Work

Lysergic Acid Diethylamide Induces Transcriptional Changes Opposing Signatures of Brain Ageing and Neurodegeneration

Year: 2026

Type: article

Abstract: Psychedelic compounds such as lysergic acid diethylamide (LSD) are increasingly studied for their neuroplastic effects and potential relevance to brain ageing and neurodegenerative conditions, including dementia. These processes are characterised by transcriptional changes involving progressive synaptic dysfunction and altered neuron-glia interactions. In computational drug discovery, the transcriptional signature reversion principle proposes that compounds inducing gene expression states opposite to disease-associated programmes may have therapeutic potential by counteracting disease-associated phenotypes. We therefore asked whether LSD-induced transcriptional changes oppose gene expression programmes associated with brain ageing and dementia, thereby providing a data-driven rationale for its potential relevance to age-associated cognitive decline and a starting point for investigating the underlying molecular mechanisms. Combining cross-species transcriptomic analyses with experimental validation, we show that transcriptional profiles induced by chronic LSD treatment in rats are strongly anti-correlated with ageing-associated gene expression changes in the human prefrontal cortex and, to a lesser extent, with dementia-associated programmes. This relationship is reproducible across datasets and species and is significantly stronger compared to a broad panel of pharmacological perturbations. Independent acute LSD treatment in mice recapitulated the opposition to ageing-associated transcriptional signatures across multiple doses. Moreover, short-term LSD treatment attenuated amyloid-β-induced structural, molecular and transcriptional alterations in primary cortical cultures. Together, these findings provide a transcriptionally grounded rationale for investigating LSD and related compounds in brain ageing and neurodegeneration, while identifying molecular and cellular programmes that can guide future mechanistic and therapeutic studies.

Source: Aging Cell

DOI: 10.1111/acel.70793