the therapeutic role of cannabidiol in mental health: a systematic … · 2020-01-02 · review...
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REVIEW Open Access
The therapeutic role of Cannabidiol inmental health: a systematic reviewRabia Khan1, Sadiq Naveed2* , Nadeem Mian3, Ania Fida4, Muhammad Abdur Raafey1 and Kapil Kiran Aedma5
Abstract
Background: The therapeutic application of cannabidiol (CBD) is gaining interest due to expanding evidence for itsuse.
Objective: To summarize the clinical outcomes, study designs and limitations for the use of CBD and nabiximols(whole plant extract from Cannabis sativa L. that has been purified into 1:1 ratio of CBD and delta-9-tetrahydrocannabinol) in the treatment of psychiatric disorders.
Materials and method: A systematic review was conducted including case reports, case series, open-label trials,non-randomized and randomized controlled trials (RCTs). The search resulted in 23 relevant studies on CBD andnabiximols in the treatment of a wide range of psychiatric disorders. The quality of evidence was judged by usingthe Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence that ranges from Level 1 to Level 5 basedon the quality and study design. These levels of evidence help in grading the recommendations, including Grade A(strong), Grade B (moderate), Grade C (weak), and Grade D (weakest).
Results: CBD and CBD-containing compounds such as nabiximols were helpful in alleviating psychotic symptomsand cognitive impairment in patients with a variety of conditions, and several studies provided evidence ofeffectiveness in the treatment of cannabis withdrawal and moderate to severe cannabis use disorder with Grade Brecommendation. There is Grade B recommendation supporting the use of CBD for the treatment of schizophrenia,social anxiety disorder and autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD).Grade C recommendation exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourettesyndrome. These recommendations should be considered in the context of limited number of available studies.
Conclusion: CBD and CBD-containing compounds such as nabiximols were helpful in alleviating symptoms ofcannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD withmoderate recommendation. However, there is weaker evidence for insomnia, anxiety, bipolar disorder,posttraumatic stress disorder, and Tourette syndrome. The evidence for the use of CBD and CBD-containingcompounds for psychiatric disorders needs to be explored in future studies, especially large-scale and well-designed RCTs.
Keywords: Cannabidiol (CBD), Nabiximols, Schizophrenia, Cannabis, Withdrawal, Dependence, Autism spectrumdisorder (ASD), Attention deficit hyperactivity disorder (ADHD), Post-traumatic stress disorder (PTSD), Tourettesyndrome, Bipolar disorder
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: [email protected] and Behavioral Sciences, Kansas University Medical Center, 3901Rainbow Blvd, Kansas City, KS KS 66160, USAFull list of author information is available at the end of the article
Journal of CannabisResearch
Khan et al. Journal of Cannabis Research (2020) 2:2 https://doi.org/10.1186/s42238-019-0012-y
IntroductionCannabis sativa, a species of cannabis plant, is wellknown to humankind, with its earliest use in ancientChinese culture dating as far back as 2700 B.C. (Zuardi,2006). The use of medical cannabis in China was re-ported in the world’s oldest pharmacopoeia (Martinet al., 1999). However, interest in the role of cannabisflourished in the late twentieth century after the recogni-tion of an endogenous cannabinoid system in the brain(Zuardi, 2006; Martin et al., 1999). More recently, re-search has centered on the description and cloning ofspecific receptors and the therapeutic effects of medicalcannabis, and different cannabinoids in the cannabisplant have gained interest (Martin et al., 1999). Recentstudies have focused on the therapeutic role of medicalcannabis in different disorders. As a result, there is agrowing need to summarize and review the evidence forits therapeutic and adverse effects as an aid to publichealth policy development, and to provide direction andimpetus to pharmaceutical research in this field.The cannabis plant has more than 140 cannabinoid
compounds, with Δ9-tetrahydrocannabinol (Δ9-THC) andcannabidiol (CBD) attracting significant interest (Cittiet al., 2018). Δ9-THC is the primary psychoactive ingredi-ent, and CBD is a non-intoxicating ingredient (Zuardi,2006; Citti et al., 2018). Evidence from preclinical studiessuggested that CBD had potential therapeutic benefitsranging from antiinflammatory to neuroprotective, anti-psychotic, analgesic, anticonvulsant, antiemetic, antioxi-dant, antiarthritic, and antineoplastic properties; for areview, see (Pertwee, 2006). CBD has several receptorsand molecular targets. This compound antagonizes the ac-tion of CB1 and CB2 receptor agonist (Blessing et al., 2015;Peres et al., 2018). The CB1 and CB2 receptors are couplednegatively through G-proteins to adenylate cyclase andpositively to mitogen-activated protein kinase (Pertwee,2006). In addition to CB1 and CB2 receptor activity, CBDis an agonist of vanilloid receptor TRPV1. It also acts as anagonist of serotonin receptor 5-hydroxytryptamine (5-HT1A), an antagonist of G-protein-coupled receptorGPR55, and an inverse agonist of GPR3, GPR6, andGPR12 (Peres et al., 2018). Data from single-photon emis-sion computed tomography showed CBD to exert anxio-lytic effects by acting on paralimbic and limbic pathways(Crippa et al., 2011). The agonist effect of CBD on 5-HT1A also supports its anxiolytic and antidepressant prop-erties (Russo et al., 2005). CBD inhibits enzymatichydrolysis and anandamide uptake through its agonist ac-tion on CB1, CB2, and TRPV1 receptors (Peres et al.,2018). In addition, CBD indirectly enhances endogenousanandamide signaling by inhibiting the intercellular deg-radation of anandamide (Leweke et al., 2012). This en-dogenous neurotransmitter exerts antipsychotic effects inpatients with schizophrenia (Leweke et al., 2012).
The pharmacokinetic profile of CBD has been exten-sively explored in the existing literature. A recently pub-lished systematic review of the pharmacokinetics of CBDfound that the area under curve (AUC0 − t) and max-imum serum concentration (Cmax) occurs between 1and 4 h (Millar et al., 2018). The AUC0 − t and Cmaxreach maximum values faster after smoking or inhalationcompared to oral or oromucosal routes. Bioavailabilitywas 31% after smoking, but no other studies reportedthe absolute bioavailability of CBD after other routes inhumans. The half-life of CBD ranges between 1.4 and10.9 h after oromucosal spray and 2–5 days after chronicoral administration (Millar et al., 2018). Fed states andlipid formulations increase Cmax (Millar et al., 2018).The bioavailability of oral CBD ranges between 11 and13%, compared to 11 to 45% (mean 31%) via inhalation(Scuderi et al., 2009). CBD is well-tolerated, yet despite arelatively lower risk of drug–drug interactions, it shouldbe used cautiously in combination with drugs metabo-lized by the CYP3A4 and CYP2C19 pathways, and thesubstrates of UDP-glucuronosyltransferases UGT1A9and UGT2B7 (Millar et al., 2018). The clinical relevanceof these interactions needs to be explored in future stud-ies (Brown & Winterstein, 2019).Dronabinol and nabilone are synthetic in origin,
whereas nabiximols is plant-based (Papaseit et al., 2018).The percentage of THC and its ratio to CBD (THC/CBD ratio) defines the potency and psychoactive effectsof a given formulation (Papaseit et al., 2018). Those withhigher CBD/Δ9-THC ratios have euphoric, anxiolytic,and relaxing effects, whereas lower CBD/Δ9-THC ratioshave sedative properties (Papaseit et al., 2018). Nabixi-mols, a CBD-containing compound, contains Δ9-THCand CBD at a 1:1 ratio (Papaseit et al., 2018). The Foodand Drug Administration has approved Epidiolex® (anoral formulation of CBD) for two forms of childhoodseizures (Lennox–Gastaut syndrome and Dravet syn-drome) in children 2 years of age and older (Papaseitet al., 2018).Previous efforts to synthesize the evidence for medical
cannabis use in patients with psychiatric disorders havebeen published (Hoch et al., 2019; Lowe et al., 2019).For example, Hoch et al. conducted an excellent system-atic review that summarized four systematic reviews and14 randomized controlled trials (RCTs), but did not con-sider non-clinical trial evidence (case reports and caseseries) (Hoch et al., 2019). A review by Mandolini et al.recently summarized the clinical findings from 14 stud-ies of psychiatric disorders, but these authors did notprovide information about nabiximols (Mandolini et al.,2018). In contrast to the review articles noted above, thepresent article aims to provide a more comprehensivereview of the use of CBD and CBD-containing com-pounds such as nabiximols to treat psychiatric disorders.
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 2 of 21
The present review included studies focused on schizo-phrenia, cannabis-related disorders, attention deficithyperactivity disorder (ADHD), comorbidities in autismspectrum disorder (ASD), social anxiety disorder (SAD),other anxiety disorders, insomnia, bipolar disorder, post-traumatic stress disorder (PTSD), psychosis in Parkin-son’s disease, and Tourette syndrome. This articlebroadly reviews the efficacy, safety, and psychiatric bene-fits of CBD and CBD-containing compounds (nabixi-mols). We distinguish clearly here between the clinicalfindings for CBD and nabiximols, as the latter also con-tains THC.
MethodsEligibility criteriaThe main inclusion criterion was studies of the psychi-atric use of CBD and CBD-containing compounds suchas nabiximols. Only case reports, case series, retrospect-ive chart reviews, open-label trials, and RCTs were con-sidered. All books, conference papers, theses, editorials,review articles, metaanalyses, in-vitro studies, laboratorystudies, animal studies, studies of participants withoutpsychiatric disorders, and abstract-only articles were ex-cluded. No restrictions on language, country, publicationyear, or patients’ age, gender, or ethnicity were applied.
Search strategyEight electronic databases were searched on October28th, 2018: PubMed, Scopus, Web of Science, POPLINE,New York Academy of Medicine Grey Literature Report,PsycINFO, Psycarticles, and CINAHL. The followingsearch strategy was used in all cases: (CBD OR Cannabi*OR nabiximols) AND (psychiat* OR Depress* OR Anx-iety OR Psycho* OR schizo* OR Bipolar OR SubstanceOR ADHD OR Attention OR Autism) AND (treatment).The manual search of references of included studies wasperformed by four independent reviewers.
Study selectionThe search results from the eight databases wereimported to Endnote v. 7 (Thompson Reuters, CA,USA) to remove any duplicates. Four independent re-viewers (RK, NM, AF, MAF) screened the titles and ab-stracts (when available), followed by full-text screeningof each included article with the predetermined eligibil-ity criteria. All articles included after full-text screeningwere then searched manually. Discrepancies were re-solved by consensus through discussion among re-viewers, or with guidance from a third reviewer (SN).
Data extraction and gradingThe data were extracted independently by the authors,and were cross-checked by discussion among the fourreviewers (RK, NM, AF, MAF), with guidance from the
senior author (SN) in case of discrepancy. The data werecategorized as pertaining to target diagnosis, study de-sign, sample size, duration of the trial, age range, doseranges, measurement scales, clinical outcomes, studylimitations, and common side effects.The Oxford Centre for Evidence-Based Medicine 2011
Levels of Evidence was used to grade the quality of evi-dence (OCEBM, 2019). Level 1 evidence is for systematicreview of RCTs or individual RCT of narrow confidenceinterval, Level 2 for cohort studies or systematic reviewof cohort studies, Level 3 for case-control studies or sys-tematic review of case-control studies, and Level 4 forcase-series for studies focused on therapy, prevention,etiology and harm (OCEBM, 2019). These levels of evi-dence are used to generate Grades of Recommendation.Grade A is for consistent level 1 studies, Grade B forconsistent level 2 or 3 studies or extrapolations fromlevel 1 studies, and Grade C for level 4 studies or extrap-olations from level 2 or 3 studies. Grade D is ranked forlevel 5 evidence or inconsistent or inclusive studies ofany level (OCEBM, 2019).
Results & discussionThe search of eight electronic databases and our manualscreening method generated 511 results. After the re-moval of duplicates, titles and abstracts were screened,resulting in the exclusion of 459 articles. Full-textscreening of 52 articles was performed, and 23 articlesmeeting the inclusion criteria were analyzed. Figure 1summarizes the screening process.Of the 23 articles, there were eight RCTs, one clinical
trial, four open-label trials, one retrospective chart re-view, seven case reports, and two case series, comprisinga total patient population of 526. The studies focused onCBD and nabiximols use in the treatment of schizophre-nia, cannabis-related disorders, ADHD, ASD and comor-bidities, anxiety, insomnia, SAD, bipolar disorder, PTSD,psychosis in Parkinson’s disease, and Tourette syndrome.No studies of substance use disorders other than canna-bis use were identified. In this review article, the authorshave used DSM-5 terminologies for most of the disor-ders except for DSM-IV-Text Revised terminology ofsubstance dependence. A comparable DSM-5 termin-ology of moderate-severe substance use disorder wasused in this case.
Qualitative synthesis of eligible studiesSchizophrenia and psychosis in Parkinson’s diseaseThere were three RCTs (164 patients), one clinical trial(27 patients), one case series (three patients), one casereport for schizophrenia, and one open-label trial (sixpatients) for psychosis in Parkinson’s disease (Table 1)(Leweke et al., 2012; Hallak et al., 2010; Boggs et al.,2018; McGuire et al., 2018; Zuardi et al., 2006; Zuardi
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 3 of 21
et al., 1995; Zuardi et al., 2009). Of the seven studies,level 2 evidence was found in three RCTs, level 3 evi-dence in two clinical trial, and level 4 evidence in onecase report and one case series (OCEBM, 2019). Sincemost of the studies were from level 2 and level 3 evi-dence, there is Grade B recommendation for schizophre-nia. The dose of CBD in these studies ranged from 200to 1500 mg daily. The highest dose was titrated to 1500mg daily as reported by Zuardi and colleagues (Zuardiet al., 1995). Irrespective of the study design, three stud-ies reported that CBD alleviated psychotic symptomsand cognitive impairment in patients with chronic can-nabis use and Parkinson’s disease (Leweke et al., 2012;Zuardi et al., 1995; Zuardi et al., 2009), while only twoRCTs and one clinical trial provided evidence for the ef-fectiveness of CBD among patients with schizophrenia,albeit with mixed results (Leweke et al., 2012; McGuireet al., 2018; Zuardi et al., 2009).In a clinical trial, Hallak and colleagues suggested an
improvement in schizophrenia-associated cognitive im-pairment with a CBD dose of 300mg/day, while no sig-nificant improvement was seen at a CBD dose of 600mg/day (Hallak et al., 2010). In another RCT, McGuire
and colleagues found that CBD (1000 mg/day) improvedpositive psychotic symptoms, but failed to improve nega-tive symptoms and general psychopathology associatedwith this illness (McGuire et al., 2018). In another RCT,Boggs and colleagues found that CBD (600mg/day)failed to improve outcomes pertaining to reasoning andproblem-solving domains (Boggs et al., 2018).In a comparison of CBD with amisulpride, Leweke and
colleagues reported similar improvements in patientstaking CBD 800mg/day and those taking amisulpride(Leweke et al., 2012). This study also indicated an in-crease in intrinsic anandamide signaling, an effect thatexplained the antipsychotic properties of CBD (Lewekeet al., 2012). Moreover, CBD treatment was associatedwith a lower risk of extrapyramidal symptoms, lessweight gain, and a lower increase in prolactin, which is apredictor of galactorrhea and sexual dysfunction(Leweke et al., 2012). An open-label study of CBD totreat psychosis in Parkinson’s disease also suggestedpromising results at a dose of 400 mg daily; however,there was a strong risk of bias because of inadequateblinding of participants, personnel and outcome asses-sors (Zuardi et al., 2009).
Fig. 1 PRISMA Flow Diagram
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 4 of 21
Table
1Stud
iesof
CBD
usein
thetreatm
entof
schizoph
reniaandpsycho
sisin
Parkinson’sdiseaseandlevelsof
eviden
ce(1
to5)*
Autho
rDiagn
osis
Pharmacolog
ical
agen
tStud
yde
sign
Streng
thof eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
Hallak
al.,2010
Schizoph
renia
CBD
RCT
Level2
CBD
300
mg=9
CBD
600
mg=8
Placeb
o=10
1mon
th>18
CBD
=300or
600mg
SCWT
-TheSC
WTandskin
cond
uctancewere
recorded
atbaselineand1
mon
thaftertheinitialtest.
Patientsreceived
CBD
orplaceb
obe
fore
thetest.
-In
thefirstsession,there
was
sign
ificant
SCWTeffect
onelectrod
ermalrespon
sefactor
only(F1,16
=5.98;
p<0.05)relatedto
time
takento
completebo
ardI.
-Themeantim
erequ
iredfor
therespon
sive
grou
pwas
77.8(SEM
=11.7)andfor
theno
n-respon
sive
itwas
was
119.7(SEM
=12.3).
-In
thesecond
assessmen
t,asign
ificant
effect
fornu
mbe
rof
errorson
boardII(F2,16
=6.027;
p=0.014).The
grou
pthat
received
CBD
600mghadahigh
erscorecomparedto
theother
two.
-SC
WTscoreim
proved
inthe
placeb
oand300mggrou
p,bu
ttheim
provem
entwas
smallerin
the600mgCBD
grou
p.Theim
provem
entin
participants
givenCBD
600mgwas
smaller
dueto
sedatio
n.
Noside
effects
wererepo
rted
.18
Leweke
etal.,
2012
Schizoph
renia
CBD
RCT
Level2
CBD
=20
Amisulpride=
19
4weeks
18–50
-Participants
werestartedon
200mg/day
ofCBD
oram
isulpride
-Thedo
sewas
increased
by200mg/
dayin
the
1stweek.
-Thetotal
dose
was
200mgfour
BPRS,
PANSS,
EPS,
serum
prolactin
,bo
dyweigh
t
-Patientsin
both
grou
psrepo
rted
acomparable
improvem
entin
PANSS
andBPRS
(1.0,95%
confiden
ceinterval12.6to
14.6,P
=0.884.
-CBD
inhibitedFA
AHactivity
andincreasedintrinsic
anandamidesign
aling,
resulting
inantip
sychotic
prop
erties.Therewas
aa
statisticallysign
ificant
associationbe
tweenhigh
eranandamidelevelsand
decrease
inpsycho
tic
Treatm
ent
with
CBD
was
associated
with
lower
risk
ofEPS,less
weigh
tgain,
andalower
increase
inprolactin
level
-apred
ictorof
galactorrhea
andsexual
dysfun
ction.
9
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 5 of 21
Table
1Stud
iesof
CBD
usein
thetreatm
entof
schizoph
reniaandpsycho
sisin
Parkinson’sdiseaseandlevelsof
eviden
ce(1
to5)*(Con
tinued)
Autho
rDiagn
osis
Pharmacolog
ical
agen
tStud
yde
sign
Streng
thof eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
times
daily
(800
mg/day)
symptom
sin
patientstreated
with
cann
abidiol(P=.0012)
Bogg
set
al.,
2018
Schizoph
renia
CBD
RCT
Level2
CBD
=18
Placeb
o=18
6weeks
18–65
CBD
=600mg/
day
MCCB,
PANSS
-ForMCC
BCom
posite
score,there
was
noeffect
ofdrug
ortim
e,bu
tasign
ificant
drug
×tim
eeffect
was
observed
(F(1,32)=5.94;
p=0.02).
-Therewas
onlyim
provem
entin
placeb
o-treatedsubjectstim
e(F
(1,32)=4.84;p
=0.03).
-Lack
ofim
provem
entin
psycho
ticsymptom
son
PANSS
(F(3,101)=
1.66;p
=0.18).
Mild
sedatio
nwas
repo
rted
in20%
ofparticipants
comparedto
5%in
placeb
o.
22
McG
uire
etal.,
2018
Schizoph
renia
CBD
RCT
Level2
CBD
=43
Placeb
o=45
6weeks
18–65
1000
mg/day
PANSS,
SANS,
CGI,GAF,
BACS
-Thepe
rcen
tage
ofrespon
ders
(patientswith
anim
provem
ent
20%
inPA
NSS
totalscore)w
ashigh
inCBD
grou
pcompared
toplaceb
ogrou
p,ho
wever,it
couldno
treachstatistical
sign
ificance.
-Abo
ut78.6%
ofparticipants
improved
inCBD
grou
pon
CGI-I
scores
(CGI-I:treatmen
tdifference=20.5,95%
CI=
−0.8,−0.1p=0.018)
comparedto
54.6%
inplaceb
oarm.
-CBD
grou
phadan
improvem
ent
intheirglob
alfunctio
ning
(treatmen
tdifference=3.0,95%
CI=
-0.4,6.4;p
=0.08)and
cogn
itive
perfo
rmance
(treatmen
tdifference=1.31,95%
CI=
−0.10,
2.72;p
=0.068),how
ever,itcould
notreachstatisticalsign
ificance.
Mild
transien
tGId
iscomfort,
hype
rlipide
mia.
23
Zuardi
etal.,
2006
Schizoph
renia
CBD
Case
series
Level4
345
days
22–23
1–5days=
Placeb
o6–35
days=
Participants
werestarted
on40
mg
twiceaday,
titratedto
1280
mg/day
depe
nding
BPRS,
PANSS,
CGI
-Case1:DuringCBD
phase,
symptom
sim
proved
at1280
mg/day,followed
byworsening
ofsymptom
safterCBD
discon
tinuatio
n.-Case2:Noim
provem
entwith
CBD
andpartialimprovem
ent
with
olanzapine
,req
uirin
gclozapine.
-Case3:Slight
improvem
entwith
CBD
.How
ever,thispatient
failed
Noside
effects
wererepo
rted
.24
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 6 of 21
Table
1Stud
iesof
CBD
usein
thetreatm
entof
schizoph
reniaandpsycho
sisin
Parkinson’sdiseaseandlevelsof
eviden
ce(1
to5)*(Con
tinued)
Autho
rDiagn
osis
Pharmacolog
ical
agen
tStud
yde
sign
Streng
thof eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
onefficacy
and
tolerability.
36–40days=
Placeb
oLast15
days=
Olanzapine
torespon
dto
olanzapine
,clozapine
,or
halope
ridol
decano
ate.
Zuardi
etal.,
1995
Schizoph
renia
CBD
Case
repo
rtLevel4
14weeks
191–4days:
Placeb
o4–30
days:
CBD
oilw
asincreasedto
1500
mg/day
individe
ddo
ses.
31–34days:
Placeb
oAfter
35days:
Halop
eridol
was
started.
BPRS
-Ope
nBPRS
scores
improved
from
42to
13andblindBPRS
scores
improved
from
50to
30,for
anim
provem
entof
69and69%,respe
ctively.
-Im
provem
entsin
followingfactorsof
BPRS:tho
ught
disturbance(62.5to
25%),ho
stility-suspiciou
sness(83.3
to33.3%),anxiety-de
pression
(62.5
to18.8%),activation(58.3to
16.7%),
andanergia(31.3to
0.0%
).
Noside
effects
wererepo
rted
.25
Zuardi
etal.,
2009
Psycho
sisin
Parkinson’s
disease
CBD
Ope
n-labe
lpilot
stud
y
Level3
64weeks
Mean
age
58.8±
14.9
years
Theinitial
dose
of150mg
was
increasedto
400mgat
theen
dof
week4,with
anincrease
of150mg/
week.
BPRS,
PPQ
-Therewas
anim
provem
enton
total
scores
ofBPRS
(P<0.001)
andfour
BPRS
factorsscores
(Thinkingdisorder
p=0.002,With
draw
al-retardatio
nP=0.007,Anxious-dep
ression
p=0.003,Activationp=0.005)
includ
ingpo
sitiveandne
gative
symptom
s.-Aredu
ctionin
scores
ofPPQ
(P=0.001)
was
observed
atthe
endp
oint
ofstud
y.
Noadverse
effect
oncogn
itive
functio
ning
was
repo
rted
.
26
BACS:BriefAssessm
entof
Cog
nitio
nin
Schizoph
renia,BP
RS:B
riefPsychiatric
Ratin
gScale,
CBD
:can
nabidiol,C
GI:Clin
ical
Globa
lImpression
s,EP
S:extrap
yram
idal
symptom
s,GAF:Globa
lAssessm
entof
Functio
ning
,GI:
Gastrointestin
al,M
CCB:
MATR
ICSCon
sensus
Cog
nitiv
eBa
ttery,PA
NSS:P
ositive
andNeg
ativeSynd
romeScale,PP
Q:P
arkinson
Psycho
sisQue
stionn
aire,R
CT:rand
omized
controlledtrial,SA
NS:ScalefortheAssessm
ent
ofNeg
ativeSymptom
s,SC
WT:Stroop
Color
WordTest,Δ
9-TH
C:Δ
9-tetrah
ydrocann
abinol
*The
OxfordCen
treforEviden
ce-Based
Med
icine20
11Levelsof
Eviden
cewas
used
tograd
ethequ
ality
ofeviden
ce(OCEB
M,2
019).Level
1eviden
ceisforsystem
aticreview
ofRC
Tsor
individu
alRC
Tof
narrow
confiden
ceinterval,Level
2forcoho
rtstud
iesor
system
aticreview
ofcoho
rtstud
ies,Level3
forcase-con
trol
stud
iesor
system
aticreview
ofcase-con
trol
stud
ies,an
dLevel4
forcase-seriesforstud
iesfocusedon
therap
y,preven
tion,
etiology
andha
rm(OCEB
M,2
019)
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 7 of 21
The remaining evidence comprised two minimal qualitycase reports and case series. Zuardi and colleagues were thefirst to report favorable findings for CBD in patients withschizophrenia (Zuardi et al., 1995). The dose of CBD rangedfrom 600 to 1500mg daily in schizophrenia studies. A caseseries of three patients with treatment-resistant schizophre-nia found improvement in only one patient (Zuardi et al.,2006). In the first case, there was an improvement in psych-otic symptoms with CBD at 1280mg/day; however, thesymptoms worsened after CBD was discontinued. In secondcase, CBD was ineffective for the symptoms. Patient had animprovement in symptoms with clozapine. In the third case,no improvement with CBD and partial improvement witholanzapine were observed, although clozapine was subse-quently required. In case 3, mild improvement was reportedwith CBD in a patient who had previously failed to respondto olanzapine, clozapine, or haloperidol decanoate. These re-sults suggest a limited role of CBD in treatment-resistantschizophrenia (Zuardi et al., 2006). The dose were not indi-vidually mentioned for case 1 and 2.Four of the included studies did not report any adverse
effects of CBD among patients with psychosis. CBD waswell-tolerated in these patients except for mild transientsedation, hyperlipidemia, and gastrointestinal distress.Patients with schizophrenia had fewer instances of extra-pyramidal symptoms, less weight gain, and a lower in-crease in prolactin levels.CBD is postulated to improve cognitive performance
in psychosis through the mediation of CB1 and CB2 re-ceptor agonism at lower concentrations (Hallak et al.,2010; Solowij et al., 2018; Manseau & Goff, 2015). Thiscognitive improvement has been hypothesized due tothe higher concentration of cannabinoid receptors in thehypothalamus, suggesting a role in superior cognitivefunctioning (Hallak et al., 2010). Naturalistic studies ofCBD report better cognitive performance includingmemory, increased grey matter in the hippocampus, andfewer psychotic symptoms in patients given higher dosesof CBD (Solowij et al., 2018).The therapeutic benefits for psychosis is hypothesized
due to the inhibition of anandamide re-uptake and degrad-ation, resulting in increased anandamide levels in the brain(Manseau & Goff, 2015). Increased anandamide levels andimprovements in the symptoms of psychosis were reportedin another 4-week-long RCT comparing the efficacy ofCBD to amisulpride for the treatment of schizophrenia(Leweke et al., 2012). Interestingly, anandamide levels wereelevated in patients with acute schizophrenia compared tochronic schizophrenia, indicating a compensatory increasein an acute state (Giuffrida et al., 2004).
Cannabis-related disordersThe present review included three RCTs (107 patients),two open-label trials (28 patients), one case series of four
patients, and two case reports for cannabis-related disor-ders as summarized in Table 2 (Solowij et al., 2018;Crippa et al., 2013; Trigo et al., 2016a; Trigo et al., 2018;Trigo et al., 2016b; Allsop et al., 2014; Pokorski et al.,2017; Shannon & Opila-Lehman, 2015). Of the eightstudies, level 2 evidence was found in three RCTs, level3 evidence in two clinical trial, and level 4 evidence intwo case reports and one case series (OCEBM, 2019).For cannabis-related disorders, there is Grade B recom-mendation based on majority of studies ranked at thelevel 2 and level 3 of evidence.Four of these studies evaluated the efficacy of
nabiximols, and four others reported the use ofCBD. The doses tested ranged from 20 mg CBD to amaximum of 1200 mg/day. Nabiximols was used inspray form at doses ranging from an average of 28.9sprays/day (equivalent to 77.5 mg THC or 71.7 mgCBD) to 40 sprays/day (equivalent to 108 mg THCor 100 mg CBD). In CBD-only studies the dose ofCBD ranged from 200 to 600 mg/day in divideddoses. All three RCTs in this section provided evi-dence for the use of nabiximols for moderate to se-vere cannabis use disorder. These trials testeddifferent doses of nabiximols ranging from 21.6 mgTHC and 20 mg CBD (twice a day) to 113.4 mg THCor 105 mg CBD per day. All trials reported lowerwithdrawal rates, better tolerance, and retentionrates in the experimental group. Moreover, no ser-ious adverse effects were reported in any of thesestudies. In one RCT, nabiximols (total dose of 21.6mg THC and 20 mg CBD at 4 and 10 in eveningand night, respectively) was associated with markedimprovement in cannabis withdrawal symptoms,leading to shorter withdrawal times and higher re-tention rates (Allsop et al., 2014). In a second RCT,a fixed dose of nabiximols produced more positiveresults compared to self-titrated administration(Trigo et al., 2016a). Patients in the fixed-dose grouphad four sprays of medications every hour comparedto four sprays as needed every hour in self-titrateddose group. The maximum dose was 40 sprays/dayin the self-titrated dose group. Medication intakewas higher with fixed doses, which were associatedwith fewer withdrawal symptoms compared to theself-titrated regimen (Trigo et al., 2016a). In anotherRCT, the efficacy and safety of nabiximols werecompared to a placebo while all participants also re-ceived weekly motivational enhancement therapy(MET) and cognitive–behavioral therapy (CBT)(Trigo et al., 2018). The dose range of 4.1 to 12.8sprays/day was reported among nabiximols group.The withdrawal scores in this study were similar inboth groups (Trigo et al., 2018). Only one of thestudies reported decreased appetite, while the
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 8 of 21
Table
2Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
cann
abis-related
disordersandlevelsof
eviden
ce(1–5)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof
eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
Allsop
etal.,
2014
Cannabis
with
draw
alRC
TNabixim
ols
Level2
Nabixim
ols=
27 Placeb
o=24
6days
ofnabiximols
orplaceb
otreatm
ent,
3days
ofwasho
ut,
and28-day
follow-up
perio
dTotal
duratio
n=
37days
18–65
Startin
gdo
se=
8sprays,total
dose
of21.6mg
THCand20
mg
CBD
at4PM
and10
PMMaxim
umdo
se=8sprays
4tim
esaday
CWS
-Nabixim
olsredu
cedCWS
scores
by66%
compared
to52%
with
placeb
ofor
duratio
nfortreatm
ent
(P=.01).
-Itresultedin
ade
crease
inappe
titeloss,d
ecreasein
cravings
(p=0.4),irritability
andaggression
(p=.o1).
-Thetim
edu
ratio
nfor
cann
abiswith
draw
alwas
3.10
days
with
Nabixim
ols
comparedto
4.9days
with
placeb
o(p
=.04)
-Theretentionrate
was
85%
with
med
ications
comparedto
50%
with
placeb
o.
Decreased
appe
tite.
Thenu
mbe
randseverity
ofadverse
even
tsdid
notdiffer
sign
ificantly
betw
een
grou
ps.
31
Trigo
etal.,
2016
Cannabis
mod
erate-
severe
use
and
with
draw
al
RCT
Nabixim
ols
Level2
168weeks
18–50
Nabixim
ols=
108mgTH
C/100mgCBD
Fixeddo
se=4
sprays
ofmed
ications
everyho
urSelf-titrated
dose:Patients
wereallowed
touse4sprays
asne
eded
everyho
ur.The
maxim
umdo
sewas
40sprays/
day.
MCQ
,CWS,
SMHSQ
,DEQ
,ARC
I,MNWS
-Med
icationintake
was
high
eron
fixed
regimen
ascomparedto
self-titratio
ncond
ition
s.Therewas
sig
nificantdifferences
betw
eencond
ition
s(F(3,
24)=
8.561,p<0.001).
-Meantim
eforhaving
feelingof
“high”
was
clearly
high
erdu
ring
SAU(6.6–7.3h)
compared
with
Sativex
(2.4–3.3h)
orplaceb
o(0.1–0.3h),as
self-repo
rted
byparticipantsin
their
smokingdiary(Fig.1c)
-Therewerelesser
with
draw
aldu
ring
self-titratedandfixed
Sativex
ascomparedto
thecorrespo
nding
placeb
ocond
ition
s(F(7,56)=3.860,p<0.01).
Nosign
ificant
differencein
side
effects
was
observed
betw
eenthe
expe
rimen
tal
andplaceb
ogrou
p.
28
Trigo
etal.,
2018
Cannabis
mod
erateto
severe
use
RCT
Nabixim
ols
Level2
Nabixim
ols
andweekly
MET/CBT
=20 Placeb
o=20
12weeks
18–65
Nabixim
ols=
113.4mgTH
C/
105mgCBD
BPRS,SAFTEE,
HAM-A,
HDRS,TLFB
forcann
abis,
tobacco,
-Nabixim
olswas
well-
toleratedwith
ado
serang
eof
4.1to
12.8sprays/
day.
-Therewas
redu
ctionin
Noserio
usadverse
even
tswere
observed
.
29
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 9 of 21
Table
2Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
cann
abis-related
disordersandlevelsof
eviden
ce(1–5)(Co
ntinued)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof
eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
caffeine
andalcoho
l,FTND,A
SI,
BDI,DEQ
,Profile
ofMoo
dStates,
MWC,M
CQ-
SF,SMHSQ
cann
abisusein
the
nabiximols(70.5%
)and
placeb
ogrou
ps(42.6%
).-Five
participantsin
the
placeb
ogrou
pandfour
participantsin
the
nabiximolsgrou
pused
othe
rrecreatio
nald
rugs.
-Highmed
icationsub-
grou
psugg
esteda
sign
ificant
effect
oftim
e(F12,90.1=10.386,p
<.001),
noeffectsof
treatm
ent
(F1,8.1=1.200,p=.305)
butasign
ificant
timex
treatm
entinteraction.
Pokorski
etal.,
2017
Cannabis
with
draw
alOpe
n-labe
lpilot
stud
y
CBD
Level3
87days
21–62
Mean
age=
40years
CBD
=600–
1200
mg/dayin
divide
ddo
ses
CWS,daily
urinesample
andbloo
dsamples
onday1,3,and
7,TH
CCOOH
andCBD
quantification
-For600mg/dayof
CBD
:2ou
tof
5participants
completed
the7-day
inpatient
treatm
ent.
These2participants
repo
rted
abstinen
ceat
follow-up(day
28)
andthe3remaining
participantsrepo
rted
decreasedcann
abis
use,confirm
edby
bloo
dandurineanalysis.
-For600mgtw
iceaday:
of3participants,2
repo
rted
abstinen
ceandthe1
remaining
onehad
decreaseduseof
cann
abis,
confirm
edby
bloo
dand
urineanalysis.
-Allparticipantsrepo
rted
ade
crease
inCWSscore.
The
participants
didno
trepo
rtany
unwantedor
adverse
effectsof
the
CBD
.
32
Solowij
etal.,
2018
Impaired
cogn
ition
and
elevated
psycho
logical
symptom
sin
patientswith
chronic
cann
abisuse
Ope
n-labe
ltrial
CBD
Level3
2010
weeks
Med
ian
age=
25.1
years
CBD
=200mg
individe
ddo
ses
BDI,STAI-I,
STAI-II,GAF,
SOFA
S,CAPE,
RAVLT,AST
-Therewas
anim
provem
ent
inseverityof
depression
(p=0.017),verballearning,
mem
orype
rform
ance,and
frequ
ency
ofpo
sitive
psycho
tic-like
symptom
s(p
=0.025)
with
decreased
levelo
fdistress
from
baselineto
endp
oint.
Noside
effectswere
repo
rted
.
19
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 10 of 21
Table
2Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
cann
abis-related
disordersandlevelsof
eviden
ce(1–5)(Co
ntinued)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof
eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
-Thestateanxietyincreased
with
nochange
intraitanxiety,functio
nal
impairm
ent,andaccuracy
oncogn
itive
tests.
Trigo
etal.,
2016
Cannabis
mod
erateto
severe
use
Case
series
Nabixim
ols
Level4
412-w
eek
follow-up
phasewith
4weekly
visitsand2
subseq
uent
mon
thly
visits
24–43
Mean
age=
35years
Self-titrated
nabiximols=
77.5–113.4mg
THC
71.5–105
mg
CBD
CWC,C
CQ,
TLFB
for
cann
abis,
tobacco,
caffeineand
alcoho
l
-Redu
ctionin
cann
abisintake
from
baselineto
endp
oint
with
nocompe
nsatory
increase
inuseof
othe
rsubstances
(F(18,54)=
4.663,
p<0.001).
-Thecravingscores
increased
initiallydu
ringthefirst2
weeks
with
asubseq
uent
redu
ctionin
cravingfro
mweek9(F(18,54)=
7.091,
p<0.001)
.-Nosign
ificant
differencein
with
draw
alscores
forthe
duratio
nof
stud
y(F(18,54)=
0.805,pvalue=no
n-sign
ificant)
Noside
effectswere
repo
rted
.
30
Crip
paet
al.,
2013
Cannabis
with
draw
alsynd
rome
Case
repo
rtCBD
Level4
110
days
19Thedo
seof
CBD
was
300
mgon
day1
and600mgon
days
2–10.
600mgwas
administeredin
divide
ddo
ses.
MWC,W
DS
-CBD
resultedin
faster,
prog
ressiverelieffro
mwith
draw
al,anxiety,and
dissociativesymptom
s.-Marijuanawith
draw
alsymptom
checklisthad
drop
ofbaselinescore
of12
tozero,from
5to
zero
forWith
draw
aldiscom
fortscale.
-Thescores
forBeck
Anxiety
Inventoryde
creasedfro
m6
tozero
and10
tozero
for
Beck
Dep
ressionInventory.
-At6mon
thfollow-up,
return
tocann
abisusebu
tat
alower
rate.
Noside
effectswere
repo
rted
.
27
Shanno
n& Lehm
an,
2015
Cannabis
mod
erateto
severe
use
Case
repo
rtCBD
Level4
1Follow-up
for129days
27Initialregimen
:24
mgCBD
(6sprays
asne
eded
durin
gthedayand2
sprays
atnigh
t).Thedo
sewas
Self-repo
rted
cann
abisuse,
PSQI,HAM-A
-Patient
was
ableto
maintain
abstinen
cefro
mcann
abis.
-Im
provem
entin
HAM-A
scorefro
m16
to8was
repo
rted
,ind
icatingmild
anxiety.
-Patient
hadaregu
larsleep
Noside
effectswere
repo
rted
.
33
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 11 of 21
Table
2Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
cann
abis-related
disordersandlevelsof
eviden
ce(1–5)(Co
ntinued)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof
eviden
ce*
Group
(n)
Duration
Age
rang
e(years)
Doserang
e(m
g)Scales
tomeasure
the
clinical
outcom
e
Clinicalou
tcom
eCom
mon
side
effects
Reference
numbe
r
decreasedto
18mgwith
6sprayat
nigh
ton
ly.
sche
duleandscores
of7
toeigh
twererepo
rted
.
ARC
I:Add
ictio
nRe
search
Cen
terInventory,ASI:A
ddictio
nSeverityInde
x,AST:A
tten
tionSw
itching
Task,B
DI:Be
ckDep
ressionInventory,BP
RS:B
riefPsychiatric
Ratin
gScale,
CAPE
:Com
mun
ityAssessm
entof
Psychic
Expe
riences-Positive
Scale,
CBD
:can
nabidiol,C
BT:cog
nitiv
e–be
havioral
therap
y,CCQ:C
anna
bisCraving
Que
stionn
aire,C
WS:Can
nabisWith
draw
alScale,
DEQ
:DrugEffectsQue
stionn
aire,FTN
D:Fag
erstrom
Test
for
NicotineDep
ende
nce,
GAF:Globa
lAssessm
entof
Functio
ning
,HAM-A:H
amilton
Anx
iety
Ratin
gScale,
HDRS
:Ham
ilton
Ratin
gScaleforDep
ression,
MCQ:M
ariju
anaCraving
Que
stionn
aire,M
CQ-SF:Mariju
anaCraving
Que
stionn
aire-Sho
rtFo
rm,M
ET:m
otivationa
lenh
ancemen
ttherap
y,MNWS:Minne
sota
NicotineWith
draw
alScale,
MWC:M
ariju
anaWith
draw
alSymptom
Che
cklist,PS
QI:Pittsburgh
SleepQua
lityInde
x,RA
VLT:Re
yAud
itory
Verbal
Learning
Test,SAFTEE:SystematicAssessm
entforTreatm
entEm
erge
ntEven
ts,SOFA
S:So
cial
andOccup
ationa
lFun
ctioning
Assessm
entScale,
SMHSQ
:StMary’sHospitalS
leep
Que
stionn
aire,S
TAI:
Spielberge
rState-TraitAnx
iety
Inventory,TLFB
:Tim
elineFo
llow-Back,WDS:With
draw
alDiscomfortScore,
THCCOOH:1
1-no
r-9-carboxy-Δ9-tetrah
ydrocann
nabinol,Δ
9-TH
C:Δ
9-tetrah
ydrocanna
bino
l“The
OxfordCen
treforEviden
ce-Based
Med
icine20
11Levelsof
Eviden
cewas
used
tograd
ethequ
ality
ofeviden
ce(OCEB
M,2
019).Level
1eviden
ceisforsystem
aticreview
ofRC
Tsor
individu
alRC
Tof
narrow
confiden
ceinterval,Level
2forcoho
rtstud
iesor
system
aticreview
ofcoho
rtstud
ies,Level3
forcase-con
trol
stud
iesor
system
aticreview
ofcase-con
trol
stud
ies,an
dLevel4
forcase-seriesforstud
iesfocusedon
therap
y,preven
tion,
etiology
andha
rm(OCEB
M,2
019)
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 12 of 21
number and severity of adverse effects were not re-ported or observed in the other two RCTs.Two open-label studies testing the effectiveness of two
different concentrations of CBD (200mg/day and 600–1200 mg/day) obtained positive outcomes with doses aslow as 600 mg/day (Hallak et al., 2010; Pokorski et al.,2017). These studies had a small sample size of eight(Solowij et al., 2018) and 20 (Pokorski et al., 2017) par-ticipants, respectively. In the former open-label trial witheight participants, a dose of 600 mg/day was tested, andtwo out of five participants completed the 7-day in-patient treatment. These two participants reported ab-stinence at follow-up (day 28), and the remaining threeparticipants reported decreased use of cannabis, con-firmed by blood and urine analysis. In the second group,participants took 600 mg twice a day. Two out of threeparticipants reported abstinence and in the remainingone, cannabis use had decreased, as confirmed by bloodand urine analysis. All participants showed a decrease inCannabis Withdrawal Scale scores. The second open-label trial tested the effectiveness of 200 mg CBD in di-vided doses in improving cognition and depressivesymptomatology among patients with chronic cannabisuse, and found improvement in severity of depression,verbal learning, and memory performance, and de-creased frequency of positive psychotic-like symptomsand level of distress from baseline to endpoint (Solowijet al., 2018). State anxiety increased with no change intrait anxiety, functional impairment, or accuracy on cog-nitive tests (Solowij et al., 2018).The remaining studies were either case series or case
reports; all found positive outcomes in withdrawal andcannabis-dependence symptoms (Crippa et al., 2013;Trigo et al., 2016b; Shannon & Opila-Lehman, 2015).Mean age in the case series was 35 years, although thefirst participant was 19 years old and the second was 27years old. The case series used self-titrated nabiximols ata dose of 77.5–113.4 mg THC and 71.5–105.0 mg CBD(Trigo et al., 2016b). Moreover, all participants reporteda significant reduction in craving (Crippa et al., 2013;Trigo et al., 2016b; Shannon & Opila-Lehman, 2015),quicker relief (Crippa et al., 2013), lower anxiety, and animproved sleep schedule (Shannon & Opila-Lehman,2015). However, the case series reported increased crav-ing scores during the first 2 weeks with a subsequent re-duction in craving at week 9. CBD was well-tolerated inthis patient population, except for decreased appetite re-ported in one study (Trigo et al., 2016b). For patients re-ceiving nabiximols or CBD, treatment should beaugmented with psychotherapeutic modalities consider-ing the positive evidence for an effect on cravings.The effectiveness and tolerability of CBD and nabixi-
mols for moderate to severe cannabis use disorder wasreported in several studies. The efficacy may also be due
to the synergetic or additive benefits of Δ9-THC andCBD rather than CBD alone. The Δ9-THC componentof nabiximols decreases the severity of withdrawal symp-toms, lowering the risk of relapse (Trigo et al., 2016a).However, there is mixed evidence for the role of nabixi-mols in cannabis-related craving (Trigo et al., 2016a;Trigo et al., 2018; Trigo et al., 2016b). Studies that in-cluded combined motivation enhancement and behav-ioral response prevention strategies suggested areduction in craving (Trigo et al., 2016a; Trigo et al.,2018). CBD is thought to modulate the euphoric, anxio-genic, psychological, and physiological effects of Δ9-THC (Crippa et al., 2013). However, these benefits ofCBD alone and in combination with THC need to be ex-plored in head-to-head studies.
Other disordersThe present review included two RCTs (54 patients),one open-label trial (53 patients), one retrospective chartreview (72 patients), and four case reports for CBD andnabiximols use in the treatment of other psychiatric dis-orders. Specifically, this review looked at ADHD (oneRCT), comorbidities in ASD (one open-label trial), anx-iety and sleep problems (one retrospective chart review),SAD (one clinical trial), bipolar disorder (one case re-port), PTSD (one case report), and Tourette syndrome(two case reports), as summarized in Table 3 (Cooperet al., 2017; Barchel et al., 2018; Bergamaschi et al., 2011;Shannon et al., 2019; Zuardi et al., 2010; Shannon &Opila-Lehman, 2016; Trainor et al., 2016; Pichler et al.,2019). Of the nine studies, level 2 evidence was found intwo RCTs, level 3 evidence in one clinical trial, and level4 evidence in one retrospective chart review, four casereports (OCEBM, 2019). There is Grade B recommenda-tion for comorbidities in patients with ASD, anxiety dis-orders including SAD and sleep problems, and ADHDwhere as bipolar disorder, PTSD and Tourette Syndromehas Grade C recommendation. However, this should beconsidered in the context of fewer studies of each thesediagnoses.The oromucosal nabiximols spray was tested to evalu-
ate its effects on cognitive performance, hyperactivity,inattention, and emotional lability in 15 participants in aplacebo-controlled RCT (Cooper et al., 2017). The meandose of nabiximols was 4.7 sprays per day (2.7 mg Δ9-THC and 2.5 mg CBD). Although an improvement inthese symptoms was observed in the intervention group,it failed to reach statistical significance (Cooper et al.,2017). However, this result may not be valid or reliabledue to the low power of the study.One case report on the use of CBD by two patients
with bipolar disorder showed limited to no improvementwith doses of 600–1200mg for bipolar mania in one ofthe patients (Shannon et al., 2019). The second patient
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 13 of 21
Table
3Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
othe
rpsychiatric
disordersandlevelsof
eviden
ce(1–5)*
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof eviden
ce
Group
(n)
Duration
Age
rang
e(years)
Dose
rang
e(m
g)
Scales
tomeasure
theclinical
outcom
e
Clinical
outcom
eCom
mon
side
effects
Reference
numbe
r
Coo
per
etal.,2017
ADHD
RCT
Nabixim
ols
Level2
Nabixim
ols
=15
Placeb
o=15
6weeks
18–55
Nabixim
ols
orom
ucosal
spray=2.7
mgΔ9-TH
Cand2.5mg
CBD
Mean
dose
=4.7
sprays
per
day
Maxim
umdo
se=14
sprays/day
QbTest
-Theexpe
rimen
tal
grou
phadbe
tter
scores
comparedto
placeb
ogrou
p(Est=0.17,95%
CI-
0.40
to0.07,p
=0.16,n
=15/11
active/placeb
o).
-Nabixim
olswas
associated
with
ano
minally
sign
ificant
improvem
entin
hype
ractivity/
impu
lsivity
(p=0.03)anda
cogn
itive
measure
ofinhibitio
n(p
=0.05),anda
tren
dtowards
improvem
entfor
inattention
(p=0.10)and
executivelearning
(p=0.11).
Muscular
seizures
and
spasms
34
Barche
let
al.,2018
ASD
and
related
comorbidities
1.Hyperactivity
2.Sleep
prob
lems
3.Self-injury
4.Anxiety
Ope
n-labe
ltrial
CBD
andΔ9-TH
CLevel3
5330–588
days
Med
ian
duratio
n=
66days
4–22
Med
ian
age=11
years
CBD
oil
solutio
nwith
CBD
andΔ9-TH
Cat
1:20
ratio
CBD
16mg/kg
(maxim
aldaily
dose
600mg)
CBD
med
ian
IQRdaily
dose
=90
(45–143)
mgΔ
9-TH
C0.8mg/kg
(maxim
aldaily
dose
40mg).
THCmed
ian
IQRdaily
dose
=7(4–
Not
men
tione
d-Thesepatientswere
taking
concom
itant
med
ications
includ
ingstim
ulants,
antip
sychotics,anti-
epileptics,mela
tonin,anti-
depressants,alph
a-agon
ists,and
anti-
muscarin
icagen
ts.
-Out
of53
patients,
74.5%
repo
rted
improvem
entin
comorbidsymptom
s.-Abo
ut68.4%
repo
rted
improvem
entin
hype
ractivity,67.6%
inself-injurio
usbe
haviors,71.4%
insleepprob
lems,and
47.1%
inanxiety
Somno
lence
andchange
inappe
tite
35
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 14 of 21
Table
3Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
othe
rpsychiatric
disordersandlevelsof
eviden
ce(1–5)*(Con
tinued)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof eviden
ce
Group
(n)
Duration
Age
rang
e(years)
Dose
rang
e(m
g)
Scales
tomeasure
theclinical
outcom
e
Clinical
outcom
eCom
mon
side
effects
Reference
numbe
r
11)mg
symptom
s.
Bergam
asci
etal.,2011
Anxiety
related
topu
blic
speaking
RCT
CBD
Level4
CBD
=12
Placeb
o=
12
Sing
ledo
seSA
D-
placeb
o=
22.8
SAD-
CBD
=24.6
Health
y=
23.3
600mg
Mini-SPIN,
VAMS,
SSPS,
SSPS-N,
BSS
-Pretreatmen
twith
asing
ledo
seof
CBD
sign
ificantly
decreasedanxiety,
cogn
itive
impairm
entand
discom
fortin
speech
perfo
rmance.Italso
resultedin
sign
ificantly
decreasedalertness
inanticipatory
speech.
-Therewere
sign
ificant
effect
ofph
ases
(F3.6,118.51/
432.7;p<0.001),
grou
p(F2,331/413.5;
p<0.001)
and
phases
bygrou
pinteraction(F7.2,
118.51/46.4;
p<0.001).
-Therewerealso
sign
ificant
differences
betw
een
placeb
oandhe
althy
controlg
roup
atthe
initial(p
<0.018),
anticipatory
(p<0.001),spe
ech
(p<0.001)
andpo
st-
speech
(0.018)
phases.
-TheCBD
grou
pdiffersfro
mthe
placeb
o(p
<0.012)
andcontrol(p<
0.007)
grou
psdu
ring
thespeech
phase
Noside
effects
wererepo
rted
.36
Shanno
net
al.,2019
Anxiety
and
insomnia
Retrospe
ctive
chartreview
CBD
Level4
Anxiety=
47 Sleep
disorder=
25
3mon
ths
Sleep
disorder=
18–72
Mean
age=
25–175
mgM
ost
patients
received
25mg/day
HAM-A,
PSQI
-Mostpatients
received
25mg/day
CBD
;ahand
fulo
fpatientsreceived
50or
75mg/day.
-2patients
discon
tinued
treatm
entdu
eto
fatig
ueand
1patient
with
37
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 15 of 21
Table
3Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
othe
rpsychiatric
disordersandlevelsof
eviden
ce(1–5)*(Con
tinued)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof eviden
ce
Group
(n)
Duration
Age
rang
e(years)
Dose
rang
e(m
g)
Scales
tomeasure
theclinical
outcom
e
Clinical
outcom
eCom
mon
side
effects
Reference
numbe
r
36.5years
Anxiety=
18–70
Mean
age=34
years
One
patient
with
schizoaffective
disorder
and
traumawas
given
upto
175mg/day.
-After
1mon
thof
treatm
ent,79.2and
66.7%
ofpatients
repo
rted
improvem
entin
anxietyandsleep,
respectively.
-After
2mon
ths,78.1
and56.1%
ofpatientsrepo
rted
improvem
entin
anxietyandsleep,
respectively,which
werealso
observed
at3-mon
thfollow-up.
-Greater
improvem
ent
inanxietyscores
than
sleepscores.
ade
velopm
ent
disorder
had
increased
sexually
inapprop
riate
behaviors,
resulting
indiscon
tinuatio
n-Transien
tmild
sedatio
nwas
also
repo
rted
insome
patients.
Zuardet
al.,
2010
Bipo
lar
disorder
Caserepo
rtCBD
Level4
238
days
34and36
1–5days
for
both
participants:
Placeb
oCase1:
5–19
days:
CBD
600mg
and
olanzapine
10–15mg
20–33days:
CBD
900–
1200
mg
Case2:
5–33
days:
CBD
600–
1200
mg
33–38days:
Placeb
o
BPRS,
YMRS
-Case1:37
and33%
improvem
enton
BPRS
andYM
RSwith
CBD
andolanzapine
,bu
tno
additio
nal
improvem
entwith
CBD
mon
othe
rapy.
-Case2:CBD
failedto
improvesymptom
sof
bipo
lardisorder
atanyof
theprescribed
doses.
Noside
effects
wererepo
rted
.38
Shanno
n&
Opila-
Lehm
an.,
2016
Posttraumatic
stress
disorder
Caserepo
rtCBD
Level4
15mon
ths
ofCBD
10CBD
oil25
mg
Liqu
idCBD
6–12
mg
SDSC
,SC
ARED
-CBD
scores
improved
from
34to
18at
endp
oint,ind
icating
noanxiety.
Noside
effects
wererepo
rted
.39
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 16 of 21
Table
3Stud
iesof
theuseof
CBD
andCBD
-con
tainingcompo
unds
such
asnabiximolsin
thetreatm
entof
othe
rpsychiatric
disordersandlevelsof
eviden
ce(1–5)*(Con
tinued)
Autho
rDiagn
osis
Stud
yde
sign
Pharmacolog
ical
agen
tStreng
thof eviden
ce
Group
(n)
Duration
Age
rang
e(years)
Dose
rang
e(m
g)
Scales
tomeasure
theclinical
outcom
e
Clinical
outcom
eCom
mon
side
effects
Reference
numbe
r
sublingu
alsprayas
need
edfor
anxiety
-SleepDisturbance
Scale
scores
improved
from
59to
38,sug
gestingno
prob
lem
with
sleep.
Traino
ret
al.,2016
Tourette
synd
rome
Caserepo
rtNabixim
ols
Level4
14weeks
26Tw
oorom
ucosal
sprays
ofnabiximols
BID
Total
dose
=10.8
mgΔ9-TH
C,10
mgCBD
perday
YGTSS,
ORVRS
-Using
theORVRS
toevaluate
tics,motor
tics
wereredu
cedby
85%
andvocalticsby
90%
-Num
berof
affected
body
areasde
creased.
-mprovem
entof
35%
onYG
TSS.
Noside
effects
wererepo
rted
.40
Pichler
etal.,2018
Tourette
synd
rome
Caserepo
rtCannabistin
cture
THCcombine
dwith
CBD
Level4
12mon
ths
4734
drop
scann
abis
tincture3
times
aday=10
mg
Δ9-TH
Ccombine
dwith
20mg
ofCBD
YGTSS
-With
thecombinatio
nof
Δ9-TH
CandCBD
,the
rewas
sign
ificant
improvem
entin
ticfre
quen
cyand
severity.
-Scores
decreased
from
73/100
to44/100
onYG
TSS.
-Patient
repo
rted
improvem
entin
quality
oflifeanden
hanced
socialactivity.
Slight
xerostom
ia41
ADHD:A
tten
tion-de
ficit/hy
peractivity
disorder,A
SD:A
utism
spectrum
disorder,B
PRS:BriefPsychiatric
Ratin
gScale,BS
S:Bo
dily
Symptom
sScale,CBD
:can
nabidiol,H
AM-A:H
amilton
Anx
iety
Ratin
gScale,IQR:
Interqua
rtile
rang
e,Mini-S
PIN:M
ini-S
ocialP
hobiaInventory,ORV
RS:O
riginal
Rush
Vide
otap
eRa
tingScale,
PSQI:PittsburgSleepQua
lityInde
x,QbT
est:Qua
ntified
Beha
vioral
Test,R
CT:rand
omized
controlledtrial,
SCARE
D:ScreenforAnx
iety
RelatedDisorde
rs,SDSC
:Sleep
Disturban
ceScaleforChildren,
SSPS
:Self-Statem
ents
DuringPu
blicSp
eaking
,SSP
S-N:N
egativeSelf-Statem
ents,V
AMS:Visual
Ana
logMoo
dScales,Y
GTSS:
Yale
Globa
lTicSeverityScale,
YMRS
:You
ngMan
iaRa
tingScale,
Δ9-TH
C:Δ
9-tetrah
ydrocann
abinol
*The
OxfordCen
treforEviden
ce-Based
Med
icine20
11Levelsof
Eviden
cewas
used
tograd
ethequ
ality
ofeviden
ce(OCEB
M,2
019).Level
1eviden
ceisforsystem
aticreview
ofRC
Tsor
individu
alRC
Tof
narrow
confiden
ceinterval,Level
2forcoho
rtstud
iesor
system
aticreview
ofcoho
rtstud
ies,Level3
forcase-con
trol
stud
iesor
system
aticreview
ofcase-con
trol
stud
ies,an
dLevel4
forcase-seriesforstud
iesfocusedon
therap
y,preven
tion,
etiology
andha
rm(OCEB
M,2
019)
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 17 of 21
was prescribed CBD 600mg (5–9 days) and olanzapine(10–15mg), followed by CBD 900–1200 mg (20–33days), and showed improvement on the Brief PsychiatricRating Scale (37% reduction) and Young Mania RatingScale (33% reduction) with CBD and olanzapine, but noadditional improvement with CBD monotherapy (Shan-non et al., 2019). This effect was consistent with resultsfrom animal studies that modeled acute mania with dex-troamphetamine (Shannon et al., 2019). The lack of ef-fectiveness can be attributed to the shorter duration oftreatment in both cases. This evidence from studies ofbipolar mania should be considered in the context of dif-ferent pharmacological agents responding differently tocertain episodes of bipolar disorder. In animal studies,CBD induced a rapid, persistent antidepressant responseby increasing brain-derived neurotrophic factor in theprefrontal cortex (Shannon et al., 2019). Given its pos-sible antidepressant benefits, the role of CBD should beexplored in unipolar and bipolar depression.In an open-label trial involving children with ASD,
Barchel and colleagues reported that a solution of CBDand Δ9-THC (1,20 ratio) was effective for hyperactivity,insomnia, self-injurious behaviors, and anxiety (Barchelet al., 2018). The median dose was 90 mg with an inter-quartile range (IQR) of 45–143 mg for CBD whereasThe medical dose was 7mg with IQR of 4–11mg. In thiscohort of 53 patients, 74.5% showed improvement intheir comorbid symptoms, 68.4% in hyperactivity, 67.6%in self-injurious behaviors, 71.4% in sleep problems, and47.1% in anxiety symptoms. This treatment regimenlasted for a median of 66 days. However, Salgado andCastellanos suggested guiding principles for the use ofCBD in this population, including a better clinical un-derstanding of CBD, open discussion with parents andpatients, addressing their perceptions, promoting in-formed consent, and exercising caution in the use ofCBD (Salgado & Castellanos, 2018). Patients with ASDmake up a heterogeneous group of individuals with dif-ferent comorbidities that should be considered.The efficacy of CBD for SAD and PTSD was explored
in three studies including one RCT, one case report, andone chart review. The RCT reported the results of a sim-ulated public speaking test among 12 healthy controlparticipants and 24 patients with SAD who received asingle dose of CBD 600mg or a placebo before the test.This study reported that pretreatment with CBD re-sulted in less anxiety, cognitive impairment, and discom-fort during their speaking performance. It also resultedin a significant reduction in alertness in their anticipa-tory speech compared to the placebo group (Berga-maschi et al., 2011).In a 10-year-old patient, 5 months of treatment with
CBD oil (25 mg) and liquid CBD (6–12mg) in a sublin-gual spray as needed was associated with less anxiety
and better sleep quality, with no adverse effects (Shan-non & Opila-Lehman, 2016). These results were repli-cated for anxiety in a recently published chart review of72 adult patients with insomnia and anxiety (Shannonet al., 2019). Most patients in this group were given 25mg CBD/day, while a few patients were given 50 or 75mg/day, and one patient with schizoaffective disorderand trauma was given up to 175mg/day. All patientsshowed less anxiety and improved sleep, with reductionsof 65–80% in the Hamilton Anxiety Rating Scale andPittsburgh Sleep Quality Index scores.Nabiximols produced improvements in patients with
Tourette syndrome at a much lower dose than what wasused for cannabis-related disorders (Trainor et al., 2016;Pichler et al., 2019). These case reports tested two oro-mucosal nabiximols sprays used twice a day (total dose10.8 mg Δ9-THC and 10 mg CBD per day) (Trainoret al., 2016), and the second also tested cannabis tincture(34 drops three times a day (Pichler et al., 2019). Bothcase reports found improvements in tic frequency (Trai-nor et al., 2016; Pichler et al., 2019), severity (Trainoret al., 2016; Pichler et al., 2019), quality of life, and socialactivity (Trainor et al., 2016). These treatments regimenswere used for 4 weeks with the oromucosal spray form(Trainor et al., 2016) and 8 weeks for cannabis tincture(Pichler et al., 2019). The therapeutic benefits can be at-tributed to the anxiolytic and sleep-inducing propertiesof CBD (Trainor et al., 2016). It is difficult to ascertainwhether these improvements were due to due to CBD,Δ9-THC, additive, or synergetic effects. The anxiolyticproperties of CBD explain the attenuation of anxiety as-sociated with the onset of tics, and the improvement intics with a combination of Δ9-THC and CBD (Trainoret al., 2016; Pichler et al., 2019).Adverse effects were reported in four of the studies,
and included muscular seizures and spasms (Cooperet al., 2017), somnolence and changes in appetite(Barchel et al., 2018), fatigue, and sexually inappropriatebehavior in a patient with developmental disorder (Shan-non et al., 2019), mild sedation (Zuardi et al., 2010), andmild xerostomia (Pichler et al., 2019).
Summary of evidenceThe present article provides a comprehensive review ofthe evidence supporting the use of CBD and CBD-containing compounds such as nabiximols to treat psy-chiatric disorders. CBD and nabiximols were effective incannabis use-related disorders, and preliminary evidencewas found in support of their use for other psychiatricdisorders. Of the 23 studies reviewed here, level 2 evi-dence was found in eight RCTs, level 3 evidence in fouropen-label trials and one clinical trial, and level 4 evi-dence in one retrospective chart review, seven case re-ports, and two case series, according to the Oxford
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 18 of 21
Centre for Evidence-Based Medicine 2011 Levels of Evi-dence (OCEBM, 2019). This review covers the evidencefor different routes of administration, e.g. oral, inhalationspray, and sublingual. The bioavailability of these routes(11–13% for oral vs. 11–43% for inhalation) varies sig-nificantly – a factor that can impact the efficacy of dif-ferent formulations.Their antipsychotic, neuroprotective, anxiolytic, and
sedating properties suggest a potential therapeutic roleof CBD and nabiximols to treat various psychiatric dis-orders. The use of CBD at higher doses (above 1200 mgper day) showed promising results in case studies ofschizophrenia and psychosis in patients with Parkinson’sdisease, except in treatment-resistant cases. Regardingthe use of CBD to treat anxiety disorders, its anxiolyticeffect can help patients with PTSD-related and socialperformance-related anxiety, and nabiximols can reducethe anxiety associated with the onset of tics. There isalso favorable evidence in patients with ASD for redu-cing hyperactivity, self-injurious behaviors, anxiety, andinsomnia. Nabiximols showed no credible effect in thetreatment of ADHD, while CBD was also found to be in-effective for bipolar disorder. Of all the cases examined,the strongest evidence was found for the treatment ofcannabis-related disorders. The use of nabiximolsyielded positive results in multiple studies of moderateto severe cannabis use disorder; however, the use ofCBD alone has not been adequately documented outsidea few cases and case series. Notably, CBD compoundswere helpful in alleviating psychotic symptoms and im-proving cognitive impairment in patients across a varietyof conditions.
Recommendations for future researchThis review found low-level evidence for the use of can-nabis and nabiximols in a variety of disorders. Despiteour comprehensive literature search, only a few RCTsrelated to the disorders of interest were found. TheseRCTs were marred by a number of limitations, most im-portantly failure to blind the outcome assessor, partici-pants, and research personnel (in the open-label trials).In addition, most RCTs had a small sample size, critic-ally reducing the power of the study to draw robust con-clusions. The findings of the RCTs reviewed here needto be validated via a series of larger, well planned, ran-domized, double-blinded, and placebo-controlled stud-ies. The present report can be used to design and planfurther studies; however, at present the use of CBD andnabiximols in clinical practice cannot be recommendedwith confidence due to the drawbacks noted above.The evidence from studies included in this review can
guide future trials by providing information pertaining tothe dosages, formulations and routes of administration ofCBD and nabiximols. Moreover, future studies should
investigate different routes of administration in light ofthe differences in bioavailability. In view of the (albeit lim-ited) evidence for treatment-resistant schizophrenia, therole of CBD should be explored in the early stages ofpsychosis or as an adjunct medication. Although CBD wasineffective for bipolar mania, its possible efficacy as anantidepressant should be assessed in studies focused onbipolar depression. Nabiximols has been helpful incannabis-related disorder and Tourette syndrome, owingto the synergetic benefits of CBD and THC. Future studiesdesigned to explore the comparative benefits of thesetreatments can shed further light on their clinical poten-tial. Future RCTs should also consider adding first-linetreatment agents as comparison arms, to ascertain thecomparative efficacy of CBD in different mental disorders.Although fewer side effects were reported overall by pa-tients in the studies reviewed here, the vulnerability to ad-diction to cannabinoids should not be ignored.
Limitations of the reviewThis review article has several limitations that should beconsidered. This review article provides evidence forCBD and CBD-containing nabiximols are two differentpharmacological agents. Nabiximols has two active com-pounds and included studies do not consider the separ-ate effects of THC VS CBD. There is need for futureanalyses to carefully consider their benefits individually.Only one-third of studies (8/23) in this review article areRCTs and most of these RCTs had a small sample sizedecreasing the power of the study to draw robustconclusions.
ConclusionThe evidence reviewed here favors CBD use for patientswith schizophrenia and psychosis in Parkinson’s diseasein four out of seven studies, except in treatment-resistant cases. There is a Grade B recommendation thisdiagnosis based on the levels of evidence. Nabiximolsand CBD were beneficial in cannabis-related disorders inalmost all studies with Grade B recommendation, result-ing in a decreased risk of withdrawal symptoms anddependence among participants. The effect on cannabis-related craving was pronounced, with an additive benefitfrom the use of psychotherapeutic options such as METor CBT. One open-label trial suggested favorable evi-dence for the use of cannabinoids CBD and Δ9-THC forhyperactivity, self-injurious behaviors, and anxiety symp-toms in patients with ASD with Grade B recommenda-tion. CBD was helpful in patients with anxiety andinsomnia related to SAD and PTSD in one chart review.Nabiximols was found to be effective in reducing the fre-quency and severity of tics and improving the quality oflife in patients with Tourette syndrome according tocase reports. There was no firm evidence to support
Khan et al. Journal of Cannabis Research (2020) 2:2 Page 19 of 21
CBD to treat bipolar mania (one case report) or nabixi-mols (one RCT) to treat ADHD. There is Grade B (mod-erate) recommendation for attention deficit hyperactivitydisorder. Grade C recommendation (weaker) exists forinsomnia, anxiety, bipolar disorder, posttraumatic stressdisorder, and Tourette syndrome. These recommenda-tions should be considered in the context of limitednumber of available studies. The authors recommendwell-planned randomized controlled trials to furtherstudy the benefits of CBD and CBD-containing optionssuch as nabiximols in patients with psychiatric disorders.It is also important to assess the individual pharmacody-namic and pharmacokinetic effects of CBD and Δ9-THCin different treatments.
Abbreviations5-HT: 5-hydroxytryptamine; ADHD: Attention deficit hyperactivity disorder;ARCI: Addiction Research Center Inventory; ASD: Autism spectrum disorder;ASI: Addiction Severity Index; AST: Attention Switching Task; AUC: AreaUnder Curve; BACS: Brief Assessment of Cognition in Schizophrenia;BDI: Beck Depression Inventory; BDNF: Brain-derived neurtrophic factor;BPRS: Brief Psychiatric Rating Scale; BSS: Bodily Symptoms Scale;CAPE: Community Assessment of Psychic Experiences-Positive Scale; CB1receptor: Cannabinoid receptor 1; CB2 receptor: Cannabinoid receptor 2;CBD: Cannabidiol; CBT: Cognitive–behavioral therapy; CCQ: Cannabis CravingQuestionnaire; CGI: Clinical Global Impression; Cmax: Maximum SerumConcentration; CSF: Cerebrospinal fluid; CWS: Cannabis Withdrawal Scale;CYP: Cytochrome P450; DEQ: Drug Effects Questionnaire; EPS: Extrapyramidalsymptoms; FTND: Fagerstrom Test for Nicotine Dependence; GAF: GlobalAssessment of Functioning; GI: Gastrointestinal; GPR: G-protein-coupledreceptor; HAM-A: Hamilton Anxiety Rating Scale; HDRS: Hamilton RatingScale for Depression; IQR: Interquartile range; MCCB: MATRICS ConsensusCognitive Battery; MCQ: Marijuana Craving Questionnaire; MCQ-SF: MarijuanaCraving Questionnaire-Short Form; MET: Motivational Enhancement Therapy;Mini-SPIN: Mini-Social Phobia Inventory; MNWS: Minnesota NicotineWithdrawal Scale; MWC: Marijuana Withdrawal Symptom Checklist;OCEBM: Oxford Centre for Evidence-based Medicine – Levels of Evidence;ORVRS: Original Rush Videotape Rating Scale; PANSS: Positive and NegativeSyndrome Scale; PPQ: Parkinson Psychosis Questionnaire; PSQI: PittsburghSleep Quality Index; PTSD: Post-traumatic Stress Disorder; QbTest: QuantifiedBehavioral Test; RAVLT: Rey Auditory Verbal Learning Test; RCT: Randomizedcontrolled trial; SAD: Social Anxiety Disorder; SAFTEE: Systematic Assessmentfor Treatment Emergent Events; SANS: Scale for the Assessment of NegativeSymptoms; SCARED: Screen for Anxiety-related Disorders; SCWT: Stroop ColorWord Test; SDSC: Sleep Disturbance Scale for Children,; SMHSQ: St Mary’sHospital Sleep Questionnaire; SOFAS: Social and Occupational FunctioningAssessment Scale; SSPS: Self-Statements During Public Speaking; SSPS-N: Negative Self-Statements; STAI: Spielberger State-Trait Anxiety Inventory;THC: Tetrahydrocannabinol; THCCOOH: 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol; TLFB: Timeline Follow-Back; TRPV: Transient receptorpotential channels; UDP-glucuronosyltransferases: Uridine 5′-diphospho-glucuronosyltransferase; USA: United States of America; VAMS: Visual AnalogMood Scales; WDS: Withdrawal Discomfort Score; YGTSS: Yale Global TicSeverity Scale; YMRS: Young Mania Rating Scale; Δ9-THC: Δ9-tetrahydrocannabinol
AcknowledgementsThe authors thank Erin Ellington (DNP, APRN, PMHNP-BC, Clinical AssociateProfessor, University of Missouri Kansas City, School of Nursing and HealthStudies), who helped us improve the language of this article, and K. Shashok(AuthorAID in the Eastern Mediterranean), who provided additional editingof the revised manuscript.
Previous submissionsThis article has not be presented or submitted previously.
Authors’ contributionsSN and RK conceived the idea of this review article. RK, SN, AF, MAR, NM,KKA extracted and analyzed data, prepared tables, and wrote the manuscript.SN was responsible for the supervision of this project. All authors approvedthe final version of this review article.
FundingNone.
Availability of data and materialsAvailable to others on request.
Ethics approval and consent to participateNot needed for this review.
Competing interestsThe authors declare that they have no competing interests.
Author details1Dow University of Health Science, Karachi, Pakistan. 2Psychiatry andBehavioral Sciences, Kansas University Medical Center, 3901 Rainbow Blvd,Kansas City, KS KS 66160, USA. 3PICACS Clinic, Bothell, WA, USA. 4KingEdward Medical University, Lahore, Pakistan. 5Child and AdolescentPsychiatrist, KVC Hospitals, Kansas, USA.
Received: 1 April 2019 Accepted: 13 December 2019
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