Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference
Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK
Abstract
Background
Cannabinoid-based medicines (CBMs) are being used widely in older people. However, information on the incidence of adverse events (AEs) is limited.
Objective
To quantify the incidence rate difference (IRD) of AEs in middle aged and older adults of age ≥50 years receiving CBMs and also examine associations with weekly doses.
Design
Systematic review and meta-analysis.
Data sources
MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library and ClinicalTrials.gov (1st Jan 1990–12th June 2023).
Methods
We included randomised clinical trials (RCTs) using CBMs with mean participant age ≥50 years for medicinal purposes for all clinical indications. Paired reviewers independently screened studies, extracted data and appraised risk of bias. We estimated pooled effect-sizes IRD under the random-effects model.
Results
Data from 58 RCTs (37 moderate-high quality studies, pooled n = 6611, mean age range 50–87 years, 50% male, n = 3450 receiving CBMs) showed that compared with controls, the incidence of all-cause and treatment-related AEs attributable to delta-9-tetrahydrocannabinol (THC)-containing CBMs were: THC alone [IRD:18.83(95% Confidence Interval [CI], 1.47–55.79) and 16.35(95% CI, 1.25–48.56)] respectively; THC:cannabidiol (CBD) combination [IRD:19.37(95% CI, 4.24–45.47) and 11.36(95% CI, 2.55–26.48)] respectively. IRDs of serious AEs, withdrawals and deaths were not significantly greater for CBMs containing THC with or without CBD. THC dose-dependently increased the incidence of dry mouth, dizziness/lightheadedness, mobility/balance/coordination difficulties, dissociative/thinking/perception problems and somnolence/drowsiness. The interaction of weekly THC:CBD doses played a role in mostly neurological, psychiatric and cardiac side-effects.
Conclusions
Although CBMs in general are safe and acceptable in middle aged and older adults, one needs to be mindful of certain common dose-dependent side-effects of THC-containing CBMs.
Untitled section
Keywords: cannabinoid-based medication, delta-9-tetrahydrocannabinol (THC), cannabidiol, adverse events, middle aged and older adults, systematic review, older people
Article notes
Untitled section
Received 2024 Apr 29; Revision requested 2024 Oct 5; Accepted 2024 Nov 14; Collection date 2024 Nov.
Key Points
- There is a particular need to quantify risk of various adverse events (AEs) with use of cannabinoid-based medicines (CBMs) in older people.
- We examined incidence rate differences of AEs in middle aged and older adults receiving CBMs for all conditions.
- Delta-9-tetrahydrocannabinol (THC) containing CBMs were associated with gastrointestinal, neurological and psychiatric side-effects in a dose-related manner.
- Cumulative weekly doses of delta-9-THC and CBDs played a role in mostly neurological, psychiatric and cardiac side-effects.
- We present age-specific safety/tolerability information about cannabinoids that is critical to prescribing in older people.
Introduction
Cannabinoid-based medicines (CBMs) are increasingly being used in the older people, a fast-growing segment of the population [1, 2]. The term cannabinoid generally refers to chemicals that have a certain (terpenophenolic) structure, which are naturally present in the extract of the cannabis plant (when they are also known as phytocannabinoids) or may have a synthetic origin. Out of 150 cannabinoids in the cannabis plant, delta-9-tetrahydorcannabinol (THC) and cannabidiol (CBD) are commonly used for medicinal purposes with a range of reported benefits [3–6].
For any novel treatment, safety and tolerability must be weighed up against clinical benefits to inform their use in different contexts. This is of particular importance in middle aged and older adults, who often have various comorbid health conditions requiring treatments that may interact with any additional treatment being prescribed. They are also more sensitive to side-effects of medications than many other demographic groups. With growing usage of CBMs, there is a particular need therefore to quantify the risk of various adverse events (AEs) associated with CBM use, so as to enable informed risk–benefit analysis during clinical use. However, to the best of our knowledge there is limited evidence in this regard. Although, a number of randomised clinical trials (RCTs) of CBMs have been carried out, the sample sizes of these RCTs on their own are underpowered to systematically and meaningfully estimate the risk of individual AEs. Against this background and in the absence of large-scale population level pharmaco-vigilance data which will only accrue over time, meta-analytic pooling of incidence rate data of individual AEs across placebo-controlled RCTs allows the best estimate of risk associated with CBM treatments based on available evidence. By estimating difference in the incidence rate between the CBM and control intervention arms, such evidence can help understand the additional risk of AEs associated with CBM use. A number of previous reviews [7–10] have examined whether CBMs are associated with greater risk (either as odds or risk ratios or incident rate ratios) of side-effects and reported them as ratios. However, estimates of relative effect such as these do not lend themselves as easily to use in a clinical context unless the risk in the control group is readily known. Incident rate difference (IRD), which in this context refers to the additional risk of AEs estimated as the number of events per person-years of exposure associated with CBM use over and above a control intervention may be more easily understood but has not been systematically examined before. Another gap in current evidence relates to understanding about how the risk of AEs relate to the range of doses or ratio of doses used in formulations containing single or multiple cannabinoids respectively being used in the clinical settings. With limited number of studies being available, there is a paucity of data for any clinical indication-specific dose–response relationships with regard to AEs (that may exist) to become easily apparent. Meta-analytic pooling of data therefore will allow for an estimation of the likelihood of such risks at different doses across clinical indications to inform clinicians and researchers. Such a detailed assessment may help inform use of CBM in older people, in whom certain side-effects may be more directly related to morbidity and even mortality. For example, dizziness, which may contribute to risk for falls in older people, can in turn result in serious injuries such as fractures, head injuries or accidental deaths [11, 12]. Furthermore, certain AEs and dose–response relationships may be systematically different between THC and THC:CBD formulations [8]. Therefore, the overarching objective of the present endeavour was to address these gaps in knowledge by conducting a search of evidence from placebo-controlled RCTs and systematically report the incidence rate of all individual AEs attributable to the use of different types of CBMs. Specifically, we aimed to quantify the IRDs of AEs in people receiving THC only and THC-CBD combination treatment in middle aged and older adults with mean age of 50 years and older. We also aimed to examine the association of AEs with the weekly doses of THC and CBD.
Methods
Search strategy and selection criteria
The review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines [13] and registered with PROSPERO (CRD42019148869). A detailed description of the bibliographic search strategy, as previously published, is presented in Supplementary Methods [8]. We identified studies published from 1 January 1990 up to 12 June 2023, from several electronic databases. Studies were independently assessed by pair of researchers (LV, KM, SP, MD) and disagreements resolved through consensus or discussions with senior researcher.
As described in our previous meta-analysis [8], studies were included if [1] published from 1990 onwards; [2] included middle aged and older adults (defined as mean age ≥50 years) or reported a distinct subgroup of middle aged and older adults and provided separate results for this subgroup; and [3] provided data on the safety and tolerability of medical cannabinoids administered by any route, at any dose, for any duration and for any indication. Studies were excluded if they [1] included exclusively younger subjects (≤50 years); [2] studied effects of cannabinoids for recreational purposes or failed to provide the dosage of cannabinoids and [3] were not reported in English language. Here we focus on results from RCTs.
Data analysis
All relevant available data for examination of the safety and tolerability of different CBMs (THC:CBD combination or THC alone) was collected from eligible studies, complemented with information from www.ClinicalTrials.gov and we also contacted study authors to supplement information. Data were extracted for study design, participant characteristics, indication, dosage and duration of intervention, all cause and treatment-related AEs and serious AEs (SAEs), AE-related withdrawals and deaths. AEs and SAEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) ‘system organ classes’ (SOC). Data were extracted for the top five (as reported by each study) AEs for each SOC, where available. Withdrawals and deaths outcomes were extracted as reported in the studies from the text and tables for each treatment arm. Data extraction and coding was verified by a medically qualified researcher and discrepancies resolved following discussions with senior researcher. The disease conditions investigated were classified into broader subgroups for analysis purpose [8]. Overall quality of evidence was assessed using recommended criteria [14] and summarised to reflect confidence in estimates [15].
Pooled effect-sizes were estimated (as square root transformed incident rate difference; IRSD) if there were two or more RCTs within each group or sub-group under the random-effects model using the restricted maximum-likelihood estimator because of anticipated heterogeneity. For reporting purposes, IRSDs have been converted to IRDs for ease of understanding, unless otherwise specified. However, for dose–response relationships (as in Tables 2 and 4), we have reported the IRSD values to allow an interested reader to estimate the expected IRD for a particular dose of CBM and shown an example calculation in table footnotes. Doses of both THC and CBD were included separately, as well as their interaction as predictors, in the same regression model for studies using THC:CBD combinations (Table 4). For each category of intervention, analyses combined both parallel-arm and crossover RCTs, with the latter treated as parallel-arm design [16] for pooled analyses. We also report results by RCT design. In studies with more than one active treatment arm, each active arm was considered as a different study. Throughout the manuscript, results are reported for analyses treating all studies as independent. We investigated heterogeneity using forest-plots and the QE statistic (and its significance; QEp) and publication bias using Egger’s regression test [17] and the ‘Trim and fill’ method [18]. Data for all clinical conditions were combined. We also examined the effect of treatment, design, clinical condition and weekly dose of THC and CBD and their interaction in THC:CBD combination studies using meta-regression except for the route of administration which was oral for all the included studies. Statistical analyses were performed using the metafor package in R (version 3.6.3) [19].
| MedDRA high-level grouping | Individual AE | MODEL | Summary estimate | 95% CI (lower, upper) | P value | N | QE | QEp |
|---|---|---|---|---|---|---|---|---|
| Gastrointestinal | Nausea | Intercept | 0.013 | −0.010, 0.036 | 0.268 | 22 | 28.800 | 0.092 |
| THC | 0.000 | −0.000, 0.000 | 0.373 | 22 | ||||
| Vomiting | Intercept | 0.016 | −0.005, 0.037 | 0.139 | 18 | 9.686 | 0.883 | |
| THC | 0.000 | 0.000, 0.000 | 0.252 | 18 | ||||
| Dry mouth | Intercept | 0.075 | 0.050, 0.100 | <0.001 | 20 | 27.136 | 0.076 | |
| THC | −0.00005 | −0.00001, 0.00003 | <0.001 | 20 | ||||
| Nervous System | Dizziness/Lightheaded | Intercept | 0.055 | 0.038, 0.071 | <0.001 | 25 | 49.357 | 0.001 |
| THC | −0.00001 | −0.00003, −0.00001 | 0.001 | 25 | ||||
| Mobility/Balance/Coordination | Intercept | 0.025 | 0.009, 0.041 | 0.002 | 17 | 16.338 | 0.360 | |
| THC | −0.000005 | −0.00001, −0.000001 | 0.027 | 17 | ||||
| Muscle weakness | Intercept | 0.003 | −0.015, 0.020 | 0.744 | 18 | 5.049 | 0.996 | |
| THC | 0.000 | 0.000, 0.000 | 0.961 | 18 | ||||
| Headache/migraine | Intercept | 0.004 | −0.095, 0.104 | 0.936 | 8 | 7.667 | 0.264 | |
| THC | 0.002 | 0.000, 0.004 | 0.094 | 8 | ||||
| Sedation | Intercept | 0.260 | 0.023, 0.498 | 0.032 | 2 | 0.000 | 1.000 | |
| THC | −0.013 | −0.032, 0.006 | 0.173 | 2 | ||||
| Psychiatric | Sleep problems/Insomnia | Intercept | 0.039 | −0.024, 0.102 | 0.222 | 16 | 8.723 | 0.848 |
| THC | 0.000 | −0.001, 0.000 | 0.338 | 16 | ||||
| Dissociative/Thinking/Perception | Intercept | 0.002 | −0.013, 0.018 | 0.761 | 17 | 9.988 | 0.820 | |
| THC | 0.00001 | 0.000002, 0.00001 | 0.006 | 17 | ||||
| Somnolence/Drowsiness | Intercept | 0.064 | 0.030, 0.097 | <0.001 | 20 | 47.142 | <0.001 | |
| THC | −0.0003 | −0.00001, −0.001 | 0.009 | 20 | ||||
| Anxiety/Depression | Intercept | −0.002 | −0.020, 0.016 | 0.824 | 13 | 2.377 | 0.997 | |
| THC | 0.000 | 0.000, 0.000 | 0.565 | 13 | ||||
| Concentration/attention problem | Intercept | 0.119 | 0.006, 0.232 | 0.039 | 5 | 1.004 | 0.800 | |
| THC | −0.001 | −0.004, 0.001 | 0.285 | 5 | ||||
| Euphoria | Intercept | 0.098 | −0.030, 0.226 | 0.135 | 6 | 3.169 | 0.530 | |
| THC | 0.000 | −0.003, 0.002 | 0.967 | 6 | ||||
| Cardiac | Dyspnoea | Intercept | 0.004 | −0.021, 0.029 | 0.744 | 16 | 1.256 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.788 | 16 | ||||
| Palpitation | Intercept | 0.000 | −0.001, 0.001 | 0.973 | 15 | 1.434 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.968 | 15 | ||||
| Chest pain | Intercept | −0.002 | −0.029, 0.025 | 0.886 | 16 | 3.706 | 0.997 | |
| THC | 0.000 | 0.000, 0.000 | 0.904 | 16 | ||||
| Vascular | Hypotension | Intercept | 0.001 | −0.026, 0.027 | 0.963 | 16 | 3.998 | 0.995 |
| THC | 0.000 | 0.000, 0.000 | 0.969 | 16 | ||||
| Infections | Unspecified | Intercept | −0.006 | −0.024, 0.011 | 0.470 | 16 | 2.312 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.514 | 16 | ||||
| UTI | Intercept | 0.001 | −0.017, 0.018 | 0.929 | 16 | 0.006 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.651 | 16 | ||||
| RTI | Intercept | 0.008 | −0.018, 0.035 | 0.534 | 15 | 7.858 | 0.853 | |
| THC | 0.000 | 0.000, 0.000 | 0.601 | 15 | ||||
| General | Pain: non-specific | Intercept | −0.009 | −0.034, 0.016 | 0.490 | 16 | 2.554 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.416 | 16 | ||||
| Fatigue/tiredness | Intercept | 0.005 | −0.012, 0.022 | 0.584 | 21 | 4.812 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.702 | 21 | 1.000 | |||
| Weakness/reduced mobility | Intercept | 0.015 | −0.012, 0.042 | 0.271 | 16 | 0.451 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.117 | 16 | ||||
| Blood/Lymphatic System | Anaemia | Intercept | 0.004 | −0.021, 0.029 | 0.761 | 16 | 2.042 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.802 | 16 | ||||
| Ear & Labyrinth | Vertigo | Intercept | 0.002 | −0.024, 0.029 | 0.871 | 15 | 3.974 | 0.991 |
| THC | 0.000 | 0.000, 0.000 | 0.892 | 15 | ||||
| Eye Disorders | Visual impairment/disturbances | Intercept | 0.010 | −0.016, 0.037 | 0.451 | 15 | 1.182 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.891 | 15 | ||||
| Injury/Poisoning | Falls & injuries | Intercept | 0.007 | −0.011, 0.025 | 0.436 | 14 | 1.845 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.486 | 14 | ||||
| Investigations | Raised gamma GT | Intercept | 0.004 | −0.023, 0.030 | 0.792 | 16 | 3.322 | 0.998 |
| THC | 0.000 | 0.000, 0.000 | 0.828 | 16 | ||||
| Metabolism/Nutritional | Fluid retention | Intercept | −0.002 | −0.024, 0.020 | 0.864 | 16 | 2.112 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.895 | 16 | ||||
| Decreased appetite | Intercept | 0.003 | −0.023, 0.029 | 0.801 | 16 | 5.367 | 0.980 | |
| THC | 0.000 | 0.000, 0.000 | 0.841 | 16 | ||||
| Increased appetite | Intercept | 0.002 | −0.024, 0.029 | 0.863 | 16 | 1.970 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.888 | 16 | ||||
| Musculoskeletal | Spasm stiffness | Intercept | 0.001 | −0.016, 0.019 | 0.894 | 17 | 1.993 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.945 | 17 | ||||
| Joint disorders | Intercept | 0.001 | −0.017, 0.018 | 0.947 | 16 | 0.003 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.737 | 16 | ||||
| Musculoskeletal pain | Intercept | 0.007 | −0.010, 0.025 | 0.396 | 18 | 10.692 | 0.828 | |
| THC | 0.000 | 0.000, 0.000 | 0.091 | 18 | ||||
| Reproductive system | Male impotence | Intercept | −0.020 | −0.042, 0.002 | 0.072 | 15 | 6.188 | 0.939 |
| THC | 0.000 | 0.000, 0.000 | 0.161 | 15 | 0.939 | |||
| Respiratory/Thoracic | Nose tenderness | Intercept | 0.003 | −0.024, 0.030 | 0.822 | 15 | 1.949 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.850 | 15 | ||||
| Skin/Subcutaneous | Other skin problem | Intercept | 0.005 | −0.021, 0.032 | 0.694 | 15 | 1.961 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.231 | 15 | ||||
| Rash | Intercept | 0.005 | −0.021, 0.032 | 0.692 | 15 | 1.856 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.738 | 15 | ||||
| Pressure sore | Intercept | 0.002 | −0.024, 0.029 | 0.864 | 15 | 0.007 | 1.000 | |
| THC | 0.000 | 0.000, 0.000 | 0.270 | 15 | ||||
| Renal and Urinary | Bladder symptoms | Intercept | 0.001 | −0.025, 0.028 | 0.915 | 15 | 0.004 | 1.000 |
| THC | 0.000 | 0.000, 0.000 | 0.898 | 15 |
| MedDRA high-level grouping | Individual AE | Model | Summary estimate | 95% CI (lower, upper) | P value | N | QE | QEp |
|---|---|---|---|---|---|---|---|---|
| Blood/Lymphatic System | Anaemia | Intercept | −0.007 | −0.089, 0.075 | 0.871 | 14 | 0.773 | 1.000 |
| THC | 0.000 | −0.001, 0.000 | 0.890 | 14 | ||||
| CBD | 0.000 | −0.001, 0.001 | 0.889 | 14 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.815 | 14 | ||||
| Cardiac | Dyspnoea | Intercept | 0.067 | −0.073, 0.208 | 0.346 | 11 | 0.047 | 1.000 |
| THC | 0.000 | −0.002, 0.001 | 0.422 | 11 | ||||
| CBD | −0.001 | −0.007, 0.005 | 0.730 | 11 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.724 | 11 | ||||
| Palpitation | Intercept | 0.437 | −0.132, 1.005 | 0.132 | 10 | 1.919 | 0.927 | |
| THC | −0.004 | −0.008, 0.000 | 0.053 | 10 | ||||
| CBD | −0.008118 | −0.016085, −0.000151 | 0.046 | 10 | ||||
| THC*CBD interaction | 0.000066 | 0.000008, 0.000124 | 0.026 | 10 | ||||
| Ear & Labyrinth | Vertigo | Intercept | 0.024 | −0.295, 0.344 | 0.881 | 11 | 5.204 | 0.635 |
| THC | −0.001 | −0.002, 0.001 | 0.535 | 11 | ||||
| CBD | 0.001 | −0.001, 0.002 | 0.352 | 11 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.920 | 11 | ||||
| Eye Disorders | Visual impairment/disturbances | Intercept | 0.018 | −1.309, 1.345 | 0.979 | 9 | 6.621 | 0.250 |
| THC | 0.000 | −0.012, 0.011 | 0.941 | 9 | ||||
| CBD | 0.000 | −0.028, 0.028 | 0.999 | 9 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.966 | 9 | ||||
| Gastrointestinal | Nausea | Intercept | 0.023 | −0.054, 0.100 | 0.555 | 21 | 14.301 | 0.646 |
| THC | 0.000 | −0.001, 0.000 | 0.112 | 21 | ||||
| CBD | 0.000 | 0.000, 0.001 | 0.202 | 21 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.925 | 21 | ||||
| Vomiting | Intercept | −0.027 | −0.159, 0.105 | 0.687 | 19 | 13.342 | 0.576 | |
| THC | 0.000 | −0.001, 0.001 | 0.848 | 19 | ||||
| CBD | 0.000 | −0.001, 0.001 | 0.410 | 19 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.930 | 19 | ||||
| Dry Mouth | Intercept | 0.020 | −0.121, 0.162 | 0.777 | 17 | 49.346 | <0.001 | |
| THC | 0.000 | −0.001, 0.001 | 0.561 | 17 | ||||
| CBD | 0.001 | 0.000, 0.002 | 0.323 | 17 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.643 | 17 | ||||
| General | Pain: non-specific | Intercept | 0.029 | −0.053, 0.111 | 0.493 | 14 | 18.617 | 0.045 |
| THC | 0.000 | −0.001, 0.000 | 0.698 | 14 | ||||
| CBD | 0.000 | −0.002, 0.001 | 0.475 | 14 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.316 | 14 | ||||
| Fatigue/tiredness | Intercept | 0.024 | −0.054, 0.102 | 0.544 | 19 | 24.526 | 0.057 | |
| THC | 0.000 | −0.001, 0.000 | 0.266 | 19 | ||||
| CBD | 0.000 | 0.000, 0.001 | 0.543 | 19 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.714 | 19 | ||||
| Weakness/reduced mobility | Intercept | −0.041 | −0.202, 0.121 | 0.623 | 14 | 5.009 | 0.891 | |
| THC | 0.000 | −0.001, 0.001 | 0.801 | 14 | ||||
| CBD | 0.001 | −0.001, 0.002 | 0.399 | 14 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.450 | 14 | ||||
| Infections | Unspecified | Intercept | −0.007 | −1.334, 1.321 | 0.992 | 8 | 0.014 | 1.000 |
| THC | 0.000 | −0.011, 0.011 | 0.994 | 8 | ||||
| CBD | 0.000 | −0.028, 0.028 | 0.991 | 8 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.991 | 8 | ||||
| UTI | Intercept | −0.063 | −0.867, 0.742 | 0.879 | 11 | 0.534 | 0.999 | |
| THC | 0.001 | −0.006, 0.007 | 0.876 | 11 | ||||
| CBD | 0.001 | −0.014, 0.016 | 0.859 | 11 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.865 | 11 | ||||
| RTI | Intercept | 0.078 | −0.279, 0.435 | 0.668 | 11 | 0.476 | 1.000 | |
| THC | 0.000 | −0.002, 0.002 | 0.674 | 11 | ||||
| CBD | −0.002 | −0.005, 0.001 | 0.242 | 11 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.238 | 11 | ||||
| Injury/Poisoning | Falls & injuries | Intercept | −0.251 | −0.820, 0.317 | 0.386 | 10 | 1.252 | 0.974 |
| THC | 0.002 | −0.002, 0.007 | 0.286 | 10 | ||||
| CBD | 0.005 | −0.003, 0.013 | 0.183 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.172 | 10 | ||||
| Investigations | Raised Gamma GT | Intercept | 0.077 | −0.434, 0.587 | 0.768 | 10 | 0.015 | 1.000 |
| THC | −0.001 | −0.004, 0.003 | 0.699 | 10 | ||||
| CBD | −0.002 | −0.010, 0.007 | 0.707 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.671 | 10 | ||||
| Metabolism/Nutritional | Decreased Appetite | Intercept | 0.053 | −0.031, 0.137 | 0.216 | 16 | 4.443 | 0.974 |
| THC | 0.000 | −0.001,0.000 | 0.296 | 16 | ||||
| CBD | 0.000 | 0.000,0.000 | 0.080 | 16 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.263 | 16 | ||||
| Increased Appetite | Intercept | −0.071 | −0.571, 0.428 | 0.779 | 10 | 2.657 | 0.850 | |
| THC | 0.000 | −0.003, 0.003 | 0.884 | 10 | ||||
| CBD | 0.002 | −0.006, 0.011 | 0.616 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.697 | 10 | ||||
| Anorexia | Intercept | −0.103 | −0.249, 0.043 | 0.167 | 14 | 10.513 | 0.397 | |
| THC | 0.000 | 0.000, 0.001 | 0.272 | 14 | ||||
| CBD | 0.001 | 0.000, 0.002 | 0.158 | 14 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.229 | 14 | ||||
| Musculoskeletal | Back pain | Intercept | 0.084 | −1.168, 1.335 | 0.896 | 10 | 0.138 | 1.000 |
| THC | −0.001 | −0.011, 0.010 | 0.898 | 10 | ||||
| CBD | −0.002 | −0.028, 0.024 | 0.887 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000, 0.000 | 0.891 | 10 | ||||
| Spasm stiffness | Intercept | 0.300 | −0.952, 1.551 | 0.639 | 10 | 4.242 | 0.644 | |
| THC | −0.003 | −0.014,0.008 | 0.578 | 10 | ||||
| CBD | −0.006 | −0.032,0.020 | 0.659 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.617 | 10 | ||||
| Musculoskeletal pain | Intercept | −0.173 | −1.500, 1.154 | 0.799 | 9 | 0.026 | 1.000 | |
| THC | 0.001 | −0.010, 0.012 | 0.859 | 9 | ||||
| CBD | 0.002 | −0.026, 0.029 | 0.915 | 9 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.929 | 9 | ||||
| Neoplasms | Neoplasms progression | Intercept | 0.120 | −0.040, 0.279 | 0.142 | 16 | 6.544 | 0.886 |
| THC | −0.001 | −0.001,0.000 | 0.123 | 16 | ||||
| CBD | −0.001 | −0.002, 0.001 | 0.340 | 16 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.283 | 16 | ||||
| Nervous system | Altered taste | Intercept | −0.077 | −0.226, 0.072 | 0.311 | 13 | 8.557 | 0.479 |
| THC | 0.000 | −0.001,0.001 | 0.759 | 13 | ||||
| CBD | 0.001 | 0.000,0.002 | 0.024 | 13 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.141 | 13 | ||||
| Dizziness/Lightheaded | Intercept | −0.018 | −0.077,0.041 | 0.549 | 24 | 60.352 | <0.001 | |
| THC | 0.000498 | 0.000080, 0.000916 | 0.020 | 24 | ||||
| CBD | 0.000 | 0.000,0.000 | 0.628 | 24 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.602 | 24 | ||||
| Headache/migraine | Intercept | 0.087 | −0.055,0.228 | 0.229 | 18 | 14.376 | 0.422 | |
| THC | −0.001 | −0.001,0.000 | 0.102 | 18 | ||||
| CBD | 0.000 | −0.001,0.001 | 0.816 | 18 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.651 | 18 | ||||
| Numbness/paraesthesia | Intercept | −0.016 | −1.343, 1.311 | 0.981 | 9 | 0.106 | 1.000 | |
| THC | 0.000 | −0.011, 0.011 | 0.985 | 9 | ||||
| CBD | 0.000 | −0.027, 0.028 | 0.977 | 9 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.979 | 9 | ||||
| Psychiatric | Sleep problems | Intercept | 0.045 | −0.117,0.206 | 0.587 | 12 | 12.044 | 0.149 |
| THC | 0.000 | −0.001,0.001 | 0.973 | 12 | ||||
| CBD | −0.001 | −0.002,0.001 | 0.311 | 12 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.459 | 12 | ||||
| Dissociative/Thinking/Perception | Intercept | 0.026 | −0.135, 0.188 | 0.751 | 12 | 9.068 | 0.337 | |
| THC | 0.000 | −0.001, 0.001 | 0.718 | 12 | ||||
| CBD | −0.001 | −0.003,0.000 | 0.162 | 12 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.294 | 12 | ||||
| Somnolence/Drowsiness | Intercept | 0.066 | −0.067, 0.199 | 0.332 | 19 | 11.992 | 0.680 | |
| THC | −0.001 | −0.001,0.000 | 0.063 | 19 | ||||
| CBD | 0.000 | −0.001,0.001 | 0.500 | 19 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.465 | 19 | ||||
| Anxiety/Depression | Intercept | −0.027 | −0.515, 0.461 | 0.915 | 11 | 16.508 | 0.021 | |
| THC | 0.000 | −0.003,0.003 | 0.887 | 11 | ||||
| CBD | 0.002 | −0.006,0.010 | 0.580 | 11 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.733 | 11 | ||||
| Concentration/attention problem | Intercept | 0.502257 | 0.145686, 0.858829 | 0.006 | 11 | 1.154 | 0.992 | |
| THC | −0.003128 | −0.005162, −0.001094 | 0.003 | 11 | ||||
| CBD | −0.003718 | −0.006809, −0.000628 | 0.018 | 11 | ||||
| THC*CBD interaction | 0.000024 | 0.000007, 0.000041 | 0.006 | 11 | ||||
| Disorientation | Intercept | 0.103 | −0.045, 0.251 | 0.173 | 15 | 8.917 | 0.630 | |
| THC | −0.001014 | −0.001833, −0.000194 | 0.015 | 15 | ||||
| CBD | 0.001 | −0.001,0.002 | 0.315 | 15 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.386 | 15 | ||||
| Renal and Urinary | Renal & urinary symptoms | Intercept | 0.490 | −0.314, 1.295 | 0.233 | 10 | 1.199 | 0.977 |
| THC | −0.004 | −0.011,0.003 | 0.237 | 10 | ||||
| CBD | −0.011 | −0.026,0.004 | 0.154 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.178 | 10 | ||||
| Respiratory/Thoracic | Nose Tenderness | Intercept | 0.024 | −0.475, 0.523 | 0.925 | 10 | 0.001 | 1.000 |
| THC | 0.000 | −0.003,0.003 | 0.895 | 10 | ||||
| CBD | −0.001 | −0.009,0.008 | 0.906 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.888 | 10 | ||||
| Skin/Subcutaneous | Other skin problem | Intercept | 0.049 | −1.277, 1.376 | 0.942 | 9 | 2.369 | 0.796 |
| THC | 0.000 | −0.011, 0.012 | 0.972 | 9 | ||||
| CBD | −0.002 | −0.030, 0.026 | 0.883 | 9 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.952 | 9 | ||||
| Rash | Intercept | 0.012 | −0.488, 0.511 | 0.964 | 10 | 0.000 | 1.000 | |
| THC | 0.000 | −0.003,0.003 | 0.949 | 10 | ||||
| CBD | 0.000 | −0.009,0.008 | 0.955 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.946 | 10 | ||||
| Pressure Sore | Intercept | −0.041 | −1.368, 1.286 | 0.952 | 9 | 0.568 | 0.989 | |
| THC | 0.000 | −0.011, 0.012 | 0.961 | 9 | ||||
| CBD | 0.001 | −0.027, 0.029 | 0.941 | 9 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.946 | 9 | ||||
| Vascular | Hypotension | Intercept | 0.328 | −0.182, 0.839 | 0.207 | 10 | 0.276 | 1.000 |
| THC | −0.003 | −0.006, 0.001 | 0.099 | 10 | ||||
| CBD | −0.007 | −0.016,0.002 | 0.109 | 10 | ||||
| THC*CBD interaction | 0.000 | 0.000,0.000 | 0.070 | 10 |
Results
A total of 58 RCTs (n = 6611 participants; 1655.84 person-years of cannabinoid exposure) from 47 published articles were included (see Fig. 1, PRISMA flow chart for summary of study selection procedure and Supplementary Table 1a-b in the Supplementary Material for main study characteristics).
Supplementary Figures 1-7 (THC studies) and Figs 8–14 (THC: CBD combination studies) show the forest-plots and results stratified according to study design, for all cause and treatment-related AEs and SAEs, withdrawals, deaths, respectively.
Overall study quality (Grading of Recommendations Assessment, Development and Evaluation, GRADE) [15] is reported in Supplementary Table 1a and 1b. Risk of bias estimates are reported in Supplementary Figs 15(a,b) and 16(a,b). Sub-group meta-analysis at SOC level was done for systems with three or more AEs for THC (Supplementary Table 2a) and THC-CBD combination treatment (Supplementary Table 2b).
THC studies
In total, 31 RCTs (15 crossover and 16 parallel-arm) from 29 articles [20–48] (see Supplementary Table 1a in the Supplementary Material), reported on 1473 patients (analysed 1429; 1255.82 person-years; mean ± SD: 40.51 ± 181.32 person-years) on active and 1265 (analysed 1224) on control intervention, with mean reported ages across studies ranging from 50–87 years (males: 0–100%). All except four studies used placebo as control [20, 23, 32, 43].
Pooled IRDs for all cause (k = 21) and treatment-related AEs (k = 9) from all RCTs were 18.83 (95% Confidence Interval [CI], 1.47–55.79) and 16.35 (95% CI, 1.25–48.56) AEs per 1000 person-years, respectively. Pooled IRDs of the most commonly reported AEs (Table 1) suggested significantly higher incidence rate of dizziness/lightheadedness, somnolence/drowsiness, impaired mobility/balance/coordination, sedation, headache, dissociative/thinking/perception disorders, euphoria and dry mouth, amounting on average to an additional incidence of 0.819 (95% CI 0.489–1.232), 0.684 (95% CI 0.055–2.014), 0.078 (95% CI 0.006–0.234), 11.103 (95% CI 0.596–34.721), 5.287 (95% CI 0.191–17.324), 0.510 (95% CI 0.260–0.844), 9.117 (95% CI 0.765–26.669) and 1.059 (95% CI 0.346–2.161) per 1000 person-years respectively in active compared to control arms.
| MedDRA high-level grouping | Individual AE | Summary estimate | 95% CI (lower, upper) | P value | N | Q | Qp |
|---|---|---|---|---|---|---|---|
| Blood/Lymphatic System | Anaemia | 0.002 | 0.162, 0.230 | 0.863 | 16 | 2.105 | 1.000 |
| Cardiac | Dyspnoea | 0.002 | 0.159, 0.233 | 0.852 | 16 | 1.329 | 1.000 |
| Palpitation | 0.000 | 0.000, 0.000 | 0.992 | 15 | 1.436 | 1.000 | |
| Chest pain | 0.000 | 0.219, 0.187 | 0.938 | 16 | 3.720 | 0.999 | |
| Ear & Labyrinth | Vertigo | 0.000 | 0.185, 0.222 | 0.929 | 15 | 3.992 | 0.996 |
| Eye Disorders | Visual impairment/disturbances | 0.141 | 0.006, 0.681 | 0.103 | 15 | 1.201 | 1.000 |
| Gastrointestinal | Nausea | 0.021 | 0.082, 0.330 | 0.511 | 22 | 29.595 | 0.100 |
| Vomiting | 0.040 | 0.047, 0.378 | 0.348 | 18 | 10.998 | 0.857 | |
| Dry Mouth | 1.059 | 0.346, 2.161 | <0.001 | 20 | 43.062 | 0.001 | |
| General | Pain: non-specific | 0.000 | 0.178, 0.209 | 0.937 | 17 | 3.552 | 0.999 |
| Fatigue/tiredness | 0.003 | 0.024, 0.067 | 0.615 | 21 | 4.958 | 1.000 | |
| Weakness/reduced mobility | 0.009 | 0.125, 0.299 | 0.674 | 16 | 2.911 | 1.000 | |
| Infections | Unspecified | 0.001 | 0.030, 0.058 | 0.754 | 16 | 2.738 | 1.000 |
| UTI | 0.009 | 0.013, 0.091 | 0.378 | 16 | 0.210 | 1.000 | |
| RTI | 0.001 | 0.178, 0.226 | 0.908 | 16 | 14.231 | 0.508 | |
| Injury/Poisoning | Falls & injuries | 0.001 | 0.029, 0.060 | 0.723 | 15 | 2.330 | 1.000 |
| Investigations | Raised Gamma GT | 0.001 | 0.171, 0.232 | 0.881 | 16 | 3.370 | 0.999 |
| Metabolism/Nutritional | Fluid retention | 0.001 | 0.157, 0.196 | 0.913 | 16 | 2.129 | 1.000 |
| Decreased appetite | 0.001 | 0.169, 0.232 | 0.877 | 16 | 5.407 | 0.988 | |
| Increased appetite | 0.001 | 0.182, 0.223 | 0.920 | 16 | 1.990 | 1.000 | |
| Musculoskeletal | Spasm stiffness | 0.000 | 0.035, 0.052 | 0.852 | 17 | 1.998 | 1.000 |
| Joint disorders | 0.005 | 0.019, 0.077 | 0.513 | 16 | 0.116 | 1.000 | |
| Musculoskeletal pain | 0.039 | 0.000, 0.163, | 0.062 | 18 | 13.544 | 0.699 | |
| Nervous System | Sedation | 11.103 | 0.596, 34.721 | 0.011 | 2 | 1.855 | 0.173 |
| Dizziness/Lightheaded | 0.819 | 0.489, 1.232 | <0.001 | 25 | 61.099 | <0.001 | |
| Mobility/Balance/Coordination | 0.078 | 0.006, 0.234 | 0.007 | 17 | 21.216 | 0.170 | |
| Muscle weakness | 0.006 | 0.016, 0.082 | 0.453 | 18 | 5.052 | 0.998 | |
| Headache/migraine | 5.287 | 0.191, 17.324 | 0.016 | 8 | 10.475 | 0.163 | |
| Psychiatric | Sleep problems/Insomnia | 0.110 | 0.158, 1.125 | 0.373 | 17 | 9.656 | 0.884 |
| Dissociative/Thinking/Perception | 0.510 | 0.260, 0.844 | <0.001 | 17 | 17.454 | 0.357 | |
| Somnolence/Drowsiness | 0.684 | 0.055, 2.014 | 0.006 | 20 | 53.934 | <0.001 | |
| Anxiety/Depression | 0.008 | 0.014, 0.089 | 0.399 | 13 | 2.708 | 0.997 | |
| Concentration/attention problem | 6.361 | 0.051, 27.778 | 0.072 | 5 | 2.146 | 0.709 | |
| Euphoria | 9.117 | 0.765, 26.669 | 0.006 | 6 | 3.171 | 0.674 | |
| Renal and Urinary | Bladder symptoms | 0.009 | 0.128, 0.295 | 0.686 | 15 | 0.020 | 1.000 |
| Reproductive system | Male impotence | 0.058 | 0.438, 0.032 | 0.260 | 15 | 8.150 | 0.881 |
| Respiratory/Thoracic | Nose tenderness | 0.001 | 0.178, 0.229 | 0.902 | 15 | 1.985 | 1.000 |
| Skin/Subcutaneous | Other skin problem | 0.072 | 0.515, 0.033 | 0.244 | 15 | 3.397 | 0.998 |
| Rash | 0.002 | 0.161, 0.249 | 0.831 | 15 | 1.968 | 1.000 | |
| Pressure sore | 0.108 | 0.606, 0.015 | 0.153 | 15 | 1.225 | 1.000 | |
| Vascular | Hypotension | 0.000 | 0.195, 0.205 | 0.980 | 16 | 3.999 | 0.998 |
Meta-regression analyses suggested a significant association between cumulative THC dose per week across THC studies and incidence rate (expressed as IRSD) of some of the AEs (Table 2) such as dry mouth, dizziness/lightheadedness, mobility/balance/coordination difficulties, dissociative/thinking perception and somnolence/drowsiness. However, these estimates need to be interpreted with caution due to heterogeneity across the studies reporting the AEs.
Pooled IRDs for all cause (k = 28) and treatment-related (k = 24) SAEs from all RCTs were 0.002 (95% CI, 0.117–0.188) and 0.908 (95% CI, 0.05–4.54) SAEs per 1000 person years respectively. Pooled IRDs for all cause (k = 14) and treatment-related withdrawals (k = 28) from all RCTs were 0.052 (95% CI, 0.43–0.04) and 0.517 (95% CI, 0.01–2.34) withdrawals per 1000 person years respectively. IRDs for all cause deaths (k = 31) from all RCTs were 0.023 (95% CI, 0.002–0.012) deaths per 1000 person-years.
Neither Egger’s test nor ‘Trim and fill’ method indicated publication or other selection bias for any of the other outcomes except for all cause AEs (Supplementary Figs 17a-f, 18a-f, 19a-e, 20a-c). For all cause AEs for all RCTs as outcome, Egger’s test was p = 0.0265, and Trim and fill method indicated one missing study. Meta-regression analyses indicated effects of clinical condition on estimated effect of THC treatment on all cause AEs, which seemed to be mainly related to a significantly lower estimated effect in crossover studies investigating neurodegenerative disorder (p = 0.005) patients compared to other conditions.
THC: CBD combination
A total of 27 studies (five crossover and 22 were parallel-arm; see Supplementary Table 1b in the Supplementary Material for additional details) from 22 articles [24, 26, 27, 31, 42, 49–64] reported on 1977 patients (analysed 1952; 400.02 person-years; mean ± SD: 14.82 ± 27.71 person-years) on active and 1896 (analysed 1872) on placebo, with mean reported ages across studies ranging from 51 to 67 years (males: 0–80%). All studies used placebo as control.
Pooled IRDs for all cause (k = 16) and treatment-related (k = 10) AEs from all RCTs was 19.37 (95% CI, 4.24–45.47) and 11.36 (95% CI, 2.55–26.48) respectively. Pooled IRDs of AEs (Table 3) from cumulative THC: CBD combination treatment across all studies per 1000 person-years for each single AE suggested significantly higher incidence rate of nausea, vomiting, dry mouth, fatigue/tiredness, dizziness/lightheadedness, somnolence/drowsiness and disorientation, amounting on average to an additional incidence of 0.674 (95% CI 0.100–1.7 54), 0.214 (95% CI 0.000–0.837), 1.227 (95% CI 0.093–3.650), 0.439 (95% CI 0.025–1.361), 2.467 (95% CI 0.519–5.862), 1.650 (95% CI 0.361–3.875) and 2.536 (95% CI 0.458–6.290)per 1000 person-years respectively in active compared to control arms.
| MedDRA high-level grouping | Individual AE | Summary estimate | 95% CI (lower, upper) | P value | N | Q | Qp |
|---|---|---|---|---|---|---|---|
| Blood/Lymphatic System | Anaemia | 0.003 | 0.115, 0.204 | 0.780 | 14 | 2.248 | 1.000 |
| Cardiac | Dyspnoea | 0.004 | 0.112, 0.212 | 0.757 | 11 | 1.349 | 0.999 |
| Palpitation | 0.002 | 0.153, 0.227 | 0.847 | 10 | 8.871 | 0.449 | |
| Ear & Labyrinth | Vertigo | 1.602 | 0.001, 6.579 | 0.056 | 11 | 24.747 | 0.006 |
| Eye Disorders | Visual impairment/disturbances | 0.354 | 0.107, 2.305 | 0.206 | 9 | 7.400 | 0.494 |
| Gastrointestinal | Nausea | 0.674 | 0.100, 1.754 | 0.001 | 21 | 24.371 | 0.227 |
| Vomiting | 0.214 | 0.000, 0.837 | 0.045 | 19 | 23.852 | 0.160 | |
| Dry mouth | 1.227 | 0.093, 3.650 | 0.007 | 17 | 52.664 | <0.001 | |
| General | Pain: non-specific | 0.005 | 0.276, 0.444 | 0.818 | 14 | 20.025 | 0.095 |
| Fatigue/tiredness | 0.439 | 0.025, 1.361 | 0.010 | 19 | 29.920 | 0.038 | |
| Weakness/reduced mobility | 0.008 | 0.107, 0.258 | 0.670 | 14 | 5.839 | 0.952 | |
| Infections | Unspecified | 0.002 | 0.159, 0.230 | 0.858 | 8 | 0.015 | 1.000 |
| UTI | 0.005 | 0.111, 0.219 | 0.740 | 11 | 0.580 | 1.000 | |
| RTI | 0.000 | 0.142, 0.176 | 0.916 | 11 | 2.693 | 0.988 | |
| Injury/Poisoning | Falls & injuries | 0.136 | 0.004, 0.644 | 0.096 | 10 | 4.121 | 0.903 |
| Investigations | Raised Gamma GT | 0.000 | 0.177, 0.201 | 0.951 | 10 | 0.323 | 1.000 |
| Metabolism/Nutritional | Decreased appetite | 0.011 | 0.076, 0.237 | 0.585 | 16 | 8.888 | 0.883 |
| Increased appetite | 0.067 | 0.065, 0.600 | 0.323 | 10 | 6.947 | 0.643 | |
| Anorexia | 0.010 | 0.078, 0.228 | 0.606 | 14 | 13.756 | 0.391 | |
| Musculoskeletal | Back pain | 0.000 | 0.187, 0.194 | 0.984 | 10 | 0.169 | 1.000 |
| Spasm stiffness | 0.002 | 0.153, 0.232 | 0.839 | 10 | 5.902 | 0.750 | |
| Musculoskeletal pain | 0.000 | 0.178, 0.205 | 0.946 | 9 | 0.682 | 1.000 | |
| Neoplasms | Neoplasms progression | 0.009 | 0.074, 0.217 | 0.606 | 16 | 9.477 | 0.851 |
| Nervous System | Altered taste | 0.237 | 0.039, 1.367 | 0.163 | 13 | 16.906 | 0.153 |
| Dizziness/Lightheaded | 2.467 | 0.519, 5.862 | <0.001 | 24 | 75.465 | <0.001 | |
| Headache/migraine | 0.024 | 0.037, 0.250 | 0.385 | 18 | 19.517 | 0.300 | |
| Numbness/paraesthesia | 0.009 | 0.284, 0.117 | 0.668 | 9 | 0.111 | 1.000 | |
| Psychiatric | Sleep problems | 0.001 | 0.148, 0.190 | 0.904 | 12 | 13.621 | 0.255 |
| Dissociative/Thinking/Perception | 0.010 | 0.098, 0.258 | 0.640 | 12 | 12.317 | 0.340 | |
| Somnolence/Drowsiness | 1.650 | 0.361, 3.875 | <0.001 | 19 | 32.569 | 0.019 | |
| Anxiety/Depression | 0.716 | 0.085, 3.933 | 0.145 | 11 | 30.209 | 0.001 | |
| Concentration/attention problem | 0.277 | 0.060, 1.685 | 0.181 | 11 | 15.614 | 0.111 | |
| Disorientation | 2.536 | 0.458, 6.290 | 0.001 | 15 | 40.301 | <0.001 | |
| Renal and Urinary | Renal & urinary symptoms | 0.001 | 0.161, 0.214 | 0.890 | 10 | 5.094 | 0.826 |
| Respiratory/Thoracic | Nose Tenderness | 0.001 | 0.136, 0.192 | 0.867 | 10 | 0.165 | 1.000 |
| Skin/Subcutaneous | Other skin problem | 0.029 | 0.072, 0.367 | 0.448 | 9 | 5.806 | 0.669 |
| Rash | 0.000 | 0.150, 0.177 | 0.935 | 10 | 0.038 | 1.000 | |
| Pressure Sore | 0.059 | 0.037, 0.463 | 0.274 | 9 | 0.605 | 1.000 | |
| Vascular | Hypotension | 0.003 | 0.141, 0.243 | 0.792 | 10 | 5.880 | 0.752 |
Meta-regression analyses suggested a significant association between individual AEs and weekly doses of THC and CBD and their interaction expressed as IRSD (Table 4) for some of the AEs such as palpitations (CBD and THC*CBD interaction), altered taste (CBD), dizziness and lightheadedness (THC), concentration and attention problems (THC, CBD, THC*CBD interaction) and disorientation (THC).
Pooled IRDs for all cause (k = 26) and treatment-related (k = 22) SAEs from all RCTs was 0.056 (95% CI, 0.02–0.39) and 0.058 (95% CI, 0.08–0.59) respectively. Pooled IRDs for all cause (k = 22) and treatment related (k = 27) withdrawals from all RCTs was 0.036 (95% CI, 0.44–0.08) and 0.489 (95% CI, 0.05–1.37) respectively. IRDs for all cause deaths (k = 27) from all RCTs were 0.010 (95% CI, 0.04–0.17).
Neither Egger’s test nor ‘Trim and fill’ method indicated significant effect of publication or other selection bias for any of the outcomes except for all cause AEs (Supplementary Figs 21a-d, 22a-f, 23a-e, 24a-c). For all cause AEs for all RCTs as outcome, Egger’s test was p = 0.0332, and ‘Trim and fill’ method indicated two missing studies. Meta-regression analysis indicated that there was a significant effect of neurodegenerative disorder on effect-size for all cause withdrawals (p = 0.044) compared to other conditions. Except these, moderators such as study design or type of intervention did not significantly influence estimated effects of THC:CBD combination treatment on any of the outcomes assessed.
Discussion
In this systematic review and meta-analysis, we estimated the additional risk of organ-specific and total AEs attributable to exposure with medicinal cannabinoids in middle aged and older adults by assessing incidence rate differences of AEs. For medications containing THC-alone, on average this amounted to an additional incidence of ~19 all-cause and ~16 treatment-related AEs, whilst for THC:CBD combination treatments, there was an additional incidence of ~19 all-cause and ~11 treatment-related AEs per 1000 person-years of exposure.
Importantly, in this meta-analysis, we identified specific AEs associated with THC in THC alone or THC: CBD combination treatments. We found that THC significantly increased the incidence of dizziness/lightheadedness, somnolence/drowsiness, impaired mobility/balance/coordination, sedation, headache, dissociative/thinking/perception disorders, euphoria and dry mouth amounting on average to an additional incidence from ˂1 to ~11 per 1000 person-years, respectively. Further, there was a dose-dependent increase in the additional incidence of the aforementioned AEs as well as dry mouth and dissociative/thinking/perception problems, such that the higher the weekly dose of THC the higher was the additional attributable incidence of these specific AEs. These individual AEs are worth noting, as they not only impair quality of life but may also contribute to risk of falls in this age group [11, 65, 66], a leading cause of fatal and nonfatal injuries amongst older people [66, 67]. Incidence of psychotic-like experiences such as dissociative/thinking/perception abnormalities was significantly increased in THC alone studies and associated with higher THC doses as noted in our previous observation [9] and can be distressing to patients and their carers.
In addition, further analysis showed that THC and CBD in combination significantly increased the incidence of nausea, vomiting, dry mouth, fatigue/tiredness, dizziness/lightheadedness, somnolence/drowsiness and disorientation, amounting on average to an additional incidence of ˂1 to ~3 per 1000 person-years, respectively. This highlights the need to be mindful of higher weekly doses of THC and CBD in the older population, who are also on other medications for multiple co-morbidities. Furthermore, there was a dose-dependent relationship of weekly CBD doses with palpitation, altered taste and problems of inattention and concentration. Some of these effects are consistent with another meta-analysis, though they also reported abnormal liver function tests, decreased appetite, diarrhoea, pneumonia [10]. However, most of the studies were in those with childhood epilepsies and authors conjectured that this may have been due to interaction of CBD with other medications such as clobazam and/or sodium valproate and excluding these studies showed only diarrhoea as an adverse event for CBD [10]. It is interesting to note that these side-effects were not found in our analysis for middle aged and older adults, although interaction with other medications was not examined.
This report, which includes data from 58 RCTs is an update of our previous meta-analysis summarising 46 RCTs, and confirms that whilst middle aged and older adults are at greater risk of both treatment-related and all cause AEs from CBMs containing THC, they are not associated with SAEs, withdrawals or death [8]. Critically, we extend previous literature by providing the first pooled estimate of incidence of AEs attributable to CBMs. As described before, previous reviews of AEs with CBMs have either been qualitative, did not specifically focus on middle aged and older adults, or did not consider the effects of THC, CBD, or their combination separately [8] or focused on specific clinical indications [7, 68–71]. They have sometimes reported conflicting findings in terms of AEs, likely contributed partly by varying pooled sample sizes, as well as the quality of included studies (details in Supplementary Discussion). In general, those with larger number of pooled participants tend to show a modest but significant increase in risk of AEs as we have reported here, though results vary in terms of specific individual AEs reported [68–71]. By pooling data across all indications, here, we extend previous evidence to provide a more comprehensive and robust CBM-specific summary of the plethora of AEs associated with CBM use in adults over the age of 50. We also provide dose–response relationship estimates that have not been reported before to the best of our knowledge, which may help clinicians and researchers in dosage decisions in different contexts [72]. Further, across different meta-analyses, AEs have commonly been reported in terms of risk ratios, odds ratios or incidence rate ratios. Whilst these metrics are useful to convey whether there are significant additional risks associated with CBMs, they do not lend themselves as easily to everyday use. One needs to be aware of the baseline risk in the control (or placebo) group, which often remains unclear, to estimate the additional incidence associated with exposure to the CBM over a period of time. By estimating the additional incidence rate of all AEs as well as specific AEs associated with CBM use, we hope that results reported here will allow easier use of this information in the clinical and research contexts, especially in terms of estimating and communicating additional risk.
Limitations
Our review has some limitations. Using GRADE Framework, we found evidence of moderate to high quality evidence in ~64% of studies and low to very low quality in 36% of studies. Some of the trials had inadequate information about randomisation, allocation concealment, selective outcome reporting and objective outcomes which restricts interpretation of results (see supplementary material for full details of bias). However, we included double-blind studies to increase the methodological rigour of the contributing evidence. Therefore, these results need to be considered in light of potential selective reporting of side-effects, often relatively short duration of treatment in included RCTs and imprecision in the estimated IRD values. Notwithstanding this, we provide estimates from a larger pool of patients with indication that publication or other selection biases are unlikely to have influenced the pooled estimates reported here [8]. Further, our dose–response relationship tables may also aid dosage and formulation decisions in clinicians and researchers using CBMs by allowing them to compute ball-park estimates of incidence of AEs at different dose ranges (see footnotes for Tables 2 and 4 for guidance on calculations).
Unlike in other recent meta-analyses, which reported summary effects separately based on indications [7, 68–71], we pooled safety and tolerability data in middle aged and older adults across a broad range of indications. Whilst this may have added to the heterogeneity of the data synthesised, it allowed us to comprehensively estimate separately the tolerability of the two broad categories of cannabinoid-based interventions i.e. THC only and THC:CBD combination, something that has not been done before. This is a key strength of the present approach, given the reported opposite effects of different cannabinoids [3, 73]. Another important strength of the present report relates to the analysis of the effects of moderators to examine the extent to which they may have influenced results, in particular relationship with cannabinoid weekly doses used and interaction.
There is growing evidence that THC and CBD may have opposing acute effects on autonomic arousal, brain [73] and cardiovascular function [74] and CBD may mitigate some of the harmful effects of THC on cognition and behaviour [73, 75, 76], consistent with their opposing effects on some of their molecular targets [3]. The suggestion that THC and CBD may have distinct tolerability profiles, with certain side-effects noticeable in those taking THC-only formulations whilst adverse effects may even be mitigated in those taking THC and CBD in combination, underscored the importance of examining their safety and tolerability separately as well as dose–response relationships as we have done here. Our findings of AEs are consistent with other meta-analyses but in addition show the association of weekly doses with some of the adverse effects of THC and CBD. Few studies have examined the drug–drug interaction of CBMs given their effect on cytochrome p450 enzymes [77], an important likely determinant of tolerability and dose adjustment in older people, and therefore worthy of investigation in future studies.
Conclusions
Results of the present study suggest that THC-containing CBMs are associated with certain gastrointestinal, neurological and psychiatric side-effects in a dose-related manner, both for THC only and for THC: CBD combinations some of which can be mitigated by CBD. Efficacy should additionally consider dose–response relationships with regard to tolerability whilst prescribing CBMs, particularly in older people.
Supplementary Material
Contributor Information
Latha Velayudhan, Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK.
Sara Pisani, Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK.
Marta Dugonjic, Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK.
Katie McGoohan, Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK.
Sagnik Bhattacharyya, Division of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK.
Declaration of Conflicts of Interest
SB has participated in advisory boards for or received honoraria as a speaker from Reckitt Benckiser, EmpowerPharm/SanteCannabis and Britannia Pharmaceuticals. All of these honoraria were received as contributions towards research support through King’s College London, and not personally. SB and LV have collaborated with Beckley Canopy Therapeutics/Canopy Growth (investigator-initiated research) wherein they supplied study drug for free for charity (Parkinson’s UK) and NIHR (BRC) funded research.
Declaration of Sources of Funding
SB and LV have received grants from Parkinson’s UK, Psychiatry Research trust, Rosetrees Trust, Alzheimer's Research UK and National Institute of Health Research. SP PhD studentship is funded by Parkinson’s UK. The funding sources had no involvement in this research.
References
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