Proceedings of the National Academy of Sciences of the United States of America
March 28, 2023
Christopher Timmermann, Leor Roseman, Sharad Haridas et al.
217 citations
Intravenous DMT, a potent psychedelic and serotonin 2A receptor agonist, profoundly alters brain function in healthy volunteers. In a placebo-controlled study with 20 participants, multimodal neuroimaging (EEG-fMRI) showed that DMT robustly increases global functional connectivity, disrupts and desegregates brain networks, and compresses the principal cortical gradient. These changes overlapped with brain regions rich in serotonin 2A receptors and associated with human-specific psychological functions. EEG and fMRI measures correlated, linking neurophysiological changes to network-level effects. The findings indicate DMT predominantly acts on the brain's transmodal association cortex, the evolutionarily recent area tied to advanced cognition and high 5-HT2A receptor density.
Neuroimage
March 8, 2020
Manesh Girn, Caitlin Mills, Leor Roseman et al.
139 citations
Creativity involves alternating between generating ideas and evaluating them. A refined Dynamic Framework of Thought describes creative generation not as one mental state but as a product of many varying states. The psychedelic state is proposed as a mental state with high potential for facilitating creative generation, making psychedelic substances useful experimental tools for studying the neuroscience of creativity.
Neuroimage
April 25, 2022
Manesh Girn, Leor Roseman, Boris Bernhardt et al.
112 citations
LSD and psilocybin flatten the brain's normal hierarchical organization, reducing the functional separation between sensory and higher-order networks and increasing cross-talk between them. Analyzing two resting-state fMRI datasets, the principal gradient of cortical connectivity—which normally runs from basic sensory areas to complex association regions—was significantly compressed under both drugs compared to placebo. This flattening was driven by decreased specialization at both ends of the hierarchy: default mode and frontoparietal networks at the top, and somatomotor networks at the bottom. The findings support a proposed mechanistic model of the psychedelic state and demonstrate that macroscale connectivity gradients can be acutely altered by a pharmacological intervention.
Neuropharmacology
December 27, 2022
Robin Carhart‐Harris, Shamil Chandaria, David Erritzøe et al.
106 citations
A theoretical model proposes that psychopathology arises from a defensive process called canalization, which narrows an individual's range of thoughts, feelings, and behaviors by increasing precision or reducing variance in neural responses. This contrasts with an early form of plasticity, TEMP (Temperature or Entropy Mediated Plasticity), which increases variance and learning rate. Canalization entrenches pathology as the agent develops expertise in their disorder, while TEMP, combined with gentle psychological support, may counter this entrenchment. The model distinguishes adaptive from maladaptive canalization and suggests concrete experiments to test its hypotheses.
Trends Cogn Sci
February 3, 2023
Manesh Girn, Fernando E. Rosas, Richard E. Daws et al.
76 citations
Psychedelics reduce the functional segregation of large-scale brain networks, but findings have been largely inconsistent. A complexity-science perspective that emphasizes the distributed, interactional, and dynamic nature of brain function may explain these inconsistencies. The authors propose that psychedelics induce a mode of brain function that is more dynamically flexible, diverse, integrated, and tuned for information sharing, consistent with greater criticality. This 'meta' perspective can unify past findings and guide intuitions toward compelling mechanistic models.
Frontiers in Psychiatry
April 5, 2023
Sharday Mosurinjohn, Leor Roseman, Manesh Girn
54 citations
Research on psychedelics often measures 'mystical' effects using psychometric tools, and clinical studies link such experiences to better mental health. However, this research rarely engages with scholarship from religious studies or anthropology, which reveal that the concept of 'mysticism' in psychedelic science carries unacknowledged biases—particularly a perennialist and Christian bias that fails to historicize the term. The authors trace the concept's history in psychedelic research, propose more culturally sensitive operationalizations, and advocate for complementary 'non-mystical' approaches to study these phenomena, aiming to build interdisciplinary bridges for stronger theoretical and empirical work.
bioRxiv (Cold Spring Harbor Laboratory)
May 3, 2020
Manesh Girn, Leor Roseman, Boris C. Bernhardt et al.
27 citations
preprint
LSD and psilocybin flatten the brain's hierarchical organization, reducing the functional separation between sensory and higher-order cognitive networks. Using a non-linear dimensionality reduction technique on resting-state fMRI data, the authors found that both drugs compressed the principal gradient of cortical connectivity, which normally spans from unimodal (sensory) to transmodal (association) cortex. This flattening was driven by decreased differentiation at both ends of the hierarchy—default and frontoparietal networks at the upper end and somatomotor networks at the lower end—and was accompanied by increased crosstalk between unimodal and transmodal regions. Changes in the principal gradient under LSD tracked self-reported ego-dissolution. The findings support a mechanistic model of the psychedelic state and demonstrate that macroscale connectivity gradients are sensitive to serotonergic modulation.
Brain
January 1, 2024
Andrea I Luppi, Manesh Girn, Fernando E Rosas et al.
25 citations
Serotonin 2A receptor (5-HT2AR) signaling drives both the evolutionary expansion and ongoing modulation of the human cerebral cortex's most complex cognitive centers. The cortex is organized along a gradient from simple sensory processing to high-level integration, with the transmodal cortex at the apex—a region disproportionately enlarged in humans and rich in 5-HT2AR expression. During early brain development, 5-HT2AR signaling on neural progenitor cells stimulates their proliferation, contributing to cortical expansion. In the adult brain, 5-HT2AR agonism promotes neuroplasticity, learning, and cognitive flexibility with therapeutic potential. The receptor thus plays a dual role in enabling cortical growth and sophisticated functioning.
Nature Medicine
April 1, 2026
Manesh Girn, Manoj K. Doss, Leor Roseman et al.
8 citations
Psychedelic drugs are being studied again for their therapeutic potential, but how they change brain function is not well understood. By combining 11 brain-scanning datasets from five different psychedelics (psilocybin, LSD, mescaline, DMT, and ayahuasca) across three continents, researchers found a common pattern: increased communication between brain networks that handle high-level thinking (default, frontoparietal, and limbic) and those that handle sensory input (visual and somatomotor). Key deep-brain regions (thalamus, caudate, putamen) and the cerebellum also changed how they connect with sensorimotor networks. Contrary to some earlier studies, reductions in within-network connectivity were weak to moderate and varied by drug. These findings help resolve previous inconsistencies and provide a comprehensive map of how psychedelics alter large-scale brain organization.
J Psychopharmacol
April 23, 2024
Evan Cole Lewis, Alexandria Jaeger, Manesh Girn et al.
6 citations
This review examines how psychedelic-assisted therapy might help treat functional seizures, a type of functional neurological disorder. The authors explore potential underlying mechanisms, focusing on how psychedelics could affect brain networks involved in emotion, self-awareness, and body perception that are disrupted in functional seizures. They suggest that psychedelics may help by promoting neuroplasticity and altering connectivity in key brain regions, potentially allowing patients to process traumatic memories and reduce seizure frequency. The review indicates that while preliminary evidence is promising, more research is needed to establish safety and efficacy.
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2024
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
4 citations
preprint
Psilocybin induces fast and sustained improvements in mental well-being, yet its long-term mechanisms are not fully understood. Four weeks after a full dose, fronto-striatal-thalamic (FST) circuitry—involved in goal-directed behavior and motivation—shows increased dynamic activity and flexibility in healthy volunteers. Computational modeling indicates that reduced structural constraints on functional dynamics cause this increased flexibility. Long-term changes include increased bottom-up and reduced top-down information flow, mediated by serotonergic (5-HT2A) and dopaminergic (D2) receptor systems. This functional re-organization of FST circuits may represent a common mechanism underlying clinical improvements across neuropsychiatric disorders such as substance abuse, major depression, and anorexia.
Hum Brain Mapp
July 1, 2026
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
A computational model predicts that a single dose of psilocybin can produce lasting changes in the dynamic activity and effective connectivity of fronto-striatal-thalamic brain circuits. The modeling suggests that psilocybin may strengthen connectivity between the prefrontal cortex and striatum while altering thalamic gating, effects that persist beyond the acute drug experience. These changes could underlie the sustained therapeutic benefits observed in clinical settings, such as reduced depressive symptoms and increased psychological flexibility. The findings provide a mechanistic framework for understanding how psilocybin induces long-term neural plasticity and highlight potential circuit targets for treating psychiatric disorders.
NeuroImage
June 10, 2026
Fran Hancock, Rachael Kee, Fernando Rosas et al.
Flow—a state of effortless immersion often experienced during video games—shows a moderate inverse relationship with global brain entropy, meaning the brain is less disordered during flow than during boredom or frustration. Synchronization and metastability do not explain flow. Boredom and frustration each display distinct patterns of brain dynamics. These findings integrate earlier observations about prefrontal activity and network synchrony into a single dynamical-systems framework, identifying complexity-based markers that could help map the neural basis of media-related benefits.
Philosophical Psychology
April 10, 2026
Eric Rundquist, Diego Nicolás Monasterio López, Juan Jonathan Oyarzo Alvarado et al.
A cognitive-linguistic analysis of interviews with a healthy volunteer after moderate-to-high psilocybin doses reveals that the participant consistently used metaphors framing abstract introspective events in terms of concrete, visible, and interpersonal events, instantiating a cognitive frame called the Observer's Model. These metaphors imply cognitive defusion and heightened metacognitive awareness during the sessions. Literal descriptions of hallucinatory visual experiences correlated semantically with metaphorical expressions, suggesting metaphorical thinking plays a role in motivating those experiences. The findings are linked to neuroscientific research on psychedelics and have psychological and therapeutic implications.
bioRxiv Preprint Server
July 11, 2025
Fran Hancock, Rachael Kee, Fernando Rosas et al.
preprint
Flow—the experience of effortless immersion—shows an inverse relationship with global brain entropy during a video game task, meaning less disorderly brain activity corresponds with more flow. Boredom and frustration each display distinct patterns of brain dynamics. These findings bring together earlier observations about prefrontal activity and network synchrony into a single framework and suggest complexity-based measures could help map the neural basis of media-related benefits.
October 14, 2024
Terence J. Lyons, Merle Spriggs, Leevi Kerkelä et al.
preprint
A single high dose of psilocybin (25 mg) produced lasting functional and anatomical brain changes in healthy, psychedelic-naive adults, detected from one hour to one month later. Diffusion imaging showed decreased axial diffusivity in prefrontal-subcortical tracts, correlating with reduced brain network modularity, which in turn correlated with improved well-being. Increased cortical signal entropy shortly after dosing predicted better psychological well-being at one month, with next-day psychological insight mediating this relationship. No such effects occurred with a 1 mg placebo dose. Cognitive flexibility, psychological insight, and well-being also increased at one month.
arXiv Preprint Archive
May 23, 2016
Kieran C. R. Fox, Manesh Girn, Cameron C. Parro et al.
Psychedelic substances produce radical psychological effects and have been surrounded by political and legal controversy since their widespread adoption about 50 years ago. This review examines functional neuroimaging studies that investigate the neural correlates of the psychedelic experience, highlighting connections with the psychological and neural bases of creativity, daydreaming, and dreaming. The authors synthesize findings from these imaging investigations to show how brain activity during psychedelic states overlaps with patterns seen during imaginative and creative thought processes.
arXiv Preprint Archive
March 21, 2016
Kieran C. R. Fox, Matthew L. Dixon, Savannah Nijeboer et al.
Meditation comprises diverse mental practices with distinct strategies. A meta-analysis of 78 neuroimaging studies (527 participants) found reliably different brain activation patterns for four common meditation styles—focused attention, mantra recitation, open monitoring, and compassion/loving-kindness—and suggestive differences for three others. Some brain regions (insula, pre/supplementary motor cortices, dorsal anterior cingulate cortex, frontopolar cortex) were recruited across multiple techniques, but convergence was the exception. Effect sizes were medium for both activations (d = .59) and deactivations (d = -.74), indicating potential practical significance. The findings support the neurophysiological dissociability of meditation practices while highlighting methodological concerns and future research directions.