ABSTRACT The effects of psychedelics encompass modulation of subjective experience, neuronal plasticity, brain activity and connectivity, constituting a complex phenomenon. Underlying these effects, molecular changes at the protein level are expected. Proteomic analysis of human brain cells can elicit a comprehensive view of proteins and biological processes regulated within the central nervous system. To explore the molecular pathways influenced by lysergic acid diethylamide (LSD), we utilized mass spectrometry-based proteomics on human brain organoids. This approach allowed for an in-depth analysis of the proteomic alterations induced by LSD, providing insights into its effects at the molecular level within a brain-like environment. Alterations in proteostasis and energy metabolism, which are required for neural plasticity, were observed. Alongside, we identified changes in protein synthesis, folding, autophagy, and proteasomal degradation, as well as in glycolysis, oxidative phosphorylation, cytoskeleton regulation, and neurotransmitter release, providing a comprehensive view of the regulation of cellular process by LSD exposure. Furthermore, the ability of LSD to induce plasticity in human brain cells was corroborated through complementary in vitro experiments focusing on neurite outgrowth. This study sheds light on the specific proteins that LSD influences, thereby enhancing neurite extension and plasticity.

LSD Modulates Proteins Involved in Cell Proteostasis, Energy Metabolism and Neuroplasticity in Human Brain Organoids