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You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:ids:ijbire. See general information about how to correct material in RePEc. For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sarah Parker email available below. Case: Mexican lodging organisations by Juan E. Sarma Cognitive, affective and conative concepts as an antecedent to parental and child purchase influence strategies-observational evidences by P. Bui Experimental investigation on analysis of performance of vortex tube through implementation of sustainable manufacturing by K. Arun The effects of sponsorship on the promotion of sports events by Mohammed T. Abu Hajar Consumers' actual purchase behaviour towards green product: a study on Bangladesh by Ummul Wara Adrita The extent of the influences of social media in creating 'impulse buying' tendencies by Mohammed T. Hassan Mohd. Economic literature: papers , articles , software , chapters , books. My serials Follow this serial. Corrections All material on this site has been provided by the respective publishers and authors. Help us Corrections Found an error or omission? RePEc uses bibliographic data supplied by the respective publishers.

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DL indicates DerSimonian and Laird. Baseline Characteristics of the Studies Included in the Meta-analysis. Question What are the frequency and risk of adverse events AEs developing in patients with epilepsy who are using cannabidiol CBD? Findings In this systematic review and meta-analysis, the frequency of any grade AEs in patients with epilepsy was more than 2 times higher for those using CBD than for those receiving placebo. Meaning The treatment of patients with epilepsy using CBD was associated with the development of several types of AEs. Importance Epilepsy is one of the most common neurologic disorders globally. Cannabidiol CBD has been approved for the treatment of epilepsy, but its use has been associated with several different adverse events AEs. Study Selection The review included all randomized clinical trials that investigated at least 1 AE from the use of CBD in patients with epilepsy. Data Extraction and Synthesis Basic information about each study was extracted. I 2 statistics were calculated using Q statistics to assess the statistical heterogeneity among the included studies. Results Nine studies were included. Overall incidences of 9. The overall risk ratios RRs for any grade and severe grade AEs were 1. Because most of the included studies had some risk of bias 3 raised some concerns and 3 were at high risk of bias , these findings should be interpreted with some caution. Conclusions and Relevance In this systematic review and meta-analysis of clinical trials, the use of CBD to treat patients with epilepsy was associated with an increased risk of several AEs. Additional studies are needed to determine the safe and effective CBD dosage for treating epilepsy. Epilepsy is one of the most common neurologic disorders globally, with a lifetime point prevalence of 7. Cannabidiol CBD is one of the naturally occurring compounds, known as cannabinoids, that are produced from the cannabis plant. Previous studies have evaluated the efficacy and safety of CBD, or medicinal cannabis, in patients with epilepsy. Moreover, there is a need to update the previously published systematic reviews and to address their limitations. Therefore, we conducted a systematic review and meta-analysis to evaluate the AEs associated with CBD use in patients with epilepsy. For this systematic review and meta-analysis, PubMed, Scopus, and the Web of Science databases were searched for articles published from database inception to August 4, , to identify publications reporting any AEs following treatment with CBD. In addition, the first 10 pages of the Google Scholar search engine were manually searched for grey literature. No filters were applied to any of the search fields, such as date, study type, or language. Backward and forward citation searches of all included studies were also performed, which means we screened all cited references of the included studies and all publications citing them to discover other qualified studies. In addition, studies included in similar previous systematic reviews were screened to identify whether there were any additional eligible articles. The searches were performed by 1 author A. A detailed description of the stages of the search for each database is given in eTable 1 in Supplement 1. The current study was approved by the ethics committee of the Shahid Beheshti University of Medical Sciences. All articles identified through the electronic and manual searches were exported to EndNote, version 20 Clarivate , and any duplicates were removed. Two authors A. ZareDini independently screened the title and abstract of the articles and excluded those that were irrelevant. In the next step, the same 2 authors reviewed the full texts of the remaining articles. Any discrepancies were resolved by discussion or consultation with other authors. All classifications of epilepsy were included, with no age restriction. Two reviewers M. Zahmatyar and B. Any disagreements were settled through discussion between the 2 reviewers or by conferring with a third reviewer A. Negative clinical events that developed in study participants after administration of CBD or placebo were considered to be AEs. The overall risk-of-bias assessment in each study was also determined. Disagreements were resolved by discussion between the 2 reviewers M. We used the robvis package in R software, version 4. Stata, version We determined the frequency of mild, moderate, severe, and all grade AEs in both experimental and control groups using the metaprop command in Stata. We calculated the I 2 statistics using Q statistics to assess the statistical heterogeneity among the included studies. The DerSimonian and Laird method was used for the random-effects models, and the inverse variance method was used for the fixed-effect models. Publication bias was only evaluated if at least 10 studies were included in the analysis. The systematic search identified records. After the removal of duplicate records, the remaining publications were screened, and 61 studies were selected for full-text review Figure 1. Following the evaluation of these studies for eligibility, 52 were excluded for the following reasons: 48 studies were not RCTs, 22 - 69 2 did not report AEs, 70 , 71 and 2 were reanalyses of previously published articles. Bias due to randomization, deviation from the intended intervention, and missing data were low risk in all included trials. However, bias due to outcome measurement and the selection and reporting of results were high risk or there were some concerns in several studies. Overall, 3 trials had a low risk of bias, 78 , 80 , 81 3 had some concerns, 74 , 75 , 82 and 3 had a high risk of bias 76 , 77 , 79 Figure 2 ; eTable 2 in Supplement 1. The included trials were published between and and involved patients with various forms of epilepsy Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis—associated epilepsy. One study 79 used and mg transdermal CBD gels twice a day, whereas other studies 74 - 78 , 80 - 82 used oral solutions twice daily. Most of the studies were multicenter, and the age of participants ranged from 1. The numbers of previous and concomitant antiepileptic drugs were fairly similar between the experimental and control arms eTable 3 in Supplement 1. The concomitant antiepileptic drugs included valproate, clobazam, lamotrigine, levetiracetam, rufinamide, vigabatrin, stiripentol, lacosamide, ethosuximide, topiramate, zonisamide, oxcarbazepine, carbamazepine, lorazepam, clonazepam, eslicarbazepine, perampanel, and phenobarbital eTable 4 in Supplement 1. The number and percentage of AEs reported in each included study can be found in eTable 5 in Supplement 1. In the intervention group, the most common AE of any grade was somnolence In the controls, upper respiratory tract infection In the CBD arm, the overall percentages were In the control arm, the overall percentages were 6. The percentage of AEs that led to the discontinuation of the trial was higher in the CBD arm than in the controls 2. The overall risk ratios RRs of any grade from all 9 studies and severe grade in 5 studies 74 , 75 , 79 , 81 , 82 AEs in the CBD group compared with the control group were 1. For any grade AEs, the incidences of diarrhea RR, 1. Among moderate grade AEs, the risks of decreased appetite RR, 3. There was no significant difference between the CBD group and controls in terms of risk of severe grade site-specific AEs eFigure 9 and eTable 6 in Supplement 1. Using data from 8 of the included studies, 74 - 81 the overall RR for the incidence of serious AEs in the CBD group compared with the control group was 2. The incidence of AEs leading to the discontinuation of treatment in 8 studies 74 - 77 , 79 - 82 were significantly higher in the CBD group than in the control group RR, 3. The incidence of AEs that resulted in dose reduction in the 3 included studies 75 , 81 , 82 was significantly higher in the CBD group than in the control group RR, 9. A subgroup analysis was performed by quality of the included studies. The results showed that the pooled RRs for incidence of overall any grade AEs were 1. The current study showed that the frequency of any grade AEs in patients with epilepsy was more than 2 times higher for those receiving CBD than for the controls, with a notably increased risk of ALT or AST elevation, decreased appetite, diarrhea, and somnolence in those receiving CBD. The current study also indicated that for those receiving CBD, the overall percentage of any grade AEs was 9. A previous systematic review and meta-analysis 11 of RCTs involving patients with uncontrolled epilepsy showed that the frequency of any grade AEs was The lower percentage of AE frequency found in our study may be as a result of including more studies in our analysis 9 vs 4. Moreover, a systematic review by Bilbao and Spanagel 83 on the safety and efficacy of cannabinoids for different diseases showed that serious or severe AEs occurred in 4. Therefore, it seems that CBD is a relatively safe option compared with other cannabinoids. The current study showed that use of CBD was associated with a 1. Similarly, a systematic review by Lattanzi et al 11 found an RR of 1. Moreover, another meta-analysis 84 of 3 trials on the safety of adjunctive CBD in patients with Dravet syndrome showed that adding CBD was nonsignificantly associated with an increased risk of developing any type of AE RR, 1. Their nonsignificant result may be because they only included Dravet syndrome, had a low sample size, and included articles in the analysis that evaluated the effects of CBD that was administered in combination with other drugs. Furthermore, the results of a systematic review and meta-analysis 86 on the efficacy and safety of CBD for pediatric refractory epilepsy found an increased risk of overall AEs of 1. The risk of any grade and serious AEs in our study were lower than the above-mentioned study 1. The current study found that there was a significantly increased incidence of diarrhea, somnolence, decreased appetite, and ALT or AST elevation among those receiving CBD. Similarly, 3 previous systematic reviews and meta-analyses 11 , 84 , 85 of patients with uncontrolled epilepsy ie, Dravet syndrome and Lennox-Gastaut syndrome showed that CBD was significantly associated with increased risks of somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. These differences may be due to the fact that the studies were examining the effect of CBD treatment after a different period 25 days vs 14 weeks in low numbers of patients with wide age ranges. Among mild, moderate, and severe manifestations of somnolence, the moderate type was statistically significantly higher than in the control group in analyses of the pooled data from 4 studies 75 , 78 , 80 , 81 RR, 3. In most of these studies, taking clobazam was associated with somnolence. However, several studies involving patients with epilepsy did not demonstrate any drug-drug interaction between CBD and clobazam, whereas exposure to N-desmethyl clobazam was enhanced by 2- to 3-fold, probably resulting from the inhibition of CYP2C19 by CBD, which leads to clobazam dose adjustments in the presence of CBD. A previous systematic review and meta-analysis of RCTs, 13 which used the RoB1 tool for quality assessment, showed that in most domains, most studies had low risks of bias, and only 2 studies had high risks of bias in the selective outcome reporting domains. Similarly, in our study, which used the RoB2 tool, we found that there were high risks of bias in the selection of reported results and in the measurement of outcomes, whereas other domains had low risks of bias. The study by Talwar et al 86 also showed that the 6 included RCTs all had a low risk of bias. Overall, it is suggested that future studies carefully consider the measurement of outcomes, register the RCT protocol, and report both significant and nonsignificant outcomes. Our study has some limitations, which should be considered when interpreting the results. Although most of the participants were treatment-resistant patients with epilepsy, there was substantial heterogeneity in the study population in terms of age, severity of the disease, CBD dosage, source of CBD, and even its route of administration. In addition, we only included AEs in the meta-analysis that were reported in at least 3 studies, so AEs that were only reported in 1 or 2 of the included studies were not reported. Furthermore, small-study bias and publication bias were not evaluated because fewer than 10 studies were included. In addition, we did not limit the selection criteria to only major RCTs, which might lead to the inclusion of studies in different phases, such as phase 2 studies with small numbers of patients and a short observation period. In this systematic review and meta-analysis, the use of CBD to treat patients with epilepsy was associated with the development of several AEs, such as somnolence, diarrhea, decreased appetite, and AST or ALT elevation. Future research needs to investigate the therapeutic effects of CBD and AEs in the presence of various dosages of other antiepileptic drugs in order to achieve a safe and effective dose for treatment-resistant patients with epilepsy. Published: April 20, Author Contributions: Drs Gharagozli and Safiri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Zahmatyar and ZareDini contributed equally to this work. Critical revision of the manuscript for important intellectual content: Fazlollahi, Nejadghaderi, Sullman, Kolahi, Safiri. Administrative, technical, or material support: Nejadghaderi, Gharagozli, Kolahi, Safiri. No other disclosures were reported. Data Sharing Statement: See Supplement 2. Download PDF Comment. Figure 1. Study Selection Process. View Large Download. RCT indicates randomized clinical trial. Figure 2. Figure 3. Table 1. Table 2. Any Grade Adverse Events in the Meta-analysis a. Supplement 1. Quality Assessment of the Included Studies eTable 3. Graded Adverse Events in the Meta-analysis eFigure 1. Supplement 2. Data Sharing Statement. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Early identification of refractory epilepsy. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a year longitudinal cohort study. The consequences of refractory epilepsy and its treatment. Palliative non-resective surgery for drug-resistant epilepsy. Medicinal use of cannabis based products and cannabinoids. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. FDA approves its first cannabis based medicine. European drug agency approves cannabis-based medicine for severe forms of epilepsy. Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis. Efficacy and adverse event profile of cannabidiol and medicinal cannabis for treatment-resistant epilepsy: systematic review and meta-analysis. Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Department of Health and Human Services. Common Terminology Criteria for Adverse Events. Version 5. November 27, Accessed March 13, RoB 2: a revised tool for assessing risk of bias in randomised trials. Risk-of-bias VISualization robvis : an R package and Shiny web app for visualizing risk-of-bias assessments. Metaprop: a Stata command to perform meta-analysis of binomial data. Cochrane Handbook for Systematic Reviews of Interventions. Analysing data and undertaking meta-analyses. In: Higgins J, Thomas J. Version Cochrane Collaboration; Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. Seizure frequency, quality of life, behavior, cognition, and sleep in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Global brain network dynamics predict therapeutic responsiveness to cannabidiol treatment for refractory epilepsy. Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience. Slow titration of cannabidiol add-on in drug-resistant epilepsies can improve safety with maintained efficacy in an open-label Study. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Safety of cannabidiol prescribed for children with refractory epilepsy. Long-term safety and efficacy of highly purified cannabidiol for treatment refractory epilepsy. Quality of life in adults enrolled in an open-label study of cannabidiol CBD for treatment-resistant epilepsy. Safety and pharmacokinetics of medical cannabis preparation in a monocentric series of young patients with drug resistant epilepsy. Longitudinal impact of cannabidiol on EEG measures in subjects with treatment-resistant epilepsy. Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy. Efficacy of medical cannabis for treating refractory epilepsy in children and adolescents, with emphasis on the Israel experience. PubMed Google Scholar. Cannabidiol in treatment of refractory epileptic spasms: an open-label study. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. White matter integrity after cannabidiol administration for treatment resistant epilepsy. Dosage related efficacy and tolerability of cannabidiol in children with treatment-resistant epileptic encephalopathy: preliminary results of the CARE-E Study. Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: a multicenter phase-2 study. Results from an Italian expanded access program on cannabidiol treatment in highly refractory Dravet syndrome and Lennox—Gastaut syndrome. Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy. Effect of cannabidiol on interictal epileptiform activity and sleep architecture in children with intractable epilepsy: a prospective open-label study. Cannabidiol treatment for seizures in tuberous sclerosis complex. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results. Cognitive functioning following long-term cannabidiol use in adults with treatment-resistant epilepsy. Cognitive and behavioral effects of cannabidiol in patients with treatment-resistant epilepsy. The safety, tolerability, and effectiveness of PTL, an oral cannabidiol formulation, in pediatric intractable epilepsy: a phase II, open-label, single-center study. Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy. Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia. Addition of cannabidiol to current antiepileptic therapy reduces drop seizures in children and adults with treatment-resistant Lennox-Gastaut syndrome. Long-term efficacy and safety of cannabidiol CBD in children with treatment-resistant epilepsy: results from a state-based expanded access program. Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: results of a long-term open-label extension trial. Purified cannabidiol for treatment of refractory epilepsies in pediatric patients with developmental and epileptic encephalopathy. Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US. Add-on cannabidiol in patients with Dravet syndrome: results of a long-term open-label extension trial. A preliminary study of the effects of cannabidiol CBD on brain structure in patients with epilepsy. Two-center experience of cannabidiol use in adults with Dravet syndrome. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Cannabidiol in patients with Lennox-Gastaut syndrome: interim analysis of an open-label extension study. Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: an open-label extension trial. Cognitive function and adaptive skills after a one-year trial of cannabidiol CBD in a pediatric sample with treatment-resistant epilepsy. Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Time to onset of cannabidiol CBD treatment effect in Lennox-Gastaut syndrome: analysis from two randomized controlled trials. Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: post hoc analysis of randomized controlled phase 3 trial GWPCARE6. A phase II randomized trial to explore the potential for pharmacokinetic drug-drug interactions with stiripentol or valproate when combined with cannabidiol in patients with epilepsy. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome: a randomized clinical trial. Adjunctive transdermal cannabidiol for adults with focal epilepsy: a randomized clinical trial. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: a placebo-controlled randomized clinical trial. A phase 2, double-blind, placebo-controlled trial to investigate potential drug-drug interactions between cannabidiol and clobazam. Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications. Adjunctive cannabidiol in patients with Dravet syndrome: a systematic review and meta-analysis of efficacy and safety. Efficacy and safety of adjunctive cannabidiol in patients with Lennox—Gastaut syndrome: a systematic review and meta-analysis. Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: a systematic review and meta-analysis. A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Get the latest research based on your areas of interest. Weekly Email. Monthly Email. Save Preferences. Privacy Policy Terms of Use. This Issue. Views 11, Citations 8. View Metrics. X Facebook More LinkedIn. Original Investigation. April 20, Search Strategy. Study Selection. Data Extraction. Quality Assessment. Statistical Analysis. Study Characteristics. Meta-analysis Results. Frequency of AEs. Serious Grade AEs. Subgroup Analysis. Back to top Article Information. Access your subscriptions. Access through your institution. Add or change institution. Free access to newly published articles. Purchase access. Rent article Rent this article from DeepDyve. Sign in to access free PDF. Save your search. Customize your interests. Create a personal account or sign in to:. Privacy Policy. Make a comment.

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