Abstract

Introduction

Cannabis sativa L. has a long tradition of medical use. However, its clinical use has been limited due to the effects on the central nervous system and the possibility of drug abuse and addiction. The plant exudes a resin containing a mix of cannabinoids with two principal components, Δ9-tetrahydrocannbinol (THC) and cannabidiol (CBD). The structure and configuration of CBD was discovered in the 60s and has gained particular attention due to the lack of psychotropic activity. Because of its excellent tolerability in humans, the lack of psychoactive action and the low abuse potential, it seems an ideal candidate for use in a clinical context [1].

In addition to its good safety profile and the lack of psychoactive effects, CBD presents also a wide range of therapeutic effects [2]. Possibly for these reasons, CBD is currently one of the most studied cannabinoids [3]. Several experimental in vitro and in vivo studies have shown that CBD has a broad range of therapeutic applications, displaying anti-inflammatory and immunomodulatory properties [4], anti-psychotic [5], analgesic [6] and anti-epileptic [7] effects, among others. Compared to Δ9-THC, CBD shows low affinity for cannabinoid receptor type 1 (CB₁) and type 2 (CB₂) [8]. CB₁ receptors are mainly found in the terminals of central and peripheral neurons and CB₂ receptors mainly in immune cells [9]. Several in vitro studies have shown that CBD, at low concentrations, has weak CB₁ and CB₂ antagonistic effect [10]. It has also been reported that it behaves as a negative allosteric modulator of CB₁, meaning that CBD does not activate the receptor directly but alter the potency and efficacy of orthosteric ligands of this receptor: Δ9-THC and 2-arachidonoylglycerol (2-AG) [11]. These preliminary results need further validation, but may explain the ability of CBD to antagonize some of the effects of Δ9-THC reported in in vitro, in vivo and clinical human studies [12]. It has also been suggested that the role of CBD as an allosteric modulator of CB₁ can explain its therapeutic role in the treatment of central and peripheral nervous system disorders [2]. CBD has also shown to have a strong inhibition effect of neutrophil chemotaxis and proliferation. In addition, it may induce stimulation of arachidonic acid release, reducing prostaglandin E2 (PGE2), and nitric oxide (NO) production. Furthermore, CBD reduces the expression of specific interleukins (IL-12 while increasing that of IL-10) by macrophages, and decreases the production and release of pro-inflammatory cytokines, such as IL-1, IL-6 and interferon gamma (IFNγ) from lipopolysaccharide (LPS)-activated microglial cells [13]. The role of CBD as an inverse agonist of CB₂ receptor may explain its known anti-inflammatory effects but this needs further investigation. There is also evidence of an antagonistic effect of CBD at the novel cannabinoid receptor G protein-coupled receptor 55 (GPR55), emerging from in vitro and in vivo studies. GPR55 has a role in bone physiology via regulating osteoclast function, formation and ultimately bone mass. CBD may affect the endocannabinoid system also indirectly, for example CBD can affect the endocannabinoid tone by increasing availability of anandamide; one possible mechanism is by inhibition of fatty acid amide hydrolase (FAAH), the enzyme that hydrolyzes the endocannabinoid anandamide [14].

However, not all physiological effects of CBD are mediated by cannabinoid receptors. Indeed CBD has numerous targets outside the endocannabinoid system and the cannabinoid receptor independent action is the subject of recent pharmacological studies on CBD [2]. Some of these physiological effects such as anti-inflammatory and immunosuppressive effect are mediated by more than one target [8]. The anti-inflammatory immunosuppressive effects are possibly mediated by activation of adenosine receptors, A_1A and A_2A and strychnine-sensitive α1 and α1β glycine receptors and the inhibition of the equilibrative nucleoside transporter [8]. The activity of CBD at one defined target may also elicit different physiological effects. For example, anti-inflammatory action and suppression of neuropathic pain are mediated by the same glycine receptors or anxiolytic, panicolytic and anti-depressant effects via serotonin 5HT_1A receptor sub-type [8]. Pisano et al (2017) showed an in-depth review of the molecular pharmacology of CBD [2]. Despite the great number of studies published on molecular pharmacology of CBD, the exact pharmacological action of CBD remains not fully characterized and ongoing efforts are directed toward fully elucidating these mechanisms [3].

The clinical studies on the effects of CBD date back to the 80s but recently the number of studies and registered trials evaluating the effectiveness of this compound has risen exponentially. Currently, CBD is commercially available in different formulations and used for several health conditions but could be indicated for several diseases or disorders in addition to or in replacement of medical marijuana or other medical therapy. However, it remains unclear in which form and dose CBD should be administered to assess safety and efficacy across indications. This might further be complected by the nature of altered dose depending on indication of intervention. To highlight administration and dosage for known indications (e.g. diseases and disorders), this systematic review reports the current evidence, literature and experiences of how and in which dose CBD could be administered as well as efficacy and safety reports.

Methods

Results

Study selection and characteristics

We identified 362 studies of which 85 were assessed for full-text eligibility (Fig. 1). Finally, 25 studies were included: 22 controlled clinical trials and three non-controlled (single arm) trials [10-34]. Among controlled clinical trials, two were non-RCTs and 20 RCTs (14 individually randomized parallel group trial, five individually randomized cross-over trials and one cluster randomized cross-over trial). Studies were conducted in five countries with the majority of studies being conducted in the UK. All studies were reported in full length journal articles. The administration of CBD varied from single doses to chronic administration, up to 48 weeks. The pure form of CBD was used in the majority of the studies except for two studies using seed CBD oil and CBD-rich botanical extracts. The most common form of drug administration was in the form of oral capsules, and other forms were vaporization and sublingual oil. The most common comparator was placebo only one study used an active-control group. Results for controlled clinical trials and non-controlled studies are presented in Table 1 [17-37] and Table 2 [38-40], providing a summary of the included studies and their principal findings.

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
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 triala	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 weeksb	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 weeksb	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 weeksa, 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

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^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.

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
Szaflarski et al (2018) [38]	Epilepsy	60	5 up to 50 mg/kg/dayd	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 instrumenta	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

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^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.

Discussion

This systematic review assessed the dosage schemes, effects and safety issues associated with the use of CBD. We included 20 RCTs, two non-RCTs and three observational studies for all indications of CBD use. In summary, 20 RCTs evaluated efficacy of CBD-use for schizophrenia, anxiety, Crohn’s disease, ulcerative colitis, dyslipidemia, nicotine addiction and cannabis use disorder. Most of these studies reported positive effect of CBD on anxiety, schizophrenia, tobacco addiction and minor effects or no effect on primary outcome measures for Crohn’s disease, ulcerative colitis, dyslipidemia and cannabis use disorder. All observational studies (skin disorders, ADR following HPV vaccine and epilepsy) reported positive effect of CBD when compared to baseline measures.

Regarding safety issues, most studies reported no AEs with acute administration and mild to moderate adverse effects with chronic administration. In comparison to other drugs, a better side effect profile was presented [29, 30]. The chronic administration of CBD for most of the included studies had a duration of few weeks (4 - 6 weeks). There is a need for longer term safety data and systematic/uniform reporting of AEs to better weight benefit and harms in future reviews. At least, two systematic reviews have been published on safety and side effects of CBD. The comprehensive review by Bergamaschi et al included animal and clinical studies reporting a favorable safety profile of CBD in humans [42]. The other review was an update of the previous focusing more on clinical data. The authors reported that most commonly side effects were tiredness, diarrhea and changes of appetite/weight. In comparison to other treatments used for epilepsy and psychotic disorders, CBD administration presented fewer side effects [43].

Most of the studies included in this review showed an improvement of anxiety levels after single doses of oral CBD with doses ranging from 300 to 600 mg [17-19, 21, 22, 24, 26, 27]. It is important to note that only two studies included a clinical population (SAD) while the majority involved healthy subjects. Both studies tested acute administration of CBD and found a reduction in subjective anxiety. A systematic review on specific anxiety conditions which included data from clinical and pre-clinical studies found strong evidence arising from pre-clinical studies to support the anxiolytic effects of CBD, and similarly that evidence from human studies was limited to acute dosing in mostly healthy subjects [44]. There is a need for better designed studies to evaluate the therapeutic potential of CBD in this clinical population, possibly with chronic dosing in a relevant clinical population.

A systematic review providing evidence from clinical studies, mainly randomized clinical trial and case series, on the efficacy of CBD in the treatment of schizophrenia and/or substance abuse disorders observed large differences in study population, doses and administration [45]. In the present review, two principal outcomes were considered for schizophrenia patients, psychotic symptoms and cognitive functioning. CBD had positive effect on psychotic symptoms especially in acutely psychotic patients [29], while it had small or no effect on chronic schizophrenia patients who had been treated with anti-psychotics. The possibility that larger effects may be observed for patients in the early phases of the disease had been suggested [28, 45]. Regarding cognitive function little or no effects were observed after chronic or acute administration. A recent systematic review including 27 RTCs that investigated the effects of CBD on different psychiatric disorders such as psychosis, moods disorders and anxiety found that because of large heterogeneity across studies CBD doses, formulations and the study populations, it was not possible to make definitive conclusion about clinical effects [44]. The authors suggested that large-scale placebo controlled studies are needed to investigate the effects of CBD as an adjunct treatment for psychiatric disorder [46].

No effect was reported in the studies included in this review for the treatment of Crohn’s disease, ulcerative colitis and type 2 diabetes with doses ranging between 20 and 250 mg/day for a treatment duration of 8 - 13 weeks [38-40]. While positive results were reported on seizure improvement with doses ranging from 350 to 2,000 mg/day and on the quality of life for patients with ADRs following HPV vaccine, with doses ranging from 25 to 150 mg/day, after 12 weeks of treatment [31, 33]. No definitive conclusion can be made on doses required for a positive effect since this may depend on the outcome assessed and study population.

In all studies, expect for one that used plant extracts [37], purified CBD was administered. Data derived from pre-clinical animal models indicate that purified CBD may have a bell shape response [47] which was also confirmed in two studies included in this review [25, 26]. It is likely that the use of a single cannabinoid may be inferior to the extract where other components synergize with CBD to obtain the desired effect, known as the “entourage effect” [48]. Further, the main route of administration for the studies included in this review was oral (either in the form of capsules or sublingual oil). Animal studies suggest that oral bioavailability is low [48]; on the other hand, as highlighted in a recent systematic review on the pharmacokinetics of the CBD in humans [49], there is a lack of data in humans [50].

We used the Cochrane risk of bias tool to assess the included RCTs [8]. Overall, several methodological weaknesses were identified, e.g. selective outcome reporting, inadequate randomization and blinding. Further, sample sizes were very small in most studies significantly decreasing strength of detecting differences between study groups. An important finding of this review is the heterogeneous use of doses, dosage schemes and formulations (inhalation, oral capsules and sublingual oil, topical gel) across all indications of CBD. This has several implications. Besides excluding the option of pooling data for a meta-analysis to evaluate efficacy, the consequence of non-consensus of CBD dose is important when evaluating safety issues. Commercially, several online “dose-calculators” are available for dose recommendations (e.g. https://www.mydosage.com/); the data to support such calculators remain unclear on appropriate doses for efficacy although it seems reasonable to guide patients to safe dosage schemes and avoid adverse effects and gathering more data on how CBD is commonly being applied [51].

Although this review followed the recommendations for rigorous systematic reviews, it bears limitations here amongst a language and date restriction applied as well as a search strategy limited to electronic databases. However unlikely, other studies may not have been identified which can limit the applicability of the findings. Most of the disorders/diseases were only evaluated in single studies providing limited experience and no option to pool data, and some studies failed to present specific inclusion criteria meaning no restriction as to study group. The studies identified that evaluated identical conditions, regrettably employed different endpoints or tools of assessment.

RCTs are needed to confirm the effect of CBD on skin disorders, epilepsy and ADR following HPV vaccine. In addition, large and robust RTCs are needed to confirm the effects of CBD particularly on anxiety and psychosis. Studies should adhere to reporting standards for trials and use similar outcomes, standard measurements/tools to assess outcomes, and comparable treatment regimens to allow comparisons in future review studies. International guidelines should be implemented before the justification of further trials.

Conclusions

Studies included in this review evaluated mainly oral administration of purified CBD with placebo group as a comparator. However, there was larger heterogeneity between studies with regard to the population, schemes and doses of CBD, outcomes and tool of measurement. There is some evidence, even though low quality, that supports anxiolytic effect of acute administration of oral CBD. There is moderate-quality evidence that chronic and acute administration of CBD can improve psychotic symptoms in schizophrenia patients. Further, large RCTs are needed to confirm the effect of CBD for the treatment of Crohn’s disease, ulcerative colitis, dyslipidemia and cannabis use disorders. Insufficient data regarding safety issues were provided, but most studies reported no AEs with acute administration and mild to moderate adverse effects with chronic administration.

Acknowledgments

References