Background: Over the last two decades, there has been growing interest and research in using cannabinoids for medical purposes in children. The main goal of my doctoral thesis was to examine the safety of cannabinoids used for medical purposes in children to generate data to guide clinical practice and future research. Methods: First, we conducted a living systematic review (LSR) to study the available evidence on cannabis products used for medical purposes in children. Second, to learn more about specific indications and safety profiles, we conducted three separate subgroup systematic reviews of studies including children with cancer, autism spectrum disorder (ASD), and a subgroup analysis of randomized controlled trials where adverse event (AEs) profiles were compared between those receiving cannabinoids and control arms. Third, a pharmacovigilance database study was conducted to evaluate the real-world safety reporting on cannabidiol (CBD) and investigate its drug interactions in children. Results: In the LSR, among identified interventional and observational studies, common indications for cannabinoids in children were refractory epilepsy (n=146 studies, 188,726 participants), followed by cancer and cancer symptom management (n=30 studies, 208,753 participants), and ASD (n=18 studies, 1285 participants). The most common cannabinoids studied in interventional studies were purified CBD (78.6%, n=66 studies, 5235 participants) with dose-range of 2-50 mg/kg/day, tetrahydrocannabinol (THC) (6%, n=5 studies, 148 participants) with dose-range of 2.5-10 mg/day (with a max dose of nabiximols containing 32.4 mg of THC) and nabilone (6%, n=5 studies, 267 participants) with dose-range of 0.5-2 mg/day. In a cancer symptom management systematic review, cannabinoids were commonly used for chemotherapy-induced nausea and vomiting (11/19, 58%) management. In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids in children with cancer compared to active control group. In the ASD review, the pooled prevalence of AEs across single-arm studies and observational studies was 44.8% (95% CI, 24.1-67.4; I2 = 94%; 9 studies) in children with ASD. Somnolence, changes in appetite, restlessness, and tiredness were the commonly reported AEs (> 10%). Validated efficacy measures were reported inconsistently across studies. Epilepsy, sleep impairment, hyperactivity, concentration impairment, and irritability were the most common symptoms managed with cannabinoids in children with ASD. In a meta-analysis of randomized controlled clinical trials, cannabinoids were associated with an overall increased risk of adverse events (risk ratio [RR], 1.09; 95% CI, 1.02-1.16; I2 = 54%; 12 trials), withdrawals due to adverse events (RR, 3.07; 95% CI, 1.73-5.43; I2 = 0%;14 trials), and serious adverse events (RR, 1.81; 95% CI, 1.21-2.71; I2 = 59%; 11 trials) compared with control group. In real-world pharmacovigilance data, Signals were detected for hospitalization [Proportional Reporting Ratio (PRR) 30.83 (95% CI, 26.03-36.51), 127 reports], sudden unexplained death in epilepsy [PRR 27.64 (95% CI, 10.06-75.91), 4 reports], seizures [PRR 19.77 (95% CI, 18.03-21.66), 328 reports] and death [PRR 14.07 (95% CI, 12.27-16.13), 176 reports]. CBD was commonly reported to interact with clobazam (n=8/19, 42.10%), valproic acid (n=4/19, 21.05%), mTOR inhibitors (everolimus and sirolimus; n=3/19, 15.78%), topiramate (n=2/19, 10.50%), and zonisamide (n=2/19, 10.50%). Conclusions This thesis's findings identified evidence gaps while synthesizing dosing, safety, and reported benefits of cannabinoid use in children for medical purposes. Long-term safety studies, especially those exploring cannabinoid-related drug interactions and tools that improve adverse event reporting and harmonize cannabis exposure definitions, are needed.