Skip to main content
SpringerLink
Log in

An MRI study of white matter tract integrity in regular cannabis users: effects of cannabis use and age

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Conflicting evidence exists on the effects of cannabis use on brain white matter integrity. The extant literature has exclusively focused on younger cannabis users, with no studies sampling older cannabis users.

Objectives

We recruited a sample with a broad age range to examine the integrity of major white matter tracts in association with cannabis use parameters and neurodevelopmental stage.

Methods

Regular cannabis users (n = 56) and non-users (n = 20) with a mean age of 32 (range 18–55 years) underwent structural and diffusion MRI scans. White matter was examined using voxel-based statistics and via probabilistic tract reconstruction. The integrity of tracts was assessed using average fractional anisotropy, axial diffusivity and radial diffusivity. Diffusion measures were compared between users and non-users and as group-by-age interactions. Correlations between diffusion measures and age of onset, duration, frequency and dose of current cannabis use were examined.

Results

Cannabis users overall had lower fractional anisotropy than healthy non-users in the forceps minor tract only (p = .015, partial eta = 0.07), with no voxel-wise differences observed. Younger users showed predominantly reduced axial diffusivity, whereas older users had higher radial diffusivity in widespread tracts. Higher axial diffusivity was associated with duration of cannabis use in the cingulum angular bundle (beta = 5.00 × 10−5, p = .003). Isolated higher AD in older cannabis users was also observed.

Conclusions

The findings suggest that exogenous cannabinoids alter normal brain maturation, with differing effects at various neurodevelopmental stages of life. These age-related differences are posited to account for the disparate results described in the literature.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL (2007) Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther 82:572–578. doi:10.1038/sj.clpt.6100200

    Article  CAS  PubMed  Google Scholar 

  • Alexander AL, Lee JE, Lazar M, Field AS (2007) Diffusion tensor imaging of the brain. Neurother J Am Soc Exp Neurother 4:316–329. doi:10.1016/j.nurt.2007.05.011

    Article  Google Scholar 

  • Arnone D, Barrick TR, Chengappa S, Mackay CE, Clark CA, Abou-Saleh MT (2008) Corpus callosum damage in heavy marijuana use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics. NeuroImage 41:1067–1074. doi:10.1016/j.neuroimage.2008.02.064

    Article  CAS  PubMed  Google Scholar 

  • Ashtari M, Cervellione K, Cottone J, Ardekani BA, Kumra S (2009) Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use. J Psychiatr Res 43:189–204. doi:10.1016/j.jpsychires.2008.12.002

    Article  PubMed  PubMed Central  Google Scholar 

  • Bava S, Jacobus J, Mahmood O, Yang TT, Tapert SF (2010) Neurocognitive correlates of white matter quality in adolescent substance users. Brain Cogn 72:347–354. doi:10.1016/j.bandc.2009.10.012

    Article  PubMed  Google Scholar 

  • Beaulieu C (2002) The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed 15:435–455. doi:10.1002/nbm.782

    Article  PubMed  Google Scholar 

  • Becker MP, Collins PF, Lim KO, Muetzel RL, Luciana M (2015) Longitudinal changes in white matter microstructure after heavy cannabis use. Dev Cogn Neurosci 16:23–35. doi:10.1016/j.dcn.2015.10.004

    Article  PubMed  Google Scholar 

  • Bilkei-Gorzo A (2012) The endocannabinoid system in normal and pathological brain ageing. Philos Trans R Soc Lond B Biol Sci 367:3326–3341. doi:10.1098/rstb.2011.0388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bossong MG, Niesink RJM (2010) Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol 92:370–385. doi:10.1016/j.pneurobio.2010.06.010

    Article  CAS  PubMed  Google Scholar 

  • Broyd SJ, van Hell HH, Beale C, Yücel M, Solowij N (2016) Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiatry 79:557–567. doi:10.1016/j.biopsych.2015.12.002

    Article  CAS  PubMed  Google Scholar 

  • Burns RM, Caulkins JP, Everingham SS, Kilmer B (2013) Statistics on cannabis users skew perceptions of cannabis use. Front Psychiatry. doi:10.3389/fpsyt.2013.00138

    Google Scholar 

  • Cascini F, Aiello C, Di Tanna G (2012) Increasing delta-9-tetrahydrocannabinol (Δ-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev 5:32–40

    Article  CAS  PubMed  Google Scholar 

  • Cheetham A, Allen NB, Whittle S, Simmons JG, Yücel M, Lubman DI (2012) Orbitofrontal volumes in early adolescence predict initiation of cannabis use: a 4-year longitudinal and prospective study. Biol Psychiatry 71:684–692. doi:10.1016/j.biopsych.2011.10.029

    Article  PubMed  Google Scholar 

  • D’Alonzo KT (2004) The Johnson-Neyman procedure as an alternative to ANCOVA. West J Nurs Res 26:804–812. doi:10.1177/0193945904266733

    Article  PubMed  PubMed Central  Google Scholar 

  • DeLisi LE, Bertisch HC, Szulc KU, Majcher M, Brown K, Bappal A, Ardekani BA (2006) A preliminary DTI study showing no brain structural change associated with adolescent cannabis use. Harm Reduct J 3:17. doi:10.1186/1477-7517-3-17

    Article  PubMed  PubMed Central  Google Scholar 

  • Development Core Team R (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  • Díaz-Alonso J, Guzmán M, Galve-Roperh I (2012) Endocannabinoids via CB1 receptors act as neurogenic niche cues during cortical development. Philos Trans R Soc Lond B Biol Sci 367:3229–3241. doi:10.1098/rstb.2011.0385

    Article  PubMed  PubMed Central  Google Scholar 

  • Epstein KA, Kumra S (2015) White matter fractional anisotropy over two time points in early onset schizophrenia and adolescent cannabis use disorder: a naturalistic diffusion tensor imaging study. Psychiatry Res Neuroimaging. doi:10.1016/j.pscychresns.2014.10.010

    Google Scholar 

  • Ezzati A, Katz MJ, Lipton ML, Zimmerman ME, Lipton RB (2015) Hippocampal volume and cingulum bundle fractional anisotropy are independently associated with verbal memory in older adults. Brain Imaging Behav. doi:10.1007/s11682-015-9452-y

    Google Scholar 

  • Filbey FM, Aslan S, Calhoun VD, Spence JS, Damaraju E, Caprihan A, Segall J (2014) Long-term effects of marijuana use on the brain. Proc Natl Acad Sci 111:16913–16918. doi:10.1073/pnas.1415297111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Janet BW (2002) Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Biometrics Research, New York State Psychiatric Institute, New York

    Google Scholar 

  • Fjell AM, Sneve MH, Storsve AB, Grydeland H, Yendiki A, Walhovd KB (2015) Brain events underlying episodic memory changes in aging: a longitudinal investigation of structural and functional connectivity. Cereb Cortex bhv102. doi: 10.1093/cercor/bhv102

  • Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL (1999) Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 2:861–863. doi:10.1038/13158

    Article  CAS  PubMed  Google Scholar 

  • Gruber SA, Yurgelun-Todd DA (2005) Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation. Cogn Brain Res 23:107–118. doi:10.1016/j.cogbrainres.2005.02.016

    Article  Google Scholar 

  • Gruber SA, Silveri MM, Dahlgren MK, Yurgelun-Todd D (2011) Why so impulsive? White matter alterations are associated with impulsivity in chronic marijuana smokers. Exp Clin Psychopharmacol 19:231–242. doi:10.1037/a0023034

    Article  PubMed  PubMed Central  Google Scholar 

  • Gruber SA, Dahlgren MK, Sagar KA, Gönenç A, Lukas SE (2014) Worth the wait: effects of age of onset of marijuana use on white matter and impulsivity. Psychopharmacology (Berl) 231:1455–1465. doi:10.1007/s00213-013-3326-z

    Article  CAS  Google Scholar 

  • Hatton SN, Lagopoulos J, Hermens DF, Hickie IB, Scott E, Bennett MR (2014) White matter tractography in early psychosis: clinical and neurocognitive associations. J Psychiatry Neurosci 39:417–427. doi:10.1503/jpn.130280

    Article  PubMed  PubMed Central  Google Scholar 

  • Hirvonen J, Goodwin RS, Li C-T, Terry GE, Zoghbi SS, Morse C, Pike VW, Volkow N, Huestis MA, Innis RB (2012) Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 17:642–649. doi:10.1038/mp.2011.82

    Article  CAS  PubMed  Google Scholar 

  • Hudkins M, O’Neill J, Tobias MC, Bartzokis G, London ED (2012) Cigarette smoking and white matter microstructure. Psychopharmacology (Berl) 221:285–295. doi:10.1007/s00213-011-2621-9

    Article  CAS  Google Scholar 

  • Jacobus J, McQueeny T, Bava S, Schweinsburg BC, Frank LR, Yang TT, Tapert SF (2009) White matter integrity in adolescents with histories of marijuana use and binge drinking. Neurotoxicol Teratol 31:349–355. doi:10.1016/j.ntt.2009.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobus J, Squeglia LM, Bava S, Tapert SF (2013) White matter characterization of adolescent binge drinking with and without co-occurring marijuana use: A 3-year investigation. Psychiatry Res Neuroimaging 214:374–381.

  • Jbabdi S, Woolrich MW, Andersson JLR, Behrens TEJ (2007) A Bayesian framework for global tractography. NeuroImage 37:116–129. doi:10.1016/j.neuroimage.2007.04.039

    Article  CAS  PubMed  Google Scholar 

  • Kaar SJ, Gao CX, Lloyd B, Smith K, Lubman DI (2015) Trends in cannabis-related ambulance presentations from 2000 to 2013 in Melbourne, Australia. Drug Alcohol Depend 155:24–30. doi:10.1016/j.drugalcdep.2015.08.021

    Article  PubMed  Google Scholar 

  • Lebel C, Walker L, Leemans A, Phillips L, Beaulieu C (2008) Microstructural maturation of the human brain from childhood to adulthood. NeuroImage 40:1044–1055. doi:10.1016/j.neuroimage.2007.12.053

    Article  CAS  PubMed  Google Scholar 

  • Long LE, Lind J, Webster M, Weickert CS (2012) Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex. BMC Neurosci 13:87. doi:10.1186/1471-2202-13-87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorenzetti V, Lubman DI, Whittle S, Solowij N, Yücel M (2010) Structural MRI findings in long-term cannabis users: what do we know? Subst Use Misuse 45:1787–1808. doi:10.3109/10826084.2010.482443

    Article  PubMed  Google Scholar 

  • Martin C (2014) Medical use of cannabis in Australia: “medical necessity“defences under current Australian law and avenues for reform. J Law Med 21:875–899

    PubMed  Google Scholar 

  • Molina-Holgado E, Vela JM, Arévalo-Martı́n A, Almazán G, Molina-Holgado F, Borrell J, Guaza C (2002) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/akt signaling. J Neurosci 22:9742–9753

    CAS  PubMed  Google Scholar 

  • Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1–25. doi:10.1002/hbm.1058

    Article  PubMed  Google Scholar 

  • Peters BD, Ikuta T, DeRosse P, John M, Burdick KE, Gruner P, Prendergast DM, Szeszko PR, Malhotra AK (2014) Age-related differences in white matter tract microstructure are associated with cognitive performance from childhood to adulthood. Biol Psychiatry 75:248–256. doi:10.1016/j.biopsych.2013.05.020

    Article  PubMed  Google Scholar 

  • Pfefferbaum A, Rosenbloom M, Rohlfing T, Sullivan EV (2009) Degradation of association and projection white matter systems in alcoholism detected with quantitative fiber tracking. Biol Psychiatry 65:680–690. doi:10.1016/j.biopsych.2008.10.039

    Article  CAS  PubMed  Google Scholar 

  • Prockop LD, Naidu KA (1999) Brain CT and MRI findings after carbon monoxide toxicity. J Neuroimaging 9:175–181. doi:10.1111/jon199993175

    Article  CAS  PubMed  Google Scholar 

  • Rigucci S, Marques TR, Di Forti M, Taylor H, Dell’Acqua F, Modelli V, Bonaccorso S, Simmons A, David AS, Girardi P, Pariante CM, Murray RM, Dazzan P (2016) Effect of high-potency cannabis on corpus callosum microstructure. Psych Med 46:841–854. doi:10.1017/S0033291715002342

    Article  CAS  Google Scholar 

  • Room R (2014) Legalizing a market for cannabis for pleasure: Colorado, Washington, Uruguay and beyond. Addiction 109:345–351. doi:10.1111/add.12355

    Article  PubMed  Google Scholar 

  • Rubino T, Prini P, Piscitelli F, Zamberletti E, Trusel M, Melis M, Sagheddu C, Ligresti A, Tonini R, Di Marzo V, Parolaro D (2015) Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiol Dis 73:60–69. doi:10.1016/j.nbd.2014.09.015

    Article  CAS  PubMed  Google Scholar 

  • Schmahmann JD, Pandya DN, Wang R, Dai G, D’Arceuil HE, de Crespigny AJ, Wedeen VJ (2007) Association fibre pathways of the brain: parallel observations from diffusion spectrum imaging and autoradiography. Brain 130:630–653. doi:10.1093/brain/awl359

    Article  PubMed  Google Scholar 

  • Schwartzman A, Lin X (2011) The effect of correlation in false discovery rate estimation. Biometrika 98:199–214. doi:10.1093/biomet/asq075

    Article  PubMed  PubMed Central  Google Scholar 

  • Shollenbarger SG, Price J, Wieser J, Lisdahl K (2015) Poorer frontolimbic white matter integrity is associated with chronic cannabis use, FAAH genotype, and increased depressive and apathy symptoms in adolescents and young adults. NeuroImage Clin 8:117–125. doi:10.1016/j.nicl.2015.03.024

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23(Supplement 1):S208–S219. doi:10.1016/j.neuroimage.2004.07.051

    Article  PubMed  Google Scholar 

  • Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31:1487–1505. doi:10.1016/j.neuroimage.2006.02.024

    Article  PubMed  Google Scholar 

  • Sobell LC, Sobell MB (1992) Timeline follow-back. In: Litten RZ, Allen JP (eds) Measuring alcohol consumption. Humana Press; 41–72.

  • Solowij N, Battisti R (2008) The chronic effects of cannabis on memory in humans: a review. Curr Drug Abuse Rev 1:81–98

    Article  PubMed  Google Scholar 

  • Solowij N, Zalesky A, Lorenzetti V, Yücel M (in press) Chronic cannabis use and axonal fibre connectivity. In: Preedy V (ed) Handbook of cannabis and related pathologies: biology, diagnosis, treatment and pharmacology. Elsevier,

  • Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH (2002) Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. NeuroImage 17:1429–1436

    Article  PubMed  Google Scholar 

  • 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. doi:10.1016/j.pbb.2008.05.010

    Article  PubMed  Google Scholar 

  • Szeszko PR, Vogel J, Ashtari M, Malhotra AK, Bates J, Kane JM, Bilder RM, Frevert T, Lim K (2003) Sex differences in frontal lobe white matter microstructure: a DTI study. Neuroreport 14:2469–2473. doi:10.1097/01.wnr.0000099475.09597.23

    Article  PubMed  Google Scholar 

  • Wechsler D (1999) Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation: Harcourt Brace & Company, New York

    Google Scholar 

  • Westlye LT, Walhovd KB, Dale AM, Bjørnerud A, Due-Tønnessen P, Engvig A, Grydeland H, Tamnes CK, Ostby Y, Fjell AM (2010) Life-span changes of the human brain white matter: diffusion tensor imaging (DTI) and volumetry. Cereb Cortex 20:2055–2068. doi:10.1093/cercor/bhp280

    Article  PubMed  Google Scholar 

  • Yendiki A, Panneck P, Srinivasan P, Stevens A, Zöllei L, Augustinack J, Wang R, Salat D, Ehrlich S, Behrens T, Jbabdi S, Gollub R, Fischl B (2011) Automated probabilistic reconstruction of white-matter pathways in health and disease using an atlas of the underlying anatomy. Front Neuroinformatics 5:23. doi:10.3389/fninf.2011.00023

    Article  Google Scholar 

  • Yendiki A, Koldewyn K, Kakunoori S, Kanwisher N, Fischl B (2014) Spurious group differences due to head motion in a diffusion MRI study. NeuroImage 88:79–90. doi:10.1016/j.neuroimage.2013.11.027

    Article  PubMed  Google Scholar 

  • Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, Lubman DI (2008) Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry 65:694–701. doi:10.1001/archpsyc.65.6.694

    Article  PubMed  Google Scholar 

  • Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, Lorenzetti V, Wang R, Searle K, Pantelis C, Seal M (2012) Effect of long-term cannabis use on axonal fibre connectivity. Brain 135:2245–2255. doi:10.1093/brain/aws136

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Health and Medical Research Council (Project Grant 459111 to N.S. and Senior Research Fellowship APP1021973 to M.Y.), the Australian Research Council (Future Fellowship FT110100752 to N.S.) and Monash University (Bridging Post-doctoral Fellowship to V.L.). The authors thank the University of Wollongong’s High Performance Computing laboratory for use of computing infrastructure.

Author information

Authors and Affiliations

  1. Graduate School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia

    David Jakabek

  2. Brain & Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, VIC, Australia

    Murat Yücel & Valentina Lorenzetti

  3. School of Psychology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia

    Nadia Solowij

Authors
  1. David Jakabek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murat Yücel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valentina Lorenzetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia Solowij
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nadia Solowij.

Ethics declarations

Ethical approval was provided by the Melbourne Health Research Ethics Committee, and informed consent was obtained from all participants in accordance with the Declaration of Helsinki.

Conflict of interests

The authors declare that they have no conflicts of interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 23 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jakabek, D., Yücel, M., Lorenzetti, V. et al. An MRI study of white matter tract integrity in regular cannabis users: effects of cannabis use and age. Psychopharmacology 233, 3627–3637 (2016). https://doi.org/10.1007/s00213-016-4398-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4398-3

Keywords

Search

Navigation