This cohort study evaluates the association of an emergency department visit involving hallucinogen use with risk of development of a schizophrenia spectrum disorder.
Key Points
Question
Do individuals who have emergency department (ED) visits involving hallucinogen use have an increased risk of incident schizophrenia spectrum disorder?
Findings
In this cohort study of 9 244 292 people, individuals with no history of psychosis who had an ED visit involving hallucinogen use had an increased risk of schizophrenia spectrum disorder compared with members of the general population of the same age and sex and after further adjustment for comorbid mental and substance use disorders.
Meaning
Individuals who require emergency care for hallucinogen use may have an increased risk of developing a schizophrenia spectrum disorder.
Abstract
Importance
Interest in and use of hallucinogens has been increasing rapidly. While a frequently raised concern is that hallucinogens may be associated with an increased risk of psychosis, there are limited data on this association.
Objectives
To examine whether individuals with an emergency department (ED) visit involving hallucinogen use have an increased risk of developing a schizophrenia spectrum disorder (SSD).
Design, Settings, and Participants
This population-based, retrospective cohort study (January 2008 to December 2021) included all individuals aged 14 to 65 years in Ontario, Canada, with no history of psychosis (SSD or substance induced). Data were analyzed from May to August 2024.
Exposure
An incident ED visit involving hallucinogen use.
Main Outcomes and Measures
Diagnosis of SSD using a medical record–validated algorithm. Associations between ED visits involving hallucinogens and SSD were estimated using cause-specific adjusted hazard models. Individuals with an incident ED visit involving hallucinogens were compared with members of the general population (primary analysis) or individuals with ED visits involving alcohol or cannabis (secondary analysis).
Results
The study included 9 244 292 individuals (mean [SD] age, 40.4 [14.7] years; 50.2% female) without a history of psychosis, with a median follow-up of 5.1 years (IQR, 2.3-8.6 years); 5217 (0.1%) had an incident ED visit involving hallucinogen use. Annual rates of incident ED visits involving hallucinogens were stable between 2008 and 2012 and then increased by 86.4% between 2013 and 2021 (3.4 vs 6.4 per 100 000 individuals). Individuals with ED visits involving hallucinogens had a greater risk of being diagnosed with an SSD within 3 years compared with the general population (age- and sex-adjusted hazard ratio [HR], 21.32 [95% CI, 18.58-24.47]; absolute proportion with SSD at 3 years, 208 of 5217 with hallucinogen use [3.99%] vs 13 639 of 9 239 075 in the general population [0.15%]). After adjustment for comorbid substance use and mental health conditions, individuals with hallucinogen ED visits had a greater risk of SSD compared with the general population (HR, 3.53; 95% CI, 3.05-4.09). Emergency department visits involving hallucinogens were associated with an increased risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68) and cannabis (HR, 1.47; 95% CI, 1.21-1.80) in the fully adjusted model.
Conclusions and Relevance
In this cohort study, individuals with an ED visit involving hallucinogen use had a greater risk of developing an SSD compared with both the general population and with individuals with ED visits for other types of substances. These findings have important clinical and policy implications given the increasing use of hallucinogens and associated ED visits.
Introduction
Over the past 2 decades, there has been a substantial increase in interest in the potential therapeutic use of hallucinogens, including psychedelics (serotonergic hallucinogens), for the treatment of mental and substance use disorders.1,2 Public interest in hallucinogens, which include lysergic acid diethylamide (LSD), dimethyltryptamine (or ayahuasca), psilocybin, methylenedioxymethamphetamine (MDMA; also known as ecstasy), and others, has similarly increased, with estimates suggesting that adult hallucinogen use began rapidly increasing starting in the mid-2010s in North America.3,4,5,6 As of 2023, an estimated 8.9% of individuals aged 19 to 30 years in the US reported past-year hallucinogen use, more than double the 4.1% in 2015.4 Results from randomized clinical trials suggest that psychedelic-assisted psychotherapy may be beneficial for treatment-resistant depression, posttraumatic stress disorder, and alcohol use disorder.7,8,9,10,11,12 While the mechanism of action is not fully understood, serotonergic hallucinogens, which include psilocybin, LSD, and dimethyltryptamine, are thought to enhance cortical neuroplasticity and neuro connectivity.13 However, there are ongoing concerns that hallucinogen use may increase the risk of serious adverse mental health outcomes, including psychosis, particularly when used outside supervised clinical settings and in populations at elevated risk of psychosis, who have historically been excluded from clinical trials.14 Critically, despite the growing popularity of hallucinogens among adults, there are limited data on potential adverse effects, such as increases in the risk of psychosis.
Studies to date on the association between psychedelic use and psychosis have been limited by small sample sizes, self-report for both exposure and outcomes, and less clinically relevant measures of psychedelic use (eg, ever used in lifetime). Two studies using health administrative data in Denmark and Norway examined the association between an episode of substance-induced psychosis and the risk of schizophrenia but included only 114 and 69 individuals with hallucinogen-induced psychosis, respectively.15,16 A survey of US and UK individuals found no association between psychedelic use and changes in psychotic symptoms 2 months later.17 However, the study included only 100 individuals who used psychedelics, and both psychedelic use and psychotic symptoms were self-reported. While psychedelic use was associated with increased risk of psychosis for individuals with a family history of psychosis, the small sample size and short follow-up period limited the power and generalizability of the study. A larger study including over 20 000 individuals who used psychedelics found no association between self-reported psychedelic use and psychotic symptoms but examined only lifetime use.18 Collectively, there remain large gaps in the understanding of the potential risks of psychosis and schizophrenia spectrum disorder (SSD) associated with hallucinogen use. Such knowledge is urgently required to help clinicians, patients, and individuals who use hallucinogens recreationally to understand associated risks, with implications for clinical, prevention, and harm-reduction efforts.
This population-based study examined whether individuals with an emergency department (ED) visit involving hallucinogen use had an increased risk of developing an SSD compared with the general population and with individuals with ED visits involving other substances. We examined variations in risk for different types of ED visits for hallucinogens (ie, psychedelic-induced psychosis or other psychedelic-related presentations) and by patient characteristics.
Methods
Study Design, Inclusion Criteria, and Data Sources
We conducted a retrospective cohort study of all residents of Ontario, Canada, aged 14 to 65 years between January 2008 and December 2021 who were eligible for the province’s health insurance program, which provides universal access to all hospital and medically necessary physician-based services. The lower age limit reflects start of eligibility for early psychosis intervention programs, and the upper limit was selected to reduce misclassification of major neurocognitive disorders as SSD.19 Clinical data on all ED visits, hospitalizations, and outpatient physician visits, along with sociodemographic characteristics, were obtained using 6 individual-level databases, which were linked using unique encoded identifiers and analyzed at ICES (formerly the Institute for Clinical Evaluative Science). We identified all individuals with an incident ED visit involving hallucinogen use. We excluded individuals who had 1 or more ED visit, hospitalization, or outpatient visit for psychosis (substance induced or nonaffective) in the 5 years prior to the index date (incident ED visit involving hallucinogens or matched date for individuals without ED visits for hallucinogens [ie, the general population]). Individuals were required to have been continually eligible for universal health coverage for the full 5 years before index to ensure capture of prevalent cases of SSD. Individuals with an incident ED visit involving hallucinogens who received a codiagnosis of SSD in the same episode of care (in the ED or during hospital admission from the ED) were also excluded (eMethods 1 in Supplement 1 provides details on databases and diagnostic codes for psychosis). This project was approved by the privacy office at ICES, which is authorized under §45 of Ontario’s Personal Health Information Protection Act to collect and analyze personal health information without patient consent for approved research projects.
Study Setting
In Canada, hallucinogens are listed under the Controlled Drugs and Substance Act, and the possession, sale, and production of hallucinogens are illegal except in specified circumstances. Individuals may obtain authorization from Health Canada to access hallucinogens legally in either clinical trials or through the Special Access Program, in which a health care professional can request access to drugs that have shown promise in clinical trials or have been approved in other countries for serious or life-threatening conditions when conventional therapies are ineffective, unsuitable, or unavailable. The first clinical trials of a hallucinogen (MDMA) in Canada began in 2015 in British Columbia, with a number of ongoing clinical trials, including in Ontario, since 2018. Starting in January 2022, health care practitioners were able to request access to hallucinogens through the Special Access Program.20
Exposures
We identified individuals with an incident ED visit involving hallucinogen use for which the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes F16.X (mental and behavioral disorders due to use of hallucinogens, including acute intoxication [F16.0], harmful use [F16.1], withdrawal and dependence [F16.2, F16.3, and F16.4], induced psychosis [F16.5, F16.7], and other and unspecified [F16.6, F16.8, and F16.9]), T40.8 (poisoning by or adverse effects of lysergide [LSD]), or T40.9 (poisoning by or adverse effects of unspecific hallucinogens) were the main or contributing reason for the visit. These definitions are from the Canadian Institute for Health Information indicator Hospital Stays for Harm Caused by Substance Use.21 We examined differences in risk for ED visits involving hallucinogens with and without hallucinogen-induced psychosis.
As a secondary exposure, to create comparison groups with less bias from unmeasured confounders, we identified individuals with an incident ED visit involving alcohol or cannabis use using the same process as for ED visits for hallucinogen use. eMethods 1 in Supplement 1 provides details.
Outcome
The primary outcome was development of SSD, which was defined using a medical record–validated algorithm (sensitivity 91.6%, specificity 61.3%) as a diagnosis of schizophrenia or schizoaffective disorder (ICD-10 codes F20 × or F25x; DSM-IV codes 295x) from a general or psychiatric hospital bed or at 2 or more outpatient or ED visits occurring within 12 months of each other. eMethods 2 in Supplement 1 provides details.22
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 health care use in the 5 years prior to the index event, including outpatient mental health visits (primary care physician or psychiatrist) and ED visits and hospitalizations for substance use (alcohol, cannabis, opioids, cocaine, amphetamines, and other) and mental (mood, anxiety, self-harm, and other) disorders using previously established coding22,23 (eMethods 1 in Supplement 1 gives details). Covariates in our study were complete except for rural residence and neighborhood income quintile (0.34% missing).
Statistical Analysis
Analyses were performed from May to August 2024. We compared the characteristics of individuals with an ED visit involving hallucinogen use and those of the general population using descriptive statistics and standardized mean differences.24 Characteristics were recorded at the time of the incident ED visit involving hallucinogen use or on a randomly assigned index date for the general population that matched the distribution of dates for incident ED visits (eMethods 3 in Supplement 1 gives details).25,26
For our primary analysis, we compared the risk of developing SSD between individuals with an ED visit involving hallucinogens and the general population using cumulative incidence functions and cause-specific Cox proportional hazards regression models accounting for the competing risk of all-cause mortality and censoring from emigration or loss of universal health coverage eligibility. We estimated hazard ratios (HRs) with 95% CIs and presented estimates at 3-year follow-up, consistent with prior work and based on data on time between symptom onset and psychosis diagnosis in high-risk populations.25,27
We completed 2 levels of adjustment in the Cox proportional hazards regression models: (1) adjustment for age (in splines at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles) and sex and (2) full adjustment for the prespecified variables age (in splines), sex, neighborhood income quintile (6 levels including missing), immigrant status, rurality (3 levels including missing), outpatient mental health care in the past 5 years (dichotomous family medicine, dichotomous psychiatry visit), substance use ED visits and hospitalizations in the past 5 years (alcohol, cannabis, cocaine, amphetamines, opioids, polysubstance use, and other substances), and mental health ED visits and hospitalizations in the past 5 years (depression, anxiety, deliberate self-harm, and other mental health conditions). Given differences in the diagnosis of SSD by age and previous evidence of a different magnitude of effect estimates between substance (ie, cannabis) use disorder and SSD across sex and age groups,25 we conducted subgroup analyses that examined age and sex strata separately.
For our secondary analysis, we compared the risk of developing SSD between individuals with an incident ED visit involving hallucinogens and individuals with incident ED visits for either alcohol or cannabis. Individuals with use of multiple substances at presentation were excluded. Individuals could contribute follow-up for up to 2 incident ED visits for substance use, and we used robust sandwich covariance estimators to account for repeat measurements of unique individuals (eMethods 3 in Supplement 1 gives details).
We completed 2 sensitivity analyses of our primary analysis. First, we included only individuals with no outpatient, ED, or hospital-based care for mental or substance use disorders in the 5 years before their incident ED visit or at a matched date in the general population with the same 2 levels of adjustment. Second, we completed an alternative analytic approach using greedy matching with a ratio of 1:4 for individuals with an ED visit involving hallucinogen use matched to individuals in the general population and including time-varying covariates for ED visits or hospitalizations for mental health, other substance use, and sociodemographics (eMethods 3 in Supplement 1 gives details). All analyses were conducted using SAS, version 8.3 (SAS Institute Inc).
Results
The study included 9 244 292 individuals without a history of substance-induced psychosis or SSD who were followed up for a median of 5.1 years (IQR, 2.3-8.6 years). Mean (SD) age was 40.4 (14.7) years; 50.2% were female, and 49.8% were male. A total of 5217 (0.1%) had an ED visit involving hallucinogen use, and 9 239 075 (99.9%) did not (the eFigure in Supplement 1 gives the cohort flow). The most common types of ED visits involving hallucinogen use were harmful use (1910 [36.6%]), intoxication (1157 [22.2%]), dependence or withdrawal (660 [12.7%]), and hallucinogen-induced psychosis (184 [3.5%]). The hallucinogen code was the main reason for most ED visits (3691 [70.7%]). Individuals with incident ED visits involving hallucinogen use were younger (mean [SD] age, 26.69 [10.65] vs 40.37 [14.69] years) and more likely to be male (3594 [70.8%] vs 4 600 732 [49.8%]), live in low-income neighborhoods (1458 [27.9%] vs 1 748 023 [18.9%] in lowest income quintile), and be a long-term resident of Canada (4791 [91.8%] vs 7 404 872 [80.1%]) compared with the general population. Individuals with an ED visit involving hallucinogen use were more likely to have had an ED visit or hospitalization for substance use (2653 [50.9%] vs 225 407 [2.4%]) or a mental disorder (1697 [32.5%] vs 327 902 [3.5%]) or an outpatient mental health or addiction visit (3777 [72.4%] vs 3 400 787 [36.8%]) in the past 5 years compared with those without an ED visit involving hallucinogen use. The sensitivity analysis included 917 individuals (17.6%) with an ED visit involving hallucinogen use who had no outpatient, ED, or inpatient mental health or substance use visits in the past 5 years and 5 750 714 (62.2%) individuals in the general population (Table 1).
Table 1. Characteristics of Individuals With an Incident ED Visit Involving Hallucinogen Use and the General Population.
| Characteristic | Individuals, No. (%) | SMD | |
|---|---|---|---|
| Hallucinogen ED visit (n = 5217) | General population (n = 9 239 075) | ||
| Reason for hallucinogen visit (ICD-10 code) | |||
| Intoxication (F16.0) | 1157 (22.2) | NA | NA |
| Harmful use (F16.1) | 1910 (36.6) | NA | |
| Dependence or withdrawal (F16.2, F16.3, F16.4) | 660 (12.7) | NA | NA |
| Psychosis (F16.5, F16.7) | 184 (3.5) | NA | NA |
| Amnesia, other, unspecified (F16.6, F16.8, F16.9) | 183 (3.5) | NA | NA |
| LSD poisoning (T40.8) | 288 (5.5) | NA | NA |
| Other hallucinogen poisoning (T40.9) | 835 (16.0) | NA | NA |
| Hallucinogen main reason for visit | 3691 (70.7) | NA | NA |
| Hallucinogen contributing reason for visit | 1526 (29.3) | NA | NA |
| Sex | |||
| Female | 1523 (29.2) | 4 638 343 (50.2) | 0.44 |
| Male | 3694 (70.8) | 4 600 732 (49.8) | 0.44 |
| Age, y | |||
| Mean (SD) | 26.69 (10.65) | 40.37 (14.69) | NA |
| 14-18 | 1189 (22.8) | 780 513 (8.4) | 0.40 |
| 19-24 | 1680 (32.2) | 985 423 (10.7) | 0.54 |
| 25-44 | 1892 (36.3) | 3 456 450 (37.4) | 0.02 |
| 45-65 | 456 (8.7) | 4 016 689 (43.5) | 0.86 |
| Rurality | |||
| Urban | 4599 (88.2) | 8 247 764 (89.3) | 0.04 |
| Rural | 567 (10.9) | 963 981 (10.4) | 0.01 |
| Neighborhood income quintile | |||
| 1 (Lowest income) | 1458 (27.9) | 1 748 023 (18.9) | 0.21 |
| 2 | 1103 (21.1) | 1 801 195 (19.5) | 0.04 |
| 3 | 926 (17.7) | 1 846 277 (20.0) | 0.06 |
| 4 | 861 (16.5) | 1 896 860 (20.5) | 0.10 |
| 5 (Highest income) | 804 (15.4) | 1 906 563 (20.6) | 0.14 |
| Long-term resident of Canada | |||
| Yes | 4791 (91.8) | 7 404 872 (80.1) | 0.34 |
| No | 426 (8.2) | 1 834 203 (19.9) | 0.34 |
| Acute care substance use visits in past 5 y | |||
| Any | 2653 (50.9) | 225 407 (2.4) | 1.31 |
| Alcohol | 1380 (26.5) | 172 707 (1.9) | 0.75 |
| Cannabis | 835 (16.0) | 25 361 (0.3) | 0.60 |
| Cocaine | 710 (13.6) | 16 793 (0.2) | 0.55 |
| Amphetamine | 362 (6.9) | 5135 (0.1) | 0.38 |
| Opioids | 608 (11.7) | 18 757 (0.2) | 0.50 |
| Polysubstance | 984 (18.9) | 30 411 (0.3) | 0.66 |
| Other | 212 (4.1) | 5030 (0.1) | 0.29 |
| Acute care mental health visits in past 5 y | |||
| Any | 1697 (32.5) | 327 902 (3.5) | 0.81 |
| Mood disorder | 755 (14.5) | 118 546 (1.3) | 0.51 |
| Anxiety disorder | 1035 (19.8) | 203 147 (2.2) | 0.59 |
| Deliberate self-harm | 672 (12.9) | 52 345 (0.6) | 0.51 |
| Other | 349 (6.7) | 39 753 (0.4) | 0.34 |
| Outpatient mental health or substance use visits in past 5 y | |||
| Any | 3777 (72.4) | 3 400 787 (36.8) | 0.77 |
| Family physician | 3643 (69.8) | 3 291 986 (35.6) | 0.73 |
| Psychiatrist | 1867 (35.8) | 675 029 (7.3) | 0.74 |
| Acute care or outpatient mental health or substance use visit in past 5 y | |||
| Yes | 4300 (82.4) | 3 488 361 (37.8) | 1.03 |
| No | 917 (17.6) | 5 750 714 (62.2) | 1.03 |
Abbreviations: ED, emergency department; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; LSD, lysergic acid diethylamide; NA, not applicable; SMD, standardized mean difference.
Changes over time in the number and rates of individuals with an incident ED visit involving hallucinogen use are shown in Figure 1. The rate of individuals with an incident visit involving hallucinogens was relatively stable between 2008 to 2012 and then increased by 86.4% between 2013 and 2021 (3.4 vs 6.4 per 100 000 individuals).
Figure 1. Annual Count and Rate of Incident Emergency Department Visits Involving Hallucinogen Use.
Cumulative incidence functions for the risk of developing SSD over time for the general population and individuals with different types of ED visits involving hallucinogens are presented in Figure 2A. Over the entire study period 330 of 5217 individuals with an ED visit involving hallucinogens (6.3%) developed SSD. Within 3 years, 208 of 5217 individuals with an ED visit involving hallucinogen use (3.99%), 37 of 184 individuals with an ED visit for hallucinogen-induced psychosis (20.11%), and 13 639 of 9 239 075 individuals in the general population (0.15%) developed SSD. After adjustment for age and sex, the risk of developing an SSD was greater for individuals with an ED visit involving hallucinogen use (HR, 21.32; 95% CI, 18.58-24.47) and for individuals with hallucinogen-induced psychosis (HR, 128.63; 95% CI, 93.15-177.61) compared with the general population. After adjustment for income, rurality, immigration status, substance use, and mental health care in the past 5 years, individuals with an ED visit involving hallucinogen use (HR, 3.53; 95% CI, 3.05-4.09) and individuals with ED visits involving hallucinogen-induced psychosis (HR, 14.66; 95% CI, 10.53-20.41) had a greater risk of developing an SSD compared with the general population (Table 2). The secondary analysis revealed that individuals with an ED visit involving hallucinogen use had a grater risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68) and cannabis (HR, 1.47; 95% CI, 1.21-1.80) in the fully adjusted model. eTable 1 in Supplement 1 gives characteristics of individuals, Figure 2B shows the cumulative incidence function, and Table 2 and eTable 2 Supplement 1 in give outcomes.
Figure 2. Cumulative Incidence Function Curves Comparing Risk of Diagnosis of Schizophrenia Spectrum Disorder (SSD) Over Time.
Shaded regions represent 95% CIs.
Table 2. Risk of Developing Schizophrenia Spectrum Disorder After an ED Visit Involving Hallucinogen Use Compared With the General Population.
| Outcome | General population | Hallucinogen use | Hallucinogen use excluding psychosis | Hallucinogen-induced psychosis | LSD poisoning |
|---|---|---|---|---|---|
| Population at risk, No. | 9 239 075 | 5217 | 5033 | 184 | 288 |
| SSD diagnosis, No. (%) | |||||
| Alla | 28 837 (0.31) | 330 (6.33) | 286 (5.68) | 44 (23.91) | 11 (3.82) |
| At 1 y | 5208 (0.06) | 127 (2.43) | 97 (1.93) | 30 (16.30) | Suppressedb |
| At 3 y | 13 639 (0.15) | 208 (3.99) | 171 (3.40) | 37 (20.11) | 7 (2.43) |
| At 5 y | 19 862 (0.21) | 264 (5.06) | 221 (4.39) | 43 (23.37) | 9 (3.13) |
| Incidence, per 100 000 person-years | 59.14 | 1632.04 | 1381.36 | 10 117.47 | 982.21 |
| Age- and sex-standardized incidence, per 100 000 person-years | 60.19 | 1827.09 | 1459.43 | 12 837.14 | 2260.45 |
| Age- and sex-adjusted HR (95% CI)c | 1 [Reference] | 21.32 (18.58-24.47) | 17.96 (15.43-20.90) | 128.63 (93.15-177.61) | 11.99 (5.73-25.09) |
| Fully adjusted HR (95% CI)c,d | 1 [Reference] | 3.53 (3.05-4.09) | 2.93 (2.39-3.44) | 14.66 (10.53-20.41) | 1.98 (0.94-4.15) |
Abbreviations: ED, emergency department; HR, hazard ratio; LSD, lysergic acid diethylamide; SSD, schizophrenia spectrum disorder.
Diagnoses over the maximum follow-up period (14 years) available.
Suppressed to avoid displaying cell counts less than 5.
At 3-year follow-up.
Adjusted for age, sex, neighborhood income quintile, rurality, immigration status, and outpatient, ED, and hospital-based care for mental health and substance use disorders in the past 5 years.
In the sensitivity analysis excluding individuals with any outpatient, ED, or hospital-based care for mental health or substance use in the past 5 years, larger increases in the risk of developing SSD were observed for individuals with ED visits involving hallucinogen use compared with the general population (fully adjusted HR, 20.94; 95% CI, 12.79-34.28) (eTable 3 in Supplement 1). The sensitivity analysis using matching and time-varying covariates achieved good covariate balance (standardized mean difference <0.1 for all variables) and revealed similar results to those of the primary analysis. The 4434 individuals with an ED visit involving hallucinogens had an increased risk of an SSD within 3 years compared with the 16 544 matched members of the general population (fully adjusted HR, 4.31 [95% CI, 3.31-5.61]; 3-year risk of SSD, 161 [3.63%] vs 115 [0.69%]) (eTable 4 in Supplement 1).
Figure 3 presents the proportion of individuals who developed SSD within 3 years based on age, sex, and having had an ED visit involving hallucinogen use. Fully adjusted HRs are available in eTable 5 in Supplement 1. The absolute risk of being diagnosed with an SSD was highest for males aged 19 to 24 years; however, compared with the general population, there were numerically similar increases in risk of SSD after an ED visit involving a hallucinogen by age and sex groups.
Figure 3. Crude Percentage of Individuals Transitioning to a Diagnosis of Schizophrenia Spectrum Disorder Within 3 Years of an Emergency Department Visit Involving Hallucinogen Use and the General Population by Age and Sex.
Discussion
In this population-based cohort study of 9 244 292 million people, we found that individuals with an ED visit involving hallucinogen use had a 21-fold greater risk of developing an SSD compared with the general population (absolute proportion with SSD at 3 years, 3.99% vs 0.15%) and continued to have a 3.5-fold greater risk after accounting for differences in sociodemographics and comorbid mental and substance use disorders. Individuals with an ED visit for hallucinogen-induced psychosis had the greatest risk (14.7-fold adjusted increase) of developing an SSD compared with the general population (3-year risk, 20.11% vs 0.15%). Emergency department visits for hallucinogens were associated with 4.7-fold and 1.5-fold higher risk of SSD compared with ED visits for alcohol and cannabis, respectively. Individuals of any age and sex who had an ED visit involving hallucinogens had a higher risk of SSD compared with a general population member of the same age or sex.
The limited available research on the association between hallucinogen use and psychotic disorders has been mixed.15,16,17,18 Importantly, this prior research has been substantially limited by small sample sizes, self-report for use and symptoms of psychosis, and use of less clinically relevant exposures to hallucinogens. Adding to the literature, we present, to our knowledge, the largest study to date on the longitudinal association between hallucinogen use leading to an ED presentation and SSD using physician diagnosis for both exposure to hallucinogens and the development of an SSD. The study included 330 individuals who developed an SSD after an ED presentation involving hallucinogen use, more than 14 times the number of cases from the largest prior population-based study to date.15,16 We additionally found that ED visits for hallucinogen use were associated with a higher risk of SSD compared with ED visits for other substances, including cannabis and alcohol.
While our findings raise caution that hallucinogen use requiring care in the ED may be associated with a high risk of subsequent SSD, there are important considerations to these findings. First, our study could not establish a causal link between hallucinogen use requiring care in the ED and SSD, and the associations presented in this study should not be interpreted as causal in nature. Nonetheless, our findings revealed a group that may have high risk of development of SSD who may benefit from close follow-up and intervention or preventative efforts. Second, our exposure captured individuals for whom the use of hallucinogens resulted in an ED visit rather than hallucinogen use. Many individuals who use hallucinogens may not have an ED visit for hallucinogen use, and the reported associations may not generalize to hallucinogen use, particularly among individuals using low (micro) doses or rarely using hallucinogens. Third, hallucinogen use and corresponding ED visits for hallucinogen use were less common than other substance use and visits. However, adult hallucinogen use has rapidly increased in North America,3,4,5,6 with ED visits involving hallucinogen use in our study increasing by 86.4% between 2013 and 2021. Whether or not increasing use of hallucinogens could impact population-level rates of psychotic disorders remains unresolved and requires further investigation.
Limitations
Our study has limitations. First, we did not have detailed data on the type of hallucinogen used, and the ICD-10 coding included both serotonergic psychedelics (eg, LSD, MDMA, phenethylamines, and psilocybin) and dissociative drugs (eg, ketamine). While we found similar elevations in risk for ED visits involving LSD as for those involving any hallucinogen, ongoing research about risk profiles of different hallucinogens (eg, psilocybin) is indicated. In addition, hallucinogens during our study time frame would have been primarily obtained from illicit sources and may have contained contaminants. Second, as previously outlined, our exposure, an ED visit involving hallucinogens, may not generalize to hallucinogen use. Third, as our outcome definition had a specificity of 61.3%, some individuals identified as having SSD were misclassified. However, these individuals still likely had a serious underlying mental illness given that they had repeated outpatient visits or psychiatric hospitalizations with a diagnostic code for SSD. Fourth, while we observed an association between ED visits involving hallucinogens and increased risk of SSD, our study design could not infer causality. We did not have data on, and consequently could not control for, a number of established environmental factors (eg, childhood trauma, pregnancy and birth complications) that may confound the relationship between hallucinogen use and schizophrenia.28 In addition, we could not control for genetic risk factors, which some evidence suggests are associated with both higher risk of schizophrenia and greater adolescent substance use.29,30 Fifth, part of the observed association between ED visits involving hallucinogens and SSD may have been due to greater surveillance after the ED visit. However, we found that elevations in risk persisted for over 5 years after ED visits and that individuals with ED visits involving hallucinogens had a higher risk of SSD than individuals with cannabis use (an active control due to its association with SSD), who may also have had increased surveillance after an ED visit. Sixth, some individuals experiencing severe mental distress, including prodromal symptoms of schizophrenia, may have been self-medicating using hallucinogens. Our sensitivity analysis excluding individuals with any prior health care for mental or substance use disorders in the past 5 years yielded larger HRs than our primary analysis, reducing but not eliminating the possibility that the results were driven by reverse causality.
Conclusions
The findings of this cohort study suggest that individuals with ED visits involving hallucinogen use may have an elevated risk of developing an SSD. Increases in risk compared with the general population were similar across age and sex. Given rapid increases in interest in and adult use of hallucinogens3,4,5,6 and the increase in ED visits involving hallucinogens found in this study, ongoing research is needed to clarify the observed association between hallucinogen use and development of SSD.
eMethods 1. Data Sources, Exposures and Covariates
eMethods 2. Schizophrenia Spectrum Disorder Definition
eMethods 3. Matching and Analyses
eFigure. Cohort Flow With Exclusions
eTable 1. Characteristics of Individuals With ED Visits for Alcohol and Cannabis
eTable 2. Risk of Developing Schizophrenia Spectrum Disorder After ED Visit Involving Hallucinogen, Cannabis or Alcohol Use
eTable 3. Sensitivity Analysis Excluding Individuals With Any Mental Health or Substance Care in the Past 5 Years
eTable 4. Sensitivity Analysis Using Matching
eTable 5. Age and Sex-Specific Hazard Ratios for Risk Developing Schizophrenia Spectrum Disorder After an ED Visit Involving Hallucinogen Relative to the General Population
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods 1. Data Sources, Exposures and Covariates
eMethods 2. Schizophrenia Spectrum Disorder Definition
eMethods 3. Matching and Analyses
eFigure. Cohort Flow With Exclusions
eTable 1. Characteristics of Individuals With ED Visits for Alcohol and Cannabis
eTable 2. Risk of Developing Schizophrenia Spectrum Disorder After ED Visit Involving Hallucinogen, Cannabis or Alcohol Use
eTable 3. Sensitivity Analysis Excluding Individuals With Any Mental Health or Substance Care in the Past 5 Years
eTable 4. Sensitivity Analysis Using Matching
eTable 5. Age and Sex-Specific Hazard Ratios for Risk Developing Schizophrenia Spectrum Disorder After an ED Visit Involving Hallucinogen Relative to the General Population
Data Sharing Statement
