Schizophrenia Bulletin vol. 38 no. 2 pp.

316–330, 2012
doi:10.1093/schbul/sbq079
Advance Access publication on July 25, 2010

The Impact of Cannabis Use on Cognitive Functioning in Patients With

Schizophrenia: A Meta-analysis of Existing Findings and New Data in a
First-Episode Sample

Murat Yücel*,1,2, Emre Bora1, Dan I. Lubman2,3, Nadia Solowij4,5, Warrick J. Brewer2, Sue M. Cotton2, Philippe Conus6,
Michael J. Takagi1,2, Alex Fornito1, Stephen J. Wood1, Patrick D. McGorry2, and Christos Pantelis1
1
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, National Neuroscience
Facility, Alan Gilbert Building, 161 Barry Street, Carlton South, Victoria 3053, Australia; 2Orygen Youth Health Research Centre, Centre for

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Youth Mental Health, University of Melbourne, Parkville, Victoria, Australia; 3Turning Point Alcohol and Drug Centre, Eastern Health
Clinical School, Monash University, Victoria, Australia; 4School of Psychology, University of Wollongong, Wollongong, New South Wales,
Australia; 5Schizophrenia Research Institute, Sydney, New South Wales, Australia; 6Département de Psychiatrie Centre Hospitalier
Universitaire Vaudois, Université de Lausanne, Clinique de Cery, Prilly, Switzerland
*
To whom correspondence should be addressed; tel: 613-8344-1877, fax 613-9348-0469, e-mail: murat@unimelb.edu.au

Cannabis use is highly prevalent among people with schizo- Key words: schizophrenia/psychosis/marijuana/drug/
phrenia, and coupled with impaired cognition, is thought to neuropsychology/comorbidity
heighten the risk of illness onset. However, while heavy
cannabis use has been associated with cognitive deficits
in long-term users, studies among patients with schizophre-
nia have been contradictory. This article consists of 2 stud- Introduction
ies. In Study I, a meta-analysis of 10 studies comprising Rates of substance use disorders among individuals with
572 patients with established schizophrenia (with and with- schizophrenia are higher than the general population,1–3
out comorbid cannabis use) was conducted. Patients with with cannabis being the most commonly abused illicit
a history of cannabis use were found to have superior neuro- drug.4 While cannabis use has been associated with poorer
psychological functioning. This finding was largely driven treatment outcomes, including symptom exacerbation,5–7
by studies that included patients with a lifetime history of whether it is also associated with cognitive deficits remains
cannabis use rather than current or recent use. In Study II, contentious. Cannabis use among healthy users has been
we examined the neuropsychological performance of 85 associated with cognitive impairments,8–12 including resid-
patients with first-episode psychosis (FEP) and 43 healthy ual deficits in memory and attention, even several days
nonusing controls. Relative to controls, FEP patients with following abstinence.13–16 Our studies in individuals with
a history of cannabis use (FEP 1 CANN; n 5 59) dis- no medical or psychiatric history have shown that long-
played only selective neuropsychological impairments while term cannabis use is associated with structural brain
those without a history (FEP 2 CANN; n 5 26) displayed abnormalities and subthreshold psychotic symptoms
generalized deficits. When directly compared, FEP 1 in a dose-dependent manner.8 However, among patients
CANN patients performed better on tests of visual mem- with schizophrenia, the association is less clear. While
ory, working memory, and executive functioning. Patients acute administration of tetrahydrocannabinol (THC) to
with early onset cannabis use had less neuropsychological patients with schizophrenia exacerbates symptoms and
impairment than patients with later onset use. Together, cognitive impairments and may have enduring effects,17
these findings suggest that patients with schizophrenia or cannabis has also been found to have some beneficial
FEP with a history of cannabis use have superior neuropsy- effects on cognition, at least in certain subgroups of
chological functioning compared with nonusing patients. patients.18–20 Thus, while cannabis use is traditionally as-
This association between better cognitive performance sociated with cognitive impairment, the relationship is
and cannabis use in schizophrenia may be driven by a sub- more complex in the case of schizophrenia.
group of ‘‘neurocognitively less impaired’’ patients, who Although a recent meta-analysis conducted by Potvin
only developed psychosis after a relatively early initiation and colleagues21 supports this notion, their analysis does
into cannabis use. not include studies conducted after 2006 and is not
Ó The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: journals.permissions@oxfordjournals.org.

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 Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

focused on cannabis specifically but includes patients each study. We used global scores of cognition from
with polysubstance abuse. Here, we present 2 studies the Study I of Løberg et al29 because their classification
that aim to clarify the nature of the association between of cognitive domains differed from the MATRICS.
cannabis use and cognitive impairments observed in
schizophrenia. The first study comprises a meta-analysis Meta-analytical Procedure. For each cognitive test, ef-
of empirical investigations of cannabis effects on cogni- fect size (Cohen’s d) and SE were calculated. Effect sizes
tion in patients with established schizophrenia. In the were defined as the mean difference between the schizo-
second study, we compared the neuropsychological func- phrenia patients’ and healthy controls’ performance
tioning of patients with first-episode psychosis (FEP) divided by the pooled SD. Effect sizes were weighted us-
with and without a history of cannabis use as well as ing the inverse variance method. A random effects model
healthy controls with no substance use history. was used. Homogeneity of the mean-weighted effect sizes
was tested using the Q-test, while publication bias was
assessed using Egger’s test. Only instances where there
Study I: Meta-analysis of Findings To Date were heterogeneity or publication biases are described
Methods in the Results. Meta-analyses were performed using

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We performed a literature search using PUBMED, Psyc- MIX software.31 Meta-regression analyses examined the
INFO, and Scopus covering the period between 1987 effect of moderator variables on between-group differ-
and March 2010. Combinations of the following key- ences. This was performed with random effects modeling
words were used: schizophrenia, psychosis, cannabis, sub- using the restricted-information maximum likelihood
stance, cognit*, and neuropsycholog*. The reference lists method with a significance level set at P < .05. These anal-
of the published articles were also reviewed. Inclusion cri- yses were conducted in SPSS version 16.0 using the macros
teria included: (1) diagnosis of schizophrenia, (2) cogni- written by DB Wilson (http://mason.gmu.edu/;dwilsonb/
tive abilities of patients with and without cannabis use ma.html). Separate meta-analyses were also performed
were directly compared, (3) cannabis was the predomi- for studies defining cannabis use as ‘‘lifetime’’ or ‘‘recent’’
nant substance used by patients, and (4) studies reported (current/last 6 months) use.
sufficient data to calculate effect sizes in d metrics.
The initial search yielded 145 studies but only 15 stud- Results
ies considered the effect of cannabis on cognition in There were significant differences between the SCZ þ
schizophrenia (table 1). Five of these studies were ex- CANN and SCZ
CANN groups for gender, age, edu-
cluded because: (1) they lacked data for calculating effect cation, age of onset of illness, and positive symptoms.
size,22,23, (2) the study sample included a mixture of The SCZ þ CANN group comprised more males
patients with schizophrenia and affective disorders,24 (RR = 1.10, CI = 0.99–1.22, Z = 1.75, P = .08), had
and (3) they were primarily FEP studies (too few studies less education (d = 0.40, CI = 0.21–0.60, Z = 4.01, P <
in this group to conduct appropriate meta-analyses).25,26 .001), a younger age (d = 0.57, CI = 0.36–0.79, Z =
In 6 of the 10 studies included in the meta-analysis, can- 5.29, P < .001), more severe positive symptoms (d =
nabis use was defined as lifetime use and in the other 4 0.65, CI = 0.41–0.90, Z = 5.15, P < .001), and earlier
studies it was defined as recent use (current use or use illness onset (d = 0.42, CI = 0.19–0.65, Z = 3.59, P =
in last 6 months). In 2 of the included studies,27,28 not .003). There were no significant between-group differ-
all patients in the substance-using groups were abusing ences for duration of illness, negative symptoms, and
cannabis, but they were still included in the meta-analysis premorbid IQ.
since cannabis was the most commonly used substance
within the samples. In one study,29 we used data from Global Cognition Index. Eight studies reported superior
the 3-month follow-up assessment only since some patients performance for SCZ þ CANN patients on global cog-
had very recently used substances at baseline or were nition (see table 3; figure 1). The studies that reported bet-
acutely intoxicated at the time of testing. Overall, our ter performance in SCZ þ CANN tended to define
meta-analysis included 10 studies involving 572 patients cannabis use as lifetime use. Overall, SCZ þ CANN
with schizophrenia (with and without comorbid cannabis patients performed significantly better than SCZ

use). CANN patients (d = 0.35). The distribution of effect sizes
observed in these studies was not homogeneous. In sep-
Neuropsychological Variables. Neuropsychological arate analyses for studies using lifetime or recent canna-
variables were grouped according to the 6 cognitive bis use criteria, no more heterogeneity was observed.
domains of the Measurement and Treatment Research SCZ þ CANN patients performed significantly better
to Improve Cognition in Schizophrenia (MATRICS) only in the studies defining use by lifetime exposure
battery30 (table 2). A ‘‘Global cognition index’’ was cal- (d = 0.55) but not in the studies using recent use criteria
culated by averaging effect sizes from each domain for (d = 0.03). Meta-regression analyses did not reveal any
317
318

M. Yücel et al.
Table 1. Studies that Investigated Cannabis Use and Cognition Association in Schizophrenia

Studies Sample Cannabis Criteria Cannabis Use Other Drugs Cognitive Tests Results

Lifetime history
Joyal et al27 16 SCZ þ Cannabis abuse or No information regarding TMT-A, TMT-B, WCST, Impaired WCST, COWAT
SUD dependency Not all the abstinence and duration/ COWAT, RCFT, WAIS in nonusers Fewer
patients use cannabis but onset of cannabis use PA, Porteus Maze, Go/ neurological soft signs
14 SCZ
cannabis was the preferred No Go
SUD substance for the sample

Stirling 24 SCZ þ Cannabis use prior to onset No information regarding Design memory, verbal SCZ þ CANN better in
et al33 CANN of psychosis abstinence and duration/ fluency, WAIS OA, BD, 7/9 measures SCZ

onset of cannabis use PC, PA, face recognition CANN more deficit
39 SCZ
memory schizophrenia and more
CANN neurological soft signs

Jockers- 19 SCZ þ At least 0.5 g daily For 2 y Abstinence, at least 4 wk Alcohol excluded, CPT-IP, TMT-A, TMT-B, SCZ þ CANN performs
Scherubl CANN prior to onset (weekly urine screenings) SCZ
no other WCST, WMS-R verbal better than SCZ

et al19 substance abuse and visual memory, CANN in some cognitive
20 SCZ
WAIS-R (BD, PA, domains. Regular use
CANN DSST, Comprehension) before 17 associated with
39 HC even better performance

Sevy et al32 14 SCZ þ Cannabis abuse or No information regarding Cannabis main substance, WRAT, CPT-IP, CVLT, No difference No impact of
CANN dependency 0.5 g/day, abstinence and duration/ 7 alcohol abuse, 3 cocaine DS (backward and alcohol
>4 d of the week. Only onset of cannabis use abuse Nicotine use is forward), TMT-A,
13 SCZ
1 subject used in last 2 mo 78% started prior to onset more in SCZ þ CANN TMT-B, COWAT
CANN of psychosis (semantic and
phonemic), IGT

Løberg 13 SCZ þ History of cannabis abuse No information regarding All abuse cannabis 8 Memory, attention, SCZ þ CANN performs
et al29 CANN or dependency abstinence and duration/ additional substance psychomotor speed, better except memory
(Study I) onset of cannabis use abuse mainly general abilities, and
18 SCZ
amphetamine executive function
CANN domains based on
various test

Schnell 35 SCZ þ Cannabis abuse or Minimum 3 wk abstinence No other substances AVLT, LNS, DSST, SCZ þ CANN better in
et al20 CANN dependency All started (self and medical reports except nicotine TMT-B, MWT-B, WM, executive functions,
prior to onset of illness and urine screening) Age CPT, Verbal fluency, and verbal memory. High
34 SCZ
(average 6 y) of onset = 17 Duration = Dual processing frequency use was
CANN 8.5 y Frequency/month = task associated with even
53 joints better performance

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 Table 1. Continued

Studies Sample Cannabis Criteria Cannabis Use Other Drugs Cognitive Tests Results

Current/recent use
Potvin 44 SCZ þ Abuse or dependence No information regarding 12 cocaine, 17 PAL, MOT SCZ þ CANN better in
et al28 CANN Not all the patients use abstinence and duration/ polysubstance MOT No difference for
cannabis but cannabis onset of cannabis use PAL. However, SCZ þ
32 SCZ
was the preferred CANN patients who use
CANN substance for the cocaine are more
sample Last 6 mo impaired in PAL. Non
cocaine user but SCZ þ
CANN patients are better
than SCZ
CANN in
PAL

Løberg 13 SCZ þ Current cannabis abuse No information regarding All abuse cannabis 10 Global cognition score In acute admission, SCZ þ
et al29 CANN or dependency Acute abstinence and duration/ also abuse other based on various CANN performs worse,
(Study II) admission with onset of cannabis use substances (4 cognitive tests in follow-up they
13 SCZ
schizophrenia or amphetamine, 3 longitudinal study, significantly improved
CANN schizophrenia like cocaine, 4 alcohol) 3 mo follow-up SCZ
CANN no change
psychoses in follow-up

Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

Ringen 117 SCZ þ Cannabis use in last DSST, Digit span, 2-Back, SCZ þ CANN performs
et al78 CANN 6 mo Verbal fluency, Logical worse in verbal memory
memory, word and attention
23 SCZ
interference, CVLT
CANN

Scholes 22 SCZ þ Current cannabis use Stroop, WCST, Spatial No difference

et al79 CANN span, LNS
49 SCZ

CANN

Note: TMT-A, Trial Making Test—Part A; TMT-B, Trial Making Test—Part B; TMT B/A, Trial Making Test—Part B minus Part A; WCST, Wisconsin Card Sorting Task;
COWAT, Controlled Oral Word Association Task; RCFT, Rey Complex Figure Test; PAL, Paired Associate Learning; MOT, Motor Screening; OA, Object Assembly; BD,
Block Design; PC, Picture Completion; PA, Picture Arrangement; DS, Digit Span; WAIS, Wechsler Adult Intelligence Scale, WRAT, Wide Range Achievement Test; CPT-
IP, Continuous Performance Task—Indentical Pairs; CVLT, California Verbal Learning Task; IGT, Iowa Gambling Task; RAVLT, Rey Auditory Verbal Learning Task;
LNS, Letter Number Sequencing; DMST, Delayed Matching to Sample Test; MWT-B, Mehrfachwahl-Wortschatztest—Form B; HC, Healthy Control; SUD, Substance Use
Disorder; FEP, First-Episode Psychosis; SCZ, Schizophrenia; DSST, digit symbol substitution task. Superscript numbers refer to the relevant reference number in the
citations list.
319

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M. Yücel et al.

Table 2. NIMH-MATRICS Cognitive Domains however, when recent use vs lifetime defining studies
was examined separately, there was no evidence for het-
Cognitive Domain Cognitive Test erogeneous distribution of effect sizes. SCZ þ CANN
patients performed significantly better than SCZ

Processing Speed Phonetic fluency, semantic fluency, Trail-
Making Test, Symbol Coding, Motor
CANN only within the lifetime defining studies (d =
Screening Task, Stroop 0.65) but not in those studies with recent use criteria
Attention Continuous Performance Test, Dual (d = 0.09).
Processing Task
Working Memory Digit span, Letter Number Sequencing, Visual Memory. Three studies assessed visual memory.
Wechsler Memory Scale—Revised Again, SCZ þ CANN patients performed better than
Verbal Memory SCZ
CANN patients (d = 0.45).
Reasoning and WAIS Block Design, Object Assembly,
Problem Picture Arrangement, Porteus Maze, Verbal Memory. Four studies reported verbal memory
Solving Wisconsin Card Sorting Test measures. There was no significant between-group differ-
Verbal Learning California Verbal Learning Test, Rey ence for verbal memory (d = 0.0). The Q-test showed ev-
and Memory Auditory Verbal Learning Test

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idence for heterogeneity for distribution of effect sizes.
When the 3 lifetime defining studies were examined sep-
Note: Abbreviations are explained in the footnote to table 1.
arately, between-group comparisons remained nonsignif-
icant (d = 0.18).
effect of demographic (effect size of age difference and
gender ratio) or clinical variables (effect size of differen- Working Memory. Four studies examined working
ces for onset of illness, duration of illness, positive, and memory. There was no significant between-group differ-
negative symptoms) on the magnitude of the between- ence (d = 0.13). While distribution of effect sizes was het-
group differences. erogeneous, the between-group difference for 2 lifetime
defining studies was d = 0.64, with the SCZ þ CANN
Attention. Three studies examined attention. There group demonstrating significantly superior performance.
were minimal between-group differences on a sustained The between-group difference for recent use criteria stud-
attention task (d = 0.26). ies was not significant (d =
0.28). There was no evidence
of heterogeneity for these separate analyses.
Processing Speed. Eight studies examined processing
speed. The SCZ þ CANN patients had significantly fast- Executive Functioning. In the 4 studies included in this
er processing speeds than SCZ
CANN patients (d = domain, cannabis use was associated with better planning
0.40). Effect sizes were not homogeneously distributed, and reasoning abilities (d = 0.47). When the lifetime

Table 3. Mean-Weighted Effect Sizes for Cognitive Domains for Cannabis Using and Nonusing Schizophrenia Patients Defined by
Lifetime Use Vs Current or Recent Use Criteria

Number SCZ þ SCZ

Test of Studies CANN CANN Cohen’s d 95 % CI z P Q-test, P Bias Test

Global cognition 10 223 349 0.35 0.09 to 0.61 2.63 .009 17.13* 0.34
Lifetime 6 121 138 0.55 0.30 to 0.80 4.29 .001 3.95
Current/recent 4 102 211 0.03
0.30 to 0.37 0.20 .84 4.59
Attention 3 68 67 0.26
0.08 to 0.61 1.51 .13 0.50 0.26
Processing speed 8 192 322 0.40 0.11 to 0.69 2.75 .006 14.62* 0.39
Lifetime 5 103 124 0.65 0.38 to 0.92 4.70 .001 1.72
Current/recent 3 89 198 0.09
0.34 to 0.52 0.42 .67 4.87
Visual memory 3 87 91 0.45 0.13 to 0.77 2.76 .006 2.24 0.98
Verbal memory 4 101 184 0.0
0.51 to 0.51 0 .99 10.1* 0.75
Lifetime 3 78 67 0.18
0.32 to 0.77 0.63 .53 4.78
Planning 4 81 122 0.47 0.05 to 0.90 2.20 .03 5.92 0.39
Lifetime 3 59 73 0.67 0.31 to 1.03 3.65 .001 1.20
Working memory 4 94 213 0.13
0.40 to 0.55 0.48 .63 11.58* 0.61
Lifetime 2 49 47 0.64 0.22 to 1.05 3.00 .003 0.16
Current/recent 2 45 166
0.28
0.61 to 0.06 1.62 .10 0.12

Note: Bold values indicate comparisons that were significantly different between the SCZ þ CANN and the SCZ
CANN groups.
*P < .05.

320
 Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

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Fig. 1. Effect Size Analysis of All Studies Conducted To Date. A summary score global cognition index was calculated by averaging effect sizes
from each domain for each study.

defining studies were examined separately, the between- Summary of Study I

group difference was larger (d = 0.67). These meta-analyses demonstrate that patients with
established schizophrenia with a cannabis use history
Recency of Cannabis Use. For this analysis, we excluded display superior cognitive abilities compared with non-
the study by Jockers et al19 as they did not exclude patients cannabis-using patients. These results may appear coun-
using cannabis in the week prior to testing. Patients with terintuitive because healthy individuals who are heavy
SCZ þ CANN without recent use demonstrated better cannabis users have cognitive deficits and brain abnor-
verbal memory performance than the SCZ
CANN malities.8,9 However, our findings are consistent with pre-
group (d = 0.46, CI = 0.05–0.88, Z = 2.20, P = .03). Dis- vious studies conducted in schizophrenia patients with
tribution of effect sizes was more homogenous with this comorbid polysubstance use,21 while showing specificity
analysis (P = .52). to a cannabis-using sample. Furthermore, we showed
that better cognitive performance is seen only in lifetime
Frequency of Cannabis Use. One study reported an as- users but not in recent users.
sociation between higher frequency of cannabis use Importantly, the majority of studies to date have been
and better cognitive performance (working memory conducted in patients with chronic illness without assess-
and attentional tasks; Schnell et al).20 ing whether cannabis use preceded the onset of psychosis.
It is possible that the cognitive profile of patients whose
Age of Onset of Cannabis Use. Only one study examined cannabis use may have contributed to the onset of their
the relationship between age of onset of cannabis use and psychosis might be different from those who started using
cognitive deficits.19 In this study, earlier starting age of cannabis after the onset of their psychosis. Studies exam-
cannabis use (ie, before 17 years of age) was associated ining cannabis use prior to the onset of FEP are especially
with superior cognitive performance. useful in this regard because cannabis use may contribute
to the onset of psychosis only in these patients. Five stud-
Effect of Other Substances. A separate meta-analysis for ies have examined cognitive functioning in a sample who
the 2 studies19,20 consisting of patients without comorbid used cannabis before the onset of psychosis.25,26,33 How-
substance use (other than nicotine) was conducted. We ever, the studies of Stirling et al,33 Jockers-Scherubl et al,19
found a similar mean effect size for global cognition and Schnell et al20 included a chronic sample, and it was
(d = 0.43) to that observed in the overall meta-analysis. not possible to exclude the effects of cannabis use after
One study also examined the effect of comorbid alcohol the onset of psychosis or illness-related factors. While
use in cannabis-using patients and failed to find any sig- the studies of de la Serna et al25 and Mata et al26 were
nificant difference between alcohol-using and nonusing also FEP samples, they only assessed cannabis use in
groups.32 One study found that cocaine-using SCZ þ the previous one month or in the previous 12 months,
CANN patients were cognitively more impaired.28 meaning that their cannabis nonuser samples were likely
321
M. Yücel et al.

to have also included patients who had a past history of based on a medical record review and structured clinical
cannabis use. interview using the Positive and Negative Syndrome
Thus, there are no FEP studies that have examined Scale,44 SCID-I/NP41 and the Royal Park Multi-diagnos-
cognitive functioning in FEP patients with a lifetime his- tic Instrument for Psychosis (McGorry et al45). For con-
tory of cannabis use. In our second study, we report on trols, we used the SCID-I (nonpatient edition). Of the 59
such a sample. Additionally, given that the age of canna- patients classified as cannabis users (FEP þ CANN), 55
bis use onset has been found to be an important moder- met criteria for past or current cannabis abuse or depen-
ator of the association between cannabis use and dence. Thirty-two of the FEP þ CANN had started to use
psychotic illness,34–37 we investigated the impact of age cannabis at 16 years of age or earlier (FEP þ CAN-
of cannabis use onset on cognitive functioning. N[early]) and 27 had started at age 17 or thereafter
(FEP þ CANN[later]). We chose to compare those
who had commenced using cannabis before or after
Study II: New Data in FEP Patients ages 16–17 years on the basis of previous literature sug-
gesting that exposure to cannabis prior to this period of
Methods adolescence has relatively greater adverse consequences

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Sample and Setting. Participants included 85 FEP compared with later initiation,12,46 and this cutoff en-
patients and 43 healthy nonusing controls. Participants abled a roughly equal division of the sample. All were ab-
were selected from a larger neuropsychological research stinent at the time of assessment (according to self-report,
database (described previously38–40) only if they were medical records/case notes, and researcher observations),
assessed for substance use. While all participants agreed 34 for >1 month, while 10 had consumed cannabis within
to a cognitive test battery, some participants had an in- the previous week, and a further 10 for between 8 and 30
complete cognitive assessment. A detailed substance use days prior to the assessment (data were missing for 5
history, including information concerning the amount, cases). Fifteen of the FEP þ CANN patients also had
frequency, duration, and type of substance use, diagno- a history of stimulant and hallucinogen use (mainly am-
sis, time since last use, and age of onset of regular use, was phetamine), and 16 others had a history of alcohol abuse.
obtained using a combination of medical history notes Most patients (n = 51) were prescribed antipsychotic med-
and structured clinical and research interviews (ie, sub- ication (35 risperidone, 14 olanzapine, and 2 typical anti-
stance use module of the Structured Clinical Interview psychotics), while 10 were prescribed mood stabilizers (5
for DSM-IV [Diagnostic and Statistical Manual of Mental lithium and 5 sodium valproate) and 7 were prescribed
Disorders, Fourth Edition], Patient version [SCID-I/P],41 antidepressants (5 SSRI, 1 imipramine, and 1 moclobe-
Clinical Global Impressions-Severity of Illness Scale42). mide). Chlorpromazine equivalents (cpz) of antipsy-
In addition, substance use data were gathered from the chotics were calculated.47
Early Psychosis File Questionnaire,43 which was used Healthy controls comprised 43 individuals with no
to systematically extract data on premorbid, entry, treat- current or past history of illicit substance abuse or depen-
ment, and discharge characteristics from consecutive dence. Healthy volunteers were recruited by approaching
medical files. Cannabis was the predominant substance ancillary hospital staff (eg, nonprofessional staff and stu-
used in FEP patients. FEP patients with a history of reg- dents) and through advertisements in local newspapers in
ular use (defined as >2 years of use and >2 g per week) the same catchment area as the patients (ie, north-western
were classified as cannabis users (n = 59; FEP þ CANN), regions of Melbourne) as well as through ‘‘word of
and a large majority of these patients met criteria for Di- mouth’’ (ie, friends of patients).
agnostic and Statistical Manual of Mental Disorders, All participants were screened for comorbid medical
Third Revision (DSM-III-R) cannabis abuse or depen- conditions. Exclusion criteria were a history of head
dence (see below). FEP patients without a history of injury causing loss of consciousness for greater than
regular cannabis use were classified as nonusers (n = 1 minute and/or hospitalization, neurological disorders,
26; FEP
CANN). Cannabis use was assessed over thyroid disorders, documented poor eyesight or hearing,
each subject’s lifetime, and none of the FEP
CANN and history of corticosteroid use. Control participants
group had ever used cannabis regularly (ie, had not with family or personal histories of psychiatric illness
used on a weekly basis for >12 months), while all FEP þ were also excluded. Local research and ethics committees
CANN patients used cannabis before the onset of the ill- approved the study, and written informed consent was
ness. Of the 26 FEP
CANN patients, 3 had a past his- obtained from all individuals prior to study participation.
tory of alcohol abuse and 4 others had experimented with
stimulants and lysergic acid diethylamide (LSD). Cognition. All participants were administered a cogni-
All patients with FEP were recruited from the Early tive test battery by experienced psychologists. Neuropsy-
Psychosis Prevention and Intervention Centre at Orygen chological tasks targeted general intelligence, processing
Youth Health and were diagnosed with schizophrenia- speed, verbal memory, visual memory, working memory,
spectrum disorders according to DSM-III-R criteria and executive functioning (planning and reasoning).
322
 Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

These domains reflect 5 of 6 dimensions in the MATRICS Table 4. Demographic and Clinical Characteristics of Patient and
battery.30 In order to facilitate comparison with the meta- Control Groups
analysis in Study I, tasks that were, and those that were
FEP þ FEP

not reflected in the MATRICS battery were allocated to
Control CANN CANN P
a relevant domain following a consensus agreement be-
tween 2 authors (E.B. and M.Y.). Number 43 (33/10) 59 (43/16) 26 (15/11) .44
(male/female)
General Intellectual Ability. Performance on the Na- Age 21.6 (5.8) 20.7 (2.8) 20.6 (3.5) .49
tional Adult Reading Test was used to estimate premorbid Education 12.3 (1.4) 10.9 (1.8) 11.6 (2.0) .001a
IQ.48 The Wechsler Adult Intelligence Scale—Revised PANSS positive 24.7 (6.3) 21.8 (6.5) .06
(WAIS-R) was used to estimate current IQ.49 PANSS negative 20.7 (7.4) 20.9 (8.2) .93
Processing Speed. The Trail-Making Test (Part A) and GAF-premorbid 70.1 (13.5) 76.2 (12.0) .20
Digit Symbol Coding were used as measures of process- GAF-entry 29.9 (8.5) 31.7 (7.5) .32
ing speed.49,50

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Note: Bold values indicate comparisons that were significantly
Visual Memory. Visual Paired Associates (part I) and different between the FEP þ CANN and the FEP
CANN
groups. GAF, Global Assessment of Functioning; PANSS,
Visual Reproduction (part I) from the Wechsler Memory
Positive and Negative Syndrome Scale. Additional abbreviations
Scale—Revised (WMS-R) provided measures of visual are explained in the footnote to table 1.
learning and memory.51 Spatial and Pattern Recognition a
FEP þ CANN < Controls.
tests from the Cambridge Automated Neuropsychologi-
cal Test Automated Battery (CANTAB) were used to in- were also used to compare FEP
CANN, FEP þ CAN-
dex recognition memory.52,53 N[early], and FEP þ CANN[later]. Significant F-
statistics were followed up with post hoc analyses using
Verbal Memory. A modified version (3 trials instead of the Tukey test. Cohen’s d also characterized between-
5) of the Rey Auditory Verbal Learning Test was used as group differences.57 Pearson product moment correlation
a measure of verbal learning and delayed recall.54 The was used to examine relationships between cognition,
Logical Memory (parts I and II) component of the parameters of cannabis use, and clinical measures.
WMS-R was also used.51
Results
Working Memory. Spatial Span and Spatial Working
Memory (SWM) from the CANTAB were used to index Demographic. There was no significant between-group
working memory.53,55 Regarding SWM, 2 scores were in- difference for age and gender (see table 4). FEP patients
cluded in the analysis: (1) total between-search errors who use cannabis were less educated than controls but
(SWM-errors), which is the number of times that a subject did not differ from FEP
CANN, while the latter did
returns to a box in which a token had already been found not differ from controls.
during a previous search sequence and (2) strategy score
(SWM-strategy), a measure of the ability to adopt a sys- FEP
CANN and FEP þ CANN vs Controls. FEP
tematic search approach (ie, initiating a search from the patients (with and without comorbid cannabis) were signif-
same token across trials shows better strategy use). While icantly impaired on all 16 tasks compared with controls.
SWM-errors is a more pure measure of short-term work- Effect sizes of these impairments in all 6 cognitive domains
ing memory, strategy score also measures central execu- were moderate to large, ranging from 0.52 to 2.11. The
tive functioning. most pronounced impairments were observed for Current
IQ (d = 2.11), Logical Memory (d = 1.70), SWM-errors (d =
Executive Functioning. Block Design from the WAIS-R 1.60), and Digit Symbol Coding (d = 1.48).
and the Tower of London (ToL) tests were used as meas- WhenwecomparedeachoftheFEPþ CANNandFEP

ures of planning and reasoning ability.49,56 CANN groups separately to controls, the FEP
CANN
patients were significantly impaired on 15 of the 16 tasks ad-
Statistical Analyses. Statistical analyses were conducted ministered across the 6 cognitive domains, while the FEP þ
using the Statistical Package for Social Sciences Version CANN group showed only selective impairments (9 of the
16.0 (SPSS 16.0). Between-group differences on categor- 16 tasks) (table 5; figure 2). Both FEP þ CANN and FEP

ical variables were tested using chi-square analysis. CANN patients were significantly impaired for all tasks of
Patients’ scores on cognitive tests were converted to z general intelligence, verbal memory, and processing speed.
scores based on the controls’ performance. ANCOVA Unlike the FEP
CANN group, the FEP þ CANN group
was used to test group differences between FEP
was not significantly different from controls on most tasks
CANN and FEP þ CANN on continuous measures of visual memory and planning/reasoning. In the working
with gender and age as covariates. ANCOVA analyses memory domain, FEP þ CANN patients were impaired
323
M. Yücel et al.

Table 5. Mean Z Scores and Between-Group Differences for Cannabis Using and Nonusing FEP Groups

N FEP þ CANN N FEP
CANN p ES

General Intelligence
Current IQ 54
1.65 (1.40)* 20
2.39 (0.96)* .07 0.40
Premorbid IQ 41
0.50 (1.14) 16
0.57 (1.24) .83 0.06
Verbal Memory
RAVLT—total 40
0.73 (0.88)* 19
1.05 (1.17)* .21 0.33
RAVLT—recall 40
0.65 (0.96)* 19
1.09 (1.24)* .15 0.44
Logical Memory 41
1.33 (0.85)* 16
1.59 (0.80)* .21 0.30
Visual Memory
Visual PA—total errors 47
0.17 (0.99) 23
0.59 (1.08)* .10 0.50
Visual Reproduction 35
0.19 (0.70) 19
0.71 (1.17)* .05 0.60
Spatial Recognition 49
0.39 (1.01) 23
0.83 (1.39)* .18 0.39
Pattern Recognition 49
1.04 (1.20)* 23
1.65 (1.50)* .09 0.47
Processing Speed

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Trails A 39
1.54 (1.58)* 19
1.98 (3.24)* .48 0.19
Digit Symbol Coding 44
1.83 (1.61)* 17
1.90 (1.60)* .67 0.04
Working Memory
SWM-errors 49
0.94 (1.13)* 22
1.80 (1.30)* .01 0.74
SWM-strategy 49
0.48 (0.91) 22
0.88 (0.86)* 0.12 0.44
Spatial Span 49
0.58 (0.91) 22
1.01 (1.02)* 0.09 0.44
Executive Functioning
Block Design 36
0.92 (1.23)* 18
1.19 (1.65)* 0.62 0.22
ToL minimum solution 24
0.19 (0.93) 12
1.15 (1.37)* 0.03 0.90

Note: Corrected for age and gender differences; ES, effect size (Cohen’s d; unadjusted values); Asterisks reflect that these measures are
significantly different to healthy controls. ‘‘p’’ represents the P values for comparisons between the FEP þ CANN and FEP
CANN
groups. Values in parentheses represent the SD of z scores. SWM, Spatial Working Memory; ToL, Tower of London. Additional
abbreviations are explained in the footnote to table 1. Bold values indicate comparisons that were significantly different between the
FEP þ CANN and the FEP
CANN groups.

in SWM-errors but not in SWM-strategy or Spatial Span. to
0.39). Similarly, no significant differences were found
FEP þ CANN patients did not differ from controls on the between the alcohol-using and nonusing FEP þ CANN
ToL task involving planning and reasoning. patients (d ranged from
0.10 to þ0.54).

FEP
CANN vs FEP þ CANN. FEP þ CANN patients Age of Onset of Cannabis Use. When comparing the non-
tended to perform better than FEP
CANN patients but cannabis-using patients (FEP
CANN) with early onset
this difference was significant only for 3 variables (table 5; (16 years; FEP þ CANN[early]) and later onset (17
figure 2). On verbal and nonverbal memory, between- years; FEP þ CANN[later]) cannabis-using patients, we
group differences were small to moderate (d ranged found group differences for 4 cognitive tests (SWM-errors,
from 0.3 to 0.6) and FEP þ CANN performed signifi- ToL, Pattern Recognition, and Spatial Recognition). The
cantly better on visual reproduction. For the working FEP
CANN patients did not differ from FEP þ CANN
memory domain, small to medium effect sizes were ob- [later] on any cognitive tests (figure 3). FEP þ CAN-
served and a between-group difference for SWM-errors N[early] patients performed significantly better than
reached significance (ie, with FEP þ CANN performing FEP
CANN on all 4 of the above cognitive tests and
better). For executive functioning, a significant between- better than FEP þ CANN[later] on 2 tests (Pattern Recog-
group difference with a large effect size (d = 0.90) was nition and Spatial Recognition). The FEP þ CANN[early]
observed for the ToL test (again with FEP þ CANN per- group were younger than the FEP þ CANN[later] group
forming better). (table 6) but did not differ in duration or monthly quantity
of cannabis use, diagnosis, treatment, or antipsychotic lev-
Comorbid Substance Use. ANCOVA analyses were con- els (based on chlorpromazine equivalents; see table 6).
ducted to examine the effect of additional illicit substance
use (over lifetime) on cognition in the FEP þ CANN Recency of Cannabis Use. FEP patients who had used
patients. FEP þ CANN patients who also used amphet- cannabis in the previous week were more impaired on
amines (n = 12) did not perform significantly differently Logical Memory compared with patients who were absti-
to the remaining (nonamphetamine using) FEP þ CANN nent for greater than 1 month prior to testing (P = .04).
patients on any cognitive measure (d ranged from
0.50 There were no significant correlations between cognition
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 Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

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Fig. 2. Mean Z Score Differences for Cannabis Using and Nonusing FEP Groups.Note: IQ, intelligence; PS, processing speed; verMEM,
verbal memory; visMEM, visual memory; wMEM, working memory; EF, executive functioning. Note that each point reflects a specific task
within the 6 domains of interest (refer to the Methods section and table 5 for the specific tasks).

and other cannabis use parameters (frequency, quantity, domains. Unlike most previous studies, we also examined
and duration of use). the effect of variables such as recency and frequency of
use and age of onset of cannabis use. The findings
Associations between Clinical Variables and Cognition. In were consistent with Study I and demonstrated that
both FEP groups, the Positive and Negative Syndrome FEP patients who used cannabis (especially those who
Scale negative symptoms score was negatively correlated used prior to age 17) also performed better than nonusing
with Digit Symbol Coding (FEP þ CANN: r =
.41, patients in some domains and were less impaired relative
P = .006, FEP
CANN: r =
.58, P = .02) and Current to healthy controls on cognitive domains, including vi-
IQ (FEP þ CANN: r =
.43, P = .002, FEP
CANN: r = sual memory, working memory, planning, and reasoning.

.55, P = .01). The positive symptoms score was not sig- When age of onset of cannabis use was considered, supe-
nificantly correlated with any cognitive measure. rior cognitive performance in cannabis-using patients
relative to nonusing patients was only observed among
Discussion those who started using cannabis at an early age (16
In Study I, we demonstrated that regular cannabis use years). Together, the findings of our meta-analysis and
was associated with better cognitive performance in empirical study suggest that comorbid cannabis use is as-
schizophrenia. Cannabis-using patients performed mod- sociated with a superior cognitive profile in schizophrenia-
erately better than nonusing patients on measures of spectrum disorders.
global cognition, visual memory, processing speed, work- Several explanations regarding the nature of the asso-
ing memory, planning, and reasoning. This difference ciation between pre-illness onset cannabis use and subse-
was largely driven by studies that included patients quent development of schizophrenia have been
with a lifetime history of cannabis use rather than just suggested. One explanation is that cannabis is a risk fac-
those with current or recent use. Consistent with previous tor that precipitates (but does not cause) the onset of psy-
studies, cannabis use was associated with a younger age chosis in genetically predisposed individuals.61 However,
of psychosis onset, male sex, and more positive symp- there is also evidence that cannabis use prior to illness
toms.7,36,58–60 Study II examined the effect of regular onset is ‘‘causally’’ related to the development of subse-
cannabis use on cognition in FEP patients. Cognitive per- quent psychosis in vulnerable individuals.62–64 Similarly,
formance of FEP patients with a history of cannabis use several recent systematic reviews have indicated that can-
was compared with FEP patients without a history of nabis may double the risk of later developing a psychotic
substance use and healthy controls on 6 cognitive illness and that this association is dose dependent.34,63,65
325
M. Yücel et al.

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Fig. 3. Mean Z Score Differences for Early and Late Cannabis Using FEP Groups.Note: IQ, intelligence; PS, processing speed; verMEM,
verbal memory; visMEM, visual memory; wMEM, working memory; EF, executive functioning. Note that each point reflects a specific task
within the 6 domains of interest (refer to the Methods section and table 5 for the specific tasks).

However, few previous studies have considered the role we did not find any current or premorbid Global Assess-
of cognition. Our findings raise a number of further ment of Functioning (GAF) differences between FEP
questions concerning the relationship between cannabis, users and nonusers in our study.
cognition, and schizophrenia. While the FEP patients with a cannabis use history
Some authors have suggested a neuroprotective role were generally superior in their cognitive profile to those
of cannabis66 to explain the association between cannabis without a history of cannabis use, the former group was
use and enhanced cognition in schizophrenia patients.19,67 not homogeneous. Indeed, the cognitive profile was
Other authors suggest that, in the short-term, cannabi- markedly different depending on the age of onset of can-
noids could stimulate prefrontal neurotransmission to nabis use, with the early onset group having superior cog-
enhance cognitive functions,22,34,67,68 but in the long- nition, which cannot be explained by differences in the
term, repeated administration is detrimental.12 However, duration or dosage of cannabis used. This finding is
these postulates remain speculative and further work is somewhat against expectation and is counterintuitive
necessary. It is well recognized that acute administration given the associations between cannabis use and cogni-
of THC impairs rather than enhances cognitive perfor- tion in healthy controls (ie, worse cognition in those
mance in both healthy controls12,17 and patients with psy- with early onset use12). It is possible that in the FEP
chosis17,69, suggesting that acute neuroprotective effects group with comorbid cannabis use (characterized by
of THC are unlikely. Findings of our meta-analysis and only relatively mild cognitive impairments), early onset
FEP study also provide evidence regarding adverse cannabis use increased the risk for developing psychosis,
effects of recent cannabis use, which may partly mask thereby facilitating the transition to frank psychosis that
the positive association between lifetime cannabis might otherwise not have occurred. That is, early canna-
use and better cognition. Another possibility is that bis use may induce psychosis onset in less cognitively vul-
cannabis-using patients had superior social skills in order nerable individuals. Schnell and colleagues20 as well as
to be able to acquire and sustain a drug habit,12,21 which Løberg and colleagues29 have proposed a similar hypoth-
is also reflected in their cognition. Few studies have esis. Support for this comes from findings that early onset
directly examined this possibility, and this notion is of cannabis use in adolescence, particularly before the age
not always supported by the extant data70; however, of 15, is associated with greater risk for the subsequent
326
 Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

Table 6. Cannabis Use and Clinical Characteristics of Patient Groups Based on Age of Onset of Cannabis Use

FEP
CANN (n = 26) FEP þ CANN[later] (n = 27) FEP þ CAN[early] (n = 32) P Value

Demographic
Age (y) 20.6 (3.5) 22.2 (2.6) 19.5 (2.5) .003a
Gender (male/female) 15/11 20/7 23/9 .39
Education 11.1 (1.6) 11.0 (1.5) 11.5 (1.5) .52
GAF-premorbid 74.8 (11.7) 64.9 (14.3) 75.8 (10.4) .06
GAF-entry 32.4 (7.5) 31.2 (6.3) 27.9 (8.9) .34
Cannabis Use
Age of Onset (y) 17.9 (1.0) 14.4 (1.6) <.001
Duration (y) 3.9 (2.4) 4.8 (2.3) .13
Quantity (g/month) 11.5 (15.8) 20.8 (21.5) .10
Diagnosis .68
Schizophreniform 8 (31%) 8 (30%) 11 (34%)
Schizophrenia 7 (27%) 11 (41%) 12 (38%)

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Mood disorder 8 (31%) 5 (18%) 6 (19%)
Other Psychoses 3 (11%) 3 (11%) 3 (9%)
Symptom
Positive 21.9 (6.7) 25.8 (6.3) 24.3 (5.8) .08
Negative 20.4 (8.1) 20.8 (7.4) 21.4 (7.3) .89
Antipsychotic use .77
Risperidone 12 (46%) 18 (67%) 18 (56%)
Olanzapine 7 (27%) 5 (19%) 7 (22%)
Typicals 2 (8%) 0 (0%) 1 (3%)
No antipsychotics 4 (16%) 4 (15%) 4 (13%)
Missing 1 (4%) 2 (6%)
Chlorpromazine equivalent 204 (259) 136 (102) 169 (141) 0.40

Note: GAF, Global Assessment of Functioning. Additional abbreviations are explained in the footnote to table 1.
a
Post hoc tests; FEP þ CANN[later] vs FEP þ CANN[early] P = .002; FEP þ CANN[later] vs FEP
CANN P = .12; FEP þ
CANN[early] vs FEP
CANN P = .36.

development of psychotic disorders, even after control- port our hypothesis of less severe cognitive impairment
ling for preexisting psychotic symptoms.46 It is possible in a subgroup of neurocognitively less vulnerable
that these individuals would have remained asymptom- patients, with more frequent and heavy use of cannabis
atic or would have been symptomatic only in subsequent necessary to induce psychosis.
years, if they did not abuse cannabis. This notion is con- Our findings should be interpreted in the context of
sistent with Jockers-Scherubl et al19 who found an asso- several limitations. First, while the preceding discussion
ciation between earlier onset of cannabis use and better raises several alternative explanations for the association
cognition in schizophrenia. Such a notion could also help between cannabis use and cognition in schizophrenia, the
explain why cessation of substance use after the first on- cross-sectional nature of the studies considered prevents
set of psychosis significantly increases the probability of firm conclusions being drawn. Longitudinal studies are
remission and improves long-term outcomes in FEP necessary to better understand causal interactions be-
patients.71 Interestingly, a recent study also found fewer tween relevant factors.
neurological soft signs in heavy cannabis-using FEP Second, our findings of poorer cognitive performance
patients, supporting the notion that these patients have in patients without comorbid cannabis use could relate to
less neurological impairment.72 a sampling bias, whereby the FEP
CANN group may
Other factors might also influence the association include a greater proportion of ‘‘deficit syndrome’’
between cannabis use and cognitive deficits in schizo- patients or patients with poorer premorbid functioning,
phrenia, including dosage and frequency of use and cu- worse cognition,73 and lower substance use.74 However,
mulative exposure. Interestingly, while higher frequency the fact that the FEP þ CANN group in our Study II did
of cannabis use could be expected to be associated with not differ from the FEP
CANN group in terms of pos-
poorer cognition, the only 2 studies that have examined itive or negative symptoms, suggests that the latter group
frequency of use in schizophrenia patients found the op- cannot be readily identified as deficit syndrome type.
posite effect (ie, better performance).20,67 While some Furthermore, prepsychotic GAF scores and education
authors propose that such results relate to the neuropro- did not differ between the 2 FEP groups. Consequently,
tective effects of cannabis,19,66,67 the findings also sup- our findings do not support this contention, but more
327
M. Yücel et al.

detailed measures of premorbid functioning are required after an early initiation of cannabis use (ie, during early
to conclusively address this issue. adolescence). However, longitudinal studies in high-risk
Third, given the high rates of cannabis use in FEP and populations are needed to test this notion more deci-
the relationship between cannabis use and the develop- sively. Together, these findings suggest that a subgroup
ment of psychotic symptoms, it is important to consider of psychotic patients may show improved outcomes
what proportion of the FEP þ CANN group had a can- (ie, partial recovery of cognitive functioning and less dis-
nabis-induced psychosis. The diagnostic criteria for sub- ability) if their cannabis use can be controlled. Moreover,
stance-induced psychosis have recently been criticized,75 our findings support the notion that, in some vulnerable
as a diagnosis of cannabis-induced psychosis is unlikely individuals, abstinence from cannabis abuse could poten-
to be made if psychotic symptoms are still apparent 1 tially prevent the development of psychosis.
month following intoxication. Therefore, better cognitive
performance, early onset use, and improvement with
abstinence may be partially explained by inclusion of Funding
FEP þ CANN patients with a cannabis-induced psycho- National Health and Medical Research Council
sis rather than an actual schizophrenia-spectrum disor- (NHMRC) of Australia (Grant 236175, 459111,

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ by guest on March 19, 2016

der. Better diagnostic instruments and longitudinal 514604) and the University of Melbourne; NHMRC
assessments are required to examine this issue further. Clinical Career Development Awards (Grant 509345/
Fourth, comorbid abuse of other substances could also 454792 to M.Y. and W.J.B.); Colonial Foundation (to
affect the results because both cocaine and alcohol use D.I.L.); NHMRC Clinical Career Developmental Award
have been associated with worse cognitive functioning and a National Alliance for Research on Schizophrenia
in schizophrenia. However, the 2 studies (including our and Depression Young Investigator Award (to S.J.W.);
own) that examined the effect of comorbid alcohol use NHMRC CJ Martin Training Fellowship (454797 to
on cognition did not find an association.21 Examination A.F.); Ronald Phillip Griffith Fellowship, Faculty of
of larger samples is necessary to properly examine the Medicine, Dentistry, and Health Sciences, the University
effect of comorbid alcohol abuse on cognition. The of Melbourne (to S.C.); NHMRC Senior Principal
study of Potvin et al21 suggested that comorbid cocaine Research Fellowship (628386) and NHMRC Program
use could have a detrimental effect on cognition in Grants (350241, 566529 to C.P.); the Leenaards Foun-
cannabis-abusing patients with schizophrenia,28 but dation Switzerland (to P.C.).
this finding is unlikely to influence the current results be-
cause there was minimal cocaine abuse in the studies in-
cluded in our meta-analysis or among patients in our Acknowledgments
FEP study. All authors have declared that there are no conflicts of
Fifth, it is possible that some components of cannabis, interest in relation to the subject of this study.
such as cannabidiol (a nonintoxicating constituent of can-
nabis sativa), might relieve psychotic symptoms and
thereby improve cognition.76,77 There is also some evidence References
to suggest that, in certain subgroups of schizophrenia 1. Gregg L, Barrowclough C, Haddock G. Reasons for in-
patients, THC administration shows beneficial effects.18 creased substance use in psychosis. Clin Psychol Rev.
However, more research is required to understand these 2007;27:494–510.
complex actions in the context of schizophrenia. 2. Mueser KT, Yarnold PR, Levinson DF, et al. Prevalence of
Sixth, the number of studies included was small and substance abuse in schizophrenia: demographic and clinical
restricted our analysis to investigate broad rather than correlates. Schizophr Bull. 1990;16(1):31–56.
specific aspects of cognition (or individual cognitive 3. Volkow ND. Substance use disorders in schizophrenia—
clinical implications of comorbidity. Schizophr Bull. 2009;35:
tasks). Finally, studies included in the meta-analysis 469–472.
had small samples and low quality of data on several im- 4. Koskinen J, Lohonen J, Koponen H, Isohanni M, Miettunen J.
portant parameters, such as duration of illness; age of on- Rate of cannabis use disorders in clinical samples of patients
set of either cannabis use or psychosis; and frequency, with schizophrenia: a meta-analysis. Schizophr Bull. 2010;36:
quantity, or duration of cannabis use. 1115–1130.
In conclusion, our meta-analysis and experimental 5. Coldham EL, Addington J, Addington D. Medication adher-
data converge to indicate that cannabis use in both ence of individuals with a first episode of psychosis. Acta Psy-
chiatr Scand. 2002;106:286–290.
FEP and established schizophrenia is associated with bet-
6. Grech A, Van Os J, Jones PB, Lewis SW, Murray RM. Can-
ter cognitive performance than nonuse, and fewer cogni-
nabis use and outcome of recent onset psychosis. Eur Psychi-
tive impairments relative to healthy controls. The atry. 2005;20:349–353.
association between better cognitive performance and 7. Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse
cannabis use is driven by a subgroup of neurocognitively and the course of recent-onset schizophrenic disorders. Arch
less impaired patients, who only developed psychosis Gen Psychiatry. 1994;51:273–279.

328
 Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia

8. Yücel M, Solowij N, Respondek C, et al. Regional brain ab- among first-episode patients with schizophrenia-spectrum
normalities associated with long-term heavy cannabis use. psychosis. Psychol Med. 2008;38:1257–1266.
Arch Gen Psychiatry. 2008;65:694–701. 27. Joyal CC, Halle P, Lapierre D, Hodgins S. Drug abuse and/
9. Solowij N, Stephens RS, Roffman RA, et al. Cognitive func- or dependence and better neuropsychological performance
tioning of long-term heavy cannabis users seeking treatment. in patients with schizophrenia. Schizophr Res. 2003;63:
JAMA. 2002;287:1123–1131. 297–299.
10. Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T. 28. Potvin S, Briand C, Prouteau A, et al. CANTAB explicit
Non-acute (residual) neurocognitive effects of cannabis use: memory is less impaired in addicted schizophrenia patients.
a meta-analytic study. J Int Neuropsychol Soc. 2003;9:679–689. Brain Cogn. 2005;59(1):38–42.
11. Harvey MA, Sellman JD, Porter RJ, Frampton CM. The re- 29. Løberg EM, Hugdahl K. Cannabis use and cognition in
lationship between non-acute adolescent cannabis use and schizophrenia. Front Hum Neurosci. 2009;3:53.
cognition. Drug Alcohol Rev. 2007;26:309–319. 30. Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS
12. Solowij N, Michie PT. Cannabis and cognitive dysfunction: Consensus Cognitive Battery, part 1: test selection, reliability,
parallels with endophenotypes of schizophrenia? J Psychiatry and validity. Am J Psychiatry. 2008;165:203–213.
Neurosci. 2007;32(1):30–52. 31. Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG. Develop-
13. Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL. Dose- ment and validation of MIX: comprehensive free software
related neurocognitive effects of marijuana use. Neurology. for meta-analysis of causal research data. BMC Med Res

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ by guest on March 19, 2016

2002;59:1337–1343. Methodol. 2006;6:50.
14. Pope HG, Jr., Gruber AJ, Hudson JI, Cohane G, Huestis MA, 32. Sevy S, Burdick KE, Visweswaraiah H, et al. Iowa gambling
Yurgelun-Todd D. Early-onset cannabis use and cognitive def- task in schizophrenia: a review and new data in patients with
icits: what is the nature of the association? Drug Alcohol De- schizophrenia and co-occurring cannabis use disorders. Schiz-
pend. 2003;69:303–310. ophr Res. 2007;92(1–3):74–84.
15. Pope HG, Jr., Gruber AJ, Yurgelun-Todd D. Residual neuro- 33. Stirling J, Lewis S, Hopkins R, White C. Cannabis use prior
psychologic effects of cannabis. Curr Psychiatry Rep. to first onset psychosis predicts spared neurocognition at 10-
2001;3:507–512. year follow-up. Schizophr Res. 2005;75(1):135–137.
16. Solowij N. Do cognitive impairments recover following cessa- 34. Cohen M, Solowij N, Carr V. Cannabis, cannabinoids and
tion of cannabis use? Life Sci. 1995;56:2119–2126. schizophrenia: integration of the evidence. Aust N Z J Psychi-
17. D’Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9- atry. 2008;42:357–368.
tetrahydrocannabinol effects in schizophrenia: implications 35. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the ef-
for cognition, psychosis, and addiction. Biol Psychiatry. fect of adolescent-onset cannabis use on adult psychosis by
2005;57:594–608. a functional polymorphism in the catechol-O-methyltransfer-
18. Schwarcz G, Karajgi B, McCarthy R. Synthetic delta-9- ase gene: longitudinal evidence of a gene X environment inter-
tetrahydrocannabinol (dronabinol) can improve the symptoms action. Biol Psychiatry. 2005;57:1117–1127.
of schizophrenia. J Clin Psychopharmacol. 2009;29:255–258. 36. Veen ND, Selten JP, van der Tweel I, Feller WG, Hoek HW,
19. Jockers-Scherubl MC, Wolf T, Radzei N, et al. Cannabis Kahn RS. Cannabis use and age at onset of schizophrenia.
induces different cognitive changes in schizophrenic patients Am J Psychiatry. 2004;161:501–506.
and in healthy controls. Prog Neuropsychopharmacol Biol 37. Gonzalez-Pinto A, Vega P, Ibanez B, et al. Impact of canna-
Psychiatry. 2007;31:1054–1063. bis and other drugs on age at onset of psychosis. J Clin Psy-
20. Schnell T, Koethe D, Daumann J, Gouzoulis-Mayfrank E. chiatry. 2008;69:1210–1216.
The role of cannabis in cognitive functioning of patients 38. Velakoulis D, Pantelis C, McGorry PD, et al. Hippocampal
with schizophrenia. Psychopharmacology (Berl). 2009;205: volume in first-episode psychoses and chronic schizophrenia:
45–52. a high-resolution magnetic resonance imaging study. Arch
21. Potvin S, Joyal CC, Pelletier J, Stip E. Contradictory cogni- Gen Psychiatry. 1999;56(2):133–141.
tive capacities among substance-abusing patients with 39. Velakoulis D, Wood SJ, Smith DJ, et al. Increased duration
schizophrenia: a meta-analysis. Schizophr Res. 2008;100: of illness is associated with reduced volume in right medial
242–251. temporal/anterior cingulate grey matter in patients with
22. Coulston CM, Perdices M, Tennant CC. The neuropsychology chronic schizophrenia. Schizophr Res. 2002;57(1):43–49.
of cannabis and other substance use in schizophrenia: review of 40. Wood SJ, Pantelis C, Proffitt T, et al. Spatial working mem-
the literature and critical evaluation of methodological issues. ory ability is a marker of risk-for-psychosis. Psychol Med.
Aust N Z J Psychiatry. 2007;41:869–884. 2003;33:1239–1247.
23. Kumra S, Thaden E, DeThomas C, Kranzler H. Correlates of 41. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured
substance abuse in adolescents with treatment-refractory Clinical Interview for DSM-IV Axis I Disorders (Clinician
schizophrenia and schizoaffective disorder. Schizophr Res. Version). 1st ed Washington, DC: APA; 1997.
2005;73:369–371. 42. Haro JM, Kamath SA, Ochoa S, et al. The Clinical Global
24. Liraud F, Verdoux H. [Effect of comorbid substance use on Impression-Schizophrenia scale: a simple instrument to mea-
neuropsychological performance in subjects with psychotic sure the diversity of symptoms present in schizophrenia. Acta
or mood disorders]. Encephale. 2002;28(2):160–168. Psychiatr Scand Suppl. 2003;107(416):16–23.
25. de la Serna E, Mayoral M, Baeza I, et al. Cognitive function- 43. Morley KI, Cotton SM, Conus P, et al. Familial psychopa-
ing in children and adolescents in their first episode of psy- thology in the First Episode Psychosis Outcome Study. Aust
chosis: differences between previous cannabis users and N Z J Psychiatry. 2008;42:617–626.
nonusers. J Nerv Ment Dis. 2010;198(2):159–162. 44. Kay SR, Fiszbein A, Opler LA. The positive and negative
26. Mata I, Rodriguez-Sanchez JM, Pelayo-Teran JM, et al. Can- syndrome scale (PANSS) for schizophrenia. Schizophr Bull.
nabis abuse is associated with decision-making impairment 1987;13:261–276.

329
M. Yücel et al.

45. McGorry PD, Kaplan I, Dossetor C, Herrman H, Copolov 63. Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk
D, Singh B. Royal Park Multidiagnostic Instrument for Psy- factor for psychosis: systematic review. J Psychopharmacol.
chosis. Melbourne, Australia: National Health and Medical 2005;19(2):187–194.
Research Council; 1989. 64. Arseneault L, Cannon M, Witton J, Murray RM. Causal as-
46. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, sociation between cannabis and psychosis: examination of the
Moffitt TE. Cannabis use in adolescence and risk for adult evidence. Br J Psychiatry. 2004;184:110–117.
psychosis: longitudinal prospective study. BMJ. 65. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis
2002;325:1212–1213. use and risk of psychotic or affective mental health outcomes:
47. Woods SW. Chlorpromazine equivalent doses for the newer a systematic review. Lancet. 2007;370:319–328.
atypical antipsychotics. J Clin Psychiatry. 2003;64:663–667. 66. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M,
48. Nelson HE, Willison JR. Restandardisation of the NART de Ceballos ML. Prevention of Alzheimer’s disease pathology
against the WAIS-R. In: Nelson HE, ed. National Adult by cannabinoids: neuroprotection mediated by blockade of
Reading Test (NART): Test Manual. Windsor, ON: NFER- microglial activation. J Neurosci. 2005;25:1904–1913.
Nelson; 1991:13–23. 67. Coulston CM, Perdices M, Tennant CC. The neuropsycho-
49. Wechsler D. Wechsler Abbreviated Intelligence Scale—Revised. logical correlates of cannabis use in schizophrenia: lifetime
San Antonio, TX: The Psychological Corporation; 1987. abuse/dependence, frequency of use, and recency of use.
50. Reitan RM, Wolfson D. The Trail Making Test as an ini- Schizophr Res. 2007;96(1–3):169–184.

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ by guest on March 19, 2016

tial screening procedure for neuropsychological impair- 68. Verrico CD, Jentsch JD, Roth RH. Persistent and anatomi-
ment in older children. Arch Clin Neuropsychol. 2004;19: cally selective reduction in prefrontal cortical dopamine
281–288. metabolism after repeated, intermittent cannabinoid adminis-
tration to rats. Synapse. 2003;49(1):61–66.
51. Wechsler D. Wechsler Memory Scale—Revised Manual. San
Antonio, TX: Psychological Corporation; 1987. 69. Morrison PD, Zois V, McKeown DA, et al. The acute effects
of synthetic intravenous Delta9-tetrahydrocannabinol on psy-
52. Owen AM, Sahakian BJ, Semple J, Polkey CE, Robbins TW.
chosis, mood and cognitive functioning. Psychol Med.
Visuo-spatial short-term recognition memory and learning af-
2009;39:1607–1616.
ter temporal lobe excisions, frontal lobe excisions or amygda-
lo-hippocampectomy in man. Neuropsychologia. 1995;33(1): 70. Ringen PA, Melle I, Birkenaes AB, et al. The level of illicit drug
1–24. use is related to symptoms and premorbid functioning in severe
mental illness. Acta Psychiatr Scand. 2008;118:297–304.
53. Sahakian BJ, Owen AM. Computerized assessment in neuro-
psychiatry using CANTAB: discussion paper. J R Soc Med. 71. Lambert M, Conus P, Lubman DI, et al. The impact of sub-
1992;85:399–402. stance use disorders on clinical outcome in 643 patients with
first-episode psychosis. Acta Psychiatr Scand. 2005;112(2):
54. Rey A. L’examen clinique en psychologie. Paris: Presses Uni- 141–148.
versitaires de France; 1964.
72. Ruiz-Veguilla M, Gurpegui M, Barrigon ML, et al. Fewer neu-
55. Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins rological soft signs among first episode psychosis patients with
TW. Planning and spatial working memory following heavy cannabis use. Schizophr Res. 2009;107(2–3):158–164.
frontal lobe lesions in man. Neuropsychologia. 1990;28:
73. Cohen AS, Saperstein AM, Gold JM, Kirkpatrick B, Carpen-
1021–1034.
ter WT, Jr., Buchanan RW. Neuropsychology of the deficit
56. Shallice T. Specific impairments of planning. Philos Trans R syndrome: new data and meta-analysis of findings to date.
Soc Lond B Biol Sci. 1982;298(1089):199–209. Schizophr Bull. 2007;33:1201–1212.
57. Cohen JD. Statistical Power Analysis for the Behavioral Scien- 74. Kirkpatrick B, Ram R, Bromet E. The deficit syndrome in the
ces. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988. Suffolk County Mental Health Project. Schizophr Res.
58. DeLisi LE. The effect of cannabis on the brain: can it cause 1996;22(2):119–126.
brain anomalies that lead to increased risk for schizophrenia? 75. Mathias S, Lubman DI, Hides L. Substance-induced psychosis:
Curr Opin Psychiatry. 2008;21(2):140–150. a diagnostic conundrum. J Clin Psychiatry. 2008;69:358–367.
59. Dubertret C, Bidard I, Ades J, Gorwood P. Lifetime positive 76. Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam
symptoms in patients with schizophrenia and cannabis abuse R, Berry EM. Cannabidiol ameliorates cognitive and motor
are partially explained by co-morbid addiction. Schizophr impairments in mice with bile duct ligation. J Hepatol.
Res. 2006;86:284–290. 2009;51:528–534.
60. Talamo A, Centorrino F, Tondo L, Dimitri A, Hennen J, 77. Morgan CJ, Curran HV. Effects of cannabidiol on schizo-
Baldessarini RJ. Comorbid substance-use in schizophrenia: phrenia-like symptoms in people who use cannabis. Br J Psy-
relation to positive and negative symptoms. Schizophr Res. chiatry. 2008;192:306–307.
2006;86:251–255. 78. Ringen PA, Vaskinn A, Sundet K, et al. Opposite relation-
61. Hambrecht M, Hafner H. Cannabis, vulnerability, and the ships between cannabis use and neurocognitive functioning in
onset of schizophrenia: an epidemiological perspective. Aust bipolar disorder and schizophrenia. Psychol Med. 2009;6:1–11.
N Z J Psychiatry. 2000;34:468–475. 79. Scholes KE, Martin-Iverson MT. Cannabis use and neuro-
62. Smit F, Bolier L, Cuijpers P. Cannabis use and the risk of psychological performance in healthy individuals and patients
later schizophrenia: a review. Addiction. 2004;99:425–430. with schizophrenia. Psychol Med. 2009;17:1–12.

330