Safety and tolerability of natural and synthetic cannabinoids in adults aged over

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Citation: Velayudhan L, McGoohan K, Bhattacharyya S (2021) Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis. PLoS Med 18(3):
e1003524.

https://doi.org/10.1371/journal.pmed.1003524

Academic Editor: Alexander C. Tsai, Massachusetts General Hospital, UNITED STATES

Received: October 7, 2020; Accepted: December 15, 2020; Published: March 29, 2021

Copyright: © 2021 Velayudhan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: SB is supported by grants from the National Institute of Health Research (NIHR) Efficacy and Mechanism Evaluation scheme (UK) (grant number 16/126/53) and SB and LV are in receipt of funding from Parkinson’s UK (grant number G-1901). The authors acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations:
AEs,
adverse event; CBD,
cannabidiol; CBM,
cannabinoid-based medicine; GRADE,
Grading of Recommendations Assessment, Development, and Evaluation; IRR,
incident rate ratio; MedDRA,
Medical Dictionary for Regulatory Activities; PRISMA,
Preferred Reporting Items for Systematic Reviews and Meta-analyses; RCT,
randomised clinical trial; RR,
risk ratio; SAE,
serious adverse event; SOC,
system organ classes; THC,
delta-9-tetrahydrocannabinol

Introduction

The cannabis plant (Cannabis sativa L.) has been used worldwide both for recreational and medicinal purposes for thousands of years. With a fast-growing aging population, its medicinal use has also caught up and is growing in the elderly [13].

Among the cannabinoids found in the cannabis plant, delta-9-tetrahydorcannabinol (THC) and cannabidiol (CBD) are the most well characterised and often considered for medicinal purposes. THC can cause intoxication [4,5] and has antiemetic, analgesic, and potentially neuroprotective and anti-inflammatory effects. On the other hand, CBD is nonintoxicating [5,6] with antiepileptic and potentially also anti-inflammatory, neuroprotective, antioxidant, and antipsychotic effects [79]. While several trials have used these cannabinoids for a wide range of diseases and indications, a majority of these have investigated younger people [10,11]. However, age-related pharmacodynamic and pharmacokinetic changes as well as higher prevalence of comorbidities and polypharmacy in the elderly mean that they may have a different profile of safety and tolerability to cannabinoids [12,13] compared to younger people, as is well known with other groups of medications especially those used for disorders of the central nervous system [14]. Both THC and CBD, the common constituents of most cannabinoid-based medicines in current use have prominent effects on brain function and cognition [15]. Therefore, evidence of safety and tolerability of cannabinoid-based medicines (CBM) established in studies in younger adults cannot be directly extrapolated to the older adults. Although a number of recent reviews and meta-analyses [12,16,17] have summarized the safety and tolerability profile of CBMs, they have all pooled data from studies investigating across the age spectrum, making it difficult to draw age-specific inferences. With increasing interest in their use in disorders typically affecting older people [1820] and growing unlicensed use [21], there is a particular need to investigate the safety and tolerability of CBMs in older people. This is also relevant, as there is a widely held view that many of the naturally derived cannabinoids are generally safe as they have been around and used for a long time.

Here, we have addressed this by investigating the safety and tolerability of CBMs in people over 50 years of age through systematically reviewing all double-blind, randomised controlled trials (RCTs) using CBMs that focused on people with mean age of 50 years and over to conduct a meta-analysis. As there is a larger evidence base of studies with mean age of participants ≥50 years than the more limited set of studies that have exclusively focused on people over 50 years and even less on people over 65 or 75 years, we have focused on studies with mean age of participants ≥50 years and complemented these results with additional analyses restricted to studies that have exclusively focused on people over 50 years and even less on people over 65. Existing meta-analytic investigations [16,17] have generally considered all CBMs together, irrespective of whether they included THC, CBD, or THC:CBD in combination. However, THC can cause intoxication and may induce anxiety and transient psychotomimetic effects [5], especially at higher doses and in vulnerable individuals, while CBD does not cause intoxication when directly compared in the same individuals [5] and may potentially ameliorate anxiety and psychosis [9,2224]. Further, there is growing evidence that THC and CBD may have opposing acute effects on autonomic arousal and brain [15] and cardiovascular function [25,26], and CBD may mitigate some of the harmful effects of THC on cognition and behaviour [15,27,28], consistent with their opposing effects on some of their molecular targets [4]. This suggests that THC and CBD may have distinct tolerability profiles, with the possibility that certain side effects may be noticeable in those taking formulations containing only THC but not in those taking formulations containing only CBD while adverse effects may even be mitigated in those taking THC and CBD in combination. This underscores the importance of examining their safety and tolerability separately. Therefore, we have addressed this issue by separately investigating the effects of THC, CBD, or THC:CBD in combination.

We hypothesized that compared to control treatments, all 3 categories of CBMs will be associated with: (i) a greater incidence of adverse events (AEs); (ii) no greater incidence of serious adverse events (SAEs) or death; and (iii) no greater risk of withdrawal from study. Further, we hypothesized a direct relationship between the dose of THC used in THC-containing CBMs and the incidence of adverse consequences in older adults.

Methods

Data sources and searches

The review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines [29] (see S1 PRISMA checklist). The study protocol was preregistered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42019148869). Ethics approval was not required for this systematic review and meta-analysis.

A detailed description of the bibliographic search strategy is presented in Methods in S1 Text. We identified studies published from 1 January 1990 up to 31 October 2020, from several electronic databases. Studies were independently assessed by 2 researchers and disagreements resolved through consensus or discussions with a third researcher.

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Safety and tolerability of natural and synthetic cannabinoids in adults aged over