Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics

Classic serotonergic (5-HT2A agonist) psychedelics such as psilocybin are increasingly studied for therapeutic potential and generally show a favourable safety profile in controlled trials when combined with psychological support. However, most clinical work has used carefully screened participants in highly structured settings, leaving uncertainty about risks arising from use in broader, naturalistic contexts. Existing guidelines therefore emphasise screening (for example, excluding people taking certain medications such as lithium) and attentiveness to set (psychological state) and setting (physical and social environment) as ways to reduce harm, but population-level data on the prevalence and correlates of challenging, difficult, or distressing psychedelic experiences are limited. Simonsson and colleagues set out to address that gap by conducting exploratory analyses of challenging experiences among lifetime users of classic psychedelics within a nationally representative sample of US adults (with respect to sex, age and ethnicity). The study aimed to estimate prevalence of such experiences, describe their phenomenology and immediate consequences, and examine associations between medication co-use, set and setting variables, and both the intensity of challenging experiences and subsequent risk of harm.

The investigators recruited a stratified sample of US residents aged 18 or older via the online platform Prolific Academic between 1–9 October 2021. The target sample size was driven by a G*Power calculation: 395 lifetime classic psychedelic users were required to detect a small effect with 80% power at alpha = .05, so the team aimed to recruit about 2,800 participants to yield that subsample. The final recruited sample was N = 2,822 and respondents who reported lifetime use of any classic psychedelic comprised the analytic subsample (n = 613). Recruitment materials did not mention psychedelics to reduce self-selection bias. The sample was stratified on sex (male, female), age (18–27, 28–37, 38–47, 48–57, 58+), and ethnicity (White, Mixed, Asian, Black, Other). The extracted text does not clearly report additional inclusion/exclusion criteria beyond age and US residency. Lifetime classic psychedelic use was assessed via self-report of ever having used ayahuasca, DMT, LSD, mescaline, peyote, San Pedro, or psilocybin. Participants who endorsed any substance were coded positive for lifetime classic psychedelic use. Those reporting lifetime use completed a battery of items concerning challenging, difficult, or distressing experiences: a global frequency item, an item on degree of functional impairment and its duration, and a modified 11-item version of the Meditation-Related Adverse Effects Scale (MRAES-MBP) to capture enduring adverse effects. A gratitude item assessed whether respondents felt glad they had used classic psychedelics. For the single most challenging experience, participants completed the 26-item Challenging Experiences Questionnaire (CEQ; 0–5 scale), for which internal consistency in this sample was excellent (alpha = .97). They also reported specific set and setting factors (e.g., preparation, mindset, social and physical environment), any helpful interventions used during the episode, whether they sought medical/psychiatric/psychological assistance afterwards, and whether they experienced thoughts or attempts to hurt themselves or others in the days or weeks following the episode. Medication use at the time of the most challenging experience was queried across several classes (tricyclics, SSRIs, SNRIs, MAOIs, St John's Wort/other serotonergic supplements, antipsychotics, lithium/other mood stabilisers, methadone or buprenorphine/suboxone). Analyses comprised multiple linear regression models for continuous outcomes (CEQ score) and multiple logistic regression models for dichotomous outcomes (overall risk of harm: thoughts or attempts to hurt self/others). Models were covariate-adjusted; all analyses were performed using Stata version 17. The extracted text does not clearly enumerate the full set of covariates included in adjusted models.

Among the 613 respondents with lifetime classic psychedelic use, 59.1% reported never having had a challenging, difficult, or distressing experience related to classic psychedelics. Regarding functional consequences, 4.6% reported severe impairment of ability to function and 8.9% reported impairment that lasted longer than one day. A majority (57.1%) endorsed at least one of the listed enduring adverse symptoms on the modified MRAES-MBP; feeling anxious was the most commonly reported enduring symptom. Most respondents agreed (from slightly agree to strongly agree) with the statement that they were glad they had used classic psychedelics. When asked which substance was associated with challenging experiences, LSD was most frequently cited (associated by 24.0% of the subsample and by 31.5% of lifetime LSD users), followed by tryptamines (15.3% overall; 19.7% of tryptamine users) and phenethylamines (4.1% overall; 14.7% of phenethylamine users). For the single most challenging experience, 11.3% reported co-use of at least one medication. The five most commonly reported set and setting factors tied to the episode were: no preparation, a negative mindset, absence of psychological support, a disagreeable social environment, and a disagreeable physical environment. The most commonly reported helpful interventions during the episode were attempting to calm the mind, changing location, asking a friend for help, altering the social environment, and smoking cannabis. In the days or weeks after the most challenging episode, about 6.7% reported thoughts or attempts to hurt themselves or others: 4.6% reported thoughts of self-harm, 2.6% reported thoughts of harming others, 1.5% reported attempts to harm themselves, and 0.7% reported attempts to harm others. A minority (2.6%) sought medical, psychiatric, or psychological assistance following the episode. Adjusted regression analyses linked co-use of lithium and co-use of other mood stabilisers at the time of the episode with higher CEQ scores (greater degree of difficulty) and with higher odds of overall risk of harm. No associations were observed for other medication classes. Several set and setting variables were associated with higher CEQ scores: no preparation, disagreeable physical environment, negative mindset, lack of psychological support, dose perceived as too large, and a major life event prior to the experience. For the dichotomous outcome of overall risk of harm, negative mindset, absence of psychological support, and a prior major life event were associated with higher odds. The extracted text references tables for unadjusted analyses and full model details but does not provide exact effect sizes, confidence intervals, or p-values in the prose.

Simonsson and colleagues interpret their findings as indicating that, within a demographically stratified US sample, most lifetime classic psychedelic users report never having had a challenging, difficult, or distressing experience, but a meaningful minority experience functional impairment or enduring symptoms and a small proportion seek formal help. The pattern that attempting to calm the mind was the most commonly reported helpful strategy aligns with prior work; the authors suggest that preparatory exercises such as mindfulness-based practices might be useful components of harm reduction and preparation. The observed associations between medication co-use—notably lithium and other mood stabilisers—and both greater acute difficulty and greater odds of post-episode risk of harm are highlighted as consistent with existing safety guidance and prior reports linking lithium co-use to adverse physiological events. Similarly, associations between several set and setting variables (negative mindset, lack of psychological support, recent major life event, disagreeable environment, excessive dose, lack of preparation) and worse outcomes reinforce contemporary recommendations to attend to extrapharmacological factors when planning psychedelic administration. The authors acknowledge several limitations: the cross-sectional design precludes causal inference; the Prolific recruitment was stratified only on sex, age and ethnicity and may not be representative on other characteristics such as socioeconomic status; and reliance on self-report introduces potential biases. They recommend longitudinal research in naturalistic user populations to clarify causal links and further inform safety practices. In sum, the study offers population-level estimates of challenging psychedelic experiences and identifies medication co-use and set-and-setting factors associated with greater difficulty and risk, which the authors propose can inform harm reduction efforts and the design of future experimental studies.