Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Deconstructing the neurobiology of cannabis use disorder

Subjects

Abstract

There have been dramatic changes worldwide in the attitudes toward and consumption of recreational and medical cannabis. Cannabinoid receptors, which mediate the actions of cannabis, are abundantly expressed in brain regions known to mediate neural processes underlying reward, cognition, emotional regulation and stress responsivity relevant to addiction vulnerability. Despite debates regarding potential pathological consequences of cannabis use, cannabis use disorder is a clinical diagnosis with high prevalence in the general population and that often has its genesis in adolescence and in vulnerable individuals associated with psychiatric comorbidity, genetic and environmental factors. Integrated information from human and animal studies is beginning to expand insights regarding neurobiological systems associated with cannabis use disorder, which often share common neural characteristics with other substance use disorders, that could inform prevention and treatment strategies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Odds ratios of psychiatric conditions associated with CUD.
Fig. 2: Overview of the dynamic patterns of the in vivo neurochemical-related alterations (based on PET, functional MRI, and proton magnetic resonance spectroscopy (H-MRS) studies) associated with CUD.
Fig. 3: Alterations of gray matter volume (based on MRI studies) detected in individuals with CUD.
Fig. 4: Differences in functional activity (based on functional MRI and electroencephalogram studies) detected in the brain of abstinent individuals with CUD during exposure to specific tasks and stimuli.
Fig. 5: Synaptic perturbations based on animal models associated with chronic THC exposure (right) as compared to control condition (left) in glutamate and GABA synapses in the cortex.
Fig. 6: Factors contributing to CUD.

References

  1. 1.

    UN Office on Drugs and Crime. World Drug Report 3: Market Analysis of Plant-Based Drugs: Opiates, Cocaine, Cannabis. (UNODC Research, 2017).

  2. 2.

    Hasin, D. S. et al. Prevalence of marijuana use disorders in the United States between 2001-2002 and 2012-2013. JAMA Psychiatry 72, 1235–1242 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Martins, S. S. et al. Changes in US lifetime heroin use and heroin use disorder: prevalence from the 2001-2002 to 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry 74, 445–455 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Kerridge, B. T. et al. Changes in the prevalence and correlates of cocaine use and cocaine use disorder in the United States, 2001-2002 and 2012-2013. Addict. Behav. 90, 250–257 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Nutt, D. J., King, L. A. & Phillips, L. D., Independent Scientific Committee on Drugs. Drug harms in the UK: a multicriteria decision analysis. Lancet 376, 1558–1565 (2010).

    PubMed  Article  Google Scholar 

  6. 6.

    Hasin, D. S. et al. Prevalence and correlates of DSM-5 cannabis use disorder, 2012-2013: findings from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Am. J. Psychiatry 173, 588–599 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Hanuš, L. O., Meyer, S. M., Muñoz, E., Taglialatela-Scafati, O. & Appendino, G. Phytocannabinoids: a unified critical inventory. Nat. Prod. Rep. 33, 1357–1392 (2016).

    PubMed  Article  Google Scholar 

  8. 8.

    ElSohly, M. A. et al. Potency trends of Δ9-THC and other cannabinoids in confiscated marijuana from 1980-1997. J. Forensic Sci. 45, 24–30 (2000).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Chandra, S. et al. New trends in cannabis potency in USA and Europe during the last decade (2008-2017). Eur. Arch. Psychiatry Clin. Neurosci. 269, 5–15 (2019).

    PubMed  Article  Google Scholar 

  10. 10.

    Mechoulam, R., Hanuš, L. O., Pertwee, R. & Howlett, A. C. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat. Rev. Neurosci. 15, 757–764 (2014).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Mechoulam, R. & Parker, L. A. The endocannabinoid system and the brain. Annu. Rev. Psychol. 64, 21–47 (2013).

    PubMed  Article  Google Scholar 

  12. 12.

    Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Busquets-Garcia, A., Bains, J. & Marsicano, G. CB1 receptor signaling in the brain: extracting specificity from ubiquity. Neuropsychopharmacology 43, 4–20 (2018).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Xi, Z. X. et al. Brain cannabinoid CB2 receptors modulate cocaine’s actions in mice. Nat. Neurosci. 14, 1160–1166 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th ed (American Psychiatric Association, 2013).

  16. 16.

    Feingold, D., Fox, J., Rehm, J. & Lev-Ran, S. Natural outcome of cannabis use disorder: a 3-year longitudinal follow-up. Addiction 110, 1963–1974 (2015).

    PubMed  Article  Google Scholar 

  17. 17.

    Verweij, K. J. et al. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction 105, 417–430 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Lynskey, M. T. et al. An Australian twin study of cannabis and other illicit drug use and misuse, and other psychopathology. Twin Res. Hum. Genet. 15, 631–641 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Gillespie, N. A., Neale, M. C. & Kendler, K. S. Pathways to cannabis abuse: a multi-stage model from cannabis availability, cannabis initiation and progression to abuse. Addiction 104, 430–438 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Agrawal, A. et al. Genome-wide association study identifies a novel locus for cannabis dependence. Mol. Psychiatry 23, 1293–1302 (2018).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Demontis, D. et al. Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nat. Neurosci. 22, 1066–1074 (2019).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Yang, J. et al. The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol. Psychiatry 20, 1467–1478 (2015).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    McKay, J. D. et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat. Genet. 49, 1126–1132 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Pasman, J. A. et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat. Neurosci. 21, 1161–1170 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Sherva, R. et al. Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks. JAMA Psychiatry 73, 472–480 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Di Forti, M. et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. Lancet Psychiatry 6, 427–436 (2019).

    PubMed  Article  Google Scholar 

  27. 27.

    Radhakrishnan, R., Wilkinson, S. T. & D’Souza, D. C. Gone to pot - a review of the association between cannabis and psychosis. Front. Psychiatry 5, 54 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Wittchen, H. U. et al. Cannabis use and cannabis use disorders and their relationship to mental disorders: a 10-year prospective-longitudinal community study in adolescents. Drug Alcohol Depend. 88(Suppl 1), S60–S70 (2007).

    PubMed  Article  Google Scholar 

  29. 29.

    Blanco, C. et al. Cannabis use and risk of psychiatric disorders: prospective evidence from a US national longitudinal study. JAMA Psychiatry 73, 388–395 (2016).

    PubMed  Article  Google Scholar 

  30. 30.

    Emery, N. N. & Simons, J. S. A reinforcement sensitivity model of affective and behavioral dysregulation in marijuana use and associated problems. Exp. Clin. Psychopharmacol. 25, 281–294 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Ridenour, T. A. et al. Neurobehavior disinhibition, parental substance use disorder, neighborhood quality and development of cannabis use disorder in boys. Drug Alcohol Depend. 102, 71–77 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Hines, L. A. et al. Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design. Psychol. Med. 48, 2786–2793 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Rogosch, F. A., Oshri, A. & Cicchetti, D. From child maltreatment to adolescent cannabis abuse and dependence: a developmental cascade model. Dev. Psychopathol. 22, 883–897 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Stinson, F. S., Ruan, W. J., Pickering, R. & Grant, B. F. Cannabis use disorders in the USA: prevalence, correlates and co-morbidity. Psychol. Med. 36, 1447–1460 (2006).

    PubMed  Article  Google Scholar 

  35. 35.

    Haberstick, B. C. et al. Prevalence and correlates of alcohol and cannabis use disorders in the United States: results from the national longitudinal study of adolescent health. Drug Alcohol Depend. 136, 158–161 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Khan, S. S. et al. Gender differences in cannabis use disorders: results from the National Epidemiologic Survey of Alcohol and Related Conditions. Drug Alcohol Depend. 130, 101–108 (2013).

    PubMed  Article  Google Scholar 

  37. 37.

    Hirvonen, J. et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. Psychiatry 17, 642–649 (2012).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Ceccarini, J. et al. [18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users. Addict. Biol. 20, 357–367 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    D’Souza, D. C. et al. Rapid changes in CB1 receptor availability in cannabis dependent males after abstinence from cannabis. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 1, 60–67 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Koob, G. F. & Volkow, N. D. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3, 760–773 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Villares, J. Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain. Neuroscience 145, 323–334 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Boileau, I. et al. Fatty acid amide hydrolase binding in brain of cannabis users: imaging with the novel radiotracer [11C]CURB. Biol. Psychiatry 80, 691–701 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Bossong, M. G. et al. Δ9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34, 759–766 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Thiruchselvam, T., Malik, S. & Le Foll, B. A review of positron emission tomography studies exploring the dopaminergic system in substance use with a focus on tobacco as a co-variate. Am. J. Drug Alcohol Abuse 43, 197–214 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Urban, N. B. et al. Dopamine release in chronic cannabis users: a [11c]raclopride positron emission tomography study. Biol. Psychiatry 71, 677–683 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    van de Giessen, E. et al. Deficits in striatal dopamine release in cannabis dependence. Mol. Psychiatry 22, 68–75 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  47. 47.

    Volkow, N. D. et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc. Natl Acad. Sci. USA 111, E3149–E3156 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Bloomfield, M. A. et al. Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol. Psychiatry 75, 470–478 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Bloomfield, M. A., Morgan, C. J., Kapur, S., Curran, H. V. & Howes, O. D. The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study. Psychopharmacology (Berl.) 231, 2251–2259 (2014).

    CAS  Article  Google Scholar 

  50. 50.

    Leroy, C. et al. Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study. Addict. Biol. 17, 981–990 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Volkow, N. D., Fowler, J. S., Wang, G. J., Baler, R. & Telang, F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 56(Suppl 1), 3–8 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Kalivas, P. W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Katona, I. Cannabis and endocannabinoid signaling in epilepsy. Handb. Exp. Pharmacol. 231, 285–316 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Colizzi, M., McGuire, P., Pertwee, R. G. & Bhattacharyya, S. Effect of cannabis on glutamate signalling in the brain: A systematic review of human and animal evidence. Neurosci. Biobehav. Rev. 64, 359–381 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Colizzi, M. et al. Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis. Mol. Psychiatry https://doi.org/10.1038/s41380-019-0374-8 (2019).

  56. 56.

    Muetzel, R. L. et al. In vivo 1H magnetic resonance spectroscopy in young-adult daily marijuana users. Neuroimage Clin. 2, 581–589 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Prescot, A. P., Locatelli, A. E., Renshaw, P. F. & Yurgelun-Todd, D. A. Neurochemical alterations in adolescent chronic marijuana smokers: a proton MRS study. Neuroimage 57, 69–75 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Mon, A., Durazzo, T. C. & Meyerhoff, D. J. Glutamate, GABA, and other cortical metabolite concentrations during early abstinence from alcohol and their associations with neurocognitive changes. Drug Alcohol Depend. 125, 27–36 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Yang, S. et al. Lower glutamate levels in rostral anterior cingulate of chronic cocaine users - A (1)H-MRS study using TE-averaged PRESS at 3 T with an optimized quantification strategy. Psychiatry Res. 174, 171–176 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Bolla, K. I., Eldreth, D. A., Matochik, J. A. & Cadet, J. L. Neural substrates of faulty decision-making in abstinent marijuana users. Neuroimage 26, 480–492 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Izquierdo, A. Functional heterogeneity within rat orbitofrontal cortex in reward learning and decision making. J. Neurosci. 37, 10529–10540 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Guttman, Z., Moeller, S. J. & London, E. D. Neural underpinnings of maladaptive decision-making in addictions. Pharmacol. Biochem. Behav. 164, 84–98 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Battistella, G. et al. Long-term effects of cannabis on brain structure. Neuropsychopharmacology 39, 2041–2048 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Chye, Y. et al. Orbitofrontal and caudate volumes in cannabis users: a multi-site mega-analysis comparing dependent versus non-dependent users. Psychopharmacology (Berl.) 234, 1985–1995 (2017).

    CAS  Article  Google Scholar 

  65. 65.

    Cheetham, A. et al. Orbitofrontal volumes in early adolescence predict initiation of cannabis use: a 4-year longitudinal and prospective study. Biol. Psychiatry 71, 684–692 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Chye, Y. et al. Cannabis-related hippocampal volumetric abnormalities specific to subregions in dependent users. Psychopharmacology (Berl.) 234, 2149–2157 (2017).

    CAS  Article  Google Scholar 

  67. 67.

    Schacht, J. P., Hutchison, K. E. & Filbey, F. M. Associations between cannabinoid receptor-1 (CNR1) variation and hippocampus and amygdala volumes in heavy cannabis users. Neuropsychopharmacology 37, 2368–2376 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    French, L. et al. Early cannabis use, polygenic risk score for schizophrenia and brain maturation in adolescence. JAMA Psychiatry 72, 1002–1011 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Cousijn, J. et al. Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls. Neuroimage 59, 3845–3851 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Koenders, L. et al. Grey matter changes associated with heavy cannabis use: a longitudinal sMRI study. PLoS One 11, e0152482 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Pagliaccio, D. et al. Shared predisposition in the association between cannabis use and subcortical brain structure. JAMA Psychiatry 72, 994–1001 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Scallet, A. C. et al. Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC). Brain Res. 436, 193–198 (1987).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Miller, M. L. et al. Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol. Psychiatry 24, 588–600 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Zahr, N. M. & Pfefferbaum, A. Alcohol’s effects on the brain: neuroimaging results in humans and animal models. Alcohol Res. 38, 183–206 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Wollman, S. C. et al. Gray matter abnormalities in opioid-dependent patients: A neuroimaging meta-analysis. Am. J. Drug Alcohol Abuse 43, 505–517 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Mackey, S. et al. Mega-analysis of gray matter volume in substance dependence: general and substance-specific regional effects. Am. J. Psychiatry 176, 119–128 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Medina, K. L., Nagel, B. J. & Tapert, S. F. Abnormal cerebellar morphometry in abstinent adolescent marijuana users. Psychiatry Res. 182, 152–159 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Schmahmann, J. D. The cerebellum and cognition. Neurosci. Lett. 688, 62–75 (2019).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Nader, D. A. & Sanchez, Z. M. Effects of regular cannabis use on neurocognition, brain structure, and function: a systematic review of findings in adults. Am. J. Drug Alcohol Abuse 44, 4–18 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    DeWitt, S. J., Ketcherside, A., McQueeny, T. M., Dunlop, J. P. & Filbey, F. M. The hyper-sentient addict: an exteroception model of addiction. Am. J. Drug Alcohol Abuse 41, 374–381 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Pujol, J. et al. Functional connectivity alterations in brain networks relevant to self-awareness in chronic cannabis users. J. Psychiatr. Res. 51, 68–78 (2014).

    PubMed  Article  Google Scholar 

  82. 82.

    Wetherill, R. R. et al. Cannabis, cigarettes, and their co-occurring use: Disentangling differences in default mode network functional connectivity. Drug Alcohol Depend. 153, 116–123 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Mak, L. E. et al. The default mode network in healthy individuals: a systematic review and meta-analysis. Brain Connect. 7, 25–33 (2017).

    PubMed  Article  Google Scholar 

  84. 84.

    Blanco-Hinojo, L. et al. Attenuated frontal and sensory inputs to the basal ganglia in cannabis users. Addict. Biol. 22, 1036–1047 (2017).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Kober, H., DeVito, E. E., DeLeone, C. M., Carroll, K. M. & Potenza, M. N. Cannabis abstinence during treatment and one-year follow-up: relationship to neural activity in men. Neuropsychopharmacology 39, 2288–2298 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Chang, L., Yakupov, R., Cloak, C. & Ernst, T. Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation. Brain 129, 1096–1112 (2006).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Broyd, S. J., van Hell, H. H., Beale, C., Yücel, M. & Solowij, N. Acute and chronic effects of cannabinoids on human cognition-a systematic review. Biol. Psychiatry 79, 557–567 (2016).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Kanayama, G., Rogowska, J., Pope, H. G., Gruber, S. A. & Yurgelun-Todd, D. A. Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study. Psychopharmacology (Berl.) 176, 239–247 (2004).

    CAS  Article  Google Scholar 

  89. 89.

    Smith, A. M., Longo, C. A., Fried, P. A., Hogan, M. J. & Cameron, I. Effects of marijuana on visuospatial working memory: an fMRI study in young adults. Psychopharmacology (Berl.) 210, 429–438 (2010).

    CAS  Article  Google Scholar 

  90. 90.

    Sagar, K. A. & Gruber, S. A. Interactions between recreational cannabis use and cognitive function: lessons from functional magnetic resonance imaging. Ann. NY Acad. Sci. 1451, 42–70 (2019).

    PubMed  Article  Google Scholar 

  91. 91.

    Schweinsburg, A. D. et al. The influence of recency of use on fMRI response during spatial working memory in adolescent marijuana users. J. Psychoactive Drugs 42, 401–412 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Padula, C. B., Schweinsburg, A. D. & Tapert, S. F. Spatial working memory performance and fMRI activation interaction in abstinent adolescent marijuana users. Psychol. Addict. Behav. 21, 478–487 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Cousijn, J. et al. Neural responses associated with cue-reactivity in frequent cannabis users. Addict. Biol. 18, 570–580 (2013).

    PubMed  Article  Google Scholar 

  94. 94.

    Filbey, F. M., Schacht, J. P., Myers, U. S., Chavez, R. S. & Hutchison, K. E. Marijuana craving in the brain. Proc. Natl Acad. Sci. USA 106, 13016–13021 (2009).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Filbey, F. M. et al. fMRI study of neural sensitization to hedonic stimuli in long-term, daily cannabis users. Hum. Brain Mapp. 37, 3431–3443 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Filbey, F. M., Schacht, J. P., Myers, U. S., Chavez, R. S. & Hutchison, K. E. Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues. Neuropsychopharmacology 35, 967–975 (2010).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Zimmermann, K. et al. Altered orbitofrontal activity and dorsal striatal connectivity during emotion processing in dependent marijuana users after 28 days of abstinence. Psychopharmacology (Berl.) 235, 849–859 (2018).

    CAS  Article  Google Scholar 

  98. 98.

    Wesley, M. J., Lile, J. A., Hanlon, C. A. & Porrino, L. J. Abnormal medial prefrontal cortex activity in heavy cannabis users during conscious emotional evaluation. Psychopharmacology (Berl.) 233, 1035–1044 (2016).

    CAS  Article  Google Scholar 

  99. 99.

    Breivogel, C. S. et al. Chronic Δ9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J. Neurochem. 73, 2447–2459 (1999).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Burston, J. J., Wiley, J. L., Craig, A. A., Selley, D. E. & Sim-Selley, L. J. Regional enhancement of cannabinoid CB1 receptor desensitization in female adolescent rats following repeated Δ9-tetrahydrocannabinol exposure. Br. J. Pharmacol. 161, 103–112 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Rubino, T. et al. Chronic Δ9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacology 33, 2760–2771 (2008).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Sim-Selley, L. J. et al. Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term cannabinoid administration. Mol. Pharmacol. 70, 986–996 (2006).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Fan, N., Yang, H., Zhang, J. & Chen, C. Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Δ9-THC exposure-impaired hippocampal synaptic plasticity. J. Neurochem. 112, 691–702 (2010).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Wang, H. & Zhang, M. The role of Ca2+-stimulated adenylyl cyclases in bidirectional synaptic plasticity and brain function. Rev. Neurosci. 23, 67–78 (2012).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Barco, A. & Marie, H. Genetic approaches to investigate the role of CREB in neuronal plasticity and memory. Mol. Neurobiol. 44, 330–349 (2011).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Steel, R. W., Miller, J. H., Sim, D. A. & Day, D. J. Delta-9-tetrahydrocannabinol disrupts hippocampal neuroplasticity and neurogenesis in trained, but not untrained adolescent Sprague-Dawley rats. Brain Res. 1548, 12–19 (2014).

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Kittler, J. T. et al. Large-scale analysis of gene expression changes during acute and chronic exposure to Δ9-THC in rats. Physiol. Genomics 3, 175–185 (2000).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Grigorenko, E. et al. Assessment of cannabinoid induced gene changes: tolerance and neuroprotection. Chem. Phys. Lipids 121, 257–266 (2002).

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Tantra, M. et al. St8sia2 deficiency plus juvenile cannabis exposure in mice synergistically affect higher cognition in adulthood. Behav. Brain Res. 275, 166–175 (2014).

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Stringer, S. et al. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium. Transl. Psychiatry 6, e769 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Skosnik, P. D., Cortes-Briones, J. A. & Hajós, M. It’s all in the rhythm: the role of cannabinoids in neural oscillations and psychosis. Biol. Psychiatry 79, 568–577 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Raver, S. M. & Keller, A. Permanent suppression of cortical oscillations in mice after adolescent exposure to cannabinoids: receptor mechanisms. Neuropharmacology 86, 161–173 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Hajós, M., Hoffmann, W. E. & Kocsis, B. Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia. Biol. Psychiatry 63, 1075–1083 (2008).

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Hwang, E.K. & Lupica, C.R. Altered corticolimbic control of the nucleus accumbens by long-term Δ9-tetrahydrocannabinol exposure. Biol. Psychiatry S0006-3223(19)31559-8 (2019).

  115. 115.

    Morel, L. J., Giros, B. & Daugé, V. Adolescent exposure to chronic delta-9-tetrahydrocannabinol blocks opiate dependence in maternally deprived rats. Neuropsychopharmacology 34, 2469–2476 (2009).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Stopponi, S. et al. Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats. Eur. Neuropsychopharmacol. 24, 1037–1045 (2014).

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Solinas, M., Panlilio, L. V. & Goldberg, S. R. Exposure to Δ-9-tetrahydrocannabinol (THC) increases subsequent heroin taking but not heroin’s reinforcing efficacy: a self-administration study in rats. Neuropsychopharmacology 29, 1301–1311 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Hurd, Y. L., Michaelides, M., Miller, M. L. & Jutras-Aswad, D. Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology 76(Pt B), 416–424 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Blanco, C., Flórez-Salamanca, L., Secades-Villa, R., Wang, S. & Hasin, D. S. Predictors of initiation of nicotine, alcohol, cannabis, and cocaine use: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Am. J. Addict. 27, 477–484 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Panlilio, L. V., Zanettini, C., Barnes, C., Solinas, M. & Goldberg, S. R. Prior exposure to THC increases the addictive effects of nicotine in rats. Neuropsychopharmacology 38, 1198–1208 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Hillard, C. J., Beatka, M. & Sarvaideo, J. Endocannabinoid signaling and the hypothalamic-pituitary-adrenal axis. Compr. Physiol. 7, 1–15 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Harte-Hargrove, L. C. & Dow-Edwards, D. L. Withdrawal from THC during adolescence: sex differences in locomotor activity and anxiety. Behav. Brain Res. 231, 48–59 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    O’Shea, M., Singh, M. E., McGregor, I. S. & Mallet, P. E. Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats. J. Psychopharmacol. 18, 502–508 (2004).

    PubMed  Article  Google Scholar 

  124. 124.

    Barrus, D. G., Lefever, T. W. & Wiley, J. L. Evaluation of reinforcing and aversive effects of voluntary Δ9-tetrahydrocannabinol ingestion in rats. Neuropharmacology 137, 133–140 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Nguyen, J. D. et al. Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology. Neuropharmacology 109, 112–120 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Bruijnzeel, A. W. et al. Behavioral characterization of the effects of cannabis smoke and anandamide in rats. PLoS One 11, e0153327 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Månsson, K. N. et al. Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder. Transl. Psychiatry 6, e727 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Yang, Z. et al. Cognitive behavioral therapy is associated with enhanced cognitive control network activity in major depression and posttraumatic stress disorder. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 3, 311–319 (2018).

    PubMed  Article  Google Scholar 

  129. 129.

    MinlanYuan et al. Cerebellar neural circuits involving executive control network predict response to group cognitive behavior therapy in social anxiety disorder. Cerebellum 16, 673–682 (2017).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Morgan, C. J., Schafer, G., Freeman, T. P. & Curran, H. V. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. Br. J. Psychiatry 197, 285–290 (2010).

    PubMed  Article  Google Scholar 

  131. 131.

    Bergamaschi, M. M. et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 36, 1219–1226 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Crippa, J. A. et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J. Psychopharmacol. 25, 121–130 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Murphy, M. et al. Chronic adolescent Δ9-tetrahydrocannabinol treatment of male mice leads to long-term cognitive and behavioral dysfunction, which are prevented by concurrent cannabidiol treatment. Cannabis Cannabinoid Res. 2, 235–246 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Zuardi, A. W., Shirakawa, I., Finkelfarb, E. & Karniol, I. G. Action of cannabidiol on the anxiety and other effects produced by δ9-THC in normal subjects. Psychopharmacology (Berl.) 76, 245–250 (1982).

    CAS  Article  Google Scholar 

  135. 135.

    Ren, Y., Whittard, J., Higuera-Matas, A., Morris, C. V. & Hurd, Y. L. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J. Neurosci. 29, 14764–14769 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Grimm, O. et al. Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity. Eur. Neuropsychopharmacol. 28, 841–849 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Beale, C. et al. Prolonged cannabidiol treatment effects on hippocampal subfield volumes in current cannabis users. Cannabis Cannabinoid Res. 3, 94–107 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Haney, M. et al. Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology 41, 1974–1982 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    White, T. et al. Paediatric population neuroimaging and the Generation R Study: the second wave. Eur. J. Epidemiol. 33, 99–125 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Szutorisz, H. & Hurd, Y. L. Epigenetic effects of cannabis exposure. Biol. Psychiatry 79, 586–594 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. 141.

    Filbey, F. M. et al. Long-term effects of marijuana use on the brain. Proc. Natl Acad. Sci. USA 111, 16913–16918 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  142. 142.

    De Bellis, M. D. et al. Neural mechanisms of risky decision-making and reward response in adolescent onset cannabis use disorder. Drug Alcohol Depend. 133, 134–145 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Nestor, L., Hester, R. & Garavan, H. Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users. Neuroimage 49, 1133–1143 (2010).

    PubMed  Article  Google Scholar 

  144. 144.

    Yücel, M. et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch. Gen. Psychiatry 65, 694–701 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  145. 145.

    Charboneau, E. J. et al. Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: preliminary results. Psychiatry Res. 214, 122–131 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Goldman, M. et al. Reward-related brain response and craving correlates of marijuana cue exposure: a preliminary study in treatment-seeking marijuana-dependent subjects. J. Addict. Med. 7, 8–16 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Brezing, C. A. & Levin, F. R. The current state of pharmacological treatments for cannabis use disorder and withdrawal. Neuropsychopharmacology 43, 173–194 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148.

    Morgan, C. J., Freeman, T. P., Schafer, G. L. & Curran, H. V. Cannabidiol attenuates the appetitive effects of Δ9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology 35, 1879–1885 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    D’Souza, D. C. et al. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Lancet Psychiatry 6, 35–45 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Kawamura, Y. et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J. Neurosci. 26, 2991–3001 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the US National Institutes of Health (NIH) DA030359.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yasmin L. Hurd.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Neuroscience thanks Rafael Maldonado and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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

Ferland, JM.N., Hurd, Y.L. Deconstructing the neurobiology of cannabis use disorder. Nat Neurosci 23, 600–610 (2020). https://doi.org/10.1038/s41593-020-0611-0

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing