drug-related side effects and adverse reactions

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 <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies.

Conclusions: This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.

In the last year, older adults in the U.S. sought medical care nearly 5 million times due to serious side effects from one or more medications. More than a quarter million of these visits resulted in hospitalizations, at a cost of $3.8 billion (see Appendix A in the full report). These numbers point to a rapidly growing epidemic of medication overload among older Americans. Over the last decade, adults age 65 and older have been hospitalized for serious drug side effects, called adverse drug events (ADEs), about 2 million times. To put this in context, there were 3.2 million opioid-related hospitalizations across the entire population during the same period.1 The trend of increasing ADEs is not propelled by drug abuse, but by the rising number of medications prescribed to older adults (called “polypharmacy” in the scientific literature). More than 40 percent of older adults take five or more prescription medications a day, a threefold increase over the past two decades.2,3 The greater the number of medications—most of which are prescribed for legitimate reasons—the greater the risk for serious adverse reactions in older patients. Medication overload is causing widespread yet unseen harm to our parents and our grandparents. It is every bit as serious as the opioid crisis, yet its scope remains invisible to many patients and health care professionals. While some clinicians are trying to reduce the burden of medications on their individual patients, no professional group, public organization, or government agency to date has formally assumed responsibility for addressing this national problem. If current trends continue, we estimate that medication overload will be responsible for at least 4.6 million hospitalizations between 2020 and 2030. It will cost taxpayers, patients and families an estimated $62 billion. Over the next decade, medication overload is expected to cause the premature death of 150,000 older Americans. In this report, the Lown Institute calls for the development of a national strategy to address medication overload and help older people avoid its devastating effects on the quality and length of their lives. A subsequent National Action Plan for Addressing Medication Overload will lay out a national strategy to address the epidemic of prescribing and ensure the safety of millions of older adults who are now at risk of preventable harm and premature death.