Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies

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Abstract
Background and objective
Although cannabinoid-based medications are increasingly used by older adults, their safety and tolerability in this age group remain unclear. The purpose of this systematic review was to examine the safety and tolerability of cannabinoid-based medications by conducting a meta-analysis of open-label observational studies of cannabinoid-based medications for all indications in individuals with a mean age of ≥50 years.

Methods
A systematic search was conducted on PubMed, PsycINFO, MEDLINE, EMBASE and CINHAL. Study quality was assessed using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. We included studies that (a) were published from 1990 onwards; (b) included older adults (mean age ≥50 years); and (c) provided data on the safety and tolerability of medical cannabinoids. Data were pooled using a random-effects approach. Risk of adverse events, serious adverse events and withdrawals was computed as the incidence rate (IR). Separate analyses were conducted by the cannabinoid-based medication used, for delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and a combination of THC and CBD (THC:CBD).

Results
Thirty-eight studies were identified (THC = 23; CBD = 6; THC:CBD = 9; N = 2341, mean age: 63.19 ± 8.08 years, men: 53.86%). THC had a very low incidence of all-cause and treatment-related adverse events (IR: 122.18, 95% confidence interval [CI] 38.23–253.56; IR: 84.76, 95% CI 0.13–326.01, respectively) and negligible serious adverse events (IR = 0). Similar IRs for CBD (all cause, IR: 111.91, 95% CI 1.24–495.93; treatment related, IR: 1.76, 95% CI 4.63–23.05) and no serious adverse events (IR = 0). CBD was not associated with a risk of treatment-related withdrawals. THC had a low risk of all-cause and treatment-related withdrawals (IR: 25.18, 95% CI 12.35–42.52; IR: 7.83, 95% CI 3.26–14.38, respectively). The THC:CBD treatment had a low risk of all-cause and treatment-related adverse events (IR: 100.72, 95% CI 0.25–383.00; IR: 55.38, 95% CI 8.61–142.80, respectively), but reported a risk of all-cause and treatment-related serious adverse events (IR: 21.32, 95% CI 0.18–93.26; IR: 3.71, 95% CI 0.21–11.56, respectively), and all-cause and treatment-related withdrawals (IR: 78.63, 95% CI 17.43–183.90; IR: 34.31, 95% CI 6.09–85.52, respectively). Significant heterogeneity (I2 >55%) was present in most analyses.

Conclusions
Although cannabinoid-based medications were generally safe and acceptable to adults aged over 50 years, these estimates are limited by the lack of a control condition and considerable heterogeneity. Nevertheless, they complement and are consistent with comparable evidence from randomised controlled trials.