Psychedelic experiences elicited by serotonergic psychedelics: Molecular mechanisms and functional connectivity changes in the brain
Neuroscience & Biobehavioral Reviews December 16, 2025 Rivka Vollebregt, A. J. Storm, Paul J. Lucassen et al. 3 citations
Classical psychedelics such as LSD, DMT, and psilocybin primarily act as serotonin 5-HT2A receptor agonists, initiating intracellular signaling that modulates neuroplasticity, glutamate release, and cortical excitability. They disrupt functional network connectivity, especially within the default mode network, while enhancing global integration across brain regions. These effects are linked to subjective experiences like ego dissolution and altered perception, which may contribute to therapeutic benefits in conditions such as treatment-resistant depression. The review synthesizes molecular and network-level findings from 1990 onward, noting that overlapping theories are beginning to bridge receptor activity with large-scale brain connectivity changes, though no single model explains all effects.