Background Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years. Methods and findings A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those, Latha Velayudhan and co-workers report a meta-analysis on safety of cannabinoid-based medicines in people aged over 50 years., Author summary Why was this study done? Use of cannabinoid-based medicines (CBMs) has been growing steadily in recent years, including in the elderly. However, their safety and tolerability in older adults remains unclear. With increasing interest in the use of CBMs in older people and growing unlicensed use, there is a particular need to examine their safety and tolerability in older adults. We analysed data on safety and tolerability from previously published double-blind, randomised controlled trials (RCT) using delta-9-tetrahydorcannabinol (THC) and cannabidiol (CBD), the common constituents of most CBMs, alone or in combination, to examine their effect on older adults. What did the researchers do and find? We pooled data from 46 published RCTs (with information from 6,216 patients; with mean participant age ≥50 years) on adverse events, serious adverse events or death, and withdrawal from study. We also examined the relationship between the dose of THC used in THC-containing CBMs and the incidence of adverse consequences in older adults. Our results suggest that compared with the control condition, treatment with THC-containing CBMs was associated on average with significantly greater incidence of all-cause and treatment-related adverse events. There was no significant increase in the incidence of serious adverse events or death with any CBMs. The risk of withdrawal from study was increased only in those receiving THC:CBD combination treatment, and this was related to THC dose. What do these findings mean? These findings suggest that CBMs in general are safe and acceptable in older adults. Our findings that THC-containing CBMs are associated with side effects and that THC:CBD combinations may be less acceptable at the dose ranges typically used in RCTs is critical to prescribing in older people.