Advertisement

The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users

  • Valentina Lorenzetti
    Affiliations
    Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne

    Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Melbourne
    Search for articles by this author
  • Nadia Solowij
    Affiliations
    School of Psychology, Centre for Health Initiatives and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia
    Search for articles by this author
  • Murat Yücel
    Correspondence
    Address correspondence to Murat Yücel, Ph.D., Brain and Mental Health Laboratory, Monash University, 770 Blackburn Road, Clayton, Victoria 3168, Australia.
    Affiliations
    Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne

    Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Melbourne
    Search for articles by this author
Open AccessPublished:December 04, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.11.013

      Abstract

      The past few decades have seen a marked change in the composition of commonly smoked cannabis. These changes primarily involve an increase of the psychoactive compound ∆9-tetrahydrocannabinol (THC) and a decrease of the potentially therapeutic compound cannabidiol (CBD). This altered composition of cannabis may be linked to persistent neuroanatomic alterations typically seen in regular cannabis users. In this review, we summarize recent findings from human structural neuroimaging investigations. We examine whether neuroanatomic alterations are 1) consistently observed in samples of regular cannabis users, particularly in cannabinoid receptor–high areas, which are vulnerable to the effects of high circulating levels of THC, and 2) associated either with greater levels of cannabis use (e.g., higher dosage, longer duration, and earlier age of onset) or with distinct cannabinoid compounds (i.e., THC and CBD). Across the 31 studies selected for inclusion in this review, neuroanatomic alterations emerged across regions that are high in cannabinoid receptors (i.e., hippocampus, prefrontal cortex, amygdala, cerebellum). Greater dose and earlier age of onset were associated with these alterations. Preliminary evidence shows that THC exacerbates, whereas CBD protects from, such harmful effects. Methodologic differences in the quantification of levels of cannabis use prevent accurate assessment of cannabis exposure and direct comparison of findings across studies. Consequently, the field lacks large “consortium-style” data sets that can be used to develop reliable neurobiological models of cannabis-related harm, recovery, and protection. To move the field forward, we encourage a coordinated approach and suggest the urgent development of consensus-based guidelines to accurately and comprehensively quantify cannabis use and exposure in human studies.

      Keywords

      Although cannabis has existed for thousands of years, the past few decades have seen a marked increase in the prevalence of highly potent cannabis strains (
      • Swift W.
      • Wong A.
      • Li K.M.
      • Arnold J.C.
      • McGregor I.S.
      Analysis of cannabis seizures in NSW, Australia: Cannabis potency and cannabinoid profile.
      ). These strains have a high proportion of the psychoactive constituent ∆9-tetrahydrocannabinol (THC) (
      • Gaoni Y.
      • Mechoulam R.
      The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish.
      ), which exerts persistent adverse effects on cognition, mental health, and the brain (
      • Volkow N.D.
      • Baler R.D.
      • Compton W.M.
      • Weiss S.R.B.
      Adverse health effects of marijuana use.
      ,
      • Di Forti M.
      • Marconi A.
      • Carra E.
      • Fraietta S.
      • Trotta A.
      • Bonomo M.
      • et al.
      Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study.
      ). In parallel, there are decreasing levels of other constituent cannabis compounds, such as cannabidiol (CBD), which has been touted as a potential therapeutic agent for conditions ranging from chronic pain and seizures to psychiatric symptoms (
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • Crippa J.A.
      • McGuire P.K.
      Neural mechanisms for the cannabinoid modulation of cognition and affect in man: A critical review of neuroimaging studies.
      ,
      • Zuardi A.W.
      • Crippa J.A.S.
      • Hallak J.E.
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • et al.
      A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.
      ,
      • Izzo A.A.
      • Borrelli F.
      • Capasso R.
      • Di Marzo V.
      • Mechoulam R.
      Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb.
      ). These recent changes in the composition of “street” cannabis create a new and complex landscape for investigators endeavoring to understand the neurobiological harm and the therapeutic potential of cannabis products.
      Specific cannabinoid compounds have distinct effects on mental health and brain function. The psychoactive and addictive properties of cannabis are primarily due to THC (
      • Lupica C.R.
      • Riegel A.C.
      • Hoffman A.F.
      Marijuana and cannabinoid regulation of brain reward circuits.
      ). Increased availability of cannabis varieties that are high in THC (e.g., “skunk”) have been consistently linked to accelerated onset of psychosis (

      United Nations Office on Drugs and Crime (2009): Why does cannabis potency matter? In: World Drug Report 2009. New York: United Nations.

      ,
      • Di Forti M.
      • Sallis H.
      • Allegri F.
      • Trotta A.
      • Ferraro L.
      • Stilo S.A.
      • et al.
      Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.
      ), increased cannabis-related hospital admissions (

      Substance Abuse and Mental Health Services Administration (2013): Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 13-4760, DAWN Series D-39. Rockville, MD: Substance Abuse and Mental Health Services Administration.

      ), and increased anxiety symptoms and psychotic-like experiences (
      • Martin-Santos R.
      • Crippa J.A.
      • Batalla A.
      • Bhattacharyya S.
      • Atakan Z.
      • Borgwardt S.
      • et al.
      Acute effects of a single, oral dose of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers.
      ,
      • Fusar-Poli P.
      • Allen P.
      • Bhattacharyya S.
      • Crippa J.A.
      • Mechelli A.
      • Borgwardt S.
      • et al.
      Modulation of effective connectivity during emotional processing by delta-9-tetrahydrocannabinol and cannabidiol.
      ,
      • Bhattacharyya S.
      • Morrison P.D.
      • Fusar-Poli P.
      • Martin-Santos R.
      • Borgwardt S.
      • Winton-Brown T.
      • et al.
      Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Crippa J.A.
      • Zuardi A.W.
      • Martín-Santos R.
      • Bhattacharyya S.
      • Atakan Z.
      • McGuire P.
      • et al.
      Cannabis and anxiety: A critical review of the evidence.
      ). Preclinical studies showed that THC is neurotoxic to brain areas rich in cannabinoid type 1 receptors, including the hippocampus (
      • Lawstone J.
      • Borella A.
      • Robinson J.K.
      • Whitaker-Azmitia P.M.
      Changes in hippocampal morphology following chronic treatment with the synthetic cannabinoid WIN 55,212-2.
      ,
      • Chan G.C.K.
      • Hinds T.R.
      • Impey S.
      • Storm D.R.
      Hippocampal neurotoxicity of ∆9-tetrahydrocannabinol.
      ,
      • Landfield P.W.
      • Caldwallader L.B.
      • Vinsant S.
      Quantitative changes in hippocampal structure following long-term exposure to Δ9-tetrahydrocannabinol: Possible mediation by glucocorticoid systems.
      ,
      • Scallet A.C.
      • Uemura E.
      • Andrews A.
      • Ali S.F.
      • McMillan D.E.
      • Paule M.G.
      • et al.
      Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC).
      ,
      • Heath R.G.
      • Fitzjarrell A.T.
      • Fontana C.J.
      • Garey R.E.
      Cannabis sativa: Effects on brain function and ultrastructure in rhesus monkeys.
      ), amygdala (
      • Heath R.G.
      • Fitzjarrell A.T.
      • Fontana C.J.
      • Garey R.E.
      Cannabis sativa: Effects on brain function and ultrastructure in rhesus monkeys.
      ), striatum (
      • Kolb B.
      • Gorny G.
      • Limebeer C.L.
      • Parker L.A.
      Chronic treatment with delta-9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats.
      ), and prefrontal cortex (PFC) (
      • Kolb B.
      • Gorny G.
      • Limebeer C.L.
      • Parker L.A.
      Chronic treatment with delta-9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats.
      ,
      • Downer E.
      • Boland B.
      • Fogarty M.
      • Campbell V.C.A.
      Delta-9-tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurons via activation of the CB1 receptor.
      ,
      • Harper J.W.
      • Heath R.G.
      • Myers W.A.
      Effects of Cannabis sativa on ultrastructure of the synapse in monkey brain.
      ). In contrast, CBD has been found to have anxiolytic, antipsychotic, and therapeutic properties (
      • Schiavon A.
      • Soares L.
      • Bonato J.
      • Milani H.
      • Guimarães F.
      • Weffort de Oliveira R.
      Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice.
      ,
      • Hermann D.
      • Schneider M.
      Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: A critical review.
      ,
      • Schubart C.D.
      • Sommer I.E.C.
      • Fusar-Poli P.
      • de Witte L.
      • Kahn R.S.
      • Boks M.P.M.
      Cannabidiol as a potential treatment for psychosis.
      ,
      • Bhattacharyya S.
      Neurobiological and neurocognitive basis of the effects of cannabinoids in animals and man: Therapeutic potential of cannabinoids in psychiatry.
      ). There is evidence suggesting that CBD is neuroprotective, mitigating the neurotoxic effects of THC (
      • Morgan C.J.
      • Gardener C.
      • Schafer G.
      • Swan S.
      • Demarchi C.
      • Freeman T.P.
      • et al.
      Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being.
      ,
      • Morgan C.J.
      • Curran H.V.
      Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis.
      ,
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ).
      The compounds THC and CBD have also been shown to have opposing effects on the functional activity and connectivity between brain regions that are high in cannabinoid receptors, such as the hippocampus, amygdala, striatum, cerebellum, and PFC (
      • Martin-Santos R.
      • Crippa J.A.
      • Batalla A.
      • Bhattacharyya S.
      • Atakan Z.
      • Borgwardt S.
      • et al.
      Acute effects of a single, oral dose of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers.
      ,
      • Fusar-Poli P.
      • Allen P.
      • Bhattacharyya S.
      • Crippa J.A.
      • Mechelli A.
      • Borgwardt S.
      • et al.
      Modulation of effective connectivity during emotional processing by delta-9-tetrahydrocannabinol and cannabidiol.
      ,
      • Bhattacharyya S.
      • Morrison P.D.
      • Fusar-Poli P.
      • Martin-Santos R.
      • Borgwardt S.
      • Winton-Brown T.
      • et al.
      Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Glass M.
      • Faull R.L.M.
      • Dragunow M.
      Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain.
      ,
      • Bhattacharyya S.
      Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • Crippa J.A.
      • Kambeitz J.
      • Prata D.
      • et al.
      Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function.
      ,
      • Bhattacharyya S.
      • Falkenberg I.
      • Martin-Santos R.
      • Atakan Z.
      • Crippa J.A.
      • Giampietro V.
      • et al.
      Cannabinoid modulation of functional connectivity within regions processing attentional salience.
      ,
      • Morrison P.D.
      • Nottage J.
      • Stone J.M.
      • Bhattacharyya S.
      • Tunstall N.
      • Brenneisen R.
      • et al.
      Disruption of frontal theta coherence by delta9-tetrahydrocannabinol is associated with positive psychotic symptoms.
      ,
      • Bhattacharyya S.
      • Fusar-Poli P.
      • Borgwardt S.
      • Martin-Santos R.
      • Nosarti C.
      • O’Carroll C.
      • et al.
      Modulation of mediotemporal and ventrostriatal function in humans by Δ9-tetrahydrocannabinol: A neural basis for the effects of Cannabis sativa on learning and psychosis.
      ). These changes in brain function, documented using functional magnetic resonance imaging (MRI), may modulate the effects of THC on anxiety and psychotic-like experiences in humans (
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • Crippa J.A.
      • McGuire P.K.
      Neural mechanisms for the cannabinoid modulation of cognition and affect in man: A critical review of neuroimaging studies.
      ,
      • Bhattacharyya S.
      Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Bhattacharyya S.
      • Crippa J.
      • Martin-Santos R.
      • Winton-Brown T.
      • Fusar-Poli P.
      Imaging the neural effects of cannabinoids: Current status and future opportunities for psychopharmacology.
      ). Similar processes may underpin the protective effects of CBD on such experiences (
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • Crippa J.A.
      • McGuire P.K.
      Neural mechanisms for the cannabinoid modulation of cognition and affect in man: A critical review of neuroimaging studies.
      ,
      • Zuardi A.W.
      • Crippa J.A.S.
      • Hallak J.E.
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • et al.
      A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.
      ,
      • Bhattacharyya S.
      Neurobiological and neurocognitive basis of the effects of cannabinoids in animals and man: Therapeutic potential of cannabinoids in psychiatry.
      ,
      • Bhattacharyya S.
      Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Bhattacharyya S.
      • Crippa J.
      • Martin-Santos R.
      • Winton-Brown T.
      • Fusar-Poli P.
      Imaging the neural effects of cannabinoids: Current status and future opportunities for psychopharmacology.
      ). Participants pretreated with CBD do not experience the psychotogenic and anxiogenic effects of THC (
      • Martin-Santos R.
      • Crippa J.A.
      • Batalla A.
      • Bhattacharyya S.
      • Atakan Z.
      • Borgwardt S.
      • et al.
      Acute effects of a single, oral dose of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers.
      ,
      • Fusar-Poli P.
      • Allen P.
      • Bhattacharyya S.
      • Crippa J.A.
      • Mechelli A.
      • Borgwardt S.
      • et al.
      Modulation of effective connectivity during emotional processing by delta-9-tetrahydrocannabinol and cannabidiol.
      ,
      • Bhattacharyya S.
      • Morrison P.D.
      • Fusar-Poli P.
      • Martin-Santos R.
      • Borgwardt S.
      • Winton-Brown T.
      • et al.
      Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Bhattacharyya S.
      Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
      ,
      • Bhattacharyya S.
      • Atakan Z.
      • Martin-Santos R.
      • Crippa J.A.
      • Kambeitz J.
      • Prata D.
      • et al.
      Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function.
      ,
      • Bhattacharyya S.
      • Falkenberg I.
      • Martin-Santos R.
      • Atakan Z.
      • Crippa J.A.
      • Giampietro V.
      • et al.
      Cannabinoid modulation of functional connectivity within regions processing attentional salience.
      ,
      • Morrison P.D.
      • Nottage J.
      • Stone J.M.
      • Bhattacharyya S.
      • Tunstall N.
      • Brenneisen R.
      • et al.
      Disruption of frontal theta coherence by delta9-tetrahydrocannabinol is associated with positive psychotic symptoms.
      ,
      • Bhattacharyya S.
      • Fusar-Poli P.
      • Borgwardt S.
      • Martin-Santos R.
      • Nosarti C.
      • O’Carroll C.
      • et al.
      Modulation of mediotemporal and ventrostriatal function in humans by Δ9-tetrahydrocannabinol: A neural basis for the effects of Cannabis sativa on learning and psychosis.
      ,
      • Bhattacharyya S.
      • Crippa J.
      • Martin-Santos R.
      • Winton-Brown T.
      • Fusar-Poli P.
      Imaging the neural effects of cannabinoids: Current status and future opportunities for psychopharmacology.
      ).
      The recent changes in the relative composition of cannabinoids found within commonly available cannabis increase the potential for psychological and neurobiological harm in the current generation of cannabis users. However, the relative contribution of the two major compounds of cannabis (i.e., THC and CBD) to such damage is unclear (
      • Bhattacharyya S.
      • Crippa J.
      • Martin-Santos R.
      • Winton-Brown T.
      • Fusar-Poli P.
      Imaging the neural effects of cannabinoids: Current status and future opportunities for psychopharmacology.
      ). In this review, we summarize the current literature on neuroanatomic alterations reported in regular cannabis users, which includes nine additional studies relative to the most recent review on the topic, reflecting an increased focus on this field of research and warranting a need to integrate the most recent findings (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • 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.
      ). We present a novel focus on the emerging evidence for differential roles of specific cannabinoids in neuroanatomic abnormalities (
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Lorenzetti V.
      • Solowij N.
      • Fornito A.
      • Lubman D.I.
      • Yucel M.
      The association between regular cannabis exposure and alterations of human brain morphology: An updated review of the literature.
      ,
      • Lorenzetti V.
      • Lubman D.I.
      • Whittle S.
      • Solowij N.
      • Yücel M.
      Structural MRI findings in long-term cannabis users: What do we know?.
      ). First, we provide an overview of findings and stratify them according to brain regions. Second, we examine the link between neuroanatomic alterations and levels of cannabis use, with a specific focus on the cannabinoid compounds THC and CBD. Finally, we identify major limitations of current research, particularly in relation to the measurement of cannabis use and cannabinoid compounds. These methodologic inadequacies limit the ability to develop evidence-based models of the effects of cannabis on neuroanatomy, whereby specific patterns (and types) of cannabis use are associated with discrete alterations in defined neural circuits. We suggest that a coordinated approach is required to move the field forward, and we offer preliminary guidelines to develop a standardized protocol to measure levels of cannabis use.

      Methods and Materials

      We performed a PubMed search on April 7, 2015, using the keywords “Cannabis OR Marijuana” AND “MRI OR Computed Tomography OR Neuroimaging” and identified 492 articles. We screened these studies according to the following inclusion criteria: 1) use of structural neuroimaging techniques and 2) examination of regular cannabis users (as defined by each study protocol). We excluded nonempirical studies and samples including any other regular substance use or major psychopathologies. We included 32 studies in this review for further inspection (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • 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.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Ashtari M.
      • Avants B.
      • Cyckowski L.
      • Cervellione K.L.
      • Roofeh D.
      • Cook P.
      • et al.
      Medial temporal structures and memory functions in adolescents with heavy cannabis use.
      ,
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ,
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      ,
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      ,
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ,
      • Jager G.
      • Van Hell H.H.
      • De Win M.M.L.
      • Kahn R.S.
      • Van Den Brink W.
      • Van Ree J.M.
      • et al.
      Effects of frequent cannabis use on hippocampal activity during an associative learning memory task.
      ,
      • Tzilos G.K.
      • Cintron C.B.
      • Wood J.B.
      • Simpson N.S.
      • Young A.D.
      • Pope Jr, H.G.
      • et al.
      Lack of hippocampal volume change in long-term heavy cannabis users.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ,
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      ,
      • Wilson W.
      • Mathew R.
      • Turkington T.
      • Hawk T.
      • Coleman R.E.
      • Provenzale J.
      Brain morphological changes and early marijuana use. A MRI and PET study.
      ,
      • Hannerz J.
      • Hindmarsh T.
      Neurological and neuroradiological examination of chronic cannabis smokers.
      ,
      • Kuehnle J.
      • Mendelson J.H.
      • Davis K.R.
      • New P.F.
      Computed tomographic examination of heavy marijuana smokers.
      ,
      • Co B.T.
      • Goodwin D.W.
      • Gado M.
      • Mickhael M.
      • Hill S.Y.
      Absence of cerebral atrophy in chronic cannabis users. Evaluation by computerized transaxial tomography.
      ,
      • Stefanis C.
      Biological aspects of cannabis use.
      ,
      • Campbell A.M.G.
      • Evans M.
      • Thomson J.L.G.
      • Williams M.J.
      Cerebral atrophy in young cannabis smokers.
      ), of which 23 were described previously (
      • Lorenzetti V.
      • Solowij N.
      • Fornito A.
      • Lubman D.I.
      • Yucel M.
      The association between regular cannabis exposure and alterations of human brain morphology: An updated review of the literature.
      ). Nine additional studies conducted since 2012 were identified (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • 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.
      ). The newest studies add to the literature five investigations of the PFC (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ) and of the hippocampus (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • 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.
      ); four investigations of the amygdala (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • 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.
      ); three investigations of the striatum (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ); two investigations of the insula (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ); and single investigations of the parietal and occipital cortices (
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ), cerebellum (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ), and pituitary gland (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ).

      Results

      Characteristics of Samples Included in Structural MRI Studies

      Key characteristics of the reviewed samples are summarized in Table 1 and Figure 1. The total sample sizes included between 15 and 30 participants [range, 8 (
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ) to 62 (
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ) control subjects and 10 (
      • Campbell A.M.G.
      • Evans M.
      • Thomson J.L.G.
      • Williams M.J.
      Cerebral atrophy in young cannabis smokers.
      ) to 57 (
      • Wilson W.
      • Mathew R.
      • Turkington T.
      • Hawk T.
      • Coleman R.E.
      • Provenzale J.
      Brain morphological changes and early marijuana use. A MRI and PET study.
      ) cannabis users]. Mean ages of cannabis users were between 17 years (
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ) and 40 years (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ). The age distribution varied within samples, ranging from 16 years (
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ) to 60 years (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ).
      Table 1Sample Characteristics of Structural Magnetic Resonance Imaging Studies of Regular Cannabis Users
      StudySample N (Males)Age (Years)CannabisAlcoholTobacco
      CBHCCBHCDuration (Years)Age of Onset (Years)
      Age of cannabis use initiation (occasional, regular, or heavy).
      Dosage
      Measures of cannabis dosage (smoking episodes, cones, joints, grams).
      Frequency
      Measures of cannabis use frequency (daily, weekly, monthly).
      SpecimensCBHCControl forCBHCControl for
      Lorenzetti et al., 2015 (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      )
      15 (15)16 (16)40 ± 936 ± 1020 ± 720 ± 7Ep./life.: 62,000; Cone/past 1 year: 77,816 ± 66,542; Cone/life.: 186,184 ± 210,022Days/month 28 ± 5UrineSD/week: 10 ± 6SD/week:7 ± 5Yes (cov.)Cig./day:17 ± 9Cig./day: 8 ± 9Yes (cov.)
      Weiland et al., 2015 (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      )
      29 (16)29 (16)28 ± 727 ± 7DailySD/month 7 ± 3; AUDIT 12 ± 7SD/month 7 ± 3; AUDIT 12 ± 8Yes (cov.)Cig./day 11 ± 8Cig./day 8 ± 8Yes (cov.)
      Battistella et al., 2014 (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      )
      For Battistella et al. (40), median and median absolute deviation values are provided.
      Reg.: 25 (0)23 ± 27 ± 316 ± 2Occ./month 63 ± 23Urine, blood, and oral fluidSD/week 10 ± 5Yes (regr.)
      Occ.: 22 (0)25 ± 28 ± 317 ± 2Occ./month 4±2SD/week 5 ± 2
      Filbey et al., 2014 (
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      )
      CB, tobacco, alcohol: 48 (33)62 (39)28 ± 830 ± 810 ± 818 ± 3Occ./week: 11 ± 1; Ep./life.
      Estimated values based on published data.
      : 5,720
      Almost dailyn = 21 drinkersYes (excl. users)n = 21 smokersYes (excl. users)
      CB only 27 (17)28 ± 99 ± 919 ± 3Occ./week: 11 ± 1; Ep./life.
      Estimated values based on published data.
      : 5,148
      No drinkersNo smokersNo smokers
      Gilman et al., 2014 (
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      )
      20 (9)20 (9)21 ± 221 ± 26 ± 317 ± 2Joints/week: 11 ± 10; Life. cone
      Estimated values based on published data.
      : 10,296
      4 ± 2UrineSD/week 5 ± 5; AUDIT 6 ± 2SD/week 3 ± 2; AUDIT 3 ± 2Yes (cov.)n = 7 occ.; n = 1 dailyNo smokersYes (cov.)
      Yip et al., 2014 (
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      )
      For Yip et al. (43), mean and SE values are provided.
      Abst. 21 days: 1320 (0)27 ± 229 ± 214 ± 313 ± 1Ep./life.
      Estimated values based on published data.
      : 2,688
      Days/month 16 ± 3UrineDays/month 4 ± 2; n = 1 abuse; n = 4 past use disorderNon = 8 smokersn = 2 smokersNo
      Current: 79 ± 214 ± 1Ep./life.
      Estimated values based on published data.
      : 3,840
      Days/month 20 ± 4Days/month 3 ± 1; n = 0 abuse; n = 4 past use disordern = 7 smokers
      Batalla et al., 2013 (
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      )
      29 (29)28 (28)21 ± 222 ± 36 ± 215 ± 1Joints/day: 3 ± 2; Joints/life.: 5,203 ± 4,192; Cone/life.
      Estimated values based on published data.
      : 15,609 ± 12,576
      DailyHair, urineSD/week: 5 ± 4; Age onset: 16 ± 2; duration years: 6 ± 2SD/week: 3 ± 3; Age onset: 16 ± 2; duration years: 6 ± 3Non = 27 smokers; Cig./day: 6 ± 5n = 9 smokers; Cig./day: 2 ± 6No
      Solowij et al., 2013 (
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      )
      15 (15)16 (16)40 ± 936 ± 1020 ± 720 ± 7Ep./life.: 62,000; Cone/past 1 year: 77,816 ± 66,542; Cone/life.: 186,184 ± 210,022Days/month 28 ± 5UrineSD/week: 10 ± 6SD/week: 7 ± 5Yes (cov.)Cig./day: 17 ± 9Cig./day: 8 ± 9Yes (cov.)
      Schacht et al., 2012 (
      • 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.
      )
      37 (14)37 (14)28 ± 827 ± 810 ± 918 ± 36 ± 1 days/weekDays/month: 7 ± 7; SD/drinking day: 3 ± 2n = 5 smokersYes (cov.)Days/month: 3 ± 4; SD/drinking day: 2 ± 1No smokersYes (cov.)
      McQueeny et al., 2011 (
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      )
      35 (27)47 (36)18 ± 118 ± 13; Abst. days: 2814Ep./life.: 44612 ep./week; 10 hits/ep.Urine, BreathalyzerEp./life.: 24 ± 44Ep./life.: 212 ± 175Yes (cov.)FTND: 0 ± 0FTND: 0.2 ± .4Yes (cov.)
      Cousijn et al., 2012 (
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.
      )
      33 (12)42 (16)21 ± 222 ± 23 ± 219 ± 2Grams/week: 3 ± 2; Joints/life.: 1580 ± 1425; Cone/life.
      Estimated values based on published data.
      : 4740 ± 4725
      5 ± 2 days/weekUrineAUDIT 6 ± 3AUDIT 5 ± 3Yes (regr.)FTND: 3 ± 2; Cig./day: 7 ± 7; Duration: 4 ± 4 yearsFTND: 1 ± 1; Cig./day: 1 ± 4; Duration: 1 ± 2 yearsYes (cov.)
      Lopez-Larson et al., 2011 (
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      )
      18 (16)18 (16)17 ± 117 ± 8Reg. use: 19 ± 1; Heavier use (months): 19 ± 1416 ± 1Ep./week: 10 ± 8; Ep./life.: 1346 ± 1372; THC ng/mL: 455 ± 352DailyUrinen = 3 drinks > once/weekNoOcc./week: 10 ± 4; Occ./life.: 1,346 ± 1,371No
      Solowij et al., 2011 (
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      )
      15 (15)16 (16)40 ± 936 ± 1020 ± 720 ± 5Cone/month: 636 ± 565; cone past 10 years: 77,816 ± 66,54228 ± 5UrineSD/week: 10 ± 6SD/week: 7 ± 5Yes (cov.)Cig./day: 17 ± 9Cig./day: 8 ± 9Yes (cov.)
      Ashtari et al., 2011 (
      • Ashtari M.
      • Avants B.
      • Cyckowski L.
      • Cervellione K.L.
      • Roofeh D.
      • Cook P.
      • et al.
      Medial temporal structures and memory functions in adolescents with heavy cannabis use.
      )
      14 (14)14 (14)19 ± 0.819 ± 15 ± 2; Abst. months: 7 ± 413 ± 2Daily joints: 6 ± 3; Joints/life.: 11,220; Cone/life.
      Estimated values based on published data.
      : 33,660
      Dailyn = 5 abuseEp./life.: <5Non = 8 abuse/dependenceEp./life.: <5No
      Churchwell et al., 2010 (
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      )
      18 (16)18 (12)17 ± 117 ± 12
      Estimated values based on published data.
      First try: 15 ± 0.3; Reg.: 16 ± 0.2Ep./life.: 1353 ± 323; Dose THC ng/mL: 429 ± 85Ep./week: 9 ± 2Hair, urinen = 2 abuseNon = 4 current useNo
      Demirakca et al., 2010 2011 (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      )
      11 (11)13 (13)22 ± 223 ± 2516 ± 2Daily THC grams: 0.3; Cone/life.
      Estimated values based on published data.
      : 5322
      DailyUrineDrinks/day = 1.5Drinks/day = 0.3Yes (cov.)n = 6 smokersn = 1 smokerYes (cov.)
      Mata et al., 2010 (
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      )
      30 (23)44 (25)26 ± 526 ± 68 ± 917 ± 4Cone/week: 27 ± 21; Cone/life.: 11,619 ± 9387Almost dailyn = 23 drinkersn = 23 drinkersYes (cov.)n = 25 smokersn = 17 smokersYes (cov.)
      Medina et al., 2010 (
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      )
      16 (12)16 (10)18 ± 118 ± 13±2; Abst. days: 107 ± 3315
      Estimated values based on published data.
      Ep./life.: 476 ± 269Urine, BreathalyzerEp./life.: 195 ± 137Ep./life.: 23 ± 47Yes (regr.)Cig./month: 29 ± 74Cig./month: 5 ± 20No
      Medina et al., 2009 (
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      )
      16 (12)16 (10)18 ± 118 ± 13 ± 2; Abst. days: 107 ± 3315
      Estimated values based on published data.
      Ep./life.: 476 ± 269Urine, BreathalyzerEp./life.: 230 ± 128Ep./life.: 25 ± 51Yes (cov.)Ep./life.: <25Ep./life.: <5No
      Yücel et al., 2008 (
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      )
      15 (15)16 (16)40 ± 936 ± 1020 ± 720 ± 7Ep./life.: 62,000; Cone/past 1 year: 77,816 ± 66,542; Cone/life.: 186,184 ± 210,022Days/month 28 ± 5UrineSD/week: 10 ± 6SD/week: 7 ± 5Yes (regr.)Cig./day: 17 ± 9Cig./day: 8 ± 9Yes (regr.)
      Medina et al., 2007 (
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      )
      26 (19)21 (14)18 ± 118 ± 12 years
      Estimated values based on published data.
      15
      Estimated values based on published data.
      Ep./life.: 402 ± 260Ep./month: 14 ± 11Urine, BreathalyzerEp./life.: 152 ± 185Ep./life.: 8 ± 16Yes (cov.)n = 9 smoked past month; Cig./day: 3 ± 3n = 1 smoked past month; Cig./day: 1No
      Medina et al., 2007 (
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      )
      16 (12)16 (11)18 ± 118 ± 13 ± 2; Abst. days: 2815
      Estimated values based on published data.
      Ep./life.: 476 ± 269Urine, BreathalyzerEp./life.: 230 ± 128Ep./life.: 25 ± 51Yes (regr.)Ep./life.: <25Ep./life.: <5No
      Jager et al., 2007 (
      • Jager G.
      • Van Hell H.H.
      • De Win M.M.L.
      • Kahn R.S.
      • Van Den Brink W.
      • Van Ree J.M.
      • et al.
      Effects of frequent cannabis use on hippocampal activity during an associative learning memory task.
      )
      For Jager et al. (61), mean values are provided.
      20 (13)20 (13)25 ± 524 ± 48 ± 516
      Estimated values based on published data.
      Joints/life. (median): 1900; Joints past 1 year (median): 333Almost dailySD/week: 10SD/week: 6Yes (cov.)Cig./week: 10Cig./week: 0Yes (cov.)
      Tzilos et al., 2005 (
      • Tzilos G.K.
      • Cintron C.B.
      • Wood J.B.
      • Simpson N.S.
      • Young A.D.
      • Pope Jr, H.G.
      • et al.
      Lack of hippocampal volume change in long-term heavy cannabis users.
      )
      22 (16)26 (19)38 ± 630 ± 9Reg.: 23 ± 6; Daily: 19 ± 816 ± 4Ep./life.: 20,140 ± 13,866DailyDrinks/life.: 6,524 ± 5,934NoLife. cig. packs: 2,727 ± 2,981No
      Matochik et al., 2005 (
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      )
      11 (11)8 (8)30 ± 525 ± 58 ± 6; Abst. days: 2016 ± 3Joints/week: 35 ± 18; Cone/life.
      Estimated values based on published data.
      : 40,599
      Almost dailyUrineSD/week: 2 ± 2SD/week: 1 ± 2NoNo
      Block et al., 2000 (
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      )
      18 (8)13 (6)22 ± 123 ± 14 ± 0.418
      Estimated values based on published data.
      Ep./week: 18 ± 2UrineDrinking days, past month & and 2 years: 6 ± 1Drinking days, past month 4 ± 1 & and past 2 years: 3 ± 1NoNo
      Wilson et al., 2000 (
      • Wilson W.
      • Mathew R.
      • Turkington T.
      • Hawk T.
      • Coleman R.E.
      • Provenzale J.
      Brain morphological changes and early marijuana use. A MRI and PET study.
      )
      57 (25); CB onset: early 16 (13), late 9 (19)31 ± 7R = 11–26; Early onset: 15 ± 6; Late onset: 14 ± 717 ± 4; Early onset: ≤17; late onset: >17Joints/year; Early onset: 194 ± 169; Late onset: 164 ± 387n = 48 drinkers; n = 2 former drinkersYes (cov.)n = 27 smokers;n = 3 former smokersNo
      Hannerz and Hindmarsh, 1983 (
      • Hannerz J.
      • Hindmarsh T.
      Neurological and neuroradiological examination of chronic cannabis smokers.
      )
      12 (8)12 (8)262610
      Kuehnle et al., 1977 (
      • Kuehnle J.
      • Mendelson J.H.
      • Davis K.R.
      • New P.F.
      Computed tomographic examination of heavy marijuana smokers.
      )
      19 (19)19 (19)24Inward study: 5 days abst.; 21 days CB use; 5 abst. daysOutward monthly joints: 35; Inward study, total joints: 111
      Co et al., 1977 (
      • Co B.T.
      • Goodwin D.W.
      • Gado M.
      • Mickhael M.
      • Hill S.Y.
      Absence of cerebral atrophy in chronic cannabis users. Evaluation by computerized transaxial tomography.
      )
      12 (12)34 (34)24267Occ.: 16; Reg.: 17Joints/day: 9
      Stefanis, 1976 (
      • Stefanis C.
      Biological aspects of cannabis use.
      )
      47 (47)40 (40)404223Daily
      Campbell et al., 1971 (
      • Campbell A.M.G.
      • Evans M.
      • Thomson J.L.G.
      • Williams M.J.
      Cerebral atrophy in young cannabis smokers.
      )
      10 (10)13 (7)2320716Daily
      Values for all measures are mean (SD).
      abst., abstinence; AUDIT, Acohol Use Disorder Identification Test; CB, cannabis users or cannabis; cig., cigarettes; cone, standardized cannabis unit; cov., covariate; ep., episodes; excl. users, excluded users with comorbid alcohol or tobacco use (or both); FTND, Fagerström Test for Nicotine Dependence scores; HC, healthy non–cannabis using control subjects; life., lifetime; occ., occasional use; past 1 year, over the past 12 months; R, range; reg., regular cannabis use; regr., regressor; SD, standard deviation; THC, ∆9-tetrahydrocannabinol.
      a Age of cannabis use initiation (occasional, regular, or heavy).
      b Measures of cannabis dosage (smoking episodes, cones, joints, grams).
      c Measures of cannabis use frequency (daily, weekly, monthly).
      d For Battistella et al. (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ), median and median absolute deviation values are provided.
      e Estimated values based on published data.
      f For Yip et al. (
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ), mean and SE values are provided.
      g For Jager et al. (
      • Jager G.
      • Van Hell H.H.
      • De Win M.M.L.
      • Kahn R.S.
      • Van Den Brink W.
      • Van Ree J.M.
      • et al.
      Effects of frequent cannabis use on hippocampal activity during an associative learning memory task.
      ), mean values are provided.
      Figure thumbnail gr1
      Figure 1Summary of sample size, mean age, and mean cannabis use characteristics of the samples included in structural magnetic resonance imaging studies of cannabis users.
      All samples of cannabis users smoked cannabis regularly, on a daily (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Ashtari M.
      • Avants B.
      • Cyckowski L.
      • Cervellione K.L.
      • Roofeh D.
      • Cook P.
      • et al.
      Medial temporal structures and memory functions in adolescents with heavy cannabis use.
      ,
      • Tzilos G.K.
      • Cintron C.B.
      • Wood J.B.
      • Simpson N.S.
      • Young A.D.
      • Pope Jr, H.G.
      • et al.
      Lack of hippocampal volume change in long-term heavy cannabis users.
      ,
      • Co B.T.
      • Goodwin D.W.
      • Gado M.
      • Mickhael M.
      • Hill S.Y.
      Absence of cerebral atrophy in chronic cannabis users. Evaluation by computerized transaxial tomography.
      ,
      • Stefanis C.
      Biological aspects of cannabis use.
      ,
      • Campbell A.M.G.
      • Evans M.
      • Thomson J.L.G.
      • Williams M.J.
      Cerebral atrophy in young cannabis smokers.
      ) or almost daily (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.
      ,
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Jager G.
      • Van Hell H.H.
      • De Win M.M.L.
      • Kahn R.S.
      • Van Den Brink W.
      • Van Ree J.M.
      • et al.
      Effects of frequent cannabis use on hippocampal activity during an associative learning memory task.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ) basis. Some studies did not provide information on frequency of use but estimated the number of smoking episodes (
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      ,
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      ,
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ,
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      ) and joints (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      ,
      • Wilson W.
      • Mathew R.
      • Turkington T.
      • Hawk T.
      • Coleman R.E.
      • Provenzale J.
      Brain morphological changes and early marijuana use. A MRI and PET study.
      ,
      • Hannerz J.
      • Hindmarsh T.
      Neurological and neuroradiological examination of chronic cannabis smokers.
      ,
      • Kuehnle J.
      • Mendelson J.H.
      • Davis K.R.
      • New P.F.
      Computed tomographic examination of heavy marijuana smokers.
      ). Most cannabis users started smoking between age 15 and 17 years. Participants in a few samples started smoking 1 or 2 years earlier [14 years (
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      )] or later [18–20 years (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      )]. Duration of use varied greatly across all examined samples and ranged from 2 years (
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ,
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ) to 23 years (
      • Tzilos G.K.
      • Cintron C.B.
      • Wood J.B.
      • Simpson N.S.
      • Young A.D.
      • Pope Jr, H.G.
      • et al.
      Lack of hippocampal volume change in long-term heavy cannabis users.
      ,
      • Stefanis C.
      Biological aspects of cannabis use.
      ) of regular use. Lifetime exposure to cannabis was computed in cumulative number of joints, cones (standard cannabis unit, with 1 joint = 3 cones, 1 g = 12 cones; for other conversions, see guidelines from the National Cannabis Prevention and Information Centre at https://ncpic.org.au/media/1593/timeline-followback.pdf) (red triangles in Figure 2), or smoking episodes (blue squares in Figure 2), which was available for all but a few studies (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      ,
      • Hannerz J.
      • Hindmarsh T.
      Neurological and neuroradiological examination of chronic cannabis smokers.
      ,
      • Kuehnle J.
      • Mendelson J.H.
      • Davis K.R.
      • New P.F.
      Computed tomographic examination of heavy marijuana smokers.
      ,
      • Stefanis C.
      Biological aspects of cannabis use.
      ,
      • Campbell A.M.G.
      • Evans M.
      • Thomson J.L.G.
      • Williams M.J.
      Cerebral atrophy in young cannabis smokers.
      ).
      Figure thumbnail gr2
      Figure 2Summary of reviewed samples’ lifetime cumulative dosage [red triangles (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • 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.
      ,
      • Lorenzetti V.
      • Lubman D.I.
      • Whittle S.
      • Solowij N.
      • Yücel M.
      Structural MRI findings in long-term cannabis users: What do we know?.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Ashtari M.
      • Avants B.
      • Cyckowski L.
      • Cervellione K.L.
      • Roofeh D.
      • Cook P.
      • et al.
      Medial temporal structures and memory functions in adolescents with heavy cannabis use.
      ,
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      ,
      • Jager G.
      • Van Hell H.H.
      • De Win M.M.L.
      • Kahn R.S.
      • Van Den Brink W.
      • Van Ree J.M.
      • et al.
      Effects of frequent cannabis use on hippocampal activity during an associative learning memory task.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ,
      • Hannerz J.
      • Hindmarsh T.
      Neurological and neuroradiological examination of chronic cannabis smokers.
      ,
      • Stefanis C.
      Biological aspects of cannabis use.
      )], computed as cones according to guidelines (https://ncpic.org.au/media/1593/timeline-followback.pdf); smoking episodes [blue squares (
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Lorenzetti V.
      • Solowij N.
      • Fornito A.
      • Lubman D.I.
      • Yucel M.
      The association between regular cannabis exposure and alterations of human brain morphology: An updated review of the literature.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ,
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      ,
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      )], and measured levels of ∆9-tetrahydrocannabinol metabolite [11-nor-9-carboxy-THC, ng/L (
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ) or ng/mg (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • 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.
      ,
      • Lorenzetti V.
      • Solowij N.
      • Fornito A.
      • Lubman D.I.
      • Yucel M.
      The association between regular cannabis exposure and alterations of human brain morphology: An updated review of the literature.
      ,
      • Lorenzetti V.
      • Lubman D.I.
      • Whittle S.
      • Solowij N.
      • Yücel M.
      Structural MRI findings in long-term cannabis users: What do we know?.
      ,
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      )] from urine toxicology (green circles) and hair [orange rhombus, reflecting ~3 months of exposure (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      )].
      Lifetime episodes of cannabis use ranged from 402 (
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ) to 5625 (
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ). Lifetime cumulative cannabis dosage (dosage × smoking days × duration of regular use) ranged from 5322 cones (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ) to 68,000 cones (
      • Co B.T.
      • Goodwin D.W.
      • Gado M.
      • Mickhael M.
      • Hill S.Y.
      Absence of cerebral atrophy in chronic cannabis users. Evaluation by computerized transaxial tomography.
      ). Most studies measured cannabinoid compounds, with three exceptions (
      • Weiland B.J.
      • Thayer R.E.
      • Depue B.E.
      • Sabbineni A.
      • Bryan A.D.
      • Hutchison K.E.
      Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.
      ,
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      ,
      • Tzilos G.K.
      • Cintron C.B.
      • Wood J.B.
      • Simpson N.S.
      • Young A.D.
      • Pope Jr, H.G.
      • et al.
      Lack of hippocampal volume change in long-term heavy cannabis users.
      ). In 20 studies, urinalysis was used to detect cannabinoid compounds. Eight studies reported the levels of cannabinoid metabolites. Mean values for 11-nor-9-carboxy-THC (THC-COOH) (green circles in Figure 2) were reported from toxicology analyses of urine samples in eight studies (
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ) and analyses of hair samples in one study (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ). In 11 studies, positive [three studies (
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ,
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ,
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      )] or negative [eight studies (
      • Ashtari M.
      • Avants B.
      • Cyckowski L.
      • Cervellione K.L.
      • Roofeh D.
      • Cook P.
      • et al.
      Medial temporal structures and memory functions in adolescents with heavy cannabis use.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      ,
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      ,
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ,
      • Jager G.
      • Van Hell H.H.
      • De Win M.M.L.
      • Kahn R.S.
      • Van Den Brink W.
      • Van Ree J.M.
      • et al.
      Effects of frequent cannabis use on hippocampal activity during an associative learning memory task.
      ,
      • Wilson W.
      • Mathew R.
      • Turkington T.
      • Hawk T.
      • Coleman R.E.
      • Provenzale J.
      Brain morphological changes and early marijuana use. A MRI and PET study.
      )] returns were reported from toxicologic analysis of urine samples without quantification.
      The reviewed studies used various specimens to detect cannabinoids or their metabolites, including urine samples in 19 studies (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Lorenzetti V.
      • Solowij N.
      • Whittle S.
      • Fornito A.
      • Lubman D.I.
      • Pantelis C.
      • et al.
      Gross morphological brain changes with chronic, heavy cannabis use.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Churchwell J.C.
      • Lopez-Larson M.
      • Yurgelun-Todd D.A.
      Altered frontal cortical volume and decision making in adolescent cannabis users.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      ,
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      ,
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ,
      • Block R.I.
      • O’Leary D.S.
      • Ehrhardt J.C.
      • Augustinack J.C.
      • Ghoneim M.M.
      • Arndt S.
      • et al.
      Effects of frequent marijuana use on brain tissue volume and composition.
      ,
      • Cousijn J.
      • Goudriaan A.E.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Wiers R.W.
      Neural responses associated with cue-reactivity in frequent cannabis users.
      ), oral fluid (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ) and blood samples (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ) in single studies, and hair in 2 studies (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ), only one of which reported the outcome of the assessment (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ) (Table 1). Some studies used several specimens [i.e., hair and urine (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Batalla A.
      • Soriano-Mas C.
      • Lopez-Sola M.
      • Torrens M.
      • Crippa J.A.
      • Bhattacharyya S.
      • et al.
      Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.
      ), blood and oral fluid (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      )]. Breathalyzers were used in five studies to screen for acute intoxication (
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Tapert S.F.
      Abnormal cerebellar morphometry in abstinent adolescent marijuana users.
      ,
      • Medina K.L.
      • McQueeny T.
      • Nagel B.J.
      • Hanson K.L.
      • Yang T.T.
      • Tapert S.F.
      Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects.
      ,
      • Medina K.L.
      • Nagel B.J.
      • Park A.
      • McQueeny T.
      • Tapert S.F.
      Depressive symptoms in adolescents: Associations with white matter volume and marijuana use.
      ,
      • Medina K.L.
      • Schweinsburg A.D.
      • Cohen-Zion M.
      • Nagel B.J.
      • Tapert S.F.
      Effects of alcohol and combined marijuana and alcohol use hippocampal volume and asymmetry.
      ). Several studies controlled for the confounding effects of alcohol (n = 18) and tobacco use (n = 13) (Table 1) by covarying for their influence in group comparisons or reanalyzing the data after excluding participants with concurrent alcohol and tobacco use.

      Neuroanatomic Alterations in Regular Cannabis Users Relative to Control Subjects

      Neuroanatomic alterations were reported in several brain regions (Table 2 and Figure 3A). Abnormalities in cannabis users, relative to control subjects, emerged most consistently in the hippocampus [seven studies (
      • Demirakca T.
      • Sartorius A.
      • Ende G.
      • Meyer N.
      • Welzel H.
      • Skopp G.
      • et al.
      Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol.
      ,
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Solowij N.
      • Walterfang M.
      • Lubman D.I.
      • Whittle S.
      • Lorenzetti V.
      • Styner M.
      • et al.
      Alteration to hippocampal shape in cannabis users with and without schizophrenia.
      ,
      • Ashtari M.
      • Avants B.
      • Cyckowski L.
      • Cervellione K.L.
      • Roofeh D.
      • Cook P.
      • et al.
      Medial temporal structures and memory functions in adolescents with heavy cannabis use.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      )]. Several studies reported alterations in the volume (i.e., sum of all voxels that are included within the boundaries of the region of interest) and gray matter density (i.e., amounts of gray or white matter concentration in each voxel) within the amygdala and striatum (
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Yip S.W.
      • DeVito E.E.
      • Kober H.
      • Worhunsky P.D.
      • Carroll K.M.
      • Potenza M.N.
      Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: An exploratory study of relationships with abstinence during behavioral treatment.
      ,
      • McQueeny T.
      • Padula C.B.
      • Price J.
      • Medina K.L.
      • Logan P.
      • Tapert S.F.
      Gender effects on amygdala morphometry in adolescent marijuana users.
      ,
      • Yücel M.
      • Solowij N.
      • Respondek C.
      • Whittle S.
      • Fornito A.
      • Pantelis C.
      • et al.
      Regional brain abnormalities associated with heavy long-term cannabis use.
      ,
      • Matochik J.A.
      • Eldeth D.A.
      • Cadet D.A.
      • Bolla K.I.
      Altered brain tissue composition in heavy marijuana users.
      ), PFC (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Filbey F.M.
      • Aslan S.
      • Calhoun V.D.
      • Spence J.S.
      • Damaraju E.
      • Caprihan A.
      • et al.
      Long-term effects of marijuana use on the brain.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      ,
      • Campbell A.M.G.
      • Evans M.
      • Thomson J.L.G.
      • Williams M.J.
      Cerebral atrophy in young cannabis smokers.
      ), parietal cortex (
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ,
      • Mata I.
      • Perez-Iglesias R.
      • Roiz-Santianez R.
      • Tordesillas-Gutierrez D.
      • Pazos A.
      • Gutierrez A.
      • et al.
      Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.
      ), insular cortex (
      • Battistella G.
      • Fornari E.
      • Annoni J.-M.
      • Chtioui H.
      • Dao K.
      • Fabritius M.
      • et al.
      Long-term effects of cannabis on brain structure.
      ,
      • Gilman J.M.
      • Kuster J.K.
      • Lee S.
      • Lee M.J.
      • Kim B.W.
      • Makris N.
      • et al.
      Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.
      ,
      • Lopez-Larson M.P.
      • Bogorodzki P.
      • Rogowska J.
      • McGlade E.
      • King J.B.
      • Terry J.
      • et al.
      Altered prefrontal and insular cortical thickness in adolescent marijuana users.
      ), and cerebellum (
      • Solowij N.
      • Yücel M.
      • Respondek C.
      • Whittle S.
      • Lindsay E.
      • Pantelis C.
      • et al.
      Cerebellar white-matter changes in cannabis users with and without schizophrenia.
      ,
      • Cousijn J.
      • Wiers R.W.
      • Ridderinkhof K.R.
      • van den Brink W.
      • Veltman D.J.
      • Goudriaan A.E.
      Grey matter alterations associated with cannabis use: Results of a VBM study in heavy cannabis users and healthy controls.