J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 12, Number 3, March 2020, pages 129-141

Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials

Figure 1. PRISMA flow diagram of literature search and selection process. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

**Table 1.** Overview of Included Studies and Principal Findings for Controlled Clinical Trials
Author, year of publication	Population (no. of participants)	Study design	CBD dose and scheme	Formulation/route	Primary outcome	Measures	Effect
^aActive-controlled trial, amisulpride. ^bConcomitant treatment. ^cCBD-rich botanical extracts capsules contained other compound (up to 4.7% THC). IR: individually randomized; NR: non-randomized; CR: cluster randomized; CBD: cannabidiol; HDL: high-density lipoprotein.
Anxiety
Bergamaschi et al (2011) [17]	Social anxiety disorder patients (24)	IR parallel group trial	600 mg; single dose	Oral capsules	Anxiety	Visual analogue mood scale (sub-scales; anxiety, cognitive impairment, discomfort and alert)	CBD significantly reduced anxiety, cognitive impairment, discomfort and alert during simulation public speaking test
Crippa et al (2011) [22]	Social anxiety disorder patients (10)	IR cross-over trial	400 mg; single dose	Oral capsules	Anxiety	Visual analogue mood scale	Acute administration reduced subjective anxiety
Arndt et al (2017) [25]	Healthy volunteers (38)	IR cross-over trial	300, 600 and 900 mg; single dose	Oral solution	Reactivity to negative stimuli	Behavioral tasks	Single doses of CBD had little effect on reactions to negative emotional stimuli
Crippa et al (2004) [21]	Healthy volunteers (10)	IR cross-over trial	400 mg; single dose	Oral capsules	Anxiety	Visual analogue mood scale (sub-scales; anxiety, physical sedation, mental sedation and other feelings and attitudes)	CBD significantly decreased subjective anxiety and increased mental sedation
Zuardi et al (2017) [19]	Healthy volunteers (60)	IR parallel group trial	100, 300 and 900 mg; single dose	Oral capsules	Anxiety	Visual analogue mood scale (anxiety and sedation factors)	CBD 300 mg reduced subjective anxiety measures and presented lower sedation level when compared with clonazepam. This was not observed with CBD 100 and 900 mg.
Martin-Santos et al (2012) [23]	Healthy volunteers (16)	NR controlled trial	600 mg; single dose	Oral	Anxiety	Spielberger State Anxiety Inventory, visual analogue mood scale	There was no difference between CBD and placebo on anxiety levels.
Bhattacharyya et al (2010) [24]	Healthy volunteers (15)	NR controlled trial	600 mg; single dose	Oral capsules	Anxiety	Visual analogue mood scale- tranquilization and calming sub-scale.	CBD single dose reduced anxiety levels.
Linares et al (2019) [18]	Healthy volunteers (57)	IR parallel group trial	150, 300 and 600 mg; single dose	Oral capsules	Anxiety	Visual analogue mood scale	300 mg of CBD significantly reduced anxiety during simulation public speaking test
Das et al (2013) [27]	Healthy volunteers (48)	IR parallel group trial	32 mg; single dose	Inhalation/vaporized	Extinction and consolidation	Skin conductance and shock expectancy measures	CBD enhanced consolidation of extinction learning
Hindocha et al (2015) [26]	High and low cannabis use and high and low schizotipy (48)	CR cross-over trial	16 mg; single dose	Inhalation/vaporized	Emotional processing	Computer-based emotional processing task	CBD improved recognition of emotional facial affect.
Hundal et al (2018) [20]	Non-clinical high paranoid group (32)	IR parallel group trial	600 mg; single dose	Oral capsules	Anxiety	Beck’s anxiety inventory	CBD apparently seemed to increase anxiety levels.
Psychotic disorders
Hallak et al (2010) [31]	Schizophrenia patients (28)	IR parallel group trial	300 or 600 mg; single dose	Oral capsules	Cognitive functioning	Stroop color word test	300 and 600 mg of CBD do not lead to cognitive improvement
Boggs et al (2018) [28]	Chronic schizophrenia patients (42)	IR parallel group trial	600 mg/day; 6 weeks	Oral capsules	Psychotic symptoms, cognitive functioning	Positive and negative syndrome scale T score of MATRICS consensus cognitive battery	Psychotic symptoms improved in both groups without significant difference, cognitive functioning improved only in placebo group.
Leweke et al (2012) [29]	Acutely psychotic patients (32)	IR parallel group trial^a	200 mg/day up to 800 mg/day; 4 weeks	Oral capsules	Psychotic symptoms	Positive and negative syndrome scale; brief psychiatric rating scale	CBD is as effective as amisulpride in improving psychotic symptoms
McGuire et al (2018) [30]	Schizophrenia patients (88)	IR parallel group trial	1,000 mg/day; 6 weeks^b	Oral solution	Psychotic symptoms	Positive and negative syndrome scale, clinical global impressions scale	Treatment with CBD improved positive psychotic symptoms and clinicians’ impressions of illness improvement.
					Cognitive functioning, level of functioning	Brief assessment of cognition in schizophrenia; global assessment of functioning scale	Improvement in cognitive performance and in the level of overall functioning with CBD although does not reach statistical significance.
Hundal et al (2018) [20]	Non-clinical high paranoid group (32)	IR parallel group trial	600 mg; single dose	Oral capsules	Persecutory ideation	State social paranoia scale, community assessment of psychic experiences scale	CBD had no effect on precursory thinking and psychotic-like experiences
Cannabis use disorder
Haney et al (2016) [32]	Healthy cannabis smokers (32)	IR cross-over trial	200, 400 and 800 mg; single dose	Oral capsules	Cannabis subjective effects	Subjective mood and drug effects measured with visual analogue scale	CBD did not alter the subjective effects of smoked cannabis
Nicotine addiction
Morgan et al (2013) [33]	Tobacco smokers (24)	IR parallel group trial	400 µg; 1 week	Inhalation/vaporized	Reduction in the number of cigarettes smoked	Number of cigarettes smoked	CBD reduced the number of cigarettes smoked during treatment and at follow-up
Hindocha et al (2018) [34]	Tobacco smokers (30)	IR parallel group trial	800 mg; single dose	Oral capsules	Nicotine withdrawal	Visual probe task and pleasantness rating task	CBD reduced the salience and pleasantness of cigarette cues, compared with placebo but did not influence tobacco craving or withdrawal
Dyslipidemia
Jadoon et al (2016) [35]	Patients with type 2 diabetes and dyslipidemia (62)	IR parallel group trial	200 mg/day; 13 weeks	Oral capsules	HDL cholesterol concentrations	Enzymatic calorimetric assays	CBD did not produce any effect on HDL levels compared to placebo
Crohn’s disease
Naftali et al (2017) [36]	Patients with diagnosis of Crohn’s disease (19)	IR parallel group trial	20 mg/day; 8 weeks^b	Sublingual oil	Disease activity	Crohn’s disease activity index	A reduction in disease activity at the end of the study but no significant difference with placebo.
Ulcerative colitis
Irving et al (2018) [37]	Patients with mild to moderate ulcerative colitis (60)	IR parallel group trial	50 mg up to 250 mg/day; 10 weeks^{a, b, c}	Oral capsules	Remission at the end of treatment	Mayo score of ≤ 2	The primary endpoint was negative but CBD may be beneficial for symptomatic treatment of ulcerative colitis

Table 1. Overview of Included Studies and Principal Findings for Controlled Clinical Trials

Author, year of publication

Population (no. of participants)

Study design

CBD dose and scheme

Formulation/route

Primary outcome

Measures

Effect

^aActive-controlled trial, amisulpride. ^bConcomitant treatment. ^cCBD-rich botanical extracts capsules contained other compound (up to 4.7% THC). IR: individually randomized; NR: non-randomized; CR: cluster randomized; CBD: cannabidiol; HDL: high-density lipoprotein.

Anxiety

Bergamaschi et al (2011) [17]

Social anxiety disorder patients (24)

IR parallel group trial

600 mg; single dose

Oral capsules

Anxiety

Visual analogue mood scale (sub-scales; anxiety, cognitive impairment, discomfort and alert)

CBD significantly reduced anxiety, cognitive impairment, discomfort and alert during simulation public speaking test

Crippa et al (2011) [22]

Social anxiety disorder patients (10)

IR cross-over trial

400 mg; single dose

Oral capsules

Anxiety

Visual analogue mood scale

Acute administration reduced subjective anxiety

Arndt et al (2017) [25]

Healthy volunteers (38)

IR cross-over trial

300, 600 and 900 mg; single dose

Oral solution

Reactivity to negative stimuli

Behavioral tasks

Single doses of CBD had little effect on reactions to negative emotional stimuli

Crippa et al (2004) [21]

Healthy volunteers (10)

IR cross-over trial

400 mg; single dose

Oral capsules

Anxiety

Visual analogue mood scale (sub-scales; anxiety, physical sedation, mental sedation and other feelings and attitudes)

CBD significantly decreased subjective anxiety and increased mental sedation

Zuardi et al (2017) [19]

Healthy volunteers (60)

IR parallel group trial

100, 300 and 900 mg; single dose

Oral capsules

Anxiety

Visual analogue mood scale (anxiety and sedation factors)

CBD 300 mg reduced subjective anxiety measures and presented lower sedation level when compared with clonazepam. This was not observed with CBD 100 and 900 mg.

Martin-Santos et al (2012) [23]

Healthy volunteers (16)

NR controlled trial

600 mg; single dose

Oral

Anxiety

Spielberger State Anxiety Inventory, visual analogue mood scale

There was no difference between CBD and placebo on anxiety levels.

Bhattacharyya et al (2010) [24]

Healthy volunteers (15)

NR controlled trial

600 mg; single dose

Oral capsules

Anxiety

Visual analogue mood scale- tranquilization and calming sub-scale.

CBD single dose reduced anxiety levels.

Linares et al (2019) [18]

Healthy volunteers (57)

IR parallel group trial

150, 300 and 600 mg; single dose

Oral capsules

Anxiety

Visual analogue mood scale

300 mg of CBD significantly reduced anxiety during simulation public speaking test

Das et al (2013) [27]

Healthy volunteers (48)

IR parallel group trial

32 mg; single dose

Inhalation/vaporized

Extinction and consolidation

Skin conductance and shock expectancy measures

CBD enhanced consolidation of extinction learning

Hindocha et al (2015) [26]

High and low cannabis use and high and low schizotipy (48)

CR cross-over trial

16 mg; single dose

Inhalation/vaporized

Emotional processing

Computer-based emotional processing task

CBD improved recognition of emotional facial affect.

Hundal et al (2018) [20]

Non-clinical high paranoid group (32)

IR parallel group trial

600 mg; single dose

Oral capsules

Anxiety

Beck’s anxiety inventory

CBD apparently seemed to increase anxiety levels.

Psychotic disorders

Hallak et al (2010) [31]

Schizophrenia patients (28)

IR parallel group trial

300 or 600 mg; single dose

Oral capsules

Cognitive functioning

Stroop color word test

300 and 600 mg of CBD do not lead to cognitive improvement

Boggs et al (2018) [28]

Chronic schizophrenia patients (42)

IR parallel group trial

600 mg/day; 6 weeks

Oral capsules

Psychotic symptoms, cognitive functioning

Positive and negative syndrome scale T score of MATRICS consensus cognitive battery

Psychotic symptoms improved in both groups without significant difference, cognitive functioning improved only in placebo group.

Leweke et al (2012) [29]

Acutely psychotic patients (32)

IR parallel group trial^a

200 mg/day up to 800 mg/day; 4 weeks

Oral capsules

Psychotic symptoms

Positive and negative syndrome scale; brief psychiatric rating scale

CBD is as effective as amisulpride in improving psychotic symptoms

McGuire et al (2018) [30]

Schizophrenia patients (88)

IR parallel group trial

1,000 mg/day; 6 weeks^b

Oral solution

Psychotic symptoms

Positive and negative syndrome scale, clinical global impressions scale

Treatment with CBD improved positive psychotic symptoms and clinicians’ impressions of illness improvement.

Cognitive functioning, level of functioning

Brief assessment of cognition in schizophrenia; global assessment of functioning scale

Improvement in cognitive performance and in the level of overall functioning with CBD although does not reach statistical significance.

Hundal et al (2018) [20]

Non-clinical high paranoid group (32)

IR parallel group trial

600 mg; single dose

Oral capsules

Persecutory ideation

State social paranoia scale, community assessment of psychic experiences scale

CBD had no effect on precursory thinking and psychotic-like experiences

Cannabis use disorder

Haney et al (2016) [32]

Healthy cannabis smokers (32)

IR cross-over trial

200, 400 and 800 mg; single dose

Oral capsules

Cannabis subjective effects

Subjective mood and drug effects measured with visual analogue scale

CBD did not alter the subjective effects of smoked cannabis

Nicotine addiction

Morgan et al (2013) [33]

Tobacco smokers (24)

IR parallel group trial

400 µg; 1 week

Inhalation/vaporized

Reduction in the number of cigarettes smoked

Number of cigarettes smoked

CBD reduced the number of cigarettes smoked during treatment and at follow-up

Hindocha et al (2018) [34]

Tobacco smokers (30)

IR parallel group trial

800 mg; single dose

Oral capsules

Nicotine withdrawal

Visual probe task and pleasantness rating task

CBD reduced the salience and pleasantness of cigarette cues, compared with placebo but did not influence tobacco craving or withdrawal

Dyslipidemia

Jadoon et al (2016) [35]

Patients with type 2 diabetes and dyslipidemia (62)

IR parallel group trial

200 mg/day; 13 weeks

Oral capsules

HDL cholesterol concentrations

Enzymatic calorimetric assays

CBD did not produce any effect on HDL levels compared to placebo

Crohn’s disease

Naftali et al (2017) [36]

Patients with diagnosis of Crohn’s disease (19)

IR parallel group trial

20 mg/day; 8 weeks^b

Sublingual oil

Disease activity

Crohn’s disease activity index

A reduction in disease activity at the end of the study but no significant difference with placebo.

Ulcerative colitis

Irving et al (2018) [37]

Patients with mild to moderate ulcerative colitis (60)

IR parallel group trial

50 mg up to 250 mg/day; 10 weeks^{a, b, c}

Oral capsules

Remission at the end of treatment

Mayo score of ≤ 2

The primary endpoint was negative but CBD may be beneficial for symptomatic treatment of ulcerative colitis

**Table 2.** Overview of Included Studies and Principal Findings for Non-Controlled Clinical Trials
Author/year of publication	Indication	No. of participants	Dose evaluated (administration scheme)	Administration method	Follow-up	Outcome	Measure	Effect
^aCortex Technologies, Hadsund, Denmark. ^bDelfin Technologies, Kuopio, Finland. ^cConcomitant treatment for the condition with anti-oxidant and pain killer. ^dConcomitant treatment with anti-seizure drugs. N/A: non-available; HPV: human papillomavirus; ADR: adverse drug reaction.
Szaflarski et al (2018) [38]	Epilepsy	60	5 up to 50 mg/kg/day^d	Oral oil	48 weeks	Seizure control	Seizure frequency, Chalfont seizure severity scale	Improved compared to baseline
Palmieri et al (2019) [39]	Skin disorders	20	N/A (two times a day/3 months)	Topical gel	3 months	Hydration	Hydration probe	Improved compared to baseline
						Transepidermal water loss	DermaLab^® USB instrument^a	Improved compared to baseline
						Skin elasticity	ElastiMeter®^b	Improved compared to baseline
						Severity of atopic dermatitis	Scoring atopic dermatitis	Improved compared to baseline
						Severity of acne	Acne disability index	Improved compared to baseline
						Severity of psoriasis	Psoriasis area severity index	Improved compared to baseline
Palmieri et al (2017) [40]	ADR following HPV vaccine	12	25 mg/mL, 150 mg/mL (one time/day × 3 months)^c	Sublingual oil drops	3 months	Quality of life	Medical outcome short-form health survey questionnaire	Improved compared to baseline

Table 2. Overview of Included Studies and Principal Findings for Non-Controlled Clinical Trials

Author/year of publication

Indication

No. of participants

Dose evaluated (administration scheme)

Administration method

Follow-up

Outcome

Measure

Effect

^aCortex Technologies, Hadsund, Denmark. ^bDelfin Technologies, Kuopio, Finland. ^cConcomitant treatment for the condition with anti-oxidant and pain killer. ^dConcomitant treatment with anti-seizure drugs. N/A: non-available; HPV: human papillomavirus; ADR: adverse drug reaction.

Szaflarski et al (2018) [38]

Epilepsy

5 up to 50 mg/kg/day^d

Oral oil

48 weeks

Seizure control

Seizure frequency, Chalfont seizure severity scale

Improved compared to baseline

Palmieri et al (2019) [39]

Skin disorders

N/A (two times a day/3 months)

Topical gel

3 months

Hydration

Hydration probe

Improved compared to baseline

Transepidermal water loss

DermaLab^® USB instrument^a

Improved compared to baseline

Skin elasticity

ElastiMeter®^b

Improved compared to baseline

Severity of atopic dermatitis

Scoring atopic dermatitis

Improved compared to baseline

Severity of acne

Acne disability index

Improved compared to baseline

Severity of psoriasis

Psoriasis area severity index

Improved compared to baseline

Palmieri et al (2017) [40]

ADR following HPV vaccine

25 mg/mL, 150 mg/mL (one time/day × 3 months)^c

Sublingual oil drops

3 months

Quality of life

Medical outcome short-form health survey questionnaire

Improved compared to baseline

**Table 3.** Cannabidiol Compared to Control for Psychotic and Anxiety Disorders
Outcomes	No. of participants (studies) follow-up	Certainty of the evidence (GRADE)^a	Impact
The outcome of interest are: anxiety symptoms, psychotic symptoms and cognitive function. A pooled effect estimate was not available and a narrative synthesis of the evidence was provided. ^aSymbols are used to describe certainty in evidence profiles. High certainty: ⨁⨁⨁⨁; Moderate certainty: ⨁⨁⨁◯; Low certainty: ⨁⨁◯◯; Very low certainty: ⨁◯◯◯. RCT: randomized controlled trial.
Anxiety symptoms assessed with visual analogue mood scale	44 (two RCTs)	⨁⨁◯◯ low	All studies showed a reduction in symptoms compared to placebo.
Psychotic symptoms assessed with positive and negative syndrome scale, brief psychiatric rating scale	171 (three RCTs)	⨁⨁⨁◯ moderate	Two studies showed improvement in psychotic symptoms. Some variability in the intervention (doses) and population (stage of illness) was noted.
Cognitive function assessed with T score of MATRICS consensus cognitive battery, stroop color word test, composite score on the brief assessment of cognition in schizophrenia	148 (three RCTs)	⨁⨁⨁◯ moderate	Two studies showed no improvement in cognitive function. One showed only small improvements.

Table 3. Cannabidiol Compared to Control for Psychotic and Anxiety Disorders

Outcomes

No. of participants (studies) follow-up

Certainty of the evidence (GRADE)^a

Impact

The outcome of interest are: anxiety symptoms, psychotic symptoms and cognitive function. A pooled effect estimate was not available and a narrative synthesis of the evidence was provided. ^aSymbols are used to describe certainty in evidence profiles. High certainty: ⨁⨁⨁⨁; Moderate certainty: ⨁⨁⨁◯; Low certainty: ⨁⨁◯◯; Very low certainty: ⨁◯◯◯. RCT: randomized controlled trial.

Anxiety symptoms assessed with visual analogue mood scale

44 (two RCTs)

⨁⨁◯◯
low

All studies showed a reduction in symptoms compared to placebo.

Psychotic symptoms assessed with positive and negative syndrome scale, brief psychiatric rating scale

171 (three RCTs)

⨁⨁⨁◯
moderate

Two studies showed improvement in psychotic symptoms. Some variability in the intervention (doses) and population (stage of illness) was noted.

Cognitive function assessed with T score of MATRICS consensus cognitive battery, stroop color word test, composite score on the brief assessment of cognition in schizophrenia

148 (three RCTs)

⨁⨁⨁◯
moderate

Two studies showed no improvement in cognitive function. One showed only small improvements.

**Table 4.** Adverse Events (Treatment-Related All Causality) by Primary System Organ Class and Duration of Follow-Up
	Follow-up < 1 day	Follow-up 1 week	Follow-up 10 weeks	Follow-up 13 weeks
Subjects experiencing any TEAE (%)	66.7	62.5	100	83.3	90	48	84.6	92.9
Nervous system disorders	33.3	37.5	66.7	33.3	83	26
Gastrointestinal system disorders	16.7	50.0	66.7	50.0	38	16
Infections and infestations			22.2	0	0	0
Psychiatric disorders			0	0	24	3
General disorders and administration site conditions			22.2	50.0	21	10
Musculoskeletal and connective tissue disorders			0	16.7	14	0
Skin and subcutaneous tissue disorders			2.2	16.7	3	0

Table 4. Adverse Events (Treatment-Related All Causality) by Primary System Organ Class and Duration of Follow-Up

Follow-up < 1 day

Follow-up 1 week

Follow-up 10 weeks

Follow-up 13 weeks

Cannabidiol (%)

Placebo (%)

Cannabidiol (%)

Placebo (%)

Cannabidiol (%)

Placebo (%)

Cannabidiol (%)

Placebo (%)

Subjects experiencing any TEAE (%)

66.7

62.5

100

83.3

84.6

92.9

Nervous system disorders

33.3

37.5

66.7

33.3

Gastrointestinal system disorders

16.7

50.0

66.7

50.0

Infections and infestations

22.2

Psychiatric disorders

General disorders and administration site conditions

22.2

50.0

Musculoskeletal and connective tissue disorders

16.7

Skin and subcutaneous tissue disorders

2.2

16.7