, Consequences and Treatment. In: Roffman, A.; Stephens, R., editors. Cambridge: Cambridge University Press. ISBN:9780511544248. 2006.Google Scholar
  31. 31.
    Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci. 2016;7:19. Epub 2016/02/13.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Morales P, Hurst DP, Reggio PH. Molecular targets of the Phytocannabinoids: a complex picture. Prog Chem Org Nat Prod. 2017;103:103–31. Epub 2017/01/26.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gaoni Y, Mechoulam R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J Am Chem Soc. 1964;86(8):1646–7.CrossRefGoogle Scholar
  34. 34.
    Zhang PW, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D, et al. Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry. 2004;9(10):916–31.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Pisanti S, Malfitano AM, Ciaglia E, Lamberti A, Ranieri R, Cuomo G, et al. Cannabidiol: state of the art and new challenges for therapeutic applications. Pharmacol Ther. 2017;175:133–50. Epub 2017/02/25.PubMedCrossRefGoogle Scholar
  36. 36.
    Mechoulam RS, Shvo Y. Hashish-I. The structure of cannabidiol. Tetrahedron. 1963;19:6.CrossRefGoogle Scholar
  37. 37.
    Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981;21(8–9 Suppl):417S–27S. Epub 1981/08/01.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791–802. Epub 2014/05/24.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Li Y, Kim J. Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. Neuroscience. 2015;311:253–67. Epub 2015/11/01.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Giacoppo S, Soundara Rajan T, Galuppo M, Pollastro F, Grassi G, Bramanti P, et al. Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis. Eur Rev Med Pharmacol Sci. 2015;19(24):4906–19. Epub 2016/01/09.PubMedGoogle Scholar
  41. 41.
    Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, et al. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol. 2011;163(7):1507–19. Epub 2011/04/01.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    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(11):1088–98. Epub 2014/09/23.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A. 2014;111(46):E5007–15. Epub 2014/11/05.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Cheng D, Spiro AS, Jenner AM, Garner B, Karl T. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014;42(4):1383–96. Epub 2014/07/16.PubMedCrossRefGoogle Scholar
  45. 45.
    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(6):964–73. Epub 2011/02/26.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Osborne AL, Solowij N, Weston-Green K. A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia. Neurosci Biobehav Rev. 2016;72:310–24. Epub 2016/11/26.CrossRefGoogle Scholar
  47. 47.
    Liput DJ, Hammell DC, Stinchcomb AL, Nixon K. Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder. Pharmacol Biochem Behav. 2013;111:120–7. Epub 2013/09/10PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Schiavon AP, Bonato JM, Milani H, Guimaraes FS, Weffort de Oliveira RM. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:27–34. Epub 2015/07/19.PubMedCrossRefGoogle Scholar
  49. 49.
    Leweke FM, Mueller JK, Lange B, Rohleder C. Therapeutic potential of cannabinoids in psychosis. Biol Psychiatry. 2016;79(7):604–12. Epub 2016/02/08.PubMedCrossRefGoogle Scholar
  50. 50.
    Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. Epub 2012/07/27.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Long LE, Malone DT, Taylor DA. Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology. 2006;31(4):795–803. Epub 2005/07/30.PubMedCrossRefGoogle Scholar
  52. 52.
    Moreira FA, Guimaraes FS. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol. 2005;512(2–3):199–205. Epub 2005/04/21.PubMedCrossRefGoogle Scholar
  53. 53.
    Peres FF, Levin R, Almeida V, Zuardi AW, Hallak JE, Crippa JA, et al. Cannabidiol, among other cannabinoid drugs, modulates prepulse inhibition of startle in the SHR animal model: implications for schizophrenia pharmacotherapy. Front Pharmacol. 2016;7:303. Epub 2016/09/27.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Zuardi AW, Rodrigues JA, Cunha JM. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology. 1991;104(2):260–4. Epub 1991/01/01.PubMedCrossRefGoogle Scholar
  55. 55.
    Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015;12(4):825–36. Epub 2015/09/06.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology. 1990;100(4):558–9. Epub 1990/01/01.PubMedCrossRefGoogle Scholar
  57. 57.
    Moreira FA, Aguiar DC, Guimaraes FS. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuro-Psychopharmacol Biol Psychiatry. 2006;30(8):1466–71. Epub 2006/08/01.CrossRefGoogle Scholar
  58. 58.
    Resstel LB, Joca SR, Moreira FA, Correa FM, Guimaraes FS. Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res. 2006;172(2):294–8. Epub 2006/06/20.PubMedCrossRefGoogle Scholar
  59. 59.
    Sartim AG, Guimaraes FS, Joca SR. Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res. 2016;303:218–27. Epub 2016/01/24.PubMedCrossRefGoogle Scholar
  60. 60.
    Linge R, Jimenez-Sanchez L, Campa L, Pilar-Cuellar F, Vidal R, Pazos A, et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology. 2016;103:16–26. Epub 2015/12/30.PubMedCrossRefGoogle Scholar
  61. 61.
    Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122–8. Epub 2009/12/17.PubMedCrossRefGoogle Scholar
  62. 62.
    Deiana S, Watanabe A, Yamasaki Y, Amada N, Kikuchi T, Stott C, et al. MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol. Behav Pharmacol. 2015;26(8 Spec No):748–65. Epub 2015/08/20.PubMedCrossRefGoogle Scholar
  63. 63.
    Rohleder C, Muller JK, Lange B, Leweke FM. Cannabidiol as a potential new type of an antipsychotic. A critical review of the evidence. Front Pharmacol. 2016;7:422. Epub 2016/11/24.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Gomes FV, Issy AC, Ferreira FR, Viveros MP, Del Bel EA, Guimaraes FS. Cannabidiol attenuates sensorimotor gating disruption and molecular changes Induced by chronic antagonism of NMDA receptors in mice. Int J Neuropsychopharmacol. 2014; 18(5): pyu041. Epub 2015/01/27.Google Scholar
  65. 65.
    Levin R, Peres FF, Almeida V, Calzavara MB, Zuardi AW, Hallak JE, et al. Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain. Front Pharmacol. 2014;5:10. Epub 2014/02/26.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Pedrazzi JF, Issy AC, Gomes FV, Guimaraes FS, Del-Bel EA. Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine. Psychopharmacology. 2015;232(16):3057–65. Epub 2015/05/07.PubMedCrossRefGoogle Scholar
  67. 67.
    Gururajan A, Taylor DA, Malone DT. Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague-Dawley rats. J Psychopharmacol. 2012;26(10):1317–32. Epub 2012/04/13.PubMedCrossRefGoogle Scholar
  68. 68.
    Gururajan A, Taylor DA, Malone DT. Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia. Behav Brain Res. 2011;222(2):299–308. Epub 2011/04/05.PubMedCrossRefGoogle Scholar
  69. 69.
    Gomes FV, Llorente R, Del Bel EA, Viveros MP, Lopez-Gallardo M, Guimaraes FS. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res. 2015;164(1–3):155–63. Epub 2015/02/15.PubMedCrossRefGoogle Scholar
  70. 70.
    Long LE, Chesworth R, Huang XF, Wong A, Spiro A, McGregor IS, et al. Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PLoS One. 2012;7(4):e34129. Epub 2012/04/18.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Osborne AL, Solowij N, Babic I, Huang XF, Weston-Green K. Improved social interaction, recognition and working memory with Cannabidiol treatment in a prenatal infection (poly I:C) rat model. Neuropsychopharmacology. 2017;42(7):1447–57. Epub 2017/02/24.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Almeida V, Levin R, Peres FF, Niigaki ST, Calzavara MB, Zuardi AW, et al. Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;41:30–5. Epub 2012/11/07.CrossRefGoogle Scholar
  73. 73.
    McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175(3):225–31. Epub 2017/12/16.PubMedCrossRefGoogle Scholar
  74. 74.
    Crippa JA, Zuardi AW, Martin-Santos R, Bhattacharyya S, Atakan Z, McGuire P, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24(7):515–23. Epub 2009/08/21.PubMedCrossRefGoogle Scholar
  75. 75.
    Harford TC, Yi HY, Faden VB, Chen CM. The dimensionality of DSM-IV alcohol use disorders among adolescent and adult drinkers and symptom patterns by age, gender, and race/ethnicity. Alcohol Clin Exp Res. 2009;33(5):868–78. Epub 2009/03/27.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Schier AR, Ribeiro NP, Silva AC, Hallak JE, Crippa JA, Nardi AE, et al. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Rev Bras Psiquiatr. 2012;34(Suppl 1):S104–10. Epub 2012/06/29.PubMedCrossRefGoogle Scholar
  77. 77.
    Lemos JI, Resstel LB, Guimaraes FS. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res. 2010;207(1):105–11. Epub 2009/10/06.PubMedCrossRefGoogle Scholar
  78. 78.
    Long LE, Chesworth R, Huang XF, McGregor IS, Arnold JC, Karl T. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol. 2009;13(7):861–76. Epub 2009/09/29.Google Scholar
  79. 79.
    Zuardi AW, Finkelfarb E, Bueno OF, Musty RE, Karniol IG. Characteristics of the stimulus produced by the mixture of cannabidiol with delta 9-tetrahydrocannabinol. Archives internationales de pharmacodynamie et de therapie. 1981;249(1):137–46. Epub 1981/01/01.PubMedGoogle Scholar
  80. 80.
    Bitencourt RM, Pamplona FA, Takahashi RN. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur Neuropsychopharmacol. 2008;18(12):849–59. Epub 2008/08/19.PubMedCrossRefGoogle Scholar
  81. 81.
    Onaivi ES, Green MR, Martin BR. Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther. 1990;253(3):1002–9. Epub 1990/06/01.PubMedGoogle Scholar
  82. 82.
    Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7(1 Suppl):82–8. Epub 1993/01/01.PubMedCrossRefGoogle Scholar
  83. 83.
    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. 1982;76(3):245–50. Epub 1982/01/01.PubMedCrossRefGoogle Scholar
  84. 84.
    Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology. 2011;36(6):1219–26. Epub 2011/02/11.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol oil for pediatric anxiety and insomnia as part of posttraumatic stress disorder: a case report. Perm J. 2016;20(4):108–11. Epub 2016/10/22.PubMedPubMedCentralGoogle Scholar
  86. 86.
    El-Alfy AT, Ivey K, Robinson K, Ahmed S, Radwan M, Slade D, et al. Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacol Biochem Behav. 2010;95(4):434–42. Epub 2010/03/25.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Shoval G, Shbiro L, Hershkovitz L, Hazut N, Zalsman G, Mechoulam R, et al. Prohedonic effect of Cannabidiol in a rat model of depression. Neuropsychobiology. 2016;73(2):123–9. Epub 2016/03/25.PubMedCrossRefGoogle Scholar
  88. 88.
    Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268–73.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    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(1):162–70.PubMedCrossRefGoogle Scholar
  90. 90.
    Castillo A, Tolon MR, Fernandez-Ruiz J, Romero J, Martinez-Orgado J. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis. 2010;37(2):434–40. Epub 2009/11/11.PubMedCrossRefGoogle Scholar
  91. 91.
    Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 2004;89(1):134–41. Epub 2004/03/20.PubMedCrossRefGoogle Scholar
  92. 92.
    Rajan TS, Giacoppo S, Iori R, De Nicola GR, Grassi G, Pollastro F, et al. Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages. Fitoterapia. 2016;112:104–15. Epub 2016/05/25.PubMedCrossRefGoogle Scholar
  93. 93.
    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(1 Pt B):231–40. Epub 2015/11/12.PubMedCrossRefGoogle Scholar
  94. 94.
    Juknat A, Kozela E, Kaushansky N, Mechoulam R, Vogel Z. Anti-inflammatory effects of the cannabidiol derivative dimethylheptyl-cannabidiol – studies in BV-2 microglia and encephalitogenic T cells. J Basic Clin Physiol Pharmacol. 2016;27(3):289–96. Epub 2015/11/06.PubMedCrossRefGoogle Scholar
  95. 95.
    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(1–2):96–107.PubMedCrossRefGoogle Scholar
  96. 96.
    Hayakawa K, Irie K, Sano K, Watanabe T, Higuchi S, Enoki M, et al. Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group box 1-inhibiting mechanism. Biol Pharm Bull. 2009;32(9):1538–44. Epub 2009/09/02.PubMedCrossRefGoogle Scholar
  97. 97.
    Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M, et al. Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box 1-inhibiting mechanism. Neuropharmacology. 2008;55(8):1280–6. Epub 2008/07/19.PubMedCrossRefGoogle Scholar
  98. 98.
    Hayakawa K, Mishima K, Hazekawa M, Sano K, Irie K, Orito K, et al. Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism. Brain Res. 2008;1188:157–64. Epub 2007/11/21.PubMedCrossRefGoogle Scholar
  99. 99.
    Pazos MR, Cinquina V, Gomez A, Layunta R, Santos M, Fernandez-Ruiz J, et al. Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology. 2012;63(5):776–83. Epub 2012/06/05.PubMedCrossRefGoogle Scholar
  100. 100.
    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. 2008;64(6):653–8. Epub 2008/08/06.PubMedCrossRefGoogle Scholar
  101. 101.
    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. 2011;70(3):272–7. Epub 2011/06/10.PubMedCrossRefGoogle Scholar
  102. 102.
    Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernandez-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci. 2007;26(4):843–51. Epub 2007/08/04.PubMedCrossRefGoogle Scholar
  103. 103.
    da Silva VK, de Freitas BS, da Silva DA, Nery LR, Falavigna L, Ferreira RD, et al. Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection. Mol Neurobiol. 2014;49(1):222–33. Epub 2013/07/31.PubMedCrossRefGoogle Scholar
  104. 104.
    Ceprian M, Jimenez-Sanchez L, Vargas C, Barata L, Hind W, Martinez-Orgado J. Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke. Neuropharmacology. 2017;116:151–9. Epub 2016/12/26.PubMedCrossRefGoogle Scholar
  105. 105.
    Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol–recent advances. Chem Biodivers. 2007;4(8):1678–92. Epub 2007/08/23.PubMedCrossRefGoogle Scholar
  106. 106.
    Pertwee R. The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V, editor. Cannabinoids. New York: Kluwer Academic/Plenum Publisher; 2004.Google Scholar
  107. 107.
    Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J. Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci. 2000;899:274–82. Epub 2000/06/23.PubMedCrossRefGoogle Scholar
  108. 108.
    Ruiz-Valdepenas L, Martinez-Orgado JA, Benito C, Millan A, Tolon RM, Romero J. Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study. J Neuroinflammation. 2011;8(1):5. Epub 2011/01/20.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Campos AC, Fogaca MV, Scarante FF, Joca SRL, Sales AJ, Gomes FV, et al. Plastic and neuroprotective mechanisms involved in the therapeutic effects of Cannabidiol in psychiatric disorders. Front Pharmacol. 2017;8:269. Epub 2017/06/08.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    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(4):845–52. Epub 2001/10/19.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037–43. Epub 2005/11/01.PubMedCrossRefGoogle Scholar
  112. 112.
    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(7):1092–101. Epub 2007/09/19.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    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. 2007;150(5):613–23. Epub 2007/01/25.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedeberg's Arch Pharmacol. 2006;372(5):354–61. Epub 2006/02/21.CrossRefGoogle Scholar
  115. 115.
    Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of Cannabidiol in neurological disorders. Neurotherapeutics. 2015;12(4):699–730. Epub 2015/08/13.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121–30. Epub 2010/09/11.PubMedCrossRefGoogle Scholar
  117. 117.
    Campos AC, Fogaca MV, Sonego AB, Guimaraes FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119–27. Epub 2016/02/05.PubMedCrossRefGoogle Scholar
  118. 118.
    Fujita S, Kiguchi M, Lee J, Terakado M, Suga K, Hatanaka H, et al. 5-HT(1A) and 5-HT(1B) receptors in the ventrolateral striatum differentially modulate apomorphine-induced jaw movements in rats. J Oral Sci. 2008;50(4):387–95. Epub 2008/12/25.PubMedCrossRefGoogle Scholar
  119. 119.
    Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, et al. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke. 2005;36(5):1077–82. Epub 2005/04/23.PubMedCrossRefGoogle Scholar
  120. 120.
    Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, et al. Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem. 2007;102(5):1488–96. Epub 2007/04/18.PubMedCrossRefGoogle Scholar
  121. 121.
    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(20):4790–805. Epub 2015/07/29.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Lunn CA, Reich EP, Bober L. Targeting the CB2 receptor for immune modulation. Expert Opin Ther Targets. 2006;10(5):653–63. Epub 2006/09/20.PubMedCrossRefGoogle Scholar
  123. 123.
    Sacerdote P, Martucci C, Vaccani A, Bariselli F, Panerai AE, Colombo A, et al. The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro. J Neuroimmunol. 2005;159(1–2):97–105. Epub 2005/01/18.PubMedCrossRefGoogle Scholar
  124. 124.
    Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, et al. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci. 2003;23(4):1398–405.PubMedCrossRefGoogle Scholar
  125. 125.
    (CSA) CSA. Comprehensive drug use prevention and control act of 1970. FDA US Food and Drug Administration 1970.Google Scholar
  126. 126.
    Ministry of Justice C. Controlled drugs and substances act; 1996.Google Scholar
  127. 127.
    Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18(32):4966–79. Epub 2012/06/22.PubMedCrossRefGoogle Scholar
  128. 128.
    Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66(1):95–105. Epub 2009/01/07.PubMedCrossRefGoogle Scholar
  129. 129.
    Winton-Brown TT, Allen P, Bhattacharyya S, Borgwardt SJ, Fusar-Poli P, Crippa JA, et al. Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology. 2011;36(7):1340–8. Epub 2011/03/18.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Zlebnik NE, Cheer JF. Beyond the CB1 receptor: is Cannabidiol the answer for disorders of motivation? Annu Rev Neurosci. 2016;39:1–17. Epub 2016/03/30.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Adrián Viudez-Martínez, María S. García-Gutiérrez, Juan Medrano-Relinque, Carmen M. Navarrón, Francisco Navarrete, Jorge Manzanares, Cannabidiol does not display drug abuse potential in mice behavior. Acta Pharmacologica Sinica, 2018. [Epub ahead of print]Google Scholar
  132. 132.
    Ortega-Alvaro A, Ternianov A, Aracil-Fernandez A, Navarrete F, Garcia-Gutierrez MS, Manzanares J. Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addict Biol. 2015;20(1):43–55. Epub 2013/07/17.PubMedCrossRefGoogle Scholar
  133. 133.
    Itzhak Y, Martin JL. Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants. Neuropsychopharmacology. 2002;26(1):130–4. Epub 2001/12/26.PubMedCrossRefGoogle Scholar
  134. 134.
    Navarrete F, Rodriguez-Arias M, Martin-Garcia E, Navarro D, Garcia-Gutierrez MS, Aguilar MA, et al. Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine. Neuropsychopharmacology. 2013;38(12):2515–24. Epub 2013/07/03.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Vezina P, Stewart J. Morphine conditioned place preference and locomotion: the effect of confinement during training. Psychopharmacology. 1987;93(2):257–60. Epub 1987/01/01.PubMedCrossRefGoogle Scholar
  136. 136.
    Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, et al. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol. Drug Alcohol Depend. 2008;94(1–3):191–8. Epub 2008/01/22.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology. 2004;175(3):360–6. Epub 2004/05/13.PubMedCrossRefGoogle Scholar
  138. 138.
    Caldwell LC, Schweinsburg AD, Nagel BJ, Barlett VC, Brown SA, Tapert SF. Gender and adolescent alcohol use disorders on BOLD (blood oxygen level dependent) response to spatial working memory. Alcohol Alcohol (Oxford, Oxfordshire). 2005;40(3):194–200. Epub 2005/01/26.CrossRefGoogle Scholar
  139. 139.
    Katsidoni V, Anagnostou I, Panagis G. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol. 2013;18(2):286–96. Epub 2012/08/07.PubMedCrossRefGoogle Scholar
  140. 140.
    Bhargava HN. Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice. Psychopharmacology. 1976;49(3):267–70. Epub 1976/09/29.PubMedCrossRefGoogle Scholar
  141. 141.
    Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci. 2009;29(47):14764–9. Epub 2009/11/27.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Gobira PH, Vilela LR, Goncalves BD, Santos RP, de Oliveira AC, Vieira LB, et al. Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: possible role of the mTOR pathway and reduction in glutamate release. Neurotoxicology. 2015;50:116–21. Epub 2015/08/19.PubMedCrossRefGoogle Scholar
  143. 143.
    Gonzalez-Cuevas G, Martin-Fardon R, Kerr TM, Stouffer DG, Parsons LH, Hammell DC, et al. Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle. Neuropsychopharmacology. 2018. [Epub ahead of print].Google Scholar
  144. 144.
    Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19–27. Epub 2012/10/09.PubMedCrossRefGoogle Scholar
  145. 145.
    Hindocha C, Freeman TP, Schafer G, Gardener C, Das RK, Morgan CJ, et al. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur Neuropsychopharmacol. 2015;25(3):325–34. Epub 2014/12/24.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Robson PJ. Therapeutic potential of cannabinoid medicines. Drug Test Anal. 2014;6(1–2):24–30. Epub 2013/09/06.PubMedCrossRefGoogle Scholar
  147. 147.
    Swift W, Wong A, Li KM, Arnold JC, McGregor IS. Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile. PLoS One. 2013;8(7):e70052. Epub 2013/07/31.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology. 2010;35(9):1879–85. Epub 2010/04/30.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. Br J Psychiatry. 2010;197(4):285–90. Epub 2010/10/05.PubMedCrossRefGoogle Scholar
  150. 150.
    Allsop DJ, Lintzeris N, Copeland J, Dunlop A, McGregor IS. Cannabinoid replacement therapy (CRT): Nabiximols (Sativex) as a novel treatment for cannabis withdrawal. Clin Pharmacol Ther. 2015;97(6):571–4. Epub 2015/03/18.PubMedCrossRefGoogle Scholar
  151. 151.
    Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiat. 2014;71(3):281–91. Epub 2014/01/17.CrossRefGoogle Scholar
  152. 152.
    Trigo JM, Soliman A, Staios G, Quilty L, Fischer B, George TP, et al. Sativex associated with behavioral-relapse prevention strategy as treatment for Cannabis dependence: a case series. J Addict Med. 2016;10(4):274–9. Epub 2016/06/05.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Trigo JM, Soliman A, Quilty LC, Fischer B, Rehm J, Selby P, et al. Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: a pilot randomized clinical trial. PLoS One. 2018;13(1):e0190768. Epub 2018/02/01.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Crippa JA, Hallak JE, Machado-de-Sousa JP, Queiroz RH, Bergamaschi M, Chagas MH, et al. Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. J Clin Pharm Ther. 2013;38(2):162–4. Epub 2012/10/26.PubMedCrossRefGoogle Scholar
  155. 155.
    Shannon S, Opila-Lehman J. Cannabidiol oil for decreasing addictive use of marijuana: a case report. Integr Med (Encinitas). 2015;14(6):31–5. Epub 2016/01/26.Google Scholar
  156. 156.
    Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, et al. Oral Cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked Cannabis. Neuropsychopharmacology. 2016;41(8):1974–82. Epub 2015/12/29.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Navarrete F, Aracil-Fernández A, Manzanares J. Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal. Br J Pharmacol. 2018;175(13):2676–88. Epub 2018 May 3.PubMedCrossRefGoogle Scholar
  158. 158.
    Aracil-Fernandez A, Almela P, Manzanares J. Pregabalin and topiramate regulate behavioural and brain gene transcription changes induced by spontaneous cannabinoid withdrawal in mice. Addict Biol. 2011;
  159. 159.
    Cook SA, Lowe JA, Martin BR. CB1 receptor antagonist precipitates withdrawal in mice exposed to Delta9-tetrahydrocannabinol. J Pharmacol Exp Ther. 1998;285(3):1150–6. Epub 1998/06/17.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • María S. García-Gutiérrez
    • 1
    • 2
  • Francisco Navarrete
    • 1
    • 2
  • Adrián Viudez-Martínez
    • 1
    • 2
  • Ani Gasparyan
    • 1
    • 2
  • Esther Caparrós
    • 1
    • 2
  • Jorge Manzanares
    • 1
    • 2
    Email author
  1. 1.Instituto de Neurociencias, Universidad Miguel Hernández-CSICAlicanteSpain
  2. 2.Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDERMadridSpain

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