Short term changes in the proteome of human cerebral organoids induced by 5-methoxy-N,N-dimethyltryptamine

Dimethyltryptamines are hallucinogenic serotonin-like molecules present in traditional Amerindian medicine (e.g. Ayahuasca) recently associated with cognitive gains, antidepressant effects and changes in brain areas related to attention. Historical and technical restrictions impaired understanding how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico systems biology analyses support 5-MeO-DMT’s anti-inflammatory effects and reveal a modulation of proteins associated with long-term potentiation, the formation of dendritic spines, including proteins involved in cellular protrusion formation, microtubule dynamics and cytoskeletal reorganization. These results offer possible mechanistic insights into the neuropsychological changes caused by the ingestion of substances rich in dimethyltryptamines.