The British Journal of Psychiatry (2008)
193, 357–363. doi: 10.1192/bjp.bp.107.046375
Review article
Effects of cannabis use on outcomes
of psychotic disorders: systematic review
Stanley Zammit, Theresa H. M. Moore, Anne Lingford-Hughes, Thomas R. E. Barnes,
Peter B. Jones, Margaret Burke and Glyn Lewis
Background
It is unclear if research findings support clinical opinion that
cannabis use leads to worse outcomes in people with
psychosis, or whether this impression is confounded by
other factors.
Aims
To systematically review the evidence pertaining to whether
cannabis affects outcome of psychotic disorders.
Method
We searched 10 relevant databases (to November 2006),
reference lists of included studies and contacted experts. We
included 13 longitudinal studies from 15 303 references. Data
extraction and quality assessment were conducted
independently and in duplicate.
Results
Cannabis use was consistently associated with increased
relapse and non-adherence. Associations with other outcome
measures were more disparate. Few studies adjusted for
baseline illness severity, and most made no adjustment for
Cannabis use is more common in people with psychotic disorders
compared with people without psychoses.1 This is perhaps
surprising given the widely held clinical opinion that cannabis
can cause deterioration or impair recovery from psychotic disorders.
Experimental studies and surveys of users provide evidence
that cannabis intoxication can produce transient psychotic and
affective experiences and can have detrimental effects on
motivation and memory.2–4 Evidence from a recently conducted
systematic review5 also indicates that cannabis may increase the
incidence of psychotic outcomes, independently of intoxication
effects. Given these effects on mental state, it seems plausible that
continued use of cannabis following the onset of a psychotic disorder may increase the severity or duration of psychotic symptoms,
decrease adherence to treatment and impair longer-term outcome.
One reason people with psychosis may use cannabis is that the
perceived benefits such as a reduction in anxiety and increased
sociability6,7 outweigh any perceived harmful consequences. However, it is also possible that the clinical impression of cannabis use
resulting in a worse outcome in psychosis is confounded by other
factors associated with poor prognosis such as alcohol or other
illicit drug use.
Most studies that have examined the effects of substance use
on psychosis have been either cross-sectional or case–control
designs, but such approaches are limited, particularly in their
ability to distinguish the direction of any associations observed.
This ability to examine the direction of association is particularly
important given the reports of increased cannabis use following
onset of psychosis.8,9
In this review we examine the strength of evidence, from
longitudinal studies, that cannabis use in people with psychosis
impacts negatively on illness severity, adherence to treatment or
other adverse outcomes, independently of the effects of alcohol
and other drugs or other confounding factors.
alcohol, or other potentially important confounders. Adjusting
for even a few confounders often resulted in substantial
attenuation of results.
Conclusions
Confidence that most associations reported were specifically
due to cannabis is low. Despite clinical opinion, it remains
important to establish whether cannabis is harmful, what
outcomes are particularly susceptible, and how such effects
are mediated. Studies to examine this further are eminently
feasible.
Declaration of interest
P.B.J. and T.R.E.B. were both invited experts on the Advisory
Council on the Misuse of Drugs Cannabis Review in 2005.
A.L.-H. has received an honorarium from Sanofi-Aventis for
attending a meeting about cannabinoid antagonists. S.Z.,
P.B.J., T.R.E.B., G.L. and A.L.-H. have all received honoraria
for lectures and talks, or consultancy fees (for work
unrelated to cannabis) from pharmaceutical companies.
Method
Study samples
Studies were included if they were longitudinal studies of people
with psychosis, or case–control studies nested within longitudinal
designs, where cannabis use was measured at a time prior to the
outcome being measured. Cohorts of individuals with dual diagnosis of psychosis and cannabis misuse or dependence were
excluded, as there could be no comparison group of people who
did not use cannabis to determine if it had any affect on outcome.
The following diagnostic groups were included for psychosis:
schizophrenia, schizophreniform, schizoaffective or psychotic disorders, non-affective or affective psychoses, psychosis not otherwise
specified (NOS), psychotic symptoms, delusions, hallucinations or
thought disorder. Primary outcomes that we specified a priori as
being markers of progression of disease and relevant to this review
were: relapse, readmission, change in symptom scores (positive,
negative or global psychopathology symptoms), harm to self or
others (including violence, criminality, suicide attempts and
mortality), non-adherence to treatment, engagement with
services, employment, homelessness, social functioning, quality
of life and patient or carer satisfaction.
Literature search
We searched the following databases from their inception to
November 2006: MEDLINE, EMBASE and the Cumulative Index
to Nursing and Allied Health Literature (CINAHL) on OVID;
PsycINFO on WebSPIRS; ISI Web of Knowledge and ISI
Proceedings; Zetoc (British Library database of journal and
conference contents); BIOSIS on EDINA; Latin American and
Caribbean Health Sciences (LILACS); and Caribbean Health
Sciences Literature (MedCarib). An experienced research librarian
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Zammit et al
(M.B.) and three investigators (G.L. T.H.M.M .and S.Z.) developed the search strategy. We searched using the format ((psychosis
OR schizophrenia OR hallucinations OR delusions OR synonyms)
AND (substance abuse AND synonyms)), using text words and
indexing (MeSH) terms (full details available from the authors
on request). The search was restricted to studies on humans but
not by language or publication status. We searched reference lists
of included studies, and wrote to experts in the field and study
authors to find other published and unpublished studies of
relevance.
studies looked at people with schizophrenia only (or related
spectrum disorders), but the other six included people with other
psychoses too. All of the seven associations with better outcomes
in cannabis users were in studies that included individuals with
any psychosis rather than specifically schizophrenia or related
spectrum disorders.
The variety in outcome and exposure measure definitions
used, as well as the content of statistical results presented, meant
that it was not possible to pool results in a meta-analysis, and we
therefore use a narrative synthesis to summarise the findings from
this systematic review.
Study selection and data extraction
We examined all titles and abstracts, and obtained full texts of
potentially relevant papers. Working independently and in
duplicate, we read the papers to determine if they met our
inclusion criteria using eligibility record forms. At the abstract
stage we had more lenient inclusion criteria and included studies
with broad descriptions of mental health problems and of drug
use. These papers were obtained in full, and rejected if the data
were not provided separately for people using cannabis or for
people with psychotic disorder as defined by our criteria. Where
information was only available as an abstract, authors were
contacted for further information; if this was not forthcoming
then the study was excluded. Disagreements were resolved by
consensus, and data extracted independently and in duplicate.
Excluded studies
We identified five studies of people with psychosis that did not
meet all our inclusion criteria but which we considered to be
‘near-misses’.23–27 These were all longitudinal studies but they
either presented data only from cross-sectional analyses, or
employed a measure of cannabis use that could have included
individuals increasing or initiating use secondary to the outcome
studied. All of these studies, including the seminal work by
Linszen et al,25 reported associations between cannabis use and
worse outcomes. Further details of these studies are available at
www.bristol.ac.uk/psychiatry/research/psychotic.html.
Results for relapse or rehospitalisation
Quality assessment
We assessed quality by recording how potential non-causal
explanations, particularly bias and confounding, were accounted
for in each study. We assessed information on sampling strategy,
response rates, missing data, attrition and attempts to address
reverse causation, intoxication effects and confounding. All
relevant MOOSE (Meta-analysis Of Observational Studies in
Epidemiology) guidelines10 were followed.
We found four studies of relapse and three studies addressing
rehospitalisation. Two studies used definitions for relapse based
on the Brief Psychiatric Rating Scale (BPRS) scores; the Brisbane9
study reported a dose-response association between cannabis use
(days per week) and increased relapse of psychosis, and a strong
association between cannabis misuse and relapse was also reported
in the Melbourne study.11 Relapse was also increased by cannabis
use in the Navarra study,17 with evidence strongest for continued
use during follow-up (64% relapse in individuals using cannabis
Results
Description of studies
Results of search
Our literature search, expert advice and search of reference lists
yielded 15 303 references. Of these, 226 (1.5%) were thought to
possibly have data relevant for our review, and 212 of these were
excluded following a more detailed assessment using eligibility
forms (Fig. 1).
Included studies (for any outcome)
We found 13 publications reporting data from 13 cohort studies.
Seven studies examined first-episode or recent onset psychoses
(onset within 5 years): the Brisbane9 and Melbourne11 studies in
Australia (Melbourne study included after additional information
provided by authors); the Calgary12 and Calgary Early Psychosis
Program (CEPP)13 studies in Canada; the South London Hospitals14 and Manchester studies15 in the UK; and the HGDH
research group study in first-episode psychosis, a multicentre trial
based in both North America and Western Europe.16 Six studies
included both incident and prevalent cases of psychosis: the
Navarra17 study; the Madrid-A18 and the Madrid-B19 studies, all
based in Spain; the Homburg20 study in Germany; and the
Sydney-A21 and Sydney-B22 studies in Australia.
Results for the 13 studies are summarised in online Table DS1.
Overall, of the 52 outcomes reported from these studies, cannabis
was associated with statistical evidence of a worse outcome in 14,
and a better outcome in 7 of these. There was no evidence of
association in either direction for the other 31 outcomes. Seven
358
Searches run in electronic
bibliographic databases, expert
contact, and search of
reference list of included studies
n=15 303
7
6
Titles and abstracts
that were very unlikely
to be relevant and
therefore excluded
n=15 077
Titles and abstracts
possibly relevant
n=226
Papers not relevant
(n=164)
7
Papers do not present
results specifically for
cannabis, or are
cross-sectional design
(n=36)
Abstract only presented
and no further data
presently available
(n=8)
6
Papers included (from 13 separate
cohort studies)
n=13
Longitudinal design but
present cross-sectional
analyses or include cannabis
at end-point as exposure
(near misses, n=5)
Fig. 1 QUOROM (Quality of Reporting of Meta-analyses)
flow chart.
Cannabis use and outcome in psychotic disorders
at baseline and follow-up compared with 17% in non-users).
Similarly, the Madrid-B study reported weak evidence for association between cannabis dependence and increased relapse.19
Neither of these two latter study reports provided the definition
of relapse used.
Cannabis misuse was associated with a greater rehospitalisation index (0.98 readmissions per year compared with 0.35 for
the non-misuse group) in the Homburg study,20 and similarly
with a greater number of admissions in the Madrid-B study.19
In the Navarra study, risk of readmission was similar in individuals who used cannabis regularly at baseline only, but not at
follow-up, compared with controls (13% and 17% respectively),
though there was some evidence for increased readmission in
those using cannabis regularly both at baseline and at follow-up
(43% v. 17%, P=0.08).17
Results for severity of symptoms
Overall we identified seven studies that examined psychopathology symptom scores that included measures of psychosis,
mood, aggression and cognitive function. The HGDH16 study, a
treatment trial of olanzapine v. haloperidol in first-episode schizophrenia, and the Sydney-A study21 were the only studies to
measure change in symptom scores from baseline to follow-up
or adjust for baseline scores.
defined response to treatment,16 length of in-patient stay,22 course
of illness,14 presence of deficit schizophrenia,15 global assessment
scale (GAS) score,20 service contact,15 productivity or employment,12,20 marital status,20 living alone20 and quality of life.12
In the South London Hospitals study14 there was some
evidence that individuals who had used cannabis frequently at
baseline had a more continuous course of illness than people
who had not used cannabis regularly (crude odds ratio
(OR)=2.4, 95% CI 0.9–6.9). Cannabis was not associated with
treatment non-response in the HGDH study,16 or with service
contact or GAS score in the Manchester15 and Homburg20 studies
respectively.
In the Calgary study,12 cannabis use at baseline was associated
with decreased levels of productivity or employment, as well as
reduced quality-of-life measures at follow-up. There was suggestive evidence that people who used cannabis in the Homburg
study20 were more likely to be single and less likely to be employed
or living alone than individuals who did not use cannabis, though
none of these associations were statistically significant.
Two studies also observed associations between cannabis use
and improved outcomes; in the Manchester study15 a state of
deficit schizophrenia was less common in people who had used
cannabis at baseline compared with non-users, and in the
Sydney-B study22 there was weak evidence that cannabis use
at baseline was associated with a clinically important shorter
duration of admission (13 days v. 21 days, P=0.07).
Positive symptoms
In the Sydney-A study,21 cannabis use was associated with a small
increase in BPRS score that persisted after adjusting for prior
BPRS scores. In the HGDH study, cannabis misuse was not significantly associated with a change in the Positive and Negative
Syndrome Scale (PANSS) total score from baseline to follow-up
in either of the two trial arms of the study.16 However, change
in score was less in both arms for the cannabis misuse group
compared with non-users, though no combined analysis of the
two trial groups was presented, thereby reducing statistical power.
Regular cannabis use at baseline was associated with increased
level of positive symptoms at follow-up in the South London
Hospitals study,14 and in the Homburg study20 cannabis misuse
was associated with 2 of 12 symptom sub-scales examined
(increased thought disturbance and hostility). Cannabis was not
associated with the positive symptom sub-scale of the PANSS in
the Madrid-B study19 or with scores on the Scale for the Assessment of Positive Symptoms (SAPS) in the Manchester study.15
Negative symptoms
Regular cannabis use was not associated with negative symptoms
scores in the South London Hospitals,14 the Manchester,15 or the
Homburg20 studies. However, an association between cannabis
dependence and a reduced score on the PANSS negative symptom
scale at follow-up was observed in the Madrid-B study.19
Other measures
Cannabis misuse was not associated with depression score in the
Sydney-A study,21 with anxiety or depression sub-scales used in
the Homburg study,20 or with Overt Aggression Scale score in
the Madrid-A study.18 Neurocognitive ability at follow-up was
greater on five out of nine sub-scales in people who had used
cannabis at baseline in the Manchester study.15
Results for measures of response to treatment
A variety of other outcomes reflecting response to treatment were
investigated in these studies. These included symptom score
Results for adherence to treatment
Three studies examined cannabis use in relation to subsequent
adherence to treatment. In the Madrid-B study19 cannabis
dependence at baseline was associated with non-adherence during
follow-up. A dose-response model of increasing baseline cannabis
use in the CEPP study13 was also associated with increased levels
of non-adherence in the crude analysis, though this association
was eliminated after adjustment for confounding. Similarly in
the Navarra study,17 continued cannabis use during follow-up
(but not use of cannabis at baseline only) was weakly associated
with reduced adherence compared with non-users (36% v. 67%,
P=0.06).
Methodological quality of included studies
We assessed the degree to which the potential effect of confounding and bias were minimised within each study (summarised in
Table 1). Although a number of factors could have led to overestimation of the true causal association between cannabis use
and poorer outcomes of psychosis in these studies, perhaps the
most likely of these is confounding, particularly by use of alcohol
and other drugs; and baseline measures of illness severity and level
of functioning (that may have led to reverse causation effects).
Of the 13 studies included in this review, only five studies
(Brisbane,9 Melbourne11, Navarra,17 Sydney-A21 and HGDH16)
made any adjustment for measures of illness severity at baseline.
Only three studies (Brisbane,9 Melbourne11 and Madrid-B19)
adjusted for both alcohol and other drug use, though this was
for only one of the five outcomes in the Madrid-B study. In the
Homburg study20 some adjustment for alcohol and other drug
use was done by exclusion of individuals mainly using drugs other
than cannabis. In the Sydney-A study,21 alcohol and other drug
use were excluded from the adjusted model as they were not
associated with the outcome, and were therefore unlikely to have
substantially confounded the relationship with cannabis. One
study adjusted for alcohol use only (CEPP),13 and one other
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Zammit et al
Table 1
Summary of quality of studies included for outcomes in psychosis
Cohort
label
Response rate
at baseline
Loss to
follow-up, %
Masking of outcome Adjusted for baseline
assessment
illness severity
Adjusted for alcohol
and other drugs
Impact of adjusting
for confounders
Brisbane9
88% of participants
approached
15
No
Yes
Yes
Association persisted
after adjustment, but no
indication as to extent of
confounding
Calgary12
Not mentioned
29
No
No
No
Some associations
eliminated after adjusting for symptoms at
follow-up
CEPP13
All first 200 incident
cases
22
No
No
Adjusted for alcohol
use
Association with baseline cannabis use eliminated by adjustment
HGDH16
Not mentioned
0.4
No
Yes for 1 of 2
outcomes (measured
score change)
No
Not assessed
Homburg20
All those identified
as cases included
Cannabis misuse No
group, 31; nonmisuse group, 33
No
Some adjustment, as
cases excluded if mainly
used drugs other than
cannabis
Not assessed
Madrid-A18
63 of 70 eligible (90%)
0
No
No
No
Not assessed
Madrid-B19
Not mentioned
0
No
No
1 of 5 outcomes studied Not assessed
was adjusted for alcohol/
other drugs
Manchester15 100%
38
No
No
No
Associations for 2 cognitive tests eliminated
after adjusting for age
at onset; 5 other
associations persisted
Melbourne11
Not mentioned
18
No
Yes
Yes
Reduced estimate by
15%
Navarra17
94%
17
No
No
No. Cannabis use was
associated with alcohol
and other drug misuse
in sample
Not assessed
Masked to baseline
cannabis; unclear
if masked to
follow-up use
No
No
Reduced estimates by
approximately 20–80%
South London 119 with baseline data 18
Hospitals14
from 227 consecutive
admissions (52%)
Sydney-A21
Not mentioned
22 for psychosis No
outcome
observations
Yes
No, but alcohol and other Reduced estimate by
drugs had non-significant 35%
effect on outcome and
thus omitted from final
model
Sydney-B22
Out of 167 patients,
45 had drug screens
done (27%)
0
No
No other illicit substances Not assessed
detected in urine for whole
of sample, but no adjustment for alcohol misuse
No
(Sydney-B)22 made some adjustment for other drug (but not
alcohol) use.
A further potential mechanism by which overestimates of
association may have resulted is by lack of masking of exposure
status when assessing outcome. In fact, a statement that outcome
measurement was performed masked to cannabis exposure was
only evident in one of the studies (South London Hospitals).14
A summary of study quality issues in relation to the different
outcomes studied is presented below.
Studies of relapse or rehospitalisation
Relapse of psychosis as defined for the Brisbane9 and Melbourne11
studies (and as implied for the Navarra study17) required a change
in symptom severity between baseline and follow-up, reducing,
though not eliminating, the possibility of confounding by factors
related to illness severity. Furthermore, in the Brisbane study9
360
results were adjusted for a wide range of potentially important
confounders, including baseline symptoms, alcohol and drug
use, and measures of social functioning and family environment.
Results for the Melbourne study11 were adjusted for baseline
symptoms and for alcohol and other drug use, and results for
the Navarra study17 were adjusted for adherence and life stresses.
None of the studies that examined rehospitalisation however
made any adjustment for illness severity at the time of discharge
from the index admission, or for markers of social function or
socio-demographic status (apart for adjustment for age and
gender in the Homburg study20).
Studies of symptom scores
For the studies that examined symptom scores as outcomes, only
two studies adjusted for baseline scores or examined change in
scores from baseline to follow-up (Sydney-A21 and HGDH16).
Cannabis use and outcome in psychotic disorders
None of the five other studies reporting associations between
cannabis and symptom severity at follow-up took into account
levels of symptom severity at baseline. In the Manchester study15
there was a strong association between cannabis use and fewer
neurological soft signs at baseline, though this was not adjusted
for in the associations reported with neurocognitive outcomes.
Studies of response to treatment
With regard to measures of response to treatment, course of illness
as examined in the South London Hospitals study14 implies
change of symptom severity during follow-up and adjustments
for age, gender and ethnicity were also made in this study. In
the Manchester study15 there were no significant baseline
differences in negative symptoms or social adjustment, indicating
that the association with deficit schizophrenia is perhaps unlikely
to be confounded by these. No adjustments for baseline severity of
illness, or any other confounders however were made in the
Sydney-B study,22 where a weak association with length of
in-patient admission was reported. Similarly in the Calgary12
and Homburg20 studies, no adjustments were made for level of
productivity or quality of life at baseline, or for baseline marital,
employment or accommodation status, when examining for
associations with these measures at follow-up.
Studies of adherence
The CEPP study13 results were adjusted for a wide range of
potentially important confounders, but no adjustment for any
confounders in relation to this outcome was done in the
Madrid-B19 or the Navarra17 studies.
Discussion
As far as we are aware this is the first systematic review to examine
whether use of cannabis has a detrimental effect on outcome in
people suffering from a psychotic illness. We found relatively
few longitudinal studies that have examined this hypothesis.
Use of cannabis was associated with increased relapse or
rehospitalisation and with decreased treatment adherence fairly
consistently across the studies that examined these outcomes.
Associations between cannabis and psychotic symptoms or other
psychopathology scores were more inconsistent, with only three
studies presenting evidence of association with increased positive
symptoms and one study reporting an association with decreased
negative symptoms. Definitions for relapse in two studies9,11 were
based on increases in positive symptoms scores however, and both
of these studies found evidence that cannabis use led to increased
relapse. Evidence for associations with other measures of
treatment response was also quite discrepant, with some studies
reporting negative outcomes of reduced quality of life, productivity or a more continuous illness course in people using
cannabis, but other studies reported associations with positive
outcomes including shorter in-patient stays and reduced deficit
schizophrenia in cannabis users.
Examination of non-causal explanations
for association
The most important consideration when attempting to interpret
the findings of this review is the methodological quality of the
studies included in relation to bias and confounding. Only four
of the thirteen studies (Brisbane,9 Melbourne,11 Sydney-A21 and
HGDH16) made any attempt to adjust for baseline illness severity
measures. Access to, and use of cannabis, may be associated with
premorbid level of functioning or illness severity, both of which
are also likely to be related to clinical outcome.
Furthermore, even basic socio-demographic characteristics
such as social class or gender that are associated both with poor
outcome28,29 and with cannabis use30,31 were only adjusted for
in six of the studies. Most studies made no adjustment for alcohol
or other drug use, though these are strongly associated with
detrimental mental health outcomes32,33 and are therefore also
likely to be confounders. They are also likely to serve as markers
of other factors such as personality traits relating to risk taking
and adherence with medical advice that could further confound
the relationship between cannabis and outcome in psychosis.
These methodological issues are particularly pertinent given that
non-adherence is likely to result in poorer clinical outcomes
generally.
Although some adjustment for confounding was undertaken
in a number of studies, only the Melbourne,11 South London
Hospitals14 and Sydney-A21 studies presented both crude and
adjusted estimates that enable us to gauge the potential impact
of confounding in these studies. Estimates were attenuated by
between 15% and 80%, although only a limited number of
potentially important confounders were adjusted for in these
studies. Given that the range of confounders adjusted for was
rather incomprehensive in most of the studies included in this
review, confidence that the associations reported are specifically
due to cannabis in these studies must therefore be rather low.
Clinical opinion has long been that use of cannabis results in a
worse outcome in people with psychotic illnesses and the original
study in this field by Linszen et al25 lent strong support to this
view. This makes it particularly important that studies measure
outcomes masked to cannabis exposure status to avoid overestimation of association due to observer measurement bias.
The South London Hospitals study14 was the only study to report
such masking.
Reverse causation was unlikely to have been a problem as we
only included longitudinal studies in this review. The Calgary,12
CEPP13 and South London Hospitals14 studies however also
included some results for measures of cannabis use at follow-up.
Results for these measures (that showed stronger associations than
for use at baseline only) were therefore omitted, as these associations could have resulted, in part, from reverse causation effects.
On the other hand, results for individuals using cannabis at
baseline but not at follow-up are likely to be underestimates of
true effects of cannabis as they ignore the impact of continued
use. However, following such a conservative approach for these
studies seemed preferable in order to firmly establish direction
of causality.
If cannabis is indeed a risk factor for causing psychotic
illnesses5 then it is perhaps surprising that these studies of the
effects of cannabis on clinical outcome are so inconsistent,
especially as our assessment of methodological quality suggests
that insufficient attention was paid to addressing overestimation
of causal effects in these studies.
Possible reasons for lack of evidence
for association
It is also possible that studies underestimated the true impact of
cannabis on the outcome of psychosis. Random misclassification
of data is probably the most likely reason for underestimation
of association. In particular, self-report measures of cannabis
use are unlikely to accurately reflect the dose of psychoactive
cannabinoids available in the brain given variations in potency
of cannabis used, and amounts of cannabinoids inhaled and
metabolised. Misclassification in accuracy of reporting is also
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Zammit et al
likely, although in the Brisbane study9 self-reports of cannabis use
(as used in the analyses) showed good reliability with drug screens
in a subsample of the cohort (Cohen’s kappa=0.90). Repeated and
detailed assessment of cannabis exposure during the follow-up
period, but before outcome measurement, would help to reduce
misclassification. However, most studies to date have used rather
limited assessments of cannabis exposure, measured only before
the follow-up period started.
Furthermore, loss to follow-up in cohort studies tends to be
greater for individuals who have more severe mental health
problems and for those with substance misuse. Such an effect of
differential attrition would have led to underestimation of the
strength of any association. The median loss to follow-up for these
studies was 17% (range 0–38%), though the only study
(Homburg20) that examined whether attrition was different for
cannabis using and non-using groups reported minimal difference
across the two groups.
Apart from the possible effects of bias, lack of statistical power
could also have led to lack of evidence for associations in some of
these studies. None of the studies that failed to observe
associations between cannabis use and clinical outcomes
presented power calculations. If we assume that 20% of patients
with psychosis relapse over a 1-year period if they do not use
cannabis and 40% relapse if they use cannabis regularly, and that
25% of patients use cannabis regularly, then a power calculation
indicates that a sample size of over 250 people with psychosis is
required to have 80% power to detect this effect. This calculation
is based on a large difference in relapse rates between cannabis
users and non-users, and yet only one of the studies included in
this review meets this required sample size.
Finally, it is also possible that variation in the diagnostic
composition of the participants with psychoses across different
studies, as well as differences in the measures of clinical outcome
and definitions of cannabis exposure, might partly explain the
diverse and at times conflicting results reported. For example,
all of the associations between cannabis use and better outcomes
were in studies that included individuals with any psychotic
diagnosis, while studies of people with schizophrenia or related
spectrum disorders appear to show more consistent evidence for
poorer outcomes in those using cannabis.
Limitations
Although we identified a large number of potential studies for
inclusion, most studies were not set up to directly address the
aim of this review and were not able to meet our criteria for
inclusion. As well as the possibility that we missed some studies
during our searches, we excluded a large number of studies by
requiring studies to be of longitudinal design as these provide
the most reliable evidence for causal association in the absence
of randomised controlled trials. Furthermore, the rather
insubstantial nature of what constitutes a ‘poor clinical outcome’
means that it is more difficult to summarise results of studies in
this review compared, for example, with reviews where disease
incidence is the studied outcome.
We also excluded a large number of studies that examined the
effects of substance use in general rather than specifically use of
cannabis. As cannabis is the most frequently used illicit substance
in most countries it could be argued that results for substance use
(that excludes alcohol or tobacco) mainly reflect the effects of cannabis. However, even in such situations, the possibility of strong
confounding by other drugs remains. Furthermore, although
uncommon, substance use may at times be dominated by
stimulant drugs such as amphetamines or cocaine.34
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Implications for future research and clinical practice
Given that psychoactive compounds within cannabis can cause or
increase psychotic experiences secondary to intoxication effects,2,3
and independently of such effects,5 it is very plausible that
cannabis might lead to increased positive symptoms and
subsequently relapse or rehospitalisation in people with psychosis.
Indeed, there is a widespread belief among psychiatrists that such
a detrimental effect does exist. We were surprised how little
empirical evidence is currently available to support this view.
Our assessment of methodological quality suggests that although
insufficient attention was paid to addressing overestimation of
causal effects, low statistical power to observe associations was also
likely to have been present in many of the studies.
Despite the clinical consensus and the plausibility of harmful
effects, we believe it is important to establish whether cannabis
is harmful, and if so, what the size of any harmful effect is. Trials
of interventions for reducing cannabis use in people with
psychosis may provide stronger evidence of possible detrimental
effects of this drug, as this would be independent of confounding
effects.
We also need to know what kinds of outcome are particularly
susceptible to the influence of cannabis; whether clinical,
employment status or other aspects of social functioning. An
understanding of the effects of different potency preparations as
well as of pattern of exposure is also required. Comparing the
effects of cannabis with other psychoactive drugs would enable
clinicians and patients to prioritise harm reduction plans.
Although most of the associations reported were with markers
of poorer clinical outcome, some studies also reported better
outcomes in individuals using this drug. It is possible that
cannabis has differential effects on different outcomes, for
example worsening positive symptoms but improving negative
ones. Further research on the specific effects of cannabis on such
outcomes may help our understanding of aetiological mechanisms, further elucidate why some individuals with psychosis
choose to use cannabis, and suggest approaches that might be
used by clinicians to engage this problem. Understanding to what
extent any associations are mediated through indirect pathways
resulting in poor outcome, such as reduced adherence, may also
enable more specific targeting of focused interventions to improve
long-term care in people with psychotic disorders.
Insufficient empirical evidence exists at present to adequately
examine whether cannabis use has detrimental effects on the outcome of psychotic disorders, or to determine the pathways by
which such effects are mediated, although these are important
and clinically relevant questions.
Future studies to address these uncertainties should be of
longitudinal design, with repeated measures of psychopathology,
use of cannabis, alcohol and other substances, as well as baseline
measures of function, illness severity and other characteristics that
are known to be associated with poorer outcome in schizophrenia.
Appropriate analyses should ensure that reverse causation effects
are minimised, for example by using time-lagged measures of
cannabis use where repeated measures are available. Reporting
of both crude and adjusted estimates, with specific reporting as
to which specific confounders have the greatest impact on the
results would aid design of future studies. Use of clearly defined
diagnostic categories and a more universal approach to measures
of cannabis exposure and outcomes (that are measured masked to
exposure status) would further help with interpreting and summarising future study findings.
Unlike the situation that exists for examining causal effects of
cannabis on incidence of psychosis, adequately powered longitudinal studies of outcome of people with psychosis should be,
Cannabis use and outcome in psychotic disorders
in comparison, relatively easy to carry out given the widespread
availability of large clinical samples.
13 Coldham EL, Addington J, Addington D. Medication adherence of individuals
with a first episode of psychosis. Acta Psychiatr Scand 2002; 106: 286–90.
14 Grech A, van Os J, Jones PB, Lewis SW, Murray RM. Cannabis use and
outcome of recent onset psychosis. Eur Psychiatry; 20: 349–53.
Stanley Zammit, PhD, Academic Unit of Psychiatry, University of Bristol, and
Department of Psychological Medicine, Cardiff University; Theresa H. M. Moore,
MSc, BSc, Anne Lingford-Hughes, BM, BCh, PhD, Academic Unit of Psychiatry,
University of Bristol; Thomas R. E. Barnes, MD, DSc, Department of Psychological
Medicine, Imperial College London; Peter B. Jones, MD, PhD, Department of
Psychiatry, Cambridge University; Margaret Burke, BA, MSc, Department of Social
Medicine, University of Bristol; Glyn Lewis, PhD, Academic Unit of Psychiatry,
University of Bristol, UK
Correspondence: Stanley Zammit, Department of Psychiatry, Cardiff University,
Heath Park, Cardiff CF14 4XN, UK. Email: [email protected]
First received 16 Oct 2007, final revision 5 May 2008, accepted 19 Jun 2008
15 Stirling J, Lewis S, Hopkins R, White C. Cannabis use prior to first onset
psychosis predicts spared neurocognition at 10-year follow-up. Schizophr
Res 2005; 75: 135–7.
16 Green AI, Tohen MF, Hamer RM, Strakowski SM, Lieberman JA, Glick I, Clark
WS; HGDH Research Group. First episode schizophrenia-related psychosis
and substance use disorders: acute response to olanzapine and haloperidol.
Schizophr Res 2004; 66: 125–35.
17 Martinez-Arevalo MJ, Calcedo-Ordonez A, Varo-Prieto JR. Cannabis
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18 Arango C, Calcedo BA, Gonzalez S, Calcedo OA. Violence in inpatients with
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Acknowledgements
We would like to thank the authors of the papers we considered for inclusion in our review;
Cheryl Corcoran, Marie-Odile Krebs, Martin Lambert, John Stirling and Ingrid Melle for their
helpful correspondence; and Blanca Bolea, Jorge Gaete and Juan Santos for help with
translation. We are especially grateful to Jean Addington and Darryl Wade for providing
us with additional data for us to consider for inclusion in our review.
This work was funded by the Department of Health, UK. S.Z. is funded through a
Clinician Scientist Award funded by the National Assembly for Wales.
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363
Summary of studies included for outcomes in psychosis (full version)
Setting and sample Baseline
size at baseline
diagnoses
Brisbane9
Consecutive
in-patient
admissions,
Brisbane, Australia
n=81
Calgary12
Cannabis
measure
Exposure
n (%)
Recent onset
(within 3 years)
DSM–IV
psychotic disorder
TLFB for days of
cannabis use
6 weeks prior to
admission and
during follow-up
Urine drug screening
used to validate
self-reports
Cannabis
dependence year
prior to admission:
57 (70.4)
6 months
Consecutive
admissions of
adolescents to
Calgary Early
Psychosis Program,
Canada
n=69
Incident cases
of DSM–IV
non-affective
psychosis
CMRS for level
of cannabis use
(scale 0–4)
–
2 years
CEPP13
Consecutive
admissions to
Calgary Early
Psychosis Program
Canada
n=200
CMRS for level
Incident cases of
of cannabis use
DSM–IV schizophrenia, schizophreniform disorder, other
schizophreniaspectrum disorders
HGDH16
Participants
recruited as part of
multicentre RCT in
North America and
Western Europe
n=262
Incident cases
(onset past 5 years)
of DSM–IV
schizophrenia,
schizoaffective
disorder or
schizophreniform
disorder
Follow-up
Outcome
n (%)
Confounders adjusted for
Relapsea
27 (39)
Number of days of cannabis
use associated with relapse
Adjusted HR=1.06 (95%
CI 1.02–1.10) (calculated
from table)
Good agreement between
urine screening and self-report
for cannabis use (Cohen’s
kappa=0.90; 60.5% of sample
tested)
Similar results if
Baseline psychotic and
exclude substanceaffective symptoms, other
induced psychoses
substance use, medication
adherence, duration of
untreated psychosis, demographic variables, measures
of social functioning prior to
admission, life stress, and
measures of family environment
1. Quality of Life
Scale at years
1 and 2
Positive or negative symptoms
1. QOL
at years 1 and 2
Cannabis at baseline and
cannabis at 1 year were both
associated with # QOL at 2 years
(P50.05) but these associations
disappeared after adjustment
2. Employment/productivity
Cannabis at baseline was
associated with # employment,
and this persisted after
adjustment:
OR for 1-year unemployment=2.0
(95% CI 1.1–3.7)
OR for 2-year unemployment=2.7
(95% CI 1.3–5.8)
2. Employment or
productivity at
years 1 and 2
–
SCID interview for
74 (28)
cannabis use disorder
(dependent
participants excluded)
Other relevant
points
Main results
1 year
Adherenceb
(adherent,
inadequate,
non-adherent)
Inadequate or
non-adherence:
110 (59)
Increasing level of cannabis
use at baseline was associated
with # 1-year adherence status,
P=0.04 in crude analysis
Non-significant in adjusted
model (though this model
includes cannabis use at
1-year)
12 weeks
1. Response:c
81 (32)
1. Non-response
Non-response results adjusted
OR in cannabis use disorder
for randomised treatment (halocompared to non-use=1.08
peridol v. olanzapine)
(95% CI 0.90–1.29)
2. Change in PANSS total
Olanzapine group, mean (s.d.)
Cannabis use=15.9 (18)
Non-cannabis=20.2 (23), P=0.31
Haloperidol group, mean (s.d.)
Cannabis use=13.4 (18)
Non-cannabis=18.6 (19), P=0.39
2. Mean change in
PANSS total
Family involvement, premorbid
function, age, 1-year cannabis
use. Also probably alcohol use,
age of onset, insight , quality of
life, though not clear if these in
final model
(continued)
The British Journal of Psychiatry (2008)
193, 357–363. doi: 10.1192/bjp.bp.107.046375
Cohort
label
Data supplement
Table DS1
1
2
Table DS1
(continued)
Cohort
label
Setting and sample Baseline
size at baseline
diagnoses
Cannabis
measure
Exposure
n (%)
Homburg20
Cohort from
patients admitted
to hospital between
1986–1992, with
matched control
cohort, Homburg,
Germany
n=78
Prevalent or
incident ICD–10
schizophrenia
Excluded if diagnosis
of drug-induced
psychosis
39 (50)
Cannabis misuse
defined as regular use
for many months and
interfered with social
function or was
prominent in therapy.
Controls had
schizophrenia but no
history of alcohol or
drug use
About 6 years
Madrid-A18
Consecutive
in-patient
admissions, Spain
n=63
Prevalent or
incident DSM–IV
schizophrenia or
schizoaffective
disorder
Cannabis misuse
7 days prior to
admission (misuse
not defined)
14 (22)
5 months
Score 52 on OAS
physical aggression
sub-scale:
16 (25)
Cannabis use was not
None
correlated with violent
behaviour during hospitalisation
No details of analysis given
Madrid-B19
Out-patient sample,
Madrid, Spain
n=82
Prevalent or
incident ICD–10
schizophrenia
Addiction Severity
Index Scale
Cannabis
dependence
20 (24)
6 months
1. PANSS scores
1. PANSS scores
Cannabis dependence
associated with # negative
symptoms, but no association
with positive symptoms
2. Relapse
Cannabis associated with "
ORe=3.6 (95% CI 0.6–21.4),
P=0.08
3. Non-adherence
Cannabis associated with "
ORe=3.1 (95% CI 1.0–10.2),
P=0.03
4. Admission
Cannabis associated with "
ORe=7.5 (95% CI 0.9–87.0);
P=0.01
Follow-up
Outcome
n (%)
Main results
1. GAS score, mean (s.d.):
Cannabis misuse=55.7 (14.8)
Non-misuse 62.5 (15.4), NS
2. Rehospitalisation 2. Rehospitalisation, mean
(admissions per year) (s.d.): Cannabis misuse=0.98
(0.8); Non-misuse=0.35 (0.3),
P50.001
3. BPRS sub-scales: 3. BPRS sub-scales:
anxiety/depression, Thought disturbance " in
anergia, activation, cannabis misuse, P50.05
hostile, thought
Other sub-scales all NS
disturbance
4. AMDP sub-scales: 4. AMDP sub-scales:
paranoid, depressive, Hostility " in cannabis
psycho-organic,
misuse, P50.05
maniform, vegetative, Other sub-scales all NS
apathetic, hostility
5. Single status
5. Single status:
Cannabis misuse=89%
Non-misuse=69%, NS
6. Living alone
6. Living alone:
Cannabis misuse=59%
Non-misuse=65%, NS
7. Employment
7. Employment: NS
Cannabis misuse=19%
Non-misuse=46%, NS
1. GAS score
2. Relapse
(not defined)
8 (9.8)
3. Non-adherenced
25 (30.5)
4. Admission to
hospital 6 (7.3)
Confounders adjusted for
Age, gender, and
year of admission
Some adjustment
for alcohol and
other drug use by
restriction of cases (excluded if
mainly misused drugs other
than cannabis)
PANSS negative results adjusted
for (some of) alcohol and other
drug dependence, and sociodemographic variables
Other relevant
points
Table DS1
Cohort
label
(continued)
Setting and sample Baseline
size at baseline
diagnoses
Cannabis
measure
Exposure
n (%)
Follow-up
Outcome
n (%)
Main results
Confounders adjusted for
Age at onset, for
neurocognitive analyses only
Manchester15 Consecutive
in-patient
admissions,
Manchester, UK
n=112
Incident cases
of psychosis
Cannabis use or
23 (36)
non-use at baseline
from self-report and
informer-report
10–12 years
1. Deficit
schizophreniaf
2. Neurocognitive
function (9 tests)
3. SANS/SAPS
4. Service contact
1. Deficit schizophrenia
# in cannabis use, P=0.032
2. Neurocognitive function
Cannabis use associated with "
score (better function) on 5 of 9
tests (design memory, verbal
fluency, object assembly, block
design, picture completion)
3. SANS/SAPS, NS
4. Service contact, NS
Melbourne11,g In-patient and
out-patient sample
from Mental Health
Services in
Melbourne, Australia
n=126
Incident cases of
psychosis
(56 months
treatment)
During follow-up:
Cannabis misuse
43 (42)
using the CUAD
scale
Measures at
assessments prior to
episode of relapse
used for analyses
15 months
Relapse:a
34 (35)
Alcohol and other substance
Cannabis misuse group:
misuse, BPRS score at baseline
Relapse n=23/40 (58%)
No substance use group:
Relapse n=8/47 (17%)
Crude ORg=5.8 (95% CI 2.2–15.0),
P50.001
Adjusted ORg=5.1 (95% CI 1.8–
14.1), P=0.002
1. Relapse
(undefined)
1. Relapse
Results for relapse were then
Non-use=16.7%
adjusted for adherence and
Baseline use=47.4%
stress though no results for any
ORe=4.5 (95% CI 1.2–21.1),
baseline cannabis use or baseline only are presented
P=0.01
Results presented from adjusted
2. Readmission
model difficult to interpret.
Non-use=16.7%
Authors state that ‘continuing
Baseline use=23.7%
cannabis consumption was
ORe=1.6 (95% CI 0.4–7.8),
strongest predictor of relapse’
P=0.51
3. Adherence
Non-use=66.7%
Baseline use=60.5%
ORe=0.8 (95% CI 0.2–2.5), P=0.63
Navarra17
Sydney-A21
Prevalent or
In-patient and
out-patient sample incident DSM–III
schizophrenia
from Community
Mental Health Centres
in Navarro, Spain
n=75
Sample recruited
from Community
Mental Health
Centres in North
Sydney, Australia
n=101
Clinical diagnoses
of schizophrenia,
schizophreniform
disorder or schizoaffective disorder
Cannabis use 52
times/week for 41
year, coded as:
non-use/use at
baseline only/use
at baseline and
follow-up
Results presented
here are for any
baseline use of
cannabis
Use at baseline only: 1 year
24 (39)
Number of days of
use in previous
month (0–28)
Cannabis use in
6-months prior to
start part of
inclusion criteria
Use at baseline and
follow-up: 14 (23)
2. Readmission
3. Adherence (with
medication and
appointments)
69% used in month
before start
10 months
1. BPRS score
2. CDSS score
1. BPRS score
Cannabis associated with " in
BPRS score (per day of use):
Crude b=0.13 (95% CI 0.00–
0.26)e. Adjusted b=0.08 (95% CI
0.02–0.15)e
2. CDSS score
Cannabis associated with " in
CDSS score (per day of use):
Crude b=0.04 (95% CI 70.70–
0.78)e. Adjusted b=NS
Other relevant
points
Cannabis users had
significantly more
positive symptoms,
and less neurological
No baseline differences in
negative symptoms, premorbid soft signs at baseline
adjustment, or social function
1. BPRS score
Prior BPRS scores, current
CDSS score, gender
2. CDSS score
Prior BPRS scores, prior CDSS
scores, current amphetamine
use, age
Alcohol and other
drug use did not
have a significant
effect on outcome
and were thus
omitted from final
model
(continued)
3
4
Table DS1
(continued)
Cohort
label
Setting and sample Baseline
size at baseline
diagnoses
Cannabis
measure
Exposure
n (%)
Follow-up
Sydney-B22
Non-random sample Prevalent or incident
who provided urine cases of DSM–III
psychoses
drug screen an
admission, Sydney,
Australia
n=45
Urine drug screen
within 48 h of
admission:
(THC positive/THC
negative)
THC positive:
23 (51)
Average
17 days
Subsample of
consecutive
admissions to
2 hospitals in
South London, UK
n=119
Use at baseline
Cannabis use
only:
(frequent/regular)
prior to baseline or 9 (9)
in 3 months prior to Use at baseline
follow-up, grouped and follow-up:
as: use at baseline 16 (16)
only/use at follow-up
only (excluded from
review)/use at both
times/no use any time
Results presented
here include results
for any baseline use
of cannabis
South
London
Hospitals14
Recent onset (in
past 5 years) cases
of DSM–III–R
psychoses
4 years
Outcome
n (%)
Main results
Length of admission THC positive:
in days
Mean 13.2 days
THC negative:
Mean 21.0 days, P=0.07
1. Positive
symptomsh
(moderate/severe
v. mild/none)
30 (31)
2. Negative
symptomsh
(present v. absent)
50 (51)
3. Course of illnessh
(continuous v.
non-continuous)
39 (40)
Confounders adjusted for
Other relevant
points
None in analyses
However, no other illicit
substances detected in urine
on screening
Age at admission,
1. Positive symptoms
Cannabis use at baseline=48% gender, ethnicity
Non-use at baseline=25%
ORe=2.8 (95% CI 1.0–8.0), P=0.03
Cannabis at baseline only v.
no use at baseline or follow-up:
Crude OR=1.68 (95% CI 0.2–9.1)
Adjusted OR=1.61 (95% CI 0.35–
7.58)
2. Negative symptoms
Cannabis use at baseline=54%
Non-use at baseline=51%
ORe=1.1 (95% CI 0.4–3.2), P=0.81
Cannabis at baseline only v. no
use at baseline or follow-up:
Crude OR=0.77 (95% CI 0.1–4.0)
Adjusted OR=0.63 (95% CI 0.29–
2.86)
3. Continuous course of illness
Cannabis use at baseline=56%
Non-use at baseline=34%
ORg=2.4 (95% CI 0.9–6.9),
P=0.055
Cannabis at baseline only v.
no use at baseline or follow-up:
Crude OR=1.64 (95% CI 0.3–8.5)
Adjusted OR=1.68 (95% CI 0.37
7.51)
Results for baseline
only likely to be
under-estimate of
true effect of
cannabis as
excludes potential
effect of continued
use
AMDP, Arbeitsgemeinschaft fur Methodik und Dokumentation in der Psychiatrie 1995; b, regression co-efficient; BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; CGI, Clinical Global Impression; CMRS, Case Manager Rating
Scale for Substance Use Disorder; CUAD, Chemical Use, Abuse and Dependence; DSM–IV, Diagnostic and Statistical Manual for Mental Disorders (4th edn); GAS, Global Assessment Scale; HR, hazard ratio; ICD–10, International Classification of Diseases (10th edn);
NS, not significant; OAS, Overt Aggression Scale; OR, odds ratio; PANSS, Positive and Negative Syndrome Scale; QOL, quality of life; RCT, randomised controlled trial; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of
Positive Symptoms; SCID, Structured Clinical Interview for DSM–III–R; TLFB, timeline followback procedure; THC, tetrahydrocannibinol.
a. Relapse defined as BPRS symptom exacerbation or psychotic relapse from algorithm detailed in paper.
b. Adherence based on persistence with programme and frequency of adherence with medication.
c. Response (defined as absence of rating 43 on PANSS sub-scales, 430% reduction in total PANSS score, and CGI score 54) v. non-response to randomised treatment.
d. Non-adherence based on non-attendance and how many times not taking medication.
e. OR and/or confidence intervals calculated from data in paper.
f. Deficit schizophrenia defined as enduring negative symptoms and failure to return to premorbid level of function.
g. Additional information provided by authors, restricting measures of cannabis use to assessments prior to relapse.
h. Positive symptoms rated using modified ‘life-chart’ instrument from the Multi-Centre Study on the Course and Outcome of Schizophrenia; negative symptoms rated using Iager Negative Symptom Scale; continuous course of illness defined as 56 months of remission.
Effects of cannabis use on outcomes of psychotic disorders:
systematic review
Stanley Zammit, Theresa H. M. Moore, Anne Lingford-Hughes, Thomas R. E. Barnes, Peter B. Jones,
Margaret Burke and Glyn Lewis
BJP 2008, 193:357-363.
Access the most recent version at DOI: 10.1192/bjp.bp.107.046375
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