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. Author manuscript; available in PMC: 2026 Jun 26.
Published in final edited form as: J Clin Psychiatry. 2026 Jun 10;87(3):25m16034. doi: 10.4088/JCP.25m16034

Hallucinogen-Psychosis Associations Are Confounded by Baseline Psychiatric History

Jacob T Steinle 1, Suraj Shankar 1, Joshua S Siegel 1, Leopoldo J Cabassa 1, Danielle R Adams 1, Patricia Cavazos-Rehg 1, Arpana Agrawal 1, Ginger E Nicol 1, Richard Grucza 1, Kevin Y Xu 1
PMCID: PMC13296641  NIHMSID: NIHMS2184410  PMID: 42283542

Abstract

Background:

Current drug policy debates often center on whether hallucinogen-related hospital admissions indicate a causal relationship with psychosis. This study examines the extent to which observed associations between hallucinogen use and psychosis are mediated by preexisting psychiatric conditions, providing important evidence for psychedelic policy formulation.

Methods:

We conducted a retrospective analysis using MarketScan Medicaid and commercial claims databases from 2015–2019. The population-based sample included individuals receiving substance use disorder treatment with documented substance-related emergency admissions or hospitalizations. We compared psychosis-related admissions occurring 30 days to 6 months postindex event between individuals with hallucinogen-related admissions versus those with nonhallucinogen substance-related admissions. Cox regression models adjusted for demographics and clinical characteristics to determine whether prior psychiatric history explained observed associations.

Results:

Among 273,466 individuals with substance-related admissions, psychosis diagnoses were more prevalent following hallucinogen-related admissions (16.4%) compared to nonhallucinogen substance admissions (6.6%, P< .001). While unadjusted models showed increased psychosis risk for hallucinogen-related admissions (hazard ratio [HR]=1.22, 95% CI = 1.19–1.25), this association became nonsignificant after adjusting for clinical characteristics (HR=0.97, 95% CI=0.95–1.00).

Conclusions:

Apparent associations between hallucinogen use and psychosis appear largely attributable to baseline psychiatric comorbidities rather than direct causal effects. These findings carry implications for evidence-based policy development, suggesting that observed epidemiologic associations may reflect underlying vulnerability factors rather than hallucinogen-induced psychosis. Policymakers should consider these results when interpreting population-level data regarding hallucinogen safety profiles and regulatory frameworks.

Psychedelics, a group of consciousness-altering substances including psilocybin, lysergic acid diethylamide (LSD), and ayahuasca, among others, have emerged as promising treatments for a variety of psychiatric conditions including major depressive disorder, posttraumatic stress disorder, anxiety, and substance use disorders (SUDs).1–3 Such compounds are referred to as classic hallucinogens, acting as 5-HT2A agonists and inducing profound alterations in perceptions of reality.4 There is presently much debate regarding the safety profile of psychedelics.5–7 Key safety concerns include SUD-related risks (ie, overdose) and psychosis.8–10 Most existing knowledge regarding the safety of the classic hallucinogens, which suggests a relatively benign safety profile and potentially even decreased risk of self-harm, comes primarily from reporting data based on use in regulated and medical contexts.11–13 Some prior studies have suggested that, even in recreational settings, psychedelic consumption is not consistently associated with an increased risk of acute care utilization and in certain cases may be associated with decreased self-reported psychological distress.14,15 Nonetheless, there remains concern related to significant adverse events from recreational, nonregulated hallucinogens use including substance-induced psychosis, a condition that appears to increase the risk for developing schizophrenia spectrum disorders (SSDs) and may be associated with increased mortality.16,17

A recent population-based analysis of hospitalizations and emergency admissions in Canada found an increased risk of subsequent SSD diagnosis in individuals presenting to the emergency department for hallucinogen use. This risk was stronger than that observed for alcohol- and cannabis-related presentations, and these findings may suggest that hallucinogens were a stronger predictor for SSD than other substance-related admissions.18 Such epidemiologic evidence has the potential to inform policy discourse around psychedelic decriminalization, influencing policymaker deliberations and regulatory discussions. Yet, several important unanswered questions remain. For example, data on psychosis admissions preceding hallucinogen admissions may not account for prior outpatient psychiatric diagnoses that often outnumber psychiatric admissions. Prior studies examining transition from substance-induced psychosis to SSD, which exclude individuals with premorbid SSD diagnosis, have not consistently found that hallucinogen-induced psychosis predicted SSD more than other substances such as cannabis and amphetamines.19,20 Additionally, hallucinogen-related adverse events may be comorbid with other SUDs and mental health problems that independently increase the risk for psychosis.21 In other words, individuals experiencing hallucinogen-related admissions may represent a higher degree of psychiatric comorbidity and predisposition to psychosis and could already be symptomatic with psychosis prior to hallucinogen use.

Using a multistate insurance and Medicaid claims database that captures both admissions and outpatient diagnoses for psychosis and substance-related disorders, we investigated whether the anticipated association between hallucinogen-related admissions and subsequent SSD diagnosis may be explained by prior psychiatric history. We analyzed a cohort of individuals with ≥1 hallucinogen-related admission in the US during 2015–2019, a period preceding widespread psychedelic decriminalization and the current resurgence in psychedelic therapeutics research.22 This timeframe provides baseline rates of psychiatric comorbidity and psychosis-related outcomes prior to such policy changes, allowing characterization of hallucinogen-related admissions in an era before increased availability through medicalization or decriminalization.23 We evaluated rates of psychiatric comorbidity (including psychotic disorders diagnoses) preceding the admission, comparing our findings to individuals with opioid-, cannabis-, alcohol-, and stimulant-related admissions.

METHODS

Study Overview

This retrospective cohort study involved analysis of the combined Merative MarketScan® Commercial and Multi-State Medicaid Databases (2015–2019). The database includes claims for emergency department visits and inpatient hospitalizations (hereby referred to as “admissions”) across >250 million children and adults (through age 64 years) in the US, providing longitudinal follow-up data from a variety of health care plans (ie, Medicaid, private insurance) through multiple years of enrollment. Data cleaning, linkage of claims, and de-identification were performed by Merative.

The observation window for the study spanned from January 1, 2015, to December 31, 2019. This timeframe precedes the first instance of decriminalization of psilocybin, allowing us to establish baseline rates of psychosis among individuals using psilocybin prior to subsequent decriminalization/legalization in certain locations.22 The MarketScan data are fully compliant with the Health Insurance Portability and Accountability Act (1996). All data were de-identified, and analyses were exempted from review by the Washington University Human Research Protection Office.

Study Population

We analyzed a preexisting cohort of 334,617 individuals, ages 16 through 64 years, with (A) ≥1 claim for a substance-related diagnosis (International Classification of Diseases, Ninth Revision [ICD-9]: 303.xx, 304.xx, 305.xx; ICD-10: F10.xx-F19.xx), (B) ≥1 claim for substance-related treatment, and (C) ≥1 claim for a substance-related admission See Supplementary Methods 1 for comprehensive administrative codes used to identify claims for (A), (B), and (C)…, which were permitted to occur during any time during enrollment.

Across all admissions, we identified 7,082 individuals with ≥1 claim for a hallucinogen-related admission and 327,535 individuals who had no claims for hallucinogen-related admissions but experienced ≥1 nonhallucinogen-related admission (opioid-, stimulant-, alcohol-, cannabis-) during enrollment (Figure 1). Among people with nonhallucinogen substance-related admissions, we tabulated the amount of nonhallucinogen-related substance admissions: 43,751 with ≥1 opioid-related admission, 82,572 with ≥1 stimulant-related admission, 198,003 with ≥1 alcohol-related admission, and 143,456 with ≥1 cannabis-related admission.

Figure 1. Derivation of the Analytic Samplea.

Figure 1.

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aThe index date is anchored on a person’s first hallucinogen-related admission or their first (nonhallucinogen) substance-related admission. For people who had both hallucinogen and nonhallucinogen admissions, the index date was anchored on the hallucinogen-related admission.

At least 6 months of continuous insurance enrollment preceding the first admission was required for thorough and accurate assessment of premorbid, baseline psychiatric covariates (see Supplementary Figure 1 for design diagram), and we thus excluded those with <180 days of continuous enrollment preadmission. Following this, our analytic cohort consisted of 6,184 people with ≥1 hallucinogen-related admission and 267,282 individuals with ≥1 nonhallucinogen substance-related admission.

Outcomes and Covariates

The primary predictor variable was the presence of ≥1 hallucinogen-related admission (binary, yes/no). Individuals who did not have any hallucinogen-related admissions were required to have ≥1 opioid-, stimulant-, alcohol-, or cannabis-related admission to be included in the analytic cohort. The index date was anchored on a person’s first hallucinogen-related admission or their first nonhallucinogen substance-related admission. For individuals who had both hallucinogen- and nonhallucinogen-related admissions (5,489 of 6,184 people with ≥1 hallucinogen-related admission), the index date was anchored on the first hallucinogen-related admission. Among individuals with multiple nonhallucinogen-related admissions, we analyzed baseline, psychiatric comorbidities preceding the first substance-related admission occurring during enrollment. Detailed codes for the identification of substance-related admissions are in Supplementary Methods and Supplementary Figure 1.

The primary outcome variable was the diagnosis of any psychotic disorder between 30 days and 6 months following the index SUD-related admission (binary, yes/no), acknowledging that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, classifies psychiatric symptoms that occur within 30 days of substance-related exposure as substance-induced.24 We subsequently conducted secondary analyses focusing specifically on admissions, rather than diagnosis, for psychotic disorders.

Recognizing that the risk of psychosis following an index hallucinogen-related admission may be impacted by baseline psychiatric comorbidities (ie, prior history of psychosis before the hallucinogen-related admission), we analyzed covariates including age, sex, calendar year, insurance type, Charlson Comorbidity Index, and baseline psychiatric conditions (mood-, anxiety-, psychotic-, co-occurring SUDs [opioid-, stimulant-, alcohol-, cannabis-related disorders] occurring prior to the index date). Diagnostic codes for the covariates are outlined in Supplementary Methods 1.

Statistical Analysis

We first conducted descriptive analyses to outline the clinical and demographic characteristics of the analytic sample. Next, using χ2 tests and Wilcoxon sum-rank tests for unadjusted comparisons, we calculated the rates of baseline psychiatric comorbidity in people with and without ≥1 hallucinogen-related admission. Secondary analysis was performed to differentiate between those who experienced solely hallucinogen-related admissions and those who experienced nonhallucinogen, substance-related admissions (Supplementary Table 2).

We subsequently used χ2 tests to compare rates of psychotic disorder–related claims (≥1 diagnosis and/or admission for psychosis) between 30 days and 6 months following the index hallucinogen-related admissions, comparing such rates to individuals with index admissions for other substance-related conditions (opioid-, cannabis-, stimulant-, alcohol-related admissions). Among people with ≥1 hallucinogen-related admission, we again differentiated between those who experienced nonhallucinogen substance-related admissions and individuals who solely experienced hallucinogen-related admissions.

We evaluated the relationship between hallucinogen-related admissions and diagnoses of postindex psychosis (regardless of inpatient vs outpatient). To analyze whether hallucinogen-related admissions conferred greater risk for postindex psychosis than nonhallucinogen other substance-related admissions, we estimated unadjusted Cox proportional hazards models, followed by models that adjusted for demographics (age, calendar year, sex/gender, insurance type, Charlson Comorbidity Index) and baseline psychiatric comorbidities.25 Furthermore, we conducted additional subgroup analyses among Medicaid enrollees in order to control for race and ethnicity, as these data are only available for the Medicaid individuals within MarketScan.

Finally, we conducted additional sensitivity analyses to assess confounding by baseline psychiatric history, temporal relationships including prodromal phase concerns, polysubstance use effects, age-specific vulnerabilities, and outcome definition sensitivity (see Supplementary Methods 2 for detailed rationale and methodology).

We found no significant collinearity after computing variance inflation factors (threshold of <2.0).26 The proportionality of hazards assumption, assessed via Schoenfeld residuals, was satisfied for all Cox models.27 Analyses were performed using SAS version 9.4 from October 3, 2024, through January 3, 2025. Statistical significance was estimated using 2-sided P values.

RESULTS

Clinical and Demographic Characteristics

As depicted in Table 1, the sample consisted of 273,466 individuals who had at least 1 substance use–related admission during insurance enrollment: 2.3% hallucinogen, 13.8% opioid, 44.6% cannabis, 25.4% stimulant, and 57.7% alcohol. Our sample was stratified into subgroups of 6,184 people with ≥1 hallucinogen-related admission and 267,282 separate individuals with ≥1 nonhallucinogen substance-related admission. As shown in Table 2, among the cohort of individuals with ≥1 hallucinogen-related admission, approximately 10% (695/6,184) exclusively experienced hallucinogen-related admissions (without nonhallucinogen substance-related admissions during enrollment).

Table 1.

Demographic and Clinical Characteristics

Characteristic All
 Hallucinogen-related admissions
 Nonhallucinogen substance-related admissions
 P
N % N % N %
Total 273,466 100% 6,184 2.3% 267,282 97.7%
Median age 34 IQR = 22 24 IQR = 16 34 IQR = 23 <.001
Age, y
 <26 y 80,003 29.3% 3,338 54.0% 76,665 28.7% <.001
 26–34 y 61,895 22.6% 1,169 18.9% 60,726 22.7%
 35–44 y 54,130 19.8% 1,042 16.9% 53,088 19.9%
 ≥45 y 77,438 28.3% 635 10.3% 76,803 28.7%
Calendar year a
 2015 83,243 30.4% 1,923 31.1% 81,320 30.4% 0.56
 2016 60,379 22.1% 1,359 22.0% 59,020 22.1%
 2017 52,688 19.3% 1,200 19.4% 51,488 19.3%
 2018, 2019 77,156 28.2% 1,702 27.5% 75,454 28.2%
Sex/gender b
 Male 150,021 54.9% 4,223 68.3% 145,798 54.6% <.001
 Female 123,445 45.1% 1,961 31.7% 121,484 45.5%
Insurance type
 Medicaid 166,528 60.9% 3,324 53.8% 163,204 61.1% <.001
 Commercial 106,938 39.1% 2,860 46.3% 104,078 38.9%
Race and ethnicity c
 Non-Hispanic white 105,450 67.5% 1,459 46.2% 103,991 68.0% <.001
 Non-Hispanic black 37,648 24.1% 1,441 45.6% 36,207 23.7%
 Hispanic 2,527 1.6% 58 1.8% 2,469 1.6%
 Multiracial/other 10,496 6.7% 200 6.3% 10,296 6.7%
Charlson Comorbidity Index (CCI) d
 CCI = 0 233,295 85.3% 5,430 87.8 227,865 85.3% <.001
 CCI = 1 25,981 9.5% 560 9.0 25,421 9.5%
 CCI ≥2 14,190 5.2% 194 3.1 13,996 5.2%
Baseline substance use disorder characteristics
Substance use disorder diagnoses
 Opioid use disorder 53,693 19.6% 1,389 22.5% 52,304 19.6% <.001
 Alcohol use disorder 47,157 17.2% 1,739 28.1% 45,418 17.0% <.001
 Stimulant use disorder 21,612 7.9% 1,003 16.2% 20,609 7.7% <.001
 Cannabis use disorder 39,088 14.3% 2,261 36.6% 36,827 13.8% <.001
 Substance-induced mental disorders 16,874 6.2% 947 15.3% 15,927 6.0% <.001
Baseline psychiatric characteristics
Mood-related disorder 102,931 37.6% 3,214 52.0% 99,717 37.3% <.001
 Bipolar-related disorder 37,942 13.9% 1,430 23.1% 36,512 13.7% <.001
 Major depressive disorder 76,155 28.0% 2,423 39.2% 73,732 27.6% <.001
Anxiety-related disorder 122,215 44.7% 3,229 52.2% 118,986 44.5% <.001
 Generalized anxiety disorder 32,297 11.8% 967 15.6% 31,330 11.7% <.001
 Panic disorder 9,805 3.6% 257 4.2% 9,548 3.6% 0.02
 Social anxiety 2,243 0.8% 102 1.7% 2,141 0.8% <.001
Posttraumatic stress disorder 18,089 6.6% 663 10.7% 17,426 6.5% <.001
Preadmission psychosis
 ≥1 diagnosis of psychotic disorder 18,131 6.6% 1,190 19.2% 16,941 6.3% <.001
 ≥1 psychosis admissione 10,719 3.9% 857 13.9% 9,862 3.7% <.001
 Diagnosed with psychosis, but no admission 7,412 2.7% 333 5.4% 7,079 2.7% <.001
Postadmission psychosis
 ≥1 diagnosis of psychotic disorder 18,549 6.8% 1,013 16.4% 17,536 6.6% <.001
 ≥1 psychosis admissione 9,283 3.4% 575 9.3% 8,708 3.3% <.001
 Diagnosed with psychosis, but no admission 9,266 3.4% 438 7.1% 8,828 3.3% <.001
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a

Calendar year of admission.

b

Sex and/or gender recorded in the claims data.

c

Race and ethnicity only available for Medicaid enrollees.

d

Computed from baseline comorbidities.

e

Psychosis-related admissions represent a subgroup of people with ≥1 diagnosis of psychotic disorder who received diagnoses in the emergency room or in an inpatient setting.

Table 2.

Comorbidity Between Hallucinogen- and Nonhallucinogen-Related Admissions (N = 273,466)

Frequency %
Number of hallucinogen- and nonhallucinogen-related admissions
 Hallucinogen 6,184 2.3
 Nonhallucinogen
  Alcohol 157,858 57.7
  Cannabis 121,846 44.6
  Stimulant 69,355 25.4
  Opioid 37,819 13.8
Combinations of hallucinogen- and nonhallucinogen-related admissions
 Alcohol only 93,326 34.1
 Cannabis only 52,148 19.1
 Stimulant only 21,387 7.8
 Opioid only 15,518 5.7
 Hallucinogens only 695 0.3
 2 nonhallucinogen admissions 63,869 23.4
 3+ nonhallucinogen admissions 21,034 7.7
 Hallucinogens +1 nonhallucinogen admission 1,840 0.7
 Hallucinogens +2+ nonhallucinogen admissions 3,649 1.3
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The median age was 34 years (interquartile range [IQR] = 22), and the cohort of individuals with hallucinogen-related admissions was younger than individuals with nonhallucinogen admissions (24 years [IQR = 16] vs 34 years [IQR=23], P< .001). Overall, 60.9% were enrolled in Medicaid vs commercial insurance (53.8% hallucinogen vs 61.1% nonhallucinogen, P < .001). Among Medicaid enrollees, the proportion of non-Hispanic White people was significantly lower in the hallucinogen-related admissions cohort compared to the nonhallucinogen-related admissions cohort (46.2% vs 68%, P< .001). For example, 22.5% of the hallucinogen-related admissions cohort had a baseline diagnosis for opioid use disorder. Similarly, these numbers were elevated at 36.6% for cannabis-, 16.2% for stimulant-, and 28.1% for alcohol use disorders. By contrast, the rates for the aforementioned baseline SUDs ranged from 6% to 19.6% preceding each enrollee’s first nonhallucinogen substance-related admission (P < .001 for all).

Baseline mental health-related claims were also more common preceding enrollees’ first hallucinogen-related admission than for other (nonhallucinogen) substance-related admissions. Baseline psychotic disorders were elevated in the hallucinogen-related admissions cohort compared to individuals with nonhallucinogen-related admissions (19.2% vs 6.3%). Overall, 16.4% of individuals within the hallucinogen-related index admissions cohort compared to 6.6% of individuals within the nonhallucinogen-related admissions cohort (P < .001) received ≥1 diagnosis for psychosis between 30 days and 6 months following their index substance-related admission (6.8% overall). Furthermore, 9.3% of hallucinogen-related admissions compared to 3.3% of nonhallucinogen-related admissions (P < .001) experienced ≥1 subsequent admission for psychosis between 30 days and 6 months following index substance-related admission (3.4% overall).

We conducted secondary analyses differentiating between (A) people who experienced hallucinogen-related admissions alone (n = 695), (B) those with hallucinogen-related admissions and other nonhallucinogen substance-related admissions (n = 5,489), and (C) individuals with nonhallucinogen substance-related admissions only (n = 267,282). As shown in Supplementary Table 1, people with both hallucinogen-related and nonhallucinogen substance-related admissions consistently had higher levels of baseline psychiatric and substance-related comorbidity than individuals with hallucinogen-related admissions alone and those with solely nonhallucinogen substance-related admissions.

Multivariable Predictors of Postindex Psychosis

Across all unadjusted analyses, individuals in the hallucinogen-related admissions cohort—compared to individuals with nonhallucinogen substance-related admissions—were more likely to show evidence of psychosis in the 30 days to 6 months following their admission. For example, χ2 tests showed significantly higher rates of postindex psychosis-related diagnoses (16.4% vs 6.6%, P < .001) and admissions (9.3% vs 3.3%, P < .001). In unadjusted Cox models, hallucinogen-related admissions—compared to nonhallucinogen substance-related admissions—were strongly associated with an increased hazard for postindex psychosis diagnoses (Figure 2; Model 1A, HR= 1.22 [95% CI = 1.19–1.25]) and psychosis admissions (Figure 2; Model 1B, HR=1.16 [1.13–1.19]).

Figure 2. Association of Hallucinogen Admissions with Post–180-Day Psychosis Diagnosesa.

Figure 2.

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aFull models in Supplementary Materials.

bUnadjusted.

cAdjusted for baseline psychosis.

dAdjusted for demographics, Charlson comorbidity index, baseline psychiatric disorders (psychosis, anxiety, mood disorders), and baseline co-occurring SUDs.

eSame as Model 3A but adjusted for race/ethnicity (limited to Medicaid enrollees).

fSame as Model 3B but adjusted for race/ethnicity (limited to Medicaid enrollees).

Adjusting for Preindex Psychosis

After adjustment for baseline psychotic disorder diagnoses (Figure 2; Model 2A), individuals with hallucinogen-related admissions were modestly more likely to incur postindex psychosis diagnoses (HR = 1.12 [1.09–1.15]) than individuals with nonhallucinogen-related admissions. After additional adjustment for baseline clinical characteristics and demographics, individuals in the hallucinogen-related admissions cohort were no longer at increased risk to experience postindex psychosis compared to individuals in the nonhallucinogen substance-related admissions (Figure 2; Model 3A, HR=0.97 [0.95–1.00]). In a subgroup analysis conducted among Medicaid enrollees, we observed a similar pattern where the unadjusted association between hallucinogen-related admissions and postindex psychosis was either nonsignificant or of modest magnitude after adjustment for baseline clinical characteristics (Supplementary Table 3B; Models 2B, 3B, and 4B). We observed a similar attenuation of the association between hallucinogen-related admissions and postindex psychosis admissions in adjusted models of Medicaid enrollees where we controlled for race/ethnicity (Supplementary Table 3B; Models 2B, 3B, and 4B). Across all adjusted models (Supplementary Table 3A–3B), baseline psychiatric disorders were consistently significant predictors of postindex diagnoses for psychosis, especially baseline psychotic admissions (HRs ranging from 1.28 to 1.35), stimulant use disorders (HRs ranging from 1.27 to 1.32), and opioid use disorder (HRs ranging from 1.28 to 1.32).

Sensitivity analyses restricting to individuals without baseline psychosis, stratifying by baseline psychiatric status, examining extended follow-up periods (12–24 months), analyzing hallucinogen-only users, age-stratified analyses (<26 years), and using alternative outcome definitions (excluding substance-induced mental disorders) yielded results consistent with the primary analysis (detailed results in Supplementary Methods 2).

DISCUSSION

While individuals within the hallucinogen-related admissions cohort were found to be more likely to experience postindex admissions for psychosis than individuals within the nonhallucinogen substance-related admissions cohort, the magnitude of effect was not significant after adjusting for baseline clinical characteristics and modest in the subgroup analysis of the Medicaid cohort (adjusted for race/ethnicity). Furthermore, a hallucinogen-related admission was not associated with significantly increased postindex psychosis risk, though baseline psychotic disorders were associated with substantially increased risk in adjusted models. Importantly, we observed that baseline psychosis was significantly more common among those within the hallucinogen-related admission cohort than among individuals within the nonhallucinogen-related admission cohort (baseline psychosis diagnoses = 19.2% vs 6.3%; baseline psychosis admissions = 13.9% vs 3.7%). Taken together, these findings raise questions about whether the risk of psychosis associated with hallucinogen exposure may be partly attributable to individuals’ underlying psychiatric history rather than the sequelae of hallucinogen ingestion, though there may be some lingering questions about the effects of race/ethnicity on this association.

An important consideration in interpreting these findings is that the median age of hallucinogen-related admissions (24 years) overlaps substantially with the typical age of onset for SSDs.28 This temporal convergence complicates efforts to establish causal relationships between hallucinogen exposure and subsequent psychosis. Prodromal symptoms of psychotic disorders may emerge years before formal diagnosis, during which time individuals may be exposed to various substances.29 When substance exposure and psychosis onset occur during overlapping developmental periods, observational data cannot reliably establish whether substance use preceded, coincided with, or followed the early manifestations of psychotic illness.19,30 Prior research in SUD populations has demonstrated that individuals with substance-induced mental disorders exhibit greater baseline psychiatric severity and comorbidity than those without such diagnoses, suggesting that substance-psychiatric associations may reflect underlying vulnerability rather than purely substance effects.17,31 These limitations in establishing temporal precedence fundamentally constrain causal inference from population-level administrative data.

Prior studies of the association between hallucinogen-related admissions and psychosis attempted to control for baseline schizophrenia-spectrum disorders by excluding individuals with prior psychosis-related admissions.18 However, our study shows that individuals with psychosis-related admissions comprise only a subset (10,719/18,131 people) of people who were diagnosed with baseline psychotic disorders. Compared to prior findings, using multivariable models which account for both premorbid psychosis diagnosis and admission (among other baseline covariates) led to an attenuation in the risk of psychosis attributable to hallucinogen-related admissions. Overall, this suggests that the risk of psychosis thought to be attributable to hallucinogen-related admissions may be impacted by residual confounding by indication. These findings are in line with the historical understanding that psychedelics appear to rarely cause prolonged psychosis, with examples primarily resulting from case studies.32–34 Further data from clinical research on LSD in 1960 showed that prolonged psychotic reactions ranged from 0.8% to 1.8%.35 This remains in stark contrast to other substances such as cannabis, which appears to have a strong relationship to the development of psychosis and SSD.36,37 The difference in psychosis risk observed between controlled clinical trials and recreational use settings may reflect multiple factors, including differences in participant selection. Clinical trials often exclude individuals with personal or family history of psychotic or bipolar disorders and implement controlled dosing and environmental conditions that may reduce adverse events.9,38 In contrast, observational data from health care encounters capture unselected populations without such safeguards. Our data show that individuals with hallucinogen-related admissions have substantially higher rates of baseline psychiatric comorbidity than those with other substance-related admissions. Whether these baseline differences fully account for observed associations, or whether residual confounding persists, remains uncertain from these data alone. Relatedly, the populations represented in administrative data may differ in important ways from those enrolled in psychedelic trials, a consideration that warrants attention as these therapies progress toward broader implementation.39,40

These findings have implications for ongoing policy discussions regarding psychedelic medicalization, decriminalization, and legalization. Epidemiologic associations between substance availability and adverse outcomes do not necessarily reflect causal relationships, particularly when baseline psychiatric vulnerability differs systematically between exposed and unexposed populations.41 While increased cannabis availability has been associated with rising rates of psychosis in some jurisdictions, findings are mixed, and the extent to which this represents substance-induced versus substance- associated psychosis in vulnerable individuals remains debated.42–45 Our findings suggest that population-level data on hallucinogen-psychosis associations may be substantially confounded by preexisting psychiatric conditions, complicating straightforward interpretations for regulatory policy. Policymakers may benefit from distinguishing between risk profiles observed in controlled medical contexts versus unregulated recreational use and from recognizing that observed associations in administrative data may overestimate causal effects when baseline psychiatric comorbidity is inadequately measured.

Interestingly, there was a low number of individuals who experienced hallucinogen-related admissions without another nonhallucinogen-related admission (695 of 6,184). This finding suggests that polysubstance use is very common among individuals who use hallucinogens. While the data are limited to few studies, there is also evidence showing that individuals who use psychedelics often have a history of polysubstance exposure (ingestion of multiple substances in the same sitting).46,47 Taken together, the majority of individuals with hallucinogen-related admission within our cohort likely engage in both temporally spaced and/or simultaneous substance use. The motivations behind such patterns of polysubstance consumption are not entirely understood but may potentially relate to a desire to alleviate negative effects while potentiating positive effects of coingested substances.48 Further research is required to understand this pattern and is of special importance given that approximately half of drug-related hospitalizations occur in individuals with more than one SUD.49

There are several limitations. First, we cannot differentiate between different subtypes of hallucinogens (ie, psilocybin, LSD, MDMA, phencyclidine [PCP], ayahuasca, ketamine), each of which has a different safety profile. The contrast in safety profiles is especially true for PCP and ketamine which have historically been recognized for their induction of psychosis via N-methyl-d-aspartate antagonism leading to the substance being used as a model for schizophrenia.50,51 Additionally, hallucinogen detection at hospital admission may be less reliable than detection of other substances such as opioids, alcohol, stimulants, and cannabis, which have standardized and widely available toxicology testing. Consequently, some psychosis-related hospitalizations involving hallucinogen use may be misclassified as nonhallucinogen cases if the substance was not identified or documented, potentially underestimating observed associations. Second, the sample is limited to individuals with substance-related admissions, which does not generalize to most individuals who are using hallucinogens recreationally without resultant functional impairment. The prevalence of different substances in community settings differs substantially from their representation in hospital admissions. Alcohol, cannabis, and stimulants are far more prevalent in community use than hallucinogens, yet hallucinogens comprise a small fraction of substance-related admissions in our data.21,52 Whether this reflects lower risk per exposure or simply lower population exposure remains uncertain from these data. As hallucinogen use continues to increase in the current era, ongoing surveillance will be needed to assess whether observed risk profiles change with shifting patterns of use. Third, a 6-month observation period may be inadequate to assess for long-term effects of hallucinogen exposure on psychosis-related outcomes. Furthermore, it is plausible that a subset of the individuals who go on to develop psychosis after a hallucinogen-related admission are in the prodromal phase of SSD development, which can last >1 year, and have not yet received formal psychiatric care and diagnosis despite being primed for their first psychotic break.53 Similarly, individuals with prior psychosis diagnoses may have undocumented hallucinogen use that preceded their initial psychiatric presentation, potentially leading to underestimation of hallucinogen-psychosis associations in either direction. This could lead to an underestimation of preexisting psychosis diagnosis in the hallucinogen-related admissions cohort.

Despite these limitations, this analysis is strengthened by the presence of linked inpatient and outpatient data, permitting assessment of psychiatric comorbidities beyond prior admissions data preceding hallucinogen-related health care encounters. As the use of classic hallucinogens is increasing over time in the US, more research is needed on longitudinal outcomes of people who use hallucinogens.54

CONCLUSIONS AND IMPLICATIONS

While the association between baseline psychiatric comorbidity and psychosis risk is well-established in clinical literature, our study provides quantitative evidence of how this confounding specifically impacts hallucinogen-psychosis associations in population-based samples. Furthermore, although this relationship may be familiar to mental health professionals, translating this nuance to policymakers and public discourse on psychedelic policy remains challenging when epidemiologic associations are interpreted without in-depth consideration of underlying confounding factors. Our sensitivity analyses, including restriction to incident psychosis cases, extended follow-up periods addressing prodromal phase considerations, and analyses of hallucinogen-only users, suggest that apparent psychosis risk may be more attributable to underlying psychiatric vulnerability than hallucinogen exposure alone. These findings, importantly, have implications for policy development and clinical practice. Regulatory discussions around psychedelic substances may benefit from nuanced risk assessment that distinguishes between population-level psychiatric comorbidity and substance-specific effects. For clinical applications, our results suggest that individuals seeking psychedelic therapy may benefit from screening that extends beyond hospitalization history to include outpatient mental health diagnoses. For harm reduction approaches, these findings may inform targeted interventions for individuals with preexisting psychiatric vulnerability.

Supplementary Material

Supplemental Material

Available at Psychiatrist.com.

Clinical Points.

  • Hallucinogen-related hospital admissions are associated with elevated rates of subsequent psychosis diagnoses, but these associations are largely explained by preexisting psychiatric conditions among those with hallucinogen-related admissions.

  • In the evaluation of patients with hallucinogen exposure and psychosis, comprehensive psychiatric assessment should include evaluation of baseline psychiatric comorbidities that may predispose individuals to both hallucinogen use and psychosis.

  • Population-level associations between hallucinogen use and psychosis may reflect underlying psychiatric vulnerability and co-occurring substance use disorders rather than hallucinogen-specific causation, informing both clinical assessment and policy discussions.

Acknowledgments:

The authors acknowledge the support of Nuri Farber, MD, and the Psychiatry Residency Research Education Program of Washington University. Dr Farber has no disclosures.

Funding/Support:

The analysis was supported by K08 DA061258 (Dr Xu) and R25 MH112473 (Drs Steinle and Shankar). Effort for some personnel was supported by the Wash U Parker Young Investigator Award (Dr Xu), Wash U Center for Perioperative Mental Health (P50 MH122351), and grant WU 6239 from the Foundation for Barnes-Jewish Hospital (Dr Xu), but these grants did not fund the data pull. Dr Cabassa was supported by Washington University’s Center for Dissemination and Implementation and the Here & Next Transcend Initiative. The Administrative Data Core Services at WashU is supported in part by the WashU Institute of Clinical and Translational Sciences grant UL1 TR002345 from the National Center for Advancing Translational Sciences of the NIH.

Role of the Sponsor:

The funding sources have no role in the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the paper for publication.

Footnotes

Relevant Financial Relationships: Dr Siegel was previously employed by Sumitomo Pharma America, received consulting fees from Longitude Capital and Otsuka Pharmaceutical, and was coinventor on a provisional patent (no. 020949/US 15060-1787) related to the use of precision functional mapping to assess target engagement of experimental therapeutics. Dr Nicol reported receiving grants from COMPASS Pathways and Usona; receiving drug supply from Usona; and being a paid consultant for Carelon, Alkermes, Sunovion, and Novartis outside the submitted work as well as serving as codirector of the WashU Center for Holistic Interdisciplinary Research in Psychedelics (CHIRP). Dr Grucza reported receiving grants from National Institutes of Health (NIH) as well as receiving honoraria for conducting grant reviews from the NIH and WashU outside the submitted work. Dr Cabassa reported receiving grants from NIH, the WashU Center for Dissemination and Implementation, and the Here & Next Transcend Initiative. The other authors report no relevant financial relationships.

Data Management:

A cleaned version of data was provided to the authors by the Center for Administrative Data Research (CADR). The authors did not access the database population used to create the study population, which is secured by CADR. Data cleaning, linkage of inpatient, outpatient, and prescription data, deduplication, and de-identification were overseen by Merative. The authors did not access the database population used to create the study population, which is secured by ICTS.

Data Sharing Statement:

The MarketScan data are proprietary and can be accessed via a request to www.merative.com. The authors will provide relevant code on reasonable written request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Material
NIHMS2184410-supplement-Supplemental_Material.docx (395.1KB, docx)

Data Availability Statement

A cleaned version of data was provided to the authors by the Center for Administrative Data Research (CADR). The authors did not access the database population used to create the study population, which is secured by CADR. Data cleaning, linkage of inpatient, outpatient, and prescription data, deduplication, and de-identification were overseen by Merative. The authors did not access the database population used to create the study population, which is secured by ICTS.

The MarketScan data are proprietary and can be accessed via a request to www.merative.com. The authors will provide relevant code on reasonable written request.

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