Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants

LSD is a classic serotonergic psychedelic that produces dose-dependent shifts in consciousness, including mystical-type experiences, synaesthesia and increased introspection. Earlier research indicates that responses to psychoactive drugs vary substantially between individuals and are influenced by non-pharmacological factors commonly framed as "set" (personality and mental state) and "setting" (environment). While such modulatory determinants have been explored for other psychedelics like psilocybin and for MDMA, modern comprehensive analyses of predictors of the LSD response are lacking. Genetic variation in metabolic enzymes, notably Cytochrome P450 2D6 (CYP2D6), has also been reported to affect LSD exposure and potentially its effects. Vizeli and colleagues set out to identify pharmacological and psychological predictors of acute physiological and subjective responses to LSD in healthy adults. Using pooled individual‑level data from nine double‑blind, mostly placebo‑controlled crossover studies covering oral doses from 25 to 200 µg, the study aimed to quantify the relative importance of dose, demographics, genetics, prior drug experience, personality, setting and pre‑drug mood for a broad set of outcome measures. The authors emphasise that this dataset is, to their knowledge, the largest uniformly collected compilation of predictor and outcome variables for psychedelic effects and the first to systematically account for actual administered LSD dose when evaluating multiple predictors.

The investigators performed a pooled analysis of raw data from nine double‑blind crossover studies conducted at the University Hospital Basel between 2014 and 2023. Eight of the nine studies included placebo conditions; the pooled sample comprised 213 healthy participants (108 female) aged 25–64 years, contributing 297 LSD‑only sessions and 189 placebo sessions. All studies obtained written informed consent and were registered at ClinicalTrials.gov. Details on exclusion criteria and study‑specific procedures are reported in the supplemental material referenced by the authors. Oral LSD base was administered as single doses of 25, 50, 100 or 200 µg, either in gelatine capsules or as an ethanol drinking solution. Analytically confirmed doses ranged from 26 to 197 µg for all but the first two studies; for those first two studies actual doses were estimated from blood‑plasma AUC. Predictor variables included sex, age, body weight, administered dose (also treated as a covariate), CYP2D6 activity score (genetically determined), number of previous hallucinogen experiences, whether an MRI was performed during the session, scores on the Adjective Mood Rating Scale (AMRS) measuring pre‑drug mood states, and the NEO Five‑Factor Inventory (NEO‑FFI) for personality. The extracted text indicates further methodological details and variable distributions are provided in supplementary figures and tables. Outcome measures comprised subjective and physiological responses. Subjective instruments were Visual Analogue Scales (VAS), the five‑dimensional Altered States of Consciousness (5D‑ASC), and the 30‑item Mystical Experience Questionnaire (MEQ30). Physiological outcomes were mean arterial pressure (MAP), heart rate, body temperature and the pharmacokinetic area under the LSD plasma concentration curve (AUC). For subjective measures the area under the effect‑time curve (AUEC, 0–11.5 h) quantified overall acute effect; physiological measures used peak change (Emax) from placebo. All response variables were analysed as difference scores between LSD and the corresponding placebo session. Statistical analyses used R. To account for repeated measures within participants (some subjects had multiple doses), linear mixed effects models with random intercepts by subject were fitted for each predictor–outcome pair, with z‑transformation of predictors and responses so coefficients are fully standardised. Because dose is a major determinant of response, actual dose was included as a fixed covariate in all models except when dose itself was the predictor. Multiple testing correction used the Benjamini–Hochberg procedure. The semi‑partial R2 (sr2) quantified variance explained by each fixed effect. As a complementary approach, Least Absolute Shrinkage and Selection Operator (LASSO) regression (R package "penalized") identified optimal predictor subsets and ranked relative importance; a sensitivity analysis restricted to one dose per study (closest to 100 µg) was also performed. The extracted text notes that some variables had missing data and were imputed, with imputation details in the supplement.

Across the analysed outcomes, administered LSD dose was the single most influential predictor for most subjective and physiological effects after standardisation and correction for multiple testing. Dose showed the largest absolute standardised regression coefficient in 21 of 29 response variables and was selected as a predictor for all response variables in the LASSO models. The one notable exception was body temperature, for which dose did not emerge as the primary predictor. Genetic CYP2D6 activity score predicted LSD plasma concentration in addition to dose, and lower CYP2D6 activity (indicating reduced metabolic function) was associated with higher 5D‑ASC total scores and particularly greater "Anxious Ego Dissolution" (a 5D‑ASC cluster including anxiety and impaired control/cognition). MRI sessions were associated with increased reports of "Impaired Control and Cognition" on the 5D‑ASC. Age and body weight showed opposite associations with VAS ratings of "bad drug" effects: older age predicted higher "bad drug" ratings while greater body weight predicted lower ratings. Female sex was linked to smaller LSD‑induced increases in VAS "good drug" effects and to lower scores on 5D‑ASC "Experience of Unity", "Insightfulness" and MEQ30 "Positive Mood"; however, these sex differences were not significant in the one‑dose‑per‑study sensitivity analysis. Prior experience with hallucinogens predicted reduced overall altered states (lower 5D‑ASC total score) and lower scores on several 5D‑ASC subscales, notably "Anxious Ego Dissolution", "Vigilance Reduction", "Disembodiment", "Impaired Control and Cognition", "Changed Meaning of Percepts", and MEQ30 "Transcendence of Space and Time." Pre‑drug mood, particularly AMRS "General Well‑Being," emerged as the second strongest predictor of subjective effects after dose and was significantly associated with nearly all subjective outcomes except a few specific subscales (e.g. VAS "bad drug", some MEQ30 items). Higher pre‑drug ratings of "Emotional Excitability", "Performance‑Related Activity", and AMRS "Anxiety" also predicted higher scores on various subjective scales and autonomic measures; notably, "Emotional Excitability" and "Anxiety" predicted heart rate and MAP. Personality traits showed trait‑specific associations: NEO‑FFI "Openness to Experience" predicted higher 5D‑ASC "Oceanic Boundlessness", "Spiritual Experience" and "Insightfulness", as well as higher MEQ30 total and subscale scores for "Mystical" and "Positive Mood." "Extraversion" predicted higher 5D‑ASC total scores and subscales related to perceptual alterations such as "Visionary Restructuralization", "Auditory Alteration" and "Audio‑Visual Synesthesia." In contrast, "Neuroticism", "Agreeableness" and "Conscientiousness" did not predict LSD effects in this dataset. LASSO models typically selected about 12 predictors per outcome (range 8–14). While dose dominated most outcomes, it was not the top predictor for several variables: VAS "good drug" effect, 5D‑ASC "Vigilance Reduction", MEQ30 "Spiritual Experience", MEQ30 "Blissful State", MEQ30 "Mystical", MEQ30 "Positive Mood" and body temperature were more strongly predicted by baseline "Well‑Being", "Extraversion" or "Emotional Excitability" depending on the outcome. Sensitivity analyses limited to one dose per study (doses close to 100 µg, N = 213) produced largely consistent results, and restricted cubic spline dose‑response checks yielded similar patterns, supporting the robustness of the reported associations. The extracted text indicates full numerical coefficients, sr2 values and statistical significance are reported in supplementary tables and figures.

The investigators interpret their findings as showing that while administered LSD dose is the dominant determinant of acute subjective and physiological effects, a range of non‑pharmacological factors exert distinct and clinically relevant influences even after adjusting for dose. Genetic variation in CYP2D6 emerged as the only other predictor associated with plasma LSD concentration, and lower CYP2D6 activity correlated with higher overall altered state scores and greater "Anxious Ego Dissolution," consistent with higher systemic exposure. Prior hallucinogen experience predicted attenuated altered states, particularly reductions in anxiety‑related and cognitive‑control‑related distress, supporting the idea that familiarity with psychedelics moderates acute intensity. Pre‑drug mental state—especially a self‑reported sense of "Well‑Being"—was a major non‑pharmacological predictor of positive subjective outcomes such as "good drug" effects, oceanic‑type experiences and mystical‑type scores on the MEQ30. The personality traits "Openness to Experience" and "Extraversion" were linked to more insightful/mystical and perceptual effects respectively, mirroring prior observations with other psychedelics. Autonomic responses (heart rate, MAP) were influenced both by dose and by pre‑drug emotional arousal, prompting the authors to suggest that psychological arousal contributes to cardiovascular changes during LSD rather than strong direct cardiostimulant action, which aligns with the authors' statement regarding LSD's cardiovascular safety profile. Key limitations acknowledged by the authors include imperfect blinding inherent to psychoactive drug trials and limited variability in setting: most sessions occurred in a quiet hospital room with a single investigator present, so broader environmental influences on the psychedelic experience (e.g. therapeutic or recreational settings) could not be explored beyond whether an MRI was performed. Music exposure was present but not systematically recorded. Genetic analyses were restricted to CYP2D6; variation in the serotonin 2A receptor gene was not assessed and might also modulate response. Potential selection bias is noted because psychedelic studies may attract individuals with higher baseline openness. Methodological caveats of the modelling approaches are described: LASSO aids variable selection but may not yield a definitive rank order when predictors explain similar variance, and linear dose‑response assumptions might not hold for all outcomes, although sensitivity checks with splines and the one‑dose‑per‑study analysis produced similar findings. The authors discuss clinical implications emphasising that "set" (pre‑drug mood and personality) matters for the acute experience and thus may influence therapeutic outcomes, given prior evidence linking mystical‑type experiences to long‑term clinical benefit. They suggest that enhancing well‑being prior to psychedelic administration, employing ascending dosing regimens and preparatory interventions could be strategies to optimise positive acute effects and reduce adverse experiences. The authors caution that translating these findings to patient populations may be challenging because patients often present with lower baseline well‑being or higher anxiety, and they call for further research to determine how preparatory or adjunctive interventions might modify predictors in clinical settings. In sum, the study highlights that both pharmacological dose and non‑pharmacological factors jointly shape the LSD experience, whereas sex and body weight had minimal influence in this pooled healthy‑participant dataset.