For more than four decades, restrictions on research with psychoactive drugs have slowed progress in understanding how such substances impact brain metabolism. Besides the historical restrictions, the impacts of drug exposure in human neural cells have been compromised by limitations of adequate models. I will present the effects of the β-carboline alkaloid harmine, component of the psychoactive plant tea known as “Ayahuasca”, and 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), found in the Sonora Desert toad, in cultures of human neural cells and brain organoids derived from induced pluripotent stem cells. Harmine increased the pool of proliferating cells, with DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase) as a target, which suggests a biological activity possibly associated with the antidepressant effects of Ayahuasca in patients with depressive disorder. Analyzing global protein expression of brain organoids exposed to 5-MeO-DMT, we found proteins broadly distributed on functional activities such as cellular protrusion formation, microtubule dynamics and cytoskeletal reorganization, which are correlated to novel dendritic spine formation. These models offer an exciting new range of opportunities to investigate the impact of psychedelics on human neural cells.