Abstract
Rationale
Cannabis use is associated with neuroanatomical alterations in the hippocampus. While the hippocampus is composed of multiple subregions, their differential vulnerability to cannabis dependence remains unknown.
Objectives
The objective of the study is to investigate gray matter alteration in each of the hippocampal subregions (presubiculum, subiculum, cornu ammonis (CA) subfields CA1–4, and dentate gyrus (DG)) as associated with cannabis use and dependence.
Methods
A total of 35 healthy controls (HC), 22 non-dependent (CB-nondep), and 39 dependent (CB-dep) cannabis users were recruited. We investigated group differences in hippocampal subregion volumes between HC, CB-nondep, and CB-dep users. We further explored the association between CB use variables (age of onset of regular use, monthly use, lifetime use) and hippocampal subregions in CB-nondep and CB-dep users separately.
Results
The CA1, CA2/3, CA4/DG, as well as total hippocampal gray matter were reduced in volume in CB-dep but not in CB-nondep users, relative to HC. The right CA2/3 and CA4/DG volumes were also negatively associated with lifetime cannabis use in CB-dep users.
Conclusions
Our results suggest a regionally and dependence-specific influence of cannabis use on the hippocampus. Hippocampal alteration in cannabis users was specific to the CA and DG regions and confined to dependent users.
Similar content being viewed by others
References
Alén F, Mouret A, Viveros M-P et al (2010) Converging action of alcohol consumption and cannabinoid receptor activation on adult hippocampal neurogenesis. Int J Neuropsychopharmacol 13:191–205
Amaral DG, Witter MP (1989) The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31:571–591
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5). American Psychiatric Publishing, Arlington, VA
Beck AT, Ward CH, Mendelson MM et al (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571
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
Burgess N, Maguire EA, O’Keefe J (2002) The human hippocampus and spatial and episodic memory. Neuron 35:625–641
Chambers RA (2013) Adult hippocampal neurogenesis in the pathogenesis of addiction and dual diagnosis disorders. Drug Alcohol Depend 130:1–12
Chye Y, Solowij N, Suo C, et al (2017) Orbitofrontal and caudate volumes in cannabis users: a multi-site mega-analysis comparing dependent versus non-dependent users. Psychopharmacology. doi:10.1007/s00213-017-4606-9
Coffey C, Carlin JB, Degenhardt L et al (2002) Cannabis dependence in young adults: an Australian population study. Addiction 97:187–194
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
Degenhardt L, Hall W, Lynskey M (2003) Exploring the association between cannabis use and depression. Addiction 98:1493–1504
Degenhardt L, Ferrari AJ, Calabria B et al (2013) The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: results from the GBD 2010 study. PLoS One 8:1–14
Demirakca T, Sartorius A, Ende G et al (2011) Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend 114:242–245
Durazzo TC, Meyerhoff DJ, Nixon SJ (2013) Interactive effects of chronic cigarette smoking and age on hippocampal volumes. Drug Alcohol Depend 133:704–711
Eisch AJ (2002) Adult neurogenesis: implications for psychiatry. Prog Brain Res 138:315–342
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
Fergusson DM, Boden JM (2008) Cannabis use and later life outcomes. Addiction 103:969–976
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, Mcqueeny T, Kadamangudi S et al (2015) Combined effects of marijuana and nicotine on memory performance and hippocampal volume. Behav Brain Res 293:46–53
First MB, Spitzer RL, Gibbon M, Williams JBW (2001) Structured clinical interview for axis I DSM-IV disorders. New York State Psychiatric Interview, New York
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
Gabrieli JD, Brewer JB, Desmond JE, Glover GH (1997) Separate neural bases of two fundamental memory processes in the human medial temporal lobe. Science 276 (80-):264–266
Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem 86:1646–1647
Gaser C, Coupé P (2010) Impact of non-local means filtering on brain tissue segmentation. Organization for Human Brain Mapping 2010 Annual Meeting, Jun 2010, United States
Gilbert PE, Brushfield AM (2009) The role of the CA3 hippocampal subregion in spatial memory: a process oriented behavioral assessment. Prog Neuro-Psychopharmacology Biol Psychiatry 33:774–781
Glass M, Dragunow M, Faull RL (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318
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
Hall RCW (1995) Global assessment of functioning. A modified scale Psychosomatics 36:267–275
Hall W, Degenhardt L (2007) Prevalence and correlates of cannabis use in developed and developing countries. Curr Opin Psychiatry 20:393–397
Han K-M, Won E, Sim Y, Tae W-S (2016) Hippocampal subfield analysis in medication-naïve female patients with major depressive disorder. J Affect Disord 194:21–29
Haukvik UK, Westlye LT, Mørch-Johnsen L et al (2015) In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder. Biol Psychiatry 77:581–588
Hyman SM, Sinha R (2009) Stress-related factors in cannabis use and misuse: implications for prevention and treatment. J Subst Abus Treat 36:400–413
Jiang W, Zhang Y, Xiao L et al (2005) Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest 115:3104–3116
Kandola A, Hendrikse J, Lucassen PJ, Yücel M (2016) Aerobic exercise as a tool to improve hippocampal plasticity and function in humans: practical implications for mental health treatment. Front Hum Neurosci 10:1–25
Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447–452
Kesner RP (2007) A behavioral analysis of dentate gyrus function. In: Scharfman HE (ed) Progress in brain research, vol 163. Elsevier, pp 567–576. doi:10.1016/S0079-6123(07)63030-1
Kochman LJ, dos Santos AA, Fornal CA, Jacobs BL (2006) Despite strong behavioral disruption, delta9-tetrahydrocannabinol does not affect cell proliferation in the adult mouse dentate gyrus. Brain Res 1113:86–93
Koenders L, Cousijn J, Vingerhoets WAM et al (2016) Grey matter changes associated with heavy cannabis use: a longitudinal sMRI study. PLoS One 11:1–13
Konings M, Bak M, Hanssen M et al (2006) Validity and reliability of the CAPE: a self-report instrument for the measurement of psychotic experiences in the general population. Acta Psychiatr Scand 114:55–61
Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238
Lawston J, Borella A, Robinson JK, Whitaker-Azmitia PM (2000) Changes in hippocampal morphology following chronic treatment with the synthetic cannabinoid WIN 55,212-2. Brain Res 877:407–410
Lee J, Im S-J, Lee S-G et al (2016) Volume of hippocampal subfields in patients with alcohol dependence. Psychiatry Res Neuroimaging 258:16–22
Lorenzetti V, Cousijn J (2016) Cannabis use disorders and brain morphology. In: Preedy V (ed) Neuropathology of drug addictions and substance misuse, 1st edn. Elsevier Inc., London, UK, pp 773–85
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 (2016a) The neurobiology of cannabis use disorder: A call for evidence. Front Behav Neurosci 10:1–3
Lorenzetti V, Solowij N, Suo C et al (2016b) Cannabis dependence and the brain reward system: disentangling the role of exposure and addiction related effects. Eur Neuropsychopharmacol 26:S701–S702
Lorenzetti V, Solowij N, Yücel M (2016c) The role of cannabinoids in neuroanatomic alterations in cannabis users. Biol Psychiatry 79:e17–e31
Lowe RH, Abraham TT, Darwin WD et al (2009) Extended urinary Δ9-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure. Drug Alcohol Depend 105:24–32
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
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
Musshoff F, Madea B (2006) Review of biologic matrices (urine, blood, hair) as indicators of recent or ongoing cannabis use. Ther Drug Monit 28:155–163
Narr KL, Thompson PM, Szeszko P et al (2004) Regional specificity of hippocampal volume reductions in first-episode schizophrenia. NeuroImage 21:1563–1575
Pedraza O, Bowers D, Gilmore R (2004) Asymmetry of the hippocampus and amygdala in MRI volumetric measurements of normal adults. J Int Neuropsychol Soc 10:664–678
Piontek D, Kraus L, Klempova D (2008) Short scales to assess cannabis-related problems: a review of psychometric properties. Subst Abuse Treat Prev Policy 3:25
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
Reuter M, Rosas HD, Fischl B (2010) Highly accurate inverse consistent registration: a robust approach. NeuroImage 53:1181–1196
Riebe CJN, Hill MN, Lee TTY et al (2010) Estrogenic regulation of limbic cannabinoid receptor binding. Psychoneuroendocrinology 35:1265–1269
Saunders JB, Aasland OG, Babor TF et al (1993) Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction 88:791–804
Schiavon AP, Bonato JM, Milani H et al (2016) Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Prog Neuro-Psychopharmacology Biol Psychiatry 64:27–34
Ségonne F, Dale AM, Busa E et al (2004) A hybrid approach to the skull stripping problem in MRI. NeuroImage 22:1060–1075
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
Small SA, Schobel SA, Buxton RB et al (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12:585–601
Smith MJ, Cobia DJ, Reilly JL et al (2015) Cannabis-related episodic memory deficits and hippocampal morphological differences in healthy individuals and schizophrenia subjects. Hippocampus 10:1–10
Sobell LC, Sobell MB (1992) Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Litten RZ, Allen JP (eds) Measuring alcohol consumption: psychosocial and biochemical methods. Humana Press, Totowa, pp 41–72
Solowij N, Michie PT, Fox AM (1995) Differential impairments of selective attention due to frequency and duration of cannabis use. Biol Psychiatry 37:731–739
Solowij N, Jones KA, Rozman ME et al (2011) Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology 216:131–144
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
Spielberger CD (1983) Manual for the State-Trait Anxiety Inventory (STAI). Consulting Psychologists Press, Palo Alto
Spitzer RL, Williams JBW, Guibbon M, First MG (1994) Structured clinical interview for DSM-IV (SCID). American Psychiatry Press, Washington, DC
Suzuki M, Hagino H, Nohara S et al (2005) Male-specific volume expansion of the human hippocampus during adolescence. Cereb Cortex 15:187–193
Svíženská I, Dubový P, Šulcová A (2008) Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures—a short review. Pharmacol Biochem Behav 90:501–511
Takagi M, Lubman DI, Walterfang M et al (2013) Corpus callosum size and shape alterations in adolescent inhalant users. Addict Biol 18:851–854
Van Leemput K, Bakkour A, Benner T et al (2009) Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI. Hippocampus 19:549–557
Verdurand M, Dalton VS, Zavitsanou K (2010) GABAA receptor density is altered by cannabinoid treatment in the hippocampus of adult but not adolescent rats. Brain Res 1351:238–245
Volkow ND, Baler RD, Compton WM, Weiss SRB (2014) Adverse health effects of marijuana use. N Engl J Med 370:2219–2227
Wechsler D (1999) Wechsler abbreviated scale of intelligence (WASI) manual. Psychological Corporation, San Antonio, TX
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
Wise LE, Thorpe AJ, Lichtman AH (2009) Hippocampal CB(1) receptors mediate the memory impairing effects of delta(9)-tetrahydrocannabinol. Neuropsychopharmacology 34:2072–2080
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, Zalesky A, Takagi MJ et al (2010) White-matter abnormalities in adolescents with long-term inhalant and cannabis use: a diffusion magnetic resonance imaging study. J Psychiatry Neurosci 35:409–412
Yücel M, Lorenzetti V, Suo C et al (2016) Hippocampal harms, protection and recovery following regular cannabis use. Transl Psychiatry 6:e710
Zalesky A, Solowij N, Yücel M et al (2012) Effect of long-term cannabis use on axonal fibre connectivity. Brain 135:2245–2255
Zhao X, Lein ES, He A et al (2001) Transcriptional profiling reveals strict boundaries between hippocampal subregions. J Comp Neurol 441:187–196
Zheng W, Chee MWL, Zagorodnov V (2009) NeuroImage improvement of brain segmentation accuracy by optimizing non-uniformity correction using N3. NeuroImage 48:73–83
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This project was funded by the National Health and Medical Research Council of Australia Project Grant (Grant number: 459111). All participants provided written informed content.
Funding
M.Y. was supported by a National Health and Medical Research Council of Australia Fellowship (App#1021973) and the David Winston Turner Endowment Fund. N.S was supported by an Australian Research Council Future Fellowship (FT110100752).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Yann Chye and Chao Suo are the Joint first authors.
Nadia Solowij and Valentina Lorenzetti are the Joint last authors.
Electronic supplementary material
ESM 1
(PDF 905 kb)
Rights and permissions
About this article
Cite this article
Chye, Y., Suo, C., Yücel, M. et al. Cannabis-related hippocampal volumetric abnormalities specific to subregions in dependent users. Psychopharmacology 234, 2149–2157 (2017). https://doi.org/10.1007/s00213-017-4620-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-017-4620-y