Psychedelics Align Brain Activity with Context

Background

The brain is a complex, dynamic system in which different regions continuously interact to process sensory information, initiate movement, and regulate emotions. Brain connectivity plays a central role in our perception of the world and in shaping subjective experience (1). Psychedelics, such as psilocybin, alter this connectivity by influencing brain structure and plasticity, which can lead to phenomena such as hallucinations (2).

Recent neuroimaging and computational modelling research has highlighted how psilocybin reconfigures brain organization, promoting greater integration between associative and sensory networks (2). For example, under psilocybin, brain activity suggests a reduced distinction between internal and external perception (3). This phenomenon is accompanied by increased connectivity in associative regions and decreased connectivity in primary sensory areas. This may explain the intensification of introspective experiences and the altered perception of environmental stimuli.

In this study, the authors aimed to understand how the reorganization of brain connectivity is altered depending on the context and during the consumption of psilocybin. To do so, they used advanced tools, including artificial intelligence techniques, to analyze brain connectivity. Their sample is the largest to date (N = 60), mainly consisting of participants with no prior experience with psychedelics (3). The study highlights how psilocybin restructures brain activity depending on the sensory context in which it is taken.

Key Findings

Psilocybin Enhances Global Functional Connectivity (GFC): Psilocybin significantly increases GFC across the brain as observed by resting-state fMRI. Brain scans showed that after taking psilocybin and in different environments (rest, music, meditation or visual stimuli), connections between brain regions—especially those involved in movement, vision, and attention—increased. Even the baseline connectivity gap between having your eyes open or closed disappeared, meaning the brain became more unified. Functional modularity decreased, indicating reduced segregation and increased interconnectivity between brain networks.

Neural Embeddings Reflect Subjective Effects: Using contrastive learning (CEBRA), the authors tracked brain activity changes under psilocybin. They found that psilocybin reorganizes BOLD activity into distinct low-dimensional trajectories linked to subjective effects. Neural trajectories showed that psilocybin altered brain activity by inducing a state of embeddedness, in which typically distinct networks for internal and external perception became more integrated and contextually responsive – an effect that correlated with the intensity of mystical experiences. Some people showed changes later than others, showing how the effects can vary from person to person.

Psilocybin Induces Mystical, Altered States and Long-Lasting Psychological Effects: The 11D ASC and MEQ30 questionnaires revealed high mystical experience scores alongside sensory changes like audiovisual synesthesia. Correlational analysis confirmed profound mystical and perceptual changes as the strongest subjective effects. Next-day mindset assessments showed that stronger mystical experiences predicted more positive psychological outcomes, including enhanced mood. Anxiety did not correlate with positive effects, suggesting long-term benefits stem from mystical experiences rather than dysphoria.

Psilocybin Enhances Music Perception: Psilocybin heightened emotional engagement with music, as measured by the AES-Music scale and fMRI scans. Music-processing regions showed greater activation, correlating with higher mystical experience scores.

Why we highlight this article

Today, we face a mental health crisis with increasing rates of depression, anxiety, and existential distress. Psilocybin is emerging as a potential treatment. Altering brain connectivity may provide relief where traditional therapies fail. From a historical perspective, humans have used psychoactive substances for thousands of years in religious, spiritual, and healing rituals. Ancient cultures, from the indigenous peoples of the Americas to the Eleusinian Mysteries of ancient Greece, have long recognized the power of altered states of consciousness. These experiences were often seen as gateways to wisdom and personal transformation. This study bridges the gap between ancient traditions and contemporary neuroscience, validating what many cultures intuitively understood: that altered states of consciousness can profoundly impact perception and well-being.

Therefore, this article is compelling because it highlights how modern neuroscience rediscovered and refined ancient wisdom, offering new tools to address persistent challenges in mental health and human experience.

Questions:

Based on the concept of “embeddedness”, your study blurs the boundary between internal and external perception. Have you considered using the EDS questionnaire to characterize this experience better?

Psilocybin was administered orally, unlike other studies using intravenous methods. Was an EEG/fMRI comparison based on the route of administration considered?

The absence of a placebo group or isolated conditions makes it difficult to disentangle psychedelic effects from sensory stimulation. Could a future factorial design help clarify this interaction?

Regarding the “meditation” group, was the initial practice guided and standardized? The experience level (beginner vs. expert) can influence subjective effects and fMRI signals. Would an intra-group or longitudinal analysis have revealed additional nuances?

You employed the MEQ-30: Would standardization using the MCQ enhance inter-study comparability?

The large sample size (N=60) increases statistical power: were subgroup analyses (e.g., gender, age, intensity) explored?

Finally, do your results differ due to the enriched context and AI tools such as CEBRA or TAVRNN in revealing new brain dynamics?

Bibliography:

(1)   Stoliker, D., et al., Neural mechanisms of psychedelic visual imagery. Molecular Psychiatry, 2025. 30(4): p. 1259-1266.

(2)   Yu, Z., et al., Alterations in brain network connectivity and subjective experience induced by psychedelics: a scoping review. Front Psychiatry, 2024. 15: p. 1386321.

(3)    Stoliker, D., et al., Psychedelics Align Brain Activity with Context. bioRxiv, 2025: p. 2025.03.09.642197.

doi: https://doi.org/10.1242/prelights.41345

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