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: snaveed@kumc.edu2Psychiatry 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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