A single dose of psilocybin temporarily disrupts and reshapes brain networks, effects that persist for weeks, potentially explaining its unique promise as a psychiatric therapy.
Study: Psilocybin’s acute and persistent brain effects: a precision imaging drug trial. Image Credit: Kateryna Kon / Shutterstock.com
In a recent study published in the journal Scientific Data, researchers compared the acute and persistent effects of psilocybin and methylphenidate on brain connectivity using precision functional magnetic resonance imaging (fMRI) in healthy individuals.
Why psilocybin’s effects on the brain matter
Can a single psychedelic dose change the brain for weeks? Psilocybin, a serotonin receptor 2A agonist, has been widely studied as a potential treatment for mental health conditions such as major depressive disorder, anxiety, alcohol use disorder, and obsessive-compulsive disorder.
The therapeutic effects of psilocybin suggest profound and possibly long-term shifts in brain activity. Importantly, traditional imaging methods are limited in their ability to capture these changes due to low resolution, motion artifacts, and between-subject variability.
Understanding how psilocybin reshapes neural circuits is essential for refining its therapeutic use in psychiatry. Further research is also needed to clarify how brain network changes contribute to sustained psychological and behavioral effects of this treatment approach.
About the study
The current randomized, double-blind, crossover precision imaging drug trial (PIDT) compared the effects of 25 milligrams (mg) of psilocybin and 40 mg of methylphenidate in seven healthy adults between 18 and 45 years of age with prior psychedelic experience. Extensive baseline imaging sessions included structural MRI, resting-state functional MRI (rs-fMRI), task-based fMRI (task-fMRI), and diffusion basis spectrum imaging (DBSI).
Study participants were scanned 60 to 90 minutes after drug administration, during the peak effect window, and longitudinally for up to two weeks. Four individuals returned for a replication protocol with a second psilocybin dose after six months.
Functional imaging was performed using a Siemens Prisma 3 Tesla scanner with high-resolution multi-echo (ME) sequences. Each visit included multiple 15-minute rs-fMRI scans. The audiovisual congruency task (AVC) was used during task-fMRI to assess sensory integration.
All study participants also completed self-reported questionnaires, such as the Mini-International Personality Item Pool (Mini-IPIP) for trait analysis and the 30-item Mystical Experience Questionnaire (MEQ30) for subjective drug effects. Physiological measures, including heart rate and respiratory rate, were recorded using a pulse oximeter and respiratory belt.
Psychedelic treatment sessions were facilitated by trained guides using curated music and eyeshades to support a focused internal experience. Both drugs were administered to all participants in a randomized order.
Safety protocols included close medical monitoring, availability of rescue medications, and follow-up integration meetings. Motion was controlled using frame-wise integrated real-time MRI monitoring (FIRMM), which provided immediate feedback to reduce movement during scans.
Characterizing acute and sustained neural effects of psilocybin
Resting-state functional connectivity revealed that psilocybin consistently disrupted communication within and between large-scale brain networks, particularly between the hippocampus and default mode network (DMN). These disruptions were evident both during the acute exposure and, in some cases, persisted for up to three weeks.
Study participants who underwent a second psilocybin session exhibited similar changes, thus indicating that the effects were reproducible within individuals over time.
Subjective experiences, as captured using the MEQ30, were significantly more intense following psilocybin treatment compared to methylphenidate. Scores for domains such as unity, positive mood, transcendence, and ineffability ranged between 3.4 and 3.8 on a five-point scale after psilocybin treatment, which was comparable to the much lower values observed with methylphenidate.
One study participant initially reported a stronger experience while under methylphenidate. However, this individual’s ratings reversed during the replication, thus suggesting that personal expectations and context can influence subjective outcomes.
Increased heart and respiration rates were observed following treatment with both psychedelics, with psilocybin increasing participants’ heart rate by 21.1 beats per minute (bpm) as compared to 16.7 bpm following methylphenidate treatment. No serious adverse events occurred; however, mild symptoms like nausea, anxiety, and headache were reported but resolved spontaneously.
Network similarity analysis confirmed that brain activity during psilocybin treatment was consistently different from baseline and methylphenidate conditions. However, different psilocybin scans from the same participant remained similar, thus highlighting the stability of its neural effects.
Psilocybin treatment temporarily decreased brain network modularity, which refers to the separation of brain systems into specialized units. This reduction returned to baseline levels after the effects of psilocybin subsided and may help explain the observed increases in psychological flexibility and emotional responsiveness.
As compared to prior psychedelic imaging trials, the current PIDT achieved higher imaging quality and volume. In fact, study participants contributed an average of about 40 usable off-drug 15-minute rs-fMRI scans and nearly five on-drug scans each.
Data quality was improved through real-time motion monitoring with FIRMM, participant training, and the use of ME sequences. The AVC task added further insights into perception and attention during altered states.
Taken together, these methods enabled researchers to analyze within-subject changes with high resolution and consistency, setting a new standard for psychedelic imaging research.
Conclusions
Psilocybin induces consistent, reproducible, and sustained changes in brain network connectivity, especially involving the DMN and hippocampus. These changes align with self-reported mystical experiences and differed significantly from those produced by methylphenidate. The temporary disruption of brain modularity observed during psilocybin exposure may support emotional openness and cognitive flexibility.
The PIDT approach used in this study allowed for high-quality, individualized observations that enhance our understanding of how psychedelics influence brain function. These findings provide the foundation for future research and may inform the clinical use of psilocybin in treating mental health conditions.
Journal reference:
- Subramanian, S., Renau, T. R., Perry, D. et al. (2025). Psilocybin’s acute and persistent brain effects: a precision imaging drug trial. Scientific Data. doi:10.1038/s41597-025-05189-0