A ground‑breaking neuroimaging study argues that psilocybin does not simply scramble brain communication into a random mire of chaos. Instead, the research suggests the psychedelic substance reorganises neural activity to align with a person’s immediate environment, producing context‑aligned patterns that track what a person is doing and experiencing. The work, led by Devon Stoliker at Monash University’s Turner Institute for Brain and Mental Health and Adeel Razi, was published in Nature.
Psilocybin is a naturally occurring compound found in certain mushrooms. Once ingested, it is converted to psilocin, which binds mainly to serotonin 2A receptors on brain cells, altering how major brain networks interact and changing perception, emotion and self‑awareness. Earlier neuroimaging work characterised psychedelic states as chaotic, with a breakdown of coordinated brain rhythms; a 2013 study reported widespread drops in coordinated electrical oscillations after psilocybin administration.
Building on these observations, the researchers framed the study within the entropic brain hypothesis, which posits that psychedelics raise the brain’s entropy and make neural activity more variable and susceptible to context. Subsequent work began to test how sensory inputs and external context, such as music or video, influence brain signals under psychedelics, suggesting environment helps shape neural activity in real time.
In addition, psychedelics have been shown to modify how higher brain regions communicate with sensory systems, potentially underpinning vivid closed‑eye imagery. The new study seeks to answer whether the brain’s activity under psychedelics is truly disordered or instead follows hidden patterns that reflect ongoing real‑world experience.
The project was led by Devon Stoliker, a Turner Impact research fellow, and Adeel Razi, a professor of computational neuroscience and director of the laboratory at Monash University’s Turner Institute. Stoliker told PsyPost that the work sought to understand how mindset and setting interact with brain function.
“Psychedelic experiences vary considerably with mindset and setting, but how these differences are reflected in brain activity remains unclear,” Stoliker explained. “Brain-imaging studies often describe disrupted networks or increased disorder, leaving a gap in explaining experiences that people find coherent and deeply meaningful. We wanted to understand how brain activity becomes reorganized during psychedelic experiences, how that reorganization is modulated by what a person is doing and experiencing, and how it relates to subsequent psychological change.”
To carry out the project, the researchers recruited 65 healthy adults aged 18 to 55 who had little or no meaningful prior experience with psychedelic substances. After exclusions, 63 participants received a standardized oral dose of 19 milligrams of psilocybin, with two taking part exiting before dosing. Each person completed two visits roughly a week apart: a baseline, drug‑free visit and an active dosing visit.
During each visit, participants underwent functional magnetic resonance imaging (fMRI) to measure brain activity and electroencephalography (EEG) to record brain waves. Imaging began about 80 minutes after dosing, with EEG recording commencing around 150 minutes post‑dose, capturing the acute effects of the drug.
Participants experienced four conditions designed to vary sensory engagement: resting with eyes closed, following a guided audio meditation, listening to an emotionally evocative music playlist with eyes closed, and watching a silent video of drifting clouds with eyes open. The sequence moved from low to high sensory input in the scanner, while the EEG session presented the movie first. Half the group had completed an eight‑week mindfulness course prior to scanning, but the authors found no statistically significant differences between meditators and non‑meditators for the primary analyses.
After quality checks to exclude scans with excessive head movement, the final imaging dataset included 60 participants at rest, 59 during meditation, 56 during music listening and 57 during movie watching. A subset of 54 participants with complete data across all four conditions fed the machine‑learning analyses, while the EEG data encompassed 58 participants per condition during psilocybin.
When looking at whole‑brain communication, the researchers found that psilocybin redistributed connectivity depending on whether eyes were open or closed. In eyes‑closed states, connectivity in sensory regions fell by up to 39 percent, while associative thinking areas strengthened by as much as 72 percent. In the eyes‑open movie condition, connectivity increased across both sensory and associative areas, and the gap between eyes‑open and eyes‑closed processing shrank by about 85 percent in the visual system after psilocybin, suggesting eye closure became more similar to eyes‑open processing under the drug.
Modularity—the typical measure of how cleanly the brain partitions into distinct networks—fell under psilocybin across all four conditions. Rest, meditation, music and movie viewing each showed substantial reductions, with effect sizes of minus 0.63, minus 0.60, minus 0.70 and minus 0.91, respectively. Crucially, these static time‑averaged modularity scores did not predict participants’ subjective experiences during the session.
“The striking finding was that reduced separation between the usual brain networks, a common finding known as reduced modularity, coexisted with the organization detectable using machine learning,” Stoliker noted. “Only the machine‑learning methods, which preserve each individual’s brain activity over time, identified an association with subjective effects.”
To move beyond static averages, the team employed machine learning to map moment‑by‑moment brain activity into smooth, lower‑dimensional trajectories. A classifier could identify which condition a participant was engaged in based on their brain trajectories, and accuracy rose with the intensity of the experience. In a closer analysis of six participants with strong subjective effects, accuracy climbed from about 62 percent at baseline to roughly 98 percent under psilocybin.
“Uniquely, this method measured each individual separately, rather than an average across the group of participants,” Stoliker said. “We think the development of similar measures that preserve each individual’s brain activity over time is an important next step, but whether the current methods can help predict or improve treatment outcomes remains to be tested.”
A second machine‑learning tool, called TAVRNN and developed in‑house by co‑author Moein Khajehnejad, tracked how connections between brain regions shift over time. The researchers reported that context‑aligned patterns emerged with greater cohesion in the connectivity within and across networks, and both analyses showed that organization varied with the strength of subjective effects. Importantly, they found a link between the neural patterns and the nature of the experience: higher classification accuracy correlated strongly with mystical‑type experiences (r = 0.64), while correlations with anxiety or impaired thinking were low.
Higher feelings of unity and other positive experiences corresponded to tightly packed neural patterns that aligned with each condition, a phenomenon the authors termed context alignment; they reserve the term embeddedness for the subjective sense of continuity with the broader context that accompanied it.
“Psychedelics may provide a window into how the brain ordinarily maintains the experience of being a separate self within the world,” Stoliker explained. “We use the term embeddedness to describe the felt continuity with a broader physical and psychological context that some participants reported. Embeddedness is the phenomenological correlate of context alignment, thus our findings suggest that this change in experience has a measurable counterpart in how brain activity is organized.”
A perturbation analysis highlighted two major brain networks—the default mode network, linked to internal self‑reflection, and the visual network, responsible for processing external visual input—as key to this context‑aligned organisation. When researchers replaced psilocybin‑altered signals in either network with a drug‑free version, classification accuracy dropped noticeably, with each network contributing roughly 23 percent to the total accuracy gain.
Subjective questionnaires confirmed the profound psychological impact of the session. More than half of participants rated the experience among the most meaningful of their lives, with 24 placing it in their top five, and most rating the overall intensity at nine or ten out of ten. Follow‑up assessments a day later showed improvements in inner peace, patience and a sense of connection to nature and others, with insightfulness during the session most strongly associated with mindset change (r = 0.65).
Commenting on the study, Enzo Tagliazucchi of the University of Buenos Aires noted that the research aligns with context‑dependent effects of psychedelics. “The findings in this study align with the context-dependent effects of psychedelics,” he said. “Today, we are familiar with terms such as ‘set’ and ‘setting,’ coined decades ago to represent the mental and environmental aspects that can influence a psychedelic trip. From this perspective, the authors found a neural signature of this sensitivity to context; that is, a much easier distinction between the ‘settings’ explored in the study during the psychedelic state compared to the baseline.”
Another expert, Alex Kwan of Cornell University, welcomed the study’s scale, noting the larger dataset for psychedelic neuroimaging. “What makes this study exciting is that it begins to connect these different aspects of the psychedelic experience to distinct patterns of brain activity. One strength of this study is its relatively large sample size, drawing on brain imaging data from more than 60 people.”
Researchers caution that the open‑label design, with no active placebo, means expectations could have influenced subjective responses. The fixed order of conditions and the MRI environment itself may also shape experiences. They stress that findings from healthy volunteers may not directly translate to clinical populations receiving psychedelic‑assisted therapy, and that future work should explore whether similar brain reorganization occurs in patients with depression, anxiety or addiction.
The authors emphasise that context matters and advocate further research into how individual characteristics, preparation before dosing, and support during sessions might optimise outcomes. Their aim, they say, is to determine whether tailoring those conditions could make therapeutic benefits more reliable and durable.
The study, titled Psychedelics align brain activity with context, involved Devon Stoliker, Leonardo Novelli, Moein Khajehnejad, Mana Biabani, Matthew D. Greaves, Tamrin Barta, Martin Williams, Sidhant Chopra, Olivier Bazin, Otto Simonsson, Richard Chambers, Frederick S. Barrett, Gustavo Deco, Katrin H. Preller, Robin L. Carhart‑Harris, Anil K. Seth, Suresh Sundram, Gary F. Egan and Adeel Razi.
