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Association of Cannabis With Long-Term Clinical Symptoms in Anxiety and Mood Disorders: A Systematic Review of Prospective Studies

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Objective: To systematically review studies examining the longitudinal associations between cannabis use and symptomatic outcomes among individuals with an anxiety or mood disorder at baseline. Data sources: A search of the literature up to May 2017 was conducted using several databases. Search terms related to the exposure (ie, cannabis) and outcome (ie, symptoms) variables of interest. There were no search restrictions. Study selection: In total, 10,191 citations were screened. Key inclusion criteria related to (1) cohort-based longitudinal study design using adults who met criteria for a mood or anxiety disorder at baseline, (2) an independent variable focusing on at least baseline cannabis use, and (3) a dependent variable focusing on the symptomatic course and/or outcomes in anxiety and mood disorders (AMD). Data extraction: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methodological characteristics and key findings were extracted from each study, and quality assessments were conducted for each study. Results: Twelve studies (with a total of 11,959 individuals) met inclusion criteria related to posttraumatic stress disorder (n = 4), panic disorder (n = 1), bipolar disorder (n = 5), and depressive disorder (n = 2). Across 11 studies, "recent" cannabis use (ie, any/greater frequency of use during the last 6 months) was associated with higher symptomatic levels over time relative to comparison groups (ie, no/lesser frequency of use). Ten of these studies further suggested that cannabis use was associated with less symptomatic improvement from treatment (eg, medication, psychotherapy for AMD). Conclusions: Recent cannabis use was associated with negative long-term symptomatic and treatment outcomes across AMD. The findings should be interpreted with caution, considering the observational designs across studies and the biases associated with the samples (eg, inpatients) and sources of cannabis consumed (ie, unregulated sources). Nonetheless, clinicians can use the insight gained to inform their own and their patients' knowledge concerning potential risks of cannabis with regard to symptoms of AMD.
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e1J Clin Psychiatry 79:4, July/August 2018
Review Article
Association of Cannabis With Long-Term Clinical
Symptoms in Anxiety and Mood Disorders:
A Systematic Review of Prospective Studies
George Mammen,PhDa,*; Sergio Rueda,PhDa; Michael Roerecke,PhDa;
Sarah Bonatob; Shaul Lev-Ran,MD,PhDc; and Jürgen Rehm,PhDa
ABSTRACT
Objective: To systematically review studies examining the longitudinal
associations between cannabis use and symptomatic outcomes among
individuals with an anxiety or mood disorder at baseline.
Data Sources: A search of the literature up to May 2017 was conducted
using several databases. Search terms related to the exposure (ie,
cannabis) and outcome (ie, symptoms) variables of interest. There were
no search restrictions.
Study Selection: In total, 10,191 citations were screened. Key inclusion
criteria related to (1) cohort-based longitudinal study design using
adults who met criteria for a mood or anxiety disorder at baseline, (2)
an independent variable focusing on at least baseline cannabis use, and
(3) a dependent variable focusing on the symptomatic course and/or
outcomes in anxiety and mood disorders (AMD).
Data Extraction: We followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses guidelines. Methodological
characteristics and key findings were extracted from each study, and
quality assessments were conducted for each study.
Results: Twelve studies (with a total of 11,959 individuals) met inclusion
criteria related to posttraumatic stress disorder (n = 4), panic disorder
(n = 1), bipolar disorder (n = 5), and depressive disorder (n = 2). Across 11
studies, “recent” cannabis use (ie, any/greater frequency of use during
the last 6 months) was associated with higher symptomatic levels over
time relative to comparison groups (ie, no/lesser frequency of use). Ten
of these studies further suggested that cannabis use was associated
with less symptomatic improvement from treatment (eg, medication,
psychotherapy for AMD).
Conclusions: Recent cannabis use was associated with negative long-
term symptomatic and treatment outcomes across AMD. The findings
should be interpreted with caution, considering the observational
designs across studies and the biases associated with the samples (eg,
inpatients) and sources of cannabis consumed (ie, unregulated sources).
Nonetheless, clinicians can use the insight gained to inform their own
and their patients’ knowledge concerning potential risks of cannabis
with regard to symptoms of AMD.
J Clin Psychiatry 2018;79(4):17r11839
To c ite : Mammen G, Rueda S, Roerecke M, et al. Association of cannabis with
long-term clinical symptoms in anxiety and mood disorders: a systematic review
of prospec tive studies. J Clin Psychiatr y. 2018;79(4):17r11839.
To share: https://doi.org/10.4088/JCP.17r11839
© Copyright 2018 Physicians Postgraduate Press, Inc.
aInstitute for M ental Health Policy Research, Centre for Addiction and Mental
Health, Toronto, Ontario, Canada
bLibrary Services, Centre for Addic tion and Mental Health, Toronto, Ont ario,
Canada
cAddiction M edicine and Dual Disorders Clinic, Lev Hasharon Medic al Center,
Pardesya, Israel
*Corresponding author: George Mammen, PhD, Institute for Mental Health Policy
Research, Centre for Addiction and Mental Health, 33 Russell St, Toronto, ON,
Canada, M5S 2W6 (george.mammen@mail.utoronto.ca).
Cannabis is commonly used among individuals
living with anxiety and mood disorders (AMD),
which are the most prevalent mental health conditions
globally.1 For instance, those diagnosed with generalized
anxiety disorder, posttraumatic stress disorder (PTSD),
bipolar disorder, and depressive disorders have higher
rates of lifetime and recent use (eg, past year and month)
than individuals without such psychiatric conditions,2–4
with around 20%–30% of users consuming cannabis
dai l y. 5–9 This frequent use has been discussed in the
context of self-medication. In line with this, AMD
lead mental health conditions in which cannabis is
used for therapeutic purposes,10–12 as users report that
cannabis relieves acute symptoms in PTSD (eg, reduces
nightmares), bipolar disorder (eg, stabilizes mood), and
depressive disorders (eg, increases motivation).13–18
However, whether cannabis positively or negatively
influences long-term symptoms in AMD is highly
debated and is an understudied area of research.19–22
The majority of longitudinal studies examining
relationships between cannabis and psychiatric
disorders have focused on the general population and
the incidence of developing mental health conditions
as predicted by cannabis use. Systematic reviews show
that higher frequencies of use may increase risk in the
onset of anxiety, depressive, and bipolar disorders,23–26
in addition to schizophrenia and psychoses.27 On the
basis of this literature, mental health experts theorize
that cannabis use most likely does not benefit long-
term symptoms but rather exacerbates the course of
illness.19,28
To the authors’ knowledge, no systematic review
has focused on the longitudinal associations between
cannabis use and AMD in a clinical population.
Wilkinson and colleagues,29 in the Journal of Clinical
Psychiatry, published a systematic review to determine
the efficacy of cannabis in psychiatric indications.
However, their review did not focus on AMD, as they
examined PTSD, in addition to Alzheimer’s disease and
Tourette’s syndrome. Narrowing the focus to AMD is
warranted, particularly given the high prevalence of
cannabis consumption in PTSD and other anxiety
(eg, social anxiety disorder) and mood disorders (eg,
major depressive disorder).2–9 Pursuing this aim can
help address if cannabis is associated with negative or
positive symptomatic outcomes, which clinicians can
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e2 J Clin Psychiatry 79:4, July/August 2018
Mammen et al
Table 1. Outline of Search Terms Used in the Study Search Strategy
Concept MeSH TermsaKeywords
Independent variable: cannabis cannabis
cannabis addiction
medical cannabis
marijuana smoking
marijuana abuse
medical marijuana
marijuana usage
cannabis*
marihuana*
marijuana*
hash
hashish
Dependent variable: anxiety and mood disorders anxiety
anxiety disorders
trauma/stressor related disorder
emotional trauma
mood disorders
adjustment disorder
depression
bipolar and related disorders
affective disorders
anxiety, anxious, phobia, phobic, panic disorder, panic attack
traumatic disorder*, post*, trauma*, stress, combat neuroses,
war neurosis, combat disorder*, combat neuroses, shellshock*,
psychological trauma, mood disorder*, mood disruptive
dysregulation, affective disorder*, seasonal affective disorder,
depress, dysthym*, premenstr* dysphoric disorder*, bipolar,
manic, mania
Association association
correlation
risk factors
relation*
causal*
aMeSH (Medical Subject Heading) search terms are the controlled vocabulary used by the US National Library of Medicine to index articles for MEDLINE/
PubMed. MeSH terminology provides a consistent way to retrieve information that may use different terminology for the same concepts; an asterisk (*)
denotes that the search term will look for any word with the given letter combination plus any combination of letters following the original combination.
use as evidence to inform patients regarding potential long-
term influence (eg, benefits, risks) of cannabis on AMD.
METHODS
To conduct this systematic review, we followed the
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines. The study protocol
was registered with PROSPERO (registration number:
CRD42017037733).
Databases and Search Terms
The following electronic databases were used for the
literature search: Embase, MEDLINE, MEDLINE in Process
and Other Non-Indexed Citations, MEDLINE Epub Ahead
of Print, and PsycInfo. Databases including gray literature (ie,
conference papers) were searched up until May 2017. There
were no year, language, or study type restrictions. Search
terms related to the exposure (ie, regulated and unregulated
cannabis) and outcome (ie, AMD) variables of interest
(Table 1). The search process was led by a professional health
science librarian (S.B.).
Screening Process and Study Eligibility Criteria
The study screening and retrieval process was conducted
in duplicate by 4 trained reviewers and documented by
DistillerSR.30 Reference lists of relevant studies and literature
reviews, in addition to “related articles” in electronic
databases, were further examined. Meeting the inclusion
criteria meant that the study (1) employed a cohort-based
longitudinal design; (2) focused on adults (ie, 18+ years
of age) meeting criteria for a mood or anxiety disorder
at baseline (without comorbidities related to physical
illness, schizophrenia, or psychoses), as determined by
either clinician interviews or screening instruments with
established cutoff thresholds; (3) assessed symptomatic
course (operationalized as using multiple follow-up
assessments in analysis) and/or symptomatic outcome
(operationalized as using only 1 follow-up measure) as the
dependent variable; (4) assessed at least baseline cannabis
use as the independent variable (isolated cannabis without
polysubstance use); and (5) included at least 1 comparison/
control group.
Data Extraction and Quality Assessments
Methodological characteristics and key findings were
extracted from each study. Authors of eligible studies were
contacted to provide missing or additional data. To assess
study quality, we used the Newcastle-Ottawa Quality
Assessment Scale for Cohort Studies,31 which examines
quality via indicators related to sample recruitment, group
comparability, and ascertainment of the exposure and
outcome variables of interest. Two appraisers performed
these assessments independently. Interrater agreement was
assessed using the κ statistic (κ = 0.79), and any discrepancies
were resolved with the coauthors of this review.
RESULTS
Retrieved Results
The search process yielded 16,251 citations. After
deduplication, 10,191 titles/abstracts were screened, resulting
Clinical Points
Whether cannabis is associated with long-term positive
or negative symptomatic outcomes in anxiety and mood
disorders is an understudied and controversial area of
research.
Clinicians can use the evidence presented in this review
to help inform their own and their patients’ knowledge
concerning potential risks of cannabis on symptom and
treatment outcomes in anxiety and mood disorders.
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e3J Clin Psychiatry 79:4, July/August 2018
Cannabis and Anxiety and Mood Disorders
Figure 1. PRISMA Flow Diagram
Abbreviation: PTSD = posttraumatic stress disorder.
10,191
Records screened
10,048
Records excluded as
study not pertinent
to this topic or not
longitudinal by
design
Additional records
identied through
other sources
8
16,251
Records identied
through database
searching
10,191
Records after
duplicates removed
PTSD
Panic disorder
Bipolar disorder
Depressive disorder
4
1
5
2
Studies included in
systematic review
12
Full-text articles
excluded:
Not clinical sample at baseline
Not adult population at baseline
Exposure variable not
cannabis specic
Outcome variable not specic
to anxiety/mood symptoms
131
23
26
27
36
No control group
Comorbid sample
with physical illness
11
8
Full-text articles
assessed for
eligibility
143
Included
Eligibility
Screening
Identication
in 12 included studies. Figure 1 displays the flow diagram
and reasoning for study exclusions. Five anxiety disorder–
based studies (PTSD, n = 4, panic disorder, n = 1) and 7 mood
disorder–based studies (bipolar disorder, n = 5; depressive
disorder, n = 2) were used in the synthesis, using data from
a total sample of 11,959 individuals (2,588 individuals “more
exposed” to cannabis, operationalized as any recent use or
greater use; 9,371 individuals “less exposed” to cannabis,
operationalized as no recent use or lesser use).
Study Characteristics and Quality
Tables 2 and 3 highlight methodological characteristics
and findings, respectively, of each study. The majority of
studies were based in the United States (n = 8), followed
by Europe (n = 3) and Australia (n = 1). Study samples
ranged from 62 to 22,948 individuals who qualified for an
anxiety or mood disorder at baseline and were psychiatric-
based patients (majority inpatients) receiving symptomatic
treatment. The baseline age ranged from 18 to 65+ years,
with the baseline mean age across the cohorts being close
to 43 years. There was fairly even representation of genders
across the bipolar, panic, and depressive disorder studies.
Among the 4 PTSD studies, 3 were heavily focused on males
(93%–100%). In terms of study design, 9 were observational
cohort studies, and 3 were based from secondary analyses of
interventions aimed at treating the anxiety or mood disorder.
Follow-up periods ranged from 2.5 months to 5 years.
Cannabis use was assessed subjectively across studies,
primarily using self-report measures via clinical interviews.
All studies focused on frequency of recent use during the
past 7 days, 1 month, 3 months, or 6 months. Six studies used
only baseline assessments of cannabis use, and 6 studies used
multiple assessments to help determine how changes in use
(eg, reducing it) affect symptomatic outcomes. In terms of
source of cannabis, all studies examined use of illicit “street
cannabis” (ie, unregulated cannabis) in relation to outcomes
of AMD.
The majority of studies (n = 10) used a version of the
DSM (eg, -III, -IV) for diagnosing AMD. In terms of the
dependent variable, various measures of symptoms were
used across the AMD (see Table 2), though all but 1 study
(ie, number of symptoms)32 used a scale of symptom severity.
Two studies used only 1 follow-up outcome of symptoms, 7
studies used multiple follow-up measures of symptoms to
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e4 J Clin Psychiatry 79:4, July/August 2018
Mammen et al
Table 2. Study Characteristics
First Author,
Country Sample (% Male)
Cannabis Use
Measure
Diagnosis and Symptom
Measure(s)
Design, Follow-Up,
Longitudinal Analysis Accounted Confounder Variables
Treatment Status for Anxiety
and Mood Disorder
PTSD
Bonn-Miller 2013,33
United States
N: 260 (100%)
Baseline age:
mean = 52.6 y
Inpatients
Interview assessing
current cannabis
abuse and
dependence
(using DSM-IV)
Diagnosis: DSM-IV
PTSD symptoms: PTSD
Checklist-Military Version
(17-item)
Design: observational
Follow-up: 2.5 months
Analysis: hierarchical linear
regression
Baseline symptoms/age/trauma/
psychological distress/polysubstance use
Patients enrolled in Veterans
Affairs residential rehabilitation
program. Medication status
unreported
Manhapra 2015,34
United States
N: 22,948 (93.2%)
Baseline age:
mean = 51.2 y
Inpatients/
outpatients
Interview assessing
days of use in
the past 1 month
(ASI)
Diagnosis: DSM-IV
PTSD symptoms: Short Form
Mississippi Scale for Combat-
Related PTSD (11-item)
Design: observational
Follow-up: 4 months after program
discharge
Analysis: analysis of covariance
Baseline symptoms/age/marital status/race/
other psychiatric issues/employment/car
ownership/sexual trauma in military
Patients enrolled in specialized
intensive PTSD program.
Medication status unreported
Ruglass 2017,35
United States
N: 136 (47.7%)
Baseline age:
mean = 42.8 y
Outpatients
Interview assessing
days of use in
the past 7 days
(Substance Use
Inventory)
Diagnosis: DSM-IV
PTSD symptoms: Clinician-
Administered PTSD scale
Design: intervention (secondary
analysis)
Follow-up: 3 months
Analysis: multivariate regression
analyses with bootstrapping
Baseline symptoms/age/sex/days of
substance use
Patients enrolled in an
intervention to reduce
PTSD (via medications
including sertraline and
riboflavin + psychotherapy)
Wilkinson 2015,36
United States
N: 2,276 (96.7%)
Baseline age:
mean = 51.7 y
Inpatients
Interview assessing
days of use in
the past 1 month
(using ASI)
Diagnosis: DSM-III/IV
PTSD symptoms: Short Form
Mississippi Scale for Combat-
Related PTSD (11-item)
Design: observational
Follow-up: 4–6 months
Analysis: analysis of covariance and
linear multiple regression
Baseline symptoms/age/marital status/race/
incarceration history/psychosis/chronic
medical problems/war zone service/length
of stay/expulsion from treatment/drug and
alcohol abuse/employment
Patients enrolled in specialized
Veterans Affairs treatment
programs. Medication status
unreported
Panic Disorder
Bricker 2007,37
United States
N: 232 (39.4%)
Baseline age:
mean = 40.4 y
Outpatients
Interview assessing
frequency of
use in the past 1
month
Diagnosis: DSM-IV
Core panic: Anxiety Sensitivity
Index
Social phobia: Social Phobia
subscale of the Fear
Questionnaire
Depression: CES-D
Design: Intervention (secondary
analysis)
Follow-up: 1 year
Analysis: random coefficient
hierarchical models and mixed-
effects linear regressions
Education/social phobia Participants enrolled in an
intervention to reduce
anxiety/panic (via
unspecified antianxiety
medications + psychotherapy)
Bipolar Disorder
Kim 2015,38
Australia
N: 213 (40.6%)
Baseline age:
mean = 41.8 y
Inpatient/
outpatient
Interview assessing
frequency of
use in the past 3
months
Diagnosis: Mini-International
Neuropsychiatric Interview
version 5
Mania: YMRS
Depression: HDRS-21
Design: observational
Follow-up: 2 years
Analysis: Kruskal-Wallis test, Mann-
Whitney U test
None reported On medication (lithium
carbonate, sodium valproate,
carbamazepine, olanzapine)
Kvitland 2015,39
Norway
N: 62 (40%)
Baseline age:
mean = 30.9 y
Inpatient/
outpatient
Interview assessing
frequency of
use in the past 6
months
Diagnosis: DSM-IV
Mania: YMRS
Depression: Inventory of
Depressive Symptoms—
Clinician Rated
Design: observational
Follow-up: 1 year
Analysis: hierarchical blockwise
multiple linear regression
Baseline symptoms/age/sex/premorbid
functioning
On medication (unspecified)
Strakowski 2007,40
United States
N: 144 (56.4%)
Baseline age:
mean = 21.6 y
Inpatients
Interview assessing
frequency of
use in the past
1 month (using
ASI)
Diagnosis: DSM-IV and
YMRS > 20
Mania: YMRS
Depression: HDRS-17
Rapid cycling: > 4 episodes
within 52 weeks
Design: observational
Follow-up: mean = 2.6 years (5 years
max)
Analysis: survival analysis and Cox
proportional hazards regression
model
Baseline symptoms/age/sex/education/
presence of psychosis/alcohol and drug
use history
On medication and hospitalized
for mania (putative mood
stabilizers including lithium,
divalproex, carbamazepine,
lamotrigine, topiramate,
atypical antipsychotic drugs)
(continued)
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e5J Clin Psychiatry 79:4, July/August 2018
Cannabis and Anxiety and Mood Disorders
Table 2 (continued).
First Author,
Country Sample (% Male)
Cannabis Use
Measure
Diagnosis and Symptom
Measure(s)
Design, Follow-Up,
Longitudinal Analysis Accounted Confounder Variables
Treatment Status for Anxiety
and Mood Disorder
van Rossum 2009,41
14 European
countries
N: 3,426 (44.6%)
Baseline age:
mean = 44.6 y
Inpatient/
outpatient
Interview assessing
frequency of
use in the past 3
months
Diagnosis: DSM-IV, ICD-10,
clinical judgment for manic/
mixed episode; CGI-BP
for overall illness, mania,
depression
Design: observational
Follow-up: 1 year
Analysis: multilevel random
regression
Baseline symptoms/age/sex/medication
compliance/age of mood onset/alcohol
use/drug use
On medication (antipsychotics,
anticonvulsants, lithium)
Zorrilla 2015,42
14 European
countries
N: 1,922 (58.8%)
Baseline age:
mean = 39.1 y
Inpatient/
outpatient
Interview assessing
frequency of
use in the past 3
months
Diagnosis: DSM-IV, ICD-10,
clinical judgment for manic/
mixed episode
Mania: CGI-BP
Design: observational
Follow-up: 2 years
Analysis: logistic regression
Alcohol/polydrug use On medication (olanzapine
antipsychotics, mood
stabilizers)
Depressive Disorder
Bahorik 2017,43
United States
N: 307 (100%)
Baseline age:
mean = 52.6 y
Outpatients
Interview assessing
days of use in the
past 1 month
Diagnosis: PHQ-9 (> 5 mild
depression)
Depression: PHQ-9
Anxiety: GAD-7
Design: intervention (secondary
analysis)
Follow-up: 6 months
Analysis: hierarchical linear
modeling (mixed-effects growth
models)
Age/sex/marital status/race/polysubstance
use/time-varying psychiatry visits
Unreported
Feingold 2017,32
United States
N: 2,348 (41.3%)
Baseline age:
18–65+ y
Unspecified
patient status
Interview assessing
any use and
cannabis use
disorder using
AUDADIS-IV
Diagnoses: DSM-IV (5 of
9 symptoms for major
depressive disorder)
Depression: DSM-IV
Design: observational
Follow-up: 3 years
Analysis: linear regression analysis
and multivariate logistic
regression analyses
Baseline symptoms/age/sex/race/education/
income/marital status/age/region
Unreported
Abbreviations: ASI = Addiction Severity Index, AUDADIS = Alcohol Use Disorder and Associated Disabilities Interview Schedule, CES-D = Center for Epidemiologic Studies Depression scale, CGI-BP = Clinical Global
Impression Bipolar Disorder Scale, DSM = Diagnostic and Statistical Manual of Mental Disorders, GAD-7 = Generalized Anxiety Disorder 7 scale, HDRS = Hamilton Depression Rating Scale, ICD = International Classification of
Diseases, PHQ = Patient Health Questionnaire, PTSD = posttraumatic stress disorder, YMRS = Young Mania Rating Scale.
help determine how cannabis affects the course
of symptoms, and 3 studies measured both course
and outcomes of symptoms.
In terms of study quality (Table 4), out
of a possible 8 stars, 3 studies were rated
7 stars, 6 studies were rated 6 stars, and 3
studies were rated 5 stars, suggesting that the
majority of studies can be considered of good
overall methodological rigor. Specifically, all
studies received maximum stars for cohort
representativeness and assessment of exposure,
and most studies received maximum stars for
the following: controlling for baseline symptoms
(n = 9) and multiple additional confounding
variables in final statistical models (n = 10) (eg,
age, sex, comorbidities, polysubstance use);
conducting follow-up assessments 1 year after
baseline (n = 7); and having high retention rates
(> 80%; n = 10). Detailed scoring of each study is
available upon request.
Cannabis and PTSD or Panic Disorder
Four studies examined the association of
cannabis with long-term symptoms in PTSD.33–36
Three studies collectively showed that recent
cannabis use (eg, past month) was associated with
a negative course33,34 and negative outcomes36 of
PTSD symptom severity, while 1 study found
no significant relationships (note that this study
included only 32 individuals in the “exposure”
group).35 Among the significant findings, 2 studies
found that “any” level of baseline cannabis use
(F = 81.83, P < .0001)34 or sustained use over time
(F = 21.47, P < .01)36 was associated with greater
PTSD symptom severity 4 months following
baseline assessments, compared to abstinence.
These studies also supported that stopping use
is associated with less severe symptoms (Cohen
d = −0.18)36 and greater improvements in
symptoms from treatment (Cohen d = −0.61)34
compared to continuing or starting cannabis
use. Bonn-Miller and colleagues33 revealed that
a baseline current cannabis use disorder (CUD)
diagnosis was associated with less improvement
from treatment regarding PTSD symptoms
(β = –0.14, P < .05) over the course of 2.5 months,
relative to the comparison group (ie, no CUD),
specifically concerning avoidance numbing
(β = –0.13, P < .05) and hyperarousal (β = –0.13,
P < .05) symptoms. In these 3 studies finding
significance, it is worth noting that all participants
were predominantly men who were enrolled
in a Veterans Affairs residential rehabilitation
program to help treat their combat-related PTSD.
Hence, the findings may not be generalizable to
females experiencing non–combat-related PTSD,
for instance.
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e6 J Clin Psychiatry 79:4, July/August 2018
Mammen et al
Table 3. Study Findings
First Author
Exposure Variables—
Cannabis Use
Dependent Variables—
Symptom Change/Outcome Key Findings
Association of Cannabis
With Symptoms
PTSD
Bonn-Miller 201333 CUD (n = 81): current CUD diagnosis
No CUD diagnosis (n = 179): no current CUD diagnosis
Used 1 assessment (at baseline)
Course of symptom severity for
PTSD
Used multiple assessments
CUD associated with higher symptom severity/less improvement in
PTSD symptoms (β = –0.14, P < .05) including avoidance numbing
= –0.13, P < .05) and hyperarousal (β = –0.13, P < .05) symptoms
relative to comparison group. No CUD associated with greater
improvements in PTSD
Cannabis use associated
with higher symptom
severity
Manhapra 201534 Not abstaining (n = 353): any level of cannabis use in past
1 month
Abstaining (n = 270): stopping use in past 1 month
Used 1 assessment (at baseline)
Course of symptom severity for
PTSD
Used multiple assessments
Abstaining from cannabis associated with lower PTSD symptom
severity and greater improvements in symptoms (Cohen d = −0.61;
F = 81.83, P < .0001) relative to comparison group
Cannabis use associated
with higher symptom
severity
Ruglass 201735 Cannabis use (n = 32): any level of cannabis use in past 7
days
No use (n = 104): no use in past 7 days
Used multiple assessments
Course and outcome of
symptom severity for PTSD
Used multiple assessments
Cannabis use not associated with PTSD symptom severity No association
Wilkinson 201536 Continued use (n = 268): continuing any level of cannabis
use in past 1 month
Starting use (n = 738): starting any level of cannabis use in
past 1 month
No use (n = 767): no cannabis use in past 1 month
Stopping use (n = 263): stopping any level of cannabis use
in past 1 month
Used multiple assessments
Outcome of symptom severity
for PTSD
Used 1 assessment (at follow-
up)
Starting and continuing use associated with higher PTSD symptom
severity (F = 21.47, P < .01) relative to no use and stopping use.
Starting use associated with more severe symptoms (Cohen
d = 0.34) relative to never use. Stopping use associated with less
severe symptoms (Cohen d = −0.18) relative to never use. Increase
in days of use associated with increase in symptom severity
= 0.17, t = 4.08, P < .0001)
Cannabis use associated
with higher symptom
severity
Panic Disorder
Bricker 200737 Monthly use (n = 29): use of cannabis at least once in the
past 1 month (but no more than once/wk)
Less than monthly use (n = 203): no use in past 1 month
Used 1 assessment (at baseline)
Course of symptom severity
for anxiety and depression
symptoms, outcome of
symptom severity for social
phobia
Used multiple assessments
for symptom severity and 1
assessment (at follow-up) for
social phobia outcome
Monthly use associated with higher severity of depression (mean
CES-D adjusted score = 28.54; 95% CI, 24.20–32.87) relative to
comparison group (mean = 21.73; 95% CI, 19.92–23.55). No
associations found for anxiety or social phobia
Cannabis use associated
with higher symptom
severity for depression
(but not anxiety)
Bipolar Disorder
Kim 201538 Regular use (n = 25): use of cannabis > 3 days/wk
Nonregular use (n = 209): no use or use < 3 days/wk
1 assessment used (at baseline)
Course of symptomatic
remission for mania (< 12 on
YMRS) and depression (< 8 on
HDRS-21)
Used multiple assessments
Regular use associated with less likelihood of total remission (P = .025)
relative to comparison group. Female users had lower remission
rates for depression only (P = .002); male users had lower remission
rates for mania only (P = .019)
Cannabis use associated
with less symptomatic
remission rates
Kvitland 201539 Continued use (n = 6): use of cannabis 2–3 times/wk
No continued use (n = 56): no use or stopping/starting use
Multiple assessments used
Outcome of symptom severity
for mania and depression
Used 1 assessment (at
follow-up)
Continued use associated with higher mania symptom severity
= 0.360, t = 2.985, P = .004) relative to comparison group. No
associations found for depression
Cannabis use associated
with higher symptom
severity
(continued)
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Cannabis and Anxiety and Mood Disorders
Table 3 (continued).
First Author
Exposure Variables—
Cannabis Use
Dependent Variables—
Symptom Change/Outcome Key Findings
Association of Cannabis
With Symptoms
Strakowski 200740 CUD i: bipolar disorder preceded CUD (n = 36)
CUD ii: CUD preceded bipolar disorder (n = 33)
No CUD (n = 75): no history of CUD
Used 1 assessment (at baseline)
Course of symptomatic recovery
(> 1 and < 5 on YMRS; < 7 on
HDRS-17), recurrence (> 5 on
YMRS; > 7 on HDRS-17), and
cycling (> 4 affective episodes
within 52 weeks) for mania
and depression
Used multiple assessments
CUD i associated with more weeks in affective episode (F2,134 = 5.9;
P = .004), manic episodes (F2,134 = 2.8; P = .06), and mixed episodes
(F2,134 = 3.8; P = .03) relative to no CUD. CUD i and ii associated with
more rapid cycling (χ21 = 4.3; P = .04) relative to no CUD
Cannabis use associated
with more symptomatic
recurrence and cycling
van Rossum 200941 Any use (n = 436): any level of current cannabis use
No use (n = 2,990): no use
Used multiple assessments
Course of symptom severity for
mania, depression
Used multiple assessments
Any use associated with higher severity of overall symptoms (β = 0.13;
CI, 0.04–0.22; P = .004) and mania symptoms (β = 0.15; CI, 0.06–0.24;
P = .001) relative to comparison group; no associations found for
depression
Cannabis use associated
with higher symptom
severity
Zorrilla 201542 Current use (n = 132): any level of cannabis use
Previous use (n = 89): stopping use
Never use (n = 1,701)
Used multiple assessments
Course of symptomatic
remission (< 3 on CGI-BP
Mania) and recurrence (> 4 on
CGI-BP Mania) for mania
Used multiple assessments
Current use associated with higher recurrence rates of mania
(OR = 1.59, P = .048) and quicker time to recurrence (OR = 1.47,
P = .034) relative to never use. Previous use not associated with any
negative symptom outcomes
Cannabis use associated
with less symptomatic
remission and more
symptomatic recurrence
Depressive Disorder
Bahorik 201743 Cannabis use (n = 125): any level of cannabis use during
past 1 month
No use (n = 182): no cannabis use during past 1 month
Used multiple assessments
Course of symptom severity for
depression and anxiety
Used multiple assessments
Cannabis use associated with higher severity/less improvement of
depressive (β = 1.24; CI, 0.466–2.015; P < .001) and anxiety (β = 0.80;
CI, 0.101–1.509; P < .001) symptoms relative to comparison group
Cannabis use associated
with higher symptom
severity
Feingold 201732 Any use, no CUD (n = 173): any level of cannabis use
(without CUD diagnoses)
CUD (n = 121): diagnosed with CUD
No use (n = 2,283): not using cannabis
Used 1 assessment (for between Waves 1 and 2)
Outcome of number of
depressive symptoms and
course of symptomatic
recurrence (depression at
Waves 1 and 2 using CES-D)
and remission (depression at
Wave 1, but not Wave 2) for
depression
Used 1 assessment (at
follow-up) for symptom
severity proxy and multiple
assessments for recurrence/
remission
CUD associated with a greater number of depressive symptoms
(proxy for severity; β = 0.62, P = .0019) relative to no use. CUD
associated with anhedonia (OR = 2.62; CI, 1.36–5.08; P = .0048) and
insomnia/hypersomnia (OR = 2.30; CI, 1.29–4.12; P = .0055) relative
to no use. No association found between any use, no CUD, and
rates of remission
Cannabis use associated
with higher symptom
severity
Abbreviations: CES-D = Center for Epidemiologic Studies Depression scale, CGI-BP = Clinical Global Impression Bipolar Disorder Scale, CUD = cannabis use disorder, HDRS = Hamilton Depression Rating Scale,
PTSD = posttraumatic stress disorder, YMRS = Young Mania Rating Scale.
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e8 J Clin Psychiatry 79:4, July/August 2018
Mammen et al
Table 4. Study Quality Assessment Scoresa
Study Selection (3) Comparability (2) Outcome (3) Total Score (8)
PTSD
Bonn-Miller 201333
★★★ ★★
6
Manhapra 201534
★★★ ★★
6
Ruglass 201735
★★★ ★★
5
Wilkinson 201536
★★★ ★★
6
Panic Disorder
Bricker 200737
★★★
★★ 6
Bipolar Disorder
Kim 201538
★★★
★★ 5
Kvitland 201539
★★★ ★★
6
Strakowski 200740
★★★ ★★
★★ 7
van Rossum 200941
★★★ ★★
★★ 7
Zorrilla 201442
★★★
★★ 6
Depression
Bahorik 201743
★★★
5
Feingold 201732
★★★
★★ ★★ 7
aEach study can be awarded a maximum of 8 stars: 3 stars for its “selection” of the
exposed cohort (1 star if cohort is representative) and nonexposed cohorts (1 star
if cohort is drawn from same community as exposed cohort), in addition to its
selection of the exposure assessment (1 star if exposure assessed via secure record or
structured interview); 2 stars for “comparability” of cohorts based on accounting for
the most important factor (1 star if study controls for baseline symptomatic scores)
and additional factors (1 star if study accounts for age, gender, and comorbidities,
polysubstance use); and 3 stars for “outcome” criteria concerning assessment of
outcome (1 star for independent blind assessment or record linkage), length of
follow-up (1 star for > 6 months follow-up), and adequacy of follow-up (1 star for
retention rate > 80%).
Abbreviation: PTSD = posttraumatic stress disorder.
One study examined the association of cannabis with symptoms
in panic disorder, using secondary data from a trial aimed to reduce
symptoms via medication and psychotherapy. Bricker et al37 showed that,
in the intervention group, there were no differences between monthly
users and less than monthly users in terms of symptomatic outcomes
over 1 year, suggesting that cannabis use did not impede recovery.
Within the control group not receiving the intervention, however,
monthly cannabis use (Center for Epidemiologic Studies Depression
Scale [CES-D] adjusted mean = 28.54, P < .01) was associated with
higher levels of depressive symptoms over 1 year compared to less than
monthly use (CES-D adjusted mean = 21.73, P < .01). No associations
were found for core panic symptoms or social phobia symptoms. The
limited findings in this study could be due to the small sample of
monthly users (ie, 29 individuals) and the focus on lower frequencies
of use (ie, using cannabis at least once in the past month but no more
than once per week was operationalized as monthly use).
Cannabis and Bipolar Disorder
Five studies examined the association of cannabis with long-term
symptoms in bipolar disorder.38–42 Each study provided indication
that recent cannabis use (eg, past month) was associated with negative
symptomatic outcomes. For instance, 2 studies revealed that “any recent
use” of cannabis (eg, 2–3 times per week) over 1 year was associated
with greater symptom severity for mania throughout the course of 1
year (β = 0.15, P = .001)41 and at 1-year follow-up39 compared to no use
or stopping use. Both studies found no significant associations related
to depressive symptoms, likely attributed, as the authors note, to the
focus on patients with more severe baseline mania than depression.
The remaining 3 studies38,40,42 collectively showed that cannabis use
was associated with greater symptom severity, as measured through
thresholds concerning symptomatic remission, recovery, and recurrence
for mania and depressive symptoms. Specifically,
Kim and colleagues38 showed that baseline
“regular” use (ie, > 3 days/week) was associated
with less occurrence of remission for mania and
depressive symptoms throughout the course of 2
years compared to nonregular use (ie, < 3 days/
week). Aligned with this finding, Zorrilla et
al42 showed that continued use over 1 year (ie,
any use) was associated with higher recurrence
rates of mania (OR = 1.59, P = .048) and quicker
time to recurrence (OR = 1.47, P = .034) over
the course of 2 years, relative to never use.
Zorrilla and colleagues’ study further suggested
that stopping cannabis use was associated with
more favorable symptomatic outcomes over
time. Lastly, Strakowski and colleagues40 found
that a baseline CUD diagnosis was associated
with more weeks spent in an affective episode
(F2,134 = 5.9; P = .004), more time in mixed
episodes (F2,134 = 3.8; P = .03), and more rapid
cycling between episodes over the course of up to
5 years compared to having no CUD diagnosis.
All bipolar disorder studies were conducted in
the context of symptomatic treatment including
medication and inpatient care, which revealed
that cannabis use was associated with less
improvement from treatment.
Cannabis and Depressive Disorder
Two studies examined the association of
cannabis with long-term symptoms in depressive
disorders. Both studies revealed that cannabis use
was associated with higher symptom severity43
and the number of symptoms.32 Specifically,
Feingold and colleagues32 showed that a CUD
diagnosis between baseline and follow-up was
associated with a greater number of depressive
symptoms (β = 0.62, P = .0019), specifically
related to anhedonia (OR = 2.62; P = .0048) and
insomnia/hypersomnia (OR = 2.30 P = .0055) at
3-year follow-up relative to no use. Bahorik and
colleagues43 showed that continued cannabis
use was associated with greater symptom
severity and less symptomatic improvement
for depressive (β = 1.24, P < .001) and anxiety
symptoms (β = 0.80, P < .001) over the course of
6 months relative to no use. This study was in the
context of cognitive behavior therapy, suggesting
that cannabis use may potentially interfere with
psychotherapy effectiveness.
DISCUSSION
This review provides consistent evidence
that—among individuals living with a baseline
PTSD, panic disorder, bipolar disorder, or
depressive disorder—recent cannabis use was
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e9J Clin Psychiatry 79:4, July/August 2018
Cannabis and Anxiety and Mood Disorders
associated with negative symptomatic outcomes (including
course of symptoms) over time. Specifically, the collective
findings suggest that individuals using cannabis (ie, any/
greater frequency of use in the last 6 months) experienced
greater symptom severity and number of symptoms and less
occurrence of symptomatic remission and recovery up to 5
years following baseline assessment relative to the comparison
groups (ie, no/lesser frequency of use). All but 1 study32 across
the review was in the context of treatment for an anxiety or
mood disorder (eg, medication, psychotherapy), implying
that cannabis use may potentially interfere with recovery
efforts and contribute to long-term persistent symptoms.
These results are supported by the broader substance use
literature inferring a detrimental effect of various substances
(eg, alcohol, tobacco) on the clinical course and treatment
outcomes in anxiety, depressive, and bipolar disorders.44–46
Although cannabis is considered less harmful than most
psychoactive substances,47,48 the results nonetheless support
its link to negative symptomatic outcomes in AMD. Specific to
the cannabis literature, the results support studies (ineligible
for inclusion in the current review; eg, no comparison
groups, not longitudinal) showing that cannabis users with
AMD experience “negative” symptoms,49,50 psychological
distress,51 and a low quality of life52 and that reducing use
may benefit symptoms.53 The evidence from the general
population, which shows cannabis use to increase the risk
in developing AMD over time23–26 and other adverse mental
health effects,54 further supports association of cannabis with
negative symptomatic outcomes in a clinical population.
Our review provides no indication that cannabis benefits
AMD over time. This finding opposes other studies
(ineligible for inclusion) suggesting that cannabis can
play a role in alleviating symptoms in PTSD (eg, reduces
nightmares), bipolar disorder (eg, stabilizes mood), and
depressive disorders (eg, increases motivation).13–18,55,56
However, these studies are primarily based on acute
therapeutic effects of cannabis. Mechanistically, acute effects
of cannabis are mediated by the human endocannabinoid
system.57 This homeostatic system serves to regulate mood,
cognition, appetite, and sleep, among other functions,
by the interactions between endogenous cannabinoids
(anandamide and 2-arachidonoylglycerol) and G-protein
cannabinoid receptors (CB1, CB2).58 When cannabis is
consumed, its constituents such as tetrahydrocannabinol
(THC) and cannabidiol (CBD), which structurally resemble
the mentioned endogenous cannabinoids, activate the
endocannabinoid system by reacting with the brain’s CB1
receptors. This mechanism is the basis by which cannabis
facilitates a “high” effect, emulating antianxiety and
antidepressive states in some individuals.
Particularly among individuals living with AMD, research
shows there are deficiencies in cannabinoid production and
signaling dysfunctions within the endocannabinoid system
that may contribute to the disorder.59–63 Targeting this system
has therefore been recommended to help treat AMD62,63 by
helping to synthesize endocannabinoids, regulate signaling,
and overall facilitate the endocannabinoid system. However,
whether exogenous cannabinoids, such as THC, can intervene
in the endocannabinoid system to sustainably improve
related symptoms is controversial and understudied. Based
on the literature and mechanisms explaining acute effects
of cannabis, in conjunction with the review’s longitudinal-
associative findings, it can be speculated that cannabis may
serve as a “Band-Aid” strategy to relieve acute symptoms, but
over time the drug may contribute to persistent symptoms
and the prevention of symptomatic recovery.
Study Limitations and Future Research
Despite the consistent results of cannabis’s association with
negative long-term symptomatic and treatment outcomes,
the review’s findings need to be interpreted with caution
when considering the individual studies’ methodological
limitations in conjunction with the broader limitations
of the systematic review. First, the observational designs
across studies disallow causal inferences to be made between
cannabis use and persisting symptoms of AMD. Though the
review found a consistent longitudinal association between
cannabis use and symptoms in AMD, the conclusion that
cannabis can negatively influence the course and outcomes
of symptoms and treatment efforts over time can only be
speculative. Second, the review’s findings may be biased
toward a sample with a higher severity of symptoms, as
the large majority of the total sample (11,959 individuals)
included psychiatric inpatients and outpatients. Including
individuals with varying degrees of symptom severity can
provide further knowledge on the influence of cannabis in
AMD, particularly among those not needing psychiatric
intervention (ie, lower severity).
Third, unaccounted confounding variables around
cannabis consumption in each study may have further
biased the results. For example, the earlier age at onset for
cannabis use significantly increases risk in developing AMD
in addition to cannabis dependence.64 Hence, the age at onset
could have mediated the association between cannabis use
and negative symptomatic outcomes.
Further, none of the studies captured the dose of cannabis
consumed, but rather the broader, subjective frequency of
recent use, which is subject to recall and social desirability
biases. Within frequency of use, there was heterogeneity in the
definitions and operationalizations of individuals “exposed”
and “nonexposed” to cannabis. For example, the exposed
groups in multiple studies may have included those who use
cannabis daily, in addition to those who used cannabis “at
least once in the past month,” whereas the nonexposed groups
in multiple studies may have included those who have never
used cannabis with those who may use cannabis at lower
frequencies. Distinguishing these users in analysis, among
low, moderate, and heavy/daily consumption, for example, is
important since the adverse psychological effects of cannabis
are considered to be frequency and dose dependent.57,65
Regarding frequency and dose, it is imperative to also
collect information on the concentrations of cannabinoids
consumed (eg, THC). A proxy for this in the review was based
on the source of cannabis used, which were unregulated-illicit
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e10 J Clin Psychiatry 79:4, July/August 2018
Mammen et al
sources. Over the last several decades, “street cannabis” has
contained increasingly potent levels of THC and decreases
in CBD production.66 Researchers have noted that the
drug’s effects and risks can depend upon the potency and
dose of THC and its ratio with CBD.57,65 At higher levels,
THC—the primary and psychoactive constituent of cannabis
responsible for the “high”—may overstimulate CB1 receptors
and contribute to adverse effects including increased acute
anxiety, paranoia, memory impairment, and sedation and
subsequent addiction issues related to withdrawal and
tolerance.58,67 Thus, the frequency of cannabis use among a
clinical population (eg, daily)68,69 and the increasingly potent
THC levels in street cannabis may help explain the review’s
findings of cannabis’s association with negative symptomatic
and treatment outcomes.
Interestingly, emerging evidence shows that THC’s adverse
effects can be limited by CBD, which is cannabis’s secondary
and nonpsychoactive constituent that has been bred out of
street cannabis. Unlike THC, CBD does not yield a “high”
experience, is perceived as having limited side effects, and
is generally well tolerated across doses.70 One role of CBD
is to mitigate THC’s effects, mechanistically explained by
its indirect antagonist actions71,72 and low affinity for CB1
receptors.73 This action helps prevent THC from acting at full
strength.74,75 Independent of THC, CBD further contains its
own antianxiety properties involving mechanisms with other
mood regulatory receptors (eg, GPR55, 5-HT1A).76 Hence,
due to its nonpsychoactive property, safety and tolerability,
and encouraging evidence as an antianxiety drug, “CBD is
possibly the cannabinoid more likely to have initial findings
translated into clinical practice.70(p1224)
Fourth, there was further heterogeneity regarding the
outcome assessments. For instance, the symptoms across
AMD were measured and operationalized by severity,
remission, recurrence, recovery, relapse, cycling, or
number of symptoms. Compounding the heterogeneity
was the review’s inclusion of individual AMD in PTSD,
panic disorder, bipolar disorder, and depressive disorder.
This decision was based on the limited number of studies
available for each disorder, and it limited the ability to
conduct a meaningful meta-analysis. Of notice was the lack
of cohort studies on generalized anxiety disorder (n = 0),
social anxiety disorder (n = 0), and depressive disorders
(n = 2). Considering that AMD are the most common mental
health conditions,1 with strong links to frequent cannabis
use,2–9 more monitoring of consumption and symptoms
within each disorder is warranted.
Overall, future research in this area needs to address
the limitations of the current literature by increasing
methodological rigor to better ascertain the influence of
cannabis on the course and outcomes of symptoms in AMD.
In addition to accounting for the potential confounding
variables noted above (eg, age at onset of use, dose of
cannabinoid concentration), greater focus is needed in
examining changes in severity scale scores between baseline
and follow-up assessments. These data would help determine
if cannabis “worsens” symptoms over time within subjects,
as opposed to the current review, which moreover indicates
that cannabis users are more likely to experience greater
symptom severity over time compared to those abstaining
from use. Additionally, clinical trials are needed to rigorously
examine cannabis’s short- and long-term medical application
for AMD, with specifics on cannabinoid concentrations
(eg, THC, CBD), route of administration (eg, pill form,
vaporization), dosage (eg, low vs moderate), different forms
of cannabis (eg, oils, dried cannabis), interactions with
medications (eg, antianxiety drugs), and mechanisms (eg,
endocannabinoid system functional magnetic resonance
imaging studies).
Clinical Implications
Though the findings of the review have clear limitations,
this systematic review is the first to provide unique insight
into the longitudinal associations between cannabis use and
symptomatic outcomes among those living with a baseline
anxiety or mood disorder. Clinicians can use this “best
available” evidence to inform their own and their patients’
knowledge concerning potential long-term risks of cannabis
on symptoms and recovery. The results can be useful for
health care professionals (eg, psychiatrists, family doctors,
nurse practitioners) who are asked to prescribe medical
cannabis from patients living with AMD. With increasing
legalization of recreational cannabis in North America (eg,
Canada in 2018), communicating this evidence to patients
requesting medical cannabis is timely and important when
one considers they will arguably have easier and quicker
access to regulated recreational cannabis than regulated
medical cannabis.
CONCLUSION
Across AMD, recent cannabis use was associated with
negative symptomatic and treatment outcomes over time.
The findings should be interpreted with caution when
considering the observational designs across studies, biases
linked with the samples (eg, inpatients) and sources of
cannabis consumed (ie, unregulated sources), and limitations
surrounding the heterogeneity in exposure and outcome
measurements. This review can inform future research to
provide more rigorous data to better ascertain cannabis’s
influence on the course and outcomes of symptoms in AMD.
Clinicians can use the insight gained from the review to help
inform their own and their patients’ knowledge concerning
potential risks of cannabis on long-term symptoms and
recovery.
Submitted: August 1, 2017; accepted November 3, 2017.
Published online: June 5, 2018.
Potentia l conicts of in terest: None.
Funding/support: This review was conducted when Dr Mammen was a
postdoctoral fellow funded by the Centre for Addiction and Mental Health
(CAMH) Fellowship Program.
Role of the sponsor: CAMH had no role in the conduct or publication of the
stu dy.
Acknowledgments: The authors acknowledge and thank Eva Pila, PhD
(University of Toronto, Toronto, Ontario, Canada); Rose Wang, MSc (Lakehead
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e11J Clin Psychiatry 79:4, July/August 2018
Cannabis and Anxiety and Mood Disorders
University, Thunder Bay, Ontario, Canada); and
Tereza Florica, BSc (McMaster University, Hamilton,
Ontario, Cana da), all of whom repor ted no conict
of interests, for their valuable contributions toward
the study screening and retrieval processes.
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... However, only a few registered drugs (usually containing CBD and THC) are of high quality [35]. In fact, in many of the above studies, the sources of cannabis are unknown or uncontrolled [199]. Moreover, several studies showed that the effects of cannabis on depression symptoms may be positive or negative, depending on the time course of administration; hence, although it was found that cannabis provided a brief relief, the long-term effects were worsening of symptoms [200]. ...
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Depression is characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. First-line medications for mood disorders mostly target the monoaminergic system; however, many patients do not find relief with these medications, and those who do suffer from negative side effects and a discouragingly low rate of remission. Studies suggest that the endocannabinoid system (ECS) may be involved in the etiology of depression and that targeting the ECS has the potential to alleviate depression. ECS components (such as receptors, endocannabinoid ligands, and degrading enzymes) are key neuromodulators in motivation and cognition as well as in the regulation of stress and emotions. Studies in depressed patients and in animal models for depression have reported deficits in ECS components, which is motivating researchers to identify potential diagnostic and therapeutic biomarkers within the ECS. By understanding the effects of cannabinoids on ECS components in depression, we enhance our understanding of which brain targets they hit, what biological processes they alter, and eventually how to use this information to design better therapeutic options. In this article, we discuss the literature on the effects of cannabinoids on ECS components of specific depression-like behaviors and phenotypes in rodents and then describe the findings in depressed patients. A better understanding of the effects of cannabinoids on ECS components in depression may direct future research efforts to enhance diagnosis and treatment.
... Many patients with cannabis dependence use cannabis to selfmedicate mood (Hser et al., 2017;Mammen et al., 2018), sleep (Bonn-Miller et al., 2014;Lee et al., 2009) or pain symptoms (Sutherland et al., 2018). The results of this study should be conveyed to individuals seeking treatment for cannabis dependence who are concerned about the possible negative effects of cannabis reduction or cessation on mood, sleep and pain symptoms. ...
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Background Mood, sleep and pain problems are common comorbidities among treatment-seeking cannabis-dependent patients. There is limited evidence suggesting treatment for cannabis dependence is associated with their improvement. This study explored the impact of cannabis dependence treatment on these comorbidities. Methods This is a secondary analysis from a 12-week double-blind placebo-controlled trial testing the efficacy of a cannabis agonist (nabiximols) against placebo in reducing illicit cannabis use in 128 cannabis-dependent participants. Outcome measurements including DASS-21 (Depression, Anxiety, and Stress subscales); Insomnia Severity Index (ISI); and Brief Pain Inventory (BPI), were performed at weeks 0, 4, 8, 12 and 24. Each was analysed as continuous outcomes and as binary cases based on validated clinical cut-offs. Results Among those whose DASS and ISI scores were in the moderate to severe range at baseline, after controlling for cannabis use, there was a gradual decrease in severity of symptoms over the course of the trial. BPI decreased significantly until week 12 and then rose again in the post-treatment period during weeks 12-24. Neither pharmacotherapy type (nabiximols vs placebo) nor number of counselling sessions contributed significant explanatory power to any of the models and were excluded from the final analyses for both continuous and categorical outcomes. Conclusions Participants in this trial who qualified as cases at baseline had elevated comorbidity symptoms. There was no evidence that nabiximols treatment is a barrier to achieving reductions in the comorbid symptoms examined. Cannabis dependence treatment reduced illicit cannabis use and improved comorbidity symptoms, even when complete abstinence was not achieved.
... [21][22][23][24][25] Cannabis use may negatively affect mental health treatment outcomes for patients with anxiety and depression, and use is associated with suicidal ideation. [26][27][28][29][30][31][32][33][34] Finally, recent data suggests that that 1 out of 5 individuals who use cannabis have a cannabis use disorder. 35 Studies that have examined the health effects of cannabis have used various measures of exposure (eg, ever use, past-year use, monthly use, daily and almost daily use); however, there is a wide spectrum of outcomes for use frequency within the past month. ...
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Individuals diagnosed with post-traumatic stress disorder (PTSD) are often comorbid for substance use disorders. Cannabis is widely used by PSTD patients, and the literature is mixed on whether cannabis use ameliorates or exacerbates patient responses to stress-associated conditioned stimuli (stress-CS). We determined if cannabis use affects responsivity to stress-CS in rats receiving 2 h stress in the presence of an odor stress-CS. Three weeks after acute stress, rats self-administered cannabinoids (delta9-tetrahydrocannabinol + cannabidiol; THC + CBD) for 15 days, and the stressed males consumed more THC + CBD than sham males. We then used the stress-CS or a novel odor (stress-NS) to reinstate THC + CBD seeking. Surprisingly, the stress-NS reinstated THC + CBD seeking, an effect blocked by N-acetylcysteine. Moreover, the stress-CS inhibited THC + CBD-CS induced reinstatement. To determine if the unexpected effects of stress-NS and -CS resulted from THC + CBD altering conditioned stress, the effect of THC + CBD use on stress-NS/CS-induced coping behaviors and spine morphology was quantified. In THC + CBD-treated rats, stress-NS increased active coping (burying). Conversely, stress-CS reduced active coping and increased passive coping (immobility) and other behavioral parameters associated with stress responses, including self-grooming and defecation. Transient spine head expansion in nucleus accumbens core is necessary for cue-induced drug seeking, and THC + CBD self-administration prevented the increase in head diameter by stress-CS in control rats. These data show THC + CBD self-administration altered the salience of environmental cues, causing neutral cues to promote active behavior (drug seeking and burying) and stress-CS to switch from active to passive behavior (inhibiting drug seeking and immobilization). We hypothesize that cannabis may exacerbate conditioned stress responses.
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Background: Research has demonstrated a strong link between trauma, posttraumatic stress disorder PTSD and substance use disorders (SUDs) in general and cannabis use disorders in particular. Yet, few studies have examined the impact of cannabis use on treatment outcomes for individuals with co-occurring PTSD and SUDs. Methods: Participants were 136 individuals who received cognitive-behavioral therapies for co-occurring PTSD and SUD. Multivariate regressions were utilized to examine the associations between baseline cannabis use and end-of-treatment outcomes. Multilevel linear growth models were fit to the data to examine the cross-lagged associations between weekly cannabis use and weekly PTSD symptom severity and primary substance use during treatment. Results: There were no significant positive nor negative associations between baseline cannabis use and end-of-treatment PTSD symptom severity and days of primary substance use. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa. Moreover, results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. Conclusion: Cannabis use was not associated with adverse outcomes in end-of-treatment PTSD and primary substance use, suggesting independent pathways of change. The theoretical and clinical implications of the reciprocal associations between weekly cannabis use and subsequent PTSD and primary substance use symptoms during treatment are discussed.
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Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-á-vis the ECS’s modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 57 is January 06, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Article
Anxiety and related disorders are the most common mental conditions affecting the North American population. Despite their established efficacy, first-line antidepressant treatments are associated with significant side effects, leading many afflicted individuals to seek alternative treatments. Cannabis is commonly viewed as a natural alternative for a variety of medical and mental health conditions. Currently, anxiety ranks among the top five medical symptoms for which North Americans report using medical marijuana. However, upon careful review of the extant treatment literature, the anxiolytic effects of cannabis in clinical populations are surprisingly not well-documented. The effects of cannabis on anxiety and mood symptoms have been examined in healthy populations and in several small studies of synthetic cannabinoid agents but there are currently no studies which have examined the effects of the cannabis plant on anxiety and related disorders. In light of the rapidly shifting landscape regarding the legalization of cannabis for medical and recreational purposes, it is important to highlight the significant disconnect between the scientific literature, public opinion, and related policies. The aim of this article is to provide a comprehensive review of the current cannabis treatment literature, and to identify the potential for cannabis to be used as a therapeutic intervention for anxiety, mood, and related disorders. Searches of five electronic databases were conducted (PubMed, MEDLINE, Web of Science, PsychINFO, and Google Scholar), with the most recent in February 2017. The effects of cannabis on healthy populations and clinical psychiatric samples will be discussed, focusing primarily on anxiety and mood disorders.
Article
Background: Depression is associated with substance-related problems that worsen depression-related disability. Marijuana is frequently used by those with depression, yet whether its use contributes to significant barriers to recovery in this population has been understudied. Method: Participants were 307 psychiatry outpatients with depression; assessed at baseline, 3-, and 6-months on symptom (PHQ-9 and GAD-7), functioning (SF-12) and past-month marijuana use for a substance use intervention trial. Longitudinal growth models examined patterns and predictors of marijuana use and its impact on symptom and functional outcomes. Results: A considerable number of (40.7%; n=125) patients used marijuana within 30-days of baseline. Over 6-months, marijuana use decreased (B=-1.20, p<.001), but patterns varied by demographic and clinical characteristics. Depression (B=0.03, p<.001) symptoms contributed to increased marijuana use over the follow-up, and those aged 50+(B=0.44, p<.001) increased their marijuana use compared to the youngest age group. Marijuana use worsened depression (B=1.24, p<.001) and anxiety (B=0.80, p=.025) symptoms; marijuana use led to poorer mental health (B=-2.03, p=.010) functioning. Medical marijuana (26.8%; n=33) was associated with poorer physical health (B=-3.35, p=.044) functioning. Limitations: Participants were psychiatry outpatients, limiting generalizability. Conclusions: Marijuana use is common and associated with poor recovery among psychiatry outpatients with depression. Assessing for marijuana use and considering its use in light of its impact on depression recovery may help improve outcomes.
Article
Cannabis use has been reported to affect the course of various psychiatric disorders, however its effect on the course of major depressive disorder (MDD) is not yet clear. We used data from Wave 1 and Wave 2 of the National Epidemiologic survey on Alcohol and Related Conditions (NESARC). Individuals with baseline MDD (N=2,348) were included in the study. Cannabis users without a Cannabis Use Disorder (CUDs) and individuals with a CUD were compared to nonusers using linear and logistic regression analyses controlling for sociodemographics, psychiatric disorders and substance use disorders at baseline. No differences were found in rates of remission between the groups. Level of cannabis use was associated with significantly more depressive symptoms at follow-up, particularly anhedonia, changes in body weight, insomnia or hypersomnia and psychomotor problems. After adjusting for baseline confounding factors, no associations were found between cannabis use and suicidality, functionality and quality of life. We conclude that many of the associations between cannabis use and a more severe course of MDD do not seem to be attributed to cannabis use itself but to associated sociodemographic and clinical factors. Further longitudinal studies using depression severity indices are required.
Article
Background The directionality and magnitude of the association of cannabis use with elevated anxiety symptoms in the general population is unclear. The aim of this meta-analysis was to investigate the association of cannabis use with the development of elevated anxiety symptoms in the general population. Methods A ‘random effects’ meta-analysis of prospective longitudinal studies was undertaken in line with Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Six databases were systematically searched up until 20 May 2016: PsycINFO, MEDLINE, EMBASE, CINAHL Plus, Social Science Citation Index and System for Information on Grey Literature in Europe (SIGLE). Searching ceased on 20 May 2016. The exposure was cannabis use (or use frequency), measured at baseline and the outcome was anxiety, using diagnosis or cut-off points on standardised scales measuring symptoms. Results The main analysis (k=10; N=58 538) demonstrated an association of cannabis use with anxiety, with a very small OR of 1.15 (95% CI 1.03 to 1.29). Restricting the analysis to high-quality studies (k=5) decreased the OR considerably (OR=1.04; 95% CI 0.91 to 1.19), as did adjusting for publication bias (OR=1.08; 95% CI 0.94 to 1.23). Studies with a baseline in the last 10 years yielded a lower pooled OR than studies with an earlier baseline and studies set in the Americas yielded a markedly higher pooled OR than European studies and Australasian studies. Conclusions The findings indicate that cannabis use is no more than a minor risk factor for the development of elevated anxiety symptoms in the general population. They may inform the debate surrounding the legalisation of cannabis.
Article
This review considers the potential influences of the use of cannabis for therapeutic purposes (CTP) on areas of interest to mental health professionals, with foci on psychological intervention and assessment. We identified 31 articles relating to CTP use and mental health, and 29 review articles on cannabis use and mental health that did not focus on use for therapeutic purposes. Results reflect the prominence of mental health conditions among the reasons for CTP use, and the relative dearth of high-quality evidence related to CTP in this context, thereby highlighting the need for further research into the harms and benefits of medical cannabis relative to other therapeutic options. Preliminary evidence suggests that CTP may have potential for the treatment of PTSD, and as a substitute for problematic use of other substances. Extrapolation from reviews of non-therapeutic cannabis use suggests that the use of CTP may be problematic among individuals with psychotic disorders. The clinical implications of CTP use among individuals with mood disorders are unclear. With regard to assessment, evidence suggests that CTP use does not increase risk of harm to self or others. Acute cannabis intoxication and recent CTP use may result in reversible deficits with the potential to influence cognitive assessment, particularly on tests of short-term memory.
Article
Objective: Marijuana has been approved for a number of psychiatric conditions in many states in the US including posttraumatic stress disorder (PTSD), agitation in Alzheimer's disease, and Tourette's disorder. In this systematic review, we examine the strength of evidence for the efficacy of marijuana and other cannabinoids for these psychiatric indications. Data sources: The literature (MEDLINE) was searched for studies published between January 1980 and March 2015 using search terms related to marijuana and other cannabinoids and the specific diagnosis. Study selection: The best quality of evidence, namely placebo-controlled, randomized clinical trials (RCTs) and meta-analyses, was sought per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. In the absence of RCTs, the next best available evidence (eg, observational studies, case reports) was reviewed. Of 170 publications that were screened, 40 were related to the topic, 29 were included in the qualitative synthesis, and 13 studies examined the efficacy of cannabinoids in humans. Data extraction: The evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method. Results: No RCTs have thus far examined the efficacy of marijuana for Tourette's disorder, PTSD, or Alzheimer's disease. Lower-quality studies examined the efficacy of marijuana, Δ⁹-tetrahydrocannabinol, and nabilone; the strength of evidence for the use of cannabinoids for these conditions is very low at the present time. The consequences of chronic cannabinoid exposure includes tolerance, dependence, and withdrawal. Early and persistent marijuana use has been associated with the emergence of psychosis. Marijuana impairs attention, memory, IQ, and driving ability. Conclusions: Given its rapidly changing legal status, there is an urgent need to conduct double-blind, randomized, placebo- or active-controlled studies on the efficacy and safety of marijuana or its constituent cannabinoids for psychiatric conditions. Physicians and policy-makers should take into account the limited existing evidence and balance that with side effects before approving medical marijuana for psychiatric indications.
Article
Background: Co-occurrence of depression, anxiety, and hazardous drinking is high in clinical samples. Hazardous drinking can worsen depression and anxiety symptoms (and vice versa), yet less is known about whether reductions in hazardous drinking improve symptom outcomes. Methods: Three hundred and seven psychiatry outpatients were interviewed (baseline, 3-, 6-months) for hazardous drinking (drinking over recommended daily limits), depression (PHQ-9), and anxiety (GAD-7) as part of a hazardous drinking intervention trial. Longitudinal growth models tested associations between hazardous drinking and symptoms (and reciprocal effects between symptoms and hazardous drinking), adjusting for treatment effects. Results: At baseline, participants had moderate anxiety (M=10.81; SD=10.82) and depressive symptoms (M=13.91; SD=5.58); 60.0% consumed alcohol at hazardous drinking levels. Over 6-months, participants' anxiety (B=-3.03, p<.001) and depressive symptoms (B=-5.39, p<.001) improved. Continued hazardous drinking led to slower anxiety (B=0.09, p=.005) and depressive symptom (B=0.10, p=.004) improvement; reductions in hazardous drinking led to faster anxiety (B=-0.09, p=.010) and depressive (B=-0.10, p=.015) symptom improvement. Neither anxiety (B=0.07, p=.066) nor depressive (B=0.05, p=.071) symptoms were associated with hazardous drinking outcomes. Limitations: Participants were psychiatry outpatients, limiting generalizability. Conclusions: Reducing hazardous drinking can improve depression and anxiety symptoms but continued hazardous use slows recovery for psychiatry patients. Hazardous drinking-focused interventions may be helpful in promoting symptom improvement in clinical populations.
Article
Background: Comorbidity between substance use disorders (SUDs) and bipolar disorder (BD) is highly prevalent to the extent it may almost be regarded the norm. This systematic review and meta-analysis aimed to estimate the prevalence rates of SUDs in treatment seeking patients diagnosed with BD in both inpatient and outpatient settings. Methods: A comprehensive literature search of Medline, EMBASE, psychINFO and CINAHL databases was conducted from 1990 to 2015. Prevalence of co-morbid SUDs and BD were extracted and odds ratios (ORs) were calculated using random effects meta-analysis. Results: There were 151 articles identified by electronic searches that yielded 22 large, multi-site studies and 56 individual studies describing comorbid rates of SUDs amongst community dwelling, BD inpatients or outpatients. The SUDs with the highest prevalence in BD were alcohol use (42%) followed by cannabis use (20%) and other illicit drug use (17%). Meta-analysis showed males had higher lifetime risks of SUDs compared to females. BD and comorbid SUDS were associated with earlier age of onset and slightly more hospitalisations than non-users. Limitations: The results do not take into account the possibility that individuals may have more than one comorbid disorder, such as having more than one SUD, anxiety disorder, or other combination. Some of the meta-analyses were based on relatively few studies with high rates of heterogeneity. Most included studies were cross-sectional and therefore causality cannot be inferred. Conclusions: This systematic review shows comorbidity between SUDs and bipolar illness is highly prevalent in hospital and community-based samples. The prevalence of SUDs was similar in patients with bipolar I and bipolar II disorders. This study adds to the literature demonstrating that SUDs are common in BD and reinforces the need to provide better interventions and properly conducted treatment trials to reduce the burden conferred by comorbid SUD and BD.