cbd dosing pdf

December 15, 2021 By admin Off

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.

Considering data from in vitro and in vivo studies, cannabidiol (CBD) seems to be a promising candidate for the treatment of both somatic and psychiatric disorders. The aim of this review was to collect dose(s), dosage schemes, efficacy and safety reports of CBD use in adults from clinical studies. A systematic search was performed in PubMed, Embase and Cochrane library for articles published in English between January 1, 2000 and October 25, 2019. The search terms used were related to cannabis and CBD in adults. We identified 25 studies (927 patients; 538 men and 389 women), of which 22 studies were controlled clinical trials (833 patients) and three were observational designs (94 patients) from five countries. Formulations, dose and dosage schemes varied significantly between studies. Varying effects were identified from the randomized controlled trials (RCTs), more apparent effects from non-RCTs and minor safety issues in general. From the controlled trials, we identified anxiolytic effects with acute CBD administration, and therapeutic effects for social anxiety disorder, psychotic disorder and substance use disorders. In general, studies were heterogeneous and showed substantial risks of bias. Although promising results have been identified, considerable variation in dosage schemes and route of administration were employed across studies. There was evidence to support single dose positive effect on social anxiety disorder, short medium-term effects on symptomatic improvement in schizophrenia and lack of effect in the short medium-term on cognitive functioning in psychotic disorders. Overall, the administration was well tolerated with mild side effects.

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.

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].

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].

Non-controlled intervention studies.

One randomized cross-over trial measured reactivity to negative stimulus through behavioral tasks and reported no effect at different incremental single doses of CBD (300, 600 and 900 mg). This measure was based on the hypotheses that drug anxiolytic effect should be manifested through changes in responses to negative stimuli, which also occur with single doses for common anxiolytics [25]. A cluster randomized cross-over trial assessed the effect of small doses (16 mg) administered through inhalation on fear extinction and consolidation and found that it was effective when compared to placebo [26]. Das et al (2013) found that acute administration of 32 mg of CBD, before training, enhances extinction of conditioned fear responses [27].

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.

Most studies reported outcomes differently and even in cases where the same outcome was reported it was measured differently. Outcome level assessment was performed only for anxiety in social anxiety disorder (SAD) and psychotic symptoms and cognitive function in schizophrenia patients following recommendations applying GRADE approach in narrative synthesis [9]. GRADE rating is presented in Table 3 . Two studies assessed anxiety in treatment-naive SAD populations, and three assessed cognitive function and positive and negative symptoms in schizophrenia patients.

AEs were reported in 10 studies. In most studies reporting on AEs [20, 28-30, 35-38, 40, 41], CBD was administered chronically, with follow-up ranging from 6 to 48 weeks, except for two studies where AEs were reported after a single dose of CBD (600 and 750 mg, respectively) [20-41]. The total number of reported patients, withdrawing from the study due to experience of side effects, was 16 in the CBD group. One study reported that side effects did not differ between the CBD and placebo groups after 8 weeks of follow-up [36], and another study reported a decrease of AEs 12 weeks after CBD initiation [38]. In another study side effects were monitored by answering question to a questionnaire [37]. The only study comprising CBD effects with an active group receiving an antipsychotic drug, amisulpride, in patients with schizophrenia reported that the CBD group had fewer extrapyramidal symptoms, less weight gain and prolactin release [29]. Results for the remaining studies, by indication and follow-up, for the number of participants experiencing any AEs compared to placebo AEs, classified by primary system organ class are reported in Table 4 .

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.

PubMed, Embase and Cochrane database were searched with all combinations of CBD and dosage in human studies. Reference lists of included studies were evaluated, and if needed, authors were contacted for further information.

The data supporting the findings of this study are available from the corresponding author upon request.

One author (CL) systematically searched PubMed, EMBASE and the Cochrane Library for published studies in English. The search was last updated on November 5, 2019. We included human studies of reporting more than 10 adult patients. We restricted our search to studies published after the year of 2000 with no demographic limitation. We included studies with single treatment of CBD, e.g. studies with other cannabinoid add-on therapy or adjuvant regimes were excluded. Studies must report dosage and dosage schemes to be included. There was no limitation regarding study design. Studies on pediatric populations were excluded. Only studies published in English, from 2000 to the date last databases were accessed. Full-text articles were interdependently assessed by two reviewers and eventual disagreement was resolved through consensus.

Four randomized parallel-group trials (196 participants) assessed the role of CBD on cognitive impairment and psychotic symptoms in patients with psychotic disorders (schizophrenia) [28-31]. One study was judged as being at high risk of bias and three at uncertain risk of bias. Studies included patients with a confirmed diagnosis of schizophrenia. CBD was administered orally, in the form of oral gelatin capsules with doses ranging from 600 to 1,000 mg/day and the effects were compared to a placebo and active control. Boggs et al (2018) assessed the effects of CBD (600 mg/day for 6 weeks) as an adjunctive treatment in chronic schizophrenia patients, for a period of 6 weeks. No significant difference was observed between placebo and CBD group on cognitive function and psychotic symptoms [28]. Leweke et al (2012) included a small group of acute schizophrenia patients who were administered 200 up to 800 mg/day for 4 weeks or amisulpride, a potent antipsychotic. CBD was as effective as amisulpride in improving psychotic symptoms and associated with marked tolerability and safety, when compared with amisulpride [29]. McGurie et al (2019) administered 1,000 mg/day for 6 weeks to a group of schizophrenia patients as an adjunct to current antipsychotic treatment and found a significant improvement on positive psychotic symptoms and clinicians’ impressions of illness improvement. Despite improvement on cognitive function and overall level of functioning, no significant difference was found compared to placebo [30]. Hallak et al (2010) included a small group of heterogeneous schizophrenia patients and administered a single dose of CBD (300 or 600 mg). They found no effect of CBD on selective attention, measured by Stroop color and word test [31].

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].

Abstract.

a Active-controlled trial, amisulpride. b Concomitant treatment. c CBD-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.

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].

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. a Symbols are used to describe certainty in evidence profiles. High certainty: ⨁⨁⨁⨁; Moderate certainty: ⨁⨁⨁◯; Low certainty: ⨁⨁◯◯; Very low certainty: ⨁◯◯◯. RCT: randomized controlled trial.

Anxiety was assessed in 11 studies (358 participants) [17-27]. Anxiety was the main outcome in eight studies, while possible anxiolytic effects were evaluated in the remaining three studies, through indirect measures such as emotional processing, reactivity to negative stimuli, etc. Among the studies providing data on anxiety, there were only two restricted analyses to patients with anxiety disorders and another to non-clinic paranoia patients. Nine studies were randomized clinical trials: one of the studies was judged at low risk of bias, four at uncertain risk and four at high risk. Single doses of pure CBD 150 – 900 mg in the form of gelatin capsules were administered in the majority of the cases. Two individually randomized parallel-group trials evaluated the effect of CBD on subjective anxiety on patients with SAD [17] or healthy subjects [18, 19] during simulated public speaking. These studies reported that acute oral administration of 600 mg (SAD subjects) and 300 mg (healthy subjects) of CBD reduced anxiety assessed by the visual analogue mood scale compared to placebo. Linares et al (2018) and Zuardi et al (2017) also tested other doses and observed no effect on anxiety levels after acute administration of 150, 600 and 900 mg of CBD on anxiety levels. No effect was found for the physiological measures such as heart rate and systolic/diastolic blood pressure [17-19]. Another small, individually randomized parallel-group trial, reported that acute administration of oral CBD (600 mg) had a negative effect on anxiety levels, measured with the Beck’s anxiety inventory, compared to placebo [20]. Single oral doses of 400 and 600 mg decreased anxiety and increased mental sedation measured with visual analogue mood scale in two individually randomized cross-over trials [21, 22]. Two small non-RCTs administered 600 mg of oral CBD to health volunteers. One found no difference between placebo and CBD group on anxiety levels [23], while the other found a reduction on anxiety measured with visual analogue mood scale [24].

In a randomized cross-over design trial, Haney et al (2016) tested a range (200, 400 and 800 mg) of oral single doses of pure CBD, on cannabis smokers to assess the reinforcing subjective and psychological effects of smoked cannabis. The authors found no evidence with this treatment and dose scheme, and CBD can reduce the reinforcing or positive effects of smoked cannabis in current smokers [32]. Optional use of inhaled pure CBD (400 µg/dose) over 1 week produced positive effects with regard to nicotine addiction, as measured by a reduction on the number of cigarette smoked in a group of healthy smokers willing to quit the habit. However, CBD did not show effect on carving symptoms [33]. After overnight tobacco abstinence single doses of 800 mg of CBD reduced the salience and pleasantness of cigarette cues which indicate that CBD may have a potential effect on motivational aspects of addiction [34]. Two studies were judged at uncertain risk of bias and one at high risk.

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.

To rate the overall quality of evidence for risk of bias, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used for each outcome of interest across all domains: methodological limitations of the studies, indirectness, imprecision, inconsistency and publication bias [16].

Discussion.

In one trial, 200 mg/day was administered for 13 weeks as an adjunct to current treatment to patients with type 2 diabetes. Compared to placebo, CBD did not have a significant effect on the level of high-density lipoproteins, the primary endpoint for this study [35]. The effect of oral administration of CBD (20 mg/day for 8 weeks) on disease activity assessed by the Crohn’s disease activity index was evaluated in a small group of patients with long-standing Crohn’s disease taking concomitant medications. CBD had no effect on disease activity at the end of treatment and at 2 weeks follow-up [36]. Irvin et al (2018) reported no effects of CBD-rich extracts (100 mg/day up to 250/day for 8 weeks) added to current treatment and administrated in the form of oral capsules to patients diagnosed with ulcerative colitis [37].

a Cortex Technologies, Hadsund, Denmark. b Delfin Technologies, Kuopio, Finland. c Concomitant treatment for the condition with anti-oxidant and pain killer. d Concomitant treatment with anti-seizure drugs. N/A: non-available; HPV: human papillomavirus; ADR: adverse drug reaction.

We extracted the following data: condition and symptoms, year of publication, country, study population, number of patients, age, gender, weight, outcome measures, effect of treatment, side effects, dosage, administration form (pills, smoking, oil, etc.), length of treatment, doses, product/brand, isolated CBD or full spectrum and funding/sponsors.

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

A label single arm trial [38] assessed long-term use of isolated CBD (5 mg/kg/day incremental doses in some patients reaching 2,000 mg/day) as an adjunct to anti-epileptic drugs, in patients refractory to conventional anti-seizure drugs and reported a decrease in seizure frequency (144.4 to 52.2, P = 0.01) and severity measured with the Chalfont seizure severity scale (from 80.7 at baseline to 39.2, P < 0.0001) at week 12, with values being stable thereafter (total follow-up 48 weeks). The other two studies [39, 40] included reported on the chronic administration effect of CBD in the form of a topical cream for skin disorders and sublingual oil drops (25 mg/day up to 150 mg/day for 12 weeks) for adverse drugs reaction (ADR) following human papilloma virus (HPV) vaccine, with a 3-month follow-up period each. The topical application produced positive results for serous skin inflammatory conditions such a psoriasis, acne and related scars, with no side effects being reported [39]. The sublingual administration of CBD also improved the quality of life in girls presenting with ADR following HPV vaccine when added to standard treatment. The evidence however arises from two case series and this should be taken into consideration when considering the results from this study [40].

Three RCTs, all individually randomized parallel group, reported on different medical conditions (one study for each category) [28-37]. Doses ranged from 20 to 250 mg/day with treatment duration from 8 to 13 weeks. Isolated compound or plant exacts rich in CBD were administered in the form of hard oral capsules or oil. One study was judged at uncertain risk of bias and two at high risk.

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].

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 (CB 1 ) and type 2 (CB 2 ) [8]. CB 1 receptors are mainly found in the terminals of central and peripheral neurons and CB 2 receptors mainly in immune cells [9]. Several in vitro studies have shown that CBD, at low concentrations, has weak CB 1 and CB 2 antagonistic effect [10]. It has also been reported that it behaves as a negative allosteric modulator of CB 1 , 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 CB 1 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 CB 2 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].

The initial search yielded 1038 records, from which 896 abstracts were reviewed, and 35 articles were included in the final analysis, comprising a total number of 1223 participants. A flow chart of article retrieval and selection is presented in Figure  1 . Fifteen studies were randomised controlled trials (RCTs), 8 were clinical trials but not both randomised and controlled in design (for example open‐label trials), and 12 articles were case reports/series. A description of each study is presented in tables  1 , ​ ,2, 2 , ​ ,3 3 according to study design. Results of the risk of bias assessment of the RCTs are presented in Figure  2 . A component of blinding was included in 74% of the RCTs . No study was reported with a high risk of selection bias, detection bias, or reporting bias. Overall, most information was from studies at low risk of bias. No study reported plasma concentrations of CBD. All studies reported oral administration of CBD, either as an oral solution ( n  = 11), capsules ( n  = 13), spray/sublingual ( n  = 4), or orally but unspecified ( n  = 6).

Different effective plasma concentrations of CBD may be required for achieving different endpoints across clinical populations, which is a recognised trait in a number of other drugs and diseases. For example, aspirin (acetylsalicylic acid) is used at low doses for antiplatelet therapy, and at higher doses as an analgesic agent.44, 45 With CBD, lower doses may be effective in anxiety relief, while higher doses may be required for effective reduction in epileptic seizures. In studies where there are good rationales for CBD use (e.g. Crohn’s disease and chronic pain46, 47), neutral results may be secondary to subtherapeutic dosing, and dose‐escalation trials with embedded pharmacokinetic studies are the next logical step.15, 22 Studies in this review using higher doses concluded that CBD was generally well‐tolerated with the most frequent side effects including drowsiness, nausea, somnolence, fatigue and vomiting.

To our knowledge, this is the first study to compile and compare all publications in which CBD was administered to clinical populations. The aim of this systematic review was to better understand the range of doses of CBD used in clinical studies. In total, 13 medical contexts were included in this review amongst 35 studies including clinical trials and case reports. A positive effect of CBD was reported in 66% of studies, covering disorders including schizophrenia, SAD, epilepsy, cannabis dependency and graft‐ vs ‐host disease, with doses ranging between <1 and 50 mg/kg/d (i.e. <62–3100 mg/d for an adult). Although we acknowledge that these results mix widely heterogeneous studies, it appears well founded to highlight the differences in average dosing for positive effect studies against those without positive effects, which is confirmed when analysing studies per medical context within each study design format. This suggests that CBD potentially displays a wide therapeutic range, and variable minimum doses are required for effect depending on primary outcomes assessed and the population group. However, it is vital to note that no conclusions can be drawn on the efficacy of CBD as larger phase III and conclusive efficacy trials have not been conducted, with exception of epilepsy. A number of phase III clinical trials are registered on clinicaltrials.gov, which should provide more evidence in the coming years in the contexts of pain, anxiety, Crohn’s disease, bipolar disorder, Fragile X syndrome, epilepsy and more.

2.1. Search strategy.

Among the clinical trial records retrieved from clinicaltrials.gov, only 60% of completed trials had results uploaded and available. This may represent a significant publication bias and is suggestive of disregard for the priority of publication of negative results, which is a well‐recognised problem.48 Unfortunately, this may potentially skew the findings presented in this review and so should be interpreted with caution and is acknowledged as a limitation. We also acknowledge that despite all routes of administration being oral, there may be further bias introduced between studies as one dose cannot be directly compared to another due to lack of standardisation of formulations and pharmacokinetic activity, including differences in bioavailability between an oral spray and an oral capsule.

The systematic review was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines. A systematic search of PubMed, EMBASE (including MEDLINE) and clinicaltrials.gov was conducted to retrieve all articles reporting CBD administration in clinical populations using ‘CBD or Cannabidiol’ as search terms. Searches were restricted to ‘humans’ and ‘clinical trials and case reports’ in PubMed and EMBASE, with no restrictions on clinicaltrials.gov. The searches were carried out by 8 August 2018 by 2 independent researchers.

Epilepsy was the most frequently studied medical condition, with all 11 studies describing beneficial effects of CBD in reducing the severity or frequency of seizures.12, 13, 16, 24, 26, 27, 28, 33, 34, 35, 36 Within the 4 conducted RCTs ( n  = 531), an average dosing of 15 mg/kg/d was used where CBD was administered successfully as an add‐on therapy to usual anti‐epileptic drugs.12, 13, 16, 24 Significant improvements were observed compared to placebo as an add‐on therapy. Within the other 3 clinical trials of prospective open‐label design ( n  = 203), CBD was administered at an average dosing of 42 mg/kg/d and significant improvements in quality of life and seizure frequency compared to baseline were observed.26, 27, 28 3 case series and 1 case report (total n  = 16) reported beneficial effects of CBD on seizure frequency, duration and severity with an average administered dose of 21 mg/kg/d.33, 34, 35, 36.

This review indicates that studies that used higher doses tended to have better therapeutic outcomes compared to lower doses overall.

A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. Twenty‐three studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 and 50 mg/kg/d. Plasma concentrations were not provided in any publication. CBD was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of CBD on reducing seizure frequency or severity (average 15 mg/kg/d within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n  = 6–62) assessing diabetes, Crohn’s disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/kg/d) were used in these studies.

Summary of included studies: case studies.

This study identifies a strong existing need for dose‐ranging clinical studies to be conducted in which plasma concentrations can provide a better indication of the therapeutic range of cannabidiol.

COMPETING INTERESTS.

Lastly, it was found that doses of 5 mg/kg/d prevented occurrence of graft‐ vs ‐host disease in a phase II clinical trial ( n  = 48) and 5–10 mg/kg/d doses have been shown in a case report to remove withdrawal symptoms from a patient with cannabis dependency.29, 38.

Results are mixed within Parkinson’s disease studies. Within an RCT in 21 patients, 1.25 or 5 mg/kg/d CBD had no effect on motor and general symptoms. However, the 5 mg/kg/d dose improved well‐being and quality of life scores.18 The remaining studies are case studies in which CBD decreased psychotic symptoms and Parkinson’s disease ratings ( n  = 6; 7 mg/kg/d),31 improved rapid eye movement sleep behaviour disorder ( n  = 4; 1 mg/kg/d),37 decreased dyskinesia with 2 to 3 mg/kg/d doses ( n  = 1), but exaggerated Parkinson’s disease symptoms with 5 and 7 mg/kg/d doses.42.

A positive effect of CBD was determined by the presence of a significant improvement in primary end points(s) or outcomes reported compared to placebo or baseline. A lack of positive effect was determined if no significant improvements were reported. Mixed findings were reported for example in case reports wherein some patients improved, others did not, or where a primary outcome was not specified (exploratory study) and in which some endpoints improved while others worsened (1 study) or remained unchanged.

Publications involving administration of CBD alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov.

Within studies that compared CBD against a placebo or control ( n  = 17 publications), only 1 compared CBD against an active control (and a greater clinical improvement and side effect profile was observed with CBD against amisulpride), 8 compared CBD against a placebo (monotherapy), and 8 studies compared CBD as an add‐on therapy (adjunctive to antipsychotic medication, antiepileptic medication, anti‐Parkinson medication or pain medication) against placebo. Analysis of these data revealed that a greater proportion of studies reported a beneficial effect of CBD in the add‐on therapy group compared to the monotherapy group ( n  = 6 and n  = 2 respectively). However, higher doses were used overall within the add‐on therapy group compared to the monotherapy group (average 11 and 6 mg/kg/d, respectively) and, due to such a small data set and heterogeneity of studies, we did not perform any further analysis.

4. DISCUSSION.

Within the RCTs, CBD did not significantly change the primary outcomes in diabetes ( n  = 62), Crohn’s disease ( n  = 19), ocular hypertension ( n  = 6), chronic pain (mostly neuropathic; n  = 24), or fatty liver disease ( n  = 25).15, 17, 21, 22, 25 However, an average dose of 2.4 mg/kg/d (range 0.3–13.3 mg/kg/d) was used in these studies, which is very low in the clinical and clinical trial setting compared to other studies. Low doses (10 mg/kg) did, however, produce positive responses in generalised social anxiety disorder (SAD) in a double‐blind RCT in 24 patients.20 Likewise, in another double‐blind placebo‐controlled study, a dose of 6.7 mg/kg reduced subjective anxiety in 10 adults with generalised SAD.5 Additionally, in a case report in a child, 0.6 mg/kg/d increased sleep quality and duration, and decreased anxiety secondary to PTSD.10.

Risk of bias summary of the randomised controlled trials included in the systematic review. Green indicates low‐risk bias, red indicates high‐risk bias, and yellow indicates intermediate or unclear risk.

Of the 15 RCTs, the range of doses investigated varied from <1 mg/kg up to 20 mg/kg per day (average 9 mg/kg/d).11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25 Seven RCTs reported CBD efficacy (average dose 14 mg/kg/d),11, 12, 13, 16, 19, 20, 24 7 studies describe neutral effects of CBD (average dose 5 mg/kg/d)14, 15, 17, 21, 22, 23, 25 and 1 study showed both positive and negative outcomes.18 In the remaining 8 clinical trials of various study design, 7 studies reported CBD positively (average dosing 23 mg/kg/d)5, 26, 27, 28, 29, 31, 32 and 1 study was neutral (8 mg/kg/d).30 Within the 12 case studies and case series, 9 described positive effects of CBD (average dosing 16 mg/kg/d),10, 33, 34, 35, 36, 37, 38, 40, 43 2 were neutral (average dosing 21 mg/kg/d)39, 41 and 1 study described mixed results (3 mg/kg/d).42.

Although larger confirmatory and efficacy clinical trials examining dosing in more detail for each medical context is required, this review summarises that CBD appears to offer a wide‐range of activity between 1 and 50 mg/kg/d, and there was a tendency of studies with positive outcomes to have used higher doses of CBD. We recommend pharmacokinetic dosing schedules in subsequent trials to consider this range along with safety data and individual patient requirements. Finally, we implore all completed trial results to be made readily available so the research community can progress and learn from equally important positive and negative outcomes for the ultimate benefit of patients.

CBD is increasingly popular, both as a food and health supplement and as a licensed medicine. Within this review, 51% of studies have been published in the last 5 years (since 2013); however, the included articles span over decades, with prominent publications first appearing in the 1980s and early 1990s.24, 40 Despite its long history of sole administration to patients, there is surprisingly little published about the pharmacokinetic properties of CBD, particularly its bioavailability, making it difficult to estimate true effective doses.8 Historically, there is a striking lack of dose‐ranging studies and, looking forward, there are no registered trials on clinicaltrials.gov including specific dose‐ranging investigations in their study design. Ideally, this review would have compared plasma concentrations of CBD in order to more accurately estimate therapeutic concentrations, but, due to the lack of reporting, this was not possible.

Due to its favourable toxicity and side effect profile, cannabidiol is under increasing investigation in the commercial and medical industry to treat many clinical indications.