Human pluripotent stem cells as a translational toolkit in psychedelic research in vitro

Psychedelics, recognized for their impact on perception, are resurging as promising treatments with rapid onset for mood and substance use disorders. Despite increasing evidence from clinical trials, questions persist about the cellular and molecular mechanisms and their precise correlation with treatment outcomes. Murine neurons and immortalized non-neural cell lines harboring overexpressed constructs have shed light on neuroplastic changes mediated by the serotonin 2A receptor (5-HT2AR) as the primary mechanism. However, limitations exist in capturing human- and disease-specific traits. Here, we discuss current accomplishments and prospects for incorporating human pluripotent stem cells (PSCs) to complement these models. PSCs can differentiate into various brain cell types, mirroring endogenous expression patterns and cell identities to recreate disease phenotypes. Brain organoids derived from PSCs resemble cell diversity and patterning, while region-specific organoids simulate circuit-level phenotypes. PSC-based models hold significant promise to illuminate the cellular and molecular substrates of psychedelic-induced phenotypic recovery in neuropsychiatric disorders.