Psychedelic experiences elicited by serotonergic psychedelics: Molecular mechanisms and functional connectivity changes in the brain

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.

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Abstract

Classical psychedelics, like lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and psilocybin, can alter perception, emotion, and cognition, and have shown promise as 're-purposed' treatments for some psychiatric disorders. Recent trials have, e.g., demonstrated rapid and sustained symptom relief in treatment-resistant depression. While promising as a treatment, the neurobiological mechanisms underlying both the subjective and clinical effects remain incompletely understood. Also, their broader influence on (intra) cellular processes, neural circuits, and brain-wide connectivity is less well documented. Here, we review the molecular and network-level alterations induced by classical serotonergic psychedelics through a systematic review of experimental and (pre)clinical studies from 1990 onward. We focus on the short-term impact on receptor activity, intracellular signaling, and functional brain connectivity underlying the psychedelic experience. Most psychedelics primarily act as serotonin 5‑HT₂A receptor agonists, initiating intracellular signaling pathways that modulate neuroplasticity, glutamate release, and cortical excitability. Psychedelics disrupt functional network connectivity, particularly within the default mode network, while enhancing global integration across brain regions. These effects are associated with subjective experiences of 'ego dissolution' and altered perception, which may contribute to their therapeutic effects. This review synthesizes findings at the molecular and systems level and their interaction during the psychedelic state. While no single model explains all effects, several overlapping theories begin to bridge receptor-level activity with large-scale brain connectivity changes. Improving our understanding of their neurobiological basis may help clarify how psychedelics act and allows for more tailored opportunities to enhance their therapeutic effects and clinical application in a stratified manner.