In a recent study published in the journal Nature, Researchers in the United States of America monitored brain changes in healthy adults before, during and after high-dose psilocybin, a psychedelic drug, and compared it with methylphenidate (MTP), a control drug. They found that psilocybin caused significant disruptions in brain functional connectivity (FC), particularly in the default mode network, which is linked to subjective experiences and lasts for weeks, which may underlie its therapeutic effects.
Individual participant FC change maps of methylphenidate (MTP) and psilocybin (PSIL). The leftmost column shows the functional networks of individuals. The 3 right columns show FC change maps, generated by computing the Euclidean distance from the baseline seed maps for each vertex. For each session the total score on the Mystical Experience Questionnaire (MEQ30: out of a maximum of 150) is given in the upper right corner. *P5 had an episode of emesis 30 minutes after drug ingestion during PSIL2. Study: Psilocybin desynchronizes the human brain
Record
Psychedelic drugs such as psilocybin, through activation of the serotonin 2A (5-HT2A) receptor, cause significant acute and persistent changes in the perception of self, time and space. Clinical trials show that a single high dose of this drug can provide quick, lasting relief for conditions such as depression, addiction and anxiety. In rodents, psilocybin promotes neuronal communication and plasticity in regions rich in 5-HT2A receptors, such as the medial frontal lobe. However, the relevant effects in humans remain unclear. In humans, psilocybin affects brain signaling, metabolism, and network segregation, but the mechanisms are poorly understood, especially in the subcortex. Specifically, the default mode network (DMN) and its connection with the hippocampus play a role in depression and treatment response.
Precision functional mapping using repeated functional magnetic resonance imaging (fMRI) scans helps track individual brain changes, highlighting the stability and variability of brain networks. In the present study, researchers used functional precision mapping in healthy young adults to investigate the effects of psilocybin and methylphenidate administration on the human brain.
About the study
In the present randomized crossover study, healthy adults aged 18–45 years (n = 7) were enrolled to assess brain connectivity changes before, during, and after psilocybin exposure. Participants with at least one prior lifetime exposure to psychedelic drugs (eg, psilocybin, mescaline, ayahuasca, LSD) but no psychedelic use in the past six months were included. Individuals with psychiatric illnesses such as depression, psychosis, or addiction as defined by the DSM-5 were excluded.
Enrolled subjects underwent MRI sessions every other day after ingesting 25 mg of psilocybin or 40 mg of MTP, a control drug that mimics the cardiovascular and dopaminergic effects of psilocybin. Imaging sessions (approximately 18 per participant) were conducted at baseline, during, between, and after drug administration. Structural and functional MRI data were collected, including resting-state and task-based scans. The primary results focused on brain network connectivity changes. In addition, secondary outcomes included hemodynamic responses, acute psychological effects using MEQ30 (short for mystical experience questionnaire) scores, and pulse or respiratory rates. Participants returned 6–12 months after the initial study for a replication protocol.
Results and discussion
Psilocybin administration significantly altered brain FC throughout the cerebral cortex, especially in association networks. The most significant changes were in DMN-connected regions of the thalamus, cerebellum, basal ganglia, and anterior hippocampus. Changes in MTP FC were located in sensorimotor systems and reflected day-to-day variability, likely due to arousal effects. Despite similar increases in heart rate, the FC effects of psilocybin were found to be over three times greater than MTP and comparable to individual differences in the brain.
The study correlated subjective psychedelic experiences with brain function data, finding that FC changes during psilocybin sessions strongly correlated with the intensity of the experience. Head movement was not found to be a significant factor. In addition, psilocybin was found to increase inter-network FC and decrease intra-network FC, similar to nitrous oxide and ketamine. In contrast, MTP reduced in-network FC in sensory, motor, and auditory regions, similar to caffeine.
Psilocybin induced the desynchronization of populations of neurons with 5-HT2A agonistic receptors, leading to increased spatial entropy or normalized global spatial complexity (NGSC). Psilocybin significantly increased NGSC, indicating greater desynchronization of brain signals, which correlated with subjective psychedelic experience and returned to baseline in subsequent sessions. This effect was observed both globally and in specific brain regions, particularly the association cortex. Similar NGSC increases were found with LSD, suggesting a common mechanism in psychedelics. During a task, the impact of psilocybin on brain desynchronization and network disruption was significantly reduced, indicating that task engagement moderates psilocybin-induced changes. Reducing desynchronization during tasks aligns with the psychological principle of “grounding,” used in psychedelic therapy to relieve anxiety.
After psilocybin administration, whole-brain FC largely returned to baseline within 3 weeks, but persistent reductions in FC occurred in the anterior hippocampus, particularly in its connection with the DMN. No significant persistent FC changes were observed after MTP. This observation reflects possible neuroplasticity associated with psilocybin-induced synaptogenesis.
Overall, psilocybin causes a profound desynchronization of the brain, reflecting a radical change in consciousness beyond simple arousal effects. This desynchronization potentially bridges micro-scale neuronal changes with macro-scale network disruptions and can lead to both acute and persistent neuroplastic changes.
conclusion
In conclusion, the study reveals that psilocybin induces significant and persistent changes in brain FC, particularly affecting the DMN and hippocampus, with persistent desynchronization aligned with subjective experiences. These changes suggest that psilocybin induces neuroplasticity, contributing to its therapeutic effects. Further research is needed in clinical settings to confirm the antidepressant potential of psilocybin to improve precision medicine approaches.
