Neuroscience and Biobehavioral Reviews 101 (2019) 78–84

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

The prevalence and clinical correlates of cannabis use and cannabis use T
disorder among patients with bipolar disorder: A systematic review with
meta-analysis and meta-regression
Jairo Vinícius Pintoa,b, Leonardo Simão Medeirosa,b, Gabriel Santana da Rosaa,b,
Carlos Eduardo Santana de Oliveiraa,b, José Alexandre de Souza Crippac,
⁎
Ives Cavalcante Passosa,b, Márcia Kauer-Sant’Annaa,b,
a
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Brazil
b
Department of Psychiatry, Federal University of Rio Grande do Sul, Brazil
c
Department of Neuroscience and Behavioral Sciences, University of São Paulo, Brazil

A R T I C LE I N FO A B S T R A C T

Keywords: Bipolar disorder (BD) is commonly associated with comorbidities, especially substance use disorders. In light of
Bipolar disorder this, the present review aimed to investigate the prevalence and clinical correlates of cannabis use in BD. Studies
Cannabis evaluating the prevalence of cannabis use among patients with BD and studies reporting a dichotomous sample
Psychosis of patients with cannabis use compared to those without the use were included. Meta-analyses using random-
Suicide
effects models were performed, and sources of heterogeneity were explored using meta-regression. The search
Substance use disorder
Meta-analysis
resulted in 2918 publications, of which 53 were included. The prevalence of cannabis use was 24%
Meta-regression (95%CI:18–29; k = 35; n = 51,756). Cannabis use was significantly associated with being younger, male, and
single; having fewer years of education and an earlier onset of affective symptoms; and lifetime psychotic
symptoms, suicide attempts, and use of tobacco, alcohol, and other substances. In conclusion, cannabis use
present in almost one-quarter of patients with BD and is associated with factors that are highly relevant for both
clinical practice and public health.

1. Introduction cope with mood symptoms or other psychological problems (American

Bipolar disorder has a prevalence of about 2% worldwide
(Merikangas et al., 2012) and commonly follows a chronic course that
may result in poor clinical outcomes (Bourne et al., 2013; Passos et al.,
2016). One comorbidity frequently found among patients with bipolar
disorder, and that often worse these outcomes, is substance use disorder
(SUD): it is known to affect over one-third of this population (Hunt
et al., 2016a). In particular, cannabis use disorder (CUD), has shown a
prevalence of about 20% in different settings (Hunt et al., 2016a,
2016b). While the cannabis use is common in the general population
worldwide, with reports that 192 million people used it at least once in
the past year(UNDOC, 2018), CUD is a problematic pattern of cannabis
use characterized by its clinical and psychosocial impacts in daily life
(American Psychiatric Association, 2013)
Individuals who use cannabis often report that it is being used to
Psychiatric Association, 2013). However, it is not so clear among pa-
tients with bipolar disorder, since it cannabis use and CUD are fre-
quently associated with higher manic symptoms negative outcomes
(Gibbs et al., 2015; Kvitland et al., 2015; Zorrilla et al., 2015). On the
other hand, it is worth noting that the plant Cannabis sativa contains
more than 600 chemical compounds; of these, 100 share similar che-
mical structures and are known as cannabinoids (Crippa et al., 2018).
Moreover, the main compounds, Δ-9-tetrahydrocannabinol (THC) and
cannabidiol, have distinct and often opposing effects on psychosis,
neurocognition, psychomotricity and mood, which may explain some
apparently conflicting findings of different neuropsychiatric symptoms
(Murray et al., 2017; Sami and Bhattacharyya, 2018). In addition, it is
well known that cannabis use affects the endocannabinoid system,
leading to a wide variety of neurobiological processes including brain
development and emotions as well as other neuropsychiatric functions

⁎
Corresponding author at: Federal University of Rio Grande do Sul, Avenida Ramiro Barcelos, 2350, CEP 90035-903, Porto Alegre, RS, Brazil.
E-mail addresses: jairovinicius@msn.com (J.V. Pinto), leosmedeiros@gmail.com (L.S. Medeiros), gabrielsantanarosa@hotmail.com (G. Santana da Rosa),
ceduardooliveira@hcpa.edu.br (C.E. Santana de Oliveira), jcrippa@fmrp.usp.br (J.A.d.S. Crippa), ivescp1@gmail.com (I.C. Passos),
mksantanna@gmail.com (M. Kauer-Sant’Anna).

https://doi.org/10.1016/j.neubiorev.2019.04.004
Received 3 January 2019; Received in revised form 4 April 2019; Accepted 8 April 2019
Available online 08 April 2019
0149-7634/ © 2019 Published by Elsevier Ltd.
J.V. Pinto, et al.
(Murray et al., 2017; Sami and Bhattacharyya, 2018).
Cannabis is the illicit drug most widely consumed worldwide
(UNDOC, 2018), and the implications of cannabis use for schizophrenia
have been extensively studied in systematic reviews with meta-analyses
(Hunt et al., 2018; Marconi et al., 2016; Rabin et al., 2011). Prior meta-
analyses evaluated the prevalence of CUD among patients with bipolar
disorder (Hunt et al., 2016a); however, including studies performed
only in separated clinical and populational settings between 1990 and
2015 and did not determine other potential moderators associated with
cannabis prevalence (e.g., demographic variables or factors related to
study design). Considering the findings available on the association
between cannabis use and poor outcomes in bipolar disorder, and that a
growing body of evidence has been pointing to an involvement of the
endocannabinoid system not only in the pathophysiology of manic
symptoms (Gibbs et al., 2015; Marwaha et al., 2017) but also in the
neurobiology of mood disorders (Agrawal et al., 2012; Bluett et al.,
2017; Bossong et al., 2013; Kranaster et al., 2017), a systematic review
and meta-analysis is needed to evaluate the clinical variables associated
with cannabis use among patients with bipolar disorder.
The hypothesis of this is study is that the prevalence of cannabis use
among patients with bipolar disorder is high and that this comorbidity
is associated with poor outcomes. Therefore, this study consists of a
systematic review and meta-analysis of clinical correlates and pre-
valence of cannabis use and CUD among patients with bipolar disorder.
In addition, sources of heterogeneity between studies were explored
using meta-regression analysis.
2. Methods
2.1. Search strategy and selection criteria
This systematic review was conducted in accordance with the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines (Moher et al., 2009) and was registered at PRO-
SPERO (CRD42018083314). The PRISMA flowchart and checklist can
Fig. 1. Flowchart of the review process and study selection.
79
Neuroscience and Biobehavioral Reviews 101 (2019) 78–84
be found in Fig. 1 Table S1, respectively. The authors searched PubMed,
Embase, and Web of Science databases for articles published in any
language up to May 12, 2018, using the keywords bipolar disorder AND
cannabis and their synonyms. The complete keywords and Medical
Subject Headings (MeSH) used in the searches are detailed in the sup-
plementary material. Three investigators (LSM, GSR, and CESO) in-
dependently screened and selected the studies. JVP made the final de-
cision in cases of disagreement. The authors did not search for articles
outside the databases (grey literature), due to the large dataset already
expected using the search strategy above. However, the reference lists
of included papers were searched, and authors contacted when neces-
sary. Articles written in other languages were translated when neces-
sary.
The inclusion criteria were: 1) Original studies with cross-sectional,
cohort, or case-control designs; 2) Studies reporting the prevalence of
cannabis use or studies assessing a dichotomous sample of patients with
bipolar disorder with cannabis use and a group of patients with bipolar
disorder without cannabis use; 3) Studies in which the diagnosis of
bipolar disorder was made using either the International Classification
of Diseases (ICD) or Diagnostic and Statistical Manual of Mental
Disorders (DSM) criteria; 4) Studies assessing cannabis use, cannabis
abuse, cannabis dependence, or CUD according to ICD or DSM criteria
or according to other objective clinical (i.e The Cannabis Use Disorders
Identification Test) or laboratory assessment (i.e. toxicological evalua-
tion). The exclusion criteria was: 1) Reviews, editorials, book chapters,
case reports or case series. The quality of the studies was evaluated
using the Newcastle-Ottawa Quality Assessment Scale (NOQAS).
2.2. Data analysis
The authors built Excel spreadsheets to extract data from the se-
lected articles and used the online version of EndNote to remove du-
plicate data. Two authors extracted the data (JVP and LSM), and a third
author (ICP) independently made the final decision in cases of dis-
agreement. The following characteristics were extracted from each
J.V. Pinto, et al.
Fig. 2. Meta-analysis of cannabis use among patients with bipolar disorder. RE: Random-effect.
study: name of the first author, publication year, sample size, gender,
age (mean and standard deviation [SD]), ethnicity, prevalence of can-
nabis use, prevalence of CUDs, type of bipolar disorder, age at onset of
bipolar disorder (mean and SD), years of education (mean and SD),
current employment status, current marital status, presence of rapid
cycling, presence of lifetime psychotic symptoms, presence of lifetime
suicide attempts, presence of lifetime hospitalizations in psychiatric
80
Neuroscience and Biobehavioral Reviews 101 (2019) 78–84
wards and number of hospital admissions (mean and SD), history of
alcohol use, history of tobacco use, history of other psychoactive sub-
stance use, family history of bipolar disorder or psychotic disorders, and
current medication (lithium, mood stabilizer, anticonvulsants, anti-
psychotics, antidepressants).
The meta-analyses were performed using the ‘metafor’ (version 2.0-
0) and the ‘meta’ (version 4.9-2) packages in R (version 3.3.3) and R
J.V. Pinto, et al.
studio version (version 1.0.136) (R Core Team, 2017). First, we per-
formed a set of analyses involving random effects meta-analysis to es-
timate the pooled prevalence of cannabis use and CUD among patients
with bipolar disorder. A random-effects model with restricted max-
imum-likelihood estimator was used to synthesize the effect size across
studies. This model incorporates both within-study variability and be-
tween-study variability (Viechtbauer, 2010, 2005). The odds ratio (OR)
was used to assess the effect size for categorical risk factors because of
the inclusion of case-control studies in the analysis (Viechtbauer, 2010).
The standardized mean difference (SMD) was used to assess the effect
size for continuous risk factors (Viechtbauer, 2010). The SMD was
calculated using Cohen’s d. The significance level for this meta-analysis
model was 0.05 (Viechtbauer, 2010). For SMD, an effect size of 0.2
indicates a low effect, 0.5 a moderate effect, and 0.8 or more a large
effect (Higgins and Green, 2008).
The existence of heterogeneity was assessed using Q statistics, the
proportion of total variability due to heterogeneity was evaluated using
I2, and the amount of heterogeneity was calculated through t2 (Higgins
and Thompson, 2002). The NOQAS score was used to assess the risk of
bias and quality of each study (Wells et al., 2019). Furthermore, when
three or more studies were included, we used Egger’s linear regression
test to assess publication bias (Egger et al., 1997). If the resulting p-
value was < 0.1, we assumed asymmetry, which may indicate pub-
lication bias. To account for this, we then employed Duval & Tweedie’s
trim and fill method and reported whether the significant effect per-
sisted. We also used the leave-one-out function for sensitivity analyses.
This method consists of removing one study at a time from the dataset
and re-running the meta-analysis. This analysis tests whether the effect
size of the meta-analysis is driven by one single study (Viechtbauer,
2010).
Meta-regression analyses with the Knapp & Hartung adjustment
(IntHout et al., 2014; Viechtbauer et al., 2015) were used to evaluate
the sources of heterogeneity in the prevalence as well as in each vari-
able with a significant effect size associated with cannabis use. Uni-
variate meta-analyses with the following moderators were performed:
mean age of the sample, proportion of men in the sample, ethnicity
(being white/Caucasian or not), bipolar disorder diagnostic criteria
(DSM or ICD), cannabis use diagnostic criteria (DSM, ICD, toxicological
analysis), classification of cannabis use (cannabis use, cannabis abuse,
cannabis dependence, or CUD), region where the study was performed,
and NOQAS score.
3. Results
A total of 2918 abstracts were identified. After the exclusion of 749
duplicates, the remaining 2169 abstracts were screened independently
based on titles and abstracts. A total of 1825 abstracts were excluded
after initial screening, then 344 full texts were reviewed, and another
279 were excluded at this stage. A final sample of 65 full texts met the
inclusion criteria. However, only 53 were included in the meta-analysis
because some papers shared the same datasets. In those cases of shared
databases, the study with the largest sample was selected. Fig. 1 sum-
marizes the selection process. The characteristics of the studies included
are described in Supplementary Tables S2 and S3.
3.1. Prevalence of cannabis use among patients with bipolar disorder
When evaluating cannabis use as a general group (cannabis use or
any type of CUD), the prevalence estimated in the meta-analysis was
24% (95% confidence interval [95%CI] 18–29; k = 35; pooled sample
size 51,756). Heterogeneity was found to be substantial (I2 = 99.81%,
Q[df = 34] = 2856.188, p < 0.001). Then, random effects sub-group
meta-analyses were also performed separately for cannabis use and
CUDs (cannabis abuse, cannabis dependence, or cannabis use disorder).
Prevalence of cannabis use was 30% (95%CI 19–41; k = 10; pooled
sample size 2,482) and again the heterogeneity relevant (I2 = 96.80%,
81
Neuroscience and Biobehavioral Reviews 101 (2019) 78–84
Q[df = 9] = 399.704, p < 0.001). The prevalence of any type of CUD
was 20% (95%CI 14–25; k = 28; pooled sample size = 49,554), with an
important heterogeneity (I2 = 99.81%, Q[df = 27] = 1233.316,
p < 0.001). Results are presented in Fig. 2, and in Supplementary
figures S1 and S2.
In the investigation of sources of heterogeneity using univariate
meta-regression analyses, we found that two predictors significantly
explained the heterogeneity of the prevalence of cannabis use and
CUDs. Gender (male) (b = 0.0857, p < 0.001) and ethnicity (white)
(b = 0.9461, p < 0.001) were positively correlated to the prevalence
of cannabis use. The multivariate meta-regression analysis of these
moderators accounted for 100% of the heterogeneity (F = 163.839,
p < 0.001, k = 10), but only being male retained a significant effect
on the association with increased risk of suicide (b = 1.4695,
p < 0.001; Supplementary Tables S4 and S5). Univariate and multi-
variate analyses also showed similar results for CUD and cannabis use
when evaluated separately (Supplementary Tables S4 and S5).
3.2. Clinical correlates associated with cannabis use
With regard to continuous variables, patients using cannabis were
younger (p < 0.001), had fewer years of education (p < 0.001) and
had an earlier age at onset of bipolar disorder (p < 0.001). Table 1
summarizes the heterogeneity of each study; forest plots are shown in
Supplementary Figures S1 to S9. Egger’s test revealed a potential
publication bias for years of education (p = 0.086). The trim and fill
method was performed and did not change the significance of that
variable (p = 0.001) (results are shown in Supplementary Table S6 and
Supplementary figure S10). Complementary analyses are summarized
in Supplementary Table S7. Effect sizes remained significant after the
leave-one-out models were used for current age, age at onset, and years
of education. However, number of hospitalizations remained significant
only after removing one of three studies. These results are shown in
Supplementary Table S8. Meta-regression analyses did not reveal a
significant moderator effect of any continuous variable.
For categorical variables, the group with bipolar disorder and can-
nabis use was significantly associated with being male (p < 0.001),
being single (p < 0.001), lifetime psychotic symptoms (p = 0.003),
history of suicide attempts (p = 0.002), history of tobacco use
(p < 0.001), history of alcohol use (p < 0.001), and history of other
psychoactive substance use (p < 0.001) (Table 1). The heterogeneity
of each study is summarized in Table 1; forest plots are shown in
Supplementary Figures S11 to S29. Egger’s test showed no potential
publication bias for categorical variables. Effect sizes remained sig-
nificant after the leave-one-out models were used for gender, marital
status, lifetime psychotic symptoms, history of tobacco use, history of
alcohol use, and lifetime comorbid substance use disorders. The vari-
able suicide attempt lost significance after removing one study
(p = 0.071). These results are summarized in Supplementary Table S9.
In our investigation for sources of heterogeneity using univariate
meta-regression analyses, we found that the classification of cannabis
use accounted for the heterogeneity of male gender as a risk factor. CUD
(as opposed to cannabis use or cannabis abuse and dependence sepa-
rately) was negatively correlated (b = −0.6472, p = 0.007) to male
gender (Supplementary Table S10). Meta-regression analyses did not
reveal a significant moderator effect of any other variable.
4. Discussion
The present study is the first meta-analysis to investigate the clinical
and demographic correlates and the prevalence of cannabis use and
CUD among patients with bipolar disorder in both clinical settings and
population-based samples. Including 35 studies (pooled sample size of
51,756; female: 60%), this study found that the overall pooled pre-
valence of cannabis use and CUD affected almost one-quarter (24%) of
the patients with bipolar disorder, even though only one-fifth of the
J.V. Pinto, et al. Neuroscience and Biobehavioral Reviews 101 (2019) 78–84

Table 1
Meta-analysis of variables associated with cannabis use in bipolar disorder.
Heterogeneity

Variables Studies, n CB no CB ES 95%CI p value Q statistic (df; p value) t² I² Egger’s test: Z statistic (p value)

Current age a
16 865 4297 −0.54 [-0.79; -0.30] < 0.001 80.7893 (15; 0.1717 82.69% 1.3638 (p = 0.172)
p < 0.001)
Genderb 13 802 4229 2.40 [1.72; 3.35] < 0.001 23.9185 (12; p = 0.021) 0.1128 43.74% 0.9398 (p = 0.347)
Ethnicityb 07 189 505 1.05 [0.67; 1.64] 0.831 2.1015 (6; p = 0.910) 0.000 0.00% 0.9025 (p = 0.367)
Marital statusb 07 608 3417 1.98 [1.65; 2.37] < 0.001 2.3564 (6; p = 0.884) 0.000 0.00% −0.0508 (p = 0.959)
Employedb 04 517 3166 0.70 [0.44; 1.09] 0.114 5.0124 (3; p = 0.171) 0.0867 38.43% 1.7471 (p = 0.080)
Years of educationa 05 146 289 −0.43 [-0.63; -0.22] < 0.001 4.9469 (4; p = 0.293) 0.0000 0.00% −1.7152 (p = 0.086)
Age of BD onseta 09 861 4167 −0.46 [-0.61; -0.31] < 0.001 19.8812 (8; p = 0.011) 0.0217 53.44% −0.0554 (p = 0.955)
Rapid cyclingb 04 553 4330 1.63 [0.95; 2.82] 0.078 14.0550 (3; p = 0.003) 0.2438 79.99% 0.7831 (p = 0.433)
Psychotic symptomsb 07 684 4538 1.76 [1.20; 2.58] 0.003 13.0083 (6; p = 0.043) 0.1227 59.35% −0.0920 (p = 0.926)
Mixed episodesb 02 213 843 1.29 [0.81; 2.07] 0.281 1.4503 (1; p = 0.228) 0.0416 31.05% NA
Suicide attemptsb 06 651 4711 1.37 [1.11; 1.67] 0.002 5.9893 (5; p = 0.307) 0.0000 0.00% −1.630 (p = 0.103)
Anxiety disordersb 02 155 1980 0.63 [0.15; 2.65] 0.526 7.4598 (1; p = 0.006) 0.9404 86.59% NA
Hospitalizations (lifetime)b 03 182 2053 1.47 [0.29; 7.49] 0.646 3.7389 (2; p = 0.154) 1.0190 41.51% −0.0948 (p = 0.924)
Number of hospitalizationsa 03 189 1800 0.16 [0.00; 0.32] 0.048 3.5020 (2; p = 0.173) 0.0000 0.01% 0.3140 (p = 0.753)
History of tobacco useb 03 188 2207 3.90 [2.83; 5.39] < 0.001 1.0243 (2; p = 0.599) 0.0000 0.00% −0.4906 (p = 0.623)
History of alcohol useb 07 749 5535 5.43 [3.28; 8.99] < 0.001 18.3585 (6; 0.005) 0.2393 74.61% 0.2349 (p = 0.814)
History of other substance useb 08 752 5560 9.68 [5.55; 16.86] < 0.001 22.3675 (7; p = 0.002) 0.3381 71.69% −0.6979 (p = 0.485)
Family history of BD or psychosisb 02 83 377 0.62 [0.28; 1.38] 0.244 1.5023 (1; p = 0.220) 0.1154 33.44% NA
Current lithium useb 03 127 266 1.11 [0.66; 1.86] 0.695 0.7494 (2; p = 0.687) 0.0000 0.00% 0.6142 (p = 0.539)
Current mood stabilizer useb 03 60 265 0.89 [0.39; 2.01] 0.769 0.7161 (2; p = 0.699) 0.0000 0.00% 0.7893 (p = 0.430)
Current anticonvulsant useb 03 127 266 0.96 [0.62; 1.49] 0.844 0.3043 (2; p = 0.859) 0.0000 0.00% 0.1510 (p = 0.880)
Current antipsychotic useb 06 176 469 0.97 [0.46; 2.08] 0.946 12.7846 (5; p = 0.025) 0.537 63.71% 1.1162 (p = 0.264)
Current antidepressant useb 04 113 304 0.65 [0.38; 1.11] 0.114 3.5165 (3; p = 0.318) 0.0000 0.00% −0.7322 (p = 0.464)

Note - CB: cannabis use; ES: effect size; df: degrees of freedom; NA: not applicable; BD: bipolar disorder.
a
The effect size used was the standardized mean difference.
b
The effect size used was odds ratio.

total number of subjects presented CUD. This result is very high com-
pared to the prevalence reported for the general population, that
ranged from around 2–7%, depending on the setting evaluated(Hasin
et al., 2017, 2016). Interestingly, in the univariate meta-regression
analyses, variables such as bipolar disorder diagnostic criteria, cannabis
use diagnostic criteria and classification of cannabis use were not sig-
nificantly associated with the varying prevalence rates reported for
cannabis use among patients with bipolar disorder. Furthermore, the
region where the study was performed and the type of sample assessed
(clinical or population-based) were not associated with variability.
This meta-analysis showed that some important clinical variables
were associated with cannabis use in patients with bipolar disorder.
Firstly, cannabis users were younger at the time of the study and also
younger at first episode. It is known that an earlier onset of affective
symptoms is associated with an increased risk of recurrence after the
first episode (Gignac et al., 2015) and with greater symptom severity
(Joslyn et al., 2016). Regarding sociodemographic data, our study
showed that cannabis use in patients with bipolar disorder was asso-
ciated with being male and single and having fewer years of education.
Regarding clinical variables related to the course of illness, cannabis
use was associated with lifetime suicide attempts, a negative outcome
of great importance in the public health scenario, as suicide rates
among people with bipolar disorder are up to 30 times greater than in
the general population (Plans et al., 2018). Moreover, the present meta-
analysis showed that patients with bipolar disorder who use cannabis
were more likely to present lifetime psychotic symptoms, a factor as-
sociated with pernicious clinical outcomes and poorer functioning
(Belizario et al., 2018; Dell’Osso et al., 2017). Conversely, this study
showed no differences in other variables associated with illness pro-
gression and cognitive impairments, such as rapid cycling and co-
morbid anxiety disorders.
Misuse of alcohol, tobacco, and other substances is common among
subjects with bipolar disorder: more than one-third of this population is
affected by a comorbid SUD (Hunt et al., 2016a). Also, these co-
morbidities are often associated with negative outcomes (Messer et al.,
2017). In this meta-analysis, patients with bipolar disorder and
cannabis use had a greater chance of presenting lifetime misuse of al-
cohol, nicotine, and other psychoactive substances.
When comparing the present data with previous findings on other
severe mental disorders, some overlaps and differences can be ob-
served. A recent meta-analysis showed that the prevalence of CUD
among patients with schizophrenia was 26.2% in clinical settings, si-
milar to our result (Hunt et al., 2018). Other meta-analyses have shown
poor outcomes associated with the comorbidity of psychotic disorder
with cannabis use, e.g., neurocognition deficits (Bogaty et al., 2018),
the severity of clinical symptoms, and worse social function (Large
et al., 2014). The prevalence of CUD among patients with major de-
pressive disorder has been shown to be lower than that found in bipolar
disorder and schizophrenia (Patten et al., 2015). Notwithstanding,
longitudinal studies have associated cannabis use during adolescence
with further development of major depressive disorder, depressive
symptoms, anxiety symptoms, and suicidal ideation (Agrawal et al.,
2017; Leadbeater et al., 2018; Schoeler et al., 2018).
An important strength of this systematic review was the search
strategy employed: a range of databases and search terms were used.
Moreover, only studies in which diagnosis was based on DSM or ICD
criteria were included. In addition, we performed the analysis not only
of the prevalence of cannabis use and CUD among patients with bipolar
disorder but also the clinical variables associated with these co-
morbidities. From a different standpoint, however, this study also has
some limitations. First, lifetime diagnoses of cannabis use were based
mainly on retrospective rather than prospective assessments, which
may have underestimated prevalence results. Second, we analyzed only
cross-sectional data, which may increase the risk of memory bias and
does not allow to determine causality. Third, high levels of between-
study heterogeneity were recorded for some meta-analyses in our study.
Still, the meta-regression analysis could explain a large portion of this
heterogeneity. Fourth, despite the large number of included studies,
some specific variables were present only in a small parcel of them;
therefore, some analyses included only few studies (i.e. years education
including only five studies).
In conclusion, the present study showed that both cannabis use and

82
J.V. Pinto, et al.
CUD are highly prevalent in clinical and population-based samples of
subjects with bipolar disorder. Also, it showed that these comorbidities
are associated with negative clinical correlates, namely suicide, psy-
chotic symptoms and other substance use disorders, and specific so-
ciodemographic factors. These findings point to an urgent need for
more studies into this topic, especially longitudinal, to allow the de-
velopment of better prevention and treatment strategies for subjects
with bipolar disorder and cannabis use, as well as studies that in-
vestigate the relationship between the pathophysiology of bipolar dis-
order and the endocannabinoid system.
Contributors
JVP, ICP, and MKS defined the study design. JVP performed the
database searches. LSM, GSR, and CESO independently screened the
abstracts and articles, and JVP made the final decision in cases of dis-
agreement. JVP and LSM performed the data extraction, and ICP made
the final decision in cases of disagreement. JVP, ICP, and MKS under-
took the statistical and meta-analysis. JVP, LSM, GSR, CESO, JAC, ICP,
and MKS are responsible for the interpretation of findings and drafted
the final manuscript. All authors have read and approved of the final
version of the manuscript and agree with the submission.
Disclosure
JVP, LSM, GSR, CESO, and ICP report no biomedical financial in-
terests or potential conflicts of interest. JVP has received a scholarship
from Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq, Brazil). MK-S has received consulting or speaking fees from
Daichii Sankyo and Shire. JAC is co-inventor (Mechoulam R, Zuardi
AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JA, Breuer A) of
the patent “Fluorinated CBD compounds, compositions and uses
thereof. Pub. No.: WO/2014/108899. International Application No.:
PCT/IL2014/050023”, Def. US no. Reg. 62193296; 29/07/2015; INPI
on 19/08/2015 (BR1120150164927). The University of São Paulo has
licensed the patent to Phytecs Pharm (USP Resolution No.
15.1.130002.1.1). The University of São Paulo has an agreement with
Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product
containing synthetic cannabidiol and prove its safety and therapeutic
efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease,
and anxiety disorders.” JAC has received travel support from and is
medical advisor of BSPG-Pharm. JAC is recipient of CNPq productivity
fellowships (1 A).
Role of funding source
JVP has received a scholarship from Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq, Brazil). MK-S has re-
ceived research grants from CNPq and Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES, Brazil). JAC has a grant from
University Global Partnership Network (UGPN)–Global priorities in
cannabinoid research excellence. Research was supported in part by a
grant from the National Institute for Translational Medicine (INCT-TM;
CNPq, Brazil). This study was financed in part by CAPES (Finance Code
001). The authors acknowledge CNPq and CAPES for grants and scho-
larships.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.neubiorev.2019.04.
004.
References
Agrawal, A., Nelson, E.C., Littlefield, A.K., Bucholz, K.K., Degenhardt, L., Henders, A.K.,
83
Neuroscience and Biobehavioral Reviews 101 (2019) 78–84
Madden, P.A.F., Martin, N.G., Montgomery, G.W., Pergadia, M.L., Sher, K.J., Heath,
A.C., Lynskey, M.T., 2012. Cannabinoid receptor genotype moderation of the effects
of childhood physical abuse on anhedonia and depression. Arch. Gen. Psychiatry 69,
732–740. https://doi.org/10.1001/archgenpsychiatry.2011.2273.
Agrawal, A., Nelson, E.C., Bucholz, K.K., Tillman, R., Grucza, R.A., Statham, D.J.,
Madden, P.A., Martin, N.G., Heath, A.C., Lynskey, M.T., 2017. Major depressive
disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant
twins: a retrospective cohort study. Lancet Psychiatry 4, 706–714. https://doi.org/
10.1016/S2215-0366(17)30280-8.
American Psychiatric Association, 2013. American Psychiatric Association: Diagnostic
and Statistical Manual of Mental Disorders, fifth. ed. American Psychiatric
Publishing, Arlington V.A.
Belizario, G.O., Silva, M., Lafer, B., 2018. Impact of predominant polarity on long-term
outcome in bipolar disorder: a 7-year longitudinal cohort study. J. Affect. Disord.
241, 37–40. https://doi.org/10.1016/j.jad.2018.07.086.
Bluett, R.J., Baldi, R., Haymer, A., Gaulden, A.D., Hartley, N.D., Parrish, W.P., Baechle, J.,
Marcus, D.J., Mardam-Bey, R., Shonesy, B.C., Uddin, M.J., Marnett, L.J., Mackie, K.,
Colbran, R.J., Winder, D.G., Patel, S., 2017. Endocannabinoid signalling modulates
susceptibility to traumatic stress exposure. Nat. Commun. 8, 14782. https://doi.org/
10.1038/ncomms14782.
Bogaty, S.E.R., Lee, R.S.C., Hickie, I.B., Hermens, D.F., 2018. Meta-analysis of neuro-
cognition in young psychosis patients with current cannabis use. J. Psychiatr. Res. 99,
22–32. https://doi.org/10.1016/j.jpsychires.2018.01.010.
Bossong, M.G., van Hell, H.H., Jager, G., Kahn, R.S., Ramsey, N.F., Jansma, J.M., 2013.
The endocannabinoid system and emotional processing: a pharmacological fMRI
study with 9-tetrahydrocannabinol. Eur. Neuropsychopharmacol. 23, 1687–1697.
https://doi.org/10.1016/j.euroneuro.2013.06.009.
Bourne, C., Aydemir, O., Balanza-Martinez, V., Bora, E., Brissos, S., Cavanagh, J.T.O.,
Clark, L., Cubukcuoglu, Z., Dias, V.V., Dittmann, S., Ferrier, I.N., Fleck, D.E., Frangou,
S., Gallagher, P., Jones, L., Kieseppa, T., Martinez-Aran, A., Melle, I., Moore, P.B.,
Mur, M., Pfennig, A., Raust, A., Senturk, V., Simonsen, C., Smith, D.J., Bio, D.S.,
Soeiro-de-Souza, M.G., Stoddart, S.D.R., Sundet, K., Szoke, A., Thompson, J.M.,
Torrent, C., Zalla, T., Craddock, N., Andreassen, O.A., Leboyer, M., Vieta, E., Bauer,
M., Worhunsky, P.D., Tzagarakis, C., Rogers, R.D., Geddes, J.R., Goodwin, G.M.,
2013. Neuropsychological testing of cognitive impairment in euthymic bipolar dis-
order: an individual patient data meta-analysis. Acta Psychiatr. Scand. 128, 149–162.
https://doi.org/10.1111/acps.12133.
Crippa, J.A., Guimaraes, F.S., Campos, A.C., Zuardi, A.W., 2018. Translational in-
vestigation of the therapeutic potential of cannabidiol (CBD): toward a new age.
Front. Immunol. 9, 2009. https://doi.org/10.3389/fimmu.2018.02009.
Dell’Osso, B., Camuri, G., Cremaschi, L., Dobrea, C., Buoli, M., Ketter, T.A., Altamura,
A.C., 2017. Lifetime presence of psychotic symptoms in bipolar disorder is associated
with less favorable socio-demographic and certain clinical features. Compr.
Psychiatry 76, 169–176. https://doi.org/10.1016/j.comppsych.2017.04.005.
Egger, M., Davey Smith, G., Schneider, M., Minder, C., 1997. Bias in meta-analysis de-
tected by a simple, graphical test. BMJ 315. https://doi.org/10.1136/bmj.315.7109.
629.
Gibbs, M., Winsper, C., Marwaha, S., Gilbert, E., Broome, M., Singh, S.P., 2015. Cannabis
use and mania symptoms: a systematic review and meta-analysis. J. Affect. Disord.
171, 39–47. https://doi.org/10.1016/j.jad.2014.09.016.
Gignac, A., McGirr, A., Lam, R.W., Yatham, L.N., 2015. Recovery and recurrence fol-
lowing a first episode of mania: a systematic review and meta-analysis of pro-
spectively characterized cohorts. J. Clin. Psychiatry 76, 1241–1248. https://doi.org/
10.4088/JCP.14r09245.
Hasin, D.S., Kerridge, B.T., Saha, T.D., Huang, B., Pickering, R., Smith, S.M., Jung, J.,
Zhang, H., Grant, B.F., 2016. Prevalence and correlates of DSM-5 Cannabis use dis-
order, 2012-2013: findings from the national epidemiologic survey on alcohol and
related Conditions-III. Am. J. Psychiatry 173, 588–599. https://doi.org/10.1176/
appi.ajp.2015.15070907.
Hasin, D.S., Sarvet, A.L., Cerda, M., Keyes, K.M., Stohl, M., Galea, S., Wall, M.M., 2017.
US adult illicit Cannabis use, Cannabis use disorder, and medical marijuana laws:
1991-1992 to 2012-2013. JAMA Psychiatry 74, 579–588. https://doi.org/10.1001/
jamapsychiatry.2017.0724.
Higgins, J., Green, S., 2008. Cochrane Handbook for Systematic Reviews of Interventions:
The Cochrane Collaboration. John Wiley & Sons, Ltd, London, England. https://doi.
org/10.1002/9780470712184.
Higgins, J.P., Thompson, S.G., 2002. Quantifying heterogeneity in a meta-analysis. Stat.
Med. 21. https://doi.org/10.1002/sim.1186.
Hunt, G.E., Malhi, G.S., Cleary, M., Lai, H.M.X., Sitharthan, T., 2016a. Prevalence of
comorbid bipolar and substance use disorders in clinical settings, 1990-2015: sys-
tematic review and meta-analysis. J. Affect. Disord. 206, 331–349. https://doi.org/
10.1016/j.jad.2016.07.011.
Hunt, G.E., Malhi, G.S., Cleary, M., Lai, H.M.X., Sitharthan, T., 2016b. Comorbidity of
bipolar and substance use disorders in national surveys of general populations, 1990-
2015: systematic review and meta-analysis. J. Affect. Disord. 206, 321–330. https://
doi.org/10.1016/j.jad.2016.06.051.
Hunt, G.E., Large, M.M., Cleary, M., Lai, H.M.X., Saunders, J.B., 2018. Prevalence of
comorbid substance use in schizophrenia spectrum disorders in community and
clinical settings, 1990-2017: systematic review and meta-analysis. Drug Alcohol
Depend. 191, 234–258. https://doi.org/10.1016/j.drugalcdep.2018.07.011.
IntHout, J., Ioannidis, J.P.A., Borm, G.F., 2014. The Hartung-Knapp-Sidik-Jonkman
method for random effects meta-analysis is straightforward and considerably out-
performs the standard DerSimonian-Laird method. BMC Med. Res. Methodol. 14, 25.
https://doi.org/10.1186/1471-2288-14-25.
Joslyn, C., Hawes, D.J., Hunt, C., Mitchell, P.B., 2016. Is age of onset associated with
severity, prognosis, and clinical features in bipolar disorder? A meta- analytic
J.V. Pinto, et al.
review. pp. 1–15. https://doi.org/10.1111/bdi.12419.
Kranaster, L., Hoyer, C., Aksay, S.S., Bumb, J.M., Leweke, F.M., Janke, C., Thiel, M., Lutz,
B., Bindila, L., Sartorius, A., 2017. Electroconvulsive therapy enhances en-
docannabinoids in the cerebrospinal fluid of patients with major depression: a pre-
liminary prospective study. Eur. Arch. Psychiatry Clin. Neurosci. 267, 781–786.
https://doi.org/10.1007/s00406-017-0789-7.
Kvitland, L.R., Melle, I., Aminoff, S.R., Demmo, C., Lagerberg, T.V., Andreassen, O.A.,
Ringen, P.A., 2015. Continued cannabis use at one year follow up is associated with
elevated mood and lower global functioning in bipolar I disorder. BMC Psychiatry 15,
11. https://doi.org/10.1186/s12888-015-0389-x.
Large, M., Mullin, K., Gupta, P., Harris, A., Nielssen, O., 2014. Systematic meta-analysis of
outcomes associated with psychosis and co-morbid substance use. Aust. N. Z. J.
Psychiatry 48, 418–432. https://doi.org/10.1177/0004867414525838.
Leadbeater, B.J., Ames, M.E., Linden-Carmichael, A.N., 2018. Age-varying effects of
cannabis use frequency and disorder on symptoms of psychosis, depression, and
anxiety in adolescents and adults. Addiction. https://doi.org/10.1111/add.14459.
Marconi, A., Di Forti, M., Lewis, C.M., Murray, R.M., Vassos, E., 2016. Meta-analysis of
the association between the level of Cannabis use and risk of psychosis. Schizophr.
Bull. 42, 1262–1269. https://doi.org/10.1093/schbul/sbw003.
Marwaha, S., Winsper, C., Bebbington, P., Smith, D., 2017. Cannabis use and hypomania
in young people: a prospective analysis. Schizophr. Bull. https://doi.org/10.1093/
schbul/sbx158.
Merikangas, K.R., Jin, R., He, J., Kessler, R.C., Lee, S., Sampson, N.A., Viana, M.C.,
Andrade, L.H., Hu, C., Karam, E.G., Ladea, M., Elena, M., Mora, M., Browne, M.O.,
2012. Prevalence and correlates fo bipolar Spectrum disorder in the world mental
healht survey initiative. Arch. Gen. Psychiatry 68, 241–251. https://doi.org/10.
1001/archgenpsychiatry.2011.12.Prevalence.
Messer, T., Lammers, G., Muller-Siecheneder, F., Schmidt, R.-F., Latifi, S., 2017.
Substance abuse in patients with bipolar disorder: a systematic review and meta-
analysis. Psychiatry Res. 253, 338–350. https://doi.org/10.1016/j.psychres.2017.02.
067.
Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., 2009. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. J. Clin. Epidemiol. 62.
https://doi.org/10.1016/j.jclinepi.2009.06.005.
Murray, R.M., Englund, A., Abi-Dargham, A., Lewis, D.A., Di Forti, M., Davies, C., Sherif,
M., McGuire, P., D’Souza, D.C., 2017. Cannabis-associated psychosis: neural substrate
and clinical impact. Neuropharmacology 124, 89–104. https://doi.org/10.1016/j.
neuropharm.2017.06.018.
Passos, I.C., Mwangi, B., Vieta, E., Berk, M., Kapczinski, F., 2016. Areas of controversy in
84
Neuroscience and Biobehavioral Reviews 101 (2019) 78–84
neuroprogression in bipolar disorder. Acta Psychiatr. Scand. 134, 91–103. https://
doi.org/10.1111/acps.12581.
Patten, S.B., Williams, J.V.A., Lavorato, D.H., Wang, J.L., McDonald, K., Bulloch, A.G.M.,
2015. Descriptive epidemiology of major depressive disorder in Canada in 2012. Can.
J. Psychiatry 60, 23–30. https://doi.org/10.1177/070674371506000106.
Plans, L., Barrot, C., Nieto, E., Rios, J., Schulze, T.G., Papiol, S., Mitjans, M., Vieta, E.,
Benabarre, A., 2018. Association between completed suicide and bipolar disorder: a
systematic review of the literature. J. Affect. Disord. 242, 111–122. https://doi.org/
10.1016/j.jad.2018.08.054.
R Core Team, 2017. R: A Language and Environment for Statistical Computing. R
Foundation for Statistical Computinghttps://doi.org/10.1007/978-3-540-74686-7.
Rabin, R.A., Zakzanis, K.K., George, T.P., 2011. The effects of cannabis use on neuro-
cognition in schizophrenia: a meta-analysis. Schizophr. Res. 128, 111–116. https://
doi.org/10.1016/j.schres.2011.02.017.
Sami, M.B., Bhattacharyya, S., 2018. Are cannabis-using and non-using patients different
groups? Towards understanding the neurobiology of cannabis use in psychotic dis-
orders. J. Psychopharmacol. 32, 825–849. https://doi.org/10.1177/
0269881118760662.
Schoeler, T., Theobald, D., Pingault, J.-B., Farrington, D.P., Coid, J.W., Bhattacharyya, S.,
2018. Developmental sensitivity to cannabis use patterns and risk for major depres-
sive disorder in mid-life: findings from 40 years of follow-up. Psychol. Med. 48,
2169–2176. https://doi.org/10.1017/S0033291717003658.
UNDOC, 2018. World Drug Report 2018. Global Overview of Drug Deman and Supply.
Viechtbauer, W., 2005. Bias and efficiency of meta-analytic variance estimators in the
random-effects model. J. Educ. Behav. Stat. 30, 261–293. https://doi.org/10.3102/
10769986030003261.
Viechtbauer, W., 2010. Conducting meta-analyses in r with the metafor package. J. Stat.
Softw. 36, 1–48. https://doi.org/10.1103/PhysRevB.91.121108.
Viechtbauer, W., Lopez-Lopez, J.A., Sanchez-Meca, J., Marin-Martinez, F., 2015. A
comparison of procedures to test for moderators in mixed-effects meta-regression
models. Psychol. Methods 20, 360–374. https://doi.org/10.1037/met0000023.
Wells, G., Shea, B., O’Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P., 2019.
The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised
Studies in Meta- analyses. n.d.. http://www.ohri.ca/programs/clinical_epidemiol-
ogy/oxford.asp.
Zorrilla, I., Aguado, J., Haro, J.M., Barbeito, S., Lopez Zurbano, S., Ortiz, A., Lopez, P.,
Gonzalez-Pinto, A., 2015. Cannabis and bipolar disorder: does quitting cannabis use
during manic/mixed episode improve clinical/functional outcomes? Acta Psychiatr.
Scand. 131, 100–110. https://doi.org/10.1111/acps.12366.