Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants
This pooled analysis of nine double-blind, placebo-controlled, cross-over studies (n=213) investigates predictors of LSD effects in healthy subjects. It finds that LSD dose is the most influential predictor, with pre-drug mental states, personality traits, and previous hallucinogen experiences also significantly affecting the subjective experience.
Authors
- Yasmin Schmid
- Patrick Vizeli
- Felix Müller
Published
Abstract
The pharmacodynamic effects of lysergic acid diethylamide (LSD) are diverse and different in different individuals. Effects of other psychoactive substances have been shown to be critically influenced by non-pharmacological factors such as personality traits and mood states. The aim of this study was to determine pharmacological and psychological predictors of the LSD effects in healthy human subjects. This analysis is based on nine double-blind, placebo-controlled, cross-over studies with a total of 213 healthy subjects receiving between 25-200 µg LSD. The influence of sex, age, dose, body weight, pharmacogenetic, drug experience, personality, setting, and mood before drug intake on the peak autonomic and total subjective responses to LSD was investigated using multiple linear mixed effects models and Least Absolute Shrinkage and Selection Operator regression. Results were adjusted for LSD dose and corrected for multiple testing. LSD dose emerged as the most influential predictor, exhibiting a positive correlation with most response variables. Pre-drug mental states such as “Well-Being”, “Emotional Excitability”, and “Anxiety” were also important predictor for a range of subjective effects but also heart rate and body temperature. The trait “Openness to Experiences” was positively correlated with elevated ratings in “Oceanic Boundlessness” and mystical-type effects. Previous experiences with hallucinogens have been negatively associated with the overall altered state of consciousness and particularly with “Anxious Ego Dissolution”. Acute anxiety negatively correlated with the genetically determined functionality of the Cytochrome 2D6 enzyme. In summary, besides the amount of drug consumed, non-pharmacological factors such as personal traits and current mood also significantly predicted the subjective drug experience. Sex and body weight were not significant factors in influencing the drug experience.
Research Summary of 'Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants'
Introduction
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.
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Vizeli, P., Studerus, E., Holze, F., Schmid, Y., Dolder, P. C., Ley, L., Straumann, I., Becker, A. M., Müller, F., Arikci, D., & Liechti, M. E. (2024). Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants. Translational Psychiatry, 14(1). https://doi.org/10.1038/s41398-024-03074-9
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