Psychedelic experiences elicited by serotonergic psychedelics: Molecular mechanisms and functional connectivity changes in the brain
Rivka Vollebregt, A. J. Storm, Paul J. Lucassen, Metten Somers
Neuroscience & Biobehavioral Reviews December 16, 2025 DOI: 10.1016/j.neubiorev.2025.106529 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Topics | Default mode network LSD Psilocybin Serotonin |
| Keywords | Functional connectivity Hallucinogen Glutamate receptor Nerve net |
| Citations | 3 |
| Key findings | Classical psychedelics primarily act as serotonin 5-HT2A receptor agonists, disrupt default mode network connectivity, and enhance global brain integration, which may underlie their therapeutic effects. |
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.
Comparable studies
Other systematic reviews and meta-analyses on serotonin, most cited first.
Citations in the library
Cited by 4
- Advancing Next-Generation Psychedelic Therapeutics through Selective 5-HT2A Activation, Precision Aerosol Delivery, and Optimized 5-MeO-DMT Treatment Paradigms ACS Medicinal Chemistry Letters July 10, 2026
- Single Ayahuasca administration attenuates alcohol relapse and associated behavioral, neurochemical, and oxidative alterations in rats Progress in Neuro-Psychopharmacology and Biological Psychiatry July 1, 2026
- Single ayahuasca administration mitigates long-term behavioral and neurochemical effects of early-life stress in rats. Journal of Neural Transmission September 19, 2026
- High ventilation breathwork as a non-pharmacological model for inducing psychedelic-like states: expert evaluations of therapeutic potential and risk npj Mental Health Research September 17, 2026
Cites 103
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and 98 more in the library