The Cerebellum, THC, and Cannabis Addiction: Findings from Animal and Human Studies

Abstract

Cannabis is the third most used psychoactive drug worldwide. Despite being legally scheduled as a drug with high harm potential and no therapeutic utility in countries like the USA, evidence shows otherwise and legislative changes and reinterpretations of existing ambiguous laws make this drug increasingly available by legal means. Nevertheless, this substance is able to generate clear addiction syndromes in some individuals who use it, which are accompanied by brain alterations resembling those caused by other addictive drugs. Moreover, there is no available pharmacological treatment for this disorder. This fact motivates a deep study and comprehension of the neural basis of addiction-relevant cannabinoid effects. Interestingly, the cerebellum, a hindbrain structure which involvement in functions not related to motor control and planning is being increasingly recognized in the last decades, seems to be involved in the effects of addictive drugs and addiction-related processes and also presents a high density of cannabinoid receptors. Preclinical research on the involvement of the cerebellum in cannabis’ effects has focused in the drug’s motor incoordinating actions, potentially underestimating its participation in addiction. Therefore, this review addresses the studies reporting cerebellar involvement in cannabis effects both in experimental animals and human subjects and the possible relevance of these changes for addiction. Additionally, future experimental approaches will be proposed and hopefully this work will stimulate research on the cerebellum in cannabis addiction and help recognizing it as an important part of the neural circuitry affected in cannabis-related disorders.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    United Nations Office on Drugs and Crime. World drug report 2015. Vienna: United Nations publications; 2016.

    Google Scholar 

  2. 2.

    European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2015. Luxembourg: Publications Office of the European Union; 2016.

    Google Scholar 

  3. 3.

    Clarke RC, Merlin MD. Cannabis: evolution and ethnobotany. Berkeley: University of California Press; 2013.

    Google Scholar 

  4. 4.

    Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014a;370(23):2219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Mead A. The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy Behav. 2017;70(Pt B):288–91.

    Article  PubMed  Google Scholar 

  6. 6.

    Nutt DJ, King LA, Phillips LD. Independent Scientific Committee on Drugs. Drug harms in the UK: a multicriteria decision analysis. Lancet. 2010;376(9752):1558–65.

    Article  PubMed  Google Scholar 

  7. 7.

    Alexander SP. Therapeutic potential of cannabis-related drugs. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;64:157–66.

    Article  CAS  Google Scholar 

  8. 8.

    Novack GD. Cannabinoids for treatment of glaucoma. Curr Opin Ophthalmol. 2016;27(2):146–50.

    Article  PubMed  Google Scholar 

  9. 9.

    Fanelli G, De Carolis G, Leonardi C, Longobardi A, Sarli E, Allegri M, et al. Cannabis and intractable chronic pain: an explorative retrospective analysis of Italian cohort of 614 patients. J Pain Res. 2017;10:1217–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kim HS, Monte AA. Colorado cannabis legalization and its effect on emergency care. Ann Emerg Med. 2016;68(1):71–5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Kilmer B. Recreational cannabis - minimizing the health risks from legalization. N Engl J Med. 2017;376(8):705–7.

    Article  PubMed  Google Scholar 

  12. 12.

    Belackova V, Wilkins C. Consumer agency in cannabis supply – exploring auto-regulatory documents of the cannabis social clubs in Spain. Int J Drug Policy. 2018;54:26–34.

    Article  PubMed  Google Scholar 

  13. 13.

    Piomelli D, Haney M, Budney AJ, Piazza PV. Legal or illegal, cannabis is still addictive. Cannabis Cannabinoid Res. 2016;1(1):47–53.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Amann M, Haug S, Wenger A, Baumgartner C, Ebert DD, Berger T, et al. The effects of social presence on adherence-focused guidance in problematic cannabis users: protocol for the CANreduce 2.0 randomized controlled trial. JMIR Res Protoc. 2018;7(1):e30.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci U S A. 1996;93(21):12040–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Filbey FM, Schacht JP, Myers US, Chavez RS, Hutchison KE. Marijuana craving in the brain. Proc Natl Acad Sci U S A. 2009;106(31):13016–21.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Zehra A, Burns J, Liu CK, Manza P, Wiers CE, Volkow ND, et al. Cannabis addiction and the brain: a review. J NeuroImmune Pharmacol. 2018 (In press;13:438–52.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci. 2009;3:31.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Anderson CM, Maas LC, Bd F, Bendor JT, Spencer TJ, Livni E, et al. Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology. 2006;31(6):1318–26.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Moulton EA, Elman I, Becerra LR, Goldstein RZ, Borsook D. The cerebellum and addiction: insights gained from neuroimaging research. Addict Biol. 2014;19(3):317–31.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Carbo-Gas M, Moreno-Rius J, Guarque-Chabrera J, Vazquez-Sanroman D, Gil-Miravet I, Carulli D, et al. Cerebellar perineuronal nets in cocaine-induced pavlovian memory: site matters. Neuropharmacology. 2017;125:166–80.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Moreno-Rius J, Miquel M. The cerebellum in drug craving. Drug Alcohol Depend. 2017;173:151–8.

    Article  PubMed  Google Scholar 

  23. 23.

    Ikai Y, Takada M, Shinonag Y, Mizuno N. Dopaminergic and non-dopaminergic neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and deep cerebellar nuclei. Neuroscience. 1992;51(3):719–28.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Etkin A, Prater KE, Schatzberg AF, Menon V, Greicius MD. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch Gen Psychiatry. 2009;66(12):1361–72.

    Article  PubMed  Google Scholar 

  25. 25.

    Cauda F, Cavanna AE, D'agata F, Sacco K, Duca S, Geminiani GC. Functional connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and structure-based meta-analysis. J Cogn Neurosci. 2011;23(10):2864–77.

    Article  PubMed  Google Scholar 

  26. 26.

    Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci U S A. 2010;107(18):8452–6.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Watson TC, Becker N, Apps R, Jones MW. Back to front: cerebellar connections and interactions with the prefrontal cortex. Front Syst Neurosci. 2014;8:4.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Tomasi D, Volkow ND. Functional connectivity hubs in the human brain. NeuroImage. 2011;57(3):908–17.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Farley SJ, Radley JJ, Freeman JH. Amygdala modulation of cerebellar learning. J Neurosci. 2016;36(7):2190–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Sang L, Qin W, Liu Y, Han W, Zhang Y, Jiang T, et al. Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. NeuroImage. 2012;61(4):1213–25.

    Article  PubMed  Google Scholar 

  31. 31.

    Yu W, Krook-Magnuson E. Cognitive collaborations: bidirectional functional connectivity between the cerebellum and the hippocampus. Front Syst Neurosci. 2015;9:177.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Iglói K, Doeller CF, Paradis AL, Benchenane K, Berthoz A, Burgess N, et al. Interaction between hippocampus and cerebellum crus I in sequence-based but not place-based navigation. Cereb Cortex. 2015;25(11):4146–54.

    Article  PubMed  Google Scholar 

  33. 33.

    Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87(5):1932–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    DeSanty KP, Dar MS. Cannabinoid-induced motor incoordination through the cerebellar CB(1) receptor in mice. Pharmacol Biochem Behav. 2001a;69(1–2):251–9.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Dar MS, Mustafa SJ. Acute ethanol/cannabinoid-induced ataxia and its antagonism by oral/systemic/intracerebellar A1 adenosine receptor antisense in mice. Brain Res. 2002;957(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    McKinney DL, Cassidy MP, Collier LM, Martin BR, Wiley JL, Selley DE, et al. Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to delta9-tetrahydrocannabinol. J Pharmacol Exp Ther. 2008;324(2):664–73.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Cutando L, Busquets-Garcia A, Puighermanal E, Gomis-González M, Delgado-García JM, Gruart A, et al. Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure. J Clin Invest. 2013;123(7):2816–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Ho BT, Taylor D, Fritchie GE, Englert LF, McIsaac WM. Neuropharmacological study of 9- and 8-L-tetrahydrocannabinols in monkeys and mice. Brain Res. 1972;38(1):163–70.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Goldman H, Dagirmanjian R, Drew WG, Murphy S. delta9-tetrahydrocannabinol alters flow of blood to subcortical areas of the conscious rat brain. Life Sci. 1975;17(3):477–82.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Dolby TW, Kleinsmith LJ. Effects of delta 9-tetrahydrocannabinol on the levels of cyclic adenosine 3′,5′-monophosphate in mouse brain. Biochem Pharmacol. 1974;23(13):1817–25.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Bartova A, Birmingham MK. Effect of delta9-tetrahydrocannabinol on mitochondrial NADH-oxidase activity. J Biol Chem. 1976;251(16):5002–6.

    CAS  PubMed  Google Scholar 

  42. 42.

    Romero J, García L, Fernández-Ruiz JJ, Cebeira M, Ramos JA. Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to delta 9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1995;51(4):731–7.

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Romero J, Garcia-Palomero E, Castro JG, Garcia-Gil L, Ramos JA, Fernandez-Ruiz JJ. Effects of chronic exposure to delta9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions. Brain Res Mol Brain Res. 1997;46(1–2):100–8.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Sim LJ, Hampson RE, Deadwyler SA, Childers SR. Effects of chronic treatment with delta9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPgammaS autoradiography in rat brain. J Neurosci. 1996;16(24):8057–66.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Casu MA, Pisu C, Sanna A, Tambaro S, Spada GP, Mongeau R, et al. Effect of delta9-tetrahydrocannabinol on phosphorylated CREB in rat cerebellum: an immunohistochemical study. Brain Res. 2005;1048(1–2):41–7.

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Rubino T, Forlani G, Viganò D, Zippel R, Parolaro D. Modulation of extracellular signal-regulated kinases cascade by chronic delta9-tetrahydrocannabinol treatment. Mol Cell Neurosci. 2004;25(3):355–62.

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Rubino T, Vigano' D, Massi P, Spinello M, Zagato E, Giagnoni G, et al. Chronic delta-9-tetrahydrocannabinol treatment increases cAMP levels and cAMP-dependent protein kinase activity in some rat brain regions. Neuropharmacology. 2000;39(7):1331–6.

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Whitlow CT, Freedland CS, Porrino LJ. Metabolic mapping of the time-dependent effects of delta 9-tetrahydrocannabinol administration in the rat. Psychopharmacology. 2002;161(2):129–36.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Senn R, Keren O, Hefetz A, Sarne Y. Long-term cognitive deficits induced by a single, extremely low dose of tetrahydrocannabinol (THC): behavioral, pharmacological and biochemical studies in mice. Pharmacol Biochem Behav. 2008;88(3):230–7.

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Amal H, Fridman-Rozevich L, Senn R, Strelnikov A, Gafni M, Keren O, et al. Long-term consequences of a single treatment of mice with an ultra-low dose of Δ9-tetrahydrocannabinol (THC). Behav Brain Res. 2010;206(2):245–53.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Fishbein M, Gov S, Assaf F, Gafni M, Keren O, Sarne Y. Long-term behavioral and biochemical effects of an ultra-low dose of Δ9-tetrahydrocannabinol (THC): neuroprotection and ERK signaling. Exp Brain Res. 2012;221(4):437–48.

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Smith AD, Dar MS. Mouse cerebellar nicotinic-cholinergic receptor modulation of Δ9-THC ataxia: role of the α4β2 subtype. Brain Res. 2006;1115(1):16–25.

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Smith AD, Dar MS. Involvement of the alpha4beta2 nicotinic receptor subtype in nicotine-induced attenuation of delta9-THC cerebellar ataxia: role of cerebellar nitric oxide. Pharmacol Biochem Behav. 2007;86(1):103–12.

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Lorivel T, Hilber P. Motor effects of delta 9 THC in cerebellar Lurcher mutant mice. Behav Brain Res. 2007;181(2):248–53.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Luthra YK, Rosenkrantz H, Braude MC. Cerebral and cerebellar neurochemical changes and behavioral manifestations in rats chronically exposed to marijuana smoke. Toxicol Appl Pharmacol. 1976;35(3):455–65.

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Matsuda LA, Bonner TI, Lolait SJ. Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol. 1993;327(4):535–50.

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Patel S, Hillard CJ. Cannabinoid CB(1) receptor agonists produce cerebellar dysfunction in mice. J Pharmacol Exp Ther. 2001;297(2):629–37.

    CAS  PubMed  Google Scholar 

  58. 58.

    DeSanty KP, Dar MS. Involvement of the cerebellar adenosine A(1) receptor in cannabinoid-induced motor incoordination in the acute and tolerant state in mice. Brain Res. 2001;905(1–2):178–87.

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ. Chronic Δ9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem. 1999;73(6):2447–59.

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Zhuang S, Kittler J, Grigorenko EV, Kirby MT, Sim LJ, Hampson RE, et al. Effects of long-term exposure to delta9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions. Brain Res Mol Brain Res. 1998;62(2):141–9.

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Breivogel CS, Scates SM, Beletskaya IO, Lowery OB, Aceto MD, Martin BR. The effects of Δ9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors. Eur J Pharmacol. 2003;459(2–3):139–50.

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    Selley DE, Cassidy MP, Martin BR, Sim-Selley LJ. Long-term administration of Δ9-tetrahydrocannabinol desensitizes CB1-, adenosine A1-, and GABAB-mediated inhibition of adenylyl cyclase in mouse cerebellum. Mol Pharmacol. 2004;66(5):1275–84.

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    Filipeanu CM, Guidry JJ, Leonard ST, Winsauer PJ. Δ9-THC increases endogenous AHA1 expression in rat cerebellum and may modulate CB1 receptor function during chronic use. J Neurochem. 2011;118(6):1101–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Colombo G, Rusconi F, Rubino T, Cattaneo A, Martegani E, Parolaro D, et al. Transcriptomic and proteomic analyses of mouse cerebellum reveals alterations in RasGRF1 expression following in vivo chronic treatment with delta 9-tetrahydrocannabinol. J Mol Neurosci. 2009;37(2):111–22.

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Rubino T, Viganò D, Premoli F, Castiglioni C, Bianchessi S, Zippel R, et al. Changes in the expression of G protein-coupled receptor kinases and beta-arrestins in mouse brain during cannabinoid tolerance: a role for RAS-ERK cascade. Mol Neurobiol. 2006;33(3):199–213.

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Tonini R, Ciardo S, Cerovic M, Rubino T, Parolaro D, Mazzanti M, et al. ERK-dependent modulation of cerebellar synaptic plasticity after chronic Δ9-tetrahydrocannabinol exposure. J Neurosci. 2006;26(21):5810–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Hutcheson DM, Tzavara ET, Smadja C, Valjent E, Roques BP, Hanoune J, et al. Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with Δ-9-tetrahydrocannabinol. Br J Pharmacol. 1998;125(7):1567–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Wise LE, Varvel SA, Selley DE, Wiebelhaus JM, Long KA, Middleton LS, et al. Δ(9)-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory. Psychopharmacology. 2011;217(4):485–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Tzavara ET, Valjent E, Firmo C, Mas M, Beslot F, Defer N, et al. Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum. Eur J Neurosci. 2000;12(3):1038–46.

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Rubino T, Viganò D, Massi P, Parolaro D. Cellular mechanisms of Δ9-tetrahydrocannabinol behavioural sensitization. Eur J Neurosci. 2003;17(2):325–30.

    Article  CAS  PubMed  Google Scholar 

  71. 71.

    Suárez I, Bodega G, Fernández-Ruiz JJ, Ramos JA, Rubio M, Fernández B. Reduced glial fibrillary acidic protein and glutamine synthetase expression in astrocytes and Bergmann glial cells in the rat cerebellum caused by Δ(9)-tetrahydrocannabinol administration during development. Dev Neurosci. 2002;24(4):300–12.

    Article  PubMed  Google Scholar 

  72. 72.

    Suárez I, Bodega G, Rubio M, Fernández-Ruiz JJ, Ramos JA, Fernández B. Prenatal cannabinoid exposure down- regulates glutamate transporter expressions (GLAST and EAAC1) in the rat cerebellum. Dev Neurosci. 2004a;26(1):45–53.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Suárez I, Bodega G, Fernández-Ruiz J, Ramos JA, Rubio M, Fernández B. Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal Δ9-tetrahydrocannabinol exposure. Cerebellum. 2004b;3(2):66–74.

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev. 1993;18(3):247–91.

    Article  CAS  PubMed  Google Scholar 

  75. 75.

    Volkow ND, Gillespie H, Mullani N, Tancredi L, Grant C, Ivanovic M, et al. Cerebellar metabolic activation by delta-9-tetrahydro-cannabinol in human brain: a study with positron emission tomography and 18F-2-fluoro-2-deoxyglucose. Psychiatry Res. 1991;40(1):69–78.

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    van Hell HH, Bossong MG, Jager G, Kristo G, van Osch MJ, Zelaya F, et al. Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study. Int J Neuropsychopharmacol. 2011;14(10):1377–88.

    Article  CAS  PubMed  Google Scholar 

  77. 77.

    Klumpers LE, Cole DM, Khalili-Mahani N, Soeter RP, Te Beek ET, Rombouts SA, et al. Manipulating brain connectivity with δ9-tetrahydrocannabinol: a pharmacological resting state FMRI study. NeuroImage. 2012;63(3):1701–11.

    Article  CAS  PubMed  Google Scholar 

  78. 78.

    Mathew RJ, Wilson WH, Turkington TG, Coleman RE. Cerebellar activity and disturbed time sense after THC. Brain Res. 1998;797(2):183–9.

    Article  CAS  PubMed  Google Scholar 

  79. 79.

    Atakan Z, Bhattacharyya S, Allen P, Martín-Santos R, Crippa JA, Borgwardt SJ, et al. Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. Psychol Med. 2013;43(6):1255–67.

    Article  CAS  PubMed  Google Scholar 

  80. 80.

    O'Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, Andreasen NC, et al. Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology. 2002;26(6):802–16.

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    O'Leary DS, Block RI, Koeppel JA, Schultz SK, Magnotta VA, Ponto LB, et al. Effects of smoking marijuana on focal attention and brain blood flow. Hum Psychopharmacol. 2007;22(3):135–48.

    Article  PubMed  Google Scholar 

  82. 82.

    Bossong MG, Jansma JM, van Hell HH, Jager G, Oudman E, Saliasi E, et al. Effects of δ9-tetrahydrocannabinol on human working memory function. Biol Psychiatry. 2012;71(8):693–9.

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    O'Leary DS, Block RI, Turner BM, Koeppel J, Magnotta VA, Ponto LB, et al. Marijuana alters the human cerebellar clock. Neuroreport. 2003;14(8):1145–51.

    Article  PubMed  Google Scholar 

  84. 84.

    Smith AM, Fried PA, Hogan MJ, Cameron I. Effects of prenatal marijuana on visuospatial working memory: an fMRI study in young adults. Neurotoxicol Teratol. 2006;28(2):286–95.

    Article  CAS  PubMed  Google Scholar 

  85. 85.

    Smith AM, Fried PA, Hogan MJ, Cameron I. Effects of prenatal marijuana on response inhibition: an fMRI study of young adults. Neurotoxicol Teratol. 2004;26(4):533–42.

    Article  CAS  PubMed  Google Scholar 

  86. 86.

    Grewen K, Salzwedel AP, Gao W. Functional connectivity disruption in neonates with prenatal marijuana exposure. Front Hum Neurosci. 2015;9:601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Medina KL, Nagel BJ, Tapert SF. Abnormal cerebellar morphometry in abstinent adolescent marijuana users. Psychiatry Res. 2010;182(2):152–9.

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Cousijn J, Wiers RW, Ridderinkhof KR, van den Brink W, Veltman DJ, Goudriaan AE. Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls. NeuroImage. 2012a;59(4):3845–51.

    Article  PubMed  Google Scholar 

  89. 89.

    Battistella G, Fornari E, Annoni JM, Chtioui H, Dao K, Fabritius M, et al. Long-term effects of cannabis on brain structure. Neuropsychopharmacology. 2014;39(9):2041–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    James A, Hough M, James S, Winmill L, Burge L, Nijhawan S, et al. Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS). Schizophr Res. 2011;128(1–3):91–7.

    Article  CAS  PubMed  Google Scholar 

  91. 91.

    Solowij N, Yücel M, Respondek C, Whittle S, Lindsay E, Pantelis C, et al. Cerebellar white-matter changes in cannabis users with and without schizophrenia. Psychol Med. 2011;41(11):2349–59.

    Article  CAS  PubMed  Google Scholar 

  92. 92.

    Wetherill RR, Jagannathan K, Hager N, Childress AR, Rao H, Franklin TR. Cannabis, cigarettes, and their co-occurring use: disentangling differences in gray matter volume. Int J Neuropsychopharmacol. 2015a;18(10):pyv061.

    Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Volkow ND, Gillespie H, Mullani N, Tancredi L, Grant C, Valentine A, et al. Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication. Psychiatry Res. 1996;67(1):29–38.

    Article  CAS  PubMed  Google Scholar 

  94. 94.

    Sneider JT, Pope HG Jr, Silveri MM, Simpson NS, Gruber SA, Yurgelun-Todd DA. Altered regional blood volume in chronic cannabis smokers. Exp Clin Psychopharmacol. 2006;14(4):422–8.

    Article  CAS  PubMed  Google Scholar 

  95. 95.

    Sneider JT, Pope HG Jr, Silveri MM, Simpson NS, Gruber SA, Yurgelun-Todd DA. Differences in regional blood volume during a 28-day period of abstinence in chronic cannabis smokers. Eur Neuropsychopharmacol. 2008;18(8):612–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Orr C, Morioka R, Behan B, Datwani S, Doucet M, Ivanovic J, et al. Altered resting-state connectivity in adolescent cannabis users. Am J Drug Alcohol Abuse. 2013;39(6):372–81.

    Article  PubMed  Google Scholar 

  97. 97.

    Cheng H, Skosnik PD, Pruce BJ, Brumbaugh MS, Vollmer JM, Fridberg DJ, et al. Resting state functional magnetic resonance imaging reveals distinct brain activity in heavy cannabis users - a multi-voxel pattern analysis. J Psychopharmacol. 2014;28(11):1030–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Wetherill RR, Fang Z, Jagannathan K, Childress AR, Rao H, Franklin TR. Cannabis, cigarettes, and their co-occurring use: disentangling differences in default mode network functional connectivity. Drug Alcohol Depend. 2015b;153:116–23.

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Skosnik PD, Edwards CR, O'Donnell BF, Steffen A, Steinmetz JE, Hetrick WP. Cannabis use disrupts eyeblink conditioning: evidence for cannabinoid modulation of cerebellar-dependent learning. Neuropsychopharmacology. 2008;33(6):1432–40.

    Article  CAS  PubMed  Google Scholar 

  100. 100.

    Steinmetz AB, Edwards CR, Vollmer JM, Erickson MA, O'Donnell BF, Hetrick WP, et al. Examining the effects of former cannabis use on cerebellum-dependent eyeblink conditioning in humans. Psychopharmacology. 2012;221(1):133–41.

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Lopez-Larson MP, Rogowska J, Bogorodzki P, Bueler CE, McGlade EC, Yurgelun-Todd DA. Cortico-cerebellar abnormalities in adolescents with heavy marijuana use. Psychiatry Res. 2012;202(3):224–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J, et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci U S A. 2014b;111(30):E3149–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Wiers CE, Shokri-Kojori E, Wong CT, Abi-Dargham A, Demiral ŞB, Tomasi D, et al. Cannabis abusers show hypofrontality and blunted brain responses to a stimulant challenge in females but not in males. Neuropsychopharmacology. 2016;41(10):2596–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Chang L, Yakupov R, Cloak C, Ernst T. Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation. Brain. 2006;129(Pt 5):1096–112.

    Article  CAS  PubMed  Google Scholar 

  105. 105.

    Block RI, O'Leary DS, Hichwa RD, Augustinack JC, Boles Ponto LL, Ghoneim MM, et al. Effects of frequent marijuana use on memory-related regional cerebral blood flow. Pharmacol Biochem Behav. 2002;72(1–2):237–50.

    Article  CAS  PubMed  Google Scholar 

  106. 106.

    Behan B, Connolly CG, Datwani S, Doucet M, Ivanovic J, Morioka R, et al. Response inhibition and elevated parietal-cerebellar correlations in chronic adolescent cannabis users. Neuropharmacology. 2014;84:131–7.

    Article  CAS  PubMed  Google Scholar 

  107. 107.

    Bolla KI, Eldreth DA, Matochik JA, Cadet JL. Neural substrates of faulty decision-making in abstinent marijuana users. NeuroImage. 2005;26(2):480–92.

    Article  PubMed  Google Scholar 

  108. 108.

    Vaidya JG, Block RI, O'Leary DS, Ponto LB, Ghoneim MM, Bechara A. Effects of chronic marijuana use on brain activity during monetary decision-making. Neuropsychopharmacology. 2012;37(3):618–29.

    Article  PubMed  Google Scholar 

  109. 109.

    Wesley MJ, Hanlon CA, Porrino LJ. Poor decision-making by chronic marijuana users is associated with decreased functional responsiveness to negative consequences. Psychiatry Res. 2011;191(1):51–9.

    Article  PubMed  Google Scholar 

  110. 110.

    Charboneau EJ, Dietrich MS, Park S, Cao A, Watkins TJ, Blackford JU, et al. Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: preliminary results. Psychiatry Res. 2013;214(2):122–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Filbey FM, Dunlop J, Ketcherside A, Baine J, Rhinehardt T, Kuhn B, et al. fMRI study of neural sensitization to hedonic stimuli in long-term, daily cannabis users. Hum Brain Mapp. 2016;37(10):3431–43.

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Filbey FM, Dunlop J. Differential reward network functional connectivity in cannabis dependent and non-dependent users. Drug Alcohol Depend. 2014;140:101–11.

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Filbey FM, Schacht JP, Myers US, Chavez RS, Hutchison KE. Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues. Neuropsychopharmacology. 2010;35(4):967–75.

    Article  CAS  PubMed  Google Scholar 

  114. 114.

    Cousijn J, Goudriaan AE, Ridderinkhof KR, van den Brink W, Veltman DJ, Wiers RW. Approach-bias predicts development of cannabis problem severity in heavy cannabis users: results from a prospective FMRI study. PLoS One. 2012b;7(9):e42394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Wise RA, Bozarth MA. Brain mechanisms of drug reward and euphoria. Psychiatr Med. 1985;3(4):445–60.

    CAS  PubMed  Google Scholar 

  116. 116.

    Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev. 1987;94(4):469–92.

    Article  CAS  Google Scholar 

  117. 117.

    Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol. 1989;40:191–225.

    Article  CAS  PubMed  Google Scholar 

  118. 118.

    Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35(1):217–38.

    Article  Google Scholar 

  119. 119.

    Ehrman R, Ternes J, O'Brien CP, McLellan AT. Conditioned tolerance in human opiate addicts. Psychopharmacology. 1992;108(1–2):218–24.

    Article  CAS  PubMed  Google Scholar 

  120. 120.

    Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278(5335):52–8.

    Article  CAS  PubMed  Google Scholar 

  121. 121.

    Ahmed SH. Escalation of drug use. In: Olmstead MC, editor. Animal models of drug addiction, neuromethods, vol. 53. New York: Humana; 2011. p. 267–92.

    Google Scholar 

  122. 122.

    Volicer L, Puri SK, Choma P. Cyclic GMP and GABA levels in rat striatum and cerebellum during morphine withdrawal: effect of apomorphine. Neuropharmacology. 1977;16(11):791–4.

    Article  CAS  PubMed  Google Scholar 

  123. 123.

    Leza JC, Lizasoain I, Cuéllar B, Moro MA, Lorenzo P. Correlation between brain nitric oxide synthase activity and opiate withdrawal. Naunyn Schmiedeberg's Arch Pharmacol. 1996;353(3):349–54.

    Article  CAS  Google Scholar 

  124. 124.

    Phillips SC, Cragg BG. Alcohol withdrawal causes a loss of cerebellar Purkinje cells in mice. J Stud Alcohol. 1984;45(6):475–80.

    Article  CAS  PubMed  Google Scholar 

  125. 125.

    Beckmann AM, Matsumoto I, Wilce PA. AP-1 and Egr DNA-binding activities are increased in rat brain during ethanol withdrawal. J Neurochem. 1997;69(1):306–14.

    Article  CAS  PubMed  Google Scholar 

  126. 126.

    Robinson TE, Berridge KC. Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond Ser B Biol Sci. 2008;363(1507):3137–46.

    Article  Google Scholar 

  127. 127.

    Bhargava HN, Kumar S. Sensitization to the locomotor stimulant activity of cocaine is associated with increases in nitric oxide synthase activity in brain regions and spinal cord of mice. Pharmacology. 1997;55(6):292–8.

    Article  CAS  PubMed  Google Scholar 

  128. 128.

    Hamamura M, Ozawa H, Kimuro Y, Okouchi J, Higasa K, Iwaki A, et al. Differential decreases in c-fos and aldolase C mRNA expression in the rat cerebellum after repeated administration of methamphetamine. Brain Res Mol Brain Res. 1999;64(1):119–31.

    Article  CAS  PubMed  Google Scholar 

  129. 129.

    Robbins TW, Ersche KD, Everitt BJ. Drug addiction and the memory systems of the brain. Ann N Y Acad Sci. 2008;1141:1–21.

    Article  CAS  PubMed  Google Scholar 

  130. 130.

    Venniro M, Caprioli D, Shaham Y. Animal models of drug relapse and craving: from drug priming-induced reinstatement to incubation of craving after voluntary abstinence. Prog Brain Res. 2016;224:25–52.

    Article  PubMed  Google Scholar 

  131. 131.

    Schneider F, Habel U, Wagner M, Franke P, Salloum JB, Shah NJ, et al. Subcortical correlates of craving in recently abstinent alcoholic patients. Am J Psychiatry. 2001;158(7):1075–83.

    Article  CAS  PubMed  Google Scholar 

  132. 132.

    Smolka MN, Bühler M, Klein S, Zimmermann U, Mann K, Heinz A, et al. Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery. Psychopharmacology. 2006;184(3–4):577–88.

    Article  CAS  PubMed  Google Scholar 

  133. 133.

    Wakeford AGP, Wetzell BB, Pomfrey RL, Clasen MM, Taylor WW, Hempel BJ, et al. The effects of cannabidiol (CBD) on Δ9-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats. Exp Clin Psychopharmacol. 2017;25(4):242–8.

    Article  CAS  PubMed  Google Scholar 

  134. 134.

    Manwell LA, Charchoglyan A, Brewer D, Matthews BA, Heipel H, Mallet PE. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part I: development and validation of a pulmonary cannabinoid route of exposure for experimental pharmacology studies in rodents. J Pharmacol Toxicol Methods. 2014;70(1):120–7.

    Article  CAS  PubMed  Google Scholar 

  135. 135.

    Manwell LA, Ford B, Matthews BA, Heipel H, Mallet PE. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents. J Pharmacol Toxicol Methods. 2014 Jul-Aug;70(1):112–9.

    Article  CAS  PubMed  Google Scholar 

  136. 136.

    Nguyen JD, Aarde SM, Vandewater SA, Grant Y, Stouffer DG, Parsons LH, et al. Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology. Neuropharmacology. 2016 Oct;109:112–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Vendruscolo JCM, Tunstall BJ, Carmack SA, Schmeichel BE, Lowery-Gionta EG, Cole M, et al. Compulsive-like sufentanil vapor self-administration in rats. Neuropsychopharmacology. 2018;43(4):801–9.

    Article  CAS  PubMed  Google Scholar 

  138. 138.

    Kallupi M, George O. Nicotine vapor method to induce nicotine dependence in rodents. Curr Protoc Neurosci. 2017;80:8.41.1–8.41.10.

    Article  Google Scholar 

  139. 139.

    de Guglielmo G, Kallupi M, Cole MD, George O. Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration. Psychopharmacology. 2017 Jul;234(13):2009–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author thanks Dr. Carl Hobbs for authorizing the use of graphic content produced by him.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Josep Moreno-Rius.

Ethics declarations

Conflict of Interest

The author declares no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moreno-Rius, J. The Cerebellum, THC, and Cannabis Addiction: Findings from Animal and Human Studies. Cerebellum 18, 593–604 (2019). https://doi.org/10.1007/s12311-018-0993-7

Download citation

Keywords

  • Cerebellum
  • Cannabis
  • Δ9-Tetrahydrocannabinol
  • Addiction
  • Withdrawal
  • Craving