Psychological Medicine (2013), 43, 12551267.

f Cambridge University Press 2012 O R I G I N A L AR T I C LE

doi:10.1017/S0033291712001924

Cannabis aects people dierently: inter-subject

variation in the psychotogenic eects of
D9-tetrahydrocannabinol: a functional magnetic
resonance imaging study with healthy volunteers

Z. Atakan1*, S. Bhattacharyya1, P. Allen1, R. Martn-Santos2, J. A. Crippa3, S. J. Borgwardt4,

P. Fusar-Poli1, M. Seal5, H. Sallis6, D. Stahl6, A. W. Zuardi3, K. Rubia7 and P. McGuire1
1
Section of Neuroimaging, Department of Psychosis Studies, Institute of Psychiatry, Kings College London, London, UK
2
Institut Municipal Investigacio Medica IMIM Hospital del Mar, Barcelona, Spain
3
Departamento de Neuropsiquiatria e Psicologia Medica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Brazil
4
Psychiatric Outpatient Department, University Hospital Basel, Basel, Switzerland
5
Murdoch Childrens Research Institute, The Royal Childrens Hospital, Parkville, Australia
6
Department of Biostatistics, Institute of Psychiatry, Kings College London, London, UK
7
Section of Developmental Neuropsychology and Neuroimaging, Institute of Psychiatry, Kings College London, London, UK

Background. Cannabis can induce transient psychotic symptoms, but not all users experience these adverse eects.
We compared the neural response to D9-tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or
did not induce acute psychotic symptoms.

Method. In a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience
of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging
measures were then recorded whilst they performed a go/no-go task.

Results. The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score
following administration of THC into transiently psychotic (TP ; n=11) and non-psychotic (NP ; n=10) groups.
During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed
dierential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal
gyri and in the right cerebellum. In these regions, THC had opposite eects on activation relative to placebo in the
two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and
cerebellum, independent of the eects of THC.

Conclusions. In this rst demonstration of inter-subject variability in sensitivity to the psychotogenic eects of THC,
we found that the presence of acute psychotic symptoms was associated with a dierential eect of THC on
activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the eects
of the drug on psychotic symptoms.

Received 17 February 2012 ; Revised 20 July 2012 ; Accepted 20 July 2012 ; First published online 1 October 2012

Key words : Cerebellum, fMRI, middle temporal gyri, parahippocampus, response inhibition, THC.

Introduction sensitivity is unclear, as is the location where

D9-tetrahydrocannabinol (THC), the main compound
Epidemiological research points towards a link be-
of the plant, mediates its psychotogenic eects.
tween the use of cannabis and the increased risk of
Individuals with a predisposition to psychosis who
developing a psychotic illness, in a dose-dependent
might be particularly vulnerable to its adverse eects
manner (Arseneault et al. 2002 ; Zammit et al. 2002 ;
were indicated by a positive family history of psy-
Moore et al. 2007). However, cannabis aects in-
chosis (McGuire et al. 1995), a schizotypal personality
dividuals dierently and not everyone who uses
(Stirling et al. 2008), the presence of subclinical psy-
it develops psychosis. The basis of this variable
chotic features (Henquet et al. 2004), being at ultra-
high risk for psychosis (Peters et al. 2009) or carrying
* Address for correspondence : Z. Atakan, M.D., Department of specic genes (Caspi et al. 2005 ; van Winkel et al. 2011 ;
Psychosis Studies, PO67, Section of Neuroimaging, Institute of
Bhattacharyya et al. 2012a).
Psychiatry, Kings College London, DeCrespigny Park, London,
SE5 8AF, UK. Elucidating which behavioural and biological fac-
(Email : [email protected]) tors confer greater risk for psychosis in cannabis users
1256 Z. Atakan et al.

is crucial, because as the availability of plants with abstinence (Tapert et al. 2007). In our previous study
higher THC content has increased, so have the related on response inhibition in participants who had seldom
health risks (Degenhardt et al. 2010 ; Cascini et al. 2011). used cannabis, but were challenged with oral THC
Although relatively few individuals develop a full- relative to placebo, THC was shown to attenuate
blown psychotic illness after cannabis use, a larger activation in the right IFC and ACG and precuneus
number (between 15 and 51 %) experience transient bilaterally (Borgwardt et al. 2008).
psychotic symptoms lasting from a few hours to a few In the present study, we supplemented our pre-
days, as a result of cannabis use (Thomas, 1996 ; Green vious sample by recruiting additional participants,
et al. 2003 ; DSouza et al. 2004, 2009 ; Morrison et al. using exactly the same criteria and methodology, to
2009). It is not yet known if there is a continuum of risk investigate brain activation in those who experienced
between those who become transiently psychotic (TP) transient psychotic symptoms after THC adminis-
and those who develop an enduring psychotic illness tration, compared with those who did not. The ad-
in relation to cannabis use. However, it would be both ministration of cannabidiol, in addition to THC and
logical and ethically feasible to study the eects of placebo, is not included in this paper, as it is not rel-
THC in healthy individuals by comparing those who evant to the investigation in question. We hypothe-
experience transient psychotic symptoms due to can- sized that participants who developed transient
nabis intoxication with those who do not. Findings psychotic symptoms with THC would show dieren-
may inform research on the mechanisms underlying tial activation relative to those that did not experience
psychotic symptoms per se, as well as examining psychotic symptoms in brain regions that have pre-
behavioural and neurobiological mechanisms that viously been implicated in the pathophysiology of
increase the potential risk to an individual. psychosis, such as the prefrontal, medial temporal and
Although there are a growing number of neuro- ventral temporal cortex.
imaging studies that have examined the acute eects of
THC administration on brain function (Martn-Santos
et al. 2010), including those from our group (Borgwardt Method
et al. 2008 ; Fusar-Poli et al. 2009 ; Bhattacharyya et al.
Design
2009, 2010 ; Winton-Brown et al. 2011), to date
none of these studies has examined the eects of THC This was a double-blind, placebo-controlled within-
according to psychotic symptom outcome. subject study, with a 1-month interval between
Response inhibition, the ability to suppress irrel- scans. The order of drug administration was pseudo-
evant acts, is a function that is impaired in cannabis randomized so that equal numbers followed each
users, since they make more inhibitory errors (Hester drug sequence. The Joint South London and Maudsley
et al. 2009 ; Ramaekers et al. 2009 ; Battisti et al. 2010a). It National Health Service and Institute of Psychiatry
is also relevant to patients with schizophrenia who are Research Ethics Committee approved the protocol.
reported to perform slowly in various response inhi- Each subject provided informed consent and was
bition tasks (Enticott et al. 2008 ; Huddy et al. 2009) and given extensive written and verbal information about
have poor error awareness (Turken et al. 2003). the eects of cannabis, including psychotic symptoms.
Furthermore, this group shows abnormal fronto-
striatal activation during inhibition tasks (Rubia et al.
Participants
2001a). A well-established response inhibition para-
digm used in imaging studies is the go/no-go task, All 21 participants were healthy, native English-
which involves the activation of the inferior frontal speaking, right-handed males. The majority (90.5 %)
cortex (IFC), dorsolateral prefrontal cortex (DLPFC), were white British. Their ages ranged from 20 to
inferior parietal cortices and anterior cingulate gyrus 42 years. All of them had used cannabis on no more
(ACG) (Rubia et al. 2001b ; Simmonds et al. 2008). than 25 occasions in their lifetime and none had used
The neuroimaging ndings regarding the eect of cannabis in the previous 3 months.
cannabis on response inhibition are inconclusive due Criterion for inclusion into the TP group was made
to methodological variations. Two studies report sig- post hoc, on the basis of those who scored 3 or more on
nicantly lower activation in regular cannabis users, at least three items of the Positive and Negative
relative to non-users, within the ACG and diuse Syndrome Scale (PANSS) positive subscale (Kay et al.
bilateral activity in the DLPFC (Gruber & Yurgelun- 1987) at 2-h measurements. DSouza et al. (2004),
Todd, 2005 ; Hester et al. 2009). Another study reports in their THC challenge study, had used the same
increased response in the right DLPFC, bilateral criterion previously. Participants who scored below
medial frontal, inferior and superior parietal lobules these thresholds were classed as non-psychotic (NP).
in cannabis users even after 28 days of monitored We identied 11 who met the criteria for transient
 Variation in the psychotogenic eects of D9-tetrahydrocannabinol 1257

psychosis. All completed the scanning procedure, ex- Functional MRI paradigm go/no-go
cept for one who became too anxious to stay in the
Participants practised the go/no-go task prior to
scanner. Therefore, the behavioural and symptomatic
scanning to ensure familiarity. The task involves
data are based on 11 TP participants and the imaging
motor response inhibition and selective attention.
data on 10.
Subjects are required to either execute or inhibit a
Participants were carefully screened and the details
motor response according to the visual cues presented
of the procedures can be found in the supplementary
on a screen. The task is described in detail in the sup-
material. They were asked to abstain from any illicit
plementary material.
drug use during the study period, from alcohol and
coee 24 and 12 h before, respectively, and cigarettes
on the morning of each session, as well as receiving a Behavioural analyses
urine drug screening prior to scans. Data were recorded on SPSS version 20.0 (SPSS, Inc.,
USA) and analysed using Stata 11 (StataCorp LP,
Procedure USA). Descriptive statistics were used to summarize
the baseline variables. Age, years of education, and
Participants were examined at the start of each session cannabis, cigarette, alcohol and other drug use were
and their pulse and blood pressure were monitored. compared between the two groups using t tests (or
They were given identical-looking red gelatine cap- equivalent non-parametric MannWhitney U tests or
sules of either 10 mg of THC (99.6 % pure ; THC- Fishers exact test). A multilevel model was used to
Pharm, Germany) or placebo (our). Both participants assess the eect of THC on each outcome measure,
and researchers were blind to the content of the cap- with subject included as a random eect and time as a
sules. The dose of THC was selected on the basis of xed eect. A second multilevel model assessed the
previous research (Chesher et al. 1990 ; Curran et al. dierence between the TP and NP groups. The distri-
2002 ; Gray et al. 2008) to produce an eect on region- bution of each measure was assessed and no gross
al brain activation without prominent intoxication. violations of normality were found, thus making
Even though oral administration is known to indicate transformations of the data unnecessary. Non-
an erratic absorption and inter-subject variability parametric methods are not advisable in this situation
(Grotenhermen, 2003), it was the preferred method in as they are unable to handle missing data. The multi-
this study in order to produce a slow peaking plasma level models used in our analysis are less restrictive
level for the duration of the imaging session regarding missingness assumptions.
(Lemberger et al. 1971 ; Ohlsson et al. 1980). When investigating task performance, two further
multilevel models were run. The rst included the
Behavioural ratings main eect of drug only, while group eect and its
interaction with drug were also added in the second.
The behavioural eects were evaluated at baseline
(before drug administration), +1 h (immediately be-
fore scanning), +2 h (immediately after scanning) and Image acquisition
at +3 h time points by using the Visual Analogue Images were acquired on a 1.5-T Signa (GE, USA)
Mood Scale (VAMS), State-Trait Anxiety Inventory system at the Maudsley Hospital, London. T2*-
(STAI), Addiction Research Centre Inventory (ARCI), weighted images were acquired with a repetition time
Analogue Intoxication Scale (AIS), Cambridge (TR) of 1.8 s, echo time (TE) of 40 ms, ip angle 90x in
Depersonalization Scale and PANSS. Further infor- 16 planes (7 mm thick), parallel to the anterior com-
mation on these scales is available in the supplemen- missureposterior commissure line. To facilitate ana-
tary material. tomic localization of activation, a high-resolution
As the focus of this paper is to explore the dier- inversion recovery image dataset was also acquired,
ences between those who become TP under THC and with 3-mm contiguous slices and an in-plane resol-
those who do not, we mainly evaluated the baseline ution of 3 mm (TR 16000 ms, inversion time 180 ms,
and 2-h measurements, when the peak intoxication is TE 80 ms).
experienced following oral administration. The 3-h
measurements are also presented in the graphs.
Data processing and analysis
Researchers stayed with the participants until all
their symptoms disappeared. In all cases symptoms A complete description of image analysis including
had resolved spontaneously within 23 h. No psycho- pre-processing and non-parametric statistical model-
pathological symptoms were reported in follow-up ling can be found in the supplementary material. A
checks the next day, and at 1 week and 1 month later. non-parametric approach (XBAM v4 ; http://www.
1258 Z. Atakan et al.

brainmap.co.uk) was used to analyse the imaging There was no signicant dierence between the TP
data, as this method does not assume that the pop- and NP groups on any symptom measure at baseline
ulation distribution is Gaussian. It is dicult to test or after placebo administration. However, 2 h after the
this assumption with neuroimaging data in small administration of THC, there was a signicant dier-
groups, and, when tested, is often found to be violated ence between the groups for VAMS tranquillization
(Rabe-Hesketh et al. 1997 ; Thirion et al. 2007). Instead, (p=0.031), PANSS negative (p=0.020) PANSS posi-
this approach uses median statistics to control outlier tive, general and total subscales (all pf0.001) ; no sig-
eects and employs permutation rather than normal nicant dierence was found for the other behavioural
theory-based inference as recommended by Hayasaka scales (Table 2, Fig. 2).
& Nichols (2003). The test statistic is computed by
standardizing for individual dierence in residual Physiological measures
noise before embarking on second-level, multi-subject
testing, using robust permutation-based methods, Under the THC condition, there was no evidence of a
employing a mixed-eects method. The group dierence in heart rates between the two groups either
activation maps for each task condition were com- at baseline or 2 h after drug administration. However,
when looking at the eect of the drug across all parti-
puted for THC and placebo by determining the me-
cipants, heart rate was signicantly increased at 2 h
dian sum of squares ratio at each voxel and then
compared using non-parametric repeated-measures after administration of either THC (pf0.001) or pla-
analysis of co-variance, with a voxelwise threshold of cebo (p=0.002). There were no signicant dierences
p=0.05. The clusterwise threshold was set such that between either systolic or diastolic blood pressure in
the total number of false-positive clusters per brain the two groups either at baseline or 2 h after adminis-
volume was <1 per map and the p value at which this tering THC. Graphs of physiological measures are
occurred is reported. provided in the supplementary material.

Task performance
Results
There was a non-signicant trend suggesting that
Of the 12 participants receiving THC in the rst ses- THC increased inhibition errors among all partici-
sion and placebo in the second, six were classied as pants (p=0.066). A signicant interaction was found
being in the TP group. The order of drug adminis- between group and drug condition (p=0.002).
tration was reversed in the remaining nine partici- Inhibition errors were signicantly higher in the TP
pants, of whom ve were subsequently included in the group than in the NP group (p<0.001), but only when
TP group. There was no evidence of an order eect, participants received THC. No signicant dierences
and no signicant group dierences with respect to were found for mean reaction time to go trials be-
age or years of education (all p>0.1). Out of 21, 13 did tween the THC and placebo conditions. A table on task
not smoke. A total of eight participants were current performance is provided in the supplementary ma-
tobacco smokers, but only two smoked more than 10 terial.
cigarettes per day and both of these were in the NP
group. Fishers exact test showed no signicant dif- Neuroimaging results
ference between the two groups in terms of cigarette
smoking, cannabis, alcohol and other drug use (all Task eect
p>1.00) (Table 1). Under the placebo condition, no-go relative to oddball
trials were associated with activation in the right ACG,
Symptom data prefrontal cortex and right middle temporal gyrus
(MTG) independent of group, but with a less con-
In all participants, a signicant change in the level of
servative signicance threshold contrast (p<0.025 ;
the following outcome measures was observed 2 h
uncorrected for <1 false-positive cluster).
after the administration of THC : STAI (p<0.001),
ARCI (p<0.001), VAMS tranquillization subscale
Main eect of drug
(p=0.007), AIS (p<0.001) and each of the PANSS
subscales (pf0.001) (Fig. 1). For each of these meas- During no-go compared with oddball trials, across all
ures an increase in score was observed, with the ex- subjects, THC increased activation in the hippocam-
ception of VAMS tranquillization, which was lower at pus, the tail of the caudate nucleus and the insula in
2 h. The dierences observed between baseline and 2 h the right hemisphere, relative to placebo. There were
were only signicant when participants received THC, no areas where THC was associated with reduced ac-
rather than placebo. tivation relative to placebo.
 Variation in the psychotogenic eects of D9-tetrahydrocannabinol 1259

Table 1. Participants sociodemographic and substance-use comparisonsa

Transiently Non-psychotic
psychotic (n=11) (n=10)

THC in rst session, n 6 6

Mean age, years (S.D.) 26.76 (5.00) 25.70 (6.27)
Mean education, years (S.D.) 15.33 (3.64) 16.78 (4.15)
Employment, n ( %)
Employed 8 (72.7) 3 (30.0)
Unemployed 0 (0) 1 (10.0)
Student 2 (18.2) 5 (50.0)
No details 1 (9.1) 1 (10.0)
Cannabis useb, n ( %)
Experimental 7 (63.6) 5 (50.0)
Occasional 4 (36.4) 5 (50.0)
Cigarette use, n ( %)
Non-smoker 7 (63.6) 6 (60.0)
Smoker 4 (36.4) 4 (40.0)
Alcohol usec, n ( %)
Occasional 6 (54.6) 5 (50.0)
Moderate 5 (45.4) 5 (50.0)
Other drugs, n ( %)
Not used 8 (72.7) 7 (70.0)
Used 3 (27.2) 3 (30.0)

THC, D9-Tetrahydrocannabinol ; S.D., standard deviation ; df, degrees of freedom.

a
No order eect (x2=0.06, df=1, p=0.80) and no signicant group dierences with
respect to age (MannWhitney U test : Z=x0.78, p=0.44), years of education
(t=0.79, df=16, p=0.44) and with Fishers exact test : use of cigarette smoking
(p=1.00), cannabis (p=0.67), alcohol (p=1.00) and other drug use (p=1.00).
b
Experimental cannabis use=less than 10 times. Occasional use=1025 times, in
lifetime.
c
Occasional alcohol use=drinking at weekends, social events. Moderate
use=drinking at least three times per week.

Main eect of group Relative to placebo, THC also increased activation in

the right MTG in the TP group (p<0.01 ; corrected for
During no-go compared with oddball trials, indepen-
<1 false-positive cluster), but it attenuated activation
dent of drug, the TP group showed less activation than
in the NP group (Fig. 4).
the NP group in the right MTG (p<0.005 ; corrected
for <1 false-positive cluster) and the vermis of the
cerebellum (p<0.005 ; corrected for <1 false-positive Discussion
cluster). There were no areas where the TP We used functional magnetic resonance imaging to
group showed greater activation than the NP group investigate dierential response to oral THC in a
(Fig. 3). group of healthy, seldom cannabis users and com-
pared the behavioural and imaging ndings of those
who developed transient psychotic symptoms with
Grouprdrug interaction
those who did not. We found signicant dierences
There was a signicant interaction (p<0.01 ; corrected between the two groups in the eects of THC in the
for <1 false-positive cluster) between the eects of left PHG, STG, MTG and cerebellum, where THC de-
drug and group in the left parahippocampal gyrus creased activation in TPs, but increased it in NPs. In
(PHG), MTG, superior temporal gyrus (STG) and in the right MTG the reverse happened ; THC increased
the region spanning the right cerebellum and adjacent activation in the TPs and decreased it in the NPs. This
fusiform gyrus. In all of these regions, relative to pla- was accompanied by a higher error rate in the TPs,
cebo, THC signicantly attenuated activation in the TP relative to the NP group, during THC condition. TPs
group, whereas it increased it in the NP group. also showed less activation than the NPs in the right
1260 Z. Atakan et al.

(a) (b)
35 25

30
20
Mean STAI state

25

Mean ARCI
15
20
10
15

5
10

0 1 2 3 0 1 2 3
Time (h) Time (h)
Non-psychotic Transiently psychotic Non-psychotic Transiently psychotic

(c) (d)
8 30

Mean VAMS - Tranquilization

6
25
Mean AIS

2
20

2 15
0 1 2 3 0 1 2 3
Time (h) Time (h)
Non-psychotic Transiently psychotic Non-psychotic Transiently psychotic

Fig. 1. Comparison of behavioural measures over time, in the D9-tetrahydrocannabinol (THC) condition : (a) Spielbergers
State-Trait Anxiety Inventory ; (b) Addiction Research Centre Inventory ; (c) Analogue Intoxication Scale ; and (d) Visual
Analogue Mood Scale (VAMS) tranquillization category. Data are means, with standard errors represented by vertical bars.
Measurements were taken just before drug administration at baseline (0) and repeated 1, 2 and 3 h after drug administration.
When conditioning on THC, a comparison of transiently psychotic and non-psychotic at 2 h after drug administration showed a
signicant dierence in the VAMS tranquillization category only (p=0.03).

MTG and the vermis of the cerebellum, independent specically related to psychotic symptoms. We cannot
of THC. exclude the possibility that the absence of dierences
between the two groups in NP symptoms was due
to limited statistical power. However, that seems un-
Symptomatic eects of THC
likely, as the groups diered signicantly not just
As the groups were dened in terms of their psychotic on psychotic symptom severity, but also in terms
experiences following THC, it is not surprising that of another behavioural measure : response inhibition
they diered in their PANSS scores. Due to the small errors.
sample size, however, formal corrections for multiple In terms of the acute eects of THC, our ndings
testing were not possible. Instead we lowered the sig- are in line with other challenge studies in which
nicance level from 5 % to 1 % at which the PANSS healthy volunteers who received THC, either orally or
positive, general and total scores remained signicant, intravenously, experienced a broad range of transient
and the negative subscale showed a trend (p=0.02). positive psychotic, negative psychotic and cognitive
Therefore the negative scale result needs to be treated symptoms (Curran et al. 2002 ; DSouza et al. 2004 ;
with caution. Even though THC signicantly aected Morrison et al. 2009). These studies also found
most measures in all participants, there were remark- that psychotic symptoms were not correlated with
ably few signicant dierences in the levels of anxiety symptoms following THC. Signicant in-
mood, anxiety and intoxication between the two creases in pulse rate occurred both in THC and pla-
groups. This may suggest that the dierential sensi- cebo conditions, possibly due to the experimental
tivity to the eects of THC was particularly and conditions.
 Variation in the psychotogenic eects of D9-tetrahydrocannabinol 1261

Table 2. Comparison of symptom scales between TP and NP groups at both baseline and 2 ha

Placebo THC

Mean dierence Mean dierence

between TP and between TP and
Time NP (95 % CI) Z p NP (95 % CI) Z p

STAI state Baseline x1.10 (x8.07 to 5.87) x0.31 0.76 x0.05 (x8.73 to 8.63) x0.01 0.99
2h 0.31 (x6.71 to 7.33) 0.09 0.93 6.12 (x2.69 to 14.92) 1.36 0.17
ARCI Baseline 2.83 (x0.94 to 6.60) 1.47 0.14 1.67 (x2.68 to 6.02) 0.75 0.45
2h 2.59 (x1.14 to 6.33) 1.36 0.17 1.47 (x2.88 to 5.82) 0.66 0.51
AIS score Baseline x0.06 (x1.70 to 1.59) x0.07 0.94 x0.34 (x2.20 to 1.52) x0.36 0.72
2h 0.24 (x1.34 to 1.83) 0.30 0.76 0.76 (x1.14 to 2.66) 0.78 0.43
VAMS Baseline x0.96 (x5.48 to 3.56) x0.42 0.68 0.65 (x4.46 to 5.75) 0.25 0.80
tranquillization
2h x0.43 (x4.88 to 4.02) x0.19 0.85 x5.62 (x10.73 to x0.52) x2.16 0.03*
PANSS positive Baseline x0.30 (x0.70 to 0.10) x1.48 0.14 x0.15 (x2.55 to 2.24) x0.13 0.90
2h 0.08 (x0.32 to 0.48) 0.40 0.69 6.94 (4.599.28) 5.81 <0.001*
PANSS negative Baseline x0.20 (x0.64 to 0.24) x0.88 0.38 x0.10 (x2.41 to 2.21) x0.08 0.93
2h x0.02 (x0.46 to 0.43) x0.08 0.94 2.68 (0.424.94) 2.33 0.02*
PANSS general Baseline x0.19 (x1.11 to 0.73) x0.41 0.68 0.60 (x4.04 to 5.25) 0.25 0.80
2h 0.48 (x0.44 to 1.40) 1.03 0.31 9.82 (5.3514.28) 4.31 <0.001*
PANSS total Baseline x0.69 (x2.05 to 0.67) x0.99 0.32 x2.10 (x7.94 to 7.94) 0.10 1.00
2h 0.55 (x0.82 to 1.91) 0.78 0.43 19.16 (11.4026.92) 4.84 <0.001*

TP, Transiently psychotic ; NP, non-psychotic ; THC, D9-tetrahydrocannabinol ; CI, condence interval ; STAI, State-Trait
Anxiety Inventory ; ARCI, Addiction Research Centre Inventory ; AIS, Analogue Intoxication Scale ; VAMS, Visual Analogue
Mood Scale ; PANSS, Positive and Negative Syndrome Scale.
a
Due to small sample size, multilevel model analyses were performed separately for THC and placebo. The only signicant
dierence between the groups was seen in VAMS tranquillization (p=0.03) and all PANSS subscales : PANSS negative (pf0.02)
and the PANSS positive, general and total subscales (all pf0.001).
* p<0.05.

Task performance reported in people with schizophrenia and bipolar

disorder during the go/no-go task (Kiehl et al. 2000 ;
We found a process-specic eect of THC on the main Fleck et al. 2011). Higher impulsivity, inability to sup-
inhibitory measure of the task (commission/inhibition press irrelevant acts and being unaware of making
errors), but not on the executive process of the task errors are likely to originate from a poorly coordinated
(mean reaction time to go trials). Across all partici- response inhibition system and may be associated
pants THC increased inhibition errors at a trend-level with the formation of some of the psychotic symp-
of signicance. Furthermore, there was a signicant toms.
groupr drug interaction on this measure, where TPs
made signicantly more commission errors than NPs.
Neural eects of go/no-go task
This nding cannot be related to performance dier-
ences, as we modelled only the correct trials. The Even though in our previous study (Borgwardt et al.
ndings show, that the eect of THC on impairing go/ 2008) relative to placebo, THC attenuated activation
no-go task performance is specic to the inhibitory in the right inferior frontal gyrus and the ACG,
process and that this eect is more pronounced in here we found that the activation of the specic motor
those who develop transient psychosis. Our partici- response inhibition network occurred only with a
pants seldom used cannabis, whilst previously lenient threshold. However, consistent with the
both occasional and heavy users of cannabis have been results of previous studies (Borgwardt et al. 2008 ;
shown to have increased reaction time with Bhattacharyya et al. 2010), we have again found that
the stop signal task, which is considered to be indica- THC signicantly increased activation in the right
tive of poor impulse control to single doses hippocampus, tail of the caudate and insula. While the
of THC (Ramaekers et al. 2009). The nding of inhi- latter two are key areas of inhibition, the hippocampus
bition decits in TPs is comparable with those is not (Chambers et al. 2009). These ndings suggest
1262 Z. Atakan et al.

(a) (b)
14
16

Mean PANSS - Negative symptoms

Mean PANSS - Positive symptoms

14 12

12
10

10
8
8

6 6

0 1 2 3 0 1 2 3
Time (h) Time (h)
Non-psychotic, placebo Non-psychotic, THC Non-psychotic, placebo Non-psychotic, THC
Transiently psychotic, placebo Transiently psychotic, THC Transiently psychotic, placebo Transiently psychotic, THC

(c) (d)
35
Mean PANSS - General psychopathology

60

Mean PANSS - Total score

30
50

25
40

20
30

15
20

0 1 2 3 0 1 2 3
Time (h) Time (h)
Non-psychotic, placebo Non-psychotic, THC Non-psychotic, placebo Non-psychotic, THC
Transiently psychotic, placebo Transiently psychotic, THC Transiently psychotic, placebo Transiently psychotic, THC

Fig. 2. Comparison of Positive and Negative Syndrome Scale (PANSS) subscales, between the transiently psychotic and
non-psychotic groups under D9-tetrahydrocannabinol (THC) and placebo conditions : (a) positive symptoms ; (b) negative
symptoms ; (c) general psychopathology ; and (d) total score. Data are means, with standard errors represented by vertical bars.
A comparison of transiently psychotic and non-psychotic participants 2 h after drug administration showed signicant
dierences in the PANSS negative subscale (p=0.02) and a highly signicant dierence in all other subscales (all pf0.001). Note
that the y-axes have dierent scales in the graphs.

increased brain-processing eort during an inhibition vermis of the cerebellum, independent of THC, which
task in a more widespread manner involving brain were reduced in the TPs. This is an interesting nding
regions other than the specic response inhibition which implies a trait dierence between the groups.
network, as has been reported previously in subjects As we excluded those with personal and family his-
who use cannabis on a regular basis (Tapert et al. 2007 ; tory of psychosis, it is unlikely that this nding reects
Roberts & Garavan, 2010). Our ndings extend those these factors. Additionally, the task we used does not
previous ndings by showing that the up-regulation normally involve the right MTG or the cerebellum. We
eect of these areas is already observed in people who can tentatively suggest that the dierences we found
use cannabis seldomly and further support the view may reect a more general dierence in participants
that THC may be disrupting the neural mechanisms vulnerability to transient psychosis or to inhibitory
involved with this task. Alternative neuroanatomic dyscontrol and could be related to variations in
recruitment such as involvement of the STG, MTG and single nucleotide polymorphisms that are associated
cerebellum have also been reported in a number of with an increased risk of psychosis. However, our
studies carried out on patients with bipolar disorder sample was not large enough to investigate this. Some
and schizophrenia during response inhibition tasks recent studies focusing on early identication of psy-
(Fleck et al. 2011 ; Hughes et al. 2012). chosis have reported that the right MTG is implicated
in at-risk or high-risk groups (Fusar-Poli et al. 2010 ;
Meijer et al. 2011). Grey matter loss in the cerebellum
Group eect
amongst rst-onset psychosis patients has also
The two groups diered inherently in terms of their been shown in a recent meta-analysis (Fusar-Poli et al.
task-related activation in the right MTG and the 2011). Other supporting evidence for the involvement
 Variation in the psychotogenic eects of D9-tetrahydrocannabinol 1263

(a) (b)

Tal (x) Tal (y) Tal (z) Side Cerebral region

58 22 15 Right Right middle temporal gyrus

7 67 24 Vermis of cerebellum

Fig. 3. Trait dierences. Analysis of all subjects, independent of drug condition, showed signicant dierences between the two
groups in two regions. (a) Crosshair showing that activation in the right middle temporal gyrus is attenuated in the transiently
psychotic (TP) group in comparison with the non-psychotic (NP) group (TP <NP, p<0.007, corrected for <1 false-positive
cluster). (b) Crosshair showing that activation in the vermis of the cerebellum is attenuated in the TP group in comparison with
the NP group (TP <NP, p<0.005, corrected for <1 false-positive cluster). The left side of the brain is shown on the left side of
the images. All coordinates in Talairach (Tal) space.

of this region to genetic vulnerability to psychosis is in the TPs, but not in the NPs, provides further sup-
found in a recently reported study, when a signicant port that this region may be implicated in psychoses.
three-way interaction between two susceptibility Additional dierences were evident in the left
genes implicated in glutamate transmission (G72 and middle/superior temporal cortices and in the cer-
DAAO) and the diagnosis of psychosis was detected at ebellum, areas that are implicated as key regions in
the right MTG (Mechelli et al. 2012). schizophrenia (for reviews, see Honea et al. 2005 ;
Smieskova et al. 2010 ; Jardri et al. 2011). The STG, as
well as the cerebellum, has been implicated in
Dierential neurophysiological processing of THC inhibitory control (Rubia et al. 2007). The increased
Our other main nding was that, as hypothesized, inhibition error rate in the TP group together with the
THC had a dierent eect on brain function in parti- increased activation in these two inhibition-related
cipants who developed transient psychotic symptoms areas may suggest that the TP group had to work
from those who did not. These eects were evident in harder to maintain their inhibitory capacity, which
the left PHG, an area that has been implicated in was still below the level of that in the NP group.
the pathophysiology of psychosis in post-mortem Conversely, THC increased activation in the right
(McDonald et al. 2000), neuropsychological (Marvel MTG in the TPs, whilst it attenuated it in the NPs. It is
et al. 2007), volumetric (Witthaus et al. 2009), functional interesting that this area is dierentially activated be-
(Wolf et al. 2007) and neurochemical (Stone et al. 2010) tween the groups whether or not THC was present. It
imaging studies. Eects in this region in relation to is dicult to interpret the two ndings in relation to
THC-induced psychosis are of particular interest be- one another as they involve dierent analyses involv-
cause of the evidence that chronic cannabis use can ing the same region.
impair memory (Battisti et al. 2010b). Our group had In all of these regions, the eect of THC on acti-
previously reported that THC increased para- vation in the group that experienced psychotic symp-
hippocampal activation bilaterally during an encoding toms was in the opposite direction to that in the group
task (Bhattacharyya et al. 2009) and attenuated it dur- that did not develop psychotic symptoms. The
ing an attentional salience task (Bhattacharyya et al. underlying processes for this dissociated eect will
2012b). Furthermore, structural and functional chan- require further research and replication. Interestingly,
ges in the parahippocampal region are frequently a ketamine challenge study with healthy volunteers
identied in relation to cannabis use (Lorenzetti et al. also reported a compelling consistency between the
2010 ; Martn-Santos et al. 2010). The nding that atte- task, region, symptom associations and those reported
nuated left parahippocampal activity is observed only in patients with schizophrenia (Honey et al. 2008).
1264 Z. Atakan et al.

(a) (b)
(a)

Activation in the left parahippocampal

0.015 0.015

Activation in the left middle temporal

0.010 0.010

gyrus (MeanSEM)

gyrus (MeanSEM)
0.005 0.005

0.000 0.000

(b) 0.005 0.005

0.010 0.010
Nonpsychotic Nonpsychotic
0.015 Psychotic 0.015 Psychotic

Placebo THC Placebo THC

(c) (d)
0.015 0.015

Activation in the right middle temporal

(c)
Activation in the cerebellum

0.010 0.010
(MeanSEM)

gyrus (MeanSEM)
0.005 0.005

0.000 0.000

(d) 0.005 0.005

0.010 0.010
Nonpsychotic Nonpsychotic
0.015 Psychotic 0.015 Psychotic

Placebo THC Placebo THC

Coordinates of regions where THC attenuated* activation in the TP group only

Size Tal (x) Tal (y) Tal (z) Side Cerebral region
10 22 59 2 L Parahippocampal/Fusiform gyri
21 43 59 2 L Middle temporal gyrus
28 32 56 13 R Cerebellum/Fusiform gyrus
Coordinates of region where THC increased* activation in the TP group only
12 51 41 13 R Middle temporal gyrus

Fig. 4. Interaction between the transiently psychotic (TP) and non-psychotic (NP) groups and drug conditions [D9-
tetrahydrocannabinol (THC) versus placebo]. Plots (a), (b) and (c) show that the administration of THC attenuated activation in
the left parahippocampal gyrus/fusiform gyrus (a crosshair), left middle temporal gyrus/superior temporal sulcus (b crosshair)
and right cerebellum/fusiform gyrus (c crosshair) in the TP group, whilst it increased activation in the same region in the NP
group (p=0.01). Plot (d) shows that THC modulated activation by increasing it in the right middle temporal gyrus (d crosshair)
in the TP group, whilst it attenuated it in the NP group (p=0.01). Data are means indexed by the mean sum of squares ratio, with
standard errors represented by vertical bars. The left side of the brain is shown on the left side of the images. All coordinates in
Talariach (Tal) space. a In the NP group THC did the reverse activity in these regions.

To our knowledge, the present study is the rst to universally, similar studies with larger samples are
demonstrate neurobiological dierences that may required to understand the basis of dierential neural
contribute to the dierential sensitivity to the psycho- responses to THC to inform the ongoing public health
togenic eects of cannabis in healthy participants. Our debate about the risks of cannabis use, as well as
ndings imply that there is an association between leading to the development of interventions designed
individual variability in brain response and sub- to reduce its use, particularly targeting those most at
sequent transitory psychotic symptom formation. risk.
Even though THC only transiently produced psy-
Limitations
chotic symptoms in some, the brain regions that were
up-regulated are also those critically implicated in This study has a modest sample size. Studies of this
schizophrenia. Whilst acknowledging that transient type are logistically dicult when participants, who
psychosis is not the same as a full-blown psychosis, seldom use cannabis, are asked to attend more than
there may be varying degrees of risk in response to the one study session. However, we have used non-para-
psychotogenic eects of THC. How THC modulates metric, repeated-measures analyses to obtain more
specic brain regions can also provide information on robust ndings in order to compensate for the low
symptom formation. Given the size of the problem numbers (Brammer et al. 1997 ; Bullmore et al. 1999).
 Variation in the psychotogenic eects of D9-tetrahydrocannabinol 1265

The use of PANSS is another limitation, as this scale is ventrostriatal function in humans by D9-
not designed for transient psychosis, even though our tetrahydrocannabinol : a neural basis for the eects of
participants experienced frank hallucinations and de- Cannabis sativa on learning and psychosis. Archives of
lusions temporarily. General Psychiatry 66, 442451.
Bhattacharyya S, Morrison PD, Fusar-Poli P,
Martn-Santos R, Borgwardt S, Winton-Brown T,
Supplementary material Nosarti C, OCarroll CM, Seal M, Allen P, Mehta MA,
Stone JM, Tunstall N, Giampietro V, Kapur S,
For supplementary material accompanying this paper Murray RM, Zuardi AW, Crippa JA, Atakan Z,
visit http://dx.doi.org/10.1017/S0033291712001924. McGuire P (2010). Opposite eects of D-9-
tetrahydrocannabinol and cannabidiol on human brain
function and psychopathology. Neuropsychopharmacology
Acknowledgements 35, 764774.
Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P,
The present study was supported by a Joint Medical
Crippa JA, Seal ML, Fraccaro V, Atakan Z,
Research Council/Priory clinical research training
Martn-Santos R, OCarroll C, Rubia K, McGuire PK
fellowship to S.B. and support from the Psychiatry (2008). Neural basis of D-9-tetrahydrocannabinol and
Research Trust, UK. We are grateful to Glynis cannabidiol : eects during response inhibition. Biological
Ivin (Department of Pharmacology, the Maudsley Psychiatry 64, 966973.
Hospital), for the storing, blinding procedure and Brammer MJ, Bullmore ET, Simmons A, Williams SCR,
dispensing of the THC and placebo. Grasby PM, Howard RJ, Woodru PWR, Rabe-Hesketh S
(1997). Generic brain activation mapping in fMRI : a
non-parametric approach. Magnetic Resonance Imaging 15,
Declaration of Interest 763770.
Bullmore ET, Suckling J, Overmeyer S, Rabe-Hesketh S,
None.
Taylor E, Brammer MJ (1999). Global, voxel and
cluster tests, by theory and permutation, for a
dierence between two groups of structural MR
References
images of the brain. IEEE Transactions on Medical Imaging
Arseneault L, Cannon M, Murray R, Poulton R, Caspi A, 18, 3242.
Mott TE (2002). Cannabis use in adolescence and risk for Cascini F, Aiello C, Di Tanna G (2011). Increasing delta-9-
adult psychosis : longitudinal prospective study. British tetrahydrocannabinol (D-9-THC) content in herbal
Medical Journal 325, 12121213. cannabis over time : systematic review and meta-analysis.
Battisti RA, Roodenrys S, Johnstone SJ, Pesa N, Current Drug Abuse Reviews 5, 3240.
Hermens DF, Solowij N (2010a). Chronic cannabis users Caspi A, Mott TE, Cannon M, McClay J, Murray R,
show altered neurophysiological functioning on Stroop Harrington H, Taylor A, Arseneault L, Williams B,
task conict resolution. Psychopharmacology 212, 613624. Braithwaite A, Poulton R, Craig IW (2005). Moderation of
Battisti RA, Roodenrys S, Johnstone SJ, Respondek C, the eect of adolescent-onset cannabis use on adult
Hermens DF, Solowij N (2010b). Chronic use of cannabis psychosis by a functional polymorphism in the catechol-O-
and poor neural eciency in verbal memory ability. methyltransferase gene : longitudinal evidence of a
Psychopharmacology 209, 319330. gene r environment interaction. Biological Psychiatry 57,
Bhattacharyya S, Atakan Z, Martn-Santos R, Crippa JA, 11171127.
Kambeitz J, Prata D, Williams S, Brammer M, Collier DA, Chambers CD, Garavan, Bellgrove MA (2009). Insights into
McGuire PK (2012a). Preliminary report of biological basis the neural basis of response inhibition from cognitive and
of sensitivity to the eects of cannabis on psychosis : AKT1 clinical neuroscience. Neuroscience and Biobehavioural
and DAT1 genotype modulates the eects of D-9- Reviews 33, 631646.
tetrahydrocannabinol on midbrain and striatal function. Chesher GB, Bird KD, Jackson DM, Perrignon A,
Molecular Psychiatry. Published online 31 January 2012. Starmer GA (1990). The eects of orally administered delta
doi :10.1038/mp.2011. 9-tetrahydrocannabinol in man on mood and performance
Bhattacharyya S, Crippa JA, Allen P, Martn-Santos R, measures : a doseresponse study. Pharmacology,
Borgwardt S, Fusar-Poli P, Rubia K, Kambeitz J, Biochemistry and Behavior 35, 861864.
OCarroll C, Seal ML, Giampietro V, Brammer M, Curran HV, Brignell C, Fletcher S, Middleton P, Henry J
Zuardi AW, Atakan Z, McGuire PK (2012b). Induction of (2002). Cognitive subjective doseresponse eects of acute
psychosis by D9-tetrahydrocannabinol reects modulation oral D9-tetrahydrocannabinol (THC) in infrequent cannabis
of prefrontal and striatal function during attentional users. Psychopharmacology 164, 6170.
salience processing. Archives of General Psychiatry 69, 2736. Degenhardt L, Coey C, Carlin JB, Swift W, Moore E,
Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martn-Santos Patton GC (2010). Outcomes of occasional cannabis
R, Nosarti C, OCarroll C, Allen P, Seal ML, Fletcher PC, use in adolescence : 10-year follow-up study in
Crippa JA, Giampietro V, Mechelli A, Atakan Z, Victoria, Australia. British Journal of Psychiatry 196,
McGuire P (2009). Modulation of mediotemporal and 290295.
1266 Z. Atakan et al.

DSouza DC, Perry E, MacDougall L, Ammerman Y, Honea R, Crow TJ, Passingham D, Mackay CE (2005).
Cooper TB, Wu YT, Braley G, Gueorguieva R, Krystal JH Regional decits in brain volume in schizophrenia : a meta-
(2004). The psychotomimetic eects of intravenous delta-9- analysis of voxel-based morphometry studies. American
tetrahydrocannabinol in healthy individuals : Journal of Psychiatry 162, 22332245.
implications for psychosis. Neuropsychopharmacology 29, Honey GD, Corlett PR, Absolam AR, Lee M,
15581572. Pomarol-Clotet E, Murray GK, McKenna PJ,
DSouza DC, Sewell RA, Ranganathan M (2009). Cannabis Bullmore ET, Menon DK, Fletcher PC (2008). Individual
and psychosis/schizophrenia : human studies. European dierences in psychotic eects of ketamine are predicted
Archives of Clinical Neurosciences 259, 413431. by brain function measure under placebo. Journal of
Enticott PG, Oglo JR, Bradshaw JL (2008). Response Neuroscience 28, 62957303.
inhibition and impulsivity in schizophrenia. Psychiatry Huddy VC, Aron AR, Harrison M, Barnes TR, Robbins TW,
Research 157, 251254. Joyce EM (2009). Impaired conscious and preserved
Fleck DE, Kotwal R, Eliassen JC, Lamy M, DelBello MP, unconscious inhibitory processing in recent onset
Adler CM, Durling M, Cerullo MA, Strakowski SM schizophrenia. Psychological Medicine 39, 907916.
(2011). Preliminary evidence for increased Hughes ME, Fulham WR, Johnston PK, Michie PT (2012).
frontosubcortical activation on a motor impulsivity task in Stop-signal response inhibition in schizophrenia :
mixed episode bipolar disorder. Journal of Aective behavioural, event-related potential and functional
Disorders 133, 333339. neuroimaging data. Biological Psychiatry 89, 220231.
Fusar-Poli P, Broome MR, Matthiasson P, Woolley JB, Jardri R, Pouchet A, Pins D, Thomas P (2011). Cortical
Johns LC, Tabraham P, Bramon E, Valmaggia L, activations during auditory verbal hallucinations in
William SC, McGuire P (2010). Spatial working memory schizophrenia : a coordinate-based meta-analysis. American
in individuals at high risk for psychosis : longitudinal fMRI Journal of Psychiatry 168, 7381.
study. Schizophrenia Research 123, 4552. Kay SR, Fiszbein A, Opler LA (1987). The Positive and
Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Negative Syndrome Scale (PANSS) for schizophrenia.
Allen P, Martn-Santos R, Seal M, Surguladze SA, Schizophrenia Bulletin 13, 261276.
OCarroll C, Atakan Z, Zuardi AW, McGuire PK (2009). Kiehl KA, Smith AM, Hare RD, Liddle PF (2000). An
Distinct eects of D9-tetrahydrocannabinol and event-related potential investigation of response inhibition
cannabidiol on neural activation during emotional in schizophrenia and psychopathy. Biological Psychiatry 48,
processing. Archives of General Psychiatry 66, 95105. 210221.
Fusar-Poli P, Radua J, McGuire P, Borgwardt S (2011). Lemberger L, Axelrod J, Kopin IJ (1971). Metabolism
Neuroanatomical maps of psychosis onset : voxel-wise disposition of D9-tetrahydrocannabinol in man.
meta-analysis of antipsychotic-nave VBM studies. Pharmacological Review 23, 371380.
Schizophrenia Bulletin. Published online 17 November 2011. Lorenzetti V, Lubman DI, Whittle S, Solowij N, Yucel M
doi :10.1093/schbul/sbr134. (2010). Structural MRI ndings in long-term cannabis
Gray KM, Hart CL, Christie DK, Upadhyaya HP (2008). users : what do we know ? Substance Use and Misuse 45,
Tolerability and eects of oral D9-tetrahydrocannabinol in 17871808.
older adolescents with marijuana use disorders. Martn-Santos R, Fagundo AB, Crippa JA, Atakan Z,
Pharmacology, Biochemistry and Behavior 91, 6770. Bhattacharyya S, Allen P, Fusar-Poli P, Borgwardt S,
Green B, Kavanagh D, Young R (2003). Being stoned : a Seal M, Busatto GF, McGuire P (2010). Neuroimaging in
review of self-reported cannabis eects. Drug and Alcohol cannabis use : a systematic review of the literature.
Review 22, 453460. Psychological Medicine 40, 383398.
Grotenhermen F (2003). Pharmacokinetics and Marvel CL, Turner BM, OLeary DS, Johnson HJ, Pierson
pharmacodynamics of cannabinoids. Clinical RK, Pnoto LL, Andreasen NC (2007). The neural correlates
Pharmacokinetics 42, 327360. of implicit sequence learning in schizophrenia.
Gruber SA, Yurgelun-Todd DA (2005). Neuroimaging of Neuropsychology 21, 761777.
marijuana smokers during inhibitory processing : a pilot McDonald B, Highley JR, Walker MA, Herron BM,
investigation. Brain Research. Cognitive Brain Research 23, Cooper SJ, Esiri MM, Crow TJ (2000). Anomalous
107118. asymmetry of fusiform and parahippocampal gyrus gray
Hayasaka S, Nichols TE (2003). Validating cluster size matter in schizophrenia : a postmortem study. American
inference : random eld and permutation methods. Journal of Psychiatry 157, 4047.
Neuroimage 20, 23432356. McGuire PK, Jones P, Harvey I, Williams M, McGun P,
Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Murray RM (1995). Morbid risk of schizophrenia for
Wittchen HU, van Os J (2004). Prospective cohort study of relatives of patients with cannabis-associated psychosis.
cannabis use, predisposition for psychosis, and psychotic Schizophrenia Research 15, 277281.
symptoms in young people. British Medical Journal 330, Mechelli A, Fusar-Poli P, Papagni SA, Tognin S,
1114. Kambeitz J, Fu C, Picchioni M, Walshe M,
Hester R, Nestor L, Garavan H (2009). Impaired error Toulopoulou T, Bramon E, Murray R, McGuire P (2012).
awareness and anterior cingulate cortex hypoactivity in Genetic vulnerability to psychosis and cortical function :
chronic cannabis users. Neuropsychopharmacology 4, epistatic eects between DAAO and G72. Current
24502458. Pharmacological Design 18, 510517.
 Variation in the psychotogenic eects of D9-tetrahydrocannabinol 1267

Meijer JH, Schmitz N, Nieman DH, Becker HE, predictors of transition to psychosis a systematic review
van Amelsvoort TA, Dingemans PM, Linszen DH, and meta-analysis. Neuroscience and Biobehavioral Reviews
de Haan L (2011). Semantic uency decits and 34, 12071222.
reduced grey matter before transition to psychosis : a Stirling J, Barkus EJ, Nabosi L, Irshad S, Roemer G,
voxelwise correlational analysis. Psychiatry Research 194, Schreudergoidheijt B, Lewis S (2008). Cannabis-induced
16. psychotic-like experiences are predicted by high
Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, schizotypy. Conrmation of preliminary results in a large
Jones PB, Burke M, Lewis G (2007). Cannabis use and risk cohort. Psychopathology 41, 371378.
of psychotic or aective mental health outcomes : a Stone JM, Howes OD, Egerton A, Kambeitz J, Allen P,
systematic review. Lancet 370, 319328. Lythgoe DJ, OGorman RL, McLean MA, Barker GJ,
Morrison PD, Zois V, McKeown DA, Lee TD, Holt DW, McGuire P (2010). Altered relationship between
Powell JF, Kapur S, Murray RM (2009). The acute eects of hippocampal glutamate levels and striatal dopamine
synthetic intravenous D9-tetrahydrocannabinol on function in subjects at ultra high risk of psychosis. Biological
psychosis, mood and cognitive functioning. Psychological Psychiatry 68, 599602.
Medicine 39, 16071616. Tapert SF, Schweinsburg AD, Drummond SPA, Paulus MP,
Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Brown SA, Yang TT, Frank LR (2007). Functional MRI of
Gillespie HK (1980). Plasma delta-9 tetrahydrocannabinol inhibitory processing in abstinent adolescent marijuana
concentrations clinical eects after oral intravenous users. Psychopharmacology 194, 173183.
administration smoking. Clinical Pharmacology and Thirion B, Pinel P, Tucholka A, Roche A, Ciuciu P,
Therapeutics 28, 409416. Mangin JF, Poline JB (2007). Structural analysis of fMRI
Peters BD, de Koning P, Dingemans P, Becker H, data revisited : improving the sensitivity and reliability of
Linszen DH, de Haan L (2009). Subjective eects of fMRI group studies. IEEE Transactions on Medical Imaging
cannabis before the rst psychotic episode. Australian and 26, 12561269.
New Zealand Journal of Psychiatry 43, 11551162. Thomas H (1996). A community survey of adverse eects of
Rabe-Hesketh S, Bullmore ET, Brammer MJ (1997). The cannabis use. Drug and Alcohol Dependence 42, 201207.
analysis of functional magnetic resonance images. Turken AU, Vuilleumier P, Mathalon DH, Swick D,
Statistical Methods in Medical Research 6, 215237. Ford JM (2003). Are impairments of action monitoring and
Ramaekers JG, Kauert G, Theunissen EL, Toennes SW, executive control true dissociative dysfunctions in patients
Moeller MR (2009). Neurocognitive performance during with schizophrenia ? American Journal of Psychiatry 160,
acute THC intoxication in heavy and occasional cannabis 18811883.
users. Journal of Psychopharmacology 23, 266277. van Winkel R ; Genetic Risk and Outcome of
Roberts GM, Garavan H (2010). Evidence of increased Psychosis (GROUP) Investigators (2011). Family-based
activation underlying cognitive control in ecstasy and analysis of genetic variation underlying psychosis-
cannabis users. Neuroimage 15, 429435. inducing eects of cannabis : sibling analysis and proband
Rubia K, Russell T, Bullmore ET, Soni W, Brammer MJ, follow-up. Archives of General Psychiatry 68, 148157.
Simmons A, Taylor E, Andrew C, Giampietro V, Winton-Brown TT, Allen P, Bhattacharrya S, Borgwardt SJ,
Sharma T (2001a). An fMRI study of reduced left Fusar-Poli P, Crippa JA, Seal M, Martn-Santos R,
prefrontal activation in schizophrenia during normal Ffytche D, Zuardi AW, Atakan Z, McGuire PK (2011).
inhibitory function. Schizophrenia Research 52, 4755. Modulation of auditory and visual processing by delta-9-
Rubia K, Russell T, Overmeyer S, Brammer MJ, tetrahydrocannabinol and cannabidiol : an fMRI study.
Bullmore ET, Sharma T, Simmons A, William SC, Neuropsychopharmacology 36, 13401348.
Giampetro V, Andrew CM, Taylor E (2001b). Mapping Witthaus H, Kaufmann C, Bohner G, Ozgurdal S,
motor inhibition : conjunctive brain activations across Gudlowski Y, Gallinat J, Ruhrmann S, Brune M, Heinz
dierent versions of go/no-go and stop tasks. Neuroimage A, Klingebiel R, Juckel G (2009). Gray matter
13, 250261. abnormalities in subjects at ultra-high risk for
Rubia K, Smith AB, Brammer MJ, Taylor E (2007). Temporal schizophrenia and rst-episode schizophrenic patients
lobe dysfunction in medication-nave boys with attention- compared to healthy controls. Psychiatry Research 173,
decit/hyperactivity disorder during attention allocation 163169.
and its relation to response variability. Biological Psychiatry Wolf DH, Gur RC, Valdez JN, Loughead J, Elliott MA,
62, 9991006. Gur R, Ragland JD (2007). Alterations of fronto-temporal
Simmonds DJ, Pekar JJ, Mostofsky SH (2008). Meta-analysis connectivity during word encoding in schizophrenia.
of go/no-go tasks demonstrating that fMRI activation Psychiatry Research 154, 221232.
associated with response inhibition task is task-dependent. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G
Neuropsychologia 46, 224232. (2002). Self reported cannabis use as a risk factor for
Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, schizophrenia in Swedish conscripts of 1969 : historical
Stieglitz RD, Drewe J, Radue EW, McGuire PK, cohort study. British Medical Journal 325,
Riecher-Rossler A, Borgwardt SJ (2010). Neuroimaging 11991201.