Cannabis Use Disorder Emergency Department Visits and Hospitalizations and 5-Year Mortality

Authors: Daniel T. Myran, Michael Pugliese, André J. McDonald, Jennifer Xiao, Benedikt Fischer, Yaron Finkelstein, Peter Tanuseputro, Joseph Firth, Amir Pakpour, Chih-Wei Hsu, Wing-Chung Chang, Marco Solmi

Affiliations: Department of Family Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; ICES uOttawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Bruyère Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Peter Boris Centre for Addictions Research, St Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada; Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada; Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada; Research & Graduate Studies, University of the Fraser Valley, Abbotsford, British Columbia, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Federal University of Sao Paulo, São Paulo, Brazil; School of Population Health, University of Auckland, Auckland, New Zealand; Divisions of Emergency Medicine and Clinical Pharmacology and Toxicology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Nursing, School of Health and Welfare, Jönköping University, Jönköping, Sweden; Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Psychiatry, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Brain & Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China; Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada; Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany

License: Copyright 2025 Myran DT et al. JAMA Network Open. CC BY 4.0 This is an open access article distributed under the terms of the CC-BY License.

Article links: DOI: 10.1001/jamanetworkopen.2024.57852  |  PubMed: 39913138  |  PMC: PMC11803479

Relevance: Moderate: mentioned 3+ times in text

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Introduction

Cannabis use is increasing globally and is the third most commonly used drug after alcohol and nicotine. Cannabis use is associated with the development of several major psychiatric illnesses, with the largest body of evidence being for psychosis and schizophrenia.^1,2,3,4,5 Prior research has shown associations between cannabis use and increased risk of self-harm and suicide in adolescents and young adults.^6,7 Intoxication with tetrahydrocannabinol (THC), the psychoactive component of cannabis, is also associated with a greater risk of fatal motor vehicle collisions.⁸ Growing data suggest that cannabis legalization and particularly commercialization of cannabis—allowing widespread retail access and promotion to cannabis—may result in increases in cannabis use, cannabis use disorders (CUDs), and other associated harms.^9,10,11,12 Importantly, despite large increases over time in patterns of cannabis use that are associated with CUDs, including daily use and high potency use, evidence on the association between CUDs and mortality is limited.¹³

A single study of 6445 individuals treated for CUD in Denmark reported a 4.7 standardized mortality ratio relative to the general population.¹³ However, the study only included 142 deaths in the CUD group, captured a very young cohort, and did not account for comorbid substance use disorders.¹³ CUDs in youths with mood disorders have been found to be associated with increased risk of all-cause mortality.⁶ A larger number of studies have examined the association between differing levels of cannabis use and mortality, with some evidence suggesting that more frequent cannabis use may be associated with increased risk of death. A study of 121 895 participants in the United Kingdom biobank found that self-reported “heavy cannabis use” (>100-lifetime episodes of cannabis use) was associated with a 1.49-fold increase in all-cause mortality and a 2.67-fold increase in cardiovascular mortality in females relative to never users.¹⁴ Longitudinal studies of Swedish men registering for compulsory military training found that individuals who had self-reported using cannabis more than 50 times by 19 years of age had a modest elevation in mortality risk over 40 years of follow-up.^15,16 US studies have found no association between current cannabis use or lifetime cannabis use at the time of survey completion and mortality.^17,18 Collectively, almost no data are available on mortality risks associated with CUDs, and studies on the association between overall cannabis use and mortality is limited by using measures of cannabis use that are less clinically relevant and lacking biological plausibility (eg, lifetime ever use), inadequate adjustment for comorbid health factors, self-report for cannabis exposures, and lack of details on causes of death.

To address these gaps we completed a population-level study in Ontario, Canada’s most populous province (15.1 million residents in 2022), where medical cannabis has been widely available since 2015 and nonmedical cannabis was legalized in October 2018.¹⁰ We examined whether individuals with hospital-based (emergency department [ED] visit or hospitalization) care for CUD were at increased risk of all-cause mortality compared with the general population or individuals with hospital-based care for another substance. We examined differences in cause-specific mortality between individual hospital-based CUD care and the general population.

Methods

Study Design

We conducted a retrospective population-level cohort study of all individuals aged 15 to 105 years in Ontario, Canada. We included all individuals who were alive and eligible for the province’s public health insurance program, which provides universal access to all hospital and medically necessary physician-based services for 97% of residents of Ontario between January 2006 and December 2021, with follow-up until December 2022 for death. We identified all individuals with an incident CUD diagnosis and compared them with matched members of the general population or individuals with another substance use disorder diagnosis. This study was approved by the privacy office at ICES. ICES is a prescribed entity under Ontario’s Personal Health Information Protection Act (PHIPA). Section 45 of PHIPA authorizes ICES to collect and analyze personal health information without patient consent for approved research projects. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline was followed in the reporting of this study.

Data Sources

Clinical data capturing all ED visits, hospitalizations, and outpatient physician visits, along with sociodemographic characteristics, were obtained using 7 individual-level databases at ICES. Overall mortality was obtained from the Registered Persons Batabase (RPDB). Cause of death was obtained from the Office of the Registrar General Vital Statistics Database (ORGD), which records the cause of death from individual death certificates. These datasets were linked using unique encoded identifiers and analyzed at ICES (formerly the Institute for Clinical Evaluative Science). In Ontario, a coroner (who must be a licensed physician) must, by law, investigate all deaths from unnatural causes to determine the cause of death. Details on additional datasets are available in eMethods 1 in Supplement 1.

Exposures

Hospital-based CUD care was defined as an ED visit or hospitalization with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes F12.X (mental and behavioral disorders due to use of cannabis) or T40.7 (poisoning by or adverse effects of cannabis, including derivatives) as the main or contributing reason for the visit. We used ICD-9 and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) codes 304.30 (cannabis dependence) and 305.20 (cannabis abuse) to identify hospitalizations in specialized mental health beds.

For a secondary analysis, we identified individuals with incident hospital-based care for other substance use disorders, including alcohol, opioids, or stimulants, and compared the risk of death between the substance use disorder types. We identified incident hospital-based care when an ICD-10 or DSM-5 code for the substance was the main or contributing reason for the visit (see eMethods 2 in Supplement 1 for codes by substance). All substance use disorder diagnoses were incident diagnoses defined as no prior hospital-based diagnoses for that substance in at least the past 3 years.

Outcomes

The primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality using ICD-10 diagnostic codes on death certificates using previously published methods.¹⁹ Each death could have more than 1 contributing cause, and we included immediate and underlying causes of death. We examined the following causes: alcohol poisoning, opioid poisoning, poisoning by other drugs, trauma (subdivided into motor vehicle collisions, fire, drowning, and falls and other accidental injuries), intentional self-harm, cancer (subdivided into lung cancer), infection, diseases of the circulatory system, respiratory system, and gastrointestinal system using previously established coding. See eMethods 3 in Supplement 1 for coding for different causes of death.¹⁹

Covariates

We obtained sociodemographic information for each individual, including age, sex, rural residence, neighborhood income quintile, and whether or not they were immigrants to Canada since 1985. We obtained information on mental and substance use health care use in the 3 years before the index event, including outpatient mental health visits (primary care clinicians or psychiatrist) and ED visits and hospitalizations for substance use (alcohol, opioids, cocaine, amphetamines, and other) and mental disorders (mood, anxiety, self-harm, and other) using previously established coding.²⁰ We identified previous diagnoses of 9 chronic health conditions using established coding.²¹ See eMethods 4 in Supplement 1 for covariate definition codes. Covariates in our study were complete except for rural residence and neighborhood income-quintile (0.60% missing).

Statistical Analysis

Main Analysis

We used greedy matching in a 1:4 ratio to compare individuals with hospital-based CUD care to general population members. We matched on age, sex, and index date of the incident ED visit or hospitalizations for CUD. We compared the characteristics of individuals using descriptive statistics and standardized mean differences (SMD).²² Characteristics were obtained at the time of the incident hospital-based CUD care or assigned index date for matched comparators. We completed analyses on all-cause mortality until December 2022 and completed analyses on cause-specific mortality until December 2018. These time points reflect the end of data availability for overall mortality and cause of death.

For our primary analysis, we compared the risk of all-cause mortality between individuals with hospital-based CUD care to the matched general population using cumulative incidence functions and cause-specific Cox proportional hazard models. We adjusted for the following prespecified variables in 3 general categories. First, sociodemographics including age (in splines at the 5th, 27.5th, 50th, 72.5th, 95th percentiles), sex, neighborhood income quintile (6 levels including missing), immigrant status, and rurality (3 levels including missing). Second, comorbid mental health and substance use, including outpatient mental health care in the past 3 years (dichotomous family medicine, dichotomous psychiatry visit), substance hospital-based care (alcohol, cocaine, amphetamines, opioids, polysubstance use, other substance) in the past 3 years, and mental health hospital-based care (schizophrenia, depression, anxiety, deliberate self-harm in the past 3 years), and other mental health condition. Third, comorbid chronic conditions with treatment in the past 3 years, including hypertension, diabetes, asthma, cardiovascular disease, chronic obstructive pulmonary disease (COPD), cancer, kidney failure, and dementia. Given anticipated differences in mortality risk by age and sex, we conducted prespecified subgroup analyses examining risk and cause of death by age and sex strata.

For our secondary analysis comparing the risk of mortality for individuals with hospital-based care for different types of substance use disorders, individuals could experience up to 4 incident substance use disorders. We used robust sandwich covariance estimators to account for repeat measurements of unique individuals.

Sensitivity Analyses

We conducted 4 sensitivity analyses of our primary analysis. First, we included only individuals with no outpatient, or hospital-based care for mental or substance use disorders in the 3 years before their index date. Second, we used an unlimited lookback period for comorbid mental and substance use disorders and chronic health conditions. Third, we compared mortality risk when the cannabis code was the primary reason for the CUD visit compared with a contributing reason for the visit. Finally, we calculated an E-value estimating the hazard ratio [HR] required by an unmeasured confounder to explain away any observed association.²³

Model statistical significance was determined by 95% CIs that did not cross 1. Statistical analyses were conducted using SAS Enterprise Guide 8.3 (SAS Institute) from September to December 2024.

Results

During the study period, 11 622 571 individuals were eligible for inclusion in analysis, of whom 107 103 (0.9%) had incident hospital-based care for CUD (eFigure 1 in Supplement 1). Our primary matched analysis included 527 972 individuals (mean [SD] age, 29.9 [13.6] years; 330 034 [62.5%] male) with a median (IQR) follow-up of 5 (3-9) years, of which 106 994 had incident CUD. Individuals with hospital-based CUD care were more likely to live in low-income neighborhoods (29.0% vs 19.7% in the lowest income quintile) and be longstanding residents of Canada (91.1% vs 81.9%) compared with matched general population members. Individuals with hospital-based CUD care were more likely to have had an ED visit or hospitalization for substance use (38.9% vs 1.7%) or a mental disorder (34.8% vs 3.0%) in the past 3 years along with an outpatient mental health or addiction visit (68.2% vs 26.1%) relative to the general population. Individuals with hospital-based CUD care were more likely to have been diagnosed with several chronic conditions including hypertension (8.0% vs 6.6%), asthma (25.9% vs 19.7%), COPD (1.6% vs 0.4%), cardiovascular disease (1.1% vs 0.6%), and kidney failure (2.1% vs 0.6%) compared with the general population with no difference in prior cancer diagnoses (13.5% vs 13.1%) (Table 1). The annual number of cases of individuals with incident hospital-based CUD care increased by 6.1-fold during our study period (456 in 2006 to 3263 in 2021). See eFigure 2 in Supplement 1 for annual changes.

Our sensitivity analysis of individuals without treatment for mental or substance use disorders in the past 3 years included 22 843 individuals (21.3%) with hospital-based CUD care and 306 691 matched members (72.9%) of the general population (Table 1). Our secondary analysis comparing individuals with hospital-based CUD care with other substance use disorders included 519 528 individuals, of which 372 820 (71.8%) had an incident hospital-based care for alcohol use disorder, 106 994 (20.6%) had an incident CUD, 78 985 (15.2%) had an incident stimulant use disorder, and 71 621 (13.8%) had an incident opioid use disorder. See eTable 1 and eFigures 3, 4, and 5 in Supplement 1 for cohort flows.

Cumulative incidence functions for mortality risk over time for individuals with hospital-based CUD care and comparators are presented in Figure 1. Within 5 years of care for CUD, 3770 individuals (3.5%) died compared with 2550 members (0.6%) of the matched general population. After adjustment for sociodemographics, prior substance use, mental health care, and chronic conditions, the risk of death was greater (adjusted HR [aHR], 2.79 [95% CI, 2.62-2.97]; E-value, 5.0) for individuals with hospital-based CUD care relative to the general population. After excluding individuals with any outpatient, or hospital-based for mental health or substance use in the past 3 years, the absolute risk of death was diminished (5-year risk of death: 1.9% vs 0.5%), but the relative increase in risk was maintained for individuals with hospital-based CUD care relative to the general population (aHR, 2.60 [95% CI, 2.33-2.91]) (Table 2). Sensitivity analysis excluding individuals with any mental health or substance use care since the start of the study look-back in 2003 and comparing mortality risk for when the CUD diagnosis was the main or contributing reason for visit showed similar results (eTable 2 in Supplement 1).

Our secondary analysis found that individuals with incident hospital-based CUD care were at a lower risk of death relative to individuals with another type of incident hospital-based substance use disorder. Alcohol use disorder (aHR, 1.30 [95% CI, 1.26-1.34]), stimulant use disorder (aHR, 1.69 [95% CI, 1.62-1.75]), and opioid use disorder (aHR, 2.19 [95% CI, 2.10-2.27]) were associated with increased risk of death at 5 years compared with individuals with hospital-based CUD care. See Figure 1C for cumulative incidence function and Table 2 for outcomes.

Figure 2 presents the proportion of individuals who died within 5 years based on age, sex, hospital-based CUD care, and comorbid substance and mental health disorders and HRs for elevations in risk. For both individuals with hospital-based CUD care and the general population, the absolute risk of death was higher in males and increased with age. Compared with the general population, there were larger relative increases in risk of death in younger individuals with hospital-based CUD care than in older individuals. For example, females aged 25 to 44 years with hospital-based CUD care and no comorbid mental health or substance use disorders were at a 5.9-fold increased risk of death relative to the general population (aHR, 5.91 [95% CI, 3.55-9.85]), compared with a 2.1-fold increased risk of death in women aged 65 years or older (aHR, 2.15 [95% CI, 1.62-2.84]) (eTable 3 in Supplement 1).

Table 3 presents the analyses of main and underlying causes of death at 5 years in individuals with hospital-based CUD care relative to the general population. Individuals with hospital-based CUD care were at increased risk of all investigated types of death, but at particularly elevated risk of death by suicide (aHR, 9.70 [95% CI, 6.04-15.57]), trauma (aHR, 4.55 [95% CI, 3.55-5.82]), opioid poisoning (aHR, 5.03 [95% CI, 2.86-8.84]), other drug poisonings (aHR, 4.56 [95% CI, 3.11-6.68]), and lung cancer (aHR, 3.81 [95% CI, 2.39-6.07]) relative to the general population. After excluding individuals with comorbid substance and health disorders, similar patterns of elevations in risk of death were observed (eTable 4 in Supplement 1). In individuals with hospital-based CUD care aged 15 to 44 years, a greater proportion of deaths involved substances, trauma, and self-harm (eTable 5 in Supplement 1); whereas in individuals aged 45 years and older, a greater proportion of deaths involved cancer and diseases of the circulatory and respiratory systems (eTable 6 in Supplement 1).

Discussion

In this longitudinal population-based cohort study of 11.6 million people, we found that individuals with hospital-based care for CUD were at a 6-fold elevated risk of death compared with individuals of the same age and sex. There continued to be a 3-fold increased risk of death when trying to isolate the effect of CUD by accounting for further differences in sociodemographic and comorbid mental and substance use disorders and other chronic health conditions. Males and females with hospital-based CUD care of all ages were at elevated risk of death, but the relative increases in risk were the greatest in individuals aged 25 to 44 years. Individuals with hospital-based CUD care were at increased risk of all investigated types of death but at particularly elevated risk of death by suicide, trauma, opioid, alcohol, and other drug poisoning and lung cancer relative to the general population. Individuals with hospital-based CUD care had a slightly lower risk of death within 5 years than individuals with alcohol use disorder and about half the risk of death of individuals with hospital-based care for stimulants or opioids.

Despite large increases in the prevalence of CUDs, to date only a single study has examined whether individuals with CUDs are at increased risk of death. Adding to the literature, to our knowledge, we present the largest study to date on the longitudinal association between hospital-based treatment for a CUD and mortality. Our sample included 106 994 individuals with CUD care, of whom 6059 (5.7%) died by the end of follow-up, more than 43 times the next largest of prior population-based studies.^13,24 CUDs may increase the risk of death through a variety of mechanisms. Exposure to and intoxication from THC has previously been associated with an increased risk of death by trauma, including motor vehicle collisions, violence, and death by suicide.^7,8,25 The largest increases in cause-specific mortality in our study were for suicide (9.7-fold greater risk) and trauma (4.6-fold greater risk). THC has short-term hemodynamic effects and can increase blood pressure and heart rate and reduce cardiac perfusion, all of which may raise the risk of cardiovascular events and deaths.²⁶ Long-term exposure to cannabis smoke and particulate matter might increase the risk of several chronic diseases, including cancer, chronic respiratory diseases and cerebrovascular disease.^27,28 We observed more than double the risk of death from cardiovascular and respiratory disease and a 3.8-fold increase for lung cancer death in individuals with hospital-based CUD care than the general population. Individuals with CUDs have high rates of alcohol and tobacco use, and part of the elevated risk of death from the chronic disease may be driven by the harmful effects of tobacco and alcohol.^29,30,31 However, emerging evidence suggests that cannabis use may be independently associated with cardiovascular disease.^28,32 Deaths in individuals with CUD are also likely confounded by concurrent high-risk behaviors. In our study over 20% of deaths in individuals with hospital-based CUD care involved alcohol, opioids or another substance. Finally, CUD may also result in the development of severe mental health disorders, including schizophrenia and bipolar disease or worsen these disorders for individuals who already have them.^4,5 Individuals with bipolar disorder and schizophrenia are at elevated risk of death compared with the general population.³³ In addition, comorbid substance use disorders in individuals with bipolar disorder and schizophrenia have been shown to worsen treatment outcomes and increase the risk of death.³⁴

We found that hospital-based CUD care was associated with slightly lower risk of death than hospital-based OUD care and a much lower risk than hospital-based StUD or OUD care However, frequent cannabis use and the use of higher-potency cannabis, the principal determinants of developing a CUD, are both increasing rapidly globally.^35,36 In 2022, an estimated 17.7 million US individuals reported daily or near daily (DND) cannabis use, a higher number than those with DND drinking.³⁷ Although our study cannot establish causality, individuals with a hospital-based diagnosis of CUD were at elevated risk of death. Although CUD may not be directly responsible, our findings highlight a growing segment of the population who are at elevated risk of death and may benefit from preventive measures.

Limitations

Our study has limitations. First, not all individuals with CUD seek or access care, and our study did not have access to information on outpatient care for CUD. Consequently, our results capture a high-risk subpopulation of people with CUD and the findings may not generalize to CUDs that do not require hospital-based care. Second, we did not have detailed data on the length, frequency (eg, monthly vs daily) and type of cannabis used (smoked vs ingested) for individuals with a hospital-based CUD diagnosis in our study which may be relevant for the relationship between CUD and mortality. Similarly, there continue to be large gaps in the relationship between cannabis use in general (eg, not necessarily CUD) and mortality which were not evaluated in this study. Third, although we observed an association between hospital-based CUD care and mortality, unmeasured confounding (eg, tobacco use, risk-taking) may have biased our estimate away from the null. However, our E-value sensitivity analysis suggested that the observed HR of 2.8 for hospital-based CUD care and mortality could only be explained away by an unmeasured confounder that was associated with both CUD and mortality by an HR of 5.0 beyond measured confounders. This ratio is much greater than the reported association between smoking and all-cause mortality (risk ratio of 2.7 to 2.8 for current vs never smoker), making it unlikely that our findings are explained entirely by unmeasured confounding.^38,39 In addition, sensitivity analyses excluding individuals with prior health care for mental or substance use disorders yielded similar associations to our primary analysis, highlighting elevated risk in populations without comorbid mental and substance use disorders.

Conclusions

The results of this cohort study suggest that individuals who require hospital-based care for a CUD are at an elevated risk of premature death. Increases in mortality risk relative to the general population were greatest in individuals aged 25 to 44 years. Hospital-based CUD care was associated with a lower risk of mortality than individuals with care for other substances. However, large increases in regular cannabis use, and especially in forms known to predict CUD over time, highlight the importance of cannabis as a public health concern, especially in young strata of the population and in light of growing interest in cannabis legalization and market commercialization.

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