Psychiatry Research 286 (2020) 112890

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Review article

Cannabidiol for the treatment of psychosis among patients with T

schizophrenia and other primary psychotic disorders: A systematic review
with a risk of bias assessment
Maykel Farag Ghabrasha,b,1, Stephanie Coronado-Montoyaa,b,1, John Aouna,b,
Andrée-Anne Gagnéa,b, Flavi Mansoura,b, Clairélaine Ouellet-Plamondona,b, Annie Trépaniera,
Didier Jutras-Aswada,b,
⁎

a
Research Center, Centre Hospitalier de l'Université de Montréal (CHUM), 900 St-Denis Street, Montréal, QC, Canada, H2X0A9
b
Department of Psychiatry and Addiction, Faculty of Medicine, Université de Montréal, 2900 Édouard-Montpetit Boulevard, Room S-750, Montréal, QC, Canada, H3T 1J4

ARTICLE INFO ABSTRACT

Keywords: Current treatments for primary psychotic disorders include antipsychotics, some of which have significant side
Cannabinoid effects or suboptimal efficacy. Cannabidiol is a cannabinoid with potential antipsychotic properties. This sys-
Cannabis tematic review examines the use of cannabidiol as an antipsychotic treatment for primary psychotic disorders.
Experimental CINAHL, EBM, EMBASE, MEDLINE and PubMed databases were searched from 1970 to 2019 for experimental
Reviews
and observational studies evaluating the antipsychotic and cognitive modulation properties of cannabidiol in
individuals with psychotic disorders. There were eight eligible studies evaluating the antipsychotic potential of
cannabidiol, involving a total of 210 participants. Due to study heterogeneity, we present the extracted data on
general psychopathology, positive and negative symptoms, cognition and functioning outcomes as a narrative
synthesis. We found limited evidence supporting antipsychotic efficacy for cannabidiol and none supporting its
benefits for cognition or functioning. Cannabidiol treatment had an advantageous side effect profile compared to
other antipsychotics and was well tolerated across studies. Observational studies had a higher risk of bias than
experimental studies. Factors potentially contributing to variability in outcome results included cannabidiol
dosage, treatment duration, use as an adjunctive treatment and participant inclusion criteria, which warrant
further investigation to determine whether cannabidiol can be effective as a treatment for psychosis.

1. Introduction Both classes show acceptable effectiveness for positive psychotic

Primary psychotic disorders such as schizophrenia represent chronic
and debilitating mental health conditions and affect approximately 1%
of the general population worldwide (Jablensky et al., 1992;
McGrath et al., 2008). Schizophrenia represents the most common
psychotic disorder (Rössler et al., 2005), characterized by psychotic
symptoms, cognitive impairment and functional deterioration
(American Psychiatry Association, 2013). Schizophrenia also entails
high risk of relapse and a chronic course of illness, with deferment of
treatment predicting poorer prognosis and longer duration of relapse
(Wiersma et al., 1998; Zipursky et al., 2014).
Typical and atypical antipsychotics represent the mainstay of care
for patients with schizophrenia (National Collaborating Centre for
Mental Health, 2014; Pringsheim et al., 2017; Remington et al., 2017).
symptoms but their side effect profiles remain problematic. Unlike first
generation typical antipsychotics, second generation atypical anti-
psychotics as a whole are associated with reduced risk of extra-
pyramidal adverse events, hyperprolactinemia and tardive dyskinesia,
thereby enhancing therapeutic benefits for patients with schizophrenia
(Meltzer, 2013; Sykes et al., 2017). Although atypical antipsychotics
may provide a more tolerable side effect profile than their typical
counterparts, they are closely linked to metabolic syndromes char-
acterized by weight gain, dyslipidemia, insulin resistance and hy-
perglycaemia (De Hert et al., 2009, 2006; Newcomer, 2005). Despite
recent advancements in neuropsychopharmacology of psychosis treat-
ment, approximately 20-30% of patients do not respond to anti-
psychotic medication (Meltzer, 1997; Samara et al., 2018) and nearly
50% relapse within 12–24 months following their first episode of

⁎
Corresponding author at: Research Center, Centre Hospitalier de l'Université de Montréal (CHUM), 900 St-Denis Street, Montréal, QC, Canada, H2X 0A9.
E-mail addresses: stephanie.coronado-montoya@umontreal.ca (S. Coronado-Montoya), didier.jutras-aswad@umontreal.ca (D. Jutras-Aswad).
1
Both authors contributed equally.

https://doi.org/10.1016/j.psychres.2020.112890
Received 24 December 2019; Received in revised form 19 February 2020; Accepted 20 February 2020
Available online 21 February 2020
0165-1781/ © 2020 Elsevier B.V. All rights reserved.
M.F. Ghabrash, et al.
psychosis (Alvarez-Jimenez et al., 2012). Hence, there is still a need for
efficacious, safe and long-lasting therapeutic alternatives that surpass
side effect profiles of currently available antipsychotics.
Implication of the endocannabinoid system in the development of
psychotic mental illness has been well-established in both animal and
human models (Fakhoury, 2017; Zamberletti et al., 2012). The past few
years have seen emerging evidence regarding the therapeutic potential
of cannabidiol (CBD), a cannabinoid derived from the cannabis plant, in
various medical and psychiatric conditions (Pisanti et al., 2017). CBD is
a non-intoxicating compound that has been linked to anxiolytic
(Zuardi et al., 2017a) and antipsychotic (Fakhoury, 2016) properties,
and which may be neuroprotective in humans (Campos et al., 2017).
CBD can reverse disruption in prepulse inhibition induced by MK-801, a
non-competitive N-methyl-D-aspartate receptor antagonist (Long et al.,
2006). This effect is also produced by several atypical antipsychotics
(Bubeníková et al., 2005; Long et al., 2006), including clozapine, and is
often a key underlying mechanism in the treatment of resistant and
refractory psychosis in schizophrenia (Remington et al., 2017). Fur-
thermore, like the atypical antipsychotic aripiprazole, CBD possesses
partial agonist properties and can inhibit binding of domperidone, a
selective D2 ligand, at dopaminergic D2 receptors in rodent striatum,
which may contribute to its potential use as an antipsychotic
(Seeman, 2016). Importantly, CBD is relatively safe, with sedation and
gastrointestinal events being reported as the main adverse events at
high doses (Iffland and Grotenhermen, 2017; Millar et al., 2019).
In light of its antipsychotic potential and its tolerability profile, CBD
may provide an alternative to typical and atypical antipsychotics for the
treatment of schizophrenia. A growing body of evidence is beginning to
address whether and how CBD can positively impact psychosis, with
emphasis on important prognostic implications pertinent to its ther-
apeutic value as an antipsychotic agent. Given the rapidly developing
field of therapeutic cannabinoid research, there is a need for an updated
systematic review, which includes the latest clinical trials, discusses
their contributions to the field and assesses the quality of evidence. The
main objective of this systematic review is to synthesize clinical evi-
dence evaluating CBD as an antipsychotic agent in human subjects with
a primary psychotic disorder.
2. Methods
This systematic review was implemented in accordance with
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines for writing systematic reviews and meta-analyses
(Moher et al., 2009).
2.1. Study inclusion and exclusion criteria
We included randomized controlled trials (RCTs), longitudinal case-
control or cohort studies, case reports and retrospective studies in
English or French involving human subjects and published between
January 1, 1970 and August 14, 2019, inclusively. Reviews, trial re-
gistrations, conference abstracts, commentaries and studies performed
in vitro or in animal models were excluded. The timeline range reflects
the appearance of records in the literature pertaining to the appraisal of
the physiological properties of CBD in humans (Perez-Reyes et al.,
1973). We included studies conducted on patients of any age and
gender diagnosed with a primary psychotic disorder (schizophrenia,
schizophreniform, schizoaffective and delusional disorders) without
limiting the diagnosis to a specific method or diagnostic tool. We ex-
cluded studies on patients with psychotic mental illnesses that are due
to medical conditions or substance-induced psychotic disorder, as well
as studies on individuals without mental health disorders or with sub-
clinical symptoms. Also included were interventions that used a quan-
tified amount of CBD in an isolated form or in combination with other
substances and that measured outcomes for positive (hallucinations,
delusions or disorganization), negative (anhedonia, apathy, abulia, etc.)
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Psychiatry Research 286 (2020) 112890
or cognitive symptoms (disturbances of attention, memory, executive
functions, etc.).
2.2. Search strategy and selection process
A comprehensive literature search strategy was developed and va-
lidated jointly with a scientific information specialist and was con-
ducted using five electronic databases, namely CINAHL Complete, EBM
reviews, EMBASE, MEDLINE and PubMed. Database searches were
performed by combining psychosis- and CBD-related words and ter-
minology from controlled vocabulary (MeSH, EMTREE and others) and
free-text search (title, abstract and author's keywords) using the
Boolean operators “OR”, “AND” and “ADJ” (adjacency operator). A
detailed description of the search strategy for MEDLINE is available in
the supplementary materials. Reference lists of reviews and included
studies were also examined to ensure inclusion of all pertinent articles.
Two investigators independently screened the abstracts and titles of
articles identified with the literature search, using the inclusion and
exclusion criteria; full-text review of articles were conducted when
necessary. In cases of inter-rater disagreement, the senior author made
the final decision on article eligibility.
2.3. Data extraction and outcome measures
Two research team members extracted the data from eligible arti-
cles and inserted them into a pre-established table. Efforts were made to
contact authors regarding missing data. Our primary outcomes were
measures of general psychopathology and positive, negative and cog-
nitive symptoms of schizophrenia. When reported, outcomes measuring
general functioning were included in our data extraction. Similarly,
when reported, serious adverse events and side effects were noted to
describe the tolerability of CBD in this population.
Two independent reviewers evaluated the quality of included stu-
dies using six criteria from the Cochrane Collaboration's risk-of-bias
tool (Higgins et al., 2011): random sequence generation, allocation
concealment, blinding of participants and personnel, blinding of out-
come assessment, incomplete outcome data and selective reporting.
Since this tool was designed to evaluate RCTs and our review also in-
cluded non-RCTs, where a study design did not correspond to a cri-
terion, we rated the study as “not applicable.” For all other criteria
where there was relevant support for judgment, studies were rated as
having low, high or an unclear risk of bias. For outcome-related criteria,
studies were evaluated by considering all outcomes described. The se-
nior author was consulted in cases of inter-rater disagreement to make
the final decision on risk of bias.
3. Results
3.1. Search results
We screened 2340 potentially relevant records and identified 106
publications for a full-text screening to assess eligibility (Fig. 1).
Amongst these, we extracted data from eight studies that were eligible
for review (Boggs et al., 2018; Hallak et al., 2010; Leweke et al., 2012;
Makiol and Kluge, 2019; McGuire et al., 2018; Schipper et al., 2018;
Zuardi et al., 2006, 1995).
3.2. Study characteristics
Characteristics of the eight included studies are presented in
Table 1, where they are grouped by study design type—experimental or
observational.
Study designs were heterogeneous and included four double-
blinded RCTs in the experimental study design category, and two case
reports and two case series among the observational study design
group. Two of the case studies tested two treatments preceded by a
M.F. Ghabrash, et al.
Fig. 1. PRISMA 2009 flow diagram showing the number of publications at each stage of the study selection process.
placebo washout period, whereby participants received CBD and an
antipsychotic in sequential order, allowing for comparisons of CBD ef-
ficacy to both placebo and an active drug (Zuardi et al., 2006, 1995).
The other observational studies were open label studies and did not
compare the intervention to a placebo or another treatment
(Makiol and Kluge, 2019; Schipper et al., 2018). All four RCTs had a
parallel-group design comparing CBD to placebo (Boggs et al., 2018;
Hallak et al., 2010; McGuire et al., 2018) or an active drug
(Leweke et al., 2012).
All 210 participants from the eight studies were adults aged be-
tween 18 and 68 years, and the number of study participants per study
ranged from one to 88. We included six out of seven participants from
the case series by Schipper et al. (2018), whose diagnosis corresponded
to our inclusion criteria, leaving out one participant with a bipolar
disorder diagnosis. While the sex of participants in the case studies was
female, male or unspecified, the larger RCT studies included two sexes
and had a higher proportion of males, ranging from 58–76%. Psychotic
disorder diagnosis was performed with a validated tool in seven of the
included studies, while one reported that diagnosis was made by clin-
icians without specifying if any standardized tool was used (Makiol and
Kluge, 2019). Some studies (Leweke et al., 2012; McGuire et al., 2018;
Zuardi et al., 1995) excluded participants with antipsychotic resistance,
based on their lack of symptom improvement in response to available
antipsychotics, but this exclusion criteria was a clinical feature of par-
ticipants in a case series and a case report (Makiol and Kluge, 2019;
Zuardi et al., 2006). Of the five trials that considered substance use in
their participants’ eligibility, three used it as an exclusion criteria
(Boggs et al., 2018; Hallak et al., 2010; Leweke et al., 2012), one did not
exclude based on substance use (McGuire et al., 2018) and one speci-
fically included participants with a psychotic disorder and a comorbid
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Psychiatry Research 286 (2020) 112890
cannabis use disorder (Schipper et al., 2018).
The included studies had heterogeneous designs. Treatment dura-
tion ranged from four to nine and a half weeks, with the exception of
one study where a single dose was tested (Hallak et al., 2010). Seven
studies administered CBD orally at varying doses, ranging from
300–1500 mg of daily CBD. In contrast, one study provided between
0.125–0.5 g/day of a dried cannabis product with a low tetra-
hydrocannabinol (0.4%) and high CBD (9%) content, which patients
were allowed to smoke on demand for a maximum of three times per
day (Schipper et al., 2018). Three studies reported the effect of CBD as a
stand-alone drug (Leweke et al., 2012; Zuardi et al., 2006, 1995), while
the remaining five studies administered CBD in addition to a concurrent
antipsychotic treatment.
3.3. Risk of bias assessment
Table 2 shows the results of the risk of bias assessment based on six
criteria. The two criteria related to selection bias, random sequence
generation and allocation concealment, could not be evaluated for the
four case studies due to their study design. Of the four experimental
studies, we found insufficient information describing the randomization
sequence for two studies (Boggs et al., 2018; Hallak et al., 2010) and the
allocation concealment for one study (Hallak et al., 2010); these studies
were rated as having an unclear bias risk. The risk of bias for blinding of
participants and personnel and for blinding of outcome assessment was
high for the four case report studies and low or unclear for the RCTs.
Outcome data were incomplete for Schipper et al. (2018), resulting in a
high risk of attrition bias. Three studies were at high risk of reporting
bias due to the selective reporting of outcomes (Hallak et al., 2010;
Zuardi et al., 2006, 1995). Overall, risk of bias assessments point to a
 M.F. Ghabrash, et al.

Table 1
Study characteristics.
Study Country Study design Population Age Sex (% Intervention Trial Adjunctive N baseline N analysed
males) length

Experimental study design

Hallak et al., 2010 Brazil DB-RCT Parallel- Schizophrenia DSM-IV No SUD history 18+ M+F First session without treatment;Second 2 testing Y 28 28
groups, CBD vs. PCB (64%) session with a single dose of CBD 600 mg, sessions
300 mg or PCB.
Leweke et al., 2012 Germany DB-RCT Parallel- Acute paranoid schizophrenia (n = 37), 18-50 M+F CBD 800 mg/day or Amisulpride 800 mg/ 4 weeks N 42 33
groups, CBD vs. schizophreniform disorder (n = 5)DSM-IV Not (76%) day; 4 weeks
Amisulpride antipsychotic resistant No positive drug screen
McGuire et al., 2018 United Kingdom (+ DB-RCT Parallel- Schizophrenia (n = 83), schizoaffective disorder 18-65 M+F CBD 1000 mg/day or PCB; 6 weeks 8 weeks Y 88 83
sites in Romania and groups, CBD vs. PCB (n = 3), schizophreniform disorder (n = 1), (58%)
Poland) delusional disorder (n = 1)DSM-IV Not
antipsychotic resistant Included SUD

4
Boggs et al., 2018 USA DB-RCT Parallel- Schizophrenia DSM-IV-TR No recent SUD or drug 18-68 M+F CBD 600 mg/day or PCB; 6 weeks 6 weeks Y 41 36
groups, CBD vs. PCB dependence (70%)
Observational study design
Zuardi et al., 1995 Brazil Case report CBD vs. Schizophrenia DSM-III-R Not antipsychotic 19 F (0%) Placebo, 4 days;CBD 1500 mg/day, 4 9 weeks N 1 1
Haloperidol resistant weeks; Placebo 4 days;Haloperidol 12.5
mg/day, 4 weeks.
Zuardi et al., 2006 Brazil Case series CBD vs. Schizophrenia DSM-IV Antipsychotic resistant 22-23 M (100%) Placebo, 5 days;CBD up to 1280 mg/day, 4 8 weeks N 3 3
Olanzapine weeks; Placebo, 5 days;Olanzapine, 2
weeks.
Schipper et al., 2018 Netherlands Case series Schizophrenia (n = 4) Schizoaffective disorder 21-57 Not Smoke 0.125-0.5 g/day of cannabis with 8 weeks Y 6 6
(n = 1) Psychotic disorder not otherwise reported 0.4% tetrahydrocannabinol and 9% CBD
specified, n = 1) DSM-IV Treatment resistant CUD max. 3 times/day; 8 weeks
Makiol and Germany Case report Schizophrenia Antipsychotic resistant 57 F (0%) CBD 1000 mg/day, 7 weeks; CBD 1500 9.5 weeks Y 1 1
Kluge, 2019 mg/day, 2.5 weeks

Legend: Adjunctive, participants took other antipsychotics in addition to intervention treatment; CBD, cannabidiol; CUD, cannabis use disorder; DB-RCT, double-blind randomized clinical trial; DSM, Diagnostic and
Statistical Manual of Mental Disorders; F, female; M, male; N, no; PCB, placebo; SUD, substance use disorder; Y, yes.
Psychiatry Research 286 (2020) 112890
M.F. Ghabrash, et al.
Table 2
Summary of the risk of bias evaluation for each included study.
Legend: green, low risk of bias; yellow, unclear risk of bias; red, high risk of bias; grey, not applicable.
higher risk of bias in observational studies compared to experimental
studies.
3.4. Outcome results
To evaluate CBD treatment efficacy and tolerability, we extracted
data collected at the end of the trial treatment period and considered
comparison to a control group or condition when possible. We cate-
gorized these outcome measures into five outcome domains: general
psychopathology, positive symptoms, negative symptoms, cognition
and functioning. We extracted side effect and adverse event data when
available. Table 3 presents a summary of measured outcomes and re-
sults.
3.4.1. Effects of CBD on general psychopathology
Psychopathology measures included the Positive and Negative
Syndrome Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), the
Interactive Observation Scale for Psychiatric Inpatients, the Clinical
Global Impression scale for illness severity and improvement and nursing
staff observations. Seven studies reported outcomes for general psycho-
pathology symptoms using scales that present a global score or using a
subscale which includes general symptoms indicative of severity. The
case presented by Zuardi et al. (1995) showed that a four-week CBD
treatment was associated with greater reduction of BPRS scores
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Psychiatry Research 286 (2020) 112890
compared to haloperidol. Scores on the Interactive Observation Scale for
Psychiatric Inpatients scale followed a similar pattern. Another case de-
scribed by Makiol and Kluge (2019) also showed PANSS total score re-
duction after a treatment period of nine and a half weeks as an adjunctive
treatment to clozapine and lamotrigine. In a RCT comparing four-week
treatments of CBD versus amisulpride, Leweke et al. (2012) did not re-
port any significant reductions in PANSS total and general subscale
scores compared to amisulpride. Although the RCT conducted by
McGuire et al. (2018) did not detect symptom improvement using the
PANSS total and general psychopathology scales, they recorded a higher
number of participants from the CBD-treated group categorized as im-
proved on the Clinical Global Impression-Improvement scale (p = 0.018)
and less severely ill on the Clinical Global Impression-Severity scale
(p = 0.044) compared to the placebo group. In contrast, in a case series
by Zuardi et al. (2006), moderate symptom improvements were observed
after CBD treatment using the BPRS total and general psychopathology
scales, although these changes were smaller than those seen in the group
treated with the reference drug, olanzapine. No symptom improvement
was noted in any of the participants who smoked cannabis with a high
CBD content (Schipper et al., 2018). Furthermore, the RCT conducted by
Boggs et al. (2018) reported that CBD administered in addition to a stable
antipsychotic treatment was not associated with significant changes in
PANSS total and general psychopathology scores compared to placebo.
 M.F. Ghabrash, et al.

Table 3
Summary of results from experimental and observational studies investigating the antipsychotic efficacy of cannabidiol.
Study Intervention and comparison Outcome domain Outcome measure Results

Experimental study design

Hallak et al., 2010 DB-RCT Parallel-groups, CBD
vs. PCB
Leweke et al., 2012 DB-RCT Parallel-groups, CBD
vs. Amisulpride
McGuire et al., 2018 DB-RCT Parallel-groups, CBD
vs. PCB
Cognition SCWT, skin conductance level Significant difference in number of errors on SCWT between groups, post-
intervention. CBD 300 mg group and placebo group showed significantly reduced
number of errors compared to CBD 600 mg group
General psychopathology BPRS, PANSS No difference compared to amisulpride
Positive sx PANSS-P No difference compared to amisulpride
Negative sx PANSS-N No difference compared to amisulpride
General psychopathology PANSS total, PANSS general, CGI-I, CGI-S, No significant difference between CBD and placebo groups for PANSS total
Participant and carer Global Impression of (p = 0.133) and general (p = 0.196) scores
change scale Significantly higher proportion of participants from CBD group were rated as
improved on the CGI-I (p = 0.018) and CGI-S scales (p = 0.044) compared to
placebo group
Positive sx PANSS-P CBD significantly reduced positive symptoms compared to placebo (p = 0.019).
Negative sx PANSS-N, SANS No significant difference between groups
Functioning GAF, Participant and carer Global No significant differences between groups for both scales
Impression of change scale

6
Cognition BACS No statistically significant improvement of composite score in CBD group
(p = 0.068).
Boggs et al., 2018 DB-RCT Parallel-groups, CBD General psychopathology PANSS total, PANSS general CBD did not significantly decrease PANSS general and total scores compared to
vs. PCB placebo (p = 0.18; p = 0.56)
Positive sx PANSS-P CBD did not significantly improve sx compared to placebo (p = 0.26)
Negative sx PANSS-N CBD did not significantly improve sx compared to placebo (p = 0.55)
Cognition MCCB Significant effect but only placebo group improved (p = 0.03)
Observational study design
Zuardi et al., 1995 Case report CBD vs. Haloperidol General psychopathology BPRS total, IOSPI Improved BPRS and IOPSI scores during CBD treatment over time
Zuardi et al., 2006 Case series CBD vs. Olanzapine General psychopathology BPRS total, BPRS general Improved scores over time in 3/3 participants treated with CBD
Positive sx BPRS-P Improved scores over time in 2/3 participants treated with CBD
Negative sx BPRS-N, PANSS-N* Improved scores over time in 3/3 participants treated with CBD
Schipper et al., 2018 Case series High CBD level General psychopathology Nursing staff observations of sx 0/6 patients improved over time
cannabis Positive sx PANSS-P 1/6 patients score improved over time
Makiol and Kluge, 2019 Case report Adjunctive CBD General psychopathology PANSS total Improved general symptoms over time
Negative sx PANSS-N Improved negative symptoms over time

Legend: BACS, Brief Assessment of Cognition in Schizophrenia; BPRS, Brief Psychiatric Rating Scale; BPRS-P, BPRS positive subscale; BPRS-N, BPRS negative subscale; CBD, cannabidiol; CGI-I, Clinical Global Impression
Improvement scale; CGI-S, Clinical Global Impression Severity scale; DB-RCT, double-blind randomized clinical trial; GAF, Global Assessment of Functioning; IOSPI, Interactive Observation Scale for Psychiatric
Inpatients; MCCB, MATRICS Consensus Cognitive Battery; PCB, placebo; PANSS, Positive and Negative Syndrome Scale; PANSS-P, PANSS positive subscale; PANSS-N, PANSS negative subscale; SANS, Scale for the
Assessment of Negative Symptoms; SCWT, Stroop color word test; Sx, symptoms;
⁎
Results not reported.
Psychiatry Research 286 (2020) 112890
M.F. Ghabrash, et al.
3.4.2. Effects of CBD on positive symptoms
Positive symptoms were specifically evaluated in four studies,
which used the PANSS positive subscale (Boggs et al., 2018;
Leweke et al., 2012; McGuire et al., 2018; Schipper et al., 2018), and in
a case series study, which used the BPRS positive subscale (Zuardi et al.,
2006). Data from the latter study showed that CBD treatment reduced
positive symptoms measured using the BPRS scale (Zuardi et al., 2006).
Another case series study showed no improvement of positive symp-
toms in all but one participant when smoked (Schipper et al., 2018). In
one RCT, CBD did not demonstrate significant differences in positive
symptoms compared to amisulpride (Leweke et al., 2012). When taken
as an adjuvant to antipsychotics, one study reported a significant re-
duction in symptoms compared to placebo (McGuire et al., 2018), while
another study did not report a significant reduction (Boggs et al., 2018).
3.4.3. Effects of CBD on negative symptoms
Five studies measured negative symptoms using either the PANSS or
BPRS negative subscales, or the Scale for the Assessment of Negative
Symptoms scale (Boggs et al., 2018; Leweke et al., 2012; Makiol and
Kluge, 2019; McGuire et al., 2018; Zuardi et al., 2006). One of these
mentioned using the PANSS but did not report the results (Zuardi et al.,
2006); we contacted the corresponding author, who stated the changes
were not significant. This study also reported results from the BPRS
negative subscale, which showed improvements in all three patients.
Leweke et al. (2012) reported no difference between the negative
symptom improvements observed using CBD compared to amisulpride.
When taken together with antipsychotics, CBD treatment did not de-
monstrate improved negative symptoms compared to placebo in two
RCT studies (Boggs et al., 2018; McGuire et al., 2018), while a sustained
improvement was observed after nine and a half weeks of adjunctive
treatment in a case report (Makiol and Kluge, 2019).
3.4.4. Effects of CBD on cognitive symptoms
Cognitive functions were measured in three studies, each using
different tools. Hallak et al. (2010) evaluated the acute effects of a
single dose of 300 mg, 600 mg of CBD or placebo on attention using the
Stroop Color Word Test and by measuring electrodermal responsiveness
following an auditory stimulus. Despite observing a learning effect in all
groups between the first and second session on the Stroop Color Word
Test, there was a significant difference between all three groups on the
number of errors post-intervention. A closer examination found that
participants who received placebo and 300 mg of CBD performed better
than the group who received 600 mg of CBD. Skin conductance levels
did not differ between the three experimental groups.
McGuire et al. (2018) used the Brief Assessment of Cognition in Schi-
zophrenia. There was no significant difference in the composite score
between the placebo and CBD groups. In the study conducted by
Boggs et al. (2018), there was a significant difference between the two
groups in cognition scores as measured with the MATRICS Consensus
Cognitive Battery after six weeks of treatment, and post hoc analyses
revealed that only placebo-treated subjects improved over time.
3.4.5. Effects of CBD on functioning
Only one study measured participants’ functioning after six weeks of
CBD adjunctive treatment to antipsychotics and reported no significant
group differences on the Global Assessment of Functioning scale and
the Participant and Carer Global Impression of Change Scale
(McGuire et al., 2018).
3.4.6. Side effects, adverse effects and tolerability
Side effects were measured in six studies (Boggs et al., 2018;
Leweke et al., 2012; Makiol and Kluge, 2019; McGuire et al., 2018;
Zuardi et al., 2006, 1995) but only reported in three studies, all of
which were RCTs. Fewer extrapyramidal symptoms were measured in
CBD-treated participants compared to amisulpride-treated patients
(p=0.006; Leweke et al. (2012)). Moreover, both McGuire et al. (2018)
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Psychiatry Research 286 (2020) 112890
and Boggs et al. (2018) reported no significant differences in side effects
related to motor function between CBD adjunctive treatment and pla-
cebo. A significant weight gain was observed in patients treated with
amisulpride (p≤0.01) but not in those treated with CBD (Leweke et al.,
2012); likewise, adding CBD to an ongoing antipsychotic medication
did not significantly change weight or waist circumference compared to
placebo in two RCTs (Boggs et al., 2018; McGuire et al., 2018). Simi-
larly, prolactin levels increased in the antipsychotic-treated group,
while levels remained stable in CBD monotherapy and CBD adjunctive-
treated groups (Leweke et al., 2012; McGuire et al., 2018). Other
measured side effects or markers that were not significantly changed
upon CBD treatment included: liver function (Leweke et al., 2012;
McGuire et al., 2018), HDL cholesterol (McGuire et al., 2018), sleep
(Boggs et al., 2018; McGuire et al., 2018), and cardiac function
(Leweke et al., 2012). However, in one study, mild sedation was more
prevalent in the CBD group (20%) compared to the placebo group (5%)
(Boggs et al., 2018). The number of discontinued interventions due to
adverse events was similar between the CBD arm and comparator arm
in RCT studies (Boggs et al., 2018; Leweke et al., 2012; McGuire et al.,
2018). The case report by Makiol and Kluge (2019) described a mild
hand tremor as the only adverse event at the end of the treatment, but
there is no comparison with baseline levels from when the patient was
already taking clozapine. Of all reported adverse events by
McGuire et al. (2018), the majority were considered mild and, among
treatment-related events, gastrointestinal events were more frequent in
the CBD group than in the placebo group. Only two mild treatment-
related events (nausea and dyslipidemia) were still ongoing at the end
of the study. However, in the case series by Schipper et al. (2018), five
out of six participants discontinued the smoked cannabis treatment by
the fifth week of an eight-week treatment, and frequent drug-seeking
behaviors were observed during the treatment period. Overall, six
studies concluded that CBD was safe and well tolerated, even when
supporting data were missing (Makiol and Kluge, 2019; Zuardi et al.,
2006, 1995).
4. Discussion
The present systematic review examined clinical evidence from
eight studies for the use of CBD as an antipsychotic agent among pa-
tients with primary psychosis. Overall, we identified limited evidence
on the effectiveness of CBD as an antipsychotic in patients with a pri-
mary psychotic illness. CBD has been associated with beneficial out-
comes for general psychopathology, positive symptoms and negative
symptoms in some trials (i.e., in one experimental RCT and three ob-
servational case series), but the evidence is mixed. There is no evidence
to conclude that CBD can improve cognition or functioning in this po-
pulation. Nevertheless, our results consistently support that CBD is safe
and may present an advantageous side effect profile compared to usual
antipsychotics.
The risk of bias assessment reported in this review suggests that this
field is still nascent, reflected by an almost equal number of observa-
tional and experimental studies in this comprehensive review, as well as
heterogeneous intervention methods, measures and population sam-
ples. Additionally, there is a lack of high-quality, double-blinded and
robustly designed trials in this field. The selective reporting of outcomes
as well as various suboptimal approaches pertaining to blinding and
randomization reporting also explain the overall high risk of bias of
included studies. This assessment underlines the need to accelerate ef-
forts to improve study designs, to standardize methods and outcome
assessments, and to use consistently reproduced, well-defined study
materials in order to facilitate comparisons between trials.
4.1. Study limitations and strengths
Certain limitations should be considered when interpreting our
findings. Firstly, we applied broad inclusion criteria to our search to
M.F. Ghabrash, et al.
capture all studies involving CBD use as an antipsychotic in human
subjects with a psychotic disorder. Heterogeneity in the pool of in-
cluded studies, both at the methodological and intervention level,
complicated study comparison. Due to major methodological differ-
ences between observational and experimental studies, we grouped si-
milar study designs together to weigh the evidence accordingly. Other
factors that accounted for heterogeneity included intervention dura-
tion, dosage, use of concomitant antipsychotics and study sample
characteristics such as comorbid substance use or stage of illness. The
potential influence of these factors on inter-study variability and gen-
eralizability of results is discussed below. Secondly, despite applying
broad inclusion criteria, our systematic review presents findings from a
small set of studies (n = 8), impeding us from extrapolating conclusions
on the efficacy of CBD as an antipsychotic. Thirdly, we did not search
for grey literature or for trial registrations and therefore may have
missed trials that were stopped prematurely or that, though un-
published, had relevant data. Finally, limiting our studies to English
and French language articles may have narrowed the number of eligible
trials we detected. However, only one study was excluded on this basis,
at the title-abstract level, a study written in German in 1974
(Dittrich and Woggon, 1974).
The strength of our systematic review lies in the rigorous assessment
and analysis of included studies, including risk of bias assessments.
Given the changing regulations around cannabis and the progressively
easier access to cannabinoid-based medicines, an up-to-date systematic
review of clinical evidence regarding the antipsychotic potential of CBD
was necessary. Our methods and analyses are intended to help the
reader interpret study findings and to explain heterogeneity, as well as
to portray a clearer picture of the current evidence base.
4.2. Intervention heterogeneity
Intervention characteristics can intrinsically affect CBD treatment
efficacy, and their variability may account for the divergent outcome
results observed between studies. Studies in this review using doses of
600 mg and below did not report efficacy – in fact, Hallak et al. (2010)
observed a worsening of cognitive function – while those administering
800 mg or more observed efficacy for at least one outcome. Perhaps the
use of higher doses can yield positive outcomes, while lower doses are
associated with more sedation without therapeutic effect. This possi-
bility is not trivial; past experience with medication development in this
field has shown that some medications may only display antipsychotic
properties at higher dosage (e.g., quetiapine). A broader analysis of
CBD efficacy in clinical populations have shown better therapeutic
outcomes at higher doses in RCTs, with tested doses as high as 1240
mg/day (Millar et al., 2019). However, other researchers have found an
inverted U-shaped dose-response curve of CBD in anxiety-related out-
comes for the general population (Linares et al., 2019; Zuardi et al.,
2017b). Future trials could explore whether these proposed models are
relevant to this population as well, or whether higher doses of CBD are
associated with better therapeutic outcomes.
Daily CBD oral dosages ranged from 300–1500 mg and were well-
tolerated in all studies. Despite sedation being a frequently reported
side effect in our study sample, CBD has a better side effect profile
compared to other antipsychotics (Leweke et al., 2012) and does not
exacerbate existing side effects when used as an adjuvant (Boggs et al.,
2018; McGuire et al., 2018). Doses as high as 1500 mg/day for a week
or a single dose of 6000 mg are well tolerated in healthy individuals
(Taylor et al., 2018), and trials testing up to 50 mg/kg/day (3500 mg
for a 70 kg adult) in the context of long-term CBD treatments in epi-
lepsy patients reported more adverse events but concluded that treat-
ments were nonetheless tolerable (Devinsky et al., 2017; Laux et al.,
2019). Together, these trials suggest that higher dosages are safe to
explore in future studies. Since antipsychotic medications often start
being effective or reach their full efficacy after several months, long-
term data on CBD's antipsychotic properties are also necessary to
8
Psychiatry Research 286 (2020) 112890
properly assess its full potential as a treatment for psychosis in people
with psychotic disorders. Another important difference between the
interventions tested was the use of CBD as a monotherapy or as an
adjunctive treatment to an ongoing antipsychotic medication. Although
the evidence is not substantial enough to confirm the effectiveness of
CBD as a stand-alone drug, findings from Leweke et al. (2012) and
Zuardi et al. (1995) suggest that CBD has the potential to improve
psychiatric symptoms in a manner comparable, but not superior, to
other antipsychotics. On the other hand, trials where CBD was used as
an adjunctive therapy were less successful (Boggs et al., 2018;
McGuire et al., 2018; Schipper et al., 2018), except for the case report
from Makiol and Kluge (2019). Otherwise, only one RCT study obtained
mixed results for general psychopathology and improvement of positive
symptoms (McGuire et al., 2018). Overall, there is a lack of clear effi-
cacy reported in these studies, which could be due to a smaller possible
effect size in a population that is already benefiting from a stable an-
tipsychotic regimen or due to a higher dose or longer treatment dura-
tion being needed to see significant improvements. Another possible
explanation is that when using CBD as an adjunctive treatment, the co-
use of medication results in a drug-drug interaction. Previous research
in people with epilepsy being treated with CBD reported drug-drug
interactions when CBD was taken adjunctively with clobazam
(Geffrey et al., 2015; Savage et al., 2019). Future studies involving the
co-use of medication could explore whether there are such interactions
in this population.
The varied intervention administration routes and formulations
used in the included studies may also have contributed to the hetero-
geneity in results of the included studies. Schipper et al. (2018) re-
ported using a different administration route (i.e., inhaled) and sche-
dule (i.e., upon request) from the other studies. As already highlighted
by Black et al. (2019), future RCTs examining therapeutic cannabinoid
research should take care in standardizing doses and administration
routes, in order to be better able to compare studies of CBD as an an-
tipsychotic. Studies testing tetrahydrocannabinol-containing products,
such as the study by Schipper et al. (2018), in people with active psy-
chotic symptoms may face important clinical and ethical challenges.
Exploring the use of CBD as a potential treatment for people with dual
diagnoses may be a more acceptable intervention for this population.
However, additional data are required to determine how the different
formulations of CBD and their characteristics might influence their ef-
fectiveness. In addition to formulation dosing and standardization of
methods, more research is also needed to compare the differential ef-
fects of CBD as an antipsychotic when using CBD-rich extracts, purified
CBD and synthetic CBD (Pamplona et al., 2018).
4.3. Population heterogeneity
As the efficacy of CBD could differ between patient subpopulations,
the contradicting results of the included studies could be attributed to
the inclusion or exclusion of participants with certain characteristics.
Substance use disorders are prevalent in patients with psychotic dis-
orders (Hunt et al., 2018) and are associated with poor outcomes within
this population (Abdel-Baki et al., 2017; Romer Thomsen et al., 2018).
The study by Schipper et al. (2018) was the only one comprised entirely
of patients having a psychotic disorder and a comorbid CUD, though it
was not the only study that included people with CUD in their sample.
Differing inclusion and exclusion criteria related to substance use across
the included studies could account for some of the variability in results
and may introduce a confounding factor. CBD may play a role in mi-
tigating substance use, as it has been linked to reduced cocaine, opioid
and psycho-stimulant use when used as a treatment component
(Prud'homme et al., 2015). There is also very preliminary evidence that
CBD may be associated with cannabis use reduction in humans
(Shannon and Opila-Lehman, 2015). Thus, it remains unclear whether
CBD can directly impact symptomatology, indirectly improve it by re-
ducing substance use or both. Future studies would benefit from
M.F. Ghabrash, et al.
including participants with substance use to characterise the relation-
ship between CBD treatment, symptomatology and substance use out-
come. Given the high prevalence of substance use in this population,
this is an important parameter to consider and characterize in order to
generalize study results to other clinical populations.
The included studies were conducted in a heterogeneous population
in terms of stage of illness, and we did not include studies in prodromal
stage populations. Treatment-resistant patients represent a non-negli-
gible proportion of people with schizophrenia (Elkis and
Buckley, 2016). In our review, studies that excluded treatment-resistant
patients showed mixed or positive outcomes (Leweke et al., 2012;
McGuire et al., 2018; Zuardi et al., 1995). On the whole, however, there
is little evidence on treatment-resistant patients (Zuardi et al., 2006);
findings from this review may not be generalizable to treatment-re-
fractory populations and data are insufficient to determine whether
stage of illness influences response to CBD (e.g., with administration as
part of early intervention being more favorable). As with other anti-
psychotics, treatment-resistant patients with schizophrenia may re-
spond differently to CBD and this possibility deserves further in-
vestigation. Taken together, and as highlighted previously by
Crippa et al. (2015), the findings underline the relevance of exploring
the therapeutic potential of CBD for earlier stages of psychotic dis-
orders, such as in the prodromal stage or first episode of psychosis.
4.4. Conclusions
The evidence showing efficacy for CBD as an antipsychotic to treat
primary psychotic disorders is limited and shows mixed results. Some
studies suggest that CBD has therapeutic potential, but this conclusion
must be interpreted with caution when considering the number of trials
and the suboptimal quality of evidence from these trials. Given the
current state of clinical evidence, this treatment should be considered
experimental. There is an urgent need to address the limitation of
previous studies in the field with adequately-powered, randomized,
double-blind, controlled clinical trials with larger samples and stan-
dardized administration, in order to determine the safety, adequate
dose range, and efficacy of cannabinoids in schizophrenia. More RCTs
are necessary to pinpoint the specific contexts in which CBD therapy
might be beneficial and for whom.
Funding sources
Authors would like to acknowledge the support from the Université
de Montréal's Faculty of Medicine and its Department of Psychiatry and
Addiction for preparation of the manuscript. They would also like to
thank the Institut Universitaire sur les Dépendances for their support to
prepare the manuscript. The funding sources had no input in the design
of this study or the data analysis or interpretation of these findings.
Declaration of Competing Interest
InSYS therapeutics provided study medication to Dr. Didier Jutras-
Aswad's team for a clinical trial funded by the Canadian Institute of
Health Research, not related to the treatment of psychosis.
Acknowledgment
DJA holds a clinical scientist career award from the Fonds de
Recherche du Québec en Santé (FRQS). The authors also thank Dr.
Anne-Julie Chabot-Doré for assistance with manuscript preparation.
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