Lysergic acid diethylamide reverses aging- and neurodegeneration-associated brain transcriptional programs
Aurora Savino, Carla Liaci, Ilaria Bertani, Simona Rando, Mattia Camera, Giorgio R. Merlo, Lidia Avalle, Valeria Poli, Nereo Kalebic, Francesco Iorio
bioRxiv May 29, 2026 preprint DOI: 10.64898/2026.05.26.727809 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Cross-species transcriptomic analyses with experimental validation |
|---|---|
| Population | Rodents and primary cortical neurons |
| Intervention | LSD |
| Dose | chronic LSD treatment (dose not specified in abstract) |
| Topics | LSD |
| Key findings | LSD induces gene expression patterns that are strongly anti-correlated with aging and neurodegeneration programs and counteracts amyloid-β-induced alterations in neurons. |
Abstract
Summary Psychedelic compounds such as lysergic acid diethylamide (LSD) are increasingly studied for their neuroplastic effects and potential relevance to brain aging and neurodegeneration. However, the molecular mechanisms linking psychedelic-induced plasticity to age-associated cognitive decline remain unclear. Brain aging and dementia are characterized by coordinated transcriptional programs that underlie synaptic dysfunction and altered neuron-glia interactions. If psychedelic-induced plasticity engages opposing molecular programs, it could counteract these conserved trajectories. In computational drug discovery, this concept has been formalized as the principle of transcriptional signature reversal, whereby compounds inducing gene expression states opposite to disease-associated programs may exert a therapeutic effect by counteracting disease-associated phenotypes. Here, we combine cross-species transcriptomic analyses with experimental validation to test whether LSD opposes conserved signatures of brain aging and dementia. By comparing transcriptional profiles induced by chronic LSD treatment in rodents with age- and dementia-associated gene expression changes in the human prefrontal cortex, we show that LSD induces gene expression patterns strongly anti-correlated with aging and neurodegeneration programs. This reversal is specific compared to other pharmacological perturbations and is reproducible across datasets and species. Moreover, LSD counteracts amyloid-β-induced structural and molecular alterations in primary cortical neurons, linking transcriptomic opposition to functional rescue under neurodegenerative stress. Together, our findings suggest that LSD modulates molecular and cellular pathways associated with brain aging and neurodegeneration, linking systems-level gene expression changes to structural and functional resilience in neurodegeneration-relevant contexts.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cites 22
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- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics Frontiers in Psychiatry September 10, 2021
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine Journal of Neuroscience November 30, 2020
and 17 more in the library