In vitro Transcriptomic Biomarker Discovery for Psychedelic Tryptamines and Its Applications for High-throughput Drug Screening Platform Development
Year: 2025
Type: dissertation
Abstract: Serotonin (5-HT) signaling, particularly through G protein-coupled receptors (GPCRs) like 5-HT2AR, underpins the effects of classic psychedelics (e.g., LSD, DMT, psilocin). The accumulating and rapidly growing body of clinical evidence has demonstrated the therapeutic potential for neuropsychiatric disorders such as Major Depressive Disorder (MDD), Treatment-Resistant Depression (TRD) and Post-Traumatic Stress Disorder (PTSD). Yet, the precise molecular mechanism and robust biomarker remain elusive. This thesis investigated psychedelic tryptamine-induced 5-HT2AR signaling cascades, transcriptomic responses, and novel biomarker candidates through molecular techniques, RNA sequencing, and bioinformatic analysis. In transgenic 5-HT2AR-expressing HEK293 cells treated with 5 psychedelic tryptamines (LSD, DMT, psilocin, bufotenin, and 5-MeO-DMT), RNA-seq confirmed significant upregulations of IEGs (e.g., c-FOS, EGR1/2) and revealed new biomarker genes that were previously not associated with psychedelic activities. Intriguingly, we identify unexpected serotonin-like agonism induced by melatonin, which is traditionally characterized as a 5-HT2AR antagonist. Lastly, we leveraged novel psychedelic-like biomarkers in this work and CRISPR-based genome editing to develop a high-throughput screening platform for next-generation psychedelic-like therapeutics. As a proof-of-concept, the leading biomarker candidate, Gene X was endogenously tagged with GFP, and GFP fluorescence was induced following psychedelic treatment, providing initial validation for this approach. Collectively, this work provides fundamental molecular insights into psychedelic actions, identifies novel biomarkers, and establishes a scalable platform for accelerating the discovery of safer, mechanism-informed neuropsychiatric therapeutics.
Author: Xiao, Wantao
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: green
OpenAlex ID: W7208800503