Psilocybin rewires the brain for weeks, study studies

Psilocybin rewires the brain for weeks, study studies

A single dose of psilocybin temporarily disrupts and remodels brain networks, causing effects that have been present for weeks and may explain its unique promise as a psychiatric therapy.

In a study recently published in the journalScientific dataResearchers compared the acute and sustained effects of psilocybin and methylphenidate on brain connectivity using precise functional magnetic resonance imaging (FMRI) in healthy individuals.

Why psilocybin's effects on the brain matter

Can a single psychedelic dose alter the brain for weeks? Psilocybin, a serotonin receptor 2A agonist, has been widely studied as a potential treatment for mental illnesses such as depression, anxiety, alcohol use disorder, and obsessive-compulsive disorder.

The therapeutic effects of psilocybin suggest a deep and potentially long-term shift in brain activity. Importantly, traditional imaging methods are limited in their ability to capture these changes due to low resolution, motion artifacts, and inter-subject variability.

Understanding how psilocybin remodels neural circuits is essential to refining its therapeutic use in psychiatry. Further research is also needed to clarify how brain network changes contribute to ongoing psychological and behavioral effects of this treatment approach.

About the study

The current randomized, double-blind, crossover precision imaging study (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, functional MRI (RS-FMRI), task-based FMRI (Task-FMRI), and diffusion base spectrum imaging (DBSI).

Study participants were scanned longitudinally 60 to 90 minutes after drug administration, during the peak effect window, and for up to two weeks. Four people returned after six months of a replication protocol with a second dose of psilocybin.

Functional imaging was performed using a Siemens Prisma 3 Tesla scanner with high-resolution multi-echo (multi-echo) sequences. Each visit included multiple 15-minute RS-FMRI scans. The audiovisual congruence 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 Pool (Mini-IPIP) for trait analysis and the 30-item questionnaire (MEQ30) for subjective drug effects. Physiological measures, including heart rate and respiratory rate, were recorded using a pulse oximeter and breathing belt.

Psychedelic treatment sessions were facilitated by trained guides with curated music and eyeshadow to support a focused internal experience. Both medications 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 in real time using integrated MRI monitoring (FirmM) with Frame-Wise, which provided immediate feedback to reduce motion during scans.

Characterize acute and sustained neuronal effects of psilocybin

Resting-state functional connectivity revealed that psilocybin consistently disrupted communication within and between large brain networks, particularly between the hippocampus and default mode network (DMN). These disorders were evident both during acute exposure and, in some cases, persisted for up to three weeks.

Study participants who underwent a second psilocybin session showed similar changes, indicating that the effects were reproducible within individuals over time.

Subjective experiences measured with the MEQ30 were significantly more intense following psilocybin treatment compared to methylphenidate. Scores for domains such as unity, positive mood, transcendence, and ineffectiveness ranged from 3.4 to 3.8 on a five-point scale after psilocybin treatment, which were comparable to the much lower scores observed with methylphenidate.

One study participant initially reported a stronger experience with methylphenidate. However, this individual's ratings were reversed during replication, suggesting that personal expectations and context may influence subjective results.

Increased heart and respiratory rates were observed after treatment with both psychedelic drugs, with psilocybin increasing participants' heart rates by 21.1 beats per minute (BPM) compared to 16.7 bpm after methylphenidate treatment. No serious adverse events occurred; However, mild symptoms such as nausea, anxiety and headache were reported but resolved spontaneously.

Network similarity analysis confirmed that brain activity during psilocybin treatment was consistently different between baseline and methylphenidate conditions. However, different psilocybin scans from the same participant remained similar, highlighting the stability of its neural effects.

Psilocybin treatment temporarily reduced 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 wore off and may help explain the observed increases in psychological flexibility and emotional reactivity.

Compared to previous psychedelic imaging attempts, the current PIDT achieved higher imaging quality and volume. In fact, study participants contributed an average of approximately 40 usable off-drug RS-FMRI scans and nearly five on-drug scans.

Data quality was improved through real-time fixed component motion monitoring, participant training, and the use of ME sequences. The AVC task added further insights into perception and attention in altered states.

Taken together, these methods allowed 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 persistent changes in brain network connectivity, particularly in the DMN and hippocampus. These changes were consistent with self-reported mystical experiences and were significantly different from those produced by methylphenidate. The transient disruption of brain modularity observed during psilocybin exposure may support emotional openness and cognitive flexibility.

The PIDT approach used in this study enabled high-quality, individual observations that increase our understanding of how psychedelics affect brain function. These results provide the basis for future research and may influence the clinical use of psilocybin in the treatment of mental illness.

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