Abstract
Rationale
Cannabis (CB) use and dependence are associated with regionally specific alterations to brain circuitry and substantial psychosocial impairment.
Objectives
The objective of this study was to investigate the association between CB use and dependence, and the volumes of brain regions critically involved in goal-directed learning and behaviour—the orbitofrontal cortex (OFC) and caudate.
Methods
In the largest multi-site structural imaging study of CB users vs healthy controls (HC), 140 CB users and 121 HC were recruited from four research sites. Group differences in OFC and caudate volumes were investigated between HC and CB users and between 70 dependent (CB-dep) and 50 non-dependent (CB-nondep) users. The relationship between quantity of CB use and age of onset of use and caudate and OFC volumes was explored.
Results
CB users (consisting of CB-dep and CB-nondep) did not significantly differ from HC in OFC or caudate volume. CB-dep compared to CB-nondep users exhibited significantly smaller volume in the medial and the lateral OFC. Lateral OFC volume was particularly smaller in CB-dep females, and reduced volume in the CB-dep group was associated with higher monthly cannabis dosage.
Conclusions
Smaller medial OFC volume may be driven by CB dependence-related mechanisms, while smaller lateral OFC volume may be due to ongoing exposure to cannabinoid compounds. The results highlight a distinction between cannabis use and dependence and warrant examination of gender-specific effects in studies of CB dependence.
This is a preview of subscription content, access via your institution.



References
Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300
Ashtari M, Avants B, Cyckowski L et al (2011) Medial temporal structures and memory functions in adolescents with heavy cannabis use. J Psychiatr Res 45:1055–1066
Batalla A, Soriano-mas C, López-solà M et al (2013) Modulation of brain structure by catechol-O-methyltransferase Val158Met polymorphism in chronic cannabis users. Addict Biol 19:722–732
Battistella G, Fornari E, Annoni J-M et al (2014) Long-term effects of cannabis on brain structure. Neuropsychopharmacology 39:2041–2048
Benjamini Y, Yekutieli D (2001) The control of the false discovery rate in multiple testing under depencency. Ann Stat 29:1165–1188
Bloomfield MAP, Morgan CJA, Egerton A et al (2014) Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol Psychiatry 75:470–478
Boes AD, Bechara A, Tranel D et al (2009) Right ventromedial prefrontal cortex: a neuroanatomical correlate of impulse control in boys. Soc Cogn Affect Neurosci 4:1–9
Bossong MG, van Berckel BN, Boellaard R et al (2009) Δ9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34:759–766
Broyd SJ, van Hell HH, Beale C et al (2016) Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiatry 79:557–567
Budney AJ, Moore BA (2002) Development and consequences of cannabis dependence. J Clin Pharmacol 42:28S–33S
Cardinal RN, Parkinson JA, Hall J, Everitt BJ (2002) Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26:321–352
Cheetham A, Allen NB, Whittle S et al (2011) Orbitofrontal volumes in early adolescence predict initiation of cannabis use: a 4-year longitudinal and prospective study. Biol Psychiatry 71:684–692
Chen CY, O’Brien MS, Anthony JC (2005) Who becomes cannabis dependent soon after onset of use? Epidemiological evidence from the United States: 2000-2001. Drug Alcohol Depend 79:11–22
Churchwell JC, Lopez-Larson M, Yurgelun-Todd DA (2010) Altered frontal cortical volume and decision making in adolescent cannabis users. Front Psychol 1:1–8
Cousijn J, Wiers RW, Ridderinkhof KR et al (2012) Grey matter alterations associated with cannabis use : results of a VBM study in heavy cannabis users and healthy controls. NeuroImage 59:3845–3851
Craft RM (2005) Sex differences in behavioral effects of cannabinoids. Life Sci 77:2471–2478
Craft RM, Marusich JA, Wiley JL (2013) Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system? Life Sci 92:476–481
Curran HV, Freeman TP, Mokrysz C et al (2016) Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17:293–306
Degenhardt L, Chiu WT, Sampson N et al (2007) Epidemiological patterns of extra-medical drug use in the United States: evidence from the National Comorbidity Survey Replication, 2001-2003. Drug Alcohol Depend 90:210–223
Downer E, Boland B, Fogarty M, Campbell V (2001) Delta 9-tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the CB1 receptor. Neuroreport 12:3973–3978
Elkashef A, Vocci F, Huestis M et al (2008) Marijuana neurobiology and treatment. Subst Abus 29:17–29
Enzi B, Lissek S, Edel M-A et al (2015) Alterations of monetary reward and punishment processing in chronic cannabis users: an fMRI study. PLoS One 10:e0119150
Ersche KD, Barnes A, Simon Jones P et al (2011) Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain 134:2013–2024
Eskildsen S, Coupe P (2011) Effect of non-local means denoising on cortical segmentation accuracy with FACE. In: Organization for Human Brain Mapping 2011 Annual Meeting, Jun 2011, Canada
Everitt BJ, Robbins TW (2013) From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. Neurosci Biobehav Rev 37:1946–1954
Everitt BJ, Robbins TW (2016) Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol 67:150807174122003
Everitt BJ, Dickinson A, Robbins TW (2001) The neuropsychological basis of addictive behaviour. Brain Res Rev 36:129–138
Everitt BJ, Belin D, Economidou D et al (2008) Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Philos Trans R Soc B Biol Sci 363:3125–3135
Fattore L, Fratta W (2010) How important are sex differences in cannabinoid action? Br J Pharmacol 160:544–548
Fattore L, Spano MS, Altea S et al (2009) Cannabinoid self-administration in rats: sex differences and the influence of ovarian function. Br J Pharmacol 152:795–804
Fellhauer I, Zöllner FG, Schröder J et al (2015) Comparison of automated brain segmentation using a brain phantom and patients with early Alzheimer’s dementia or mild cognitive impairment. Psychiatry Res Neuroimaging 233:299–305
Filbey FM, Dunlop J (2014) Differential reward network functional connectivity in cannabis dependent and non-dependent users. Drug Alcohol Depend 140:101–111
Filbey FM, Yezhuvath U (2013) Functional connectivity in inhibitory control networks and severity of cannabis use disorder. Am J Drug Alcohol Abuse 39:382–391
Filbey FM, Schacht JP, Myers US et al (2009) Marijuana craving in the brain. Proc Natl Acad Sci U S A 106:13016–13021
Filbey FM, Aslan S, Calhoun VD et al (2014) Long-term effects of marijuana use on the brain. Proc Natl Acad Sci 111:16913–16918
Fineberg NA, Potenza MN, Chamberlain SR et al (2010) Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology 35:591–604
Fischl B, Salat DH, Busa E et al (2002) Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33:341–355
Free SL, Bergin PS, Fish DR et al (1995) Methods for normalization of hippocampal volumes measured with MR. Am J Neuroradiol 16:637–643
Gaser C, Coupé P (2010) Impact of non-local means filtering on brain tissue segmentation. Organ. Hum. Brain Mapp. 2010 Annu. Meet. United States
Gatzke-Kopp LM, Beauchaine TP, Shannon KE et al (2009) Neurological correlates of reward responding in adolescents with and without externalizing behavior disorders. J Abnorm Psychol 118:203–213
van de Giessen E, Weinstein JJ, Cassidy CM et al (2016) Deficits in striatal dopamine release in cannabis dependence. Mol Psychiatry 22:1–8
Gillan CM, Papmeyer M, Morein-zamir S et al (2011) Disruption in the balance between goal-directed behavior and habit learning in obsessive-compulsive disorder. Am J Psychiatry 168:718–726
Gilman JM, Kuster JK, Lee S et al (2014) Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. J Neurosci 34:5529–5538
Gossop M, Darke S, Griffiths P et al (1995) The severity of dependence scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction 90:607–614
Gremel CM, Costa RM (2013) Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nat Commun 4:2264
Haber SN (2016) Corticostriatal circuitry. Dialogues Clin Neurosci 18:7–21
Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E (1995) The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 15:4851–4867
Hasin DS, O’Brien CP, Auriacombe M et al (2013) DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry 170:834–851
Hayashi T, Ko JH, Strafella AP, Dagher A (2013) Dorsolateral prefrontal and orbitofrontal cortex interactions during self-control of cigarette craving. Proc Natl Acad Sci U S A 110:4422–4427
Hernandez-Avila CA, Rounsaville BJ, Kranzler HR (2004) Opioid-, cannabis- and alcohol-dependent women show more rapid progression to substance abuse treatment. Drug Alcohol Depend 74:265–272
Houck JM, Bryan AD, Feldstein Ewing SW (2013) Functional connectivity and cannabis use in high-risk adolescents. Am J Drug Alcohol Abuse 39:414–423
Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4:1770–1804
Ito R, Dalley JW, Robbins TW, Everitt BJ (2002) Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J Neurosci 22:6247–6253
Jager G, Block RI, Luijten M, Ramsey NF (2012) Tentative evidence for striatal hyperactivity in adolescent cannabis-using boys: a cross-sectional multicenter fMRI study. J Psychoactive Drugs 45:156–167
Kable JW, Glimcher PW (2007) The neural correlates of subjective value during intertemporal choice. Nat Neurosci 10:1625–1633
Kringelbach ML, Rolls ET (2004) The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol 72:341–372
Kühn S, Schubert F, Gallinat J (2010) Reduced thickness of medial orbitofrontal cortex in smokers. Biol Psychiatry 68:1061–1065
Lecrubier Y, Sheehan DV, Weiller E et al (1997) The MINI International neuropsychiatric interview (MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. Eur Psychiatry 12:224–231
Li Y, Yuan K, Cai C et al (2015) Reduced frontal cortical thickness and increased caudate volume within fronto-striatal circuits in young adult smokers. Drug Alcohol Depend 151:211–219
Lorenzetti V, Solowij N, Fornito A et al (2012) P.1.B.003 the impact of regular cannabis use on human brain structure. Eur Neuropsychopharmacol 22:S164–S165
Lorenzetti V, Solowij N, Fornito A et al (2014) The association between regular cannabis exposure and alterations of human brain morphology: an updated review of the literature. Curr Pharm Des 20:2138–2167
Lorenzetti V, Solowij N, Whittle S et al (2015) Gross morphological brain changes with chronic, heavy cannabis use. Br J Psychiatry 206:77–78
Lorenzetti V, Cousijn J, Solowij N et al (2016) The neurobiology of cannabis use disorder: a call for evidence. Front Behav Neurosci 10:1–3
Ma N, Liu Y, Fu XM et al (2011) Abnormal brain default-mode network functional connectivity in drug addicts. PLoS ONE 6:e16560
Manjón JV, Coupé P, Buades A et al (2012) New methods for MRI denoising based on sparseness and self-similarity. Med Image Anal 16:18–27
Martin G, Copeland J, Gates P, Gilmour S (2006) The severity of dependence scale (SDS) in an adolescent population of cannabis users: reliability, validity and diagnostic cut-off. Drug Alcohol Depend 83:90–93
Martinez D, Slifstein M, Broft A et al (2003) Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23:285–300
Mashhoon Y, Sava S, Sneider JT et al (2015) Cortical thinness and volume differences associated with marijuana abuse in emerging adults. Drug Alcohol Depend 155:275–283
Matsuo K, Nicoletti M, Nemoto K et al (2009) A voxel-based morphometry study of frontal gray matter correlates of impulsivity. Hum Brain Mapp 30:1188–1195
Mcqueeny T, Padula CB, Price J et al (2011) Gender effects on amygdala morphometry in adolescent marijuana users. Behav Brain Res 224:128–134
Medina KL, Schweinsburg AD, Cohen-Zion M et al (2007) Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry. Neurotoxicol Teratol 29:141–152
Moore TJ (2007) Monograph no. 14: working estimates of the social costs per gram and per user for cannabis, cocaine, opiates and amphetamines. National Drug and Alcohol Research Centre, Sydney
Morales AM, Lee B, Hellemann G et al (2012) Gray-matter volume in methamphetamine dependence: cigarette smoking and changes with abstinence from methamphetamine. Drug Alcohol Depend 125:230–238
Narr KL, Woods RP, Thompson PM et al (2007) Relationships between IQ and regional cortical gray matter thickness in healthy adults. Cereb Cortex 17:2163–2171
Narum SR (2006) Beyond Bonferroni: less conservative analyses for conservation genetics. Conserv Genet 7:783–787
Nelson HE (1982) National adult reading test. NFER-Nelson, Windsor
Ng Cheong Ton JM, Gerhardt GA, Friedemann M et al (1988) The effects of delta 9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study. Brain Res 451:59–68
Peters J, Buchel C (2009) Overlapping and distinct neural systems code for subjective value during intertemporal and risky decision making. J Neurosci 29:15727–15734
Rajkowska G (2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 48:766–777
Rajkowska G, Miguel-Hidalgo JJ, Wei J et al (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098
Redish AD, Jensen S, Johnson A (2008) A unified framework for addiction: vulnerabilities in the decision process. Behav Brain Sci 31:415–437 -487
Reuter M, Rosas HD, Fischl B (2010) Highly accurate inverse consistent registration: a robust approach. NeuroImage 53:1181–1196
Ruge H, Wolfensteller U (2016) Distinct contributions of lateral orbito-frontal cortex, striatum, and fronto-parietal network regions for rule encoding and control of memory-based implementation during instructed reversal learning. NeuroImage 125:1–12
Scherk H, Falkai P (2006) Effects of antipsychotics on brain structure. Curr Opin Psychiatry 19:145–150
Schmand B, Bakker D, Saan R, Louman J (1991) The Dutch reading test for adults: a measure of premorbid intelligence level. Tijdschr Gerontol Geriatr 22:15–19
Schoenbaum G, Roesch MR, Stalnaker TA (2006) Orbitofrontal cortex, decision-making and drug addiction. Trends Neurosci 29:116–124
Ségonne F, Dale AM, Busa E et al (2004) A hybrid approach to the skull stripping problem in MRI. NeuroImage 22:1060–1075
Sheehan DV, Lecrubier Y, Sheehan KH et al (1997) The validity of the MINI International neuropsychiatric interview (MINI) according to the SCID-P and its reliability. Eur Psychiatry 12:232–241
Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97
Smith MJ, Cobia DJ, Wang L et al (2014) Cannabis-related working memory deficits and associated subcortical morphological differences in healthy individuals and schizophrenia subjects. Schizophr Bull 40:287–299
Solowij N, Walterfang M, Lubman DI et al (2013) Alteration to hippocampal shape in cannabis users with and without schizophrenia. Schizophr Res 143:179–184
Spinella M (2002) Correlations between orbitofrontal dysfunction and tobacco smoking. Addict Biol 7:381–384
Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality (2014) Treatment episode data set (TEDS): 2002–2012. National admissions to substance abuse treatment services. BHSIS Series S-71, HHS Publication No. (SMA) 14–4850., Rockville, MD
Sullivan EV, Deshmukh A, De Rosa E et al (2005) Striatal and forebrain nuclei volumes: contribution to motor function and working memory deficits in alcoholism. Biol Psychiatry 57:768–776
Swift W, Copeland J, Hall W (1998) Choosing a diagnostic cut-off for cannabis dependence. Addiction 93:1681–1692
Tanaka SC, Balleine BW, O’Doherty JP (2008) Calculating consequences: brain systems that encode the causal effects of actions. J Neurosci 28:6750–6755
Tremblay L, Schultz W (1999) Relative reward preference in primate orbitofrontal cortex. Nature 398:704–708
Tseng AH, Craft RM (2001) Sex differences in antinociceptive and motoric effects of cannabinoids. Eur J Pharmacol 430:41–47
Turner JA (2014) The rise of large-scale imaging studies in psychiatry. Gigascience 3:29
Tzilos GK, Cintron CB, Wood JBR et al (2005) Lack of hippocampal volume change in long-term heavy cannabis users. Am J Addict 14:64–72
United Nations Office on Drugs and Crime (2014) World drug report 2014. United Nations publication, Sales No. E.14.XI.7
United Nations Office on Drugs and Crime (2015) World drug report 2015. United Nations publication, Sales No. E.15.XI.6
van der Pol P, Liebregts N, de Graaf R et al (2013) Reliability and validity of the severity of dependence scale for detecting cannabis dependence in frequent cannabis users. Int J Methods Psychiatr Res 22:138–143
Volkow ND, Fowler JS (2000) Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex 10:318–325
Volkow ND, Fowler JS, Wang G-J, Goldstein RZ (2002) Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem 78:610–624
Volkow ND, Baler RD, Compton WM, Weiss SRB (2014a) Adverse health effects of marijuana use. N Engl J Med 370:2219–2227
Volkow ND, Wang G-J, Telang F et al (2014b) Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci 111:E3149–E3156
Volkow ND, Swanson JM, Evins AE et al (2016) Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA psychiatry 73:292–297
Vollstädt-Klein S, Wichert S, Rabinstein J et al (2010) Initial, habitual and compulsive alcohol use is characterized by a shift of cue processing from ventral to dorsal striatum. Addiction 105:1741–1749
Voon V, Derbyshire K, Rück C et al (2015) Disorders of compulsivity: a common bias towards learning habits. Mol Psychiatry 20:345–352
Voruganti LNP, Slomka P, Zabel P et al (2001) Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res - Neuroimaging 107:173–177
Wechsler D (1997) WAIS-III administration and scoring manual. The Psychological Corporation, San Antonio
Wechsler D (1999) Wechsler abbreviated scale of intelligence (WASI) manual. Psychological Corporation, San Antonio
Weiland XBJ, Thayer RE, Depue XBE, et al (2015) Daily marijuana use is not associated with brain morphometric measures in adolescents or adults. J Neurosci 35:1505–1512
Wetherill RR, Jagannathan K, Hager N et al (2015) Cannabis, cigarettes, and their co-occurring use: disentangling differences in gray matter volume. Int J Neuropsychopharmacol 18:1–8
Woodward ND, Zald DH, Ding Z et al (2009) Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study. NeuroImage 46:31–38
Yip SW, DeVito EE, Kober H et al (2014) Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: an exploratory study of relationships with abstinence during behavioral treatment1. Drug Alcohol Depend 140:33–41
Yücel M, Solowij N, Respondek C et al (2008) Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry 65:694–701
Yücel M, Lorenzetti V, Suo C et al (2016) Hippocampal harms, protection and recovery following regular cannabis use. Transl Psychiatry 6:e710
Zheng W, Chee MWL, Zagorodnov V (2009) NeuroImage improvement of brain segmentation accuracy by optimizing non-uniformity correction using N3. NeuroImage 48:73–83
Acknowledgments
The Amsterdam sample was obtained with the support of grants from the Netherlands Organisation for Scientific Research–Health Research and Development, ZON-Mw grant #31180002 and an Amsterdam Brain Imaging Platform grant. The Barcelona sample was obtained with the support of grant PNSD:2011/050, Plan Nacional sobre Drogas. Ministerio de Sanidad y PolÃtica Social and grant SGR2014/1114, Generalitat de Catalunya, Spain. The Wollongong sample was obtained with the support of grants from the Clive and Vera Ramaciotti Foundation for Biomedical Research, and the Schizophrenia Research Institute with infrastructure funding from NSW Health. The Melbourne sample was obtained with the support of the National Health and Medical Research Council (NHMRC) of Australia Project Grant (#459111).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
This study was approved by the Monash University Human Research Ethics Committee. All participants provided written informed consent.
Conflict of interests
M.Y. was supported by a National Health and Medical Research Council of Australia Fellowship (App#1117188) and the David Winston Turner Endowment Fund. The authors declare that they have no conflict of interest.
Additional information
Valentina Lorenzetti and Murat Yücel are joint last author
Electronic supplementary material
ESM 1
(PDF 553Â kb)
Rights and permissions
About this article
Cite this article
Chye, Y., Solowij, N., Suo, C. et al. Orbitofrontal and caudate volumes in cannabis users: a multi-site mega-analysis comparing dependent versus non-dependent users. Psychopharmacology 234, 1985–1995 (2017). https://doi.org/10.1007/s00213-017-4606-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-017-4606-9