Journal of Cannabis Research

REVIEW Open Access

Rabia 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 its use. 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-9tetrahydrocannabinol) 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 and nabiximols in the treatment of a wide range of psychiatric disorders. The quality of evidence was judged by using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence that ranges from Level 1 to Level 5 based on 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 symptoms and cognitive impairment in patients with a variety of conditions, and several studies provided evidence of effectiveness in the treatment of cannabis withdrawal and moderate to severe cannabis use disorder with Grade B recommendation. 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 Tourette syndrome. 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 of cannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD with moderate 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-containing compounds for psychiatric disorders needs to be explored in future studies, especially large-scale and welldesigned RCTs. Keywords: Cannabidiol (CBD), Nabiximols, Schizophrenia, Cannabis, Withdrawal, Dependence, Autism spectrum disorder (ASD), Attention deficit hyperactivity disorder (ADHD), Post-traumatic stress disorder (PTSD), Tourette syndrome, Bipolar disorder

* Correspondence: [email protected] 2Psychiatry and Behavioral Sciences, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS KS 66160, USA Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the 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.

Introduction

Cannabis sativa, a species of cannabis plant, is well known to humankind, with its earliest use in ancient Chinese culture dating as far back as 2700 B.C. (Zuardi, 2006). The use of medical cannabis in China was reported in the world’s oldest pharmacopoeia (Martin et al., 1999). However, interest in the role of cannabis flourished in the late twentieth century after the recognition of an endogenous cannabinoid system in the brain (Zuardi, 2006; Martin et al., 1999). More recently, research has centered on the description and cloning of specific receptors and the therapeutic effects of medical cannabis, and different cannabinoids in the cannabis plant have gained interest (Martin et al., 1999). Recent studies have focused on the therapeutic role of medical cannabis in different disorders. As a result, there is a growing need to summarize and review the evidence for its therapeutic and adverse effects as an aid to public health policy development, and to provide direction and impetus to pharmaceutical research in this field.

The cannabis plant has more than 140 cannabinoid compounds, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) attracting significant interest (Citti et al., 2018). Δ9-THC is the primary psychoactive ingredient, and CBD is a non-intoxicating ingredient (Zuardi, 2006; Citti et al., 2018). Evidence from preclinical studies suggested that CBD had potential therapeutic benefits ranging from antiinflammatory to neuroprotective, antipsychotic, analgesic, anticonvulsant, antiemetic, antioxidant, antiarthritic, and antineoplastic properties; for a review, see (Pertwee, 2006). CBD has several receptors and molecular targets. This compound antagonizes the action of CB1 and CB2 receptor agonist (Blessing et al., 2015; Peres et al., 2018). The CB1 and CB2 receptors are coupled negatively through G-proteins to adenylate cyclase and positively to mitogen-activated protein kinase (Pertwee, 2006). In addition to CB1 and CB2 receptor activity, CBD is an agonist of vanilloid receptor TRPV1. It also acts as an agonist of serotonin receptor 5-hydroxytryptamine (5HT1A), an antagonist of G-protein-coupled receptor GPR55, and an inverse agonist of GPR3, GPR6, and GPR12 (Peres et al., 2018). Data from single-photon emission computed tomography showed CBD to exert anxiolytic effects by acting on paralimbic and limbic pathways (Crippa et al., 2011). The agonist effect of CBD on 5HT1A also supports its anxiolytic and antidepressant properties (Russo et al., 2005). CBD inhibits enzymatic hydrolysis and anandamide uptake through its agonist action on CB1, CB2, and TRPV1 receptors (Peres et al., 2018). In addition, CBD indirectly enhances endogenous anandamide signaling by inhibiting the intercellular degradation of anandamide (Leweke et al., 2012). This endogenous neurotransmitter exerts antipsychotic effects in patients with schizophrenia (Leweke et al., 2012).

The pharmacokinetic profile of CBD has been extensively explored in the existing literature. A recently published systematic review of the pharmacokinetics of CBD found that the area under curve (AUC0 − t) and maximum serum concentration (Cmax) occurs between 1 and 4 h (Millar et al., 2018). The AUC0−t and Cmax reach maximum values faster after smoking or inhalation compared to oral or oromucosal routes. Bioavailability was 31% after smoking, but no other studies reported the absolute bioavailability of CBD after other routes in humans. The half-life of CBD ranges between 1.4 and 10.9 h after oromucosal spray and 2–5 days after chronic oral administration (Millar et al., 2018). Fed states and lipid formulations increase Cmax (Millar et al., 2018). The bioavailability of oral CBD ranges between 11 and 13%, compared to 11 to 45% (mean 31%) via inhalation (Scuderi et al., 2009). CBD is well-tolerated, yet despite a relatively lower risk of drug–drug interactions, it should be used cautiously in combination with drugs metabolized by the CYP3A4 and CYP2C19 pathways, and the substrates of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 (Millar et al., 2018). The clinical relevance of these interactions needs to be explored in future studies (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 effects of a given formulation (Papaseit et al., 2018). Those with higher CBD/Δ9-THC ratios have euphoric, anxiolytic, and relaxing effects, whereas lower CBD/Δ9-THC ratios have sedative properties (Papaseit et al., 2018). Nabiximols, a CBD-containing compound, contains Δ9-THC and CBD at a 1:1 ratio (Papaseit et al., 2018). The Food and Drug Administration has approved Epidiolex® (an oral formulation of CBD) for two forms of childhood seizures (Lennox–Gastaut syndrome and Dravet syndrome) in children 2 years of age and older (Papaseit et al., 2018).

Previous efforts to synthesize the evidence for medical cannabis use in patients with psychiatric disorders have been published (Hoch et al., 2019; Lowe et al., 2019). For example, Hoch et al. conducted an excellent systematic review that summarized four systematic reviews and 14 randomized controlled trials (RCTs), but did not consider non-clinical trial evidence (case reports and case series) (Hoch et al., 2019). A review by Mandolini et al. recently summarized the clinical findings from 14 studies of psychiatric disorders, but these authors did not provide information about nabiximols (Mandolini et al., 2018). In contrast to the review articles noted above, the present article aims to provide a more comprehensive review of the use of CBD and CBD-containing compounds such as nabiximols to treat psychiatric disorders.

The present review included studies focused on schizophrenia, cannabis-related disorders, attention deficit hyperactivity disorder (ADHD), comorbidities in autism spectrum disorder (ASD), social anxiety disorder (SAD), other anxiety disorders, insomnia, bipolar disorder, posttraumatic stress disorder (PTSD), psychosis in Parkinson’s disease, and Tourette syndrome. This article broadly reviews the efficacy, safety, and psychiatric benefits of CBD and CBD-containing compounds (nabiximols). We distinguish clearly here between the clinical findings for CBD and nabiximols, as the latter also contains THC.

Methods

Eligibility criteria

The main inclusion criterion was studies of the psychiatric use of CBD and CBD-containing compounds such as nabiximols. Only case reports, case series, retrospective chart reviews, open-label trials, and RCTs were considered. All books, conference papers, theses, editorials, review articles, metaanalyses, in-vitro studies, laboratory studies, animal studies, studies of participants without psychiatric disorders, and abstract-only articles were excluded. No restrictions on language, country, publication year, or patients’ age, gender, or ethnicity were applied.

Search strategy

Eight electronic databases were searched on October 28th, 2018: PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine Grey Literature Report, PsycINFO, Psycarticles, and CINAHL. The following search strategy was used in all cases: (CBD OR Cannabi* OR nabiximols) AND (psychiat* OR Depress* OR Anxiety OR Psycho* OR schizo* OR Bipolar OR Substance OR ADHD OR Attention OR Autism) AND (treatment). The manual search of references of included studies was performed by four independent reviewers.

Study selection

The search results from the eight databases were imported to Endnote v. 7 (Thompson Reuters, CA, USA) to remove any duplicates. Four independent reviewers (RK, NM, AF, MAF) screened the titles and abstracts (when available), followed by full-text screening of each included article with the predetermined eligibility criteria. All articles included after full-text screening were then searched manually. Discrepancies were resolved by consensus through discussion among reviewers, or with guidance from a third reviewer (SN).

Data extraction and grading

The data were extracted independently by the authors, and were cross-checked by discussion among the four reviewers (RK, NM, AF, MAF), with guidance from the

senior author (SN) in case of discrepancy. The data were categorized as pertaining to target diagnosis, study design, sample size, duration of the trial, age range, dose ranges, measurement scales, clinical outcomes, study limitations, and common side effects.

The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM, 2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on therapy, prevention, etiology and harm (OCEBM, 2019). These levels of evidence are used to generate Grades of Recommendation. Grade A is for consistent level 1 studies, Grade B for consistent level 2 or 3 studies or extrapolations from level 1 studies, and Grade C for level 4 studies or extrapolations from level 2 or 3 studies. Grade D is ranked for level 5 evidence or inconsistent or inclusive studies of any level (OCEBM, 2019).

Results & discussion

The search of eight electronic databases and our manual screening method generated 511 results. After the removal of duplicates, titles and abstracts were screened, resulting in the exclusion of 459 articles. Full-text screening of 52 articles was performed, and 23 articles meeting the inclusion criteria were analyzed. Figure 1 summarizes the screening process.

Of the 23 articles, there were eight RCTs, one clinical trial, four open-label trials, one retrospective chart review, seven case reports, and two case series, comprising a total patient population of 526. The studies focused on CBD and nabiximols use in the treatment of schizophrenia, cannabis-related disorders, ADHD, ASD and comorbidities, anxiety, insomnia, SAD, bipolar disorder, PTSD, psychosis in Parkinson’s disease, and Tourette syndrome. No studies of substance use disorders other than cannabis use were identified. In this review article, the authors have used DSM-5 terminologies for most of the disorders except for DSM-IV-Text Revised terminology of substance dependence. A comparable DSM-5 terminology of moderate-severe substance use disorder was used in this case.

Qualitative synthesis of eligible studies Schizophrenia and psychosis in Parkinson’s disease

There were three RCTs (164 patients), one clinical trial (27 patients), one case series (three patients), one case report for schizophrenia, and one open-label trial (six patients) 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

et al., 1995; Zuardi et al., 2009). Of the seven studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in one case report and one case series (OCEBM, 2019). Since most of the studies were from level 2 and level 3 evidence, there is Grade B recommendation for schizophrenia. The dose of CBD in these studies ranged from 200 to 1500 mg daily. The highest dose was titrated to 1500 mg daily as reported by Zuardi and colleagues (Zuardi et al., 1995). Irrespective of the study design, three studies reported that CBD alleviated psychotic symptoms and cognitive impairment in patients with chronic cannabis use and Parkinson’s disease (Leweke et al., 2012; Zuardi et al., 1995; Zuardi et al., 2009), while only two RCTs and one clinical trial provided evidence for the effectiveness of CBD among patients with schizophrenia, albeit with mixed results (Leweke et al., 2012; McGuire et al., 2018; Zuardi et al., 2009).

In a clinical trial, Hallak and colleagues suggested an improvement in schizophrenia-associated cognitive impairment with a CBD dose of 300 mg/day, while no significant improvement was seen at a CBD dose of 600 mg/day (Hallak et al., 2010). In another RCT, McGuire

and colleagues found that CBD (1000 mg/day) improved positive psychotic symptoms, but failed to improve negative symptoms and general psychopathology associated with this illness (McGuire et al., 2018). In another RCT, Boggs and colleagues found that CBD (600 mg/day) failed to improve outcomes pertaining to reasoning and problem-solving domains (Boggs et al., 2018).

In a comparison of CBD with amisulpride, Leweke and colleagues reported similar improvements in patients taking CBD 800 mg/day and those taking amisulpride (Leweke et al., 2012). This study also indicated an increase in intrinsic anandamide signaling, an effect that explained the antipsychotic properties of CBD (Leweke et al., 2012). Moreover, CBD treatment was associated with a lower risk of extrapyramidal symptoms, less weight gain, and a lower increase in prolactin, which is a predictor of galactorrhea and sexual dysfunction (Leweke et al., 2012). An open-label study of CBD to treat psychosis in Parkinson’s disease also suggested promising results at a dose of 400 mg daily; however, there was a strong risk of bias because of inadequate blinding of participants, personnel and outcome assessors (Zuardi et al., 2009).

were reported. 18

9

- a predictor of

No side effects

with lower risk

Clinical outcomeCommon side

prolactin level

with CBD was

weight gain,

galactorrhea

dysfunction.

and a lower

of EPS, less

increase in

and sexual

associated

Treatment

effects

= 0.014). The group that receivedp

of errors on board II (F2,16 = 6.027;

The improvement in participants

and BPRS (1.0, 95% confidence

was significant SCWT effect on

a significant effect for number

interval 12.6 to 14.6,= 0.884.P

given CBD 600 mg was smaller

score compared to the other

- SCWT score improved in the

- CBD inhibited FAAH activity

placebo and 300 mg group,

- The mean time required for

association between higher

recorded at baseline and 1

smaller in the 600 mg CBD

month after the initial test.

taken to complete board I.

but the improvement was

- In the second assessment,

CBD 600 mg had a higher

the responsive group was

the non-responsive it was

resulting in antipsychotic

properties. There was a a

Patients received CBD or

77.8 (SEM = 11.7) and for

- In the first session, there

< 0.05) related to timep

factor only (F1,16 = 5.98;

placebo before the test.

- Patients in both groups

improvement in PANSS

electrodermal response

anandamide levels and

reported a comparable

was 119.7 (SEM = 12.3).

anandamide signaling,

and increased intrinsic

decrease in psychotic

statistically significant

600 mg SCWT- The SCWT and skin

conductance were

due to sedation.

1. Table 1Studies of CBD use in the treatment of schizophrenia and psychosis in Parkinson’s disease and levels of evidence (1 to 5)*

group.

two.

prolactin,

outcome

(years) Dose range (mg)Scales to

measure

PANSS,

weight

clinical

serum

BPRS,

body

EPS,

the

were started on

200 mg four

200 mg/day

1 month> 18CBD = 300 or

amisulpride

by 200 mg/

19 4 weeks18–50- Participants

day in the

of CBD or

increased

dose was

1st week.

- The dose

- The total

was

range

evidence* Group (n)Duration Age

Amisulpride =

Placebo = 10

2012 Schizophrenia CBDRCTLevel 2CBD = 20

CBD 600

al., 2010 Schizophrenia CBDRCTLevel 2CBD 300

mg = 9

mg = 8

design Strength

of

agent Study

AuthorDiagnosisPharmacological

Leweke

Hallak

et al.,

hyperlipidemia. 23

22

were reported. 24

No side effects

5% in placebo.

Clinical outcomeCommon side

GI discomfort,

Mild transient

Mild sedation

was reported

compared to

participants

in 20% of

effects

with olanzapine, requiring clozapine.

but a significant drug × time effect

- Lack of improvement in psychotic

cognitive performance (treatment

- For MCCB Composite score, there

symptoms on PANSS (F (3, 101) =

2.72;= 0.068), however, it couldp

difference = 1.31, 95% CI =0.10,−

- CBD group had an improvement

CBD. However, this patient failed

- Case 3: Slight improvement with

not reach statistical significance.

- There was only improvement in

mg/day, followed by worsening

(treatment difference = 3.0, 95%

(patients with an improvement

20% in PANSS total score) was

- The percentage of responders

was no effect of drug or time,

- Case 2: No improvement with

CBD and partial improvement

was observed (F (1, 32) = 5.94;

to placebo group, however, it

high in CBD group compared

placebo-treated subjects time

(800 mg/day) symptoms in patients treated

symptoms improved at 1280

CGI-I scores (CGI-I: treatment

Table 1Studies of CBD use in the treatment of schizophrenia and psychosis in Parkinson’s disease and levels of evidence (1 to 5)*(Continued)

with cannabidiol (= .0012)P

- About 78.6% of participants

improved in CBD group on

- Case 1: During CBD phase,

in their global functioning

CI = -0.4, 6.4;= 0.08) andp

CI =0.8,0.1= 0.018)p−−

could not reach statistical

(F (1, 32) = 4.84;= 0.03).p

of symptoms after CBD

compared to 54.6% in

difference = 20.5, 95%

discontinuation.

1.66; p = 0. 18).

placebo arm.

significance.

= 0.02).p

CGI, GAF,

outcome

(years) Dose range (mg)Scales to

measure

Placebo = 45 6 weeks18–651000 mg/dayPANSS,

PANSS,

clinical

PANSS

day MCCB,

SANS,

BPRS,

BACS

CGI

the

Placebo = 18 6 weeks18–65CBD = 600 mg/

1280 mg/day

were started

times daily

twice a day,

6–35 days =

Participants

depending

series Level 4345 days22–231–5 days =

titrated to

on 40 mg

Placebo

range

evidence* Group (n)Duration Age

2018 Schizophrenia CBDRCTLevel 2CBD = 43

2018 Schizophrenia CBDRCTLevel 2CBD = 18

design Strength

of

agent Study

2006 Schizophrenia CBDCase

AuthorDiagnosisPharmacological

McGuire

Zuardi

Boggs

et al.,

et al.,

et al.,

BACS: Brief Assessment of Cognition in Schizophrenia, BPRS: Brief Psychiatric Rating Scale, CBD: cannabidiol, CGI: Clinical Global Impressions, EPS: extrapyramidal symptoms, GAF: Global Assessment of Functioning, GI:

Gastrointestinal, MCCB: MATRICS Consensus Cognitive Battery, PANSS: Positive and Negative Syndrome Scale, PPQ: Parkinson Psychosis Questionnaire, RCT: randomized controlled trial, SANS: Scale for the Assessment

number

confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on

*The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM,2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow

26

were reported. 25

No side effects

Clinical outcomeCommon side

was reported.

functioning

No adverse

cognitive

effect on

effects

to 13 and blind BPRS scores improved

from 50 to 30, for an improvement of

BPRS factors scores (Thinking disorder

- Improvements in following factors of

BPRS- Open BPRS scores improved from 42

to respond to olanzapine, clozapine,

- There was an improvement on total

to 18.8%), activation (58.3 to 16.7%),

scores of BPRS (< 0.001) and fourP

BPRS: thought disturbance (62.5 to

to 33.3%), anxiety-depression (62.5

25%), hostility-suspiciousness (83.3

= 0.002, Withdrawal-retardationp

including positive and negative

(= 0.001) was observed at theP

= 0.003, Activation= 0.005)pp

= 0.007, Anxious-depressionP

- A reduction in scores of PPQ

1. Table 1Studies of CBD use in the treatment of schizophrenia and psychosis in Parkinson’s disease and levels of evidence (1 to 5)*(Continued)

and anergia (31.3 to 0.0%).

or haloperidol decanoate.

69 and 69%, respectively.

endpoint of study.

symptoms.

outcome

(years) Dose range (mg)Scales to

measure

clinical

BPRS,

PPQ

the

Last 15 days =

After 35 days:

1500 mg/day

36–40 days =

week 4, with

increased to

increased to

CBD oil was

was started.

Haloperidol

31–34 days:

an increase

of 150 mg/

tolerability.

on efficacy

the end of

Olanzapine

4–30 days:

400 mg at

in divided

The initial

report Level 414 weeks191–4 days:

Placebo

Placebo

Placebo

dose of

150 mg

doses.

week.

was

and

58.8 ±

range

Level 364 weeksMean

years

evidence* Group (n)Duration Age

14.9

age

ΔΔof Negative Symptoms, SCWT: Stroop Color Word Test,9-THC:9-tetrahydrocannabinol

design Strength

of

disease CBDOpen-

agent Study

study

label

therapy, prevention, etiology and harm (OCEBM,2019)

1995 Schizophrenia CBDCase

pilot

AuthorDiagnosisPharmacological

2009 Psychosis in

Parkinson’s

Zuardi

Zuardi

et al.,

et al.,

The remaining evidence comprised two minimal quality case reports and case series. Zuardi and colleagues were the first to report favorable findings for CBD in patients with schizophrenia (Zuardi et al., 1995). The dose of CBD ranged from 600 to 1500 mg daily in schizophrenia studies. A case series of three patients with treatment-resistant schizophrenia found improvement in only one patient (Zuardi et al., 2006). In the first case, there was an improvement in psychotic symptoms with CBD at 1280 mg/day; however, the symptoms worsened after CBD was discontinued. In second case, CBD was ineffective for the symptoms. Patient had an improvement in symptoms with clozapine. In the third case, no improvement with CBD and partial improvement with olanzapine were observed, although clozapine was subsequently required. In case 3, mild improvement was reported with CBD in a patient who had previously failed to respond to olanzapine, clozapine, or haloperidol decanoate. These results suggest a limited role of CBD in treatment-resistant schizophrenia (Zuardi et al., 2006). The dose were not individually mentioned for case 1 and 2.

Four of the included studies did not report any adverse effects of CBD among patients with psychosis. CBD was well-tolerated in these patients except for mild transient sedation, hyperlipidemia, and gastrointestinal distress. Patients with schizophrenia had fewer instances of extrapyramidal symptoms, less weight gain, and a lower increase in prolactin levels.

CBD is postulated to improve cognitive performance in psychosis through the mediation of CB1 and CB2 receptor agonism at lower concentrations (Hallak et al., 2010; Solowij et al., 2018; Manseau & Goff, 2015). This cognitive improvement has been hypothesized due to the higher concentration of cannabinoid receptors in the hypothalamus, suggesting a role in superior cognitive functioning (Hallak et al., 2010). Naturalistic studies of CBD report better cognitive performance including memory, increased grey matter in the hippocampus, and fewer psychotic symptoms in patients given higher doses of CBD (Solowij et al., 2018).

The therapeutic benefits for psychosis is hypothesized due to the inhibition of anandamide re-uptake and degradation, resulting in increased anandamide levels in the brain (Manseau & Goff, 2015). Increased anandamide levels and improvements in the symptoms of psychosis were reported in another 4-week-long RCT comparing the efficacy of CBD to amisulpride for the treatment of schizophrenia (Leweke et al., 2012). Interestingly, anandamide levels were elevated in patients with acute schizophrenia compared to chronic schizophrenia, indicating a compensatory increase in an acute state (Giuffrida et al., 2004).

Cannabis-related disorders

The 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 disorders 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 eight studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in two case reports and one case series (OCEBM, 2019). For cannabis-related disorders, there is Grade B recommendation based on majority of studies ranked at the level 2 and level 3 of evidence.

Four of these studies evaluated the efficacy of nabiximols, and four others reported the use of CBD. The doses tested ranged from 20 mg CBD to a maximum of 1200 mg/day. Nabiximols was used in spray form at doses ranging from an average of 28.9 sprays/day (equivalent to 77.5 mg THC or 71.7 mg CBD) to 40 sprays/day (equivalent to 108 mg THC or 100 mg CBD). In CBD-only studies the dose of CBD ranged from 200 to 600 mg/day in divided doses. All three RCTs in this section provided evidence for the use of nabiximols for moderate to severe cannabis use disorder. These trials tested different doses of nabiximols ranging from 21.6 mg THC and 20 mg CBD (twice a day) to 113.4 mg THC or 105 mg CBD per day. All trials reported lower withdrawal rates, better tolerance, and retention rates in the experimental group. Moreover, no serious adverse effects were reported in any of these studies. In one RCT, nabiximols (total dose of 21.6 mg THC and 20 mg CBD at 4 and 10 in evening and night, respectively) was associated with marked improvement in cannabis withdrawal symptoms, leading to shorter withdrawal times and higher retention rates (Allsop et al., 2014). In a second RCT, a fixed dose of nabiximols produced more positive results compared to self-titrated administration (Trigo et al., 2016a). Patients in the fixed-dose group had four sprays of medications every hour compared to four sprays as needed every hour in self-titrated dose group. The maximum dose was 40 sprays/day in the self-titrated dose group. Medication intake was higher with fixed doses, which were associated with fewer withdrawal symptoms compared to the self-titrated regimen (Trigo et al., 2016a). In another RCT, the efficacy and safety of nabiximols were compared to a placebo while all participants also received weekly motivational enhancement therapy (MET) and cognitive–behavioral therapy (CBT) (Trigo et al., 2018). The dose range of 4.1 to 12.8 sprays/day was reported among nabiximols group. The withdrawal scores in this study were similar in both groups (Trigo et al., 2018). Only one of the studies reported decreased appetite, while the

28

29

31

No significant

was observed

experimental

between the

and placebo

difference in

The number

events were

and severity

significantly

side effects

side effects

No serious

events did

Decreased

of adverse

observed.

Clinical outcomeCommon

not differ

1. Table 2Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of cannabis-related disorders and levels of evidence (1–5)

between

appetite.

adverse

groups.

group.

range of 4.1 to 12.8 sprays/

cravings (= 0.4), irritabilityp

higher on fixed regimen as

compared to 4.9 days with

- It resulted in a decrease in

SAU (6.6–7.3 h) compared

3.10 days with Nabiximols

with Sativex (2.4–3.3 h) or

compared to self-titration

conditions. There was sig

scores by 66% compared

CWS- Nabiximols reduced CWS

appetite loss, decrease in

cannabis withdrawal was

(F(7,56) = 3.860,< 0.01).p

and aggression (= .o1).p

to 52% with placebo for

Sativex as compared to

compared to 50% with

- There was reduction in

- The retention rate was

smoking diary (Fig.1c)

duration for treatment

- Medication intake was

tween conditions (F(3,

85% with medications

nificant differences be

placebo (0.1–0.3 h), as

24) = 8.561,< 0.001).p

- Mean time for having

- The time duration for

tolerated with a dose

self-titrated and fixed

- Nabiximols was well-

”wasfeeling of“high

clearly higher during

participants in their

placebo conditions

the corresponding

withdrawal during

- There were lesser

placebo (= .04)p

self-reported by

(= .01).P

placebo.

day.

105 mg CBD BPRS, SAFTEE,

for cannabis,

measure the

ARCI, MNWS

HDRS, TLFB

MCQ, CWS,

outcome

(mg) Scales to

tobacco,

SMHSQ,

HAM-A,

clinical

DEQ,

dose of 21.6 mg

THC and 20 mg

maximum dose

every hour. The

dose = 8 sprays

18–65Starting dose =

to use 4 sprays

113.4 mg THC/

was 40 sprays/

Fixed dose = 4

dose: Patients

8 sprays, total

4 times a day

were allowed

108 mg THC/

12 weeks18–65Nabiximols =

RCTNabiximolsLevel 2168 weeks18–50Nabiximols =

CBD at 4 PM

100 mg CBD

medications

(years) Dose range

Self-titrated

every hour

and 10 PM

as needed

Maximum

sprays of

day.

range

of evidence* Group (n)DurationAge

and 28-day

or placebo

nabiximols

duration =

treatment,

follow-up

washout,

Placebo = 24 6 days of

3 days of

37 days

period

Total

withdrawal RCTNabiximolsLevel 2Nabiximols =

Placebo = 20

and weekly

severe use RCTNabiximolsLevel 2Nabiximols

MET/CBT =

20

27

agent Strength

design Pharmacological

AuthorDiagnosisStudy

moderate to

withdrawal

severe use

moderate-

2018 Cannabis

2014 Cannabis

2016 Cannabis

and

Allsop

et al.,

et al.,

et al.,

Trigo

Trigo

Table 2Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of cannabis-related disorders and levels of evidence (1–5)(Continued)

reported. 19

32

effects of the

unwanted or

effects were

participants

side effects

report any

Clinical outcomeCommon

No side

adverse

did not

CBD.

The

of 3 participants, 2 reported

- There was an improvement

(F12,90.1 = 10.386,< .001),p

decreased use of cannabis,

(= 0.017), verbal learning,p

memory performance, and

(= 0.025) with decreasedp

- All participants reported a

blood and urine analysis.

psychotic-like symptoms

confirmed by blood and

other recreational drugs.

in severity of depression

significant effect of time

- For 600 mg twice a day:

placebo group and four

- For 600 mg/day of CBD:

placebo groups (42.6%).

(F1,8.1 = 1.200,= .305)p

no effects of treatment

but a significant time x

decrease in CWS score.

nabiximols (70.5%) and

nabiximols group used

- Five participants in the

2 out of 5 participants

- High medication sub-

treatment interaction.

abstinence and the 1

baseline to endpoint.

frequency of positive

completed the 7-day

participants reported

at follow-up (day 28)

level of distress from

and the 3 remaining

reported abstinence

These 2 participants

inpatient treatment.

decreased cannabis

cannabis use in the

remaining one had

group suggested a

participants in the

use, confirmed by

urine analysis.

quantification

7, THC COOH

SOFAS, CAPE,

Mood States,

urine sample

day 1, 3, and

measure the

MWC, MCQ-

and alcohol,

STAI-II, GAF,

samples on

RAVLT, AST

SF, SMHSQ

doses BDI, STAI-I,

and blood

divided doses CWS, daily

FTND, ASI,

BDI, DEQ,

outcome

Profile of

and CBD

(mg) Scales to

caffeine

clinical

1200 mg/day in

CBD = 200 mg

CBD = 600–

(years) Dose range

in divided

40 years

trial CBDLevel 32010 weeksMedian

CBDLevel 387 days21–62

range

age =

age =

Mean

years

of evidence* Group (n)DurationAge

25.1

agent Strength

design Pharmacological

withdrawal Open-

Open-

AuthorDiagnosisStudy

study

label

label

pilot

cognition and

psychological

patients with

symptoms in

cannabis use

2017 Cannabis

2018 Impaired

elevated

chronic

Pokorski

Solowij

et al.,

et al.,

1. Table 2Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of cannabis-related disorders and levels of evidence (1–5)(Continued)

reported. 27

reported. 33

reported. 30

effects were

effects were

effects were

side effects

Clinical outcomeCommon

No side

No side

No side

- Reduction in cannabis intake

- At 6 month follow-up, return

- The craving scores increased

- Patient was able to maintain

duration of study (F(18,54) =

substances (F(18,54) = 4.663,

Inventory decreased from 6

- The scores for Beck Anxiety

- The state anxiety increased

- No significant difference in

Beck Depression Inventory.

- Patient had a regular sleep

from baseline to endpoint

abstinence from cannabis.

to zero and 10 to zero for

impairment, and accuracy

reduction in craving from

weeks with a subsequent

withdrawal scores for the

reported, indicating mild

initially during the first 2

to cannabis use but at a

week 9 (F(18,54) = 7.091,

withdrawal, anxiety, and

- Improvement in HAM-A

increase in use of other

of 12 to zero, from 5 to

symptom checklist had

score from 16 to 8 was

dissociative symptoms.

trait anxiety, functional

with no compensatory

progressive relief from

drop of baseline score

MWC, WDS- CBD resulted in faster,

- Marijuana withdrawal

0.805,value = non-p

zero for Withdrawal

with no change in

on cognitive tests.

discomfort scale.

< 0.001) .p

significant)

lower rate.

p < 0.001).

anxiety.

cannabis use,

Self-reported

PSQI, HAM-A

measure the

caffeine and

CWC, CCQ,

cannabis,

outcome

(mg) Scales to

tobacco,

TLFB for

alcohol

clinical

sprays at night).

administered in

and 600 mg on

needed during

for 129 days 27Initial regimen:

77.5–113.4 mg

divided doses.

the day and 2

24 mg CBD (6

The dose was

CBD was 300

mg on day 1

71.5–105 mg

nabiximols =

600 mg was

report CBDLevel 4110 days19The dose of

(years) Dose range

Self-titrated

days 2–10.

sprays as

CBD

THC

35 years

24–43

range

age =

Mean

of evidence* Group (n)DurationAge

subsequent

visits and 2

phase with

report CBDLevel 41Follow-up

follow-up

4 weekly

monthly

series NabiximolsLevel 4412-week

visits

agent Strength

design Pharmacological

AuthorDiagnosisStudy

severe use Case

severe use Case

syndrome Case

moderate to

moderate to

withdrawal

Cannabis

2016 Cannabis

2013 Cannabis

Shannon

Lehman,

Crippa

et al.,

et al.,

Trigo

2015

&

Nicotine Dependence, GAF: Global Assessment of Functioning, HAM-A: Hamilton Anxiety Rating Scale, HDRS: Hamilton Rating Scale for Depression, MCQ: Marijuana Craving Questionnaire, MCQ-SF: Marijuana Craving

1. Table 2Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of cannabis-related disorders and levels of evidence (1–5)(Continued)

ARCI: Addiction Research Center Inventory, ASI: Addiction Severity Index, AST: Attention Switching Task, BDI: Beck Depression Inventory, BPRS: Brief Psychiatric Rating Scale, CAPE: Community Assessment of Psychic

Questionnaire-Short Form, MET: motivational enhancement therapy, MNWS: Minnesota Nicotine Withdrawal Scale, MWC: Marijuana Withdrawal SymptomChecklist, PSQI: Pittsburgh Sleep Quality Index, RAVLT: Rey

Experiences-Positive Scale, CBD: cannabidiol, CBT: cognitivebehavioral therapy, CCQ: Cannabis Craving Questionnaire, CWS: Cannabis Withdrawal Scale, DEQ: Drug Effects Questionnaire, FTND: Fagerstrom Testfor–

Auditory Verbal Learning Test, SAFTEE: Systematic Assessment for Treatment Emergent Events, SOFAS: Social and Occupational Functioning Assessment Scale, SMHSQ: St Marys Hospital Sleep Questionnaire, STAI:’

confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on

The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM,2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow“

side effects

Clinical outcomeCommon

ΔΔΔSpielberger State-Trait Anxiety Inventory, TLFB: Timeline Follow-Back, WDS: Withdrawal Discomfort Score, THCCOOH: 11-nor-9-carboxy-9-tetrahydrocannnabinol,9-THC:9-tetrahydrocannabinol

schedule and scores of 7

to eight were reported.

measure the

outcome

(mg) Scales to

clinical

spray at night

18 mg with 6

decreased to

(years) Dose range

only.

range

of evidence* Group (n)DurationAge

agent Strength

design Pharmacological

therapy, prevention, etiology and harm (OCEBM,2019)

AuthorDiagnosisStudy

number and severity of adverse effects were not reported or observed in the other two RCTs.

Two open-label studies testing the effectiveness of two different concentrations of CBD (200 mg/day and 600– 1200 mg/day) obtained positive outcomes with doses as low 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) participants, respectively. In the former open-label trial with eight participants, a dose of 600 mg/day was tested, and two out of five participants completed the 7-day inpatient treatment. These two participants reported abstinence at follow-up (day 28), and the remaining three participants reported decreased use of cannabis, confirmed by blood and urine analysis. In the second group, participants took 600 mg twice a day. Two out of three participants reported abstinence and in the remaining one, cannabis use had decreased, as confirmed by blood and urine analysis. All participants showed a decrease in Cannabis Withdrawal Scale scores. The second openlabel trial tested the effectiveness of 200 mg CBD in divided doses in improving cognition and depressive symptomatology among patients with chronic cannabis use, and found improvement in severity of depression, verbal learning, and memory performance, and decreased frequency of positive psychotic-like symptoms and level of distress from baseline to endpoint (Solowij et al., 2018). State anxiety increased with no change in trait anxiety, functional impairment, or accuracy on cognitive tests (Solowij et al., 2018).

The remaining studies were either case series or case reports; all found positive outcomes in withdrawal and cannabis-dependence symptoms (Crippa et al., 2013; Trigo et al., 2016b; Shannon & Opila-Lehman, 2015). Mean age in the case series was 35 years, although the first participant was 19 years old and the second was 27 years old. The case series used self-titrated nabiximols at a dose of 77.5–113.4 mg THC and 71.5–105.0 mg CBD (Trigo et al., 2016b). Moreover, all participants reported a 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 an improved sleep schedule (Shannon & Opila-Lehman, 2015). However, the case series reported increased craving scores during the first 2 weeks with a subsequent reduction in craving at week 9. CBD was well-tolerated in this patient population, except for decreased appetite reported in one study (Trigo et al., 2016b). For patients receiving nabiximols or CBD, treatment should be augmented with psychotherapeutic modalities considering the positive evidence for an effect on cravings.

The effectiveness and tolerability of CBD and nabiximols for moderate to severe cannabis use disorder was reported in several studies. The efficacy may also be due

to the synergetic or additive benefits of Δ9-THC and CBD rather than CBD alone. The Δ9-THC component of nabiximols decreases the severity of withdrawal symptoms, lowering the risk of relapse (Trigo et al., 2016a). However, there is mixed evidence for the role of nabiximols in cannabis-related craving (Trigo et al., 2016a; Trigo et al., 2018; Trigo et al., 2016b). Studies that included combined motivation enhancement and behavioral response prevention strategies suggested a reduction in craving (Trigo et al., 2016a; Trigo et al.,

1. 2018). CBD is thought to modulate the euphoric, anxiogenic, psychological, and physiological effects of Δ9THC (Crippa et al., 2013). However, these benefits of CBD alone and in combination with THC need to be explored in head-to-head studies.
2. 2019). Of the nine studies, level 2 evidence was found in two RCTs, level 3 evidence in one clinical trial, and level 4 evidence in one retrospective chart review, four case reports (OCEBM, 2019). There is Grade B recommendation for comorbidities in patients with ASD, anxiety disorders including SAD and sleep problems, and ADHD where as bipolar disorder, PTSD and Tourette Syndrome has Grade C recommendation. However, this should be considered in the context of fewer studies of each these diagnoses.

The oromucosal nabiximols spray was tested to evaluate its effects on cognitive performance, hyperactivity, inattention, and emotional lability in 15 participants in a placebo-controlled RCT (Cooper et al., 2017). The mean dose of nabiximols was 4.7 sprays per day (2.7 mg Δ9THC and 2.5 mg CBD). Although an improvement in these 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 reliable due 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 improvement with doses of 600–1200 mg for bipolar mania in one of the patients (Shannon et al., 2019). The second patient

appetite 35

spasms 34

and change in

1. Table 3Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of other psychiatric disorders and levels of evidence (1–5)*

Somnolence

seizures and

outcome Common

Muscular

effects

side

comorbid symptoms.

including stimulants,

sleep problems, and

- These patients were

scores compared to

antipsychotics, anti-

hyperactivity, 67.6%

taking concomitant

behaviors, 71.4% in

depressants, alpha-

- Out of 53 patients,

muscarinic agents.

cognitive measure

agonists, and anti-

executive learning

(Est = 0.17, 95%CI-

QbTest- The experimental

group had better

associated with a

improvement for

47.1% in anxiety

0.40 to 0.07,=p

improvement in

improvement in

improvement in

(= 0.05), and ap

(= 0.03) and ap

active/placebo).

- Nabiximols was

epileptics, mela

74.5% reported

in self-injurious

0.16,= 15/11n

placebo group

trend towards

(= 0.10) andp

hyperactivity/

- About 68.4%

of inhibition

medications

inattention

tonin, anti-

impulsivity

significant

nominally

(= 0.11).p

reported

Clinical

mentioned

the clinical

outcome

(mg) Scales to

measure

Not

CBD median

THC median

dose = 7 (4–

Δ9-THCand

Δmg9-THC

at 1:20 ratio

oromucosal

and 2.5 mg

Δmg9-THC

6 weeks18–55Nabiximols

sprays/day

spray = 2.7

daily dose

daily dose

sprays per

dose = 4.7

Maximum

0.8 mg/kg

dose = 90

dose = 14

16 mg/kg

with CBD

(maximal

(maximal

IQR daily

IQR daily

(45–143)

600 mg)

solution

CBD oil

40 mg).

range

Mean

(years) Dose

CBD

CBD

day

age = 11

Median

range

years

4–22

evidence Group (n)DurationAge

duration =

Median

66 days

trial ΔCBD and9-THCLevel 35330–588

days

et al., 2017 ADHDRCTNabiximolsLevel 2Nabiximols

Placebo

= 15

= 15

agent Strength

of

AuthorDiagnosisStudy designPharmacological

Open-label

1. 1. Hyperactivity
2. 2. Sleep

comorbidities

1. 3. Self-injury
2. 4. Anxiety

problems

et al., 2018 ASD and

related

Cooper

Barchel

1. Table 3Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of other psychiatric disorders and levels of evidence (1–5)*(Continued)

37

were reported. 36

treatment due

to fatigue and

1 patient with

No side effects

discontinued

1. - Most patients
2. - 2 patients

outcome Common

effects

side

discomfort in speech

0.007) groups during

(p < 0.001) and post-

placebo and healthy

control group at the

differences between

group (F2,331/413.5;

- Pretreatment with a

phases (F3.6,118.51/

performance. It also

decreased alertness

placebo (< 0.012)p

single dose of CBD

significant effect of

(p < 0.001), speech

decreased anxiety,

the speech phase

initial (< 0.018),p

phases by group

432.7;< 0.001),p

and control (<p

interaction (F7.2,

impairment and

- There were also

differs from the

- The CBD group

< 0.001) andp

speech (0.018)

in anticipatory

118.5 1/4 6.4;

anticipatory

significantly

significantly

- There were

11) mgsymptoms.

resulted in

p < 0.001).

significant

cognitive

speech.

phases.

Clinical

the clinical

600 mgMini-SPIN,

outcome

(mg) Scales to

measure

HAM-A,

SSPS-N,

VAMS,

SSPS,

PSQI

BSS

received 25

mgMost

patients

mg/day

25–175

range

(years) Dose

disorder =

placebo =

Healthy =

CBD =

18–72

range

age =

Mean

3 monthsSleep

dose SAD-

SAD-

evidence Group (n)DurationAge

22.8

24.6

23.3

12 Single

disorder =

Placebo =

chart review CBDLevel 4Anxiety =

speaking RCTCBDLevel 4CBD = 12

Sleep

47

25

agent Strength

of

AuthorDiagnosisStudy designPharmacological

insomnia Retrospective

et al., 2011 Anxiety related

et al., 2019 Anxiety and

to public

Bergamasci

Shannon

Table 3Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of other psychiatric disorders and levels of evidence (1–5)*(Continued)

were reported. 39

were reported. 38

discontinuation

a development

- Transient mild

inappropriate

No side effects

No side effects

also reported

sedation was

disorder had

resulting in

behaviors,

increased

patients.

in some

outcome Common

sexually

effects

side

improve symptoms of

at 3-month follow-up.

in anxiety scores than

- Greater improvement

- CBD scores improved

any of the prescribed

- Case 2: CBD failed to

BPRS and YMRS with

CBD and olanzapine,

endpoint, indicating

- After 2 months, 78.1

- Case 1: 37 and 33%

treatment, 79.2 and

were also observed

CBD monotherapy.

respectively, which

improvement with

up to 175 mg/day.

bipolar disorder at

anxiety and sleep,

anxiety and sleep,

trauma was given

but no additional

patients reported

66.7% of patients

One patient with

improvement on

- After 1 month of

from 34 to 18 at

improvement in

improvement in

schizoaffective

and 56.1% of

disorder and

sleep scores.

respectively.

no anxiety.

reported

doses.

Clinical

the clinical

outcome

(mg) Scales to

measure

SCARED

SDSC,

YMRS

BPRS,

CBD 600 mg

disorder Case reportCBDLevel 4238 days34 and 361–5 days for

participants:

20–33 days:

33–38 days:

Liquid CBD

olanzapine

of CBD 10CBD oil 25

5–19 days:

5–33 days:

10–15 mg

CBD 900–

CBD 600–

6–12 mg

1200 mg

1200 mg

Placebo

Placebo

Case 1:

Case 2:

range

(years) Dose

both

and

mg

36.5 years

Anxiety =

age = 34

18–70

range

Mean

years

evidence Group (n)DurationAge

stress disorder Case reportCBDLevel 415 months

agent Strength

of

AuthorDiagnosisStudy designPharmacological

Posttraumatic

2010 Bipolar

Zuard et al.,

Shannon &

Lehman.,

Opila-

2016

1. Table 3Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of other psychiatric disorders and levels of evidence (1–5)*(Continued)

SCARED: Screen for Anxiety Related Disorders, SDSC: Sleep Disturbance Scale for Children, SSPS: Self-Statements During Public Speaking, SSPS-N: Negative Self-Statements, VAMS: Visual Analog Mood Scales, YGTSS:

confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on

Interquartile range, Mini-SPIN: Mini-Social Phobia Inventory, ORVRS: Original Rush Videotape Rating Scale, PSQI: Pittsburg Sleep Quality Index,QbTest: Quantified Behavioral Test, RCT: randomized controlled trial,

were reported. 40

xerostomia 41

*The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM,2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow

ADHD: Attention-deficit/hyperactivity disorder, ASD: Autism spectrum disorder, BPRS: Brief Psychiatric Rating Scale, BSS: Bodily Symptoms Scale, CBD: cannabidiol, HAM-A: Hamilton Anxiety Rating Scale, IQR:

No side effects

outcome Common

effects

Slight

side

Δof9-THC and CBD, there

scores improved from 59

- Sleep Disturbance Scale

evaluate tics, motor tics

improvement in quality

from 73/100 to 44/100

body areas decreased.

YGTSS- With the combination

were reduced by 85%

and vocal tics by 90%

of life and enhanced

to 38, suggesting no

- mprovement of 35%

problem with sleep.

- Using the ORVRS to

- Number of affected

tic frequency and

- Scores decreased

- Patient reported

improvement in

was significant

social activity.

on YGTSS.

on YGTSS.

severity.

Clinical

the clinical

outcome

(mg) Scales to

measure

YGTSS,

ORVRS

day = 10 mg

Δmg9-THC,

oromucosal

with 20 mg

10 mg CBD

dose = 10.8

needed for

nabiximols

sublingual

combined

tincture 3

sprays of

with CBD Level 412 months4734 drops

cannabis

spray as

Δ9-THC

per day

times a

anxiety

of CBD

range

(years) Dose

Total

syndrome Case reportNabiximolsLevel 414 weeks26Two

BID

range

evidence Group (n)DurationAge

ΔΔYale Global Tic Severity Scale, YMRS: Young Mania Rating Scale,9-THC:9-tetrahydrocannabinol

agent Strength

of

syndrome Case reportCannabis tincture

AuthorDiagnosisStudy designPharmacological

THC combined

therapy, prevention, etiology and harm (OCEBM,2019)

et al., 2016 Tourette

et al., 2018 Tourette

Trainor

Pichler

was prescribed CBD 600 mg (5–9 days) and olanzapine

1. (10–15 mg), followed by CBD 900–1200 mg (20–33 days), and showed improvement on the Brief Psychiatric Rating Scale (37% reduction) and Young Mania Rating Scale (33% reduction) with CBD and olanzapine, but no additional improvement with CBD monotherapy (Shannon et al., 2019). This effect was consistent with results from animal studies that modeled acute mania with dextroamphetamine (Shannon et al., 2019). The lack of effectiveness can be attributed to the shorter duration of treatment in both cases. This evidence from studies of bipolar mania should be considered in the context of different pharmacological agents responding differently to certain episodes of bipolar disorder. In animal studies, CBD induced a rapid, persistent antidepressant response by increasing brain-derived neurotrophic factor in the prefrontal cortex (Shannon et al., 2019). Given its possible antidepressant benefits, the role of CBD should be explored in unipolar and bipolar depression.

In an open-label trial involving children with ASD, Barchel and colleagues reported that a solution of CBD and Δ9-THC (1,20 ratio) was effective for hyperactivity, insomnia, self-injurious behaviors, and anxiety (Barchel et al., 2018). The median dose was 90 mg with an interquartile range (IQR) of 45–143 mg for CBD whereas The medical dose was 7 mg with IQR of 4–11 mg. In this cohort of 53 patients, 74.5% showed improvement in their comorbid symptoms, 68.4% in hyperactivity, 67.6% in self-injurious behaviors, 71.4% in sleep problems, and 47.1% in anxiety symptoms. This treatment regimen lasted for a median of 66 days. However, Salgado and Castellanos suggested guiding principles for the use of CBD in this population, including a better clinical understanding of CBD, open discussion with parents and patients, addressing their perceptions, promoting informed consent, and exercising caution in the use of CBD (Salgado & Castellanos, 2018). Patients with ASD make up a heterogeneous group of individuals with different comorbidities that should be considered.

The efficacy of CBD for SAD and PTSD was explored in three studies including one RCT, one case report, and one chart review. The RCT reported the results of a simulated public speaking test among 12 healthy control participants and 24 patients with SAD who received a single dose of CBD 600 mg or a placebo before the test. This study reported that pretreatment with CBD resulted in less anxiety, cognitive impairment, and discomfort during their speaking performance. It also resulted in a significant reduction in alertness in their anticipatory speech compared to the placebo group (Bergamaschi et al., 2011).

In a 10-year-old patient, 5 months of treatment with CBD oil (25 mg) and liquid CBD (6–12 mg) in a sublingual spray as needed was associated with less anxiety

and better sleep quality, with no adverse effects (Shannon & Opila-Lehman, 2016). These results were replicated for anxiety in a recently published chart review of 72 adult patients with insomnia and anxiety (Shannon et al., 2019). Most patients in this group were given 25 mg CBD/day, while a few patients were given 50 or 75 mg/day, and one patient with schizoaffective disorder and trauma was given up to 175 mg/day. All patients showed less anxiety and improved sleep, with reductions of 65–80% in the Hamilton Anxiety Rating Scale and Pittsburgh Sleep Quality Index scores.

Nabiximols produced improvements in patients with Tourette syndrome at a much lower dose than what was used for cannabis-related disorders (Trainor et al., 2016; Pichler et al., 2019). These case reports tested two oromucosal nabiximols sprays used twice a day (total dose 10.8 mg Δ9-THC and 10 mg CBD per day) (Trainor

1. et al., 2016), and the second also tested cannabis tincture (34 drops three times a day (Pichler et al., 2019). Both case reports found improvements in tic frequency (Trainor et al., 2016; Pichler et al., 2019), severity (Trainor et al., 2016; Pichler et al., 2019), quality of life, and social activity (Trainor et al., 2016). These treatments regimens were 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 attributed to the anxiolytic and sleep-inducing properties of CBD (Trainor et al., 2016). It is difficult to ascertain whether these improvements were due to due to CBD, Δ9-THC, additive, or synergetic effects. The anxiolytic properties of CBD explain the attenuation of anxiety associated with the onset of tics, and the improvement in tics with a combination of Δ9-THC and CBD (Trainor et al., 2016; Pichler et al., 2019).
2. et al., 2017), somnolence and changes in appetite (Barchel et al., 2018), fatigue, and sexually inappropriate behavior in a patient with developmental disorder (Shannon et al., 2019), mild sedation (Zuardi et al., 2010), and mild xerostomia (Pichler et al., 2019).

Summary of evidence

The present article provides a comprehensive review of the evidence supporting the use of CBD and CBDcontaining compounds such as nabiximols to treat psychiatric disorders. CBD and nabiximols were effective in cannabis use-related disorders, and preliminary evidence was found in support of their use for other psychiatric disorders. Of the 23 studies reviewed here, level 2 evidence was found in eight RCTs, level 3 evidence in four open-label trials and one clinical trial, and level 4 evidence in one retrospective chart review, seven case reports, and two case series, according to the Oxford

Centre for Evidence-Based Medicine 2011 Levels of Evidence (OCEBM, 2019). This review covers the evidence for different routes of administration, e.g. oral, inhalation spray, and sublingual. The bioavailability of these routes

1. (11–13% for oral vs. 11–43% for inhalation) varies significantly – a factor that can impact the efficacy of different formulations.

Their antipsychotic, neuroprotective, anxiolytic, and sedating properties suggest a potential therapeutic role of CBD and nabiximols to treat various psychiatric disorders. The use of CBD at higher doses (above 1200 mg per day) showed promising results in case studies of schizophrenia and psychosis in patients with Parkinson’s disease, except in treatment-resistant cases. Regarding the use of CBD to treat anxiety disorders, its anxiolytic effect can help patients with PTSD-related and social performance-related anxiety, and nabiximols can reduce the anxiety associated with the onset of tics. There is also favorable evidence in patients with ASD for reducing hyperactivity, self-injurious behaviors, anxiety, and insomnia. Nabiximols showed no credible effect in the treatment of ADHD, while CBD was also found to be ineffective for bipolar disorder. Of all the cases examined, the strongest evidence was found for the treatment of cannabis-related disorders. The use of nabiximols yielded positive results in multiple studies of moderate to severe cannabis use disorder; however, the use of CBD alone has not been adequately documented outside a few cases and case series. Notably, CBD compounds were helpful in alleviating psychotic symptoms and improving cognitive impairment in patients across a variety of conditions.

Recommendations for future research

This review found low-level evidence for the use of cannabis and nabiximols in a variety of disorders. Despite our comprehensive literature search, only a few RCTs related to the disorders of interest were found. These RCTs were marred by a number of limitations, most importantly failure to blind the outcome assessor, participants, and research personnel (in the open-label trials). In addition, most RCTs had a small sample size, critically reducing the power of the study to draw robust conclusions. The findings of the RCTs reviewed here need to be validated via a series of larger, well planned, randomized, double-blinded, and placebo-controlled studies. The present report can be used to design and plan further studies; however, at present the use of CBD and nabiximols in clinical practice cannot be recommended with confidence due to the drawbacks noted above.

The evidence from studies included in this review can guide future trials by providing information pertaining to the dosages, formulations and routes of administration of CBD and nabiximols. Moreover, future studies should

investigate different routes of administration in light of the differences in bioavailability. In view of the (albeit limited) evidence for treatment-resistant schizophrenia, the role of CBD should be explored in the early stages of psychosis or as an adjunct medication. Although CBD was ineffective for bipolar mania, its possible efficacy as an antidepressant should be assessed in studies focused on bipolar depression. Nabiximols has been helpful in cannabis-related disorder and Tourette syndrome, owing to the synergetic benefits of CBD and THC. Future studies designed to explore the comparative benefits of these treatments can shed further light on their clinical potential. Future RCTs should also consider adding first-line treatment agents as comparison arms, to ascertain the comparative efficacy of CBD in different mental disorders. Although fewer side effects were reported overall by patients in the studies reviewed here, the vulnerability to addiction to cannabinoids should not be ignored.

Limitations of the review

This review article has several limitations that should be considered. This review article provides evidence for CBD and CBD-containing nabiximols are two different pharmacological agents. Nabiximols has two active compounds and included studies do not consider the separate effects of THC VS CBD. There is need for future analyses to carefully consider their benefits individually. Only one-third of studies (8/23) in this review article are RCTs and most of these RCTs had a small sample size decreasing the power of the study to draw robust conclusions.

Conclusion

The evidence reviewed here favors CBD use for patients with schizophrenia and psychosis in Parkinson’s disease in four out of seven studies, except in treatmentresistant cases. There is a Grade B recommendation this diagnosis based on the levels of evidence. Nabiximols and CBD were beneficial in cannabis-related disorders in almost all studies with Grade B recommendation, resulting in a decreased risk of withdrawal symptoms and dependence among participants. The effect on cannabisrelated craving was pronounced, with an additive benefit from the use of psychotherapeutic options such as MET or CBT. One open-label trial suggested favorable evidence for the use of cannabinoids CBD and Δ9-THC for hyperactivity, self-injurious behaviors, and anxiety symptoms in patients with ASD with Grade B recommendation. CBD was helpful in patients with anxiety and insomnia related to SAD and PTSD in one chart review. Nabiximols was found to be effective in reducing the frequency and severity of tics and improving the quality of life in patients with Tourette syndrome according to case reports. There was no firm evidence to support

CBD to treat bipolar mania (one case report) or nabiximols (one RCT) to treat ADHD. There is Grade B (moderate) recommendation for attention deficit hyperactivity disorder. Grade C recommendation (weaker) exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies. The authors recommend well-planned randomized controlled trials to further study the benefits of CBD and CBD-containing options such as nabiximols in patients with psychiatric disorders. It is also important to assess the individual pharmacodynamic and pharmacokinetic effects of CBD and Δ9-THC in different treatments.

Abbreviations 5-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: Area Under 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; CB1 receptor: Cannabinoid receptor 1; CB2 receptor: Cannabinoid receptor 2; CBD: Cannabidiol; CBT: Cognitive–behavioral therapy; CCQ: Cannabis Craving Questionnaire; CGI: Clinical Global Impression; Cmax: Maximum Serum Concentration; CSF: Cerebrospinal fluid; CWS: Cannabis Withdrawal Scale; CYP: Cytochrome P450; DEQ: Drug Effects Questionnaire; EPS: Extrapyramidal symptoms; FTND: Fagerstrom Test for Nicotine Dependence; GAF: Global Assessment of Functioning; GI: Gastrointestinal; GPR: G-protein-coupled receptor; HAM-A: Hamilton Anxiety Rating Scale; HDRS: Hamilton Rating Scale for Depression; IQR: Interquartile range; MCCB: MATRICS Consensus Cognitive Battery; MCQ: Marijuana Craving Questionnaire; MCQ-SF: Marijuana Craving Questionnaire-Short Form; MET: Motivational Enhancement Therapy; Mini-SPIN: Mini-Social Phobia Inventory; MNWS: Minnesota Nicotine Withdrawal 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 Negative Syndrome Scale; PPQ: Parkinson Psychosis Questionnaire; PSQI: Pittsburgh Sleep Quality Index; PTSD: Post-traumatic Stress Disorder; QbTest: Quantified Behavioral Test; RAVLT: Rey Auditory Verbal Learning Test; RCT: Randomized controlled trial; SAD: Social Anxiety Disorder; SAFTEE: Systematic Assessment for Treatment Emergent Events; SANS: Scale for the Assessment of Negative Symptoms; SCARED: Screen for Anxiety-related Disorders; SCWT: Stroop Color Word Test; SDSC: Sleep Disturbance Scale for Children,; SMHSQ: St Mary’s Hospital Sleep Questionnaire; SOFAS: Social and Occupational Functioning Assessment Scale; SSPS: Self-Statements During Public Speaking; SSPSN: Negative Self-Statements; STAI: Spielberger State-Trait Anxiety Inventory; THC: Tetrahydrocannabinol; THCCOOH: 11-nor-9-carboxy-Δ9tetrahydrocannnabinol; TLFB: Timeline Follow-Back; TRPV: Transient receptor potential channels; UDP-glucuronosyltransferases: Uridine 5′-diphosphoglucuronosyltransferase; USA: United States of America; VAMS: Visual Analog Mood Scales; WDS: Withdrawal Discomfort Score; YGTSS: Yale Global Tic Severity Scale; YMRS: Young Mania Rating Scale; Δ9-THC: Δ9tetrahydrocannabinol

Acknowledgements The authors thank Erin Ellington (DNP, APRN, PMHNP-BC, Clinical Associate Professor, University of Missouri Kansas City, School of Nursing and Health Studies), who helped us improve the language of this article, and K. Shashok (AuthorAID in the Eastern Mediterranean), who provided additional editing of the revised manuscript.

Previous submissions This article has not be presented or submitted previously.

Authors’ contributions SN 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 approved the final version of this review article.

Funding None.

Availability of data and materials Available to others on request.

Ethics approval and consent to participate Not needed for this review.

Competing interests The authors declare that they have no competing interests.

Author details

Dow University of Health Science, Karachi, Pakistan. 2Psychiatry and Behavioral Sciences, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS KS 66160, USA. 3PICACS Clinic, Bothell, WA, USA. 4King Edward Medical University, Lahore, Pakistan. 5Child and Adolescent Psychiatrist, KVC Hospitals, Kansas, USA.

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