tj’s cbd formula dosage

December 15, 2021 By admin Off

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

AEDs, anti‐epileptic drugs; CBD, cannabidiol; GW, GW Pharmaceuticals; HDL, high density lipoprotein; NA, not available; NIDA, National Institute on Drug Abuse; RCT, randomised controlled trial; SAD, social anxiety disorder; STI, STI Pharmaceuticals; THC, THC Pharm.

Cannabidiol (CBD) is a non‐intoxicating major constituent of the Cannabis sativa plant that has been increasing in interest due to its potentially diverse range of therapeutic properties and its favourable safety and tolerability profile.1 Side effects are generally mild and infrequent, such as sleepiness, diarrhoea or increased temperature. It is also reported that clinically significant drug‐interactions pose a low risk.2 There is no evidence for dependency or abuse potential with CBD use, as concluded by the World Health Organisation Expert Committee on Drug Dependence.1 The purported effects of CBD include analgesic, anti‐inflammatory, antioxidant, anxiolytic, anticonvulsant and cytotoxic effects, which are mediated through signalling mechanisms including the cannabinoid receptor 1 (weak agonist), the cannabinoid receptor 2 (inverse agonist), the serotonin 1a receptor (5‐HT 1A ), G protein‐coupled receptor 55 (GPR55), G protein‐coupled receptor 18 (GPR18) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors, amongst others.3.

What is already known about this subject.

As this review included studies of participants of all ages (from infants to adults), dosing is reported in mg/kg of body weight to allow for comparison. Where not available as mg/kg (24 studies), dose was converted for adults using an average adult body weight of 62 kg.9 In only 1 publication, a case report on a child, an average child weight of 40 kg had to be used to convert reported mg/d dose into mg/kg/d.10.

The included articles were analysed, and the following data extracted: sample size, clinical population/medical context; study design and length; administration route of CBD; source of CBD; dose of CBD; side effects; and primary outcome results. All data entry was checked by an additional independent researcher. Risk of bias of the 15 randomised controlled trials was assessed using the 2011 Cochrane Collaboration’s tool for assessing risk of bias.

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.

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).

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.

Seven studies were conducted in the context of schizophrenia and bipolar disorder. Within the RCTs, 2 conducted with an average dosing of 15 mg/kg/d over 4 or 8 weeks reported positive reductions in psychotic or psychiatric symptoms and a better side effect profile ( n  = 130).11, 19 One of these compared CBD against an active control (amisulpride), and the other as an add‐on therapy to usual medication compared to placebo as an add‐on therapy. However, a third RCT employing CBD as an add‐on therapy did not report any improvements in cognition or symptoms of schizophrenia after a lower average dose of 10 mg/kg/d over 6 weeks ( n  = 36).14 An acute dose of 5 or 10 mg/kg/d did not improve selective attention in a placebo‐controlled trial of 28 schizophrenia patients.30 A number of case studies have also been conducted by Zuardi and colleagues in this medical context. In 2 patients with bipolar disease, 20 mg/kg/d was ineffective in treating manic episodes.39 CBD was similarly unable to improve symptoms in 3 schizophrenia patients, although 1 patient described mild improvement.41 Another case report described improvement in psychiatric ratings following an average dose of 25 mg/kg/d over 4 weeks.40.

2.3. Data acquisition and analysis.

Despite the prevalence of CBD use and current hype, guidance on dose recommendations has not advanced and is not clear, additionally hampered by the striking lack of accessible pharmacokinetic and bioavailability data of CBD in humans.8 No published study to date has reported the absolute oral bioavailability of CBD in humans.8 Limited dose‐determination studies have left a paucity in data surrounding desired plasma concentrations to achieve minimum effective doses. Additionally, the lack of information on the role of different formulations and routes of administration on absorption are also apparent. The aim of this review was to comprehensively collate all published data relating to CBD administration in clinical populations to describe the range of CBD doses assessed across different pathological states.

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.

The titles and abstracts of retrieved studies were examined by 2 independent researchers, and inappropriate articles were rejected. Inclusion criteria were as follows: an original, peer‐reviewed published paper that involved administration of CBD to a clinical population, or reported on clinicaltrials.gov, and included an outcome measurement to assess the efficacy of CBD i.e. improvement in disease. Exclusion criteria were: administration in healthy participants only; CBD administered in combination with other cannabinoids such as with δ‐9‐tetrahydrocannibinol or as whole cannabis extracts; article not in English; no stated concentration of CBD used; or no statistical results reported. The reference lists of included studies were hand‐searched for additional relevant studies.

Flow chart of study retrieval and selection.

What this study adds.

Summary of included studies: randomised controlled trials.

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.

Summary of included studies: clinical 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.

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.

The founders of TJ’s Gardens, along with a few parents looking for alternative medicine for their children, realized that there was a substantial need for affordable pediatric solutions within the cannabis industry. Prices of CBD oil, especially from high quality sources, have recently skyrocketed in some areas within the past few years. In response, TJ’s Gardens unanimously voted to offer their medicinal CBD oil at no cost to children with their medical marijuana cards. Although the program was quite small to begin with, it has now grown to include over 100 families as more parents are seeking affordable alternatives for their children.

TJ’s Gardens is proud to introduce The Forrest Initiative, a center dedicated to serving the needs of under-resourced families in our community. This important program was originally founded in 2014 as the TJ’s Kids and Families Program, but it has since evolved into an organization with a much broader mission. The Forrest Initiative’s mission is to help families source CBD oil at no cost for their children in dire need of this life changing oil. Cannabidiol (aka CBD) oil is a natural, non-psychoactive product derived from cannabis plants. Because there is no psychoactive quality that makes you feel “high,” this product is given to people suffering from seizures, anxiety, insomnia, neuropathic pain, ulcers, and other medical symptoms.

The Initiative originally began with one child, Forrest, hence the namesake. Forrest started on a low dose regime of this non-psychoactive cannabis oil to treat his seizures after his pharmaceutical medication did not help him. Forrest was suffering from extremely negative side effects as a result of the pharmaceutical medication, so his parents decided to seek a different route. Forrest has now been completely seizure free for the first 6 months since his original dose of CBD oil, and he gets to experience a significantly improved quality of life. Therefore, we believe that this special gift needs to be shared with other families in need of this oil. The Forrest Initiative continues to greatly improve the lives of both children and families across Oregon by constantly striving to grow the program to help as many families in our community as we can. Please contact TJ’s Gardens today about how you can contribute to this special program.

TJ’s Gardens provides cannabis to people suffering from Epilepsy.

About the Program.

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.

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.

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.

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 .

Non-controlled intervention studies.

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.

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.

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.

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].

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].

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].

Clinical heterogeneity was assessed by grouping studies by indication and outcome (including disease-specific outcomes and if specified adverse events (AEs)) and scheme of drug administration. Data were too heterogeneous to be pooled, so we used a narrative synthesis.

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].

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.

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].

Other conditions.

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.

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.

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.

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].

Among the randomized trials, three were judged at low risk of bias, eight were judged at high risk of bias and nine at uncertain risk. Major potential sources of bias were frequent in the following domains: randomization process and selection of the reported results. Most studies reported were randomized and double-blinded but few reported methods of randomization or participants and outcome assessor blinding. Selective outcome reporting was also a potential source of bias, since some studies did not report data for all outcomes specified in the methods section or trial register or changed the primary outcome from what was specified in the trial register.

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.

Table 2.

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].

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

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

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.

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].

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].

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.