Psychedelic Hormesis: LSD Activates Adaptive Stress Transcriptional Programs in the Prefrontal Cortex
- 1Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Turin, Italy.
Abstract
Background Classic psychedelics are serotonergic agents increasingly recognized for their ability to produce rapid and long-lasting therapeutic effects in several neuropsychiatric conditions, yet the molecular mechanisms that translate acute serotonergic perturbation into long-term brain adaptation remain poorly understood. Psychedelic action is commonly attributed to enhanced neuronal plasticity, but emerging evidence suggests broader engagement of stress-responsive and homeostatic processes across neural and non-neural cell types. Methods To define the temporal structure of psychedelic-induced transcriptional responses, we profiled gene expression in the prefrontal cortex of mice at early and delayed time points following a single administration of lysergic acid diethylamide (LSD). Differentially expressed genes were then contextualized through pathway-level and cross-dataset comparisons with established models of adaptive and chronic stress. Results LSD induced a coherent, temporally organized transcriptional program extending beyond immediate neuronal activation. Early responses reflected adaptive metabolic and stress-related signaling, whereas later ones involved circadian and neuroendocrine regulation. A persistent transcriptional core spanning both time points indicated sustained regulation of metabolic, circadian, and stress-responsive pathways. Comparative analyses showed that, although LSD-induced transcriptional profile shares features with general stress responses, its preferentially aligns with adaptive, hormetic stress paradigms rather than maladaptive chronic stress. Conclusions These findings indicate that in the prefrontal cortex LSD activates adaptive stress transcriptional programs consistent with hormetic adaptation, providing a molecular framework to interpret the enduring effects of psychedelics beyond synaptic plasticity.
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BibTeX
@misc{savino2026psychedelic,
title = {{Psychedelic Hormesis: LSD Activates Adaptive Stress Transcriptional Programs in the Prefrontal Cortex}},
author = {A. Savino and C. Liaci and G. R. Merlo and L. Prandi and L. Avalle and V. Poli},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.751070},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.751070v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Psychedelic Hormesis: LSD Activates Adaptive Stress Transcriptional Programs in the Prefrontal Cortex
AU - A. Savino
AU - C. Liaci
AU - G. R. Merlo
AU - L. Prandi
AU - L. Avalle
AU - V. Poli
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.751070
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.751070v1
AB - Background Classic psychedelics are serotonergic agents increasingly recognized for their ability to produce rapid and long-lasting therapeutic effects in several neuropsychiatric conditions, yet the molecular mechanisms that translate acute serotonergic perturbation into long-term brain adaptation remain poorly understood. Psychedelic action is commonly attributed to enhanced neuronal plasticity, but emerging evidence suggests broader engagement of stress-responsive and homeostatic processes across neural and non-neural cell types. Methods To define the temporal structure of psychedelic-induced transcriptional responses, we profiled gene expression in the prefrontal cortex of mice at early and delayed time points following a single administration of lysergic acid diethylamide (LSD). Differentially expressed genes were then contextualized through pathway-level and cross-dataset comparisons with established models of adaptive and chronic stress. Results LSD induced a coherent, temporally organized transcriptional program extending beyond immediate neuronal activation. Early responses reflected adaptive metabolic and stress-related signaling, whereas later ones involved circadian and neuroendocrine regulation. A persistent transcriptional core spanning both time points indicated sustained regulation of metabolic, circadian, and stress-responsive pathways. Comparative analyses showed that, although LSD-induced transcriptional profile shares features with general stress responses, its preferentially aligns with adaptive, hormetic stress paradigms rather than maladaptive chronic stress. Conclusions These findings indicate that in the prefrontal cortex LSD activates adaptive stress transcriptional programs consistent with hormetic adaptation, providing a molecular framework to interpret the enduring effects of psychedelics beyond synaptic plasticity.
ER -