10 CIP patients and 12 NPCU were recruited for this study. All patients were recruited at the psychiatric inward of the University Policlinico Hospital of Milan, Italy, whereas the cannabis users were enrolled in the Milan catchment area. All patients were in stable pharmacological treatment. Either left- or right- handed participants were included. All participants had a habitual cannabis consumption and the type of drug, the frequency and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. The study was approved by the local ethical committee.
1. Participants
2. Clinical and psychosocial evaluation
NOTE: Several clinical and psychosocial scales were administered to all the participants.
3. Magnetic resonance imaging
4. Pre-processing steps
NOTE: A voxel-based morphometry analysis should be performed using Statistical Parametric Mapping (SPM12) implemented in MATLAB.
5. Statistical analyses
Socio-demographic, clinical and psychosocial results
There were no differences in terms of gender (χ2 =0.6, p=0.4), age (t=-0.21; p=0.83), age of onset of dependency (t=-0.79; p=0.44) and educational level (t=1.21; p=0.24) between CIP patients and NPCU. However, some differences between the two groups were observed in one temperament dimension (Harm Avoidance, t=3.71; p=0.001) and one-character dimension (Self-Transcendence, t=2.94; p=0.008) of the TCI where CIP patients showed higher scores compared to NPCU. Finally, NPCU also showed higher scores compared to CIP patients in one sub-dimension of the Neighborhood Scale (NS-E) (t=-3.55; p=0.002), in the SES total (t=-2.13; p=0.046), in the Quality of Life-Index (t=-8.1; p=0.0001), in the GAF (t=-4.71; p=0.0001) and in one character dimension of the TCI (Self Directedness, t=-3.97; p=0.001).
Specifically, for CIP, the frequency of cannabis dependency was daily for 9 subjects (90%) and several times a week for 1 subject (10%). Instead, the frequency of cannabis dependency in the NPCU group was daily for 7 subjects (60%), several times a week for 4 subjects (30%), and multiple times a month for 1 subject (10%). The mean age of onset of dependency was at 18 years old for CIP patients and at 16 years old for the NPCU group. Although all participants were taking cannabis, some CIP patients (N=6) and NPCU (N=3) also reported previous use of other drugs, including cocaine, LSD and heroin/methadone, but with lower frequency than cannabis. The frequency of cannabis use did not differ between the two groups (χ2=1.69, p=0.42). Moreover, no statistical difference in type and frequency of cocaine, heroin/methadone and LSD use was observed between the two groups (cocaine: χ2=0.06, p=0.79 and χ2=4.1, p=0.39; heroin/methadone: χ2=1.2, p=0.26 and χ2=1.2, p=0.26; LSD: χ2=0.01, p=0.89 and χ2=2.0, p=0.36). Although we are aware that the presence of poly-consumption in the sample might have negatively affected the generalizability of the findings, it is important to highlight that the use of other drugs was very limited compared to cannabis use. Indeed, in contrast to cannabis use, the consumption of other drugs was lifetime and not occurring during the time of the study. Nonetheless, our results should be taken cautiously and need to be replicated in a more homogeneous sample.
VBM results
VBM analysis showed that CIP patients had extensive GM decreases compared to NPCU in right superior frontal gyrus ((Brodmann area [BA] 10), right precentral (BA 4) , right superior temporal gyrus (BA 22), insula bilaterally (BA13), right precuneus (BA7), right medial occipital gyrus (BA 19), right fusiform gyrus (BA 37) and left hippocampus (p < 0.001 uncorrected; Table 2 and Figure 1). No GM differences were observed in NPCU compared to CIP patients.
Correlations between GM regions and clinical scales
In CIP patients, the results showed a negative correlation between a domain of the BPRS, BPRS-Activity, and selective GM volumes within left superior temporal cortex (BA 38, x=-40 y=17 z=-35, z=5.9, cluster size=19) and left cerebellum (x=-12 y=-36 z=-20, z=6.1, cluster size=18). Moreover, the same scale was positively correlated with cuneus bilaterally (BA 18; left: x=-9 y=-90 z=9, z=7.0, cluster size=24; right: x=15 y=-85 z=24, z=7.3, cluster size=13), left inferior occipital gyrus (BA 17; x=-9 y=-88 z=-6, z=7.4, cluster size=34), right inferior parietal lobule (BA 40; x=58 y=-35 z=22, z=6.7, cluster size=33), right superior prefrontal cortex (BA 9; x=3 y=51 z=29, z=6.2, cluster size=23) (all p<0.05 pFWE corrected). No significant correlations in any of the other clinical scales were observed in CIP patients.
Figure 1: Regions with significant GM difference between Substance-induced psychosis (CIP) patients and non-psychotic cannabis users (p<0.001, uncorrected, k=30). Please click here to view a larger version of this figure.
CIP patients | Non-psychotic cannabis users | Statistics | p-value | |
n=10 | n=12 | |||
Age, mean (SD) | 27 (9.21) | 26 (0.89) | t= -0.213 | p=0.833 |
Sex, male/female | 8/2 | 11/1 | χ2=0.630 | p=0.427 |
Age of onset of cannabis use, mean (SD) | 18 (9.69) | 16 (1.83) | t= -0.786 | p=0.441 |
Type (N); frequency of other drug use | Cannabis (N=10); Daily (N=9), multiple times a week (N=1). | Cannabis (N=12); Daily (N=7), multiple times a week (N=4), multiple times a month (N=1). | Frequency: χ2=1.69, | p=0.42 |
Cocaine (N=4); multiple times a week (N=2), multiple times a month (N=2). | Cocaine (N=3); multiple times a week (N=1), multiple times a month (N=1), less than one a month (N=1). | Type: χ2=0.06 | Type: p=0.79 | |
Frequency: χ2=4.1 | Frequency: p=0.39 | |||
Heroin/Methadone (N=1); multiple times a week. | No Heroin/Methadone users. | Type: χ2=1.2 | Type: p=0.26 | |
Frequency: χ2=1.2 | Frequency: p=0.26 | |||
LSD (N=1); less than one a month. | LSD (N=1); multiple times a month. | Type: χ2=0.01 | Type: p=0.89 | |
Frequency: χ2=2.0 | Frequency: p=0.36 | |||
Age of onset, mean (SD) | 25 (8.46) | – | – | – |
BPRS TOT, mean (SD) | 43 (9) | 20 (3) | t=8.860 | p=0.0001 |
Anxiety-Depression | 10 (5) | 6 (2) | t=2.629 | p=0.016 |
Anergia | 8 (3) | 4 (1) | t=3.284 | p=0.004 |
Thought Disorders | 12 (3) | 4 (0) | t=9.754 | p=0.0001 |
Activity | 6 (2) | 3 (0) | t=4.557 | p=0.0001 |
Hostility- Suspiciousness | 8 (4) | 3 (0) | t=4.053 | p=0.001 |
HAM-D, mean (SD) | 11 (6.42) | 4 (4.96) | t=3.258 | p=0.004 |
HAM-A, mean (SD) | 11 (6.62) | 3 (3.93) | t=3.487 | p=0.002 |
MADRS, mean (SD) | 14 (7.76) | 6 (6.35) | t=2.635 | p=0.016 |
YMRS, mean (SD) | 13 (7.92) | 0 (1.44) | t=5.378 | p=0.0001 |
CECA-Q, mean (SD) | ||||
CECA-QMA | 13 (5.20) | 13 (3.89) | t=-0.069 | p=0.946 |
CECA-QMN | 19 (5.83) | 19 (4.64) | t=-0.284 | p=0.779 |
CECA-QPA | 14 (6.44) | 14 (5.56) | t=-0.130 | p=0.990 |
CECA-QPN | 24 (11.69) | 24 (7.12) | t=0.070 | p=0.945 |
Neighbourhood scale*, mean (SD) | ||||
NS- A | 9 (1.78) | 8 (2.23) | t=0.782 | p=0.443 |
NS- B | 6 (2.50) | 7 (1.56) | t=-1.070 | p=0.298 |
NS- C | 9 (5.87) | 10 (7.66) | t=-0.265 | p=0.794 |
NS-D | 6 (2.31) | 5 (1.53) | t=1.378 | p=0.183 |
NS-E | 3 (1.35) | 4 (0.29) | t=-3.546 | p=0.002 |
SES** total, mean (SD) | 33.6 (12.60) | 45.3 (13.05) | t=-2.132 | p=0.046 |
Study | 11.3 (4.22) | 15.3 (5.93) | t=-1.800 | p=0.087 |
Occupation | 22.3 (10.39) | 30.0 (8.79) | t=-1.885 | p=0.074 |
QL – Index, mean (SD) | 6 (1.65) | 10 (0.62) | t=-8.098 | p=0.0001 |
GAF, mean (SD) | 58 (15.21) | 83 (9.68) | t=-4.715 | p=0.0001 |
MANSA, mean (SD) | 54 (14.16) | 61 (6.01) | t=-1.250 | p=0.226 |
TCI, mean (SD) | ||||
TCI Ns | 59.92 (10.75) | 55.95 (12.86) | t=0.173 | p=0.864 |
TCI Ha | 55.67 (7.71) | 45.61 (5.68) | t=3.708 | p=0.001 |
TCI Rd | 48.67 (10.41) | 50.49 (9.02) | t=-0.668 | p=0.512 |
TCI P | 49.82 (11.49) | 39.32 (8.83) | t=2.033 | p=0.056 |
TCI Sd | 28.64 (11.85) | 49.89 (7.42) | t=-3.969 | p=0.001 |
TCI Co | 42.15 (12.21) | 49.07 (5.60) | t=-1.430 | p=0.168 |
TCI St | 65.56 (12.34) | 50.82 (8.16) | t=2.940 | p=0.008 |
Table 1: Socio-demographic, clinical and psychosocial variables of the whole sample. BPRS (Brief Psychiatric Rating Scale); CECA-Q (Childhood Experience of Care and Abuse Questionnaire); CIP (Cannabis-Induced Psychosis); GAF (Global Assessment of Functioning); HAM-A (Hamilton Anxiety Rating Scale); MADRS (Montgomery-Asberg Depression Rating Scale); HAM-D (Hamilton Depression Rating Scale); MANSA (Manchester Short Assessment of Quality of Life); NS-A (Neighbourhood satisfaction); NS-B (Feelings of safety); NS-C (Neighbourhood incivilities); NS-D (Collective efficacy); NS-E (Cannabis acceptance); SD (Standard Deviation); SES (Socio Economic Status); QL-Index (Quality of Life-Index); ); TCI (Temperament and Character Inventory); TCI Ns (Novelty Seeking); TCI Ha (Harm Avoidance); TCI Rd (Reward Dependence); TCI P (Persistence); TCI Sd (Self Directedness); TCI Co (Cooperativeness); TCI St (Self Transcendence); YMRS (Young Mania Rating Scale). * NS-A ranges from 0 to 16, where 16 represented extreme satisfaction with the area of residence; NS-B ranges from 0 to 8, where 8 represented a strong feeling of safety; NS-C ranges from 0 to 32, where 32 indicated a high level of incivilities; NS-D ranges from 0 to 12, where 8 represented a high level of collective efficacy amongst neighbours; NS-E ranges from ‘agree strongly’ (score of 4) to ‘disagree strongly’ (score of 0). ** Lower levels of schooling are associated to lower scores while higher levels of schooling are associated to higher scores (ie. Less than 7th grade = 3; Graduate degree= 21). Similarly, Occupations with lower cognitive engagement are associated to lower scores, while occupations requiring more cognitive resources are associated to higher scores (Farm worker= 5; Physician= 45).
Gyrus | BA | Laterality | MNI coordinates | Cluster size | z-values | Cohen’s d effect size | ||
x y z | ||||||||
CIP patients < non-psychotic cannabis users | ||||||||
Superior Frontal | 10 | Right | 13 | 65 | 22 | 38 | 3.4 | -1,26 |
Precentral | 4 | Right | 59 | -5 | 26 | 61 | 3.8 | -0,83 |
Superior Temporal | 22 | Right | 62 | -7 | 3 | 146 | 4.2 | -0,60 |
Insula | 13 | Right | 36 | -21 | 13 | 142 | 4.1 | -0,43 |
Insula | 13 | Left | -33 | -23 | 14 | 32 | 3.8 | -0,46 |
Precuneus | 7 | Right | 6 | -66 | 50 | 41 | 3.7 | -0,51 |
Medial Occipital | 19 | Right | 33 | -86 | 21 | 80 | 4 | -0,84 |
Fusiform | 37 | Left | -25 | -47 | -8 | 32 | 3.7 | -0,29 |
Hippocampus | – | Left | -33 | -22 | -5 | 36 | 3.8 | -0,68 |
Non-psychotic cannabis users < CIP patients | ||||||||
No suprathreshold clusters |
Table 2: VBM results. Brain regions showing significant reduced grey matter volumes between the CIP patients and non-psychotic cannabis users (P< 0.001 uncorrected). BA (Brodmann area); CIP (Cannabis-Induced Psychosis); MNI (Montreal Neurological Institute)
Not applicable | Not applicable | Not applicable | Not applicable |
Cannabis is the illicit drug most commonly used worldwide, and its consumption can both induce psychiatric symptoms in otherwise healthy subjects and unmask a florid psychotic picture in patients with a prior psychotic risk. Previous studies suggest that chronic and long-term cannabis exposure may exert significant negative effects in brain areas enriched with cannabinoid receptors. However, whether brain alterations determined by cannabis dependency will lead to a clinically significant phenotype or to a psychotic outbreak at some point of an abuser’s life remains unclear. The aim of this study was to investigate morphological brain differences between chronic cannabis users with cannabis-induced psychosis (CIP) and non-psychotic cannabis users (NPCU) without any psychiatric conditions and correlate brain deficits with selective socio-demographic, clinical and psychosocial variables.
3T magnetic resonance imaging (MRI) scans of 10 CIP patients and 12 NPCU were acquired. The type of drug, the frequency, and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. CIP patients had extensive grey matter (GM) decreases in right superior frontal gyrus, right precentral, right superior temporal gyrus, insula bilaterally, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus in comparison to chronic cannabis users without psychosis. Finally, in CIP patients, the results showed a negative correlation between a domain of the Brief Psychiatric Rating Scale (BPRS), BPRS-Activity, and selective GM volumes. Overall, the results suggest that cannabis-induced psychosis is characterized by selective brain reductions that are not present in NPCU. Therefore, neuroimaging studies may provide a potential ground for identifying putative biomarkers associated with the risk of developing psychosis in cannabis users.
Cannabis is the illicit drug most commonly used worldwide, and its consumption can both induce psychiatric symptoms in otherwise healthy subjects and unmask a florid psychotic picture in patients with a prior psychotic risk. Previous studies suggest that chronic and long-term cannabis exposure may exert significant negative effects in brain areas enriched with cannabinoid receptors. However, whether brain alterations determined by cannabis dependency will lead to a clinically significant phenotype or to a psychotic outbreak at some point of an abuser’s life remains unclear. The aim of this study was to investigate morphological brain differences between chronic cannabis users with cannabis-induced psychosis (CIP) and non-psychotic cannabis users (NPCU) without any psychiatric conditions and correlate brain deficits with selective socio-demographic, clinical and psychosocial variables.
3T magnetic resonance imaging (MRI) scans of 10 CIP patients and 12 NPCU were acquired. The type of drug, the frequency, and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. CIP patients had extensive grey matter (GM) decreases in right superior frontal gyrus, right precentral, right superior temporal gyrus, insula bilaterally, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus in comparison to chronic cannabis users without psychosis. Finally, in CIP patients, the results showed a negative correlation between a domain of the Brief Psychiatric Rating Scale (BPRS), BPRS-Activity, and selective GM volumes. Overall, the results suggest that cannabis-induced psychosis is characterized by selective brain reductions that are not present in NPCU. Therefore, neuroimaging studies may provide a potential ground for identifying putative biomarkers associated with the risk of developing psychosis in cannabis users.
Cannabis is the illicit drug most commonly used worldwide, and its consumption can both induce psychiatric symptoms in otherwise healthy subjects and unmask a florid psychotic picture in patients with a prior psychotic risk. Previous studies suggest that chronic and long-term cannabis exposure may exert significant negative effects in brain areas enriched with cannabinoid receptors. However, whether brain alterations determined by cannabis dependency will lead to a clinically significant phenotype or to a psychotic outbreak at some point of an abuser’s life remains unclear. The aim of this study was to investigate morphological brain differences between chronic cannabis users with cannabis-induced psychosis (CIP) and non-psychotic cannabis users (NPCU) without any psychiatric conditions and correlate brain deficits with selective socio-demographic, clinical and psychosocial variables.
3T magnetic resonance imaging (MRI) scans of 10 CIP patients and 12 NPCU were acquired. The type of drug, the frequency, and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. CIP patients had extensive grey matter (GM) decreases in right superior frontal gyrus, right precentral, right superior temporal gyrus, insula bilaterally, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus in comparison to chronic cannabis users without psychosis. Finally, in CIP patients, the results showed a negative correlation between a domain of the Brief Psychiatric Rating Scale (BPRS), BPRS-Activity, and selective GM volumes. Overall, the results suggest that cannabis-induced psychosis is characterized by selective brain reductions that are not present in NPCU. Therefore, neuroimaging studies may provide a potential ground for identifying putative biomarkers associated with the risk of developing psychosis in cannabis users.