- Email: [email protected]
Cannabis use in early adolescence is associated with higher negative schizotypy in females
G Model
EURPSY 3561 1–7 European Psychiatry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
European Psychiatry journal homepage: http://www.europsy-journal.com 1 2 3 4
Original article
Cannabis use in early adolescence is associated with higher negative schizotypy in females Albertella a,b,d,*, M.E. Le Pelley a, J. Copeland c,d
5
Q1 L.
6 7 8 9 10
Q2 a School of Psychology, UNSW Sydney, Sydney, Australia b
Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton,
Q3 VIC, Australia c d
Cannabis Information and Support, Sydney, Australia National Cannabis Prevention and Information Centre, UNSW Sydney, Sydney, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 May 2017 Received in revised form 17 July 2017 Accepted 18 July 2017 Available online xxx
The current study examined the relationship between early onset cannabis use (before age 16) and different schizotypy dimensions, and whether gender moderates these associations. Participants were 162 cannabis users, aged 15–24 years, who completed an online assessment examining alcohol and other drug use, psychological distress, and schizotypy. Participants were divided according to whether or not they had started using cannabis before the age of 16 (early onset = 47; later onset = 115) and gender (males = 66; females = 96). The interaction between gender and onset group was significantly associated with the dimension of introvertive anhedonia. Follow-up analyses showed that early onset cannabis use was associated with higher levels of introvertive anhedonia in females only. The current findings suggest that gender is an important moderator in the association between early onset cannabis use, schizotypy, and possibly, psychosis risk.
C 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Marijuana Introvertive anhedonia Gender Sex Psychosis
11 12
1. Introduction
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
A considerable proportion of adolescents have used cannabis recently. For instance, in Australia, up to 15% of adolescents (aged 14–19) have used cannabis in the past year, of which 30% are using it at least weekly [1]. These data are of concern in the context of animal and human research suggesting that adolescent exposure to cannabis is associated with risk of poorer psychosocial consequences, psychosis-related outcomes, and cognitive impairment [2–7]. Research showing that adolescent cannabis use is associated with a range of negative consequences, coupled with research implicating the endocannabinoid system in the regulation of neurodevelopmental processes [8,9], suggests that cannabis use in adolescence may disrupt neurodevelopmental processes and result in brain changes resembling those associated with psychosis risk [10], or even psychosis itself [11]. The growing recognition of psychosis symptoms and disorders as dimensional in nature (as opposed to categorical, for diagnostic purposes) has seen a growing interest in the examination of
* Corresponding author. Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, VIC, Australia. E-mail address: [email protected] (L. Albertella).
schizotypy to inform psychosis research [12]. Schizotypy refers to a collection of personality traits, including those relating to the positive symptoms of psychosis (known as positive schizotypy, and including unusual perceptions and magical thinking), those relating to disorganised thought symptoms (disorganised schizotypy), and those relating to negative symptoms (negative schizotypy, e.g., anhedonia and avolition) [13], which are considered related to psychosis risk [14]. Indeed, a large number of studies have now linked cannabis use to schizotypy, with the strongest association being with positive schizotypy [15]. Unfortunately, despite research indicating that age of first cannabis use is an important factor in determining the extent to which exposure to cannabis increases psychosis risk (e.g., [2,3]), very few studies have examined age of cannabis use onset in relation to schizotypy. One study [16] that has examined age of use onset in relation to schizotypy dimensions found that frequent use of cannabis was associated with both higher positive and negative schizotypy, and that this effect was much larger among users who had started using cannabis in early adolescence. A further limitation of current studies examining the relationship between cannabis use and different schizotypy dimensions is the failure to include a number of important moderating and/or confounding variables that may impact the relationships. For instance, research suggests that sex may be an important
http://dx.doi.org/10.1016/j.eurpsy.2017.07.009 C 2017 Elsevier Masson SAS. All rights reserved. 0924-9338/
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53
G Model
EURPSY 3561 1–7 2
L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
moderator of the effects of cannabinoid exposure on psychosisrelated behaviour, cognitive impairments, and brain changes [17– 20]. Sex, however, has largely been ignored in research examining the relationship between cannabis use and schizotypy. Another example is the lack of consideration of various cannabis use parameters. Most studies simply compare current use with never use, without regard to other important variables such as quantity of cannabis use. Research shows that quantity is an important predictor of cannabis use problems, i.e., independently of frequency [21], and further, has been associated with a number of psychosis-related symptoms in cannabis-using adolescents attending treatment [22]. The current study aims to address these gaps in the literature, by investigating: (1) whether early onset cannabis use is associated with different schizotypy dimensions; (2) whether sex moderates the association between early onset cannabis use and schizotypy; and (3) various cannabis use parameters in relation to different schizotypy dimensions.
72
2. Materials and methods
73
2.1. Participants
74 75 76 77 78 79 80 81 82 83 84
Participants were 162 young people who reported having ever used cannabis and had complete study data. These participants were part of a longitudinal study, in which the overall sample at baseline was 324 (or 327, if including 3 participants with missing data, none of which were cannabis users). Participants were recruited Australia-wide, via advertisements placed on websites, local newspapers, community notice boards, and update lists. Inclusion criteria included being aged between 14 and 24 years and fluent in English. Exclusion criteria included having a past head injury, history of neurological disorders, and having ever received a diagnosis of schizophrenia or schizoaffective disorder.
85
2.2. Procedure
86 87 88 89 90 91 92 93 94 95 96
The study was conducted via the Internet with all measures implemented using Inquisit Millisecond Software Web version 4.0.2. Eligible participants who consented to take part were emailed a link to the study assessment. Within two weeks of having completed the assessment, participants were emailed a $20 electronics store voucher. Parental consent was not obtained for participants under 16, since this requirement may have rendered the study less accessible to drug-using adolescents, thus reducing the generalisability and/or validity of the data. This and all other aspects of the study were approved by the UNSW Sydney Human Research Ethics Committee.
97
2.3. Measures
98 99 100 101 102 103 104 105 106 107 108 109 110 111 112
2.3.1. Demographic & substance use information. The baseline assessment covered demographic information including sex, age, education, and family history of psychosisrelated disorders. The questionnaire also asked about lifetime and current tobacco, alcohol, and illicit drug use. Participants who reported having ever used any drug were asked what age they first used it, followed by whether they had used it in the past six months. If they had used it in the past six months, they were asked about the extent to which they had used it; i.e. less than once a month, about once a month, once a week or more, or daily. This information was used to categorize participants who had ever used cannabis into two groups. One group included participants who had used cannabis but had used it less than weekly (including not at all) in the past six months (occasional users), while the second group included participants who used cannabis once a week or
more often in the past six months (frequent users). Such a grouping for frequent cannabis use has been used in previous studies, across the same timeframe (6 months), and found to be associated with a number of negative outcomes (e.g., [23]). Further questions included items from the Brief Treatment Outcome Measure (BTOM; [24]). For cannabis use, age of first use was also obtained. This information was used to split participants into two groups, those who used cannabis before the age of 16, and those who used it for the first time after 16. This split is commonly used and associated with psychosis risk and a range of other negative outcomes (e.g., [2]).
113 114 115 116 117 118 119 120 121 122 123
2.3.2. Schizotypy To measure schizotypy, we used the short form of the OxfordLiverpool Inventory of Feeling and Experiences (OLIFE; [25]), which comprises four subscales: unusual experiences, introvertive anhedonia, cognitive disorganisation, and impulsive non-conformity. The unusual experiences scale measures odd perceptual and cognitive experiences related to the positive symptoms of schizophrenia (e.g., ‘‘Have you ever thought that you had special, almost magical powers?’’). This scale is often referred to as positive schizotypy. The introvertive anhedonia scale assesses the inability to experience pleasure and other experiences related to the negative symptoms of schizophrenia (e.g., ‘‘Do you like mixing with people?’’), and this scale is often referred to as negative schizotypy. Cognitive disorganisation items relate to disorganised thought/speech and distractibility (e.g., ‘‘Are you easily distracted when you read or talk to someone?’’). Finally, impulsive nonconformity items relate to impulsivity and emotional instability (e.g., ‘‘Do you often feel the impulse to spend too much money which you know you can’t afford?’’).
124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142
2.3.3. Psychological distress Participants completed the brief Depression Anxiety Stress Scales (DASS-21; [26]). The DASS-21 contains 21 items assessing depression, anxiety, and stress/tension symptoms. Total score was used to control for psychological distress, as opposed to the three subscales separately, due to high correlations among the latter.
143 144 145 146 147 148
2.4. Analyses
149
Independent samples t-tests examined differences between early onset users (those who reported first use before the age of 16) and later onset users (those who reported first use at age 16 years or over), as well as gender, on normally distributed variables. Mann-Whitney U tests were used to examine differences on nonnormally distributed variables, which included tobacco, alcohol, and other drug use. Chi2 tests examined differences between groups on gender, and family history of schizophrenia. Four multiple regressions were run, one for each schizotypy dimension (Unusual experiences, introvertive anhedonia, cognitive disorganization, and impulsive nonconformity). Within each model, the following variables were entered as predictors/ covariates: age, gender, family history of schizophrenia, alcohol, tobacco, illicit drug use, psychological distress, various cannabis use parameters (frequent use in the past 6 months, quantity of use, and onset before 16 years), as well as non-dependent schizotypy dimensions. These variables were selected due to study aims and/or research showing their influence on schizotypy or related variables [22,27–31]. The interaction between gender and early use onset was examined using mean-centered values to avoid multicollinearity. A significant interaction was followed up by conducting linear regressions split by gender, with early onset use in the model along with any other variable that was P < .1 in the overall regression.
150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
175
3. Results
176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200
Participants were 162 young adults, with a mean age of 20.4 years (SD = 2.4) and 59% female. Participants in this present sample did not differ significantly in age, t(322) = 1.67, P = 0.096, or sex, x2 = 0.01, P = 0.910, from participants in the overall sample (i.e., the remainder of the sample who had never used cannabis). Table 1 shows the descriptive statistics of the sample and compares early onset vs later onset users. Early onset users were significantly younger than later onset users, t(160) = 2.5, P = 0.014, and more likely to have a family history of schizophrenia, x2 = 5.8, P = .016. They were also more likely to be frequent cannabis users, x2 = 10.3, P = 0.001, to use tobacco more frequently, Z = 3.3, P = 0.001, to have used more illicit drugs, Z = 3.5, P = 0.001, and to be more psychologically distressed than later onset users, t(160) = 2.9, P = 0.004. Finally, early onset users had higher scores on unusual experiences, t(160) = 2.5, P = 0.014, introvertive anhedonia, t(160) = 2.1, P = 0.038, and impulsive nonconformity, t(160) = 2.2, P = 0.027. Fig. 1 presents the means and SEMs of each schizotypy dimension as a function of gender and early use. Table 2 presents the results from the regression models. For the model with unusual experiences as the dependent variable, the total variance explained by the model was 49.9%, F (14, 147) = 10.5, P < 0.001. For introvertive anhedonia, the total variance explained by the model was 39.1%, F (14, 147) = 6.7, P < 0.001. For cognitive disorganisation, the total variance explained by the model was 47.9%, F (14, 147) = 9.7, P < 0.001. For impulsive nonconformity,
3
the total variance explained by the model was 43.0%, F (14, 147) = 7.9, P < 0.001. Scores on the unusual experiences scale were positively associated with cognitive disorganisation (Beta = 0.30, P < 0.001), impulsive nonconformity (Beta = 0.33, P < 0.001), and psychological distress (Beta = 0.23, P = 0.003). A greater number of illicit drugs ever used was associated with lower unusual experiences (Beta = 0.20, P = 0.012). Greater scores on the introvertive anhedonia scale were associated with higher levels of cognitive disorganisation (BeBeta = .30, P = .001) and greater psychological distress (Beta = .33, P < .001). Importantly, early onset cannabis use interacted with sex to predict introvertive anhedonia (Beta = 0.23, P = .029). Table 3 presents the results of the follow-up linear regression conducted separately on males and females in order to investigate this interaction further. Both models were significant overall (Ps < 0.001). In males, psychological distress (Beta = .30, P = .030) and cognitive disorganisation (Beta = .34, P = 0.015) were associated with higher introvertive anhedonia, but early use was not (P = 0.698). In contrast, higher levels of introvertive anhedonia in females were associated with cognitive disorganisation (Beta = 0.25, P = 0.012), psychological distress (BeBeta = 0.41, P < 0.001), and early onset use (Beta = 0.21, P = 0.023). Specifically, females who started using cannabis before the age of 16 showed significantly higher levels of introvertive anhedonia than females who started using cannabis after turning 16.
Table 1 Sample descriptive statistics. Cannabis onset group Female (n = 96) Age of onset Agea n Mean (SD) Family Hxa/% Unusual experiencesa [max = 12] Mean (SD) Introvertive anhedoniaa [max = 10] Mean (SD) Cognitive disorganisation [max = 11] Mean (SD) Impulsive nonconformitya [max = 10] Mean (SD) DASS-21 totala,b Mean (SD) Cannabis statusa/% Cannabis frequencya,b Median (Range) Cannabis quantity (SCUs)a,b Median (Range) Age of first cannabis usea Mean (S.D) Alcohol frequency Median (Range) Tobacco frequencya Median (Range) Other drug usea Median (Range)
Male (n = 66)
Overall (n = 162)
Before 16
16 & over
Before 16
16 & over
Before 16
16 & over
30 20.0 (2.7) 27%
66 20.8 (2.1) 11%
17 19.2 (2.4) 12%
49 20.6 (2.3) 4%
47 19.7 (2.6) 21.3%
115 20.7 (2.2) 7.8%
5.5 (3.0)
4.7 (2.8)
6.4 (3.8)
4.3 (3.0)
5.8 (3.3)
4.5 (2.8)
3.5 (1.9)
2.8 (1.7)
2.5 (1.6)
2.2 (1.6)
3.2 (1.8)
2.5 (1.7)
7.7 (2.6)
7.8 (2.6)
7.8 (2.4)
6.3 (3.1)
7.7 (2.5)
7.2 (2.9)
5.7 (2.3)
4.8 (2.2)
5.5 (2.1)
4.8 (2.2)
5.6 (2.2)
4.8 (2.1)
21.9 (13.7) 30%
17.1 (12.8) 18%
19.9 (11.6) 71%
12.4 (9.7) 22%
21.2 (12.9) 45%
15.1 (11.8) 20%
0 (0–23)
0 (0–30)
10 (0–30)
0 (0–30)
2 (0–30)
0 (0–30)
0 (0–3)
0 (0–6.7)
1 (0–5)
0 (0–3.3)
1 (0–5)
0 (0–6.7)
14.1 (0.9)
18.1 (1.7)
14.4 (.9)
18.2 (1.9)
14.2 (.9)
18.1 (1.7)
5.5 (0–20)
4 (0–28)
3 (0–20)
6 (0–25)
4 (0–20)
5 (0–28)
3 (0–30)
0 (0–30)
1 (0–30)
0 (0–30)
3 (0–30)
0 (0–30)
2 (0–6)
0 (0–6)
3 (0–5)
0 (0–6)
2 (0–6)
0 (0–6)
N.B. ‘Cannabis status’: percentage of cannabis users who reported having used cannabis weekly, or more often, in the past six months. ‘Cannabis frequency’, ‘Alcohol frequency’, and ‘Tobacco frequency’: number of days used in the past month. ‘Cannabis quantity’: quantity of cannabis used per typical day of use in the past month (measured in Standard Cannabis Units [SCUs]). ‘Other drug use’: total number of types of different illicit drugs ever used, excluding cannabis. For each of the schizotypy dimensions (unusual experiences, introvertive anhedonia, cognitive disorganisation and impulsive nonconformity), ‘max’ refers to the number of items on that subscale of the OLIFE, and hence the maximum possible score for that dimension. a Indicates a significant difference between onset groups (P < 0.05). b Indicates a significant difference between sexes (P < 0.05).
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
4
Fig. 1. Schizotypy scores (mean and SEM). Early onset refers to the onset of cannabis use before the age of 16. *: denotes a significant difference between early and later onset groups (P < 0.05).
228 229 230 231 232 233 234 235 236 237 238 239 240 241 242
With regard to the regression model using cognitive disorganisation as the dependent variable, higher levels of cognitive disorganisation were associated with higher unusual experiences (Beta = 0.31, P = 0.001), introvertive anhedonia (Beta = 0.25, P = 0.001), and psychological distress (Beta = 0.20, P = 0.017). In contrast, lower cognitive disorganisation was associated with greater tobacco use (Beta = 0.16, P = 0.023). There was a trend toward greater cannabis use quantity being associated with greater cognitive disorganisation (Beta = .16, P = 0.071) and an interaction between early onset cannabis use and gender (Beta = 0.18, p = 0.073). Finally, higher impulsive nonconformity was associated with higher unusual experiences (Beta = 0.38, P < 0.001), greater drug use (Beta = 0.21, P = 0.011), and younger age (Beta = 0.17, P = 0.010).
243
4. Discussion
244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266
The current study found that females who started using cannabis early (i.e., before the age of 16) had higher levels of introvertive anhedonia (negative schizotypy) than females who started using cannabis later in adolescence. Early use of cannabis was not found to be associated with introvertive anhedonia in males. Further, cognitive disorganisation showed two trend-level associations related to cannabis use: Greater quantity of cannabis use was associated with higher levels of cognitive disorganisation, and gender interacted with early onset cannabis use. A final finding worth special mention was early onset users being more likely to have a positive family history of schizophrenia. The finding of greater negative schizotypy among female early onset cannabis users could be interpreted as females being more susceptible to the disruptive effects of cannabis on neurodevelopmental processes, and thereby, possibly, psychosis-related risk. Support for this interpretation comes from animal research showing that females may be more susceptible than males to the effects of adolescent cannabinoid exposure on frontal brain changes. For instance, in studies comparing males and females, adolescent cannabinoid exposure is shown to cause long-term reductions in prefrontal CB1 receptors and increases in D1 receptors only in female rats [32]. In another study, following repeated THC administration, female adolescent rats showed
relatively greater desensitization of cannabinoid receptors in frontal areas compared to older females and males (both adolescent and adult) [33]. There is some evidence from human studies also suggesting that females may be more susceptible than males to the effects of cannabis use on negative emotionality, psychosis onset, cognitive impairment, and/or related brain functioning and structures [17– 19,34]. For example, a recent study [34] found that female cannabis users showed reduced frontal brain metabolism compared to healthy female controls, a difference which was not seen in males. Importantly, frontal metabolism correlated with negative emotionality, particularly reduced social closeness (i.e., alienation), a construct closely related to negative schizotypy. The current study extends these findings by showing that it is females who start using cannabis before the age of 16 years specifically that might be most susceptible. Together, the current study and the abovementioned animal and human findings support the possibility that females, by virtue of being more susceptible to neurodevelopmental disruption by cannabinoids, may be more likely than males to show long-term consequences of early onset cannabis use. An alternative interpretation is that higher negative schizotypy increases risk of early onset cannabis use in females only. This interpretation would need to be reconciled with studies showing that it is typically enhanced reward sensitivity that is linked to early onset substance use [35,36], but it might be that multiple — and possibly gender-specific — processes may contribute to early onset use. Nonetheless, such an interpretation would have important implications for prevention and early intervention programs. Regardless of interpretation (i.e., direction of the causal relationship between cannabis use and negative schizotypy), the current findings highlight negative schizotypy as an important dimension to consider in relation to early onset cannabis use and psychosis risk. That is, even under the ‘reversed’ interpretation wherein negative schizotypy leads to cannabis use, negative schizotypy could be considered as a mediator of psychosis risk through increasing the risk of exposure to cannabis during a sensitive neurodevelopmental period. Importantly, future research examining how cannabis use may be linked to psychosis risk will benefit from an approach that considers all dimensions of schizotypy, rather than focusing primarily or exclusively on
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx Table 2 Regression results.
Table 3 Follow-up regression results for females and males.
Dependent variable: unusual experiences
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Introvertive anhedonia Cognitive disorganisation Impulsive nonconformity
Beta
P
0.01 0.03 0.05 0.23 0.20 0.07 0.11 0.08 0.12 0.04 0.14 0.07 0.30 0.33
0.895 0.759 0.435 0.003 0.012 0.273 0.120 0.301 0.180 0.550 0.155 0.379 0.000 0.000
Beta
P
0.03 0.28 0.13 0.33 0.17 0.07 0.10 0.13 0.07 0.03 0.23 0.08 0.30 0.12
0.695 0.008 0.068 0.000 0.051 0.282 0.205 0.160 0.451 0.713 0.030 0.379 0.001 0.159
Beta
P
0.08 0.01 0.03 0.20 0.13 0.11 0.16 0.07 0.16 0.01 0.18 0.31 0.25 0.11
0.231 .929 0.626 0.015 0.101 0.092 0.023 0.431 0.071 0.891 0.073 0.000 0.001 0.159
Beta
P
0.17 0.08 0.07 0.11 0.21 0.09 0.08 0.06 0.03 0.01 0.06 0.38 0.11 0.12
0.010 0.420 0.290 0.218 0.011 0.159 .311 0.500 0.726 0.942 0.557 0.000 0.159 0.159
Dependent variable: introvertive anhedonia
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Unusual experiences Cognitive disorganisation Impulsive nonconformity Dependent variable: cognitive disorganisation
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Unusual experiences Introvertive anhedonia Impulsive nonconformity Dependent variable: impulsive nonconformity
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Unusual experiences Introvertive anhedonia Cognitive disorganisation
308 309 310 311
5
positive schizotypy. Indeed, positive schizotypy was not found to be related significantly to cannabis use in the present study, once important confounders were considered. The fact that the association between positive schizotypy and cannabis use went
Females Age Family Hx DASS-21 Illicit drug use Before 16 Cognitive disorganisation Males Age Family Hx DASS-21 Illicit drug use Before 16 Cognitive disorganisation
Q5
Beta
P
0.041 0.143 0.412 0.162 0.208 0.246
0.640 0.114 0.000 0.104 0.023 0.012
0.106 0.081 0.302 0.060 0.044 0.339
0.362 0.468 0.030 0.596 0.698 0.015
away once confounders were controlled for suggests that the commonly found relationship between cannabis use and positive schizotypy might be best explained as being driven by common related factors, such as family history of schizophrenia, stress, etc. Disorganised schizotypy was also found to be associated with various cannabis use variables, albeit at trend level. Given the exploratory nature of the current study, these trend-level findings will be given some consideration here. The finding that participants who use cannabis in greater quantities have higher levels of disorganised schizotypy highlights the importance of examining a range of cannabis use parameters in relation to psychosis risk, and not just those pertaining to frequency. The interaction between early onset use and gender is also interesting. Fig. 1 suggests that the interaction is driven by early onset cannabis use being associated with different levels of disorganised schizotypy only in males and not in females, with early onset males showing higher levels than later onset males. This differential expression of schizotypy dimensions in early onset cannabis users depending on gender, in the context of greater psychological distress, raises the possibility that early onset cannabis use is associated with enhanced stress sensitivity, which is then expressed differently in males and females. Specifically, psychological distress was significantly higher among both male and female early onset cannabis users compared to later onset users. Stress has been shown to have very different effects on males versus females; i.e., in females, acute stress reduces striatal activity whereas it enhances striatal activity in males [37]. Also, acute stress enhances risk-taking in men but reduces it in females [38]. Over time, this differential responding to stress, especially during a time that the brain is still developing, might be expected to result in very different brain changes and corresponding psychological profiles. Finally, early onset cannabis use was associated with a positive family history of schizophrenia. This finding extends past research showing that psychosis-related genetic risk is associated with cannabis use [39] by implicating the involvement of early use specifically. This is a very meaningful extension as it highlights a potential pathway by which genes could mediate further psychosis risk through exposure to environmental factors at critical neurodevelopmental time-points. The current study has a number of limitations. The first is the relatively lower numbers of males (n = 17) compared to females (n = 30) in the early onset groupings. It should be noted however that this split was chosen to make it easier to represent the findings visually. All the current results obtained using the early onset split are replicated (at least at trend level) when age of first use (continuous, from 15 to 24) is used. This applies both to the findings in relation to introvertive anhedonia and cognitive disorganisation, and related follow-up analyses.
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
Q6
312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
6
361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394
A second limitation of the current study is that it is crosssectional and thus cannot determine the directionality of the association between cannabis use and schizotypy. Longitudinal studies are needed to better understand how gender and cannabis use are related to schizotypy over time. A further limitation is that all alcohol and drug use data was based on self-report, which is potentially subject to bias and random error. However, previous studies have found self-reported alcohol and other drug use to be valid measures [40,41]. Finally, due to the nature of study methodology (e.g., recruitment strategy, internet access requirements, etc.), the current study sample may not be representative of the population of cannabis users (aged 14–24) in Australia. Comparison of the current sample with national survey data (e.g., the National Drug Strategy Household Survey; AIHW, 2014) suggests some similarities and differences. For instance, age of first cannabis use appears similar across the samples (current sample = 17.1 years, NDSHS sample = 16.7 years). In contrast, while in the NDSHS data males appear to have a greater lifetime prevalence of cannabis use than females (38.7% vs 30.9%), the current sample shows comparable rates between males and females (50.4% vs 49.7%), both considerably higher than national rates. Thus, the overall study sample over-represents cannabis users, females particularly, which in turn limits to the generalisability of study findings. In conclusion, the current study found females who started using cannabis before the age of 16 displayed higher levels of negative schizotypy than females who started using cannabis later in adolescence, whereas early onset use was not associated with negative schizotypy in males. The opposite appeared to be the case for disorganised schizotypy, with male early onset cannabis users showing higher disorganised schizotypy than later onset cannabis users, whereas early onset use was not associated with disorganised schizotypy among females. These findings highlight gender as an important factor in influencing risk.
395
Disclosure of interest
The authors have not supplied their declaration of competing 396 Q4 397 interest.
[11]
[12]
[13] [14]
[15]
[16]
[17]
[18]
[19]
[20] [21]
[22]
[23]
[24]
[25]
398
References
[26]
399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429
[1] AIHW. National Drug Strategy Household Survey detailed report: 2013; 2014. [2] Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: Longitudinal prospective study. Bmj 2002;325(7374):1212–3. [3] Di Forti M, Marconi A, Carra E, Fraietta S, Trotta A, Bonomo M, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatr 2015;2(3):233– 8. [4] Ehrenreich H, Rinn T, Kunert HJ, Moeller MR, Poser W, Schilling L, et al. Specific attentional dysfunction in adults following early start of cannabis use. Psychopharmacology 1999;142(3):295–301. http://dx.doi.org/10.1007/s002130050892. [5] Henquet C, Krabbendam, Spauwen J, Kaplan C, Lieb R, Wittchen H, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. Bmj 2004;330(7481):11. http:// dx.doi.org/10.1136/bmj.38267.664086.63. [6] Schneider M, Koch M. Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology 2003;28(10):1760–9. http://dx.doi.org/10.1038/sj.npp.1300225. [7] Silins E, Horwood LJ, Patton GC, Fergusson DM, Olsson CA, Hutchinson DM, et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatr 2014;1(4):286–93. [8] Ellgren M, Artmann A, Tkalych O, Gupta A, Hansen HS, Hansen S, et al. Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects. Eur Neuropsychopharmacol 2008;18(11):826– 34. [9] Ferna´ndez-ruiz J, Go´mez M, Herna´ndez M, Miguel R, Ramos J. Cannabinoids and gene expression during brain development. Neurotox Res 2004;6(5):389– 401. http://dx.doi.org/10.1007/BF03033314. [10] Viveros M, Llorente R, Suarez J, Llorente-Berzal A, Lo´pez-Gallardo M, Rodriguez de Fonseca F. The endocannabinoid system in critical neurodevelopmental
[27] [28]
[29] [30]
[31]
[32]
[33]
[34]
[35]
periods: sex differences and neuropsychiatric implications. J Psychopharmacol 2012;26(1):164–76. http://dx.doi.org/10.1177/0269881111408956. Bossong MG, Niesink RJM. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol 2010;92(3):370–85. http://dx.doi.org/10.1016/j.pneurobio.2010.06.010. Barrantes-Vidal N, Grant P, Kwapil TR. The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders. Schizophr Bull 2015;41:S408–16. http://dx.doi.org/10.1093/schbul/sbu191. Mason O, Linney Y, Claridge G. Short scales for measuring schizotypy. Schizophr Res 2005;78(2–3):293–6. http://dx.doi.org/10.1016/j.schres.2005.06.020. Nelson MT, Seal ML, Pantelis C, Phillips LJ. Evidence of a dimensional relationship between schizotypy and schizophrenia: a systematic review. Neurosci Biobehav Rev 2013;37(3):317–27. http://dx.doi.org/10.1016/j.neubiorev.2013.01.004. Szoke A, Galliot A-M, Richard J-R, Ferchiou A, Baudin G, Leboyer M, et al. Association between cannabis use and schizotypal dimensions–a meta-analysis of cross-sectional studies. Psychiatr Res 2014. Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 2004;99(10):1333–41. http://dx.doi.org/10.1111/j.13600443.2004.00806.x. Albertella L, Le Pelley ME, Copeland J. Frequent cannabis use is associated with reduced negative priming among females. Exp Clin Psychopharmacol 2016;24(5):313–9. Allegri F, Murri MB, Paparelli A, Marcacci T, Braca M, Menchetti M, et al. Current cannabis use and age of psychosis onset: a gender-mediated relationship. Results from an 8-year FEP incidence study in Bologna. Psychiatry Res 2013;210(1):368–70. Medina KL, McQueeny T, Nagel BJ, Hanson KL, Yang TT, Tapert SF. IMAGING STUDY: Prefrontal cortex morphometry in abstinent adolescent marijuana users: subtle gender effects. Addict Biol 2009;14(4):457–68. http://dx.doi.org/ 10.1111/j.1369-1600.2009.00166.x. Rubino T, Parolaro D. Sex-dependent vulnerability to cannabis abuse in adolescence. Front Psychiatr 2015;6. Norberg MM, Mackenzie J, Copeland J. Quantifying cannabis use with the Timeline Followback approach: a psychometric evaluation. Drug Alcohol Depend 2012;121(3):247–52. http://dx.doi.org/10.1016/j.drugalcdep.2011.09.007. Albertella L, Norberg MM. Mental health symptoms and their relationship to cannabis use in adolescents attending residential treatment. J Psychoactive Drugs 2012;44(5):381–9. Swift W, Coffey C, Carlin JB, Degenhardt L, Patton GC. Adolescent cannabis users at 24 years: trajectories to regular weekly use and dependence in young adulthood. Addiction 2008;103(8):1361–70. http://dx.doi.org/10.1111/ j.1360-0443.2008.02246.x. Lawrinson P, Copeland J, Indig D. Development and validation of a brief instrument for routine outcome monitoring in opioid maintenance pharmacotherapy services: The Brief Treatment Outcome Measure (BTOM). Drug Alcohol Depend 2005;80(1):125–33. http://dx.doi.org/10.1016/j.drugalcdep.2005.04.001. Mason O, Claridge G, Jackson M. New scales for the assessment of schizotypy. Personality and Individual differences 1995;18(1):7–13. Lovibond SH, Lovibond PF. Manual for the Depression Anxiety Stress Scales. Sydney: Psychology Foundation; 1995 [2nd. Ed.]. Albertella L, Le Pelley ME, Copeland J. Cannabis use, schizotypy, and negative priming. Psychiatry research 2015;228(3):404–10. Calkins ME, Curtis CE, Grove WM, Iacono WG. Multiple dimensions of schizotypy in first degree biological relatives of schizophrenia patients. Schizophr Bull 2004;30(2):317–25. Nunn JA, Rizza F, Peters ER. The incidence of schizotypy among cannabis and alcohol users. J Nerv Ment Dis 2001;189(11):741–8. Tarbox SI, Pogue-Geile MF. A multivariate perspective on schizotypy and familial association with schizophrenia: a review. Clin Psychol Rev 2011;31(7):1169–82. Williams JH, Wellman NA, Allan LM, Taylor E, Tonin J, Feldon J, et al. Tobacco smoking correlates with schizotypal and borderline personality traits. Personality and Individual differences 1996;20(2):267–70. http://dx.doi.org/ 10.1016/0191-8869(95)00179-4. Zamberletti E, Prini P, Speziali S, Gabaglio M, Solinas M, Parolaro D, et al. Gender-dependent behavioral and biochemical effects of adolescent delta-9tetrahydrocannabinol in adult maternally deprived rats. Neuroscience 2012;204:245–57. http://dx.doi.org/10.1016/j.neuroscience.2011.11.038. Burston JJ, Wiley JL, Craig AA, Selley DE, Sim-Selley LJ. Regional enhancement of cannabinoid CB1 receptor desensitization in female adolescent rats following repeated D9-tetrahydrocannabinol exposure. Br J Pharmacol 2010;161(1):103–12. Wiers CE, Shokri-Kojori E, Wong CT, Abi-Dargham A, Demiral SB, Tomasi D, et al. Cannabis Abusers show hypofrontality and blunted brain responses to a stimulant challenge in females but not in males. Neuropsychopharmacology 2016;41(10):2596–605. http://dx.doi.org/10.1038/npp.2016.67. Urosˇevic´ S, Collins P, Muetzel R, Schissel A, Lim KO, Luciana M. Effects of reward sensitivity and regional brain volumes on substance use initiation in adolescence. Soc Cogn Affect Neurosci 2015;10(1):106–13. http://dx.doi.org/ 10.1093/scan/nsu022.
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
515 516 517 518 519 520 521 522 523 524
[36] van Hemel-Ruiter ME, de Jong PJ, Ostafin BD, Oldehinkel AJ. Reward-related attentional bias and adolescent substance use: a prognostic relationship? PLoS ONE 2015;10(3):e0121058. http://dx.doi.org/10.1371/journal.pone.0121058. [37] Lighthall NR, Sakaki M, Vasunilashorn S, Nga L, Somayajula S, Chen EY, Mather M. Gender differences in reward-related decision processing under stress. Soc Cogn Affect Neurosci 2012;7(4):476–84. http://dx.doi.org/10.1093/scan/ nsr026. [38] Lighthall NR, Mather M, Gorlick MA. Acute stress increases sex differences in risk seeking in the balloon analogue risk task. PLoS ONE 2009;4(7):e6002.
7
[39] Power RA, Verweij KJH, Zuhair M, Montgomery GW, Henders AK, Heath ACNG. Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol Psychiatry 2014. http://dx.doi.org/10.1038/mp.2014.51. [40] Hesselbrock M, Babor TF, Hesselbrock V, Meyer RE, Workman K. Never believe an alcoholic’’? On the validity of self-report measures of alcohol dependence and related constructs. Int J Addictions 1983;18(5):593–609. http:// dx.doi.org/10.3109/10826088309027359. [41] Martin G, Copeland J, Swift W. The Adolescent Cannabis Check-Up: Feasibility of a brief intervention for young cannabis users. J Subst Abuse Treat 2005;29(3):207–13. http://dx.doi.org/10.1016/j.jsat.2005.06.005.
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
525 526 527 528 529 530 531 532 533 534
EURPSY 3561 1–7 European Psychiatry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
European Psychiatry journal homepage: http://www.europsy-journal.com 1 2 3 4
Original article
Cannabis use in early adolescence is associated with higher negative schizotypy in females Albertella a,b,d,*, M.E. Le Pelley a, J. Copeland c,d
5
Q1 L.
6 7 8 9 10
Q2 a School of Psychology, UNSW Sydney, Sydney, Australia b
Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton,
Q3 VIC, Australia c d
Cannabis Information and Support, Sydney, Australia National Cannabis Prevention and Information Centre, UNSW Sydney, Sydney, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 May 2017 Received in revised form 17 July 2017 Accepted 18 July 2017 Available online xxx
The current study examined the relationship between early onset cannabis use (before age 16) and different schizotypy dimensions, and whether gender moderates these associations. Participants were 162 cannabis users, aged 15–24 years, who completed an online assessment examining alcohol and other drug use, psychological distress, and schizotypy. Participants were divided according to whether or not they had started using cannabis before the age of 16 (early onset = 47; later onset = 115) and gender (males = 66; females = 96). The interaction between gender and onset group was significantly associated with the dimension of introvertive anhedonia. Follow-up analyses showed that early onset cannabis use was associated with higher levels of introvertive anhedonia in females only. The current findings suggest that gender is an important moderator in the association between early onset cannabis use, schizotypy, and possibly, psychosis risk.
C 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Marijuana Introvertive anhedonia Gender Sex Psychosis
11 12
1. Introduction
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
A considerable proportion of adolescents have used cannabis recently. For instance, in Australia, up to 15% of adolescents (aged 14–19) have used cannabis in the past year, of which 30% are using it at least weekly [1]. These data are of concern in the context of animal and human research suggesting that adolescent exposure to cannabis is associated with risk of poorer psychosocial consequences, psychosis-related outcomes, and cognitive impairment [2–7]. Research showing that adolescent cannabis use is associated with a range of negative consequences, coupled with research implicating the endocannabinoid system in the regulation of neurodevelopmental processes [8,9], suggests that cannabis use in adolescence may disrupt neurodevelopmental processes and result in brain changes resembling those associated with psychosis risk [10], or even psychosis itself [11]. The growing recognition of psychosis symptoms and disorders as dimensional in nature (as opposed to categorical, for diagnostic purposes) has seen a growing interest in the examination of
* Corresponding author. Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, VIC, Australia. E-mail address: [email protected] (L. Albertella).
schizotypy to inform psychosis research [12]. Schizotypy refers to a collection of personality traits, including those relating to the positive symptoms of psychosis (known as positive schizotypy, and including unusual perceptions and magical thinking), those relating to disorganised thought symptoms (disorganised schizotypy), and those relating to negative symptoms (negative schizotypy, e.g., anhedonia and avolition) [13], which are considered related to psychosis risk [14]. Indeed, a large number of studies have now linked cannabis use to schizotypy, with the strongest association being with positive schizotypy [15]. Unfortunately, despite research indicating that age of first cannabis use is an important factor in determining the extent to which exposure to cannabis increases psychosis risk (e.g., [2,3]), very few studies have examined age of cannabis use onset in relation to schizotypy. One study [16] that has examined age of use onset in relation to schizotypy dimensions found that frequent use of cannabis was associated with both higher positive and negative schizotypy, and that this effect was much larger among users who had started using cannabis in early adolescence. A further limitation of current studies examining the relationship between cannabis use and different schizotypy dimensions is the failure to include a number of important moderating and/or confounding variables that may impact the relationships. For instance, research suggests that sex may be an important
http://dx.doi.org/10.1016/j.eurpsy.2017.07.009 C 2017 Elsevier Masson SAS. All rights reserved. 0924-9338/
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53
G Model
EURPSY 3561 1–7 2
L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
moderator of the effects of cannabinoid exposure on psychosisrelated behaviour, cognitive impairments, and brain changes [17– 20]. Sex, however, has largely been ignored in research examining the relationship between cannabis use and schizotypy. Another example is the lack of consideration of various cannabis use parameters. Most studies simply compare current use with never use, without regard to other important variables such as quantity of cannabis use. Research shows that quantity is an important predictor of cannabis use problems, i.e., independently of frequency [21], and further, has been associated with a number of psychosis-related symptoms in cannabis-using adolescents attending treatment [22]. The current study aims to address these gaps in the literature, by investigating: (1) whether early onset cannabis use is associated with different schizotypy dimensions; (2) whether sex moderates the association between early onset cannabis use and schizotypy; and (3) various cannabis use parameters in relation to different schizotypy dimensions.
72
2. Materials and methods
73
2.1. Participants
74 75 76 77 78 79 80 81 82 83 84
Participants were 162 young people who reported having ever used cannabis and had complete study data. These participants were part of a longitudinal study, in which the overall sample at baseline was 324 (or 327, if including 3 participants with missing data, none of which were cannabis users). Participants were recruited Australia-wide, via advertisements placed on websites, local newspapers, community notice boards, and update lists. Inclusion criteria included being aged between 14 and 24 years and fluent in English. Exclusion criteria included having a past head injury, history of neurological disorders, and having ever received a diagnosis of schizophrenia or schizoaffective disorder.
85
2.2. Procedure
86 87 88 89 90 91 92 93 94 95 96
The study was conducted via the Internet with all measures implemented using Inquisit Millisecond Software Web version 4.0.2. Eligible participants who consented to take part were emailed a link to the study assessment. Within two weeks of having completed the assessment, participants were emailed a $20 electronics store voucher. Parental consent was not obtained for participants under 16, since this requirement may have rendered the study less accessible to drug-using adolescents, thus reducing the generalisability and/or validity of the data. This and all other aspects of the study were approved by the UNSW Sydney Human Research Ethics Committee.
97
2.3. Measures
98 99 100 101 102 103 104 105 106 107 108 109 110 111 112
2.3.1. Demographic & substance use information. The baseline assessment covered demographic information including sex, age, education, and family history of psychosisrelated disorders. The questionnaire also asked about lifetime and current tobacco, alcohol, and illicit drug use. Participants who reported having ever used any drug were asked what age they first used it, followed by whether they had used it in the past six months. If they had used it in the past six months, they were asked about the extent to which they had used it; i.e. less than once a month, about once a month, once a week or more, or daily. This information was used to categorize participants who had ever used cannabis into two groups. One group included participants who had used cannabis but had used it less than weekly (including not at all) in the past six months (occasional users), while the second group included participants who used cannabis once a week or
more often in the past six months (frequent users). Such a grouping for frequent cannabis use has been used in previous studies, across the same timeframe (6 months), and found to be associated with a number of negative outcomes (e.g., [23]). Further questions included items from the Brief Treatment Outcome Measure (BTOM; [24]). For cannabis use, age of first use was also obtained. This information was used to split participants into two groups, those who used cannabis before the age of 16, and those who used it for the first time after 16. This split is commonly used and associated with psychosis risk and a range of other negative outcomes (e.g., [2]).
113 114 115 116 117 118 119 120 121 122 123
2.3.2. Schizotypy To measure schizotypy, we used the short form of the OxfordLiverpool Inventory of Feeling and Experiences (OLIFE; [25]), which comprises four subscales: unusual experiences, introvertive anhedonia, cognitive disorganisation, and impulsive non-conformity. The unusual experiences scale measures odd perceptual and cognitive experiences related to the positive symptoms of schizophrenia (e.g., ‘‘Have you ever thought that you had special, almost magical powers?’’). This scale is often referred to as positive schizotypy. The introvertive anhedonia scale assesses the inability to experience pleasure and other experiences related to the negative symptoms of schizophrenia (e.g., ‘‘Do you like mixing with people?’’), and this scale is often referred to as negative schizotypy. Cognitive disorganisation items relate to disorganised thought/speech and distractibility (e.g., ‘‘Are you easily distracted when you read or talk to someone?’’). Finally, impulsive nonconformity items relate to impulsivity and emotional instability (e.g., ‘‘Do you often feel the impulse to spend too much money which you know you can’t afford?’’).
124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142
2.3.3. Psychological distress Participants completed the brief Depression Anxiety Stress Scales (DASS-21; [26]). The DASS-21 contains 21 items assessing depression, anxiety, and stress/tension symptoms. Total score was used to control for psychological distress, as opposed to the three subscales separately, due to high correlations among the latter.
143 144 145 146 147 148
2.4. Analyses
149
Independent samples t-tests examined differences between early onset users (those who reported first use before the age of 16) and later onset users (those who reported first use at age 16 years or over), as well as gender, on normally distributed variables. Mann-Whitney U tests were used to examine differences on nonnormally distributed variables, which included tobacco, alcohol, and other drug use. Chi2 tests examined differences between groups on gender, and family history of schizophrenia. Four multiple regressions were run, one for each schizotypy dimension (Unusual experiences, introvertive anhedonia, cognitive disorganization, and impulsive nonconformity). Within each model, the following variables were entered as predictors/ covariates: age, gender, family history of schizophrenia, alcohol, tobacco, illicit drug use, psychological distress, various cannabis use parameters (frequent use in the past 6 months, quantity of use, and onset before 16 years), as well as non-dependent schizotypy dimensions. These variables were selected due to study aims and/or research showing their influence on schizotypy or related variables [22,27–31]. The interaction between gender and early use onset was examined using mean-centered values to avoid multicollinearity. A significant interaction was followed up by conducting linear regressions split by gender, with early onset use in the model along with any other variable that was P < .1 in the overall regression.
150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
175
3. Results
176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200
Participants were 162 young adults, with a mean age of 20.4 years (SD = 2.4) and 59% female. Participants in this present sample did not differ significantly in age, t(322) = 1.67, P = 0.096, or sex, x2 = 0.01, P = 0.910, from participants in the overall sample (i.e., the remainder of the sample who had never used cannabis). Table 1 shows the descriptive statistics of the sample and compares early onset vs later onset users. Early onset users were significantly younger than later onset users, t(160) = 2.5, P = 0.014, and more likely to have a family history of schizophrenia, x2 = 5.8, P = .016. They were also more likely to be frequent cannabis users, x2 = 10.3, P = 0.001, to use tobacco more frequently, Z = 3.3, P = 0.001, to have used more illicit drugs, Z = 3.5, P = 0.001, and to be more psychologically distressed than later onset users, t(160) = 2.9, P = 0.004. Finally, early onset users had higher scores on unusual experiences, t(160) = 2.5, P = 0.014, introvertive anhedonia, t(160) = 2.1, P = 0.038, and impulsive nonconformity, t(160) = 2.2, P = 0.027. Fig. 1 presents the means and SEMs of each schizotypy dimension as a function of gender and early use. Table 2 presents the results from the regression models. For the model with unusual experiences as the dependent variable, the total variance explained by the model was 49.9%, F (14, 147) = 10.5, P < 0.001. For introvertive anhedonia, the total variance explained by the model was 39.1%, F (14, 147) = 6.7, P < 0.001. For cognitive disorganisation, the total variance explained by the model was 47.9%, F (14, 147) = 9.7, P < 0.001. For impulsive nonconformity,
3
the total variance explained by the model was 43.0%, F (14, 147) = 7.9, P < 0.001. Scores on the unusual experiences scale were positively associated with cognitive disorganisation (Beta = 0.30, P < 0.001), impulsive nonconformity (Beta = 0.33, P < 0.001), and psychological distress (Beta = 0.23, P = 0.003). A greater number of illicit drugs ever used was associated with lower unusual experiences (Beta = 0.20, P = 0.012). Greater scores on the introvertive anhedonia scale were associated with higher levels of cognitive disorganisation (BeBeta = .30, P = .001) and greater psychological distress (Beta = .33, P < .001). Importantly, early onset cannabis use interacted with sex to predict introvertive anhedonia (Beta = 0.23, P = .029). Table 3 presents the results of the follow-up linear regression conducted separately on males and females in order to investigate this interaction further. Both models were significant overall (Ps < 0.001). In males, psychological distress (Beta = .30, P = .030) and cognitive disorganisation (Beta = .34, P = 0.015) were associated with higher introvertive anhedonia, but early use was not (P = 0.698). In contrast, higher levels of introvertive anhedonia in females were associated with cognitive disorganisation (Beta = 0.25, P = 0.012), psychological distress (BeBeta = 0.41, P < 0.001), and early onset use (Beta = 0.21, P = 0.023). Specifically, females who started using cannabis before the age of 16 showed significantly higher levels of introvertive anhedonia than females who started using cannabis after turning 16.
Table 1 Sample descriptive statistics. Cannabis onset group Female (n = 96) Age of onset Agea n Mean (SD) Family Hxa/% Unusual experiencesa [max = 12] Mean (SD) Introvertive anhedoniaa [max = 10] Mean (SD) Cognitive disorganisation [max = 11] Mean (SD) Impulsive nonconformitya [max = 10] Mean (SD) DASS-21 totala,b Mean (SD) Cannabis statusa/% Cannabis frequencya,b Median (Range) Cannabis quantity (SCUs)a,b Median (Range) Age of first cannabis usea Mean (S.D) Alcohol frequency Median (Range) Tobacco frequencya Median (Range) Other drug usea Median (Range)
Male (n = 66)
Overall (n = 162)
Before 16
16 & over
Before 16
16 & over
Before 16
16 & over
30 20.0 (2.7) 27%
66 20.8 (2.1) 11%
17 19.2 (2.4) 12%
49 20.6 (2.3) 4%
47 19.7 (2.6) 21.3%
115 20.7 (2.2) 7.8%
5.5 (3.0)
4.7 (2.8)
6.4 (3.8)
4.3 (3.0)
5.8 (3.3)
4.5 (2.8)
3.5 (1.9)
2.8 (1.7)
2.5 (1.6)
2.2 (1.6)
3.2 (1.8)
2.5 (1.7)
7.7 (2.6)
7.8 (2.6)
7.8 (2.4)
6.3 (3.1)
7.7 (2.5)
7.2 (2.9)
5.7 (2.3)
4.8 (2.2)
5.5 (2.1)
4.8 (2.2)
5.6 (2.2)
4.8 (2.1)
21.9 (13.7) 30%
17.1 (12.8) 18%
19.9 (11.6) 71%
12.4 (9.7) 22%
21.2 (12.9) 45%
15.1 (11.8) 20%
0 (0–23)
0 (0–30)
10 (0–30)
0 (0–30)
2 (0–30)
0 (0–30)
0 (0–3)
0 (0–6.7)
1 (0–5)
0 (0–3.3)
1 (0–5)
0 (0–6.7)
14.1 (0.9)
18.1 (1.7)
14.4 (.9)
18.2 (1.9)
14.2 (.9)
18.1 (1.7)
5.5 (0–20)
4 (0–28)
3 (0–20)
6 (0–25)
4 (0–20)
5 (0–28)
3 (0–30)
0 (0–30)
1 (0–30)
0 (0–30)
3 (0–30)
0 (0–30)
2 (0–6)
0 (0–6)
3 (0–5)
0 (0–6)
2 (0–6)
0 (0–6)
N.B. ‘Cannabis status’: percentage of cannabis users who reported having used cannabis weekly, or more often, in the past six months. ‘Cannabis frequency’, ‘Alcohol frequency’, and ‘Tobacco frequency’: number of days used in the past month. ‘Cannabis quantity’: quantity of cannabis used per typical day of use in the past month (measured in Standard Cannabis Units [SCUs]). ‘Other drug use’: total number of types of different illicit drugs ever used, excluding cannabis. For each of the schizotypy dimensions (unusual experiences, introvertive anhedonia, cognitive disorganisation and impulsive nonconformity), ‘max’ refers to the number of items on that subscale of the OLIFE, and hence the maximum possible score for that dimension. a Indicates a significant difference between onset groups (P < 0.05). b Indicates a significant difference between sexes (P < 0.05).
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
4
Fig. 1. Schizotypy scores (mean and SEM). Early onset refers to the onset of cannabis use before the age of 16. *: denotes a significant difference between early and later onset groups (P < 0.05).
228 229 230 231 232 233 234 235 236 237 238 239 240 241 242
With regard to the regression model using cognitive disorganisation as the dependent variable, higher levels of cognitive disorganisation were associated with higher unusual experiences (Beta = 0.31, P = 0.001), introvertive anhedonia (Beta = 0.25, P = 0.001), and psychological distress (Beta = 0.20, P = 0.017). In contrast, lower cognitive disorganisation was associated with greater tobacco use (Beta = 0.16, P = 0.023). There was a trend toward greater cannabis use quantity being associated with greater cognitive disorganisation (Beta = .16, P = 0.071) and an interaction between early onset cannabis use and gender (Beta = 0.18, p = 0.073). Finally, higher impulsive nonconformity was associated with higher unusual experiences (Beta = 0.38, P < 0.001), greater drug use (Beta = 0.21, P = 0.011), and younger age (Beta = 0.17, P = 0.010).
243
4. Discussion
244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266
The current study found that females who started using cannabis early (i.e., before the age of 16) had higher levels of introvertive anhedonia (negative schizotypy) than females who started using cannabis later in adolescence. Early use of cannabis was not found to be associated with introvertive anhedonia in males. Further, cognitive disorganisation showed two trend-level associations related to cannabis use: Greater quantity of cannabis use was associated with higher levels of cognitive disorganisation, and gender interacted with early onset cannabis use. A final finding worth special mention was early onset users being more likely to have a positive family history of schizophrenia. The finding of greater negative schizotypy among female early onset cannabis users could be interpreted as females being more susceptible to the disruptive effects of cannabis on neurodevelopmental processes, and thereby, possibly, psychosis-related risk. Support for this interpretation comes from animal research showing that females may be more susceptible than males to the effects of adolescent cannabinoid exposure on frontal brain changes. For instance, in studies comparing males and females, adolescent cannabinoid exposure is shown to cause long-term reductions in prefrontal CB1 receptors and increases in D1 receptors only in female rats [32]. In another study, following repeated THC administration, female adolescent rats showed
relatively greater desensitization of cannabinoid receptors in frontal areas compared to older females and males (both adolescent and adult) [33]. There is some evidence from human studies also suggesting that females may be more susceptible than males to the effects of cannabis use on negative emotionality, psychosis onset, cognitive impairment, and/or related brain functioning and structures [17– 19,34]. For example, a recent study [34] found that female cannabis users showed reduced frontal brain metabolism compared to healthy female controls, a difference which was not seen in males. Importantly, frontal metabolism correlated with negative emotionality, particularly reduced social closeness (i.e., alienation), a construct closely related to negative schizotypy. The current study extends these findings by showing that it is females who start using cannabis before the age of 16 years specifically that might be most susceptible. Together, the current study and the abovementioned animal and human findings support the possibility that females, by virtue of being more susceptible to neurodevelopmental disruption by cannabinoids, may be more likely than males to show long-term consequences of early onset cannabis use. An alternative interpretation is that higher negative schizotypy increases risk of early onset cannabis use in females only. This interpretation would need to be reconciled with studies showing that it is typically enhanced reward sensitivity that is linked to early onset substance use [35,36], but it might be that multiple — and possibly gender-specific — processes may contribute to early onset use. Nonetheless, such an interpretation would have important implications for prevention and early intervention programs. Regardless of interpretation (i.e., direction of the causal relationship between cannabis use and negative schizotypy), the current findings highlight negative schizotypy as an important dimension to consider in relation to early onset cannabis use and psychosis risk. That is, even under the ‘reversed’ interpretation wherein negative schizotypy leads to cannabis use, negative schizotypy could be considered as a mediator of psychosis risk through increasing the risk of exposure to cannabis during a sensitive neurodevelopmental period. Importantly, future research examining how cannabis use may be linked to psychosis risk will benefit from an approach that considers all dimensions of schizotypy, rather than focusing primarily or exclusively on
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx Table 2 Regression results.
Table 3 Follow-up regression results for females and males.
Dependent variable: unusual experiences
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Introvertive anhedonia Cognitive disorganisation Impulsive nonconformity
Beta
P
0.01 0.03 0.05 0.23 0.20 0.07 0.11 0.08 0.12 0.04 0.14 0.07 0.30 0.33
0.895 0.759 0.435 0.003 0.012 0.273 0.120 0.301 0.180 0.550 0.155 0.379 0.000 0.000
Beta
P
0.03 0.28 0.13 0.33 0.17 0.07 0.10 0.13 0.07 0.03 0.23 0.08 0.30 0.12
0.695 0.008 0.068 0.000 0.051 0.282 0.205 0.160 0.451 0.713 0.030 0.379 0.001 0.159
Beta
P
0.08 0.01 0.03 0.20 0.13 0.11 0.16 0.07 0.16 0.01 0.18 0.31 0.25 0.11
0.231 .929 0.626 0.015 0.101 0.092 0.023 0.431 0.071 0.891 0.073 0.000 0.001 0.159
Beta
P
0.17 0.08 0.07 0.11 0.21 0.09 0.08 0.06 0.03 0.01 0.06 0.38 0.11 0.12
0.010 0.420 0.290 0.218 0.011 0.159 .311 0.500 0.726 0.942 0.557 0.000 0.159 0.159
Dependent variable: introvertive anhedonia
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Unusual experiences Cognitive disorganisation Impulsive nonconformity Dependent variable: cognitive disorganisation
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Unusual experiences Introvertive anhedonia Impulsive nonconformity Dependent variable: impulsive nonconformity
Age Sex Family Hx DASS-21 Illicit drug use Alcohol use Tobacco use Frequent vs occasional cannabis use Quantity Before 16 Before 16 Sex Unusual experiences Introvertive anhedonia Cognitive disorganisation
308 309 310 311
5
positive schizotypy. Indeed, positive schizotypy was not found to be related significantly to cannabis use in the present study, once important confounders were considered. The fact that the association between positive schizotypy and cannabis use went
Females Age Family Hx DASS-21 Illicit drug use Before 16 Cognitive disorganisation Males Age Family Hx DASS-21 Illicit drug use Before 16 Cognitive disorganisation
Q5
Beta
P
0.041 0.143 0.412 0.162 0.208 0.246
0.640 0.114 0.000 0.104 0.023 0.012
0.106 0.081 0.302 0.060 0.044 0.339
0.362 0.468 0.030 0.596 0.698 0.015
away once confounders were controlled for suggests that the commonly found relationship between cannabis use and positive schizotypy might be best explained as being driven by common related factors, such as family history of schizophrenia, stress, etc. Disorganised schizotypy was also found to be associated with various cannabis use variables, albeit at trend level. Given the exploratory nature of the current study, these trend-level findings will be given some consideration here. The finding that participants who use cannabis in greater quantities have higher levels of disorganised schizotypy highlights the importance of examining a range of cannabis use parameters in relation to psychosis risk, and not just those pertaining to frequency. The interaction between early onset use and gender is also interesting. Fig. 1 suggests that the interaction is driven by early onset cannabis use being associated with different levels of disorganised schizotypy only in males and not in females, with early onset males showing higher levels than later onset males. This differential expression of schizotypy dimensions in early onset cannabis users depending on gender, in the context of greater psychological distress, raises the possibility that early onset cannabis use is associated with enhanced stress sensitivity, which is then expressed differently in males and females. Specifically, psychological distress was significantly higher among both male and female early onset cannabis users compared to later onset users. Stress has been shown to have very different effects on males versus females; i.e., in females, acute stress reduces striatal activity whereas it enhances striatal activity in males [37]. Also, acute stress enhances risk-taking in men but reduces it in females [38]. Over time, this differential responding to stress, especially during a time that the brain is still developing, might be expected to result in very different brain changes and corresponding psychological profiles. Finally, early onset cannabis use was associated with a positive family history of schizophrenia. This finding extends past research showing that psychosis-related genetic risk is associated with cannabis use [39] by implicating the involvement of early use specifically. This is a very meaningful extension as it highlights a potential pathway by which genes could mediate further psychosis risk through exposure to environmental factors at critical neurodevelopmental time-points. The current study has a number of limitations. The first is the relatively lower numbers of males (n = 17) compared to females (n = 30) in the early onset groupings. It should be noted however that this split was chosen to make it easier to represent the findings visually. All the current results obtained using the early onset split are replicated (at least at trend level) when age of first use (continuous, from 15 to 24) is used. This applies both to the findings in relation to introvertive anhedonia and cognitive disorganisation, and related follow-up analyses.
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
Q6
312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
6
361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394
A second limitation of the current study is that it is crosssectional and thus cannot determine the directionality of the association between cannabis use and schizotypy. Longitudinal studies are needed to better understand how gender and cannabis use are related to schizotypy over time. A further limitation is that all alcohol and drug use data was based on self-report, which is potentially subject to bias and random error. However, previous studies have found self-reported alcohol and other drug use to be valid measures [40,41]. Finally, due to the nature of study methodology (e.g., recruitment strategy, internet access requirements, etc.), the current study sample may not be representative of the population of cannabis users (aged 14–24) in Australia. Comparison of the current sample with national survey data (e.g., the National Drug Strategy Household Survey; AIHW, 2014) suggests some similarities and differences. For instance, age of first cannabis use appears similar across the samples (current sample = 17.1 years, NDSHS sample = 16.7 years). In contrast, while in the NDSHS data males appear to have a greater lifetime prevalence of cannabis use than females (38.7% vs 30.9%), the current sample shows comparable rates between males and females (50.4% vs 49.7%), both considerably higher than national rates. Thus, the overall study sample over-represents cannabis users, females particularly, which in turn limits to the generalisability of study findings. In conclusion, the current study found females who started using cannabis before the age of 16 displayed higher levels of negative schizotypy than females who started using cannabis later in adolescence, whereas early onset use was not associated with negative schizotypy in males. The opposite appeared to be the case for disorganised schizotypy, with male early onset cannabis users showing higher disorganised schizotypy than later onset cannabis users, whereas early onset use was not associated with disorganised schizotypy among females. These findings highlight gender as an important factor in influencing risk.
395
Disclosure of interest
The authors have not supplied their declaration of competing 396 Q4 397 interest.
[11]
[12]
[13] [14]
[15]
[16]
[17]
[18]
[19]
[20] [21]
[22]
[23]
[24]
[25]
398
References
[26]
399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429
[1] AIHW. National Drug Strategy Household Survey detailed report: 2013; 2014. [2] Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: Longitudinal prospective study. Bmj 2002;325(7374):1212–3. [3] Di Forti M, Marconi A, Carra E, Fraietta S, Trotta A, Bonomo M, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatr 2015;2(3):233– 8. [4] Ehrenreich H, Rinn T, Kunert HJ, Moeller MR, Poser W, Schilling L, et al. Specific attentional dysfunction in adults following early start of cannabis use. Psychopharmacology 1999;142(3):295–301. http://dx.doi.org/10.1007/s002130050892. [5] Henquet C, Krabbendam, Spauwen J, Kaplan C, Lieb R, Wittchen H, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. Bmj 2004;330(7481):11. http:// dx.doi.org/10.1136/bmj.38267.664086.63. [6] Schneider M, Koch M. Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology 2003;28(10):1760–9. http://dx.doi.org/10.1038/sj.npp.1300225. [7] Silins E, Horwood LJ, Patton GC, Fergusson DM, Olsson CA, Hutchinson DM, et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatr 2014;1(4):286–93. [8] Ellgren M, Artmann A, Tkalych O, Gupta A, Hansen HS, Hansen S, et al. Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects. Eur Neuropsychopharmacol 2008;18(11):826– 34. [9] Ferna´ndez-ruiz J, Go´mez M, Herna´ndez M, Miguel R, Ramos J. Cannabinoids and gene expression during brain development. Neurotox Res 2004;6(5):389– 401. http://dx.doi.org/10.1007/BF03033314. [10] Viveros M, Llorente R, Suarez J, Llorente-Berzal A, Lo´pez-Gallardo M, Rodriguez de Fonseca F. The endocannabinoid system in critical neurodevelopmental
[27] [28]
[29] [30]
[31]
[32]
[33]
[34]
[35]
periods: sex differences and neuropsychiatric implications. J Psychopharmacol 2012;26(1):164–76. http://dx.doi.org/10.1177/0269881111408956. Bossong MG, Niesink RJM. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol 2010;92(3):370–85. http://dx.doi.org/10.1016/j.pneurobio.2010.06.010. Barrantes-Vidal N, Grant P, Kwapil TR. The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders. Schizophr Bull 2015;41:S408–16. http://dx.doi.org/10.1093/schbul/sbu191. Mason O, Linney Y, Claridge G. Short scales for measuring schizotypy. Schizophr Res 2005;78(2–3):293–6. http://dx.doi.org/10.1016/j.schres.2005.06.020. Nelson MT, Seal ML, Pantelis C, Phillips LJ. Evidence of a dimensional relationship between schizotypy and schizophrenia: a systematic review. Neurosci Biobehav Rev 2013;37(3):317–27. http://dx.doi.org/10.1016/j.neubiorev.2013.01.004. Szoke A, Galliot A-M, Richard J-R, Ferchiou A, Baudin G, Leboyer M, et al. Association between cannabis use and schizotypal dimensions–a meta-analysis of cross-sectional studies. Psychiatr Res 2014. Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 2004;99(10):1333–41. http://dx.doi.org/10.1111/j.13600443.2004.00806.x. Albertella L, Le Pelley ME, Copeland J. Frequent cannabis use is associated with reduced negative priming among females. Exp Clin Psychopharmacol 2016;24(5):313–9. Allegri F, Murri MB, Paparelli A, Marcacci T, Braca M, Menchetti M, et al. Current cannabis use and age of psychosis onset: a gender-mediated relationship. Results from an 8-year FEP incidence study in Bologna. Psychiatry Res 2013;210(1):368–70. Medina KL, McQueeny T, Nagel BJ, Hanson KL, Yang TT, Tapert SF. IMAGING STUDY: Prefrontal cortex morphometry in abstinent adolescent marijuana users: subtle gender effects. Addict Biol 2009;14(4):457–68. http://dx.doi.org/ 10.1111/j.1369-1600.2009.00166.x. Rubino T, Parolaro D. Sex-dependent vulnerability to cannabis abuse in adolescence. Front Psychiatr 2015;6. Norberg MM, Mackenzie J, Copeland J. Quantifying cannabis use with the Timeline Followback approach: a psychometric evaluation. Drug Alcohol Depend 2012;121(3):247–52. http://dx.doi.org/10.1016/j.drugalcdep.2011.09.007. Albertella L, Norberg MM. Mental health symptoms and their relationship to cannabis use in adolescents attending residential treatment. J Psychoactive Drugs 2012;44(5):381–9. Swift W, Coffey C, Carlin JB, Degenhardt L, Patton GC. Adolescent cannabis users at 24 years: trajectories to regular weekly use and dependence in young adulthood. Addiction 2008;103(8):1361–70. http://dx.doi.org/10.1111/ j.1360-0443.2008.02246.x. Lawrinson P, Copeland J, Indig D. Development and validation of a brief instrument for routine outcome monitoring in opioid maintenance pharmacotherapy services: The Brief Treatment Outcome Measure (BTOM). Drug Alcohol Depend 2005;80(1):125–33. http://dx.doi.org/10.1016/j.drugalcdep.2005.04.001. Mason O, Claridge G, Jackson M. New scales for the assessment of schizotypy. Personality and Individual differences 1995;18(1):7–13. Lovibond SH, Lovibond PF. Manual for the Depression Anxiety Stress Scales. Sydney: Psychology Foundation; 1995 [2nd. Ed.]. Albertella L, Le Pelley ME, Copeland J. Cannabis use, schizotypy, and negative priming. Psychiatry research 2015;228(3):404–10. Calkins ME, Curtis CE, Grove WM, Iacono WG. Multiple dimensions of schizotypy in first degree biological relatives of schizophrenia patients. Schizophr Bull 2004;30(2):317–25. Nunn JA, Rizza F, Peters ER. The incidence of schizotypy among cannabis and alcohol users. J Nerv Ment Dis 2001;189(11):741–8. Tarbox SI, Pogue-Geile MF. A multivariate perspective on schizotypy and familial association with schizophrenia: a review. Clin Psychol Rev 2011;31(7):1169–82. Williams JH, Wellman NA, Allan LM, Taylor E, Tonin J, Feldon J, et al. Tobacco smoking correlates with schizotypal and borderline personality traits. Personality and Individual differences 1996;20(2):267–70. http://dx.doi.org/ 10.1016/0191-8869(95)00179-4. Zamberletti E, Prini P, Speziali S, Gabaglio M, Solinas M, Parolaro D, et al. Gender-dependent behavioral and biochemical effects of adolescent delta-9tetrahydrocannabinol in adult maternally deprived rats. Neuroscience 2012;204:245–57. http://dx.doi.org/10.1016/j.neuroscience.2011.11.038. Burston JJ, Wiley JL, Craig AA, Selley DE, Sim-Selley LJ. Regional enhancement of cannabinoid CB1 receptor desensitization in female adolescent rats following repeated D9-tetrahydrocannabinol exposure. Br J Pharmacol 2010;161(1):103–12. Wiers CE, Shokri-Kojori E, Wong CT, Abi-Dargham A, Demiral SB, Tomasi D, et al. Cannabis Abusers show hypofrontality and blunted brain responses to a stimulant challenge in females but not in males. Neuropsychopharmacology 2016;41(10):2596–605. http://dx.doi.org/10.1038/npp.2016.67. Urosˇevic´ S, Collins P, Muetzel R, Schissel A, Lim KO, Luciana M. Effects of reward sensitivity and regional brain volumes on substance use initiation in adolescence. Soc Cogn Affect Neurosci 2015;10(1):106–13. http://dx.doi.org/ 10.1093/scan/nsu022.
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514
G Model
EURPSY 3561 1–7 L. Albertella et al. / European Psychiatry xxx (2017) xxx–xxx
515 516 517 518 519 520 521 522 523 524
[36] van Hemel-Ruiter ME, de Jong PJ, Ostafin BD, Oldehinkel AJ. Reward-related attentional bias and adolescent substance use: a prognostic relationship? PLoS ONE 2015;10(3):e0121058. http://dx.doi.org/10.1371/journal.pone.0121058. [37] Lighthall NR, Sakaki M, Vasunilashorn S, Nga L, Somayajula S, Chen EY, Mather M. Gender differences in reward-related decision processing under stress. Soc Cogn Affect Neurosci 2012;7(4):476–84. http://dx.doi.org/10.1093/scan/ nsr026. [38] Lighthall NR, Mather M, Gorlick MA. Acute stress increases sex differences in risk seeking in the balloon analogue risk task. PLoS ONE 2009;4(7):e6002.
7
[39] Power RA, Verweij KJH, Zuhair M, Montgomery GW, Henders AK, Heath ACNG. Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol Psychiatry 2014. http://dx.doi.org/10.1038/mp.2014.51. [40] Hesselbrock M, Babor TF, Hesselbrock V, Meyer RE, Workman K. Never believe an alcoholic’’? On the validity of self-report measures of alcohol dependence and related constructs. Int J Addictions 1983;18(5):593–609. http:// dx.doi.org/10.3109/10826088309027359. [41] Martin G, Copeland J, Swift W. The Adolescent Cannabis Check-Up: Feasibility of a brief intervention for young cannabis users. J Subst Abuse Treat 2005;29(3):207–13. http://dx.doi.org/10.1016/j.jsat.2005.06.005.
Please cite this article in press as: Albertella L, et al. Cannabis use in early adolescence is associated with higher negative schizotypy in females. European Psychiatry (2017), http://dx.doi.org/10.1016/j.eurpsy.2017.07.009
525 526 527 528 529 530 531 532 533 534