Unusual experiences and early-onset psychosis associated to hallucinogen use in adolescents: a systematic review and meta-analysis.

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Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Child Adolesc Psychiatry Ment Health . 2026 Mar 8;20:56. doi: 10.1186/s13034-026-01060-1 Search in PMC Search in PubMed View in NLM Catalog Add to search Unusual experiences and early-onset psychosis associated to hallucinogen use in adolescents: a systematic review and meta-analysis Maite Armanino-Irigaray Maite Armanino-Irigaray 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain Find articles by Maite Armanino-Irigaray 1 , Ana Catalán Ana Catalán 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain 2 Neuroscience Department, University of Basque Country (UPV/EHU), Leioa, Spain 3 Biobizkaia Health Research Institute, Barakaldo, Spain 4 CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain Find articles by Ana Catalán 1, 2, 3, 4, ✉ , Claudia Aymerich Claudia Aymerich 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain 4 CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain 5 Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK Find articles by Claudia Aymerich 1, 4, 5 , Borja Pedruzo Borja Pedruzo 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain 2 Neuroscience Department, University of Basque Country (UPV/EHU), Leioa, Spain 3 Biobizkaia Health Research Institute, Barakaldo, Spain 4 CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain Find articles by Borja Pedruzo 1, 2, 3, 4 , Ignacio Argüelles Ignacio Argüelles 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain Find articles by Ignacio Argüelles 1 , Alazne Ramírez Alazne Ramírez 3 Biobizkaia Health Research Institute, Barakaldo, Spain Find articles by Alazne Ramírez 3 , Eleonora Armyra Eleonora Armyra 5 Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK Find articles by Eleonora Armyra 5 , Miguel Ángel González-Torres Miguel Ángel González-Torres 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain 2 Neuroscience Department, University of Basque Country (UPV/EHU), Leioa, Spain 3 Biobizkaia Health Research Institute, Barakaldo, Spain 4 CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain Find articles by Miguel Ángel González-Torres 1, 2, 3, 4 , Gonzalo Salazar de Pablo Gonzalo Salazar de Pablo 4 CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain 5 Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK 6 Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK 7 Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Madrid, Spain Find articles by Gonzalo Salazar de Pablo 4, 5, 6, 7 Author information Article notes Copyright and License information 1 Department of Psychiatry, Basurto University Hospital, Bilbao, Spain 2 Neuroscience Department, University of Basque Country (UPV/EHU), Leioa, Spain 3 Biobizkaia Health Research Institute, Barakaldo, Spain 4 CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain 5 Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK 6 Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK 7 Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Madrid, Spain ✉ Corresponding author. Received 2025 Nov 25; Accepted 2026 Feb 19; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13081284  PMID: 41796365 Abstract Background Hallucinogen use among adolescents is increasing worldwide. In this context, in recent years, hallucinogens have re-emerged in scientific and public discourse. However, whether there is an association between hallucinogens use in adolescents and the impact of such use in individuals with Early-Onset Psychosis (EOP), remains unclear. This systematic review and meta-analysis evaluated the prevalence and impact of hallucinogen use in adolescents with EOP, and the association between hallucinogen exposure and psychotic symptoms in community samples. Methods We carried out a PRISMA-compliant systematic search (PubMed, Web of Science, Cochrane Library, PsycINFO; last search in July 2025). We included observational studies enrolling individuals under 18 years. Independent reviewers performed study selection, data extraction, and risk-of-bias assessment (using the Newcastle–Ottawa Scale). We conducted a random-effects meta-analysis to estimate the prevalence of hallucinogen use in adolescents with EOP. Other clinical and functional outcomes, as well as evidence from community-based samples, were synthesized narratively. This was due to heterogeneity in design and reporting, which precluded the meta-analysis. Results Twelve articles met our inclusion criteria. 39.9% included individuals were female and the mean age was 16.1 years. In EOP, pooled prevalence of any hallucinogen use was 14.3% (k = 6; N = 713; 95% CI: 3.9%–40.9%). LSD use in the included studies ranged from 1.8 to 12.5%. MDMA use ranged from 3.5 to 42.9%. Hallucinogen use in EOP was consistently associated with polysubstance use and indicators of clinical complexity, including suicidality, conduct disorder, reduced educational attainment, and depot antipsychotic treatment. In the general population, hallucinogen use showed weak and inconsistent associations with psychotic symptoms and manic symptoms, but which largely attenuated after adjustment for other drugs and genetic vulnerability. Newcastle-Ottawa Scale (NOS) scores ranged from 4 to 9, with a mean score of 6.4. Conclusions Hallucinogen use is common in adolescents with EOP and seems to be associated with more complex clinical trajectories, particularly higher rates of suicidality. Although not an isolated causal trigger, hallucinogens may contribute to symptom exacerbation in neurodevelopmentally or genetically predisposed youth. Future research should prioritise longitudinal, large-scale studies and introduce clinical trials in the field. Supplementary Information The online version contains supplementary material available at 10.1186/s13034-026-01060-1. Keywords: Early-onset psychosis, Hallucinogens, Psychedelics, MDMA, LSD, Psychotic symptoms Introduction Early-Onset Psychosis (EOP), defined as the onset of psychotic symptoms before the age of 18 years, represents a particularly severe and disabling form of psychotic disorder [ 1 ]. Compared with adult-onset psychosis, EOP is associated with more neurodevelopmental difficulties [ 2 ], poorer premorbid adjustment [ 3 ], as well as higher levels of negative symptoms [ 4 ] and increased impulsivity [ 5 ], among other adverse outcomes. Prognosis is further worsened by the early disruption of developmental trajectories, which interferes with cognitive, educational, and occupational development [ 3 , 6 ]; thereby highlighting the need to identify modifiable risk factors that may influence onset, progression, and treatment response. Adolescence is a developmental period often characterised by experimentation with psychoactive substances [ 7 ]. According to the 2025 European Union Drugs Agency report, among students aged 15–16 years, alcohol and nicotine were the most frequently used substances, followed by cannabis, cocaine, ecstasy/3,4-methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD) [ 8 ]. Comparable data from the United States indicate that in 2023, an estimated 8.8 million people aged 12 or older (about 3.1% of the U.S. population) reported past-year use of hallucinogens according to the National Survey on Drug Use and Health [ 9 ]. Substance use is particularly relevant in the context of EOP, as affected individuals show markedly higher rates of substance use disorders (SUD) [ 10 ]. SUD has, in turn, been associated with earlier psychosis onset and poorer long-term outcomes [ 11 ]. Hallucinogens are psychoactive substances that alter perception, cognition, and mood [ 12 ]. These substances can be broadly classified into two pharmacological groups: classical hallucinogens, also known as psychedelics, acting as agonists at serotonin (5-HT)2 A receptors – which primarily modulate perception and self-experience through alterations in cortical network integration [ 13 ]– which include LSD, dimethyltryptamine (DMT), mescaline and psilocybin [ 14 ]; and dissociative hallucinogens, such as ketamine and phencyclidine (PCP), primarily acting through antagonism of the N-methyl-D-aspartate (NMDA) receptor and producing psychotomimetic effects via glutamatergic dysregulation [ 15 ]. Although MDMA is structurally an amphetamine derivative, it shares neurobiological properties with hallucinogens and is often considered within the same conceptual class [ 16 ]. MDMA affects multiple neurotransmitter systems, inducing alterations in serotonergic, dopaminergic, and GABAergic signalling, and has been shown to disrupt memory and learning processes through hippocampal dysfunction via dopaminergic and NMDA receptor alterations [ 17 ]. This neurobiological profile is associated with effects in emotional processing, social cognition, and affective salience [ 18 ]. Given the overlap of mechanisms with those implicated in both classical serotonergic psychedelics and dissociative agents, and consistent with prior literature [ 19 ], MDMA was considered relevant to a unified hallucinogen-related exposure framework. In vulnerable individuals, the neuropharmacological effects of hallucinogens might precipitate acute psychotic episodes, the severity and duration of which depend on both individual vulnerability and contextual factors, consistent with stress-vulnerability models of psychosis [ 20 ]. Historically, these effects led to the use of terms such as psychotomimetic (psychosis-mimicking), psycholytic (psyche-loosening), and psychedelic (mind-manifesting), reflecting their capacity to induce transient alterations in perception, cognition and self-experience [ 12 ]. While the association between cannabis and psychosis has been robustly demonstrated [ 21 ], the potential role of hallucinogenic substances remains comparatively understudied, particularly in younger populations. Recent advances in hallucinogen neuroscience have begun to clarify the biological basis of these responses. Neuroimaging studies indicate that both classic and dissociative hallucinogens induce transient dysregulation of large-scale brain networks, including the default mode network, salience network and limbic circuits, that are centrally involved in self-processing, emotional regulation and perceptual integration [ 22 ]. Consistent with this framework, phenomenological analyses suggest that hallucinations arising in relation to substance use often differ qualitatively from those observed in endogenous psychoses, being more commonly characterised by altered perceptual salience and disrupted self-boundaries, and dissociative experiences [ 23 ]. During adolescence, a developmental period marked by ongoing synaptic pruning and cortical maturation [ 24 ], such network-level perturbations may be more likely to elicit psychotomimetic responses. In recent years, hallucinogens have re-emerged in both scientific and public discourse driven by renewed research into their therapeutic potential for conditions such as depression, anxiety, SUD, obsessive-compulsive disorder and post-traumatic stress disorder [ 25 ]. While the previously mentioned network-level changes may underpin therapeutic effects in controlled clinical settings, they may also contribute to unpredictable outcomes in vulnerable individuals, intensifying concerns regarding hallucinogen-induced acute or long-lasting psychotic symptoms, especially in individuals with a genetic or clinical vulnerability to psychosis [ 19 , 26 ]. Several systematic reviews and meta-analyses have examined the relationship between hallucinogens and psychosis in adults [ 19 , 26 , 27 ], yet findings remain inconclusive. Some studies report an association with the onset or exacerbation of psychosis [ 26 ], whereas others—particularly those based on community samples—show no clear link [ 27 ]. A recent meta-analysis [ 19 ] synthesized the evidence across healthy individuals and people with pre-existing psychotic disorders on the relationship between hallucinogens and psychosis, but focused exclusively on adults, leaving unanswered how hallucinogen use relates to unusual experiences and EOP. In this context, ‘unusual experiences’ refers to subthreshold psychosis-spectrum phenomena, commonly described as psychotic-like experiences, that do not meet criteria for a psychotic disorder. Critically, evidence specific to youth remains limited. Data on the prevalence of hallucinogen use in clinical (EOP) and community populations remain scarce, and the associated clinical correlates and prognostic implications are poorly understood. Determining whether hallucinogen use during adolescence contributes to the emergence or worsening of psychotic symptoms— or to the transition toward a full-blown psychotic disorder— is particularly relevant, given the neurodevelopmental vulnerability of this period. This systematic review aims to synthesize the available evidence on hallucinogen use in adolescents by addressing first, the prevalence of hallucinogen use among individuals with EOP; second, the clinical correlates and potential impact of such use on the course of illness; and third, the association between hallucinogen exposure and psychotic or psychotic-like symptoms in adolescents from community samples. Methods This study protocol was registered on PROSPERO (CRD420251160656). The study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline) [ 28 ] (Table S1 ) checklist, following the EQUATOR (Enhancing Quality and Transparency of Health Research) reporting guidelines [ 29 ]. Search strategy and selection criteria A systematic, multistep literature search was conducted independently by two researchers (MA, AC), who screened all titles/abstracts and full texts for eligibility. Discrepancies were resolved through discussion or consultation with a senior researcher (GSP). The web of Science database (Clarivate Analytics), incorporating the Web of Science Core Collection, PubMed, BIOSIS Citation Index, KCI-Korean Journal Database, MEDLINE, Russian Science Citation Index, and SciELO Citation Index, Cochrane Central Register of Reviews as well as Ovid/PsycINFO databases, were searched from inception until July 17, 2025. The complete search terms are available in Supplement 1. Articles identified were first screened as abstracts, and after excluding those not relevant, the full texts of the remaining articles were assessed for eligibility. We also manually screened the reference lists of relevant studies and previous systematic reviews to identify any additional eligible articles. Inclusion criteria were: [ 1 ] studies conducted in children or adolescents (mean age under 18 years); [ 2 ] studies including either (a) individuals with EOP, in which the exposure or impact of hallucinogen use or hallucinogen use disorder was evaluated, or (b) individuals from the general population or community samples, in which the association between hallucinogen use and the occurrence of psychotic or psychotic-like symptoms was examined; [ 3 ] studies reporting original data from cross-sectional or longitudinal observational designs; [ 4 ] studies with or without a control group; and [ 5 ] studies published in any language. For the EOP group, studies were included if they included children and adolescents under 18 years of age (mean age < 18 years) diagnosed according to DSM or ICD criteria [ 30 , 31 ] including schizophrenia spectrum disorders (e.g. schizophrenia, schizoaffective disorder, brief psychotic disorder, or other specified/unspecified psychoses). For the general population group, studies were included if they investigated the prevalence, correlates, or consequences of hallucinogen use in community samples of adolescents (mean age < 18 years), with or without psychotic-like experiences or subthreshold psychotic symptoms (‘unusual experiences’, as defined above). Studies were excluded if they [ 1 ] were reviews, case reports, small case series (< 5 participants), conference abstracts, or theses; [ 2 ] enrolled only participants with a mean age 18 years. No restrictions were applied regarding the context of hallucinogen use. In this review, we use “hallucinogens” as an umbrella term encompassing classical serotonergic psychedelics, dissociative agents and MDMA. Although the latter is not a classical or dissociative hallucinogen, it has been included within the same exposure domain based on shared and converging neurobiological effects relevant to psychosis vulnerability, and consistent with prior literature. The term “psychedelics” is used only when referring specifically to classical serotonergic compounds. Outcome measures and data extraction Two researchers (AR, IA) independently extracted data from all included studies. All extracted information was double-checked by a third researcher (BP) to ensure consistency and accuracy. Discrepancies or unclear entries were discussed and resolved through consensus with a senior researcher (GSP). The variables extracted are specified in the Supplement 2. During data extraction, information on the reported context of hallucinogen use was recorded when available. For each study, the type of outcome assessed, and the method of outcome ascertainment were extracted and are reported in Table 1 . When studies included mixed-age cohorts, subgroup-specific denominators corresponding to the adolescent estimates were extracted and are reported where available. Table 1. Characteristics of included studies Included studies Main study outcome Main outcome ascertainment method NOS Main findings Baeza et al. [ 40 ] Severity and evolution of psychotic symptoms PANSS 7 Substance use (mainly cannabis) was present in one third of patients. LSD use was rare. Cannabis users had higher PANSS positive and lower negative scores than non-users; those who ceased use at 6 months had the best outcomes. de Angelis et al. [ 37 ] Adaptation to social rehabilitation program Chart audit 7 Females were more prone to chronic PCP use than males (68.2% vs. 31.8%; p < 0.01). No significant differences were found in terms of race ( p = 0.80). No schizophrenia cases or PCP-induced psychosis were noted among the sample. Eseroglu et al. [ 44 ] Evolution of psychotic symptoms PANSS 5 SUD comorbidity was associated with male sex, earlier onset of substance use, and higher PANSS positive scores at discharge, though treatment duration and overall improvement did not differ between groups. Hsiao and McClellan [ 42 ] Prevalence of SUD in adolescents with schizophrenia, BD or psychosis NOS SCID 6 Hallucinogen use (11.5%) and cannabis (31.8%) were the most frequent illicit drugs after alcohol and tobacco. Substance use preceded psychosis onset in most cases. No significant association between specific substances and symptom severity was found. Kuzenko et al. [ 34 ] Association between use of psychedelics, cocaine or amphetamines and psychotic symptoms in a community sample M-CIDI 7 The use of psychedelics was associated with a higher likelihood of psychotic symptoms after adjusting for alcohol, nicotine, cannabis, and other drug use disorders, any other mood or anxiety disorder, and childhood adversities (OR = 2.37; 95% CI: 1.20–4.66), and after adjusting for age, sex, social class and urbanicity (OR = 4.99; 95% CI:: 2.83–8.82). Luukkonen et al. [ 39 ] Association between substance use and bullies, victims or bullies-victims Non-structured part of K-SADS-PL for victims (self-reported), K-SADS-PL criteria for conduct disorder for bullies 4 Adolescents hospitalized for severe psychiatric disorders (mean age 15.8 years), among whom hallucinogen use was uncommon (11/508; 2.2%), typically within polysubstance use rather than as a primary drug. Cannabis and alcohol were the predominant substances. No specific associations with diagnosis, symptom severity, or functional outcomes were found compared with non-users. Myran et al. [ 35 ] Development of SSD after ED visits related to hallucinogen use ICD-10 9 Hallucinogen-related ED visits were more common in younger individuals (23.2% were aged 14–18). Among adolescents (14–18 years), the association between a hallucinogen-related ED visit and subsequent development of a SSD was significant for males only (HR = 3.26; 95% CI: 2.09–5.08), but not for females (HR = 1.86; 95% CI: 0.73–4.73). Estimates were adjusted for income quintile, rurality, immigration status, and outpatient, ED, and hospital-based care for mental health and substance use disorders in the past 5 years. Palmer et al. [ 38 ] Personality profiles in adolescents with SUD MMPI-A 4 Adolescents with hallucinogen (psilocybin) dependence scored significantly higher on the MMPI-A Hypochondriasis (F = 3.85; p = 0.03), Schizophrenia (F = 4.39; p = 0.02), and Adolescent-Bizarre Mentation (F = 4.55; p = 0.01) scales compared to the cannabis group. No significant differences emerged on the Paranoia scale ( p = 0.15) or on the remaining clinical scales of the MMPI-A. Paruk et al. [ 41 ] Substance use, especially cannabis, characteristics in adolescents with first episode EOP compared to adolescents with first episode non psychotic mental illness WHO ASSIST 5 Lifetime hallucinogen use was rare (4.4%) but ASSIST involvement scores for hallucinogens were significantly higher in EOP than controls, suggesting increased vulnerability. Cannabis was the predominant substance, often preceding psychosis onset. Shoval et al. [ 43 ] Lifetime history of suicide attempts in adolescent inpatients with schizphrenia or schizoaffective disorder. Retrospective medical record review using a standardized definition of suicide attempt (Mann et al. 2001) 7 Significant association was found between history of suicide attempts and the use of LSD (OR = 5.7; p < 0.01) and inhalants (OR = 5.5; p < 0.01), and, to a lesser extent, alcohol (OR = 3.1; p = 0.01) and MDMA (OR = 2.6; p = 0.04). Simonsson et al. [ 36 ] Self-reported psychotic or manic symptoms at age 15 Auto-informed scales: Adolescent Psychotic-Like Symptom Screener, Child Mania Rating Scale Brief Version 8 In unadjusted analyses, psychedelic use was associated with more psychotic and manic symptoms (β, 0.09; 95% CI: 0.00–0.18 and β, 0.38; 95% CI: 0.27–0.48, respectively). In drug-adjusted analyses, this association was reversed (i.e., psychedelic use was associated with fewer psychotic and manic symptoms). The association between psychedelic use and manic symptoms seems to depend on genetic vulnerability to schizophrenia or bipolar I disorder. Turan et al. [ 10 ] Clinical outcomes in EOS comparing patients with versus without comorbid SUD DSM-V K-SADSPL DSM-V PANSS Medical charts review 8 In multivariate analysis, SUD in EOS (not restricted to hallucinogen use) was associated with male sex ( p = 0.04), fewer years of education ( p < 0.01), older age at onset ( p < 0.01), conduct disorder ( p < 0.01), PTSD ( p = 0.01), alcohol use ( p = 0.04), and zuclopenthixol LAI treatment ( p < 0.01) compared with non-SUD EOS. Associations with DUP, clozapine use, and number of hospitalizations did not remain significant after multivariate adjustment. Open in a new tab BD Bipolar Disorder, DSM Diagnostic and Statistical Manual of Mental Disorders, ED Emergency Department, EOS Early-Onset Schizophrenia, FEP First Episode Psychosis, K-SADSPL Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, LAI Long-Acting Injectable, LSD Lysergic Acid Diethylamide, MDMA 3,4-Methylenedioxymethamphetamine, NOS Newcastle–Ottawa Scale, PANSS Positive and Negative Syndrome Scale, Psychosis NOS Psychosis Not Otherwise Specified, PCP Phencyclidine, PTSD Post-Traumatic Stress Disorder, SSD schizophrenia spectrum disorders, SCID Structured Clinical Interview for DSM, SUD Substance Use Disorder, WHO ASSIST World Health Organization Alcohol, Smoking and Substance Involvement Screening Test Outcomes were categorised a priori into four conceptual domains to enhance coherence and comparability across studies: [ 1 ] unusual experiences (subthreshold psychosis-spectrum phenomena assessed through self-report or screening instruments); [ 2 ] clinically diagnosed psychotic disorders (DSM/ICD-based diagnoses or clinician-assessed psychosis outcomes); [ 3 ] manic symptoms with psychotic features; and [ 4 ] administrative or service-use outcomes (e.g., emergency department visits, hospitalisations, or registry-based diagnoses). All eligibility criteria, data extraction procedures, and narrative synthesis were aligned with this predefined outcome framework. Quality, bias and certainty assessments Risk of bias was assessed independently by two researchers (AR, IA) using the Newcastle-Ottawa Scale for observational studies (NOS). Interrater agreement was high (Cohen’s κ = 0.83). Discrepancies were discussed and resolved through consensus, with input from a third researcher (BP) when necessary. Please see Supplement 3 for individual criteria. Data synthesis We conducted a quantitative meta-analysis exclusively for prevalence estimates of hallucinogen use among adolescents with EOP. Only studies providing suitable quantitative data on prevalence in EOP samples were included in the meta-analysis. Pooled prevalence estimates were calculated using a random-effects model to account for between-study heterogeneity. Proportions were logit-transformed prior to pooling to stabilize variances and subsequently back-transformed for interpretability. Between-study variance (τ²) was estimated using the restricted maximum likelihood (REML) method. Confidence intervals for pooled estimates were calculated using the Hartung–Knapp [ 32 ] adjustment, given the small number of studies and substantial heterogeneity. Heterogeneity was quantified using τ² and the I² statistic. A 95% prediction interval was computed to reflect the expected range of prevalence estimates in comparable future settings. Exact (Clopper–Pearson) confidence intervals were calculated for individual study proportions. No zero-event studies were present in the pooled analysis. Influence analyses (leave-one-out diagnostics), sequentially omitting each study and recalculating the pooled effect size and heterogeneity statistics, were conducted to assess robustness. Given the substantial heterogeneity in study design, exposure definitions, and outcome reporting, meta-analysis of clinical, functional, and psychopathological outcomes was not feasible. Therefore, these outcomes were synthesized narratively. The narrative synthesis was structured according to population type (clinical vs. community samples) and main outcomes assessed. For clinical samples, we summarized data on hallucinogen use prevalence and its reported associations with symptom severity, functioning, relapse, hospitalization, cognition, and treatment response. For community samples, we synthesized evidence on hallucinogen use prevalence and its association with psychotic or unusual experiences (e.g., perceptual distortions, paranoia, hallucinations). Where possible, findings were contextualized according to potential moderators such as age, sex, diagnosis, comorbidities, and polysubstance use. All analyses were conducted using R (version 4.4.0) [ 33 ] with the ‘metafor’ package. Results The literature search identified 3,805 records, plus one additional record through manual screening (total = 3,806). After removal of 1,877 duplicates, 1,929 records were screened by title and abstract. A total of 108 full-text articles were assessed for eligibility, of which 96 were excluded—most commonly because the mean age of the sample was ≥ 18 years. Twelve studies met the inclusion criteria and were included in the final review (Fig. 1 ). Reasons for exclusion are detailed in Table S2. The average percentage of females was 39.9%. The mean age was 16.1 years. Of the twelve included studies, six contributed quantitative data to the meta-analysis of hallucinogen use prevalence in adolescents with EOP, while the remaining six were included in the narrative synthesis. Fig. 1. Open in a new tab PRISMA 2020 flow diagram outlining the study selection process Characteristics of the studies included Twelve studies met inclusion criteria (Table 2 ): three community-based [ 34 – 36 ], two inpatient SUD samples [ 37 , 38 ], one inpatient clinical psychiatric sample [ 39 ] and six clinical EOP cohorts [ 10 , 40 – 44 ]. Four studies originated from North America, seven from Europe and one from Asia. Table 2. Characteristics of included samples Included studies Country Year Study type N Study population Female % Mean age (SD) Hallucinogen use prevalence (%) Context of hallucinogen use Comorbid substance use Diagnostic tool for SUD Baeza et al. [ 40 ] Spain 2009 PC 110 Clinical; children/ adolescents with FEP 32.7 15.5 (1.8) LSD (1.8%) Not reported Cannabis (29.1%), Alcohol (21.8%), Cocaine (8.2%), Amphetamines (2.7%) K-SADS-PL de Angelis et al. [ 37 ] USA 1978 RC 87 Clinical; inpatient users in an adolescent social rehabilitation program 41.6 16.5 (N.a.) PCP (Occasional use: 26.44%; Chronic use: 25.29%) Not reported Not reported Clinical and self-report Eseroglu et al. [ 44 ] Turkey 2019 RC 56 Clinical; inpatient adolescents (14–18 y) with FEP +/- SUD 32.1 16.7 (1.1) MDMA lifetime use: 42.8% of total sample, 92.3% of SUD subgroup Not reported 46.4% any SUD Lifetime use in SUD group: synthetic cannabinoids (84.6%), cannabis (92.3%), MDMA (92.3%), solvents (65.4%) DSM-5 Hsiao and McClellan [ 42 ] USA 2008 PC 69 Clinical; adolescents with schizophrenia or other EOP disorders +/- SUD 41.0 14.8 (2.2) Hallucinogens (11% in schizophrenia, 9% in BD, 15% in psychosis NOS) Not reported 45% any SUD (abuse/dependence) DICA-R Kuzenko et al. [ 34 ] Germany 2010 PC 2,588 Non-clinical; representative community sample of adolescents and young adults 50.4 17.1 (2.9) Psychedelics lifetime use (3.2%) Not reported Not reported M-CIDI Luukkonen et al. [ 39 ] Finland 2010 RC 508 Clinical; psychiatric inpatients aged 13–17 years 59.1 15.8 (2.0) Hallucinogens (2.2%) Not reported High cannabis and alcohol use K-SADS-PL Myran et al. [ 35 ] Canada 2024 RC 1189 Non-clinical; subjects attending emergency service for hallucinogen use, compared to the general population N.a. N.a. (range 14-18) Sample selected according to hallucinogen use (100%) Not reported Not reported ICD-10 Palmer et al. [ 38 ] USA 2005 CS 60 Clinical; inpatient users in a residential SUD rehabilitation program 10.0 15.8 (N.a.) Psilocybin total sample (33.3%) Not reported Not reported MMPI-A Paruk et al. [ 41 ] South Africa 2016 CS 45 Clinical; adolescents (10–18 years) with EOP vs. matched psychiatric controls 31.1 15.9 (1.8) Lifetime hallucinogens in EOP subgroup (4.4%) Not reported Cannabis (55.6%), Alcohol (64.4%), Nicotine (48.9%), Amphetamines (13.3%), Inhalants (11.1%) WHO ASSIST Shoval et al. [ 43 ] Israel 2006 RS 178 Clinical; individuals with schizophrenia or schizoaffective disorder admitted to an inpatient unit for at least 5 days 34.8 17.4 (1.7) LSD (8.4%); MDMA (12.9%) Not reported High rates of cannabis use (23.0%) among the whole sample DSM-IV Simonsson et al. [ 36 ] Sweden 2024 CS 16,255 Non-clinical; cross-sectional study of twins 54.7 15.0 (N.a.) LSD & Psilocybin; lifetime use (3.3%) Not reported Alcohol (98.5%); Tobacco (38.3%); Cannabis (97.4%); Stimulants (97.6%); Opioids (97.4%) Auto-reportedscales: Adolescent Psychotic-Like Symptom Screener, Child Mania Rating Scale Brief Version Turan et al. [ 10 ] Turkey 2025 RC 255 Clinical; individuals with EOS or schizoaffective disorder admitted into a tertiary-care inpatient unit +/- SUD 42.4 17.0 (2.6) MDMA (3.5%), Other hallucinogens (2%) Not reported 18.4% any SUD DSM-5 Open in a new tab If the reported sample includes stratified characteristics for subjects < 18 years old, those characteristics are reported in Table 2 BD Bipolar Disorder, CS Cross-Sectional, DICA-R Diagnostic Interview for Children and Adolescents Revised, DSM Diagnostic and Statistical Manual of Mental Disorders, DSM-IV TR Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, ED Emergency Department, EOS Early-Onset Schizophrenia, FEP First Episode Psychosis, K-SADS-PL Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, LAI Long-Acting Injectable, LSD Lysergic Acid Diethylamide, M-CIDI DSM-IV Munich Composite International Diagnostic Interview DSM-IV version, MDMA 3,4-Methylenedioxymethamphetamine, MMPI-A Minnesota Multiphasic Personality Inventory-Adolescent, NOS Newcastle–Ottawa Scale, PANSS Positive and Negative Syndrome Scale, Psychosis NOS Psychosis Not Otherwise Specified, PC Prospective Cohort, PCP Phencyclidine, PTSD Post-Traumatic Stress Disorder, RC Retrospective Cohort, RS Retrospective Study, SCID Structured Clinical Interview for DSM, SSD Schizophrenia Spectrum Disorder, SUD Substance Use Disorder, WHO ASSIST World Health Organization Alcohol, Smoking and Substance Involvement Screening Test Outcome domain 1: clinically diagnosed psychotic disorders (EOP samples) A pooled analysis of six clinical studies including adolescents with EOP (total n = 713) yielded a random-effects prevalence estimate of 14.3% (95% CI: 3.9%–40.9%). Between-study heterogeneity was substantial (I² = 88.5%, p < 0.001). The 95% prediction interval ranged from 0.5% to 84.4%, indicating marked variability in prevalence estimates across clinical settings. Study-level estimates ranged from 1.8% to 42.9%, likely reflecting differences in sample characteristics and patterns of polysubstance use (Fig. 2 ). LSD use in the included studies ranged from 1.8 to 12.5%. MDMA use ranged from 3.5 to 42.9% (Fig. 3 ). Fig. 2. Open in a new tab Pooled prevalence of hallucinogen use in adolescents with EOP. CI Confidence Interval Fig. 3. Open in a new tab Prevalence of individual hallucinogen use in individual studies. LSD Lysergic Acid Diethylamide, MDMA 3,4 Methylenedioxymethamphetamine Among the clinical correlates of hallucinogen use among EOP samples, a significant association was found between history of suicide attempts and hallucinogen use, both for MDMA [ 43 ] (21.2% vs. 9.5%; p < 0.01) and LSD (19.2% vs. 4.0%; p < 0.01), respectively. Suicide attempters were significantly more likely to have used hallucinogens: LSD (OR 5.7, 95% CI: 1.8–17.8, p = 0.002) and MDMA (OR = 2.6, 95% CI: 1.04–6.22, p = 0.048) use was increased in attempters compared with non-attempters. However, only the association with LSD persisted as significant after Bonferroni adjustment. Turan et al. [ 10 ] analysed a larger sample of 255 adolescents hospitalized with early-onset schizophrenia or schizoaffective disorder, identifying that 18.4% met diagnostic criteria for an illicit SUD. Within this subgroup, cannabis, synthetic cannabinoids, and stimulants were most common, but 19.2% reported MDMA use and 10.6% reported use of other hallucinogens. Adolescents with early-onset schizophrenia and SUD were more frequently male ( p = 0.001), had fewer years of education (7.5 vs. 8.3, p = 0.005), had a longer duration of untreated psychosis (DUP) (median 4 vs. 3 months, p = 0.038), more hospitalisations (median 2 vs. 1, p = 0.002), more nicotine consumption (59.6% vs. 29.8%, p < 0.001), and higher rates of conduct disorder (44.7% vs. 11.5%, p < 0.001) and PTSD (12.8% vs. 4.3%, p = 0.038) than their non-SUD counterparts. They were also more frequently treated with clozapine (44.7% vs. 28.8%, p = 0.035) and zuclopenthixol LAI (8.5% vs. 1.4%, p = 0.023) than their counterparts without SUD. However, in multivariate logistic regression, differences in hospitalisations, duration of untreated psychosis, and clozapine use lost significance. No stratified results were provided for the hallucinogen user subgroup. Outcome domain 2: unusual experiences and dimensional psychotic symptomatology Simonsson et al. [ 36 ] analysed 16,255 15-year-old twins from the Swedish Twin Registry to explore links between psychedelic use and psychotic-like or manic experiences. Psychedelic use was reported by 3.3% of participants and was almost invariably accompanied by other substance use. In unadjusted analyses, psychedelic users showed more psychotic and manic symptoms, but these associations reversed after adjusting for use of other drugs. The only significant interaction involved genetic vulnerability: adolescents with higher polygenic risk for schizophrenia or bipolar I disorder showed greater manic symptoms when exposed to psychedelics. Kuzenko et al. [ 34 ] provided longitudinal evidence from a community-based cohort of 2,588 adolescents and young adults in Germany, who were followed prospectively for up to 10 years. Overall, 3.2% of participants reported repeated psychedelic use. The use of psychedelics was associated with a higher likelihood of psychotic symptoms after adjusting for other substance use, mood or anxiety disorders, and childhood adversities (OR = 2.37; 95% CI: 1.20–4.66), and after adjusting for age, sex, social class and, urbanicity (OR = 4.99; 95% CI: 2.83–8.82). Notably, the association was even stronger among participants without affective or anxiety disorders (adjusted OR = 3.56; 95% CI: 1.20–10.61). Palmer and Daiss [ 38 ], in a residential SUD sample, found that adolescents with psilocybin dependence scored significantly higher on the Minnesota Multiphasic Personality Inventory-Adolescent Schizophrenia ( p = 0.02) and Adolescent-Bizarre Mentation ( p = 0.01) scales compared with cannabis-dependent adolescents, suggesting increased dimensional psychotic-like features. Additional inpatient psychiatric and rehabilitation samples reported hallucinogen use predominantly within polysubstance patterns, without consistent associations with structured psychotic diagnoses or symptom severity [ 37 , 39 ]. Outcome domain 3: manic symptoms with psychotic features In Simonsson et al. [ 36 ], psychedelic use was also associated with higher levels of manic symptoms in unadjusted analyses. Importantly, a significant interaction with polygenic risk for schizophrenia or bipolar I disorder was observed, indicating that manic symptom expression following psychedelic exposure may depend on underlying genetic vulnerability. Outcome domain 4: administrative and service-use outcomes Myran et al. [ 35 ] conducted a population-based retrospective cohort study in Canada, including individuals aged 14 to 65 years with no prior history of psychosis. Among those with an emergency department (ED) visit involving hallucinogen use, 1,189 were adolescents aged 14 to 18 years. Age- and sex-stratified analyses showed that, within the 14–18 age group, the association between hallucinogen-related ED visits and subsequent transition to a schizophrenia spectrum disorder was significant for males (HR = 3.26; 95% CI: 2.09–5.08), but not for females (HR = 1.86; 95% CI: 0.73–4.73), after adjustment for income quintile, rurality, immigration status, and outpatient, ED, and hospital-based mental health and substance use care in the past 5 years. Quality of the included studies The methodological quality of the included studies was moderate overall. NOS scores ranged from 4 to 9, with a mean score of 6.4. Discussion In this systematic review and meta-analysis, we found that hallucinogen use is relatively common among adolescents with EOP, but marked variability was observed across clinical settings and study designs. This heterogeneity likely reflects contextual factors - such as local patterns of polysubstance use, including hallucinogen exposure within broader dual-disorder presentations - rather than demographic or methodological differences across studies. Interpretation of these findings should also consider that some included studies comprised mixed-age samples [ 10 , 34 , 35 , 37 , 43 ], which may limit inferences strictly applicable to adolescent populations. Cannabis is the most used illicit drug during adolescence [ 45 ] and has been consistently associated with an earlier onset of psychosis and poorer clinical outcomes in young people with EOP [ 46 , 47 ]. However, although hallucinogens are less commonly used, emerging evidence suggests that their impact may be clinically relevant [ 26 ]. Recent systematic reviews indicate that psychedelic exposure can precipitate or exacerbate psychotic symptoms in vulnerable individuals [ 19 ], raising concern in populations already at heightened neurodevelopmental risk. Evidence from individual studies suggests that hallucinogen use in adolescents with EOP may have clinically relevant implications. For instance, LSD use was significantly associated with suicidal behaviour [ 43 ], while in a follow-up analysis of the same population, cannabis users also showed higher rates of suicide attempts compared with non-users (11.5% vs. 6.25%) [ 48 ]. This association points to interacting risk mechanisms that probably combine pharmacodynamic effects with underlying traits such as impulsivity, affective dysregulation, and polysubstance use, within the context of overall illness severity and diagnostic complexity. However, these findings should be interpreted with caution, as high rates of concomitant cannabis use and the severity of the psychotic condition may have contributed to the observed association between LSD use and suicidality. In addition, the retrospective design and high rates of polysubstance use limit the ability to fully disentangle primary psychosis from substance-related symptom modulation. Beyond these factors, dissociative phenomena may also represent a mechanistic link between cannabis exposure and vulnerability to EOP. Prospective evidence points towards dissociation as a mediator in the relationship between cannabis use and the emergence of early psychotic symptoms, suggesting that alterations in self-experience may play an active role in illness trajectories, supporting a continuum model of self-disturbance, whereby cannabis-related dissociative states may increase susceptibility to both acute hallucinatory experiences and more persistent psychotic symptoms [ 49 ]. Such a framework may also be relevant when considering hallucinogen exposure, as both substances converge on transient disruption of self-boundaries, perception and consciousness, potentially amplifying risk in neurodevelopmentally vulnerable adolescents. In this context, routine assessment of hallucinogen use in EOP should be warranted, given its potential association with more complex trajectories and poorer prognosis. Evidence from transitional-aged youth supports a bidirectional relationship between early substance use and psychiatric comorbidity, whereby pre-existing mental health conditions may increase vulnerability to substance use, while substance use may, in turn, exacerbate symptom severity and illness course. A recent narrative review highlights that co-occurring mental disorders are common in this age group and emphasizes the mutual reinforcement between substance use disorders and comorbid psychopathology, including psychotic symptoms and suicidality [ 50 ]. Accordingly, the associations observed in this review are unlikely to reflect a simple unidirectional mechanism, but rather a multifactorial developmental pathway. The clinical profile described by Turan et al. [ 10 ] - predominantly male adolescents with EOS and comorbid SUD, lower educational attainment, greater behavioural comorbidity, and higher exposure to clozapine and long-acting zuclopenthixol use - suggests that substance use in this population is not a benign comorbidity but a marker of illness complexity and treatment resistance. Within a dual disorders framework, polysubstance use is associated with poorer adherence, higher relapse rates and more unstable illness trajectories [ 51 ]. In this context, the use of hallucinogens, often occurring alongside cannabis and other substances, may identify a subgroup of patients with particularly complex dual disorders and heightened vulnerability to relapse. Accordingly, the need for clozapine and depot antipsychotics likely reflects chronicity, poor adherence, and limited engagement with care [ 6 , 52 ], rather than a treatment choice alone, supporting the clinical relevance of long-acting formulations and partial D2 agonists in managing severe dual-disorder presentations [ 53 ]. In adults, hallucinogen-related psychotic reactions are uncommon, with meta-analytic data showing incidences of 0.002% in population studies, 0.2% in uncontrolled trials, and 0.6% in randomized controlled trials [ 19 ]. Large-scale registry data confirm that substance-induced psychosis represents a strong predictor of later transition to schizophrenia-spectrum disorders. In the Danish national cohort of 6,788 individuals with substance-induced psychosis, 32.2% developed either schizophrenia or bipolar disorder over 20 years, with half of the conversions to schizophrenia occurring within the first 3 years [ 54 ]. Conversion risk varied markedly by substance, reaching 47.4% for cannabis, 32.3% for amphetamines, and 27.8% for hallucinogens. The hazard ratio for conversion to schizophrenia after any substance-induced psychosis was 77.3 (95% CI: 65.2–91.7) relative to matched controls, highlighting the magnitude of vulnerability once psychosis has been triggered. Although hallucinogen-induced psychosis accounted for a smaller proportion of cases, its conversion rate remained clinically relevant and similar in magnitude to other stimulant-related forms. These findings suggest that hallucinogen-related psychoses, while infrequent, often identify a subgroup with pre-existing neurobiological or psychosocial vulnerability rather than de novo drug-induced illness. The data again underscore the importance of long-term monitoring following any psychotic episode related to hallucinogen use, as risk of transition persists for years and is particularly high among younger individuals. When considering unusual experiences in community samples, population-based evidence shows that lifetime psychedelic use is associated with an increased likelihood of reporting psychotic-like experiences, even after controlling for sociodemographic factors, common mental disorders, and other substance use [ 34 ]. Notably, the association persisted among participants without affective or anxiety disorders, suggesting that psychedelic exposure may influence psychotic phenomena through mechanisms not entirely explained by general psychopathological vulnerability. Associations between substance use and schizophrenia outcomes may be driven by polysubstance patterns and premorbid functioning rather than by hallucinogens per se [ 55 ]. Regarding manic symptoms with psychotic features, repeated psychedelic use in community samples is associated with transient manic experiences [ 36 ], and these effects appear moderated by genetic liability. In contrast to psychotic-like experiences, manic symptom expression seems particularly sensitive to underlying polygenic vulnerability, reinforcing a differential susceptibility model [ 36 ]. Together, these findings are best understood within a stress-vulnerability framework, in which hallucinogens may act as catalysts rather than independent causal agents, interacting with pre-existing vulnerability factors such as dissociative traits, impulsivity, trauma exposure and familial risk. Accordingly, hallucinogen exposure may lower the threshold for affective manifestations in neurodevelopmentally vulnerable adolescents, underscoring the importance of early identification of vulnerability markers and substance-use screening in young people. From a mechanistic standpoint, hallucinogens act primarily through 5-HT 2A receptor agonism and NMDA receptor antagonism, neurotransmitter systems that are central to the pathophysiology of psychosis [ 56 ]. During adolescence, when cortical circuits undergo extensive synaptic pruning and neuroplastic reorganisation, such pharmacological effects could transiently disrupt network integration, particularly in individuals with heightened neurobiological susceptibility [ 57 ]. Experimental data indicate that repeated 5-HT 2A stimulation may induce perceptual distortions and transient alterations in cognition and self-experience that resemble attenuated psychotic phenomena [ 14 ]. From a neurobiological perspective, the serotonergic and glutamatergic modulation induced by hallucinogens [ 12 ] may transiently exacerbate dysconnectivity in developing cortical networks, amplifying risk in individuals with neurodevelopmental or genetic susceptibility [ 6 , 52 ]. The impact of these effects is unlikely to be uniform across individuals: vulnerability factors such as genetic liability to schizophrenia or bipolar disorder may moderate the psychotogenic potential of hallucinogens, consistent with differential susceptibility models. Within this framework, hallucinogen use may not independently cause psychosis but could precipitate or exacerbate psychotic symptoms in individuals who are already predisposed. Several factors may account for the heterogeneity across studies examining hallucinogen use and psychosis. First, the pattern of substances used has shifted over time, from dissociative hallucinogens such as PCP and ketamine—both potent NMDA antagonists strongly linked to psychotic reactions—to classic serotonergic psychedelics like psilocybin or LSD, which have milder and transient effects, with empathogens such as MDMA occupying an intermediate profile characterised by effects on affective and cognitive processing [ 15 , 18 , 58 ]. Second, two distinct user profiles likely coexist: heavy polysubstance users, in whom psychotic outcomes are more frequent, and occasional experimental users of psilocybin or similar compounds, among whom persistent effects are rare [ 59 , 60 ]. Third, there is marked variability in dosage, purity, and the emergence of novel psychoactive substances, which remain largely unregulated and differ widely in pharmacodynamics [ 61 , 62 ]. Finally, outcome definitions vary substantially across studies—from transient psychotic-like experiences to clinically diagnosed psychotic disorders—introducing both statistical and conceptual heterogeneity [ 26 , 36 , 63 ]. These findings highlight the need to systematically address hallucinogen use in early assessment and care-planning for young people at risk of psychosis, alongside cannabis and other commonly co-used substances, particularly given the increasing availability of hallucinogens for recreational and therapeutic purposes and the evidence of rising exposure in young adult populations [ 64 ]. Incorporating structured screening tools into routine clinical assessments, including the assessment of dissociative symptoms as potential markers of vulnerability and clinical instability, together with targeted psychoeducation for patients and families, could enhance early identification of risk and facilitate more tailored preventive interventions. Furthermore, strengthening collaboration between early psychosis services and substance use treatment programmes is essential to ensure integrated care pathways, consistent risk monitoring, and optimisation of both symptom management and functional recovery. In adolescents with polysubstance use and recurrent relapses, adherence-enhancing strategies, such as the use of long-acting injectable antipsychotics, may warrant consideration within a dual-disorder framework. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit profiles of these substances and to communicate such risks to prospective study participants and the public [ 65 ]. The current regulatory vacuum surrounding many novel hallucinogens highlights the need for coordinated international efforts to establish monitoring and control mechanisms, as their unregulated availability poses increasing public health risks. Furthermore, psychoeducation is essential to counteract the growing perception of hallucinogens as inherently safe, a misconception partly fuelled by their increasing medical and therapeutic promotion [ 66 , 67 ]. Public health messaging should emphasise that, outside controlled clinical settings, these substances remain unregulated and may entail unpredictable psychological effects. Limitations This study has several limitations. First, we observed substantial heterogeneity across studies, both in methodological quality and in the operationalisation of key variables, including heterogeneous definitions of hallucinogen exposure, outcome constructs, and ascertainment methods, which complicates direct comparison and synthesis of findings. Second, all included studies were observational, many of them retrospective, and residual confounding cannot be excluded; other factors such as genetic liability or environmental adversity may have contributed to the observed associations. Third, polysubstance—especially cannbis use—was common across samples, and although some studies adjusted for co-occurring substance use, others relied on unadjusted associations of broader substance use disorder groupings, complicating causal attribution specifically to hallucinogens. Notably, in population-based studies, associations attenuated after adjustment, underscoring the need for cautious interpretation. Fourth, in population-based cohorts, both exposure and outcomes were frequently based on self- or parent-report rather than clinical assessment, which may have introduced misclassification bias. Outcomes also differed substantially in construct and meaning, spanning self-reported psychotic-like experiences, clinically diagnosed psychotic disorders, and manic symptoms with psychotic features. Moreover, in some reports, psychotic outcomes were aggregated under broader substance use disorders rather than isolated hallucinogen use, limiting the specificity of interpretation. Fifth, the small number and modest size of available studies precluded a formal meta-analytic synthesis and highlighted the need for further large-scale longitudinal research in adolescent populations, given the neurodevelopmental vulnerability of this period. Sixth, although the review focused on adolescents, some included studies comprised mixed-age samples [ 10 , 34 , 35 , 37 , 43 ]; the inclusion of a small proportion of participants older than 18 years may therefore limit strict age-specific generalizability. Longitudinal data on the course and prognosis of EOP patients with hallucinogen use remain virtually absent, limiting our ability to determine temporal or causal relationships. Conclusions Hallucinogen use is common in adolescents with EOP and seems to be associated with more complex clinical trajectories, particularly higher rates of suicidality, although evidence remains preliminary and heterogeneous. While population-based data do not clearly indicate a generalised increase in psychotic symptoms, hallucinogens may precipitate affective or psychotic reactions in genetically or neurodevelopmentally vulnerable individuals. Clinicians should therefore systematically assess hallucinogen use in EOP, especially when evaluating suicide risk or atypical mood presentations. Future research should prioritise longitudinal, large-scale, and stratified designs that differentiate specific substances and integrate genetic, environmental, and clinical moderators to clarify causal mechanisms and inform prevention strategies. Supplementary Information Supplementary Material 1. (114.7KB, docx) Author contributions M.A-I., C.A., B.P., I.A. and A.R. carried out data curation and investigation; A.C. and G.S.P led the conceptualization, methodology, project administration and original drafting; M.A.G-T. provided supervision and project administration. All authors reviewed and approved the final version of the manuscript. Funding The publication of this article was funded by IIS Biobizkaia with support from the Research Commission of OSI Bilbao-Basurto. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Competing interests AC reports grants and personal fees from the Instituto de Salud Carlos III. She has also received research support from the Basque Government and honoraria from Janssen-Cilag, ROVI, Otsuka, Lundbeck, Viatris, and Neurotorium all outside the submitted work. C.A. is supported by the Alicia Koplowitz Foundation and has received personal fees or grants from Janssen Cilag outside the current work. GSP has received personal fees or grants from Janssen Cilag and Lundbeck outside the current work. The rest of the authors have no conflicts of interest to declare. 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