This prospective cohort study (n=654 start, n=212 end) investigated delusional ideation, magical thinking, and HPPD symptoms in participants before and after planned psychedelic use. Results showed reduced delusional ideation after one month, no changes in magical thinking, and HPPD-like effects in 30% of participants (though rarely distressing at <1%), with younger age, female gender, psychiatric history, and baseline trait absorption predicting HPPD-like effects.
Interest in using psychedelic drugs to treat psychiatric disorders is growing rapidly. While modern controlled clinical trials show a favorable safety and efficacy profile, it remains unclear if the risk of side effects would increase with broader use in more heterogeneous populations. To address this, we investigated the frequency and baseline predictors of delusional ideation, magical thinking, and hallucinogen persisting perception disorder (HPPD)-related symptoms following psychedelic use in a self-selected naturalistic sample. Using a prospective cohort study, symptoms were assessed in ( N = 654 ) participants at one week before a planned psychedelic experience, and at two and four weeks afterward. Across the sample, delusional ideation was found to be reduced one month after psychedelic use ( P < 0.001 ) with no changes detected in magical thinking. These findings were in seeming opposition to positive correlations between lifetime psychedelic use at baseline with magical thinking ( r s = 0.12 , P = 0.003 ) and delusional ideation ( r s = 0.11 , P = 0.01 ), suggesting that schizotypal traits, instead of being caused by, may merely correlate with psychedelic use. Importantly, over 30% of the sample reported HPPD-type effects at the 4-week endpoint, although rarely perceived as distressing (< 1% of the population). Younger age, female gender, history of a psychiatric diagnosis and baseline trait absorption predicted the occurrence of HPPD-like effects. This is in line with prior studies showing a high prevalence of HPPD-like symptoms in psychedelic users, which, however, appear to remain at a subclinical severity in most cases, explaining the comparatively lower prevalence of HPPD diagnoses.
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Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
Carhart-Harris, R. L., Kaelen, M., Bolstridge, M. et al. · Psychological Medicine (2016)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Stauffer, C., Anderson, B. T., Ortigo, K. M. et al. · ACS Pharmacology and Translational Science (2020)
After a long hiatus, research into classic serotonergic psychedelics (for example psilocybin, LSD, mescaline, and DMT) has expanded rapidly because these compounds induce profound alterations in perception, mood and cognition and show therapeutic promise for several psychiatric conditions. Despite generally favourable safety profiles in controlled trials, case reports and naturalistic surveys have raised concerns about rare but potentially persistent adverse outcomes, notably prolonged psychotic reactions or increased schizotypal traits, and enduring visuoperceptual disturbances clinically recognised as hallucinogen persisting perception disorder (HPPD). HPPD is commonly described in two subtypes: transient “flashbacks” (type 1) and chronic visuoperceptual aberrations (type 2), such as motion trails, halos and intensified colours. Observational studies of naturalistic psychedelic use are particularly important because clinical trials typically exclude individuals considered at-risk, leaving uncertainty about frequency and predictors of iatrogenic effects in broader populations. Zhou and colleagues designed a prospective, naturalistic study to examine changes in delusional ideation and magical thinking surrounding a planned psychedelic experience, and to estimate the prevalence and baseline predictors of HPPD-type visual symptoms. The investigators hypothesised that baseline delusional ideation and magical thinking would correlate positively with lifetime psychedelic use and performed exploratory regression analyses to test whether demographics, trait absorption, psychiatric history, aspects of drug use or features of the acute experience predicted HPPD-type effects or shifts in schizotypal measures over a four-week follow-up period.
This was a large-scale prospective online survey recruiting English-speaking adults who planned to use a psychedelic (psilocybin, LSD/1P-LSD, ayahuasca, DMT/5-MeO-DMT, salvia, mescaline, or iboga/ibogaine) within three months. Sign-up was via a purpose-built website and recruitment channels included social media and drug-related websites. Data were collected at three timepoints: baseline (one week before the planned experience), a sub-acute assessment (one day after the experience for acute-experience details), and follow-ups at two and four weeks post-experience; HPPD-type symptoms were assessed only at the 4-week endpoint. The baseline survey captured demographics (age, gender, education, employment), lifetime psychedelic use, psychiatric history, and psychometric measures: the Peters’ Delusions Inventory (PDI) for delusional ideation, the 15-item Magical Ideation Scale (MIS) for magical thinking, and the 15-item Modified Tellegen Absorption Scale (MODTAS) for trait absorption. An investigator-constructed HPPD checklist asked about nine specific visual symptoms (for example intensified colours, positive afterimages, motion trails, halos, macropsia/micropsia); participants endorsing any effect answered follow-up questions about distress and whether symptoms were attributable to medical causes. Acute-experience variables included drug type, dose, setting (retreat vs non-retreat) and concomitant non-psychedelic drug use. Statistical analyses used Spearman correlations to test associations between lifetime psychedelic use and baseline PDI/MIS scores, with partial correlations adjusting for age. Longitudinal changes in PDI and MIS were tested with Friedman and Wilcoxon signed-rank tests, and between-group comparisons (novice vs experienced users) used Mann–Whitney U tests. Change scores were dichotomised (>0 versus ≤0) to define increases in PDI or MIS and analysed with logistic regression including predictors that passed collinearity checks (variance inflation factor < 10). A separate logistic regression model examined predictors of reporting at least one HPPD symptom at 4 weeks; a multinomial model explored specific psychiatric diagnoses. Analyses were performed in Python and statistical significance was set at P < 0.05. The extracted text does not clearly report precise dosing regimens, nor detailed measures of prior dosing frequency or purity of substances used.
At baseline 654 participants completed the survey, with 315 and 212 participants completing the two- and four-week follow-ups respectively. Mean age was 28.9 years (SD = 10.5); 74.2% were male (n = 485), 77.1% had university-level education or above (n = 504), and 51.2% were employed (n = 337) while 39.1% were students (n = 256). Participants were categorised as “novice” (< 6 lifetime psychedelic experiences; n = 250, 38.2%) or “experienced” (≥ 6 experiences; n = 404, 61.8%). About a third (33.0%) reported a lifetime psychiatric diagnosis. During the indexed acute experience, most reported using LSD/1P-LSD (n = 143, 54.0%) or psilocybin/magic mushrooms/truffles (n = 108, 40.8%); 17.7% (n = 67) reported the acute experience occurring in a retreat setting. Cross-sectionally at baseline, weak but statistically significant positive correlations were observed between lifetime psychedelic use and delusional ideation (Spearman r_s = 0.11, P = 0.01) and between lifetime use and magical ideation (r_s = 0.12, P = 0.003). These relationships remained after adjusting for age (PDI r_s = 0.11, P = 0.004; MIS r_s = 0.13, P = 0.001). The distress component of the PDI did not correlate with lifetime psychedelic use (r_s = 0.01, P = 0.06). Longitudinally, the overall sample showed a statistically significant reduction in delusional ideation after the psychedelic experience (χ2 = 15.47, P ≤ 0.001). Pairwise comparisons showed decreases from baseline to 2 weeks (Z = -3.60, P ≤ 0.001) and from baseline to 4 weeks (Z = -5.19, P ≤ 0.001). Novice users exhibited significant reductions in PDI scores from baseline (mean = 5.89, SD = 3.87) to 2 and 4 weeks (4-week mean = 3.91, SD = 3.21). No significant changes in magical ideation were observed for experienced users over the 4-week period. Regarding increases in schizotypal measures, 23.8% of participants showed increased delusional ideation at 4 weeks (mean change 1.8 points), but a logistic regression did not identify significant predictors for persistent PDI increases. Increased magical ideation occurred in 28.1% of participants; the authors report that higher baseline trait absorption was associated with increased odds of reporting greater magical ideation after the experience. The extracted text gives an odds increase figure of 6.0% per absorption unit (P < 0.001) but the associated confidence interval as extracted appears inconsistent and is not clearly reported. At the 4-week endpoint, 68 of 212 respondents (32.1%) endorsed at least one HPPD-type visual symptom; roughly half of these reported two or more effects (n = 35). The most frequently reported symptoms were intensified colours (n = 29, 18.6%) and positive afterimages (n = 28, 17.9%); macropsia (n = 6, 3.8%) and micropsia (n = 5, 3.2%) were least common. There was no significant difference in HPPD reporting between novice and experienced users (P = 0.64). Only two participants (< 1% of the total sample; 2.9% of those reporting any HPPD effects) described their symptoms as distressing; both were experienced users with > 10 prior uses. One additional participant endorsed all nine symptoms but did not report distress. In a multivariable logistic regression predicting any HPPD-type symptom at 4 weeks, several baseline factors were associated with altered odds: male sex was associated with lower odds compared with female (odds reduced by about 63.4%; reported 95% CI [0.15, 0.91]), each year of higher age reduced odds by approximately 6.2% (95% CI [0.90, 0.97]), and higher baseline absorption increased odds modestly (reported increase about 3.4% per absorption unit; 95% CI [1.01, 1.06]). A reported history of a psychiatric diagnosis substantially increased the odds of reporting at least one HPPD-type effect (authors indicate an increase of about 202%), though specific diagnostic categories did not emerge as significant predictors in a secondary model. Drug type (binary LSD vs non-LSD), dose and polydrug use were not identified as strong predictors in the extracted results. The authors note that the secondary logistic model had a low pseudo R-squared of 0.015, indicating limited explanatory power.
Zhou and colleagues interpret their findings as showing that, in this naturalistic prospective sample, delusional ideation decreased over the month following a planned psychedelic experience, which contradicts the simple hypothesis that increased lifetime psychedelic exposure causes elevated schizotypal traits. They suggest alternative explanations for the observed baseline association between lifetime use and higher schizotypy, including self-selection (persons with higher trait schizotypy or greater risk-taking being more likely to try psychedelics), self-medication for latent pathology, or a transient post-use reduction in schizotypal thinking that might rebound later. The authors caution that the observed short-term decreases could represent temporary ‘‘honeymoon’’ effects and call for studies examining longer follow-up intervals to determine durability. The cohort showed higher-than-average baseline magical ideation relative to general populations, and lifetime use correlated with magical thinking at baseline; the investigators note that prior research has also reported group-level shifts in metaphysical beliefs after psychedelic use, but underscore that correlation does not imply causation. Trait absorption emerged as a consistent predictor: it predicted increases in magical ideation and was associated with HPPD-type symptoms, which the authors link to absorption’s relationship with imagination and hallucination-proneness. While higher absorption may be associated with some adverse perceptual aftereffects, the authors observe that it is also predictive of types of acute subjective experiences thought to be therapeutically meaningful. HPPD-type visual phenomena were relatively common (about one-third at 4 weeks) but almost never reported as distressing, implying that clinically relevant HPPD is much rarer—likely under 1% in this sample—consistent with prior naturalistic surveys and lower than the DSM‑V prevalence estimate for HPPD. The authors propose that features of the acute setting (for example eyes-closed experiences or use of eyeshades in therapeutic contexts) might reduce risk of persistent visual disturbances and note that age, female sex and psychiatric history were associated with greater odds of HPPD-type effects. Proposed mechanisms include age-related windows for perceptual learning, sex differences in pharmacokinetics or dose-to-weight effects, and greater neurobiological sensitivity in people with psychiatric histories. However, they acknowledge that the drug-type variable (LSD vs non-LSD) was dichotomous and may have failed to capture dose–frequency nuances. Key limitations acknowledged include reliance on self-report and online recruitment leading to potential sample bias, lack of data on age at initiation, prior dose history, baseline prevalence of HPPD-like symptoms, and substance purity, and substantial attrition between baseline and follow-ups which may bias prevalence estimates. The authors also caution that some extracted numerical details and confidence intervals in their reported models are unclear in the provided text. Overall, they recommend larger, better-controlled studies, including more granular measurement of dose, setting and prior use, and argue for careful screening and aftercare when expanding access to psychedelic treatments.
In this prospective naturalistic sample Zhou and colleagues report a short-term reduction in delusional ideation four weeks after a planned psychedelic experience, despite cross-sectional associations between lifetime psychedelic use and higher baseline schizotypal traits. HPPD-type visual effects were commonly reported at four weeks but were almost never described as distressing, indicating that clinically significant HPPD was very rare in this cohort. Younger age, female sex, a history of psychiatric diagnosis, and higher baseline trait absorption were associated with increased odds of reporting HPPD-like symptoms. The authors call for larger, better-controlled studies and careful clinical screening and aftercare to better characterise causal relationships and risk factors as psychedelic use expands.
Following a decades-long human research hiatus, the investigation of the potential that psychedelic-induced altered states of consciousness may possess for aiding the treatment of mental health conditions has seen enormous growth in recent years. Classic psychedelics, such as psilocybin (found in socalled "magic mushrooms"), and lysergic acid diethylamide (LSD), mescaline (found in peyote and san pedro cacti), and dimethyltryptamine (DMT, found in various plants and the amazonian brew ayahuasca), are serotonin 2A-agonists that induce profound alterations in perception, mood, and cognition. In addition to promising results for the treatment of mood and addictive disorders, psychedelic use and psychedelic therapy in particular has been associated with rapid and enduring improvements in mood and wellbeing, as well as other behavioral and personality changes-including creative thinking, nature relatednessand social connectedness. Although the use of psychedelics in modern controlled research is generally considered to have a positive safety profile, case reports of serious adverse reactions linked to poorly monitored or uncontrolled psychedelic use existsupporting the view that use of these substances carries real risk. In consideration of the possibility that psychedelic substanceassisted treatments may soon be integrated into mental health practice, alongside an ongoing rise in psychedelic use in the general population, it becomes increasingly pertinent to explore the potential for any long-term, adverse effects of psychedelic use. Not including adverse reactions driven more distinctly by external factors, such as harm due to accidents, abuse, or coercion by others, the most salient concerns regarding the risks of psychedelic drugs (reviewed e.g. by Schlag et al.) refer to their potential to (i) trigger psychotic episodes, or more subtly, enhance schizotypal tendencies in healthy individuals, and (ii) to induce enduring visuoperceptual aberrations, that, when distressing, are clinically recognized as hallucinogen persisting perception disorder (HPPD). HPPD-related phenomena was identified in the literature as early as 1960and is nowadays considered to include two subtypes. The first, known as HPPD type 1, is defined as "flashbacks"strictly speaking, not limited to the perceptual domain, these refer to brief (seconds-to-minutes), though full-fledged recurrences of subjective psychedelic effects, including altered perception, cognition, and mood, typically within days to weeks after the initial drug experience. The second type, HPPD type 2 or chronic HPPD, is differentiated from flashbacks based on the persisting nature of its symptoms. This, arguably more core domain of HPPD-is typically limited to visuoperceptual aberrations which may wax and wane over months or even years and can include motion "trails," "halo" effects and intensified colors. Early work with psychedelics recognized their ability to produce transient psychological effects mimicking some important domains of psychosis, including perceptual changes, bizarre ideation, thought-disorder, and sometimes paranoid or delusional thinking. Prolonged adverse effects caused by medical interventions however, appeared to be rare, particularly in controlled settings. Analysing data from 44 physicians who administered more than 25,000 doses of lysergic acid diethylamine (LSD) or mescaline to approximately 5,000 subjects between 1950 and 1960, Cohenfound an incidence of as few as 10 prolonged psychotic reactions, that is in 0.2% of individuals, leading him to conclude that under controlled conditions, the administration of LSD was generally safe. A similar study of UK clinicians using LSD has found a somewhat higher incidence of 37 prolonged psychoses across 49,000 LSD sessions in 4,300 patients, or 0.9% of subjects. Only into the late 1960s, following the popularization of LSD use, did Cohen and other medical professionals begin to warn against the risks of psychedelic use. Several commentators have hypothesized that extra-pharmacological or contextual factors may also impact the likelihood of experiencing prolonged adverse reactions, such as psychotic episodes or HPPD, with recent supportive evidence for this here. To investigate these hypotheses, observational studies of realworld psychedelic use are essential, considering that rigorous screening procedures in modern controlled trials tend to exclude subjects considered at-risk for adverse outcomes. Indeed, analysis of the long-term effects of psilocybin in 110 healthy subjects, using pooled experimental data, found no persisting perception disorders, prolonged psychosis, or other long-term impairment of functioning in any of the subjects, although one case of short-lived psychological iatrogenesis was described. Similarly, until one recent multisite trial in treatment-resistant depression, only a small number of serious adverse events had been reported in modern clinical studies of serotonergic psychedelics for depression, end of life anxiety, or substance use disorders, including no cases of HPPD. In comparison, cross-sectional survey studies of naturalistic psychedelic users have found incidences of visual abnormalities lingering post-psychedelic use ranging from 11% (2) to as high as 60%, although far fewer (4%) experienced these symptoms as distressing, a necessary criterion for diagnosing HPPD. To our knowledge, no representative data exist that could inform on the prevalence of prolonged psychotic reactions following naturalistic psychedelic use, although large-scale population studies finding lowered rates of psychotic symptoms in psychedelic users, compared with nonpsychedelic users, suggest that this frequency is unlikely to be high. Moreover, one recent study of ours which specifically sought to recruit such cases, also supported their low prevalence and context-sensitivity, when they do indeed occur. The present study sought to investigate changes in delusional and magical ideation before vs. after psychedelic use, using online naturalistic prospective sampling. We also assessed the prevalence, and predictors of HPPD-type effects. Data were collected through a specially designed prospective online survey recruiting individuals who were planning to take a psychedelic through their own initiative. Measures were recorded at multiple time points before and after the psychedelic experience. It was hypothesized that baseline levels of delusional ideation and magical thinking would positively correlate with lifetime psychedelic use. Exploratory regression models were conducted to assess whether demographics, personality trait absorption, drug use history, and details of use during the acute experience, would predict the occurrence of HPPD-type effects and changes in delusional and magical ideation.
The following sample sizes were collected for each of the surveys at baseline (Table), 2 weeks post-acute experience, and 4 weeks post-acute experience: N = 654, N = 315, N = 212. The average age was 28.9 years (SD = 10.5). The majority of the population was male (n = 485, 74.2%), university educated or above (n = 504, 77.1%), and around half were employed (n = 337, 51.2%), with the rest comprised of students (n = 256, 39.1%). Just over a third of the cohort were "novice" users (five or fewer psychedelic experiences, n = 250, 38.2%) with the remaining two-thirds "experienced" (six or more past experiences, n = 404, 61.8%). Nearly, a third reported having ever been diagnosed with at least one psychiatric condition (33.0%). Just over half the cohort reported taking LSD/1P-LSD (n = 143, 54.0%) during the acute experience, followed by Psilocybin/magic mushrooms/truffles (n = 108, 40.8%) (Table). Only a minority of the cohort had an acute experience in a retreat setting (n = 67, 17.7%) (Table).
There was a weak, but significant positive correlation between lifetime psychedelic use and baseline delusional ideation (r s = 0.11, P = 0.01; Fig.). There was also a weak, but significant, positive correlation between lifetime psychedelic use and baseline magical ideation (r s = 0.12, P = 0.003; Fig.). These persisted when correcting for age (Peters' Delusions Inventory [PDI]: r s = 0.11, P = 0.004. Magical Ideation Scale [MIS]: r s = 0.13, P = 0.001; Fig.). Exploring the "distress" component of the PDI, there was no correlation with lifetime psychedelic use (r s = 0.01, P = 0.06).
The study population as a whole, demonstrated a statistically significant reduction in delusional ideation after the acute psychedelic experience (χ 2 = 15.47, P ≤ 0.001; Fig.). The decrease in delusional ideation from baseline to 2 weeks (Z = -3.60, P ≤ 0.001), persisted to 4 weeks (Z = -5.19, P ≤ 0.001; Fig.) after the psychedelic experience. Novice users (< 6 lifetime psychedelic experiences), exhibited significant reductions in delusional ideation from baseline (M = 5.89, SD = 3.87) to 2 weeks after the acute experience (Z = -2.59, P = 0.010), and 4 weeks (M = 3.91, SD = 3.21; Z = -3.31, P ≤ 0.001) after the experience. There were no significant changes in magical ideation from baseline to 4 weeks after the acute experience (Fig.) within experienced users (> 5 lifetime psychedelic experiences).
Slightly less than a quarter (23.8%) of participants showed increased delusional ideation at the 4-week endpoint, with a mean change of 1.8 points. A logistic regression model to investigate persistent increases in delusional ideation at 4 weeks did not find any significant predictors (SI appendix Table). However, the odds for reporting increased magical ideation, which occurred in 28.1% of participants was found to increase by 6.0% (95% CI [0.98, 1.03], P < 0.001) for a one-unit increment in baseline personality trait absorption (Table).
One-third of the 212 individuals who continued to the 4-week endpoint reported at least one HPPD-like effect (n = 68, 32.1%) (Table), with approximately half of this subgroup reporting two or more effects (n = 35). The most frequently reported HPPD-related symptoms were "intensified colors" (n = 29, 18.6%) and "positive afterimages" (n = 28, 17.9%). Visual distortions such as "macropsia" (n = 6, 3.8%) and "micropsia" (n = 5, 3.2%) were the least common. There was no significant difference in the likelihood of reporting HPPD effects between novice and experienced participants (P = 0.64). Amongst the 68 users reporting at least 1 HPPD-related effect, only 2 subjects (< 1% of the total sample, or 2.9% of those who reported any HPPD-type effects) expressed that these effects were distressing to them. Both subjects also confirmed that these effects were not due to any preexisting medical condition, but were rather perceived to be a consequence of their psychedelic use. One of these individuals endorsed experiencing all nine HPPD-type effects listed in the questionnaire, compared with the other who reported only one effect, namely, "false perceptions of movement in peripheral visual fields." Both were experienced users, claiming to have used psychedelics more than 10 times. One other individual also reported all nine effects but did not report them to be distressing.
A logistic regression model was performed to analyze relationships between HPPD-related symptomatology and age, gender, psychiatric history (yes/no), baseline personality trait absorption and the frequency of psychedelic use during the last 6 months, plus aspects of the acute experience, including setting (retreat vs nonretreat), drug dose, drug type (LSD vs. other psychedelic), and nonpsychedelic drug use (i.e. polydrug use) (Table). It was found that, holding all other predictor variables constant, the odds of HPPD-type effects occurring decreased by 63.4% (95% CI [-1.91 , -0.10]) for males compared with females, decreased by 6.2% (95% CI [-0.10 , -0.02]) with each unit increment in age, and increased by 202% (95% CI) for 3.4% (95% CI [0.001, 0,06]) for each unit increment in baseline personality trait absorption. It was found that, holding all other predictor variables constant, the odds of HPPD-type effects occurring decreased by 63.4% (95% CI [0.15, 0.91]) for males compared with females and decreased by 6.2% (95% CI [0.90, 0.97]) with each unit increment in age. The odds of HPPD-type effects occurring increased by 3.4% (95% CI [1.01, 1.06]) for each unit increment in baseline personality trait absorption. Additionally, history of a psychiatric diagnosis significantly increased the odds of at least one HPPD-type effect by 202.0% (95% CI). No specific psychiatric diagnosis was found to significantly predict HPPD-type effects (SI appendix Table).
The present study sought to investigate potentially undesirable psychological outcomes occurring within a 4-week period of an acute psychedelic experience. Specifically, we assessed delusional thinking and magical ideation, and persisting visual alterations corresponding to HPPD-type effects.
Directionally contradicting a prior hypothesis of ours, we observed a decrease in delusional ideation after (vs. prior to) a psychedelic experience. This result emphasizes caution when inferring a causal connection between observations of elevated schizotypal traits among individuals with greater lifetime psychedelic use, i.e. the association, while real, may not have been caused via psychedelic use. There are a few possible explanations for this apparent paradox. One is that the relationship between lifetime psychedelic use and trait schizotypy is driven by other underlying factors. Greater impulsivity and risk-taking tendencies-coincident with higher trait schizotypy (58, 59)-may draw certain individuals towards sampling psychedelics and their novel effects. Additionally, latent or manifest pathology might be a factor, motivating certain individuals, including those with higher schizotypal traits, to seek self-medication via psychedelics. Another possibility is that the decreases in schizotypal thinking observed within 4 weeks of psychedelic use were temporary or usedependent. For example, schizotypal thinking may rebound after an initial decrease-perhaps due to a precarious short-lived impact on mental health-i.e. a so-called "honeymoon" or "too good to be true" type phenomenon. Additionally, while wellintentioned psychedelic use could improve mental health outcomes, repeated use (or abuse) of psychedelics could flip the relationship in an overly iatrogenic direction-i.e. reflecting an "inverse U" type relationship between psychedelic use and mental health outcomes. Future work is required to examine whether trait schizotypy is especially vulnerable to such a phenomenon. The average delusional ideation score of our sample lies within the range of mean PDI scores found in other nonpsychiatric populations. In the present sample, experienced users reported higher scores than novice users, on average endorsing one more item in the scoring system. For reference, "deluded or psychotic populations" score much higher, ranging from 7.4 (66) to 11.9. Baseline magical ideation in the present self-selected sample was nearly twice as high as scores reported in general populations, suggesting a skew toward magical ideation in psychedelic users. In line with this, the frequency of lifetime psychedelic use at baseline was found to correlate with higher baseline levels of magical ideation. While this relationship does not entail causality, we are reminded of previous findings of group-level shifts in metaphysical beliefs including supernatural beliefs following psychedelic use both naturalistically and in a clinical trial (68) that could be viewed as suggestive of psychedelic use itself being causal in driving increases in magical ideation. Among predictors of post-psychedelic use changes in schizotypal traits, baseline absorption was found to be a strong predictor of magical ideation, which was unsurprising considering a component of the MODTAS scale of absorption is defined by "proneness to imaginative states." Moreover, absorption itself, by-definition, refers to a propensity to become absorbed or immersed in mental imagery, particularly fantasy. Although no significant predictors for increased delusional ideation were found, future work should further investigate other aspects such as drug type or personality traits to determine an at-risk profile. We advise caution on interpreting mild-to-moderate scores on absorption, delusional ideation (without distress), or magical ideation as reflecting pathology. It is possible that such phenotypes could confer certain adaptive advantages, such as enhanced divergent thinking and related creative problem solving.
HPPD-related effects were endorsed by close to a third of participants (32.1%), although only two subjects (i.e. < 1%) perceived these to be distressing, thus disqualifying a HPPD diagnosis for 97% of those who reported HPPD-related effects. This pattern of high rates of HPPD-related effects but low rates of actual HPPD (i.e. lacking the crucial distress component) is consistent with prior studies on HPPD frequency. While the DSM-V proposes a prevalence of HPPD in 4-4.5% of psychedelic drug users (American Psychiatric Association, 2013), a questionnaire-based study on the website erowid.org found that as many as 61.7% of respondents reported having had unusual visual experiences lingering on at least one occasion after psychedelic drug use. In another previous online survey, which specifically assessed visual effects in response to psychedelics, 40% endorsed persistent changes in visual perception, closer to the present findings of 32%. Importantly, however, the proportion of people reporting distressing HPPD-type effects is remarkably convergent across studies, at 3-4% of those who report any visual aftereffects of psychedelic use (present study and). Across these studies, the frequency of HPPD among psychedelic users overall, would thus be estimated at < 1%, which is at least four times lower than the estimate provided by the DSM-V. This suggests that the DSM-V reported prevalence should be revised to better reflect existing and emerging data. The point to emphasize strongly, is that for most users, HPPD-related aftereffects are not considered distressing. To our knowledge, no cases of HPPD have been reported in participants of clinical trials of psychedelics (2, 52, 56, 74)-even when formally probed using a similarly structured (DSM-V-consistent) method, as used in the trial of psilocybin vs. escitalopram for depression. Offering speculative explanations for this apparent discrepancy between naturalistic data for and psychedelic therapy, it is possible that yet uninvestigated factors, such as the use of eyeshades and closed-eye experiences may be protective of persistent visual disturbances. Conceivably, the visual system might be subject to greater stress in the context of open-eye visual hallucination where drug-induced anomalous visual experiences need to be reconciled with visual input from the environment. From a predictive coding perspective, altered visual perception induced by the drug could update perceptual priors-and this effect could be more likely with eyes-open as prediction errors will occur due to input-to-inference mismatch. Future studies on psychedelic effects in humans may benefit from assessing setting in a more structured way, including time spent by participants with open eyes, as opposed to closed eyes, or wearing eyeshades. The finding of trait absorption being linked to HPPD-type symptoms is unsurprising considering its association with hallucination-proneness (75) and recent work linking trait absorption to HPPD in a retrospective sample. Whilst in this context, greater trait absorption might potentially seem undesirable, it is important to consider that a propensity to become deeply immersed in stimuli-as displayed by individuals with high absorption-may confer certain psychological advantagesand has also been found to be predictive of some of the acute subjective effects that are known to render psychedelic experiences therapeutically meaningful. We also found that younger age was associated with a greater likelihood of reporting HPPD-related effects. This suggests that the role of age and critical windows for perceptual learning should be considered when investigating psychedelic effects in humans. Adolescence represents the peak age of onset for mental disordersand the adolescent brain is known to be particularly vulnerable to the negative consequences of substance use. Heightened), or other stressors, which may have increased the likelihood of experiencing persistent perceptual effects-confounders that should be controlled for in future observational studies. There is also the possibility that they may have taken the psychedelic with less education and therapeutic intention, and in higher-than-average doses. The observed higher likelihood of HPPD-type effects in female participants was surprising, considering that gender has not previously been identified as a predictor of response to psilocybin. Sexually dimorphic differences in drug pharmacokinetics may account for the effect, with studies finding pharmacokinetics to strongly predict adverse drug effects in females, albeit not in a manner exclusive to psychedelics, and neither are there clear sex differences in serotonin 2A receptor functioning. The lower-than-average weight of femaleswill affect dose to weight ratio-potentially conferring more intense responses in females with the same dose, although BMI has not been found to predict the intensity of subjective effects with psychedelics. Menstrual-cycle-related hormonal and biochemical effects may be investigated in the future to further examine any sex-differences. The finding that a history of a psychiatric diagnosis was associated with a greater odds of experiencing HPPD-type effects was expected. This is in line with existing literature, which has consistently found more pronounced neurobiological responses to psychedelics in individuals with psychiatric conditions, and greater susceptibility to perceptual disturbances. These results highlight the importance of carefully screening for mental health conditions and stress the need for enhanced support such as continuous monitoring and comprehensive aftercare, to mitigate the risk of persistent visual disturbances and other adverse effects. While LSD use is often associated with various perceptual disturbances, it did not emerge as a key predictor of HPPD-type symptoms. This implies that other factors, such as age, gender, or preexisting mental health conditions, may play a more critical role in determining the susceptibility to HPPD-type effects than substance type. The binary classification of the drugtype variable to (LSD vs non-LSD) might, however, fail to capture important nuances that could influence the relationship between psychedelic type and HPPD symptoms. For example, it does not account for within-group variations such as differences in the frequency and dosage of prior LSD use, which are factors that have been demonstrated to significantly impact the likelihood of experiencing perceptual disturbances. It is also possible that an interaction between dose and substance type exists , e.g. high-dose LSD users might experience significant perceptual disturbances, while low-dose or therapeutic users might not, leading to an overall null effect when combined into a single binary category. Future research could employ multivariate analyses to understand how different variables, such as dose and frequency, interact to influence the outcomes. Although anxiety is frequently found to be associated with greater risk of HPPD and other disturbances, it was not found to be a significant predictor. The secondary logistic regression model has a low pseudo R-squared value of 0.015, indicating a poor fit. Further research with larger sample sizes are necessary.
For a general discussion of the strengths and limitations of this study's design, see Haijen. We briefly summarize some of these here. Firstly, online self-surveying is vulnerable to poor control and accuracy of reporting. The present study design recorded an extensive range of details about the study cohort and their acute psychedelic experience; however, important data such as the age of initiation of psychedelics, average time periods between occasions of use, the dose and type taken during previous occasions, and the frequency of HPPD effects at baseline, before the assessed psychedelic experience, were not included. Whether individuals had previously microdosed or taken high doses of psychedelics and other substances, was also unaccounted for. Some have speculated that certain psychedelic drugs such as LSD, in addition to nonpsychedelic substances such as phencyclidine and cannabinoids, may raise the likelihood of developing HPPD symptoms compared with psilocybin. Respondents to a questionnaire on the perceptions of "hallucinogens", tended to associate more perceptual changes to LSD than psilocybin, for example. As discussed earlier, characteristics of the study population, such as psychiatric history, alcohol history and other putative psychological risk-factors such as high trait anxiety should be included in future studies investigating cognition or HPPD-like effects following psychedelic use. As participants supplied their own substances, it was not possible to control for substance purity, which may have reduced the accuracy of the results. A study examining the purity and adulteration of substances bought online and offline found the purity of 2C-B to vary significantly. However, in comparison to other psychoactive drugs of potential misuse such as cocaine or MDMA, psychedelic substances are generally less likely to be adulterated and if adulterated, tend to be tainted with other psychedelic substances (99, 100). This study was advertised via online postings, including on social media and drug-related websites. Whilst this helped to enhance the study population size, it may have introduced sample biases. Compared with the general population, the sample may have been more educated about psychedelic harm reduction practices and more likely to use psychedelics with welldeliberated intentions, thereby creating a favorable bias toward the occurrence or reporting of positive outcomes from use of these substances. We have already determined that the sample demonstrates higher than average levels of magical ideation at baseline. The self-selecting and self-reporting nature of the sample and study may have caused an under-estimation of iatrogenic responses to psychedelics (e.g. as discussed by Bremler et al.). Additionally, large dropout rates and the potential for attrition biases renders definitive estimations of the frequency of HPPD-like symptoms difficult based on the current sample alone, although prior work in this same population has shown dropout not to be predicted by (negative) responses to the psychedelic, but rather generic predictors of attrition, such as younger age and low conscientiousness (101).
Here we present evidence of reduced schizotypal or delusional thinking 4 weeks after vs. before psychedelic use, contradicting prior hypotheses and correlational data which indicated a positive relationship between these phenotypes and lifetime psychedelic use. HPPD-like effects were common, but when qualified by distress, clinically relevant cases were extremely rare. Younger age, female gender, history of a psychiatric diagnosis and higher baseline trait absorption were associated with an elevated odds of HPPD-type effects. Future work would benefit from larger sample sizes and better experimental controls in order to enable stronger inferences about causal effects and contributing variables linked to iatrogenic responses to psychedelics. We hope this study can serve as an inspiration of greater empirical scrutiny of the potential risks of psychedelics, including in laterphase multisite clinical trials that often carry an implicit incentive not to test such things-i.e. because of a fear that they may discover information that could jeopardize the goal of medical approval. We hope a steady commitment to scientific enquiry will accompany forthcoming changes in policy and access to psychedelic drugs.
Data were collected as part of a large-scale, prospective online survey. Only data and aspects of the design deemed relevant to this current study are discussed. For a full review of the study design, see Haijen. The online survey was advertised through social media platforms and drug-related websites. Prospective participants, who had a good grasp of the English language, and who were planning to use psilocybin/magic mushrooms/truffles, LSD/1P-LSD, ayahuasca, DMT/5-MeO-DMT, salvia divinorum, mescaline, or iboga/ibogaine in the next 3 months, were invited to register for the survey. Sign up and email reminders were performed through the purpose-built website www.psychedelicsurvey.com. All data were recorded at three timepoints, except for HPPD-type effects which were only recorded at the key 4-week endpoint. The baseline timepoint was 1 week before the planned psychedelic experience. Questions regarding the acute experience, including drug dose, type, and subjective effects, were assessed 1 day after the experience date, sub-acute endpoints were at 2 and 4 weeks post experience.
The following relevant data were collected at baseline: age, gender, education level, employment status, nationality, history of a psychiatric diagnosis, lifetime psychedelic use, previous psychedelic use, the two primary measures of delusional ideation and magical thinking, and the secondary measures of wellbeing, state and trait anxiety, and personality trait absorption. Data relating to the acute psychedelic experience were also collected, including the drug type, drug dose, and setting. The three primary outcome measures were assessed according to PDIfor delusional ideation, the MIS for magical thinking (102), and a set of self-constructed questions evaluating HPPD-type effects (SI appendix Fig.). PDI ()-The 21-item PDI is used to assess proneness to psychosis, measuring distress, preoccupation, and conviction regarding delusional ideas. These include questions such as, "Do you ever feel as if there is a conspiracy against you," "Do you ever think people can communicate telepathically?," or "Do you ever feel as if you have been chosen by God in some way?." A sum score is calculated by totaling the number of endorsed delusional ideas. Secondary outcomes measuring the distress level, frequency of thought recurrence, and conviction in its veracity, are rated on Likert scales with values ranging from 1 to 5 for each endorsed idea. The pathological relevance of PDI items was further analyzed in this study by calculating a distress score, totaling the ratings of the question, "How distressing is this thought?." MIS (102)-The 15-item brief version of the validated MIS was used in the current study, where respondents rated items binarily as false or true. The scale measures the rate of aspects such as false beliefs, invalid causations, and unrealistic, magical-type ideas. Example items include, "I have felt there were messages for me in the way things were arranged, like in a store window," "I have sometimes felt that strangers were reading my mind," "Numbers like 13 and 7 have 0 special powers," or "Horoscopes are right too often for it to be a coincidence." A sum score is calculated by totaling the number of times an item was rated true. HPPD-type symptoms scale (SI appendix Fig.)-The selfconstructed HPPD questionnaire was comprised of three components. First, a comprehensive checkbox list enquired about the presence of nine different visual symptoms following cessation of psychedelic use, including geometric hallucinations, false perception of movement in peripheral visual fields, flashes of colors, intensified colors, trails of images of moving objects, positive afterimages, halos around objects, macropsia, and micropsia. Participants who indicated the presence of at least one effect subsequently answered the yes-no question "Do these cause significant distress or impairment in social, occupational, or other important areas of functioning?." Any participants answering affirmatively to distress, then received a follow-up yes-no question, "These symptoms are not due to a general medical condition (e.g. anatomical lesions and infections of the brain, visual epilepsies) and are not better accounted for by another mental disorder (e.g. delirium, dementia, Schizophrenia) or hypnopompic hallucinations." Modified Tellegen Absorption Scale (MODTAS) (103)-The 15 category MODTAS scale measures trait absorption, exploring individual response to stimuli and imagery. Each item is rated either true or false. Items include, "Is responsive to engaging stimuli," "Is responsive to 'inductive' stimuli," "Often thinks in images," "Can summon vivid and suggestive images," "Has 'crossmodal' experiences (e.g. synesthesia)," "Can become absorbed in own thoughts and imaginings," "Can vividly reexperience the past," "Has episodes of expanded (e.g. ESP-like) awareness," and "Has experienced altered states of consciousness."
To test the association between lifetime psychedelic use and the primary measures of delusional and magical ideation, two-tailed Spearman correlations were performed. Secondary partial correlations were carried out to adjust for age as a potential confounding factor. To explore the prospective effect of the acute psychedelic experience on delusional and magical ideation, participants were further assigned into groups based on previous psychedelic use experience, in order to ensure that significant effects would not be lost due to previous psychedelic-induced changes, i.e. ceiling effects due to changes induced by prior use. To do this, participants with a lifetime psychedelic use of less than six times were assigned to a "novice" group, and those who had used more than five times were assigned to an "experienced" group. Friedman and Wilcoxon signed rank tests were used to compare the scores measured at each timepoint. Comparisons made between novice and experienced groups were performed with Mann-Whitney U tests. To evaluate whether changes in the primary measures were associated with changes in the secondary measures, two-tailed Pearson correlations were performed with week 4 and baseline score differences. To investigate predictors of increased PDI and MIS after the acute psychedelic experience, a logistic regression model was performed with variables which did not exhibit collinearity based on variance inflation factors using a limit of < 10 (104). PDI and MIS outcome was binarized into groups based on whether the score did or did not increase after the acute psychedelic experience, categorized by a change score of > 0 or ≤ 0, respectively. The variables included were age, gender ( female = 0, male = 1), baseline personality trait absorption and frequency of psychedelic use during the last 6 months, and aspects of the acute psychedelic experience including setting (nonretreat = 0, retreat = 1), drug type (LSD vs. other psychedelic), drug dose, and concomitant nonpsychedelic drug use (polydrug use). Odds ratios were calculated to interpret the results. To investigate the predictors of HPPD-type symptoms, a logistic regression model was performed including the same predictor variables as above with the addition of psychiatric history (yes vs. no), again with variables exhibiting collinearity removed based on variance inflation factors using a limit of < 10 (104). The outcome was binarized into groups based on whether or not subjects reported at least one HPPD symptom. A secondary multinomial logistic regression model was performed to investigate whether any specific psychiatric diagnosis was a predictor. Corresponding correlational matrices can be accessed in the SI appendix Figs. S2, S3, S4. Statistical analyses were performed using the NumPy, Scipy, SKlearn, Statsmod, and Pinguoin libraries in Python. A P < 0.05 value was considered statistically significant. "Weak" and "moderate" correlations were determined using conventional thresholds for r and r s values "0.1-0.3," "0.4-0.6", respectively (105).
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