Search tips
Search criteria 


Curr Pharm Des. 2012 November; 18(32): 5070–5080.
Published online 2012 November. doi:  10.2174/138161212802884861
PMCID: PMC3474956

Effects of Cannabis Use on Human Brain Structure in Psychosis: A Systematic Review Combining In Vivo Structural Neuroimaging and Post Mortem Studies


It is unclear yet whether cannabis use is a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms. We therefore systematically reviewed structural brain imaging and post mortem studies addressing the effects of cannabis use on brain structure in psychosis. Studies with schizophrenia (SCZ) and first episode psychosis (FEP) patients as well as individuals at genetic (GHR) or clinical high risk for psychosis (ARMS) were included. We identified 15 structural magnetic resonance imaging (MRI) (12 cross sectional / 3 longitudinal) and 4 post mortem studies. The total number of subjects encompassed 601 schizophrenia or first episode psychosis patients, 255 individuals at clinical or genetic high risk for psychosis and 397 healthy controls. We found evidence for consistent brain structural abnormalities in cannabinoid 1 (CB1) receptor enhanced brain areas as the cingulate and prefrontal cortices and the cerebellum. As these effects have not consistently been reported in studies examining non-psychotic and healthy samples, psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure

Keywords: Cannabis, post-mortem, neuroimaging, At-risk mental state (ARMS), psychosis, magnetic resonance imaging (MRI)


Cannabis is the world’s most widely used illicit drug with about 10% of young adults in developed countries being regular users. Behavioural and pharmacological studies indicate that both acute and chronic exposure to cannabinoids is associated with impairments in a range of cognitive processes [1-7]. Neuroimaging methods have provided powerful tools to study the in vivo effects of cannabis on brain function. While there are brain functional differences, such as reduced resting-state, prefrontal and anterior cingulate cortex blood flow, between cannabis users and controls in healthy populations, brain structural abnormalities related to cannabis use have been reported inconsistently [8-10]. In contrast, a neurotoxic effect (e.g. shrinkage of neuronal cell bodies and nuclei) of cannabis in animals has been confirmed in many cases [11, 12]. It is assumed, that Δ9-tetrahydrocannabinol (THC), the main psychoactive substance in cannabis, is the neurotoxic substance [13]. The effects of cannabis on brain structure and function are of particular interest in psychosis patients, as cannabis is known to be a risk factor for psychosis [14-16] and is widely used in patients with psychosis [17]. There is evidence from structural imaging studies showing robust volume reductions in fronto-temporal cortices and in the anterior cingulate in patients with schizophrenia [18-37] suggesting that these changes are underlying pathophysiological processes of this disorder. Cannabis use may therefore be a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms.

De Lisi [38] reviewed evidence to suggest that there are detectable brain changes occurring as a consequence of cannabis use that lead to increased risk of psychosis. It was concluded that this is unlikely as cannabis might even have protective effects on brain structure and not produce deleterious damage. However, only four MRI studies of people with schizophrenia who used cannabis had been considered in this review. In the meantime, many more MRI studies have been published to this subject. This review therefore systematically reviewed structural neuroimaging studies addressing the effects of cannabis use on brain structure in psychosis. In addition, findings from post mortem studies investigating the effect of cannabis on cannabinoid receptor density were included. In order to contribute to the question whether cannabis use is associated with structural brain abnormalities during development of psychosis, subjects at high clinical risk and with an at risk mental state (ARMS) as well as genetic high-risk (GHR) individuals were included.


2.1. Selection strategy

2.1.1. Search Strategy

Electronic searches were performed using ISI Web of Knowledge and PUBMED database. We included all studies published until end of November 2011 without any language restriction, according to well defined inclusion criteria - see below here. The following key words were used: “psychosis”, “schizophrenia”, “first episode”, “at-risk mental state”, “high risk”, combined with “cannabis”, “marijuana”, “delta-9-tetrahydro-cannabinol” (THC), and “brain structure”, “neuroimaging”, “brain imaging”, “brain abnormalities”, “magnetic resonance” (MRI), “diffusion tensor MRI” (DTI), “post mortem”, “quantitative autoradiography”, “radioligand binding”, “in situ hybridization”. Patients met diagnostic criteria for schizophrenia, schizophreniform or schizoaffective disorder according to Diagnostic and Statistical Manual of Mental Disorders DSM-III-R or DSM-IV criteria. Subjects at risk for psychosis fulfilled the At Risk Mental State (ARMS) criteria [39] or were at familial risk for schizophrenia (siblings [40] / at least two members of family from subject suffer from schizophrenia [41, 42]). We also carefully searched the reference lists of the included articles identified in the original search for further relevant articles.

2.1.2. Selection Criteria

We initially performed a general review of all studies investigating brain structure of patients (established schizophrenia, individuals at clinical risk for psychosis and individuals at genetic risk for psychosis) in relation to cannabis use. Studies were only included if they met the following criteria: (a) be an original publication in a peer-reviewed journal (b) studying the brain of psychosis patients (first episode, FEP or chronic schizophrenia, SCZ) or individuals at risk for psychosis (ARMS) or individuals at genetic risk for psychosis (GHR) in relation to cannabis use, applying in vivo structural neuroimaging or post mortem autoradiography or in situ hybridization techniques (c) including both cannabis smokers and non-smokers (d) extracting the specific effects of cannabis on brain if subjects had a general substance abuse or substance dependence disorder diagnosis. As this review was focused on brain structure, we only included structural imaging studies (MRI/DTI) investigating both gray and white matter. Functional brain imaging studies (e.g. fMRI, PET) were excluded. Post mortem brain studies allow localization of abnormalities in the endogenous cannabinoid system. We restricted the analyses to brain regions least subject to autolytic processes and on CB1 receptors given its central role in mediating endogenous cannabinoid function. To quantify changes in CB1 receptors in schizophrenia, the following methods have been used: 1) in situ radioligand binding and autoradiography and 2) in situ hybridization and immunocytochemistry.

We included all studies which involved cannabis using patients, regardless of whether they fulfilled the criteria for a substance use disorder or not. The amount of how much cannabis was consumed by the subjects varied widely across the studies. Although there were studies with overlapping samples [41-49], they analysed different brain regions or used cross sectional vs. longitudinal contrasts.

2.2. Recorded Variables

Two of the authors extracted the data independently (CR and HB). When there was no agreement, a third author (SB) reviewed the paper independently. Results were reported in different tables to assist the reader in establishing an independent view on the topic. We have included two summary tables of all reviewed structural MRI (Table 11) and post mortem studies (Table 22), one table illustrating the in vivo effects of cannabis on brain imaging results (Table 33) and one table presenting the post mortem results (Table 44). The recorded variables for each article included in the review were: centre where the study was performed, authors and year of publication, main subject, study design, number of subjects overlapping with other studies, number of subjects, mean age, percentage males/females, instrument for cannabis use assessment, definition of cannabis use, image analysis method, regions and structures of interest. The primary outcome measures of interest for MRI studies were global and regional gray and white matter volumes/density as well as density of cannabinoid receptor binding for the post mortem studies.

Table 1.
Overview of Structural MRI Studies Investigating Cannabis Effects
Table 2.
Overview of Post Mortem Studies Investigating Cannabis Effects
Table 3.
Brain Structural Abnormalities Revealed by MRI Studies
Table 4.
Brain Structural Abnormalities Revealed by Post Mortem Studies

2.3. Risk of Bias in Individual Studies

Publication bias expresses the higher probability of a study being published when it has a positive result [50] – thus, an intrinsic bias towards a positive result could be incorporated into a review study. From the studies included in this review, 12 studies did find a structural difference between cannabis users and non-users and 7 did not find one. All the included studies were published in peer-review journals suggesting high quality of data and methodology. We did not find differences in outcome-level assessment of risk bias.


3.1. Identified Studies

All included studies were published between 2001 and 2011, whereby 9 (out of 19) were published in 2011. Out of 33 initially screened studies, 13 were excluded because they did not fulfil the inclusion criteria. Functional studies were not considered in this review because we aimed to look for effects of cannabis on brain structure. The flowchart of the selection procedure with the included/excluded studies is summarized in (Fig. 11) and was based on the template of the PRISMA flow diagram [51] available on For included and excluded studies see (Fig. 11). The remaining studies were grouped according to centre/population of the study, method (sMRI, post mortem autoradiography) and study design (cross sectional vs. longitudinal) (Fig. 11, Table 11 and 22). The systematic review of the literature uncovered 15 in-vivo structural gray/white matter MRI/DTI studies and 4 post mortem studies (three autoradiography and one in situ hybridization study). The total number of subjects included in this review encompassed 601 FEP / SCZ (mean age = 27.05 years, age range 16.3 – 47.9, 20.4% females) (of which around 280 were cannabis users), 255 ARMS / GHR (mean age = 23.8 years, age range 21.16-29.5, 47% females) (around 160 cannabis users) and 397 healthy controls (HC) (mean age = 28.17 years, age range: 16.4-48.0, 30% females (around 70 cannabis users).

Fig. 1. Flow diagram (selection strategy) of included studies
a Mancini-Marie et al. 2006 [76]; Jockers-Scherübl et al. 2003 [68]; Leweke et al. 2007 [77]; Safont et al. 2011 [78]; Wobrock et al. 2010 [88]; Loberg et al. (2011) [79]; Potvin et al. 2007 [80]. b Parkar et al. 2001 [81]; Newell et al. 2006 ...

Within our included studies we did not find any differences in risk of bias. In the following, the results of our systematic review are summarized with respect to in vivo (section 3.2.) and post mortem (section 3.3.) studies.

3.2. In Vivo Structural Imaging results

The results of all in vivo studies (n = 15) are specified in Table 33.

3.2.1. Cross Sectional Structural Imaging Studies

Twelve studies have investigated cross-sectionally how cannabis affects brain structure in psychosis. Eight have looked at established psychosis and included SCZ or FEP (section Four studies included subjects at high-risk for psychosis with 228 GHR and 54 ARMS subjects ( Cross Sectional Structural Imaging Studies in Established Adult-onset Psychosis

Three studies focused on cerebellar changes in cannabis users. Solowij et al. [52] examined cerebellar grey and white matter in cannabis users (C+) and non-users (C-) with and without chronic schizophrenia. They found that cerebellar white matter in healthy cannabis users (C+ HC) was 23.9% and 29.7% smaller in schizophrenic cannabis users (C+ SCZ) than in non-using healthy controls (C- HC). As the difference in cerebellar white matter volume between schizophrenia patients who did not use cannabis (C- SCZ) and healthy controls (C- HC) was 17.7%, the authors concluded that cannabis might have a greater adverse effect on white matter than the effect of schizophrenia. Another recently published study [53] of a FEP sample found that cannabis use was associated with reduced cerebellar grey matter volume in a dose-dependent matter in C+ HC. However, in FEP, there was neither an effect of cannabis use, nor an interaction between cannabis use and diagnosis on cerebellar grey matter. Cahn et al. [45] compared total brain volumes, cerebral, cerebellar, caudate, lateral and third ventricle volumes between recent onset schizophrenic patients with a comorbid DSM IV cannabis abuse/dependence diagnosis (C+ SCZ) and without (C- SCZ). No differences in these brain regions of interest between C+ SCZ and C- SCZ were found.

Szeszko et al. [54] investigated the superior frontal gyrus, anterior cingulate gyrus and the orbital frontal lobe in a sample of first episode psychosis patients with and without DSM IV cannabis use/dependence disorder (C+ FEP / C- FEP) and a non-consuming healthy control sample (C- HC). They found that C+ FEP had significantly less anterior cingulate grey matter than C- FEP and C- HC. This finding could be replicated in a similar study [55] in the posterior cingulate cortex, which reported that C+ FEP had significantly less right posterior cingulate cortex and less left hippocampal volume than C- FEP. Further analyses in this study of C+ FEP versus C- HC showed a trend for a decrease in the right posterior cingulate grey matter. No differences were noted between C- FEP and C- HC.

A recent study by Ho et al. [56] examined the effect of cannabinoid receptor 1 (CB1) gene polymorphisms and cannabis use on brain structure in a sample of SCZ. The hypothesis was that patients with specific CB1 genotypes would be more vulnerable to the damaging effects of cannabis abuse regarding to brain volume.

C+ SCZ had smaller frontal white matter than C- SCZ. Grey matter, parietal white matter and lateral ventricle volumes did not differ between the two groups. Cross-sectional Imaging Studies in Psychotic Psychosis Subjects During Adolescence

James et al. [57] examined the effects of cannabis use during adolescence in a sample of adolescent onset SCZ [57]. All subjects were aged between 13 and 18 years. The hypotheses were that the effects of chronic cannabis use in schizophrenia would be particularly severe during adolescence critically involved in neurodevelopmental processes. The results showed that C+ SCZ had reduced grey matter in temporal fusiform gyrus, parahippocampal gyrus, ventral striatum, right middle temporal gyrus, insular cortex, precuneus, right paracingulate gyrus, dorsolateral prefrontal cortex, left postcentral gyrus, lateral occipital cortex and cerebellum. They also showed decreased fractional anisotropy (FA) in brain stem, internal capsule, corona radiate, superior and inferior longitudinal fasciculus compared to C- SCZ.

Two DTI studies from Amsterdam [46, 47] assessed retrospectively whether heavy cannabis use occurred before age 17 or not. The first earlier study [47] compared recent onset SCZ aged around 22 years with cannabis use before age 17 versus patients without cannabis use before age 17 versus C- HC. Fractional anisotropy in the anterior internal capsule, fasciculus uncinatus and frontal white matter was higher in C+ SCZ before age 17 compared to C- HC. There was no significant difference between C- HC and C- SCZ before age 17. However, most C- SCZ before age 17 also did not smoke cannabis after. Therefore, it could not be excluded that the results were due to the cannabis effect in general rather than to critical use during adolescence. The later study from the same centre [46] showed reduced white matter density in the left posterior

corpus callosum, right occipital and left temporal lobe in C- SCZ compared to early onset C+ SCZ. Cross-sectional Structural Imaging Studies in Subjects at Clinical or Genetic Risk for Psychosis

Four studies examined the effect of cannabis use on brain morphology in subjects at risk for psychosis with three studies of subjects at genetic high risk for psychosis (GHR) and one study of subjects with an at risk mental state (ARMS) [58] sample. The results from a longitudinal study with GHR subjects will be presented later [42].

A prospective cohort study with case control comparison design [41] analysed the association between substance misuse (alcohol and cannabis), brain morphology and subsequent schizophrenia in GHR subjects. Correlational analyses showed significant negative dose-dependent associations between cannabis use and lateral and third ventricle sizes. These associations were absent in the control group. Additionally, those GHR subjects with at least regular use of cannabis had a higher risk of later developing schizophrenia than those with isolated or no use.

Another study with GHR subjects was conducted by Habets et al. [40] who included C+ and C- of three groups: SCZ, GHR and HC. They found a significant group × cannabis interaction on cortical thickness, indicating that the effect of cannabis varied as a function of group. C+ SCZ had significantly lower cortical thickness values than C- SCZ. This pattern was similar in GHR but not in HC.

The only study with ARMS subjects [39] reported a negative correlation between cannabis intake and grey matter volume in prefrontal cortex, cingulate and left insula. However, there was no difference between ARMS and HC, suggesting no specific susceptibility to the effects of cannabis on brain structure in ARMS.

3.2.2. Longitudinal Structural Imaging Studies

Three longitudinal studies examined the effect of cannabis use over time on brain structure in psychosis patients and GHR individuals. Rais et al. [43] found that C+ FEP, C- FEP and C- HC did not differ with regards to global brain volumes at baseline. However, at follow up after 5 years, cannabis using patients (C+ FEP) showed larger gray matter volume loss and larger lateral and third ventricles than patients who did not consume cannabis during the scan interval (C- FEP) and compared to C- HC. This group [44] similarly reported no differences between the three groups at baseline but progressive regional density reduction during follow-up in the right supplementary cortex, left anterior cingulate cortex and left occipital lobe in FEP relative to HC. Patients who used cannabis during that time (C+ FEP) showed additional density reduction in the dorsolateral prefrontal cortex, left anterior cingulate cortex and left occipital lobe compared to C- FEP.

Welch et al. [42] compared the thalamus and amygdala-hippocampus complex in GHR individuals with cannabis use during a scan interval of two years with high risk subjects who did not use cannabis during this period of time. At baseline, C+ GHR and C- GHR did not differ with regards to whole brain, thalamic or amygdala-hippocampal complex volumes. Cannabis exposure over time was associated with bilateral thalamic volume loss which was highly significant on the right side.

3.3. Post Mortem Results

Three studies investigated cannabinoid receptor binding in brains of SCZ at death and additionally reported the effects on the receptors caused through the use of cannabis. For an overview on the results of the studies refer to Table 44.

Dean et al. 2001 [59] used in situ radioligand binding and autoradiography to measure the binding of [3H]CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex, caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects. Five out of the 14 SCZ and four out of the 14 HC had a history of cannabis use and THC in their blood at death. SCZ showed an increase in the density of [3H]CP-55940 binding in the dorsolateral prefrontal cortext compared to HC. A significant increase in the density of [3H]CP-55940 binding in tissue was noted in the subjects who had THC in the blood at death. However, there were no differences in binding between lifetime C+ SCZ and C- SCZ. The same techniques were used in another study [49] which measured the binding of [3H]SR141716A on anterior cingulate cortex, an antagonist that specifically targets CB1 receptors. A significant increase in density of CB1 receptors receptors was found in SCZ compared to HC. No differences were noted in CB1 binding between C+ SCZ and C- SCZ. A later study from the same group [48] investigated binding densities of [3H]SR141716A and [3H]CP-55940 to the CB1 receptors in the superior temporal gyrus in the same sample. In contrast to the earlier results, no significant difference was found between SCZ and HC in receptor binding and there was also no effect of cannabis use. Another post mortem study [60] used in situ hybridization and immunocytochemistry techniques to measure the cortical levels of CB1 and protein in the dorsolateral prefrontal cortex in schizophrenic patients and controls. Levels of CB1R messenger RNA were significantly reduced in SCZ compared to HC but history of cannabis use did not account for any group differences.


In this systematic review it was investigated whether cannabis use has an effect on brain morphology in psychosis patients and in subjects at clinical or genetic risk for psychosis. The present review focused on structural MRI and additionally reviewed post mortem studies examining brain structure based on cannabinoid receptor density. Our systematic search strategy and literature review uncovered consistent brain structural abnormalities in CB1 receptor-enhanced brain areas such as the cingulate, the prefrontal cortex and the cerebellum.

Few structural neuroimaging studies have investigated cannabis use in non-psychiatric populations yet and results were inconsistent. Limited evidence of major effects of cannabis on brain structure has so far been reported [8, 9] with the strongest effects being found in medial temporal regions [10]. We focused here on psychiatric patients affected with early or chronic phases of psychosis. Some methodological limitations must soon be acknowledged. For example, comparing results between studies presented in this systematic review is hindered by differences in subject selection and design of the studies. Not all studies used DSM-IV criteria for cannabis dependence or abuse and studies varied in how they set criteria to define their cannabis using (C+) and non-using (C-) group. A solution to overcome could have been to include cannabis as a continuous variable rather than creating dichotomous groups as it was done by a few studies in this review [40, 41]. However, the problem with most studies is also that cannabis intake is poorly measured across studies yielding to high between-samples heterogeneity. This point is very important because smoking styles and quantities vary largely and it has also been reported, that the THC content of smoked cannabis has increased over the past 20 years [61]. Another problem for quantitatively comparing the different included studies is the variety regarding the inclusion of a control group: some studies included a non-psychiatric sample and others did not. Within those studies that included a non-psychiatric sample, only few also analysed cannabis using healthy controls.

Despite these factors that make it difficult to compare the included studies at meta-analytical level, a few conclusions can be drawn. Within the 15 in vivo structural MRI studies included in this review, 11 found that cannabis use (as individually defined in each study) was associated with a decrease in global or specific brain structures in psychosis patients [40, 44, 52, 54-57, 62] or subjects at clinical/genetic risk for psychosis [39, 40, 42, 63]. These effects seemed to be particularly strong in brain regions rich on CB1 receptors, such as the cingulum [54, 55], the dorsolateral prefrontal cortex [44, 57] and the cerebellum [52, 57]. Two studies reported no difference between users and non users [45, 53] in psychosis and two studies reported that early onset cannabis users showed more white matter than cannabis naïve patients and controls [46, 47]. Conversely, none of the post mortem studies found an effect of cannabis use on cannabinoid receptor density except for Dean et al. [59] who reported an increase of CB1 receptors in the caudate-putamen from subjects who had recently ingested cannabis.

The effects of cannabis on the patient and control groups were differentially reported: while one study found that the effects of cannabis on brain structure are equally both in ARMS and controls [39], other studies showed that the negative effects of cannabis use on brain structure were significantly more pronounced in psychosis patients and genetic high risk subjects than in healthy controls [40, 41, 52]. In general, this review shows that effects of cannabis on brain in psychosis subjects seem to be more distinct than in studies investigating non-psychiatric samples [8, 9]. This could be an indication that people with schizophrenia or at genetic high risk for this disease may have a particular sensitivity to brain tissue loss on exposure to cannabis, which is also in line with previous research reporting that the use of alcohol and amphetamines is associated with greater structural brain abnormalities than this would be expected in healthy individuals with a comparable level of exposure [64, 65]. However, the question remains whether brain abnormalities are only an expected consequence of substance misuse or whether they also predispose it: cortical and hippocampal dysfunctions in schizophrenia could also be responsible for the greater reinforcement of drugs leading to more drug problems, which underlines the latter assumption [66].

4.1. Potential Mechanisms Underlying Cannabis Action on Brain Structure in Psychosis

There could be two ways in which cannabis affects brain structure in psychosis: cannabis could either directly affect brain morphology or the volumetric changes might be indirectly caused through the psychotic symptoms which are associated with cannabis use [67]. The direct mechanism could be explained as follows: two post mortem studies [49, 59] showed significant differences in CB1 receptor binding between schizophrenia patients and healthy controls. This suggests that changes in the endogenous cannabinoid system may be involved in the pathophysiology of schizophrenia. The endogenous cannabinoid system is fully reviewed in a separate paper published in the present issue. Dean et al. [59] additionally showed that acute cannabis use was associated with change in density of CB1 in tissue. Therefore, a plausible consequence of chronic cannabis use would be that these structures change in volume, which may also happen in other regions rich on CB1 receptors. However, change in receptor density due to cannabis was only shown in one post mortem study out of four [59].

It was postulated that the interaction of endogenous cannabinoids with CB1 receptors is critically involved in brain development during the sensitive period of adolescence through its regulating role in the release of glutamate. THC disturbs this normal physiological process through its action on CB1 receptors. Consequently, glutamate release is hindered which leads to neurotoxic effects and cortical structural abnormalities [13]. In contrast, two studies showed that cannabis use during adolescence was associated with more white matter compared to cannabis-naïve patients [46, 47] suggesting that cannabis-naïve individuals who develop schizophrenia might have a more vulnerable brain structure compared with that of cannabis users who develop the disease. A direct neurotoxic effect of cannabis on brain was shown by Jockers-Scherubl et al. [68] who reported that schizophrenia patients with regular cannabis use had significantly raised nerve growth factor serum levels compared to controls and schizophrenic patients not consuming cannabis. Additional evidence directly implicating abnormal glutamate levels in the early phases of psychosis is available from recent molecular imaging studies [69, 70].

Next to direct mechanisms, there might also be even more complex interactions between cannabis use and genetic factors that lead to brain morphologic changes, known to be involved in schizophrenia. Ho et al. (2011) found evidence for gene environment interactions, showing that rs12720071 genotype significantly interacts with marijuana use on white matter in schizophrenic patients. More indirectly, cannabis use was shown to be associated with poorer clinical outcome [67, 71], which in turn could also lead to a higher “toxic” effect of the psychotic state on the brain [72].

4.2. Limitations

Most studies included in this review had small sample sizes, leading to limited statistical power. Also, large differences in secondary variables across studies (i.e. gender, medication status, etc.) and the high overlap between cannabis and other illicit drug use may have played a confounding role. In many studies, it could therefore not explicitly be excluded that the observed effects were secondary to cannabis in contrast to other drug use. A further caveat is that there may be differences between oral ingestion and smoking cannabis; however studies did not explicitly present the methods of cannabis intake. Similar, not all studies presented mean dosage of cannabis intake prevailing any analyses on dose-response effects. For future studies we suggest including control group of cannabis-using subjects. Most studies so far have only compared cannabis using and non-using patients with cannabis naïve controls. However, this approach does not enable conclusions regarding to whether brain structural differences are caused through cannabis use or the disease of schizophrenia.

4.3. Conclusions

This review suggests that cannabis use in psychosis is associated with volume loss of global and specific brain structures, whereby the effects seem to be particularly strong in CB1 rich brain regions such as the cingulum, the dorsolateral prefrontal cortex and the cerebellum. As the current literature did not uncover strong similar effects in healthy samples yet, psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure.


We would like to thank Fabian Probst and Michael Kometer for their help in preparing the manuscript.


 = At-Risk Mental State
 = Cannabis using group
 = Cannabis non-using group
 = First Episode Psychosis patients
 = Individuals at genetic high risk for psychosis
 = Healthy controls


All authors report no financial interests or potential conflicts of interest with respect to this study.


1. Bhattacharyya S, Fusar-Poli P, Borgwardt S, et al. Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch Gen Psychiatry. 2009;66:442–51. [PubMed]
2. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35:764–74. [PMC free article] [PubMed]
3. Fusar-Poli P, Allen P, Bhattacharyya S, et al. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int J Neuropsychopharmacol. 2010;13:421–32. [PubMed]
4. Fusar-Poli P, Crippa JA, Bhattacharyya S, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66:95–105. [PubMed]
5. Winton-Brown TT, Allen P, Bhattacharyya S, et al. Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology. 2011;36:1340–8. [PMC free article] [PubMed]
6. Borgwardt SJ, Allen P, Bhattacharyya S, et al. Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol Psychiatry. 2008;64:966–73. [PubMed]
7. Bhattacharyya S, Crippa JA, Allen P, et al. Induction of psychosis by {delta}9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry. 2012;69:27–36. [PubMed]
8. Martin-Santos R, Fagundo AB, Crippa JA, et al. Neuroimaging in cannabis use: a systematic review of the literature. Psychological Medicine. 2010;40:383–398. [PubMed]
9. Quickfall J, Crockford D. Brain neuroimaging in cannabis use: A review. J Neuropsychiatry Clinical Neurosci. 2006;18:318–32. [PubMed]
10. Lorenzetti V, Lubman DI, Whittle S, Solowij N, Yücel M. Structural MRI Findings in Long-Term Cannabis Users: What Do We Know? Substance Use & Misuse. 2010;45:1787–808. [PubMed]
11. Lawston J, Borella A, Robinson JK, Whitaker-Azmitia PM. Changes in hippocampal morphology following chronic treatment with the synthetic cannabinoid WIN 55,212-2. Brain Research. 2000;877:407–10. [PubMed]
12. Chan GCK, Hinds TR, Impey S, Storm DR. Hippocampal neurotoxicity of Delta(9)-tetrahydrocannabinol. Journal of Neuroscience. 1998;18:5322–32. [PubMed]
13. Bossong MG, Niesink RJM. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Progress in Neurobiology. 2010;92:370–85. [PubMed]
14. Konings M, Henquet C, Maharajh HD, Hutchinson G, Van Os J. Early exposure to cannabis and risk for psychosis in young adolescents in Trinidad. Acta Psychiatrica Scandinavica. 2008;118:209–13. [PubMed]
15. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: A longitudinal population-based study. Am J Epidemiol. 2002;156:319–27. [PubMed]
16. Casadio P, Fernandes C, Murray RM, Di Forti M. Cannabis use in young people: The risk for schizophrenia. Neuroscience and Biobehavioral Reviews. 2011;35:1779–1787. [PubMed]
17. Barnett JH, Werners U, Secher SM, et al. Substance use in a population-based clinic sample of people with first-episode psychosis. British Journal of Psychiatry. 2007;190:515–20. [PubMed]
18. Honea R, Crow TJ, Passingham D, Mackay CE. Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies. American Journal of Psychiatry. 2005;162:2233–45. [PubMed]
19. Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia - A systematic and quantitative review of volumetric magnetic resonance imaging studies. British Journal of Psychiatry. 1998;172:110–20. [PubMed]
20. Wright IC, Rabe-Hesketh S, Woodruff PWR, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. American Journal of Psychiatry. 2000;157:16–25. [PubMed]
21. Fusar-Poli P, Borgwardt S, Crescini A, et al. Neuroanatomy of Vulnerability to Psychosis: A Voxel-Based Meta-Analysis. Neurosci Biobehav Rev. 2011;35:1175–85. [PubMed]
22. Fusar-Poli P, Radua J, McGuire P, Borgwardt S. Neuroanatomical Maps of Psychosis Onset: Voxel-wise Meta-Analysis of Antipsychotic-Naive VBM Studies. Schizophr Bull. 2011. Epub. [PMC free article] [PubMed]
23. Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Moller HJ, Riecher-Rossler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011. [PMC free article] [PubMed]
24. Mechelli A, Riecher-Rossler A, Meisenzahl EM, et al. Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study. Arch Gen Psychiatry. 2011;68:489–95. [PubMed]
25. Smieskova R, Fusar-Poli P, Allen P, et al. Neuroimaging predictors of transition to psychosis – A systematic review and meta-analysis. Neurosci Biobehavioural Rev. 2010;34:1207–22. [PubMed]
26. Smieskova R, Fusar-Poli P, Aston J, Simon A, Bendfeldt K, Lenz C, Stieglitz RD, McGuire P, Riecher-Rössler A, Borgwardt SJ. Insular volume abnormalities associated with different transition probabilities to psychosis Psychological Medicine. Available on CJO. 2011. doi: 10.1017/S0033291711002716. [PMC free article] [PubMed]
27. Smieskova R, Fusar-Poli P, Allen P, et al. The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia?--a systematic review. Current pharmaceutical design. 2009;15:2535–49. [PubMed]
28. Borgwardt SJ, Radue EW, Gotz K, et al. Radiological findings in individuals at high risk of psychosis. Journal of neurology, neurosurgery, and psychiatry. 2006;77:229–33. [PMC free article] [PubMed]
29. Borgwardt SJ, Riecher-Rossler A, Dazzan P, et al. Regional gray matter volume abnormalities in the at risk mental state. Biological psychiatry. 2007;61:1148–56. [PubMed]
30. Haller S, Borgwardt SJ, Schindler C, Aston J, Radue EW, Riecher-Rossler A. Can cortical thickness asymmetry analysis contribute to detection of at-risk mental state and first-episode psychosis? A pilot study. Radiology. 2009;250:212–21. [PubMed]
31. Borgwardt SJ, McGuire PK, Aston J, et al. Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis. Br J Psychiatry Suppl. 2007;51:s69–75. [PubMed]
32. Borgwardt SJ, McGuire PK, Aston J, et al. Reductions in frontal, temporal and parietal volume associated with the onset of psychosis. Schizophr Res. 2008;106:108–14. [PubMed]
33. Velakoulis D, Wood S, Wong M, et al. Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry. 2006;63:139–49. [PubMed]
34. Borgwardt SJ, McGuire P, Fusar-Poli P, Radue EW, Riecher-Rossler A. Anterior cingulate pathology in the prodromal stage of schizophrenia. Neuroimage. 2008;39:553–4. [PubMed]
35. Borgwardt SJ, Picchioni MM, Ettinger U, Toulopoulou T, Murray R, McGuire PK. Regional gray matter volume in monozygotic twins concordant and discordant for schizophrenia. Biol Psychiatry. 2010;67:956–64. [PubMed]
36. Borgwardt S, McGuire P, Fusar-Poli P. Gray matters!--mapping the transition to psychosis. Schizophrenia Research. 2011;133:63–7. [PubMed]
37. Fusar-Poli P, McGuire P, Borgwardt S. Mapping prodromal psychosis: A critical review of neuroimaging studies. Eur Psychiatry. 2011. [PubMed]
38. DeLisi LE. The effect of cannabis on the brain: can it cause brain anomalies that lead to increased risk for schizophrenia? Current Opinion in Psychiatry. 2008;21:140–150. [PubMed]
39. Stone JM, Bhattacharyya S, Barker G, McGuire PK. Substance use and regional grey matter volume in individuals at high risk of psychosis. European Neuropsychopharmacology. 2011;21:S63–64.
40. Habets P, Marcelis M, Gronenschild E, Drukker M, van Os J. Group. Reduced Cortical Thickness as an Outcome of Differential Sensitivity to Environmental Risks in Schizophrenia. Biological Psychiatry. 2011;69:487–94. [PubMed]
41. Welch KA, McIntosh AM, Job DE, et al. The Impact of Substance Use on Brain Structure in People at High Risk of Developing Schizophrenia. Schizophrenia Bulletin. 2011;37:1066–76. [PMC free article] [PubMed]
42. Welch KA, Stanfield AC, McIntosh AM, et al. Impact of cannabis use on thalamic volume in people at familial high risk of schizophrenia. Br J Psychiatry. 2011. [PubMed]
43. Rais M, Cahn W, Van Haren N, et al. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry. 2008;165:490–6. [PubMed]
44. Rais M, van Haren NEM, Cahn W, et al. Cannabis use and progressive cortical thickness loss in areas rich in CB1 receptors during the first five years of schizophrenia. European Neuropsychopharmacology. 2010;20:855–65. [PubMed]
45. Cahn W, Hulshoff Pol HE, Caspers E, van Haren NEM, Schnack HG, Kahn RS. Cannabis and brain morphology in recent-onset schizophrenia. Schizophrenia Research. 2004;67:305–7. [PubMed]
46. Dekker N, Schmitz N, Peters BD, van Amelsvoort TA, Linszen DH, de Haan L. Cannabis use and callosal white matter structure and integrity in recent-onset schizophrenia. Psychiatry Research-Neuroimaging. 2010;181:51–6. [PubMed]
47. Peters BD, de Haan L, Vlieger EJ, Majoie CB, den Heeten GJ, Linszen DH. Recent-Onset Schizophrenia and Adolescent Cannabis Use: MRI Evidence for Structural Hyperconnectivity? Psychopharmacology Bulletin. 2009;42:75–88. [PubMed]
48. Deng C, Han M, Huang XF. No changes in densities of cannabinoid receptors in the superior temporal gyrus in schizophrenia. Neuroscience Bulletin. 2007;23:341–7. [PubMed]
49. Zavitsanou K, Garrick T, Huang XF. Selective antagonist [H-3]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Progress in NeuroPsychopharmacology & Biological Psychiatry. 2004;28:355–60. [PubMed]
50. Callcut RA, Branson RD. How to Read a Review Paper. Respiratory Care. 2009;54:1379–85. [PubMed]
51. Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surgery. 2010;8:336–41. [PubMed]
52. Solowij N, Yucel M, Respondek C, et al. Cerebellar white-matter changes in cannabis users with and without schizophrenia. Psychological Medicine. 2011;41:2349–59. [PubMed]
53. Cohen M, Rasser PE, Peck G, et al. Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults. The International Journal of Neuropsychopharmacology. 2011;FirstView:1–11. [PubMed]
54. Szeszko PR, Robinson DG, Sevy S, et al. Anterior cingulate grey-matter deficits and cannabis use in first-episode schizophrenia. British Journal of Psychiatry. 2007;190:230–236. [PubMed]
55. Bangalore SS, Prasad KMR, Montrose DM, Goradia DD, Diwadkar VA, Keshavan MS. Cannabis use and brain structural alterations in first episode schizophrenia — A region of interest, voxel based morphometric study. Schizophrenia Research. 2008;99:1–6. [PubMed]
56. Ho BC, Wassink TH, Ziebell S, Andreasen NC. Cannabinoid receptor 1 gene polymorphisms and marijuana misuse interactions on white matter and cognitive deficits in schizophrenia. Schizophrenia Research. 2011;128:66–75. [PMC free article] [PubMed]
57. James A, Hough M, James S, et al. Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS) Schizophrenia Research. 2011;128:91–7. [PubMed]
58. Yung AR, Yuen HP, McGorry PD, et al. Mapping the onset of psychosis: The comprehensive assessment of at-risk mental states. Australian and New Zealand Journal of Psychiatry. 2005;39:964–71. [PubMed]
59. Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. Studies on [H-3]CP-55940 binding in the human central nervous system: Regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience. 2001;103:9–15. [PubMed]
60. Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Archives of General Psychiatry. 2008;65:772–84. [PMC free article] [PubMed]
61. Ashton CH. Pharmacology and effects of cannabis: a brief review. British Journal of Psychiatry. 2001;178:101–6. [PubMed]
62. Rais M, Cahn W, Van Haren N, et al. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. American Journal of Psychiatry. 2008;165:490–6. [PubMed]
63. Welch KA, McIntosh A, Moorhead W, et al. The Impact of Substance Use on Brain Structure in People at Genetically High Risk of Schizophrenia. Schizophrenia Bulletin. 2011;37:182–2. [PMC free article] [PubMed]
64. Mathalon DH, Pfefferbaum A, Lim KO, Rosenbloom MJ, Sullivan EV. Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Archives of General Psychiatry. 2003;60:245–52. [PubMed]
65. Berman S, O'Neill J, Fears S, Bartzokis G, London ED. Abuse of Amphetamines and Structural Abnormalities in the Brain. Addiction Reviews 2008. 2008;1141:195–220. [PMC free article] [PubMed]
66. Chambers RA, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biological Psychiatry. 2001;50:71–83. [PMC free article] [PubMed]
67. Dubertret C, Bidard I, Ades J, Gorwood P. Lifetime positive symptoms in patients with schizophrenia and cannabis abuse are partially explained by co-morbid addiction. Schizophrenia Research. 2006;86:284–90. [PubMed]
68. Jockers-Scherubl MC, Matthies U, Danker-Hopfe H, Lang UE, Mahlberg R, Hellweg R. Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. Journal of Psychopharmacology. 2003;17:439–45. [PubMed]
69. Fusar-Poli P, Stone JM, Broome MR, et al. Thalamic Glutamate Levels as a Predictor of Cortical Response During Executive Functioning in Subjects at High Risk for Psychosis. Arch Gen Psychiatry. 2011;68:881–90. [PubMed]
70. Stone JM, Howes OD, Egerton A, et al. Altered Relationship Between Hippocampal Glutamate Levels and Striatal Dopamine Function in Subjects at Ultra High Risk of Psychosis. Biological Psychiatry. 2010;68:599–602. [PubMed]
71. Grech A, Van Os J, Jones PB, Lewis SW, Murray RM. Cannabis use and outcome of recent onset psychosis. European Psychiatry. 2005;20:349–53. [PubMed]
72. Lieberman J, Chakos M, Wu HW, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biological Psychiatry. 2001;49:487–99. [PubMed]
73. Robins LN, Wing J, Wittchen HU, et al. The Composite International Diagnostic Interview - an Epidemiologic Instrument Suitable for Use in Conjunction with Different Diagnostic Systems and in Different Cultures. Archives of General Psychiatry. 1988;45:1069–77. [PubMed]
74. Ho BC, Flaum M, Hubbard W, Arndt S, Andreasen NC. Validity of symptom assessment in psychotic disorders: information variance across different sources of history. Schizophrenia Research. 2004;68:299–307. [PubMed]
75. Darke S, Ward J, Hall W, Heather N, Wodak A. The Opiate Treatment Index (OTI) Researcher's Manual. National Drug and Alcohol Research Centre: Sydney. 1991.
76. Mancini-Marie A, Potvin S, Fahim C, Beauregard M, Mensour B, Stip E. Neural correlates of the affect regulation model in schizophrenia patients with substance use history: A functional magnetic resonance imaging study. Journal of Clinical Psychiatry. 2006;67:342–50. [PubMed]
77. Leweke FM, Giuffrida A, Koethe D, et al. Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: Impact of cannabis use. Schizophrenia Research. 2007;94:29–36. [PubMed]
78. Safont G, Corripio I, Escarti MJ, et al. Cannabis use and striatal D2 receptor density in untreated first-episode psychosis: An in vivo SPECT study. Schizophrenia Research. 2011;129:169–71. [PubMed]
79. Loberg EMM, Jorgensen HA, Nygard M, Berle JO, Hugdahl K. Cannabis Use and Brain Functioning in Schizophrenia: An Fmri Study. Schizophrenia Bulletin. 2011;37:144–5.
80. Potvin S, Mancini-Maeie A, Fahim C, Mensour B, Stip E. Processing of social emotion in patients with schizophrenia and substance use disorder: An fMRI study. Social Neuroscience. 2007;2:106–16. [PubMed]
81. Parkar SR, Ramanathan S, Nair N, et al. Are the effects of cannabis dependence on glucose metabolism similar to schizophrenia? An FDG PET understanding. Indian J Psychiatry. 2011;53:13–20. [PMC free article] [PubMed]
82. Newell KA, Deng C, Huang XF. Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Experimental Brain Research. 2006;172:556–60. [PubMed]
83. Dalton VS, Long LE, Weickert CS, Zavitsanou K. Paranoid Schizophrenia is Characterized by Increased CB1 Receptor Binding in the Dorsolateral Prefrontal Cortex. Neuropsychopharmacology. 2011;36:1620–30. [PMC free article] [PubMed]
84. Potvin S, Mancini-Marie A, Fahim C, et al. Increased striatal gray matter densities in patients with schizophrenia and substance use disorder: A voxel-based morphometry study. Psychiatry Research-Neuroimaging. 2007;154:275–9. [PubMed]
85. Wobrock T, Sittinger H, Behrendt B, D'Amelio R, Falkai P. Comorbid substance abuse and brain morphology in recent-onset psychosis. European Archives of Psychiatry and Clinical Neuroscience. 2009;259:28–36. [PMC free article] [PubMed]
86. Ebdrup BH, Glenthoj B, Rasmussen H, et al. Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia. Journal of Psychiatry & Neuroscience. 2010;35:95–104. [PMC free article] [PubMed]
87. Koethe D, Llenos IC, Dulay JR, et al. Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transmission. 2007;114:1055–63. [PubMed]
88. Wobrock T, Hasan A, Malchow B, et al. Increased cortical inhibition deficits in first-episode schizophrenia with comorbid cannabis abuse. Psychopharmacology. 2010;208:353–363. [PMC free article] [PubMed]

Articles from Bentham Open Access are provided here courtesy of Bentham Science Publishers