Systematic review · 2025
Systematic review of how classic psychedelics act in the brain, from receptors to networks
- Original title
- Psychedelic experiences elicited by serotonergic psychedelics: Molecular mechanisms and functional connectivity changes in the brain.
- Authors
- Vollebregt R, Storm AEM, Lucassen PJ, et al.
- Journal
- Neuroscience and biobehavioral reviews, 2025
- Molecules
- Psilocybin, LSD, DMT
- Conditions
- Treatment-resistant depression, Healthy volunteers
- Evidence grade
- Low
- Source
- Read the original paper
The question
How do classic serotonergic psychedelics such as LSD, DMT and psilocybin change brain chemistry and brain-wide communication, and how might that relate to the experiences they produce?
What they did
The authors carried out a systematic review of experimental and (pre)clinical studies published from 1990 onward. They looked at short-term effects on receptor activity, signalling inside cells, and functional brain connectivity (how different brain regions communicate). Both laboratory and human brain-imaging work was included.
What they found
Most classic psychedelics act mainly by switching on the serotonin 5-HT2A receptor. This sets off signalling inside cells that affects neuroplasticity (the brain’s ability to reorganize), glutamate release and the excitability of the cortex. At the network level, the drugs disrupt connectivity within the default mode network, a set of regions active during self-focused thought, while increasing integration across the brain as a whole. These changes were linked with subjective effects such as ‘ego dissolution’ and altered perception, which the authors suggest may contribute to therapeutic effects. No single model accounted for all the observed effects.
The fine print
This is a review of mechanisms, not a test of whether psychedelics help patients, and it does not report how many studies or people were included. It mixes preclinical and human research, so findings from cells or animals may not transfer to people. The link between brain-network changes and clinical improvement remains an association, not a demonstrated cause. This summary is based on the abstract only.
What it means
Researchers can describe several consistent biological effects of classic psychedelics, from a specific serotonin receptor to changes in brain-wide communication, but they still cannot fully explain why these drugs produce the experiences or the clinical changes reported in trials.
Evidence grade: Low. A systematic review that summarizes mechanisms across laboratory, animal and human studies without pooling results or reporting participant numbers, so it cannot show how well psychedelics work.
This summary is based on the study’s published abstract.