Adolescent Psychedelic Use and Psychotic or Manic Symptoms

Recent increases in LSD use among adolescents and rising interest in 5-HT2A agonist psychedelics such as psilocybin have prompted concern about psychiatric risks associated with naturalistic psychedelic use, particularly psychotic or manic symptoms. While controlled clinical settings have provided some safety data, prior observational evidence is vulnerable to familial confounding and other biases, and contemporary trial guidelines exclude individuals with personal or family histories of psychotic or bipolar disorders, limiting empirical characterisation of risk in those groups. The introduction therefore frames a gap in understanding how adolescent psychedelic use relates to psychotic and manic symptoms and whether familial or genetic vulnerability explains any observed associations. Simonsson and colleagues set out to address this gap by analysing data from a large, genetically informative sample of Swedish twins. Their aims were to (1) estimate associations between lifetime naturalistic use of LSD or psilocybin and self-reported psychotic and manic symptoms at age 15, (2) use co-twin control models to assess whether associations persist after accounting for familial confounding, and (3) test gene–environment interactions by examining whether associations vary with polygenic liability for schizophrenia or bipolar I disorder.

The study used data from the Child and Adolescent Twin Study in Sweden (CATSS). Twins and their parents were first assessed at age 9, with follow-ups at ages 15, 18, and 24; the primary analyses reported here are cross-sectional and use responses collected at age 15. Of the 16 255 adolescents who answered questions about past LSD or psilocybin use, 15 862 and 15 717 provided self-reports of psychotic and manic symptoms, respectively. Genotype data were available for 9 426 participants. Ethical approval and informed consent procedures were followed. Psychedelic exposure was coded as a binary variable (past use of LSD or psilocybin: yes/no). Past use of other substances at age 15 was captured in eight binary variables (alcohol, tobacco, cannabis, stimulants, sedatives, opioids, inhalants, performance enhancers), with ‘‘don’t know’’ or ‘‘prefer not to answer’’ coded as missing. Psychotic-like experiences were measured with a seven-item self-report scale corresponding broadly to an adolescent psychotic-like symptom screener (items scored 0–2, sum 0–14). Manic symptoms were measured with the 10-item Child Mania Rating Scale Brief Version (items scored 0–3, sum 0–30). Parent-reported outcomes were available for supplementary analyses but were not primary. Genetic vulnerability was operationalised with standardised polygenic scores for schizophrenia and bipolar I disorder derived from external genome-wide association study summary statistics, processed with SBayesR and calculated in PLINK2. Twenty principal components for ancestry and the genotyping platform were included as covariates in analyses involving polygenic scores to adjust for population structure and batch effects. Statistical analyses comprised linear regression models (unadjusted and adjusted), within-pair co-twin control analyses restricted to monozygotic pairs discordant for psychedelic use, and interaction models testing whether polygenic scores moderated associations between psychedelic use and symptoms. Two approaches to adjust for other substance use were applied: (1) substance-specific adjustment controlling for sex and each of alcohol, tobacco, cannabis, stimulants, sedatives, opioids, and inhalants, and (2) substance-aggregated adjustment collapsing alcohol/tobacco and all other drugs into two variables. Sex was included as a covariate in non-twin analyses; age was not controlled because participants were the same age. Robust clustered standard errors were used to account for relatedness; analyses were complete-case for variables in each model. Symptom scales were standardised and a two-sided P < .05 threshold was used.

In the analytic sample of 16 255 adolescents (8 889 female, 7 366 male), 541 (3%) reported past use of LSD or psilocybin. Nearly all adolescents who reported psychedelic use (535 of 541, 99%) also reported lifetime use of other drug categories (cannabis, stimulants, sedatives, opioids, inhalants, or performance enhancers). There were 119 monozygotic twin pairs discordant for psychedelic use. The genotyped subsample had lower proportions of males and of some other drug use. In unadjusted linear regressions (controlled for sex only), psychedelic use was associated with slightly higher self-reported psychotic symptoms (β = 0.09; 95% CI, 0.00 to 0.18) and higher manic symptoms (β = 0.38; 95% CI, 0.27 to 0.48). After adjustment for other substance use, the direction of associations reversed: in substance-specific adjusted models, psychedelic use was associated with fewer psychotic symptoms (β = -0.79; 95% CI, -1.18 to -0.41) and fewer manic symptoms (β = -1.02; 95% CI, -1.44 to -0.59). Using the substance-aggregated adjustment, psychedelic use remained associated with lower psychotic symptoms (β = -0.39; 95% CI, -0.50 to -0.27) and lower manic symptoms (β = -0.17; 95% CI, -0.30 to -0.05). Co-twin control analyses within monozygotic pairs yielded mixed findings. In unadjusted co-twin models there was no significant association between psychedelic use and psychotic symptoms, whereas manic symptoms were higher in the twin who used psychedelics (β = 0.31; 95% CI, 0.12 to 0.51). When co-twin models were adjusted for other substances, psychedelic use was associated with fewer psychotic symptoms in the twin who used psychedelics (substance-specific adjusted β = -0.89; 95% CI, -1.61 to -0.16; substance-aggregated adjusted β = -0.24; 95% CI, -0.48 to -0.01). For manic symptoms, a substance-specific adjusted co-twin association suggested fewer manic symptoms in users (β = -1.64; 95% CI, -2.39 to -0.89) but this was not observed in the substance-aggregated adjusted co-twin models. Gene–environment interaction tests showed no evidence that associations between psychedelic use and psychotic symptoms varied by polygenic risk for schizophrenia or bipolar I disorder. By contrast, manic symptoms did show statistically significant interactions: higher polygenic risk for schizophrenia or bipolar I disorder amplified the association between psychedelic use and manic symptoms (interaction βs in the range ~0.11 to 0.20 across unadjusted and adjusted models, with 95% CIs excluding zero in several models). Parent-reported psychotic symptoms at age 15 yielded some significant interactions with polygenic risk for schizophrenia, which differed from the nonsignificant self-report results. The authors note that nearly all psychedelic users also used other drugs, and that sample sizes, measurement and cross-sectional design constrain causal inference.

Using a large sample of Swedish adolescent twins, Simonsson and colleagues report that, after adjusting for other substance use, naturalistic lifetime use of LSD or psilocybin was associated with lower self-reported psychotic symptoms at age 15 in both conventional regression and co-twin control analyses. They further observed that the association between psychedelic use and manic symptoms was moderated by genetic liability: individuals with higher polygenic scores for schizophrenia or bipolar I disorder showed a greater association between psychedelic use and manic symptoms than those with lower polygenic risk. The absence of gene–environment interactions for psychotic symptoms and the co-twin results indicate that familial confounding does not fully explain the inverse association with psychotic symptoms, though the authors caution that findings are complex. The investigators situate these results relative to prior work by emphasising the value of genetically informative designs for disentangling familial confounding from putative causal effects, a design rarely used in psychedelic research to date. They acknowledge that reverse causality cannot be excluded in cross-sectional data and that co-twin control analyses cannot by themselves establish causal direction. The authors discuss possible mechanisms for the observed interaction with manic symptoms, including a speculative parallel to treatment-emergent affective switch seen with some antidepressants, but stress that mechanistic evidence is limited. Key limitations the study team acknowledges include missing data across measures, the low predictive accuracy of current polygenic scores for psychiatric traits, absence of contextual information on psychedelic episodes (dose, frequency, setting), potential confounding by acute intoxication in symptom reports, self-report biases, limited generalisability beyond adolescents, the high co-occurrence of other drug use among psychedelic users (99%), and the lack of correction for multiple testing given the exploratory nature of analyses. Taken together, the authors present these findings as preliminary and call for replication with larger, longitudinal samples and more objective clinical outcomes to better characterise risks and inform inclusion/exclusion guidance for psychedelic research.

The authors conclude that genetically informative observational data can help delineate complex relationships between adolescent psychedelic use, genetic vulnerability, and psychotic or manic symptoms. In this sample, psychedelic use was associated with fewer self-reported psychotic symptoms after accounting for other substances, while associations with manic symptoms appeared conditional on polygenic risk for schizophrenia or bipolar I disorder. They recommend replication in other age groups with longitudinal designs, larger samples, and more objective outcome measures before drawing firmer conclusions or changing clinical or policy guidance.