The Association between Regular Cannabis ...

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The Association between Regular Cannabis Exposure and Alterations of Human Brain Morphology: An Updated Review of the Literature Valentina Lorenzetti1,2, Nadia Solowij2, Alex Fornito1,2,3,4, Dan Lubman5 and Murat Yücel1,2,* 1

Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Melbourne, Australia; 1Monash Clinical & Imaging Neuroscience, Monash University, Melbourne, Australia; 2School of Psychology, University of Wollongong, Wollongong, Australia; 3Centre for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia, 3010; 4NICTA Victorian Research Laboratory, The University of Melbourne, Parkville, Victoria, Australia, 3010; 3Turning Point Alcohol and Drug Centre, Eastern Health and Monash University, Melbourne, Australia Abstract: Cannabis is the most widely illicit drug of use worldwide, though it is unclear whether its regular use is associated with persistent alterations of brain morphology. This review examines evidence from human structural neuroimaging investigations of regular cannabis users and focuses in achieving three main objectives. These include examining whether the literature to date provides evidence that alteration of brain morphology in regular cannabis users: i) is apparent, compared to non-cannabis using controls; ii) is associated with patterns of cannabis use; and with iii) measures of psychopathology and neurocognitive performance. The published findings indicate that regular cannabis use is associated with alterations in medial temporal, frontal and cerebellar brain regions. Greater brain morphological alterations were evident among samples that used at higher doses for longer periods. However, the evidence for an association between brain morphology and cannabis use parameters was mixed. Further, there is poor evidence for an association between measures of brain morphology and of psychopathology symptoms/neurocognitive performance. Overall, numerous methodological issues characterize the literature to date. These include investigation of small sample sizes, heterogeneity across studies in sample characteristics (e.g., sex, comorbidity) and in employed imaging techniques, as well as the examination of only a limited number of brain regions. These factors make it difficult to draw firm conclusions from the existing findings. Nevertheless, this review supports the notion that regular cannabis use is associated with alterations of brain morphology, and highlights the need to consider particular methodological issues when planning future cannabis research.

Keywords: Cannabis, brain, sMRI, hippocampus, amygdala, prefrontal cortex, cerebellum. INTRODUCTION Cannabis is the most widely used illicit drug, with 14.8 million people aged 15 to 64 years reporting a lifetime history of use [1]. However, most people use cannabis for only a limited period (e.g., HC male for PFC. Neg. Assoc. PFC & Exec. in CB. Medina (2009)

CB = HC for ICV.

_

_

_

Pos. Assoc. PFC & Exec. In HC.

_

Pos. Assoc. PFC WM & Exec. Pos. Assoc. Anterior Ventral PFC, PFC WM & recent use. Neg. Assoc. Posterior PFC & Recent CB Use, Alcohol Dep. in HC. CB < HC for Amy Vol.

CB < HC for Hipp Vol. Yücel (2008)

CB = HC for WBV, Tot GM, Tot WM. No Assoc. with Age of Onset & WRAT.

Neg. Assoc. of Left Hipp & Life Dosage, Pos. Psychotic Symptoms.

_

No Assoc. with RAVLT.

No Assoc. with Dosage, Pos. Psychotic Symptoms, RAVLT.

_

_

CB = HC for Hipp.

Medina (2007) A

CB = HC for ICV.

Pos. Assoc. of Left>Right Hipp Asymm, Left Hipp & CB Abuse & Dep.

_

_

_

_

_

_

_

_

CB = HC for Para-Hipp GM or WM Density.

_

_

_

_

_

_

Pos. Assoc. Hipp/Hipp Left>Right Asymm. & CVLT in HC. CB = HC for ICV. Medina (2007) B

Jager (2007)

Neg. Assoc. of Tot WM & BDI in CB, and of Tot WM & HAMD scores in CB & HC.

_

CB = HC for Hipp/ICV. No Assoc. with BDI, HAMD.

_

No Assoc. with CB Use, Associative Learn.

Tzilos (2005)

CB = HC & Early Onset = Late Onset for Tot GM, Tot WM, CSF, WBV. No Assoc. with Age of Onset.

CB = HC & Early Onset = Late Onset for Hipp, Hipp/WBV. No Assoc. with Age of Onset, N° Ep, Memo & Learn (BSRT, WMS, BVRT).

CB = HC & Early Onset = Late Onset for Para-Hipp.

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(Table 2) Contd…. Examined Brain Regions Author (Year)

Matochik (2005)

Global Brain Measures

CB = HC for Tot GM & WM. No Assoc. with Age of Onset.

Hippocampus

CB < HC for Hipp GM Density. Neg. Assoc. Hipp GM Density & Duration. No Assoc. with Age of Onset, Freq.

ParaHippocampus

Amygdala

PFC

Cerebellum

_

_

_

_

_

_

CB = HC for Cerebellar Volume

Early Onset < Late Onset for Frontal GM.

_

Early Onset = Late Onset for Amy/WBV.

CB < HC for Para-Hipp GM Density. CB > HC for Para-Hipp WM Density. No Assoc. with Age of Onset, Freq, Duration.

CB < HC for Ventricular CSF. Block (2000)

CB = HC for ICV, CSF, Tot GM, Tot WM.

CB = HC for Hipp Vol.

No Assoc. with Age of Onset. Early Onset < Late Onset for Tot GM. Wilson (2000)

Early Onset > Late Onset for Tot WM.

Early Onset = Late Onset for Hipp/ WBV.

Early Onset = Late Onset for WBV & Ventricles.

No Assoc. with Duration.

Early Onset = Late Onset for Cingulate Vol.



_

Hannerz (1983)

CB = HC for Cortical Sulci, Ventricles & Cistern Shapes.

_

_

_

_

Kuehnle (1977)

CB = HC for Ventricles & SubArachnoid Sizes.

_

_

_

_

_

_

_

_

(1977)

CB = HC for Ventricles & Brain Sizes.

Stefanis (1976)

CB = HC for 3rd Ventricle Size.

_

_

_

_

_

_

_

CB > HC for Frontal Sulci.

Co

Campbell (1971)

CB > HC for Lateral & 3rd Ventricle Body & Frontal, Temporal Horn.

_

_

_

_

_

Abnormal Shape of Lateral Ventricle in CB. Red fonts, significant group differences; Blue font, no group difference. Author= first author; Y= publication year; CB=cannabis users; HC= non=cannabis using controls; ICV=IntraCranial Volume; right volumes [24] in one study, while not being associated with hippocampal volumes in other investigations [34]. Depression [15, 34], attention-deficit hyperactivity disorder, dependence on alcohol and nicotine [34] were not associated with hippocampal volumes, with the exception of positive psychotic symptoms being related to smaller hippocampi in one study [25]. Significant associations between measures of verbal learning and hippocampal volumes was apparent in HC only [13, 20, 24], but not in CB users [13, 20, 24, 25], suggesting an alteration of normal


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Fig. (3). Associations between lifetime cannabis cones exposure (Y axis) and significant group differences (CB vs. HC, % difference) in hippocampal volumes by study (X axis) [13, 17, 20, 25, 30, 32]; Medina 2007a= [24]; Medina 2007b=[15].

brain-behaviour relationship in regular CB users. In summary, there is preliminary evidence for associations between psychopathology/neurocognitive measures and hippocampal volumes. However, the paucity of the conducted investigations prevents the ability to clearly interpret these data. b. Para-hippocampus Only a paucity of investigations examined para-hippocampal volumes in CB populations (see Table 2). These reported both nonsignificant [20, 31] and significant differences between CB users and HC [32]. Notably, the only study reporting alteration in parahippocampal volumes in CB users i.e., decreased GM and increased WM compared to HC [32] examined a sample with a higher frequency of use than that of studies reporting no difference between CB and HC groups [20, 31]. The only study that investigated the association between para-hippocampal volume and measures of neurocognitive function (e.g. associative memory) found no relationship [31]. In summary, there is little evidence for parahippocampal alterations in CB users, which may be due to the small number of conducted studies. However, differences in the parahippocampus were reported in CB groups with higher exposure to cannabis, suggesting that these differences may be related to ongoing neurotoxicity. The paucity of studies in para-hippocampal volumes in CB users prevents the ability however, to make any clear interpretation of the reviewed para-hippocampal findings. c. Amygdala Group Comparison Most of the studies investigating amygdala volumes across CB users and HC (i.e., 3 out of 4) found no significant group difference [13, 34, 35]. The only study that showed amygdala volumetric reduction in CB users [25] investigated a CB group that had cumulative cannabis dosage higher than that of CB samples showing no volumetric alteration [13, 34, 35], as illustrated in Table 2. Interestingly, two of the studies reporting no alteration in amygdala volumes examined CB groups composed of abstinent and treatmentseeking CB participants [13, 35], as opposed to other investigations examining non-treatment seeking CB users [25, 34], raising concerns regarding their non-significant finding. For instance, amygdala volumetric alterations that were observed in regular CB users may not last beyond periods of prolonged abstinence.

Association with Cannabis use Patterns/other Variables Only 3 out of 5 studies examined the association between amygdala volumes and cannabis use patterns, measures of psychopathology symptoms and of neurocognitive performance [13, 25, 34]. Cannabis use patterns were not associated with amygdala volumes, such as age of onset [13, 16, 25, 34], duration of regular use and dosage [25, 34]. Evidence of an association between amygdala volumes and psychopathology symptoms was mixed. Smaller amygdala volumes were related to lower anxiety symptoms [35] and higher cannabis dependence scores [34]. Amygdala volumes were positively associated with depressive symptoms in one [35] but not another investigation [34]. Amygdala volumes were not related to symptoms of positive psychosis [25], attention-deficithyperactivity disorder, dependence on nicotine and alcohol [34] and neurocognitive measures such as verbal learning [13, 25] and IQ [13]. In summary, these findings suggest that cannabis use patterns do not affect amygdala volumes in CB users, while revealing preliminary associations between amygdala volumes and psychopathology symptoms. Interpretation of these data is profoundly limited by the low number of conducted investigations on the relationship between amygdala volumes and these variables. d. Prefrontal Cortex Group Comparisons Studies investigating PFC regions have resulted in mixed findings (see Table 2), with both presence [21, 27, 28, 33] and absence of group differences between CB users and HC [17, 27-29, 33]. Examination of total PFC volume led to non-significant findings [16, 17, 28, 29, 33]. In contrast, examination of volume [27], sulcal concavity [21, 28] and cortical thickness [28, 33] of a variety of PFC subregions revealed group effects, exception being for one study finding no difference between CB users and HC for OFC and ACC volumes [34]. The direction of alteration of PFC measures of sulcal concavity and cortical thickness was mixed, being found to be both increased [21, 28] and decreased [28, 33] in CB users than HC. In summary, regular cannabis exposure may affect PFC subregions rather than global PFC measures. The identification of which

The Association between Regular Cannabis Exposure and Alterations

PFC subregions are particularly vulnerable to the impact of regular cannabis exposure may be prevented by the considerable interindividual variability in PFC sulcal-gyral anatomy, the detection of which is limited in automated approaches to image analysis [4446], which have been utilised in most of the studies of the PFC [17, 28, 33, 34]. Association with Cannabis use Patterns Several studies have examined the association between PFC regions and cannabis use patterns. Age of onset appeared to be more consistently associated with PFC morphological measures, as opposed to dosage and duration of cannabis use [21, 27, 28, 33, 34]. Three out of the five studies investigating the association between age of onset and prefrontal measures [16, 27, 28, 34], found that earlier age of onset was associated with reduced PFC volumes [16, 27] and thickness [33]. The evidence investigating the association between cannabis dosage and PFC morphology provided mixed findings. Smaller PFC volumes were related to lower levels of exposure in one study [29], while lower cortical thickness was related to higher levels of THC (i.e., ng/mg) in another investigation [33]. Other studies reported no significant association between cannabis dosage and PFC thickness [28] and volumes [34]. Amongst cannabis use patterns, younger age of onset may affect measures of PFC morphology (i.e., cortical thickness and volume), but further research is required to replicate these findings. Association with other Psychopathology Symptoms/Neurocognitive Measures PFC morphology was not associated with psychopathology symptoms for depression, attention-deficit and hyperactivity disorder [34], measures of impulsivity [27] and problematic use (i.e., abuse and dependence) of cannabis, nicotine [34] and alcohol [29, 34]. Conversely, there was emerging evidence for an association between PFC and selected neurocognitive measures (i.e., executive functioning [29] but not verbal fluency [33]). As most of the findings on the association between PFC morphology and psychopathology symptoms/neurocognitive performance were related to single studies, further research is warranted to validate their results. e. Cerebellum Group Comparisons Studies assessing cerebellar volumes in CB samples led to mixed findings, with both presence and absence of differences between CB users and HC (see Table 2). Group differences were more likely to occur in a variety of sub-regions of the cerebellum [14, 26, 34] but not when the cerebellum was examined as a whole [14, 17, 26], suggesting that cerebellar sub-regions are particularly vulnerable to regular cannabis exposure. Alterations in cerebellar subregions included larger inferior posterior lobules VIII-X [14] and WM of the anterior lobes [34] and smaller cerebellar WM [26]. The discrepancy between findings (i.e., presence and absence of group differences in cerebellar measures) was not associated with different levels of cannabis exposure across the CB samples. Indeed, studies identifying group differences in cerebellar volumes were heterogeneous for cannabis use patterns such as duration, frequency and dosage [14, 26, 34]. One investigation leading to negative findings [17] examined CB users with similar levels of cannabis exposure to those of studies leading to positive findings (i.e., significant cerebellar difference between CB users and HC). These inconsistencies prevented the identification of cannabis use patterns that may have been driving the reported findings. Association with Cannabis use Patterns, Psychopathology/Neurocognitive Measures Only four studies examined the association between cerebellar morphology and cannabis use patterns, psychopathology symptoms and neurocognitive measures, leading mostly to negative findings [14, 26, 34]. First, there was no association between cerebellar volumes and cannabis use patterns such as age of onset, dosage and

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duration of regular use [26, 34]. Second, while one study showed that higher depressive symptoms were related to lower cerebellar WM volume [26], there was other evidence for no association between cerebellar volumes and a range of psychopathology symptoms, including depression, anxiety, attention-deficit-hyperactivity disorder, dependence on cannabis, nicotine and alcohol [34]. Third, the only investigation examining the association between cerebellar volumes and neurocognitive measures, reported that larger cerebellar vermis were related to lower executive functioning, but not to psychomotor speed and time estimate [14]. In summary, cannabis use patterns were not associated with cerebellar volumes and there was scarce evidence for cerebellar measures being related to psychopathology symptoms and neurocognitive performance. Given the paucity of available data, it is not possible to draw any firm conclusions from these findings. f. Other Brain Areas A handful of studies have investigated a number of other brain regions. Two studies investigated the insular cortex, reporting either no difference between the CB and HC groups [28] or a reduction of the insular cortex in CB users compared to HC [33]. One investigation found that several brain regions (i.e., thalamus, parietal lobule, fusiform gyrus, lentiform nucleus, pons) were altered in CB users compared to HC [32], while other evidence found that the CB group had flatter sulcal concavity of temporal and parietal lobes than HC [28]. Instead, there was no difference between CB users and HC for striatal areas [34], parietal and occipital lobes [17] and the subcortical region as a whole [17]. Overall, there have been few studies and replication studies are needed to allow interpretation of findings on these brain areas. DISCUSSION This review identified 23 studies examining brain morphology in regular CB users. Findings were reviewed as a function of brain region, within which results on group comparisons, as well as on the association between brain morphology and cannabis use patterns, psychopathology symptoms and neurocognitive measures were examined. Notably, the conducted studies examined brain regions that are high in CB1 receptors and ascribed to the regulation of psychopathology symptoms and of neurocognitive performance altered in regular CB users (i.e., hippocampus, the amygdala, PFC and the cerebellum). The findings emerging from this review provide evidence that: i) regular cannabis exposure is associated with regional brain alterations compared to non-users; ii) there is mixed evidence that alterations of brain morphology in CB users are associated with cannabis use patterns and, to a lesser extent, with measures of psychopathology symptoms and of neurocognitive performance. This section summarises the sMRI findings to date, discusses the discrepancy between human and animal findings and attempts to identify key factors and pathophysiological processes that mediate brain morphological alterations in CB users (e.g., demographics, cannabis use patterns and psychopathology/neurocognitive measures). Finally, limitations are discussed and future directions are proposed. Summary of the Reviewed Findings on Group Comparisons The first objective of this work was to examine whether the reviewed literature provides evidence for structural brain abnormalities in CB users compared to HC. Regular cannabis exposure appeared to be associated with stable adverse effects on the morphology of specific, as opposed to global, brain regions. Specifically, CB users showed volumetric alterations within regions of the medial temporal lobe (i.e., hippocampus and amygdala) as well as subregions of the PFC and of the cerebellum. Group differences in brain regions were however not always consistent across studies. Volumetric reductions observed in the hippocampus, parahippocampus and amygdala emerged more consistently in CB samples with heavier cannabis use patterns (e.g., higher cumulative


dosage and frequency of use), while group differences in PFC and cerebellar areas (i.e., both larger and smaller volumes) emerged in specific subregions, the location of which was inconsistent across studies. There was also preliminary evidence that alteration in brain morphology does not resolve after prolonged abstinence in CB users. Indeed, regional brain differences were identified in CB samples that were abstinent for prolonged periods [13, 14, 32]. These preliminary findings have been shown for the para-hippocampus [32], cerebellum [14], PFC [29] and for the hippocampus from some [13, 32] but not other studies [15]. Emerging Discrepancy between Human and Animal Findings Overall, the reviewed evidence shows that regular cannabis exposure, especially in CB samples with heavier cannabis use patterns, may be related to alterations in human brain structure. However, findings from human structural imaging studies are not as robust as that reported in animal studies, which demonstrated profound THC-induced neurotoxic effects on brain areas (i.e., including the hippocampus, amygdala, PFC and cerebellum) high in CB1 receptors [47-56] and mediating emotional [57-65] and neurocognitive processes that are altered with regular cannabinoid exposure [6, 66-77]. Profound differences between animal and human studies may explain the discrepancy of their findings. First, animals metabolise THC at slower rates than humans, making them more vulnerable to the potential adverse effects of THC [78]. Second, patterns of cannabinoid exposure such as dose and duration of regular administration may be heavier in animal models as opposed to those of human CB samples. However, human and animal studies with comparable duration and frequency of administration reported similar brain alterations, particularly in terms of hippocampal volumes. Indeed, Yücel et al (2008) reported hippocampal volumetric reduction in CB users smoking most days of the week for 20 years [25], and this alteration mirrors that reported by Landfield et al (1998), who found significant cannabis-induced decreases within the hippocampus in rats that were administered THC five times a week for 8 months (i.e., approximately 30% of a rat’s life-span) [9]. Thus, amongst regular CB users, those with heavier patterns of cannabis use may be more subject to the adverse impact of cannabis on brain structure. Third, profound differences between animals and humans in PFC morphology and on regions that are functionally associated with PFC, such as medial temporal, stress related areas, may affect the association between regular cannabinoid exposure and the morphology of the PFC [79]. Finally, the contradictory findings between human and animal studies may be related to the additional confound of inter-study differences across the human literature that complicate the interpretation of findings, which are discussed in the following section. Factors Mediating Structural Brain Alterations in Regular CB Users Inconsistencies across human sMRI studies likely stem from heterogeneity across CB sample characteristics. These include difference in terms of demographics (i.e., age and sex), cannabis use patterns (e.g., dosage, frequency, duration and age of onset) and degree of (i.e., diagnosable and threshold), level of psychopathology and of neurocognitive impairment. a. Demographics Age The age of the samples was accounted for in most investigations, being either matched between CB users and HC or retained as a covariate in most of the analyses. Preliminary evidence suggests that the age of CB users mediates the association between cannabis exposure and brain morphology in a region-dependent manner. For example, reduction in the volumes of the hippocampus [13, 25, 30, 32] and the amygdala [25] were reported in adult CB users only. In

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contrast, PFC alterations were observed in both adult and adolescent CB users [21, 27-29, 33]. Notably, the PFC is subject to marked neurodevelopmental changes during adolescence [80]. Thus, PFC regions, as opposed to medial temporal lobe areas, may be particularly vulnerable to regular cannabis exposure in adolescent CB users. This may occur via alteration of the endocannabinoid system, which plays an important role in neurodevelopment [81], the latter markedly affecting the structure of PFC regions [80, 82]. However, the design of the conducted structural imaging studies was cross-sectional, and it is unclear whether morphological alterations observed in adolescent CB users persist throughout adulthood. Further, it is unclear whether volumetric alterations in medial temporal lobe areas observed in adult CB users may have occurred during adolescent exposure to cannabis, as age of onset of most of the examined CB samples was in adolescence. Indeed, previous animal evidence showed that adolescent exposure to cannabinoids leads to structural brain alterations in medial temporal lobe areas (i.e., amygdala), as well as their ascribed emotional processes (e.g., reward sensitivity, depressive like behaviour) that persist throughout adulthood [83, 84]. In summary, these findings highlight the importance of accounting for the impact of the age of CB samples, as well as of age of onset, when examining the association between regular cannabis exposure and brain structure. Sex Only a paucity of studies examined the impact of sex on structural brain alterations in CB groups, leading mostly to nonsignificant findings [14-17, 20, 24, 28, 31, 34]. However, the majority of the examined CB samples were composed mostly of males, limiting examination of the role of sex in mediating the association between regular cannabis use and human brain morphology. The few studies investigating CB samples with a balanced male to female ratio showed that sex mediates the association between regular cannabis exposure and brain areas such as the amygdala and PFC sub-regions [29, 35]. Indeed, female CB users showed larger volumes in these brain regions than female HC, while male CB users showed smaller PFC volumes than male HC [29, 35]. Animal studies also support the notion that sex plays an important role on persistent alterations in brain structure and ascribed reward and emotional processes [83, 85, 86]. Chronic THC administration in adolescent female rats was found to reduce CB1 receptor density and function (i.e., coupling) in the hippocampus and the amygdala [83, 85, 86]. These effects persisted throughout adulthood and were exacerbated by the interaction of THC and ovarian hormone status [83, 85, 86]. Regular THC exposure also induced down-regulation and desensitisation of CB1 receptors in all brain areas of female rats, with adolescents showing greater desensitisation in the hippocampus and PFC [86]. In summary, sex membership may be an important mediator of the association between cannabis exposure and brain structure, especially in brain regions such as the hippocampus, the amygdala and PFC. However, this issue has been under investigated and underscores the need to conduct studies examining the neurobiology of cannabis use across both males and females. b. Association with Cannabis use Patterns The second objective of this review was to examine whether the literature to date show evidence that brain morphological alterations in CB users are associated with cannabis use patterns. The conducted studies provide preliminary evidence that volumetric alterations (i.e., for hippocampus, amygdala and para-hippocampus) were most apparent in CB samples with greater lifetime exposure to cannabis. There is however mixed evidence that cannabis use patterns are associated with brain volumetric alterations in CB users (see Table 3).


Table 3.


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Summary on findings on cannabis use patterns impact on brain volumes.

Author (Year)

Cousijn (2011)


Weekly Dosage, Age of Onset, Duration, Joint/Life

Lopez-Larson (2011)

_

Solowij (2011)

Age of Onset

Ashtari (2011)

_

ParaHippocampus

Amygdala

PFC

Cerebellum

Age of Onset, Duration, Joint/Life

_




_

_

_

Age of Onset, THC levels,

Hippocampus

Weekly Dosage.

_

Duration _

Dosage.

_

_

_

Age of Onset

_

Age of Onset, Dosage, Abst. Duration

_

_

_

_

Age of Onset, Freq., Dosage

_

_

_

_

_

Age of Onset, Duration, Dosage

_

Age of Onset, Abst. Duration

Age 1st Try. Churchwell (2010)

_

_

Demirakca (2010)

_

Mata (2010)

Age of Onset

_

_

_

Medina (2009)

_

_

_

_

THC/CBD CBD

Recent CB Use,

_

Recent CB use. Yücel (2008)

Age of Onset

Life Dosage

_

Dosage

_

_

Jager (2007)

_

_

CB Use

_

_

_

Tzilos (2005)

Age of Onset

Age of Onset, N° Ep

_

_

_

_

Matochik (2005)

Age of Onset

Duration.

Age of Onset, Freq, Duration

_

_

_

Age of Onset, Freq _

_

_

_

_

Duration

_

Duration

Duration

_

Block (2000)

Wilson (2000)

Age of Onset Age of Onset Age of Onset

In red fonts, Negative Associations. In blue fonts, Positive Associations. In black fonts, No Association. Joint/Life= cumulative number of lifetime joints; Age of Onset= age of regular cannabis use initiation; THC= Delta-9-Tetrahydrocannabinol, mg/ng; Duration= duration of regular cannabis use; Abst.= abstinence; CBD= cannabidiol ng/mg; Recent CB use= measures of recent cannabis exposure; Age 1st try= age at first cannabis try; CB Use= regular cannabis exposure.

Associations between cannabis use and brain morphology were examined only in 14 out of the 23 reviewed studies. Significant associations were apparent for hippocampal volumes, PFC and global brain measures. Measures of cannabis dosage were associated with smaller hippocampal volumes in most investigations that assessed this association, while emerging in only 1 out of 3 studies conducted in PFC morphology. Age of onset, which was examined in 17 analyses, only emerged to be related to PFC measures (i.e., in 2 out of the 4 conducted investigations), and to global brain measures (i.e., in 1 out of 8 investigations). Interestingly, some studies

reported that the association between age of onset and brain volumes was regional dependent, with early onset being related to smaller frontal GM but not to volumes of the cingulate cortex [16]. Duration of regular cannabis exposure was examined in 13 investigations, and was associated with hippocampal volumes in only in 1 out of 4 studies examining this brain region. Also, the direction of the association between (not-specified) measures of recent exposure to cannabis and PFC morphology was dependent on the PFC subregion that was examined, being positive with anterior ventral and total white matter of the PFC, and negative with


posterior PFC volumes [29]. In summary, heavier dosage may be relevant for hippocampal volumetric alterations in CB users, while age of onset may play a subtle influence on alterations of PFC morphology. c. Association with Psychopathology and Neurocognitive Performance The third objective of this review was to examine whether the literature to date provides evidence that alterations of brain morphology in regular CB users are associated with measures of psychopathology symptoms and of neurocognitive performance. A number of studies have investigated these associations [15, 20, 24, 25, 31, 34, 35]. There were too few conducted investigations within each region to make observations relevant within each brain area (i.e., global brain measures, hippocampus, para-hippocampus, amygdala, PFC, cerebellum). Nevertheless, considering these associations across regions allowed the observation of a few trends (see Table 4). Psychopathology and Stress Levels There was some evidence for an association between brain structure (i.e., white matter, cerebellum, hippocampus, amygdala) and psychopathology measures in the CB group including cannabis dependence [34], depressive [15, 26, 35] and positive psychotic symptoms [25]. The reported association between brain morphology measures and psychopathological symptoms suggest that brain alterations in CB users are related the onset of adverse mental health outcomes. Indeed, cannabis use is associated with psychotic, depressive and anxiety disorders [87, 88]. However, the association between brain morphology and stress levels, the alteration of which is related to both regular cannabis exposure [70, 89, 90] and psychopathology [91-93], has not been investigated by any study to date. Therefore, it is not possible to disentangle the role played by stress levels on the observed alteration of brain morphology. Measures of Neurocognitive Performance There was little evidence that measures of neurocognitive performance (i.e., associative memory, verbal learning and IQ) are associated with brain regions that are ascribed to their regulation [20, 24, 25, 31]. However, there was preliminary evidence for worse executive functioning being related to alterations of PFC morphology [14, 29]. Interestingly, some studies reported that the direction of the association between neurocognitive measures and PFC volumes was opposite in CB users and HC, which was negative and positive, respectively [29]. These emerging findings suggest that regular cannabis exposure is associated with normal brain-behaviour associations depending on the type of neurocognitive task and brain region being examined. For instance, associations are observed between executive function and PFC morphometry as opposed to between learning, memory and hippocampal structure. Psychopathology (e.g., depression, anxiety, psychosis [87, 88]) and elevated stress levels (e.g., circulating stress hormones [70, 89, 90]) that are associated with regular cannabinoid exposure have been shown to adversely affect neurocognitive performance [77, 90, 94]. However, these variables were not accounted for in any of the conducted analyses. This issue raises questions regarding whether psychopathology and stress levels may have confounded the association between neurocognitive measures and brain measures in CB users by either exacerbating worse neurocognitive performance (e.g., executive functioning) or masking the association between brain structure and neurocognitive performance (e.g., hippocampal volume and learning and memory processes). Notably, most of the associations were investigated via performing correlational analyses and it was not possible to examine the independent association between each variable and measures of brain morphology. In other words, the effects shared between different variables on brain morphology were not parcelled out.

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Overall, the limited number of studies on the association between brain morphology and psychopathology symptoms/neurocognitive processes in CB users makes it difficult to understand the nature and the relevance of these relationships. Interpretation of existing findings is further complicated by the heterogeneity across samples in the nature and degree of comorbid psychopathology, which prevent a direct comparison of the results across studies. Further research is required to confirm the presence of a relationship between psychopathology/neurocognitive measures and brain morphology in CB users. This issue is particularly relevant, as cannabis use patterns have been related to more adverse outcomes in clinical [87, 88, 95, 96], neurocognitive [5, 62, 97-99] and functional imaging studies [62-65, 100, 101]. There is also sMRI evidence that cannabis use interacts with psychopathology to detrimentally affect brain morphology, particularly in key regions that are high in CB1 receptors (e.g., cingulate and dorsal-lateral prefrontal cortices [102-105]. This notion is supported from studies of early onset and first episode cannabis using (vs. non-using) schizophrenia participants showing reduced grey matter at baseline [103]; and a more marked reduction in brain volumes at 5 year follow up [102, 104]. Also sub-threshold psychopathology has been shown to interact with cannabis use in detrimentally affect brain morphology, with cannabis users at high risk of developing a psychotic illness showing an association between cannabis use and reduced prefrontal grey matter [105]. Thus, regular cannabis use in vulnerable individuals (i.e., at risk of developing or receiving a diagnosis of psychopathology) may interact with psychopathology to detrimentally affect brain morphology. These findings highlight the need to characterize psychopathology symptoms and examine their association with brain morphology in cannabis users when investigating the impact of cannabis use on the human brain. Genetic Factors The heterogeneity of the reviewed findings may be ascribed to variation in genetic sensitivity to the detrimental effects of cannabis across the reviewed individuals and samples. There is evidence that variation in key genetic polymorphisms implicated in neurotransmitters that mediate the psychoactive effects of cannabis (e.g., dopamine [106]) and that are altered in psychopathologies associated with cannabis use (e.g., schizophrenia) may determine the individual vulnerability to the adverse effects of cannabis exposure (e.g., psychotic symptoms [107-111]; for a review, see [112]). For instance, longitudinal evidence shows that carriers of the valine allele in the catechol-O-methyltransferase (COMT) gene, which is implicated in the emzimatic activaction and PFC breakdown of dopamine [112], were more likely to show psychotic symptoms and to develop schizophreniform disorders with cannabis use [107]. Also variation in the AKT1 genotype, which codes for a protein kinase involved in dopamine signaling, may mediate the likelihood to develop a psychotic disorder as a result of cannabis exposure. Indeed, participants carrying a c/c polymorphism show a higher likelihood of receiving diagnosis of psychotic disorder [108, 111]. Despite the available evidence on variation in key genetic polymorphisms mediating the adverse effects of cannabis in selected, genetically vulnerable individuals, no study to date has examined whether: i) genetic polymorphism may interact with cannabis use to predispose to the development of brain morphological alterations in vulnerable individuals; ii) the reviewed samples of CB users with no comorbid psychopathology are characterized by a specific genetic polymorphisms that protect from developing a psychiatric disorder as a result of cannabis exposure. (Potential) Mechanisms Mediating Brain Volumetric Alterations in Regular CB Users Structural brain alterations were most apparent in the hippocampus, PFC and cerebellum whilst being less marked in the amygdala, para-hippocampus and not detected in global brain measures. These findings indicate that the association between


Table 4.


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Summary of psychopathology and neurocognitive measures association with brain measures. Examined Brain Regions

Author (Year)


Hippocampus

ParaHippocampus

Amygdala

PFC

Cerebellum

_

_

_

Depression, Anxiety

_

_

CB, Cig & Alcohol Dep,, ADHD & BDI


_

Cig & Alcohol Dep, ADHD & BDI


CB, Cig. & Alcohol Dep,, ADHD & BDI

Lopez-Larson (2011)

_

_

_

_

Verbal Fluency

_

Solowij (2011)

_

_

_

_

_

HAMD

Ashtari (2011)

_

_

_

WRAT, CVLT

_

_

Churchwell (2010)

_

_

_

_

Impulsivity

_

_

Psychomotor Speed, Time Estimate.

McQueeny (2011) Cousijn (2011)

CB Dep.

Exec. Funct. Medina (2010)

_

_

_

_

Medina (2009)

_

_

_

_

Yücel (2008)

WRAT

Exec. Funct.

_

Exec. Funct Pos. Psychosis

_

Pos. Psychotic Symptoms, RAVLT

_

_

_

_

_

_

RAVLT CB Abuse & Dep.

Medina (2007) a

CVLT

Medina (2007) b

BDI, HAMD

BDI, HAMD

_

_

_

_

Jager (2007)

_

_

Associative Learn

_

_

_

Tzilos (2005)

_

_

_

_

Memo & Learn (BSRT, WMS, BVRT).

Blue Ink, Positive Association; Red Ink, Negative Associations, Black Ink, No Association. CB= cannabis; Cig= cigarettes; Dep= dependence; ADHD= attention-deficit hyperactivity disorder symptoms; BDI= Beck Depression Inventory scores [40]; WRAT= Wide Range of Achievement Test [38]; CVLT= California Verbal Learning Test scores; HAMD= Hamilton Depression Rating Scale scores [37]; Exec. Funct.= executive function; Pos. Psychosis= positive psychotic symptoms; RAVLT= Rey Auditory Verbal Learning Test [39]; BSRT= Buschke Selective Reminding Test scores [41]; WMS= Wechsler Memory Scale scores; BVRT= Benton Visual Retention Test scores.

regular cannabis exposure and brain morphological alterations is regionally dependent, which is consistent with previous notions on the effect of cannabinoids on the brain [113, 114]. This section proposes a number of pathophysiological mechanisms that may be related to the patterns of regional brain volumetric alterations observed across the reviewed findings. These include the presence of neurotoxic effects on brain morphology; adverse effects related to dysregulation of HPA axis activity, the brain reward system and the emotional regulation system. a. THC-induced Neurotoxicity The magnitude of volumetric reduction observed in samples of regular CB users was regionally dependent. Interestingly, the CB1 receptor distribution differs across brain regions the morphology of

which was examined in CB users. CB1 receptor concentration is greater in areas where structural alterations were more apparent (e.g., the PFC, hippocampus and cerebellum) compared to that of areas where morphological alterations were found less consistently (e.g., the amygdala [56]). These data suggest that the regiondependent presence of CB1 receptors reflect the magnitude of the morphological alterations that was observed in the reviewed CB samples when compared to HC. The volumetric alterations observed in the reviewed studies may reflect structural changes in the neurons and synapses of those brain regions that are more consistently reported to have higher, as opposed to lower, CB1 receptor concentrations. Evidence for downregulation of CB1 receptors (i.e., decreased functionality and num-


ber [56, 85, 86, 115]), and for neurotoxic changes in neural structure [8-11, 19, 116-119] is strongest for the hippocampus, the PFC and the cerebellum, where a large number of animal studies, as well as human evidence shows consistent alterations. Thus, morphometric alterations reported in the hippocampus and the PFC, less markedly, in other regions (e.g., the amygdala) may be related to structural alterations of neurons and synapses demonstrated by animal models. Still, other brain regions that were less consistently altered in the reviewed literature may be adversely affected via this path. For instance, a number of studies report that regular cannabinoid exposure downregulates the CB1 receptors and detrimentally affect the neuronal structure of the amygdala. Overall, the exact mechanisms that may be driving these structural changes are yet to be fully elucidated. Chronic sub-optimal Levels of Neural Activity Regular cannabinoid exposure has been associated with chronic alterations of neuronal activity and synaptic signaling in animal models in neurons of areas that showed morphological alterations in the reviewed literature. Regular exposure to cannabinoids may be associated with chronic sub-optimal levels of neuronal activity in the reviewed brain regions, as previously demonstrated (i.e., hippocampus [120-122], PFC [123] and amygdala [124-127]) and that have been ascribed to an adverse impact of cannabinoids on the cerebellum [128]. The region-dependent degree of volumetric alteration may be ascribed to cannabinoid-induced alteration of neuronal activity, more markedly in regions that are particularly high in CB1 receptor concentration (e.g., the hippocampus, PFC and cerebellum). Indeed, animal models have demonstrated that chronic cannabinoid exposure alters neural signaling beyond acute intoxication and prolonged abstinence in areas where THC-induced neurotoxic effects were observed [117]. Human studies showing associations between circulating THC levels and hippocampal volumetric reduction in CB users [30] may have been mediated by alterations of this path. Regular cannabinoid exposure alters neurotransmitter systems in a region-dependent manner. Indeed, cannabis-induced alteration of both GABAergic and glutamatergic neurotransmitters has been shown in the hippocampus. This pathway may be similarly affected in the cerebellum, the CB1 receptors of which are located in GABAergic [129, 130] and glutamatergic neurons [131-133]. In contrast, cannabinoid-induced alteration of glutamatergic, over GABAergic neurotransmitter systems has been demonstrated in the amygdala [126]. In addition, chronic cannabinoid exposure has been shown to reduce dopamine metabolism in the PFC [134, 135] (i.e., and not in the nucleus accumbens and striatum [135]). Cannabinoid-induced alteration of region-specific neural activity/neurotransmitter systems may mediate the different degree of impairment of neural function and, in the long term, of morphological alterations across brain regions, as previously suggested [136]. Nevertheless, the exact pathway mediating the onset of these alterations has yet to be determined. Neurotoxicity from Direct Exposure to Cannabinoids As previously suggested [119], regular exposure to cannabinoids may stimulate the release of agents such as intracellular arachidonic acid and production of reactive oxygen species (ROS) that are implicated in cell damage [137] and death [138-141]. Excessive cannabinoid exposure could trigger a greater release of neurotoxic ROS in brain regions that are particularly rich in CB1 receptors (i.e., including the PFC, cerebellum and hippocampus, as opposed to other brain areas). This may result in more severe cannabinoidinduced neurotoxic effects on prefrontal, cerebellar and hippocampal neurons, as opposed to those of other brain areas. In turn, neuronal damage occurring in key brain areas may give raise to alteration of brain morphology in a region-dependent manner.

Lorenzetti et al.

Role of Cannabis use Patterns The lack of consistent associations, in the reviewed literature, between cannabis use patterns and regional brain morphology does not provide strong evidence for an impact of chronicity of use across the examined brain regions. However, some trends were apparent (see Fig. 3). These included associations between dosage and age of onset with the morphology of specific brain regions (i.e., the hippocampus and the PFC, respectively), but not with that of other areas of the brain. These trends may indicate that key cannabis use patterns exert, by triggering neurotoxicity, an adverse impact on brain morphology in a region-dependent manner. Nevertheless, the role played by the recency of exposure to high cannabis dosage (i.e., over the past few weeks or months, as opposed to lifetime) and by the age of cannabis use onset (i.e., in early adolescence, as opposed to late adolescence and adulthood), in these regionally dependent associations has been poorly investigated and has yet to be fully clarified. Overall, these (and previously discussed) factors profoundly limit speculations on how cannabis use patterns affect pathophysiological mechanisms that mediate brain morphological alterations in CB users. Also issues associated with the validity and reliability of measurements of cannabis use patterns can introduce noise and reduce power for detecting associations between cannabis use patterns and brain morphometry b. Stress-induced Effects The morphological alterations reported in the reviewed literature may reflect adverse effects of dysregulation of the HPA axis activity (i.e., the main biological substrate of the stress response [142, 143]) on the morphology of the reviewed brain regions. Indeed, regular cannabis exposure has been associated with alteration of the HPA axis activity [9, 70, 89, 90, 144-146]. In addition, the brain regions that were reviewed in this work are involved in regulating the activity of the HPA axis via inhibitory (i.e., PFC and hippocampus) and excitatory projections (i.e., amygdala and cerebellum), respectively [142, 143, 147, 148]. Within these brain areas, cannabinoid-induced alteration of HPA axis activity is mediated via interaction of both CB1 receptors and glucocorticoid receptors [149]. Regular cannabinoid exposure, by downregulating CB1 receptors in the reviewed brain regions, may lead to alteration of their regulatory projections to the HPA axis. This process may result in hyperactivity of the HPA axis in CB users [150, 151]. Alteration of the activity of the HPA axis in CB users may mediate the reported association between regular cannabinoid exposure and high stress and anxiety levels [9, 150, 152-156]. Consistent with prior reports [87, 88, 157-159], most of the studies that investigated subthreshold psychopathology symptoms in their samples (e.g., anxiety, depression, psychosis and internalizing disorders) found that CB users, compared to HC, showed higher measures of psychopathology (i.e., 6 investigations [15, 25, 26, 33-35], with one exception [27]). This data provides indirect evidence for altered stress levels in CB using samples. Indeed, level of anxiety, depressive and psychotic symptoms are directly associated with stress hormones [160, 161]. Alteration of stress levels in CB users may adversely affect regional brain morphometry via a plausible mechanism. Dysregulated cross talk between CB1 and glucocorticoid receptors in brain regions implicated in the regulation of the HPA axis activity (e.g., the hippocampus, PFC, cerebellum and the amygdala) may trigger dysfunctional cellular mechanisms and lead to high levels of circulating glucocorticoids. In turn, excessive circulating levels of glucocorticoids may induce apoptosis in the neurons of areas where morphological alterations were observed (e.g., hippocampus, PFC, amygdala and PFC), which have a high concentration of both CB1 and glucocorticoid receptors. This mechanism has been previously implicated in animal models of regular cannabinoid exposure [9, 162, 163]. Also, this mechanism been ascribed to brain volumetric


alterations in psychiatric disorders [57, 91-93, 152, 164, 165] the symptoms of which were higher in the reviewed CB samples compared to HC and associated with brain morphology where this relationship was examined ([15, 25, 26, 34] with one exception [35], see Table 4). No study to date has investigated the association between regional brain morphology and biological measures of stress (e.g., circulating stress hormones, volume of the pituitary gland), and a stress-mediated alteration of regional brain volumes in CB users is yet to be tested. Future studies should further explore the role of HPA axis activity alterations in psychopathology symptoms and regional volumetric alterations in CB users. c. Alteration of the Brain Reward Circuit Alteration of the mesolimbic-mesocortical dopaminergic system (i.e., brain reward system) may be another path mediating morphological changes observed in the reviewed CB samples. Indeed, regular cannabinoid exposure is associated with alteration of dopaminergic projections within the brain reward system [166], which has been ascribed to the co-localisation of CB1 receptors and dopamine’ neuronal markers (i.e., tyrosine hydroxylase in regions of the brain reward circuit [167]). Regular cannabis exposure is also associated with dysregulation of processes that are mediated by the brain reward system, including desensitization to natural rewards (e.g., diminished dopamine release [168-171]) and hyper-sensitivity to the rewarding value of cannabis [60, 169, 172, 173]. Several brain regions that showed morphometric alterations in the reviewed literature interact with regions of the brain reward system to process the association between cannabis and its rewarding value [74, 174-178]. For instance, the PFC and the amygdala are involved in processing the rewarding properties of cannabis, by receiving striatal dopaminergic projections that trigger glutamatergic activity [52, 75, 179, 180]. Also, hippocampal neurons interact with the ventral striatum to code and consolidate memories of cannabis’ rewarding value [167, 176, 181, 182]. While the interaction between the cerebellum and the striatum in processing the rewarding properties of cannabis has yet to be elucidated., the cerebellum, along with the striatum and the PFC, mediates the development of tolerance to the effects of cannabis [56, 183], and is involved in reward-based learning, which is impaired with regular cannabinoid exposure [184]. Chronic cannabis use, via disruption of the brain reward circuit, may have mediated brain morphology alterations in CB users. Prior reports provide evidence that regular cannabinoid exposure is related to low affectivity, which has been ascribed to alteration of the brain reward circuit [185, 186]. In this review, several studies examined psychopathology symptoms characterized by low affectivity and related to reward processing (e.g., internalizing, depressive and negative psychotic symptoms [15, 25-27, 33-35]). Most of these investigations (i.e., with one exception [27]) found that CB users had higher psychopathology symptoms than HC. Counter to the notion that the observed regional brain alterations are related to dysregulation of the brain reward circuit, there was scarce and preliminary evidence for associations between measures of reward processing and regional volumes, raising questions of whether the reported alterations reflect dysregulation of the brain reward circuit. The lack of sMRI data on striatal brain regions that are key components of the brain reward circuit does not allow further exploration of this notion. Further, due to the complex interactions of cannabinoid exposure with other neurotransmitter systems including dopamine, glutamate, GABA, opioid, serotonin [187], which are still yet to be clearly understood, it is unclear how exactly chronic CB exposure alters the brain reward system. d. Alteration of the Emotional Regulation Circuit Another possibility is that volumetric alterations observed in regular CB users reflect an adverse impact of regular cannabis exposure on the emotional regulation system. Indeed, morphological alterations were observed in brain regions that constitute an integral


19

part (e.g., PFC, hippocampus, amygdala [188]) and are heavily involved with the emotional regulation system (e.g., cerebellum [189]). Regular exposure to cannabinoids, by affecting the neuronal activity in regions of the emotional regulation circuit, is related to alteration of emotional behaviour and mediates cannabis induced emotional states (e.g., dysphoria, anxiety and mood dysregulation [150, 190-194]). Also, the alterations in the morphology of the reviewed regions have been found in psychopathologies that are associated with dysregulation of the emotional regulation system, including depression and psychosis [165, 189, 195-197]. Notably, symptoms of these psychopathologies are heightened in regular CB users reviewed in this paper and investigated in previous research [88, 186]. These data suggest that regular cannabis exposure is related to alteration of the emotional regulation circuit, which mediates mood and emotional states [164]. Indeed, brain regions that showed morphological alterations in the reviewed studies constitute an integral part of this circuit [188, 189]. Counter to this notion, there was scarce evidence for an association between regional brain morphometry and psychopathology symptoms in regular CB users (see Table 4). This evidence suggests that cannabis exposure was not a key factor mediating the presence of heightened (subthreshold) psychopathology symptoms in CB users. It cannot be excluded, however, that the analyses conducted in the reviewed literature could not capture an existing association between psychopathology symptoms and regional brain volumes in CB users. The lack of examination, in the reviewed literature, of other components of the emotional regulation circuit (e.g., striatal areas) and of their association with psychopathology symptoms in regular CB users prevented elucidation of this notion. e. Summary of putative mechanisms mediating brain alterations in CB users The observed structural brain alterations in regular CB users may be mediated by several potential pathophysiological mechanisms including THC-induced neurotoxicity, stress-related effects, alteration of the reward and of the emotional regulation circuits. Nevertheless, the exact mechanism driving the observed volumetric alterations in CB users is far to be elucidated. Further, this work revealed the presence of preliminary associations between measures of cannabis use patterns, and, to a lesser extent, of psychopathology symptoms, and regional brain volumes in regular CB users. These associations do not allow interpretation of the results in a linear fashion and potentially reflect complex pathophysiological mechanisms mediating the association between regular cannabis exposure and regional brain morphology. Limitations This section discusses methodological limitations that must be acknowledged with respect to the reviewed work and proposes directions for future research to further elucidate these issues. Limitations include a poor understanding of the impact of psychopathology and of exposure to substances other than cannabis in CB users, issues associated with examination of level and recency of cannabis exposure, heterogeneity of employed imaging methodology, a limited number of examined brain regions, the lack of studies with a longitudinal design and other factors. a. Confounding Impact of Psychopathology and Exposure to Substances other than Cannabis on Brain Morphology in CB Users Whether the reviewed imaging findings were confounded by confounding factors including psychopathology and exposure to substances other than cannabis is yet to be fully elucidated. First, the level of (diagnosable and subthreshold) comorbid psychopathology and of exposure to substances other than cannabis was heterogeneous across studies. Indeed, although most of the samples were free of major psychopathology and used cannabis was the primary drug of use, most of the reviewed investigations utilised


different inclusion and exclusion criteria for level of psychopathology and of substance use. There is extensive evidence for an association between these factors (i.e., psychopathology and exposure to substances other than cannabis) and abnormal brain morphology in the regions that were reviewed in this work (i.e., hippocampus, amygdala, PFC and cerebellum [102-105, 165, 198-201]. Thus, heterogeneity of level of psychopathology and of exposure to substances other than cannabis across studies makes it difficult to directly compare the findings on brain morphological abnormalities across the examined samples. For instance, confounding factors may have affected (i.e., altered) the morphology of the brain more in those CB samples with high compared to those with minimal level of comorbidity. Second, only a few studies examined the level of (subthreshold) psychopathology symptoms and of exposure to substances other than cannabis in their samples, the majority of which found that CB users had higher scores in these measures than HC. Only a minority of these investigations, nevertheless, performed statistical analyses that assess the association between brain morphology and these confounders (e.g., psychopathology symptoms/level of exposure to substances other than cannabis) and that parcel out the effects exerted by cannabis exposure (e.g., regression models). This issue prevents the understanding of whether such variables (i.e., psychopathology symptoms and exposure to substances other than cannabis) exerted either a confounding or an independent effect, from that of cannabis exposure, on brain structure in the examined CB samples. In light of these limitations, the present review could not capture and assess whether level of psychopathology and exposure to substances other than cannabis exerted a confounding impact on the reviewed results [202]. To better elucidate the association between regular cannabis exposure and brain morphology, future studies should: i) utilize strict exclusion criteria for comorbid psychiatric disorders and for significant use of substances other than cannabis; ii) implement statistical analyses that examine whether confounding variables exert an interactive or an independent impact on brain morphology from that of cannabis exposure; and iii) match CB users and HC for level of psychopathology and exposure to substances other than cannabis. However, examination of CB users matched with HC for all variables of interest could reflect unusually ‘healthy’ CB users who are not representative of the general CB using population. Alteration of these measures in the reviewed CB samples compared to HC may in fact reflect a realistic representation of regular CB using population. b. Level of Cannabinoid Exposure Patterns of Cannabis Use Across the reviewed studies, cannabis use patterns were poorly described and examined, potentially explaining their inconsistent association with brain structural measures. First, a number of protocols relied on self-reported recent measures of cannabis use patterns, making it difficult to capture the level of cumulative cannabis exposure during CB participants’ smoking history that could have affected brain structural measures. Therefore, it is still unclear whether recent, as opposed to lifetime exposure to cannabis detrimentally impacts on brain morphology in CB users. Second, a significant number of studies failed to report the methodology that was utilised to compute measures of cannabis use patterns, making it difficult to assess the validity of the utilised measures. Third, as for measures of psychopathological symptoms, most of the reviewed studies assessed the association between cannabis use patterns and brain morphology with correlation analyses. These analyses did not parcel out the effects shared between different cannabis use patterns on brain morphology. This issue questions whether specific cannabis use patterns are a determinant in affecting brain structural measures in CB users. Four, for a number of protocols it was unclear whether age of onset reflected the age at which cannabis was

Lorenzetti et al.

tried for the first time rather than age of regular cannabis use initiation. Whilst these two variables can overlap, age of cannabis try often precedes age of regular cannabis use initiation. This issue has important implications for understanding the role of these distinct variables on the human brain. Finally, low variability in cannabis use patterns within the examined CB samples made it difficult to examine whether different degrees of cannabis exposure are related to structural brain alterations in CB users. In summary, examination of the association between cannabis use patterns and brain morphology may be improved by utilising comprehensive description of cannabis use patterns reflecting both lifetime and recent levels of use, the use of statistical models allowing the identification of the contribution of each cannabis use pattern to brain morphological measures and by examining CB samples with variable levels of cannabis use patterns. Quantification of Cannabis Exposure Measures of cannabis use patterns that were utilised in the reviewed literature may have been limited with respect to a number of factors, including the use of self-reported measures of cannabis use and the lack of standardised measures of cannabis dosage. First, most of the conducted studies relied on measures of cannabis use patterns that were obtained via assessment of self-reports, the validity of which has been previously recognised [203, 204]. Indeed, the validity of self-report has been reported to be 70% or higher, and approximately 90% in some instances [205, 206]. The lack of assessment of long-term biological measures of cannabis exposure, such as THC content in hair analyses (i.e., only 2 studies assessed this variable [15, 30]), did not allow corroborating selfreported long-term measures of cannabis use in most investigations, other than by the urinalyses that were conducted (i.e., in 16 out of 23 studies). Nevertheless, the detection of THC content in hair allows corroborating regular and long-term exposure to cannabinoids, and has been associated with abnormal brain morphology in CB users [30]. These preliminary data suggest that examining THC levels in hair is crucial for understanding the association between regular cannabis exposure and alterations of brain structure. Another issue regarding the obtained self-report measures of regular cannabis exposure may have been compromised by the presence of memory problems in the reviewed CB samples, and more markedly in those long-term CB users whose smoking history dated back >10 years prior to assessment. However, several studies have conducted comprehensive interviews on cannabis use history, which may have (partially) addressed this issue. Second, the validity of measures of cannabis use patterns was maximised in some studies by conducting thorough semi-structured interviews on history of cannabis use. Nevertheless, inter- and intraindividual variability in the amount of cannabis utilised in the various routes of administrations (e.g., joints, bongs, pipes) affect the standardisation of these measures (as previously observed [136]). Further, studies were heterogeneous in measuring participants’ levels of exposure and dosage (e.g., estimated grams and cones as opposed to number of joints and bongs, number of smoking episodes) and in the period over which levels of exposure were measured (e.g., usual weekly/monthly dosage or smoking episodes, lifetime cumulative dosage). This issue did not allow for direct comparison of the levels of cannabis exposure across the reviewed CB samples. In this review, we attempted to overcome this issue by converting, where appropriate (e.g., see Fig. 3), the levels of exposure to cones, a standardized measure of cannabis dosage (i.e., according to guidelines available in the website in http: //ncpic.org.au/ static/pdfs/assessment-tools/timeline-followback.pdf). Still, the methods that were performed to quantify cannabis dosage (i.e., other than hair analysis) were not informative in regards to the potency of the cannabis preparations that also determine the amount of cannabinoid exposure.


Further research is clearly needed to improve the existing methods measuring exposure to cannabis. Indeed, achieving more accurate and valid characterisation of CB users is needed to enable an examination of associations between measures of cannabis exposure and adverse brain and behavioural outcomes. This goal may be achieved by several means. First, achieving larger agreement on methods used to quantify cannabis exposure is warranted. Second, more valid standardised measures of cannabis exposure (e.g., measures of dosage), is recommended. Third, the use of semi-structured interviews on recent and lifetime cannabis use history is warranted to capture information on cannabis use patterns, routes of administration, problematic use and their changes over time. Finally, corroboration of self-reports by conducting toxicology tests on biological assays measuring recent cannabis use (e.g., saliva swabs), cumulative levels of cannabinoids (e.g., hair analyses), and residual levels of cannabinoids (e.g., urine samples) is needed to validate self-reported measures of cannabis exposure. The use of toxicology tests may be particularly relevant to improve the understanding of the role that different cannabinoids play in mediating brain morphological alterations in CB users. Notably, the level of distinct cannabinoids such as THC and CBD varies across cannabis strains, which is notable because these cannabinoids are associated with different, sometimes opposing, effects on brain structure [30], function [207] and on symptoms of psychopathologies associated with cannabis exposure [207-210]. Thus, the use of toxicology tests is warranted to further explore how cannabinoids mediate the impact of cannabis on brain morphology. Duration of Abstinence from Cannabis The heterogeneity of abstinence duration across the examined CB samples may have affected inter-study consistency in psychopathology/neurocognitive measures that vary as a function of recency of use, potentially contributing to the inconsistency of brainbehaviour associations across studies. Lack of Biological Assays Corroborating Self-reported Abstinence Self-reports on cannabis use, while being shown to constitute valid measurements, were limited by the lack of corroboration by biological assays [203, 204]. Urine toxicology tests, which were performed in some of the investigated CB groups (16 studies, see Results on descriptive data, abstinence duration), could not be utilised for this purpose. Urine toxicology tests were performed to confirm recent exposure to cannabinoids by detecting their circulating residual levels. However, they cannot be used to index abstinence duration due to the high inter-individual variability in cannabinoid’ rates of absorption (that was not quantified in the studies that employed this technique) and in usual dosage and frequency of cannabis use. Thus, whether CB participants did not comply with protocol requirements in regards to duration of abstinence before assessment could not definitely be confirmed (i.e., exception being those studies that performed daily urine toxicology tests on their samples to monitor ongoing abstinence over a prolonged period of time [13, 15, 24, 29, 32, 35]). This may constitute an issue as recent cannabis intoxication may have confounded and led to interindividual variability in psychopathology and neurocognitive measures that were thought to reflect a non-intoxicated state. Such issue may have undermined the validity of the associations between brain morphology and measures of psychopathology/neurocognitive performance. Specifically, this issue may be related to the low number of associations detected between ‘clinical’ variables and regional volumes (illustrated in Table 4). Inter-study and Inter-individual Variability in Abstinence Duration Duration of self-reported abstinence from cannabis was highly variable across the examined CB samples (i.e., from a few hours to several months); and may have affected psychopathology/neurocognitive measures. Indeed, recent abstinence from cannabis use is related to changes in measures of psychopathology symptoms (e.g.,


21

anxiety, psychotic and depressive symptoms) and of neurocognitive performance (e.g., in memory and learning tasks) as a function of recent intoxication and of symptoms of withdrawal and craving [5, 77, 97, 211-214]. The inter-individual and inter-sample variability in abstinence duration, by affecting psychopathology and neurocognitive measures within and across the examined CB samples, may have: 1) caused inconsistencies in psychopathology/neurocognitive measures within the reviewed samples; 2) played a role in the general lack of association between these psychopathology/neurocognitive measures and brain volumes in CB users. As symptoms of intoxication, withdrawal and craving were poorly assessed in CB users across the reviewed studies, the influence of these variables on the obtained psychopathology/neurocognitive measures could not be clearly determined. Other Cannabis Using Groups The reviewed CB samples comprised mostly regular, nontreatment seeking CB users and several abstinent, treatment-seeking CB users, without significant psychiatric disorders and exposure to substances other than cannabis. The findings emerging from the literature to date are not generalisable to other CB using groups (including occasional CB users, CB users with comorbid psychiatric comorbidity, and early to middle adolescent CB users) the examination of which may further our understanding of the association between cannabis exposure and brain morphology. First, while the largest proportion of the CB using population is composed of occasional users, it is still unclear whether occasional use is associated with any adverse outcomes on regional brain volumes. Investigating cohorts of occasional cannabis users may address this issue. Second, future studies comparing regional brain volumes in groups of non-treatment seeking CB users, treatment seeking CB users and CB users with diagnosable psychiatric disorders may shed some light on the association between psychopathology and brain regional volumes in regular CB users, which remains to be fully elucidated. Third, given the lack of clarity on the impact of age of onset in brain regional volumes in CB users, examination of CB samples with high variability in age of onset, comprising CB users commencing regular use in early adolescence, middle adolescence and in young adulthood may help to more fully elucidate the impact of age of onset. Another under-investigated issue concerns the impact of regular cannabis exposure on brain morphology in early and middle adolescence, where high levels of cannabis exposure have been observed. Indeed, while 7 studies examined CB samples that were composed of adolescents, their participants were aged approximately 17 to 18 years (see Table 1). Examining structural brain measures in both male and female adolescent CB users is warranted to elucidate whether alterations are observable during brain development and the role of sex in these alterations at this stage. c. Imaging Methodology Inconsistencies across the human literature may also be due to differences in the quality and precision of imaging techniques and methodologies. For example, studies that utilised echoencephalography [21, 22], CT [18, 23] or sMRI with large voxel sizes [20] may have not been powerful or sensitive enough to detect subtle alterations in brain structure. Across the sMRI studies, heterogeneity of approaches to brain image analysis, such as manual ROI compared to automated ROI and VBM, which rely on different criteria to delineate brain regions, may have affected the obtained measures of brain morphology and contributed to the discrepancy of findings in group comparisons across studies [215]. For example, there are no standardised analysis and statistical thresholding protocols for VBM studies, which can partially explain the heterogeneity of findings. Greater consistency in analytic and reporting practices across different laboratories could facilitate the generalisability of findings. Additionally, inter-individual variations in sulcal and gyral anatomy affect automated segmentation of brain volumes by altering the relative volumes of the surrounding cortex and produce


errors in spatial normalisation, especially in small samples [45, 202, 216]. This means that systematic anatomical differences between groups can confound the interpretation of findings, particularly for PFC and cerebellar areas, the anatomy of which is characterised by high inter-individual variability. Accordingly, the localisation of subregional alterations for PFC and cerebellum was inconsistent across studies. d. Examined Brain Regions The literature to date examined a limited range of brain regions, which prevents a full understanding of the nature of the impact of regular cannabis exposure on brain structure. Cannabis use may affect the morphology of other brain regions involved in processes altered in CB users, including the striatum, the insula and key components of the HPA axis. Striatum The role of the striatum in the neurobiology of regular cannabis exposure has been relatively under investigated, although such brain region may play an important role in this regard. Indeed, regular cannabinoid exposure downregulates striatal CB1 receptors [56, 85, 86, 118, 217-219], which are abundant in this area [51, 220]. The striatum, along with the PFC, is also implicated in mediating the rewarding value of cannabis and the development of addictive behaviours [168, 221]. Further, cannabis craving is associated with striatal functional alterations [59, 60]. This evidence suggests that alteration of striatal morphology may be associated with regular cannabis exposure. The only sMRI study examining striatal morphology in CB users provided however evidence of no alteration [34]. Clearly, validation studies are needed to corroborate this finding. Furthermore, investigating striatal morphology may inform on the pathophysiological mechanisms that mediate the morphological alterations observed in the reviewed CB samples. For instance, the striatum interacts with the PFC, amygdala [74, 75, 177] and the hippocampus [181] to mediate addictive behaviours and reward processing. Notably, alteration of these processes is associated with regular cannabinoid exposure [169, 170]. Future studies may provide evidence that morphological alteration of the brain reward circuit mediates addictive behaviours in regular CB users. Insula The insula, a cortical brain region mediating a variety of cognitive, emotional and homeostatic processes [222], may also be detrimentally affected by regular cannabinoid exposure. The role played by this brain region in the neurobiology of regular cannabinoid exposure has nevertheless received little attention. Notably, functional alterations of the insula are implicated in mediating the cannabis’ psychotropic effects [223] and craving [59], as well as reward processing in regular CB users (i.e., loss outcomes [224]). Insular functional alterations have also been shown in abstinent CB users during neurocognitive performance (i.e., working memory [225]). These findings show preliminary evidence that alteration of reward processing and neurocognition in regular CB users are mediated by the insula, and suggest that this brain region may by subject to persistent alteration in CB users. The morphology of the insula in regular CB users has however been investigated by only two sMRI studies. Such data has provided mixed evidence of insula alterations in CB users compared to HC [28, 33]. Clearly, further investigations are needed to elucidate whether regular cannabis exposure exerts a detrimental impact on the morphology of the insula. Exploring this notion may provide evidence on the pathophysiology of the regional volumetric alterations reported in the current review. For instance, the insula interacts with the amygdala, with which it has strong reciprocal connections [226], to mediate emotional processing [227]. Furthermore, the insula, similarly to the PFC, hippocampus, cerebellum and amygdala, is involved in psychopathologies associated with regular cannabis exposure. These psychiatric disorders include anxiety [228, 229], emotional

Lorenzetti et al.

dysregulation [189, 230-232] and depression [165, 189, 233]. Thus, morphological alteration of the insula, in addition to that reported in the amygdala, may mediate altered emotional and reward processes, as well as psychopathology symptoms in regular CB users. Key Components of the HPA Axis Investigating measures of HPA axis activity may prove useful to understanding the nature of neurobiological alterations observed in regular CB users. Preliminary evidence demonstrates that HPA axis activity alterations are associated with regular cannabis exposure [9, 70, 89, 90, 234, 235] and with THC-induced neurotoxic effects on brain regions such as the hippocampus [9], suggesting that structural brain alterations in regular CB users may be potentially be mediated via this path. Further evidence supports the notion that stress levels alterations are relevant to the neurobiology of cannabis exposure, with cannabis-related anxiogenic states [154, 236, 237], withdrawal [152] and intoxication [238] being mediated by HPA axis activity alterations. In addition, psychopathologies associated with regular cannabis exposure such as mood, anxiety and psychotic disorders [2, 57, 87, 88, 96, 186, 239-241] are associated with alteration of measures of HPA axis activity [57, 91-93, 152, 242]. This evidence suggests that HPA axis activity is relevant to the neurobiology of regular cannabinoid exposure and that may be related to structural brain alterations that have been observed in regular CB users. Notably, the activity of the HPA axis can be indirectly measured by quantifying the volume of the pituitary gland (i.e., PGV [142, 143]). Indeed, the PGV has a positive association with high circulating levels of stress hormones [243], which is thought to reflect larger size and number of pituitary’ corticotrophic neurons [93, 243-246]. PGV measurements can be reliably and quickly obtained with analysis of sMRI data [93]. Examining PGV in regular CB users may be ideal to examine whether alteration of the stress response is related to that of regional brain volumes observed in regular CB users, providing evidence that the adverse impact of cannabis exposure on the brain may be mediated via this path. e. Study Design The reviewed studies relied on cross-sectional, retrospective designs, which, as opposed to prospective studies [77], have the advantage of being relatively low time consuming investigations of the adverse outcomes related to regular cannabis exposure [6]. However, the cross-sectional designs of the conducted investigations also constitute one of the major limitations of the literature to date. As such, it could not be determined whether the observed alterations in regional brain volumes, psychopathology symptoms and neurocognitive measures: i) further exacerbate with continued cannabis use, ii) pre-dated cannabis use onset or ii) persist, rather than normalise, beyond prolonged abstinence from cannabis use. These issues are yet to be resolved and could be addressed by conducting longitudinal studies. Continued Cannabis use Could Exacerbate Adverse Neurobiological, Mental Health and Neurocognitive Outcomes Whether continued cannabis use exacerbates alterations of regional brain volumes, psychopathology symptoms and neurocognitive performance in CB users is to be determined. Longitudinal studies following up CB users who continue regular cannabis administration could examine whether: i) continued cannabis use results in further reduction of regional brain volumes over time; ii) changes in cannabis use patterns (e.g., heavier or lighter frequency and dosage) in regular CB users are related to changes in regional brain volumes. Brain Volumetric Alterations May Pre-exist Cannabis use Onset Animal studies showed that regular exposure to cannabinoids resulted in striking neurotoxic changes in neurons of brain regions that are high in CB1 receptors, suggesting that similar processes


may have been driving the observed brain morphological alterations observed in the reviewed literature. It cannot be excluded however that brain morphology was altered prior to cannabis use onset in the reviewed CB groups. In fact, previous research demonstrated that brain volumetric alterations predict the onset of regular cannabis use, albeit this was demonstrated only for the OFC and not for the hippocampus or amygdala [247]. Nevertheless, this evidence is worthy of further research that may explain the emerging association between age of onset of cannabis use and regional brain morphology in CB users. A number of other factors associated with cannabis use onset are related to regional volumetric alterations. Personality and temperamental traits, as well as dysfunctional family interactions, which are identified as risk factors for cannabis use onset [2, 3, 240, 241] have been associated with regional volumetric alterations in brain regions including the PFC, hippocampus and amygdala [248250]. Further, child maltreatment, personality disorders and internalising/externalising symptoms that predispose to regular cannabis use and the development of cannabis dependence [251, 252] have also been associated with regional volumetric alterations in regional brain volumes such as those of the pituitary gland [253]. Notably, these factors have not been investigated in the reviewed literature, and it is yet to be clarified whether they exerted an impact on the reported regional brain alterations in CB users pre-existing cannabis use commencement. Longitudinal studies may prove useful to shed some light on this issue. Longitudinal examination of regional brain volumes in cohorts of non-cannabis using adolescents may prove useful to identify and follow up those participants who initiate regular cannabis consumption, as well as age and sex-matched participants who do not become regular CB users. In this context, it could be examined whether: i) CB users showed altered brain morphology prior to cannabis use onset compared to those participants who do not initiate regular cannabis use later in life; ii) Early cannabis onset users present distinct regional brain volumes compared to late onset users and HC prior to cannabis use onset; iii) Regular cannabis exposure affects regional brain volumes soon after cannabis use onset; iii) Regular cannabis exposure affects regional brain volumes by affecting trajectories of brain development during adolescence, rather than emerging later in adulthood. Brain Volumetric Alterations May Recover After Prolonged Abstinence Brain structural measures, such as volumes, are robust to transient alteration of psychopathology symptoms and neurocognitive measures associated with recent abstinence from cannabis use. However, the cross sectional design adopted by the reviewed studies did not allow for determining whether, and to what degree, structural brain alterations observed in CB users either persist or recover after prolonged abstinence periods. Despite the fact that investigations examining CB users after prolonged abstinence periods (i.e., ranging between approximately 3 [14, 29] and 7 months [13]) found evidence of brain morphological alterations, the stability of structural brain alterations over time has yet to be fully determined. Longitudinal examination of regional brain volumes in CB users before and after cessation of cannabis use may help to address this issue. In this context, assessing the level of residual circulating cannabinoids in CB users before and after cannabis use cessation may also elucidate whether washout of cannabinoids in abstinent CB users occurring over time parallels ‘recovery’ of brain structural alterations following prolonged abstinence. f. Other Limitations A number of other limitations may have affected the results obtained from the reviewed literature. Most studies lacked a detailed description of their sample’s (i.e., both CB users and HC) history of substance use (i.e., including cannabis), psychiatric symptoms and neurocognitive measures, making it difficult to dis-


23

cern whether differences across the samples for these characteristics might have confounded the reported results. Further, although this review has identified 23 investigations of brain morphology in CB, six different publications investigated the same sample for different brain regions [14, 15, 24-26, 29]. As such, the total number of reviewed studies investigates a smaller number of samples, potentially limiting the generalisability of the literature’s finding to CB using populations. CONCLUSIONS We investigated the association between regular cannabis exposure, cannabis use patterns and psychopathology/neurocognitive variables and brain morphology in the structural imaging literature to date. The reviewed studies led to the identification of the following key trends. First, there is emerging evidence that regular cannabis use is associated with alterations in the morphology of specific (e.g., medial temporal, PFC, cerebellar), as opposed to global, brain measures. Second, while structural brain alterations were observed particularly in CB samples with heavier patterns of cannabis use, there is mixed evidence for an association between levels of cannabis exposure (i.e., cannabis use patterns) and brain morphology in CB users. Third, there is evidence for preliminary associations between psychopathology/neurocognitive measures with brain structure in CB users. However, the paucity of studies and inconsistency between findings prevented a plausible speculation on their meaning. Overall, there is emerging evidence that regular cannabis exposure may be associated with neuroanatomical abnormalities in brain regions that are high in CB1 receptors and that mediate processes that are altered in CB users. These alterations may mediate longterm adverse outcomes on mental health and neurocognition associated with regular cannabinoid exposure. Future research is warranted to explore the pathophysiological mechanisms and the functional implications related to regional volumetric alterations in regular CB users. Such findings may play an important role in raising awareness on the potential harmful and persistent effects associated with regular cannabis exposure. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Ms Lorenzetti is supported by the Melbourne Neuroscience Institute Post-Doctoral fellowship. Associate Professor Solowij is supported by an Australian Research Council Future Fellowship (FT110100752). Associate Professor Fornito is supported by a NH&MRC CJ Martin Fellowship (ID#454797). Professor Yücel is supported by a NH&MRC fellowship (ID#1021973). ABBREVIATIONS ACC = Anterior Cingulate Cortex BDI = Beck Depression Inventory CB = Cannabis CB1 = Cannabinoid Receptor, Type 1 CBD = Cannabidiol CN = Caudate Nucleus CSF = Cerebral-Spinal Fluid CT = Computed Tomography fMRI = Functional Magnetic Resonance Imaging GABA = Gamma-Amino Butyric acid GM = Grey Matter HC = Non-cannabis using controls HPA = Hypothalamus-Pituitary-Adrenal ICV = Intra-Cranial Volume


IQ MRI MWCL OFC PET PFC PGV ROI sMRI THC VBM WBV WM

= = = = = = = = = = = = =

Intelligence Quotient Magnetic Resonance Imaging Marijuana Withdrawal Checklist Orbital frontal cortex Positron Emission Tomography Prefrontal Cortex Pituitary gland volume Region-of-Interest approach Structural Magnetic Resonance Imaging Delta-9-Tetrahydrocannabinol Voxel-Based Morphometry Whole Brain Volume White Matter

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Received: May 13, 2013

Accepted: June 10, 2013


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