June 10, 2021
Drummond E-Wen Mcculloch, Gitte M. Knudsen, Frederick S. Barrett et al.
14 citations
preprint
Research into psychedelic drugs like psilocybin, LSD, and DMT is growing, with clinical trials showing promise for psychiatric conditions. Resting-state fMRI is a common method to study brain mechanisms in these contexts. A review of 42 articles from 17 datasets found high heterogeneity in methods and analyses; two datasets underlie over half the publications, and terms like "entropy" are used inconsistently. The authors suggest that the field needs greater methodological consistency and replicability to identify stable neural markers of psychedelic effects, and encourage development of new models and quantification methods.
bioRxiv (Cold Spring Harbor Laboratory)
December 9, 2020
Jonathan W. Kanen, Qiang Luo, Mojtaba Rostami Kandroodi et al.
14 citations
preprint
Lysergic acid diethylamide (LSD) increases the speed at which the brain updates the value of actions following feedback, particularly after rewards, and makes behavior more exploratory. In a within-subjects experiment, healthy volunteers received intravenous LSD or placebo and performed a probabilistic reversal learning task where they learned which of three stimuli was most often rewarded, with contingencies later reversing. Computational modeling showed LSD enhanced the reward learning rate and also elevated the punishment learning rate, while reducing stimulus stickiness—a measure of choice repetition regardless of outcomes. Conventional measures of immediate feedback sensitivity were unaffected. These findings suggest LSD induces a state of heightened plasticity that may help revise maladaptive associations in clinical settings.
July 7, 2022
Richard J. Zeifman, Meg J. Spriggs, Hannes Kettner et al.
13 citations
preprint
The Relaxed Beliefs Under pSychedelics (REBUS) model suggests that psychedelics reduce the strength of deeply held beliefs. In a preliminary test of this idea, 11 healthy adults received a low (1 mg) and a high (25 mg) dose of psilocybin four weeks apart. Confidence in negative self-beliefs decreased after the high dose but not after the low dose. Greater brain signal entropy and stronger subjective effects during the high dose correlated with larger decreases in negative belief confidence, both during the session and four weeks later. Reduced confidence in negative beliefs was strongly linked to improved well-being at the four-week follow-up. These findings provide initial psychological support for the REBUS model, though replication in larger and clinical samples is needed.
April 12, 2023
Rebecka Bremler, Nancy Katati, Parvinder Shergill et al.
12 citations
preprint
Negative psychological responses to psychedelics, lasting at least 72 hours, are real and can include new psychiatric diagnoses or worsened symptoms, particularly anxiety. In a sample of 32 individuals who reported such experiences, 37.5% received a new psychiatric diagnosis after psychedelic use, and 87% experienced new or worsened anxiety. In-depth interviews with 15 of the most severe cases suggested that contributing factors include unsafe environments, unpleasant acute experiences, prior psychological vulnerabilities, high or unknown drug doses, and young age. The study's small, self-selected sample means these findings cannot estimate how common such harms are.
Research Square
May 20, 2021
Richard E. Daws, Christopher Timmerman, Bruna Giribaldi et al.
11 citations
Across two clinical trials, psilocybin therapy produced robust antidepressant effects that were linked to a decrease in brain network modularity measured by resting-state fMRI. In an open-label study of 16 adults with treatment-resistant depression, Beck Depression Inventory scores dropped sharply at one week and six months, and the reduction in network modularity one day after treatment correlated with clinical improvement at six months. In a double-blind randomized trial of 43 adults with major depressive disorder, the psilocybin arm showed superior antidepressant effects at two and six weeks compared with escitalopram, and improvements correlated with decreased modularity. These convergent findings suggest that psilocybin therapy may work by reducing the brain's network modularity.
Research Square
September 20, 2022
Jakub Vohryzek, Joana Cabral, Louis-David Lord et al.
10 citations
Psilocybin therapy for depression shows promise, but how it works is unclear. By comparing responders (those with >50% reduction in symptoms) to non-responders after 10mg and 25mg doses, whole-brain modeling identified specific brain regions whose dynamics shift from a depressive to a healthy state. These regions overlap with maps of serotonin 5-HT2A and 5-HT1A receptors, which psilocin—the active metabolite of psilocybin—activates. The findings provide causal evidence linking serotonergic transmission and recovery from depression via psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
July 16, 2019
Lionel Barnett, Suresh Muthukumaraswamy, Robin Carhart‐Harris et al.
10 citations
preprint
Psychedelic drugs such as LSD, psilocybin, and low-dose ketamine reduce directed functional connectivity—the flow of information—across the brain, as measured by Granger causality in source-localised MEG recordings. This breakdown in organised information flow supports the idea that the psychedelic state disrupts normal patterns of neural communication. With LSD specifically, directed connectivity decreased while undirected connectivity (measured by correlation and coherence) increased, an opposite movement that highlights the importance of using multiple connectivity measures when analyzing time-resolved neuroimaging data. The non-psychedelic anticonvulsant tiagabine was included for comparison.
bioRxiv (Cold Spring Harbor Laboratory)
July 25, 2018
Louis-David Lord, Paul Expert, Selen Atasoy et al.
10 citations
preprint
Brain activity can be viewed as exploring a landscape of different activity patterns over time, shifting between stable states of functional connectivity that support various mental processes. In a study using fMRI data from healthy participants given intravenous psilocybin (the active compound in magic mushrooms), researchers analyzed how this dynamical landscape changes during the psychedelic state. They found that a connectivity state linked to the fronto-parietal control system became strongly destabilized, while transitions toward a globally synchronized state increased. These changes suggest the psychedelic state biases the brain toward global integration at the cost of local network segregation, offering a mechanistic perspective on the subjective psychedelic experience and potential guidance for pharmacological interventions in neuropsychiatric disorders.
Drug Science Policy and Law
September 1, 2025
David Nutt, David Erritzøe, Anne Katrin Schlag et al.
9 citations
The field of psychedelic research lacks standardized terminology for clinical development, dosing, safety monitoring, and regulatory classification. A comprehensive framework is proposed that classifies psychedelics by pharmacology (serotonergic, glutamatergic, kappaergic, GABAergic, and atypical), introduces dose-dependent categories (microdose, minidose, mididose, macrodose), and standardizes terms like “short-acting” with specific pharmacokinetic parameters. Safety considerations include cardiovascular and psychological effects, with risk mitigation protocols for higher-risk compounds like ibogaine. A three-phase treatment model—preparation, dosing, and integration—is recommended as a minimum standard. The lack of comparative research on psychotherapy modalities is identified as a critical gap.
Psychedelic Medicine
January 20, 2025
Marianna Graziosi, Gabrielle Agin-Liebes, Mary P Cosimano et al.
9 citations
Psilocybin and other serotonergic psychedelics are used in research settings with safety measures including controlled environments, staff presence, screening, and psychoeducation. An analysis of study materials from psilocybin trials over the past two decades found that psychoeducation documents varied but commonly emphasized biological and physical safety, psychological safety and well-being, aspects of setting, and the potential for expectancies. The materials prioritized biological and psychological safety across all sites. The authors also identified elements unrelated to safety that may contribute to participant expectancies and suggest these extrapharmacological factors be studied systematically to maximize safety while minimizing extraneous expectancies.
bioRxiv (Cold Spring Harbor Laboratory)
March 11, 2025
Devon Stoliker, Leonardo Novelli, Moein Khajehnejad et al.
8 citations
preprint
Psychedelics like psilocybin alter consciousness by reorganizing brain connectivity in a context-sensitive way. In the largest psychedelic neuroimaging dataset to date, 62 adults underwent functional MRI and EEG before and after ingesting 19 mg of psilocybin, during rest and naturalistic stimuli. Under psilocybin, brain signals during eyes-closed conditions became similar to those during eyes-open conditions, with increased global functional connectivity in associative regions and decreased connectivity in sensory areas. Machine learning linked subjective effects to structured neural activity patterns. Stronger self-dissolving effects were associated with more distinct neural representations and next-day mindset changes, revealing a state of 'embeddedness' where networks that usually segregate internal and external processing integrate coherently, aligning neural dynamics with context.
bioRxiv (Cold Spring Harbor Laboratory)
May 31, 2024
Jakub Vohryzek, Selen Atasoy, Gustavo Deco et al.
8 citations
preprint
Psychedelic substances like DMT, psilocybin, LSD, and ketamine alter brain function by reshaping the repertoire of connectome harmonics—patterns of neural activity that depend on the brain's structural network of white matter pathways. Under DMT, the entropy of these harmonics increases, indicating a more diverse range of brain states. For the first time, changes in the energy spectrum and entropy of connectome harmonics were shown to track the intensity of subjective experience in real time, suggesting a close link between the brain's harmonic activity and conscious experience.
November 15, 2022
Katie Zhou, D. de Wied, Robin Carhart‐Harris et al.
8 citations
preprint
About a third (32.7%) of people reported symptoms of hallucinogen persisting perception disorder (HPPD) four weeks after a real-world psychedelic experience, but only 2.94% found those symptoms distressing. Delusional ideation was slightly higher among those with more lifetime psychedelic use at baseline, yet it decreased significantly four weeks after the experience, suggesting the baseline correlation may not be causal. Younger age, female gender, a personality trait called absorption, less non-psychedelic substance use in the prior six months, and using psychedelics outside a retreat setting predicted HPPD-like symptoms. The findings are limited by the observational design.
bioRxiv (Cold Spring Harbor Laboratory)
February 15, 2022
Matthew B. Wall, Cynthia Lam, Natalie Ertl et al.
8 citations
preprint
Psychedelic-assisted psychotherapy with psilocybin, which often incorporates music, may enhance the brain's response to emotional stimuli. In nineteen patients with treatment-resistant depression, functional MRI scans taken before and after two psilocybin dosing sessions showed that music listening, compared to resting-state, triggered greater brain activity in the bilateral superior temporal cortex after treatment. The right ventral occipital lobe showed increased activity during the resting-state scan post-treatment. Activity in music-related brain regions correlated with the intensity of subjective effects experienced during dosing. These results suggest psilocybin therapy specifically elevates responsiveness to music, linked to the drug's subjective effects.
bioRxiv (Cold Spring Harbor Laboratory)
January 11, 2019
Tf Varley, Robin Carhart‐Harris, Leor Roseman et al.
8 citations
preprint
Psychedelic drugs like LSD and psilocybin increase the fractal dimension of brain activity, indicating a shift toward a critical state between order and chaos. Using fMRI data, researchers measured the fractal dimension of functional connectivity networks and BOLD time-series. Both drugs significantly increased the fractal dimension of functional connectivity networks; LSD also significantly increased the fractal dimension of BOLD signals, while psilocybin showed a non-significant trend in the same direction. Changes localized to the dorsal-attentional network. These findings support the Entropic Brain Hypothesis, which proposes that psychedelics alter consciousness by moving the brain closer to a critical tipping point.
medRxiv
June 3, 2023
Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi et al.
7 citations
preprint
Psilocybin therapy for major depressive disorder may work through a different brain mechanism than the SSRI escitalopram. In a trial comparing two groups—one receiving two 25 mg psilocybin doses plus daily placebo, the other receiving daily escitalopram plus two inactive 1 mg psilocybin doses—brain responses to emotional faces were measured with fMRI before and after six weeks of treatment. The escitalopram group showed significantly reduced brain activity in response to fear, happy, and neutral faces, including a specific reduction in amygdala response to fear faces. The psilocybin group showed no such reduction and even a slight increase in brain responsiveness, despite large improvements in depressive symptoms. Reduced emotional responsiveness may be a biomarker of SSRIs' antidepressant action not shared by psilocybin therapy.
Frontiers in Psychology
June 6, 2025
William Roseby, Hannes Kettner, Leor Roseman et al.
6 citations
Psychedelics like psilocybin strongly increase the sense that life has meaning, based on three different studies: a clinical trial for depression, a healthy volunteer study, and naturalistic retreats. The 'presence of meaning' rose substantially after a psychedelic experience, while the 'search for meaning' dropped only slightly. These meaning enhancements were moderately linked to improvements in mental health, such as greater wellbeing and reduced depression. Mystical, ego dissolution, and emotional breakthrough experiences were associated with increased meaning, though the strength varied by context. The evidence converges to show a robust, lasting positive effect of psychedelics on meaning in life, with context influencing outcomes.
Neuroscience Applied
December 2, 2024
Kate Godfrey, Brandon Weiss, Joseph Peill et al.
5 citations
A single high dose of psilocybin (25 mg) given to healthy volunteers who had never used psychedelics reduced neuroticism one month later, consistent with prior research. The reduction was linked to how meaningful the experience felt and to the dread of ego dissolution during the drug's acute effects. Personality was measured with the Big Five Inventory and Big Five Aspect Scale; acute effects were tracked with the Altered States of Consciousness questionnaire and Psychological Insight Scale. Electroencephalography measured alpha power and Lempel-Ziv complexity. The findings suggest that acute psychedelic states can catalyze lasting personality changes in a beneficial direction, with implications for therapy and understanding personality.
bioRxiv (Cold Spring Harbor Laboratory)
April 28, 2024
Kenneth Shinozuka, Prejaas Tewarie, Andrea I. Luppi et al.
5 citations
preprint
LSD weakens the brain's directed connectivity hierarchy by increasing the balance between senders and receivers of neural signals. This finding supports the REBUS theory, which proposes that psychedelics flatten the hierarchy of information flow in the brain. Analyzing magnetoencephalography data from 16 healthy participants given 75 micrograms of intravenous LSD, the study found that LSD diminishes the asymmetry of directed connectivity averaged over time. Machine learning classifiers distinguished LSD from placebo more accurately when trained on hierarchy metrics than on traditional functional connectivity measures.
Research Square (Research Square)
February 23, 2024
Ari Brouwer, Joshua K. Brown, Earth Erowid et al.
5 citations
Psychedelic therapy may work partly because its temporal structure mirrors the narrative arc of the Hero's Journey. A qualitative analysis of self-reported onset (comeup) and offset (comedown) phases of psilocybin experiences found that the comeup is more often characterized by negatively valenced feeling states, while the comedown is more often characterized by positively valenced feeling states resembling recovery from illness or adversity. This trajectory suggests that initially distressing altered states can ultimately resolve distress, offering a framework for understanding the therapeutic benefits of psychedelics.
bioRxiv (Cold Spring Harbor Laboratory)
July 13, 2022
Andrea I. Luppi, Justine Y. Hansen, R. Adapa et al.
5 citations
preprint
Psychoactive drugs reshape brain function by engaging multiple neurotransmitter systems simultaneously. By mapping the distribution of 19 neurotransmitter receptors and transporters (via PET) and the connectivity changes caused by 10 drugs (anesthetics, psychedelics, and stimulants), the study shows that drug effects are organized along hierarchical gradients of brain structure and function. Additionally, brain regions susceptible to drug-induced changes are also vulnerable to structural alterations from brain disorders. These findings reveal systematic links between molecular neurochemistry and large-scale functional reorganization.
Brain and Behavior
July 1, 2025
Megan Calnan, Grace Blest‐hopley, Chris Busch et al.
4 citations
Military veterans who attended psilocybin or ayahuasca retreats showed significant improvements in eight measures of mental health and community reintegration, with the largest gains in depression (29.1% reduction on the PHQ-9) and PTSD (26.1% reduction on the PCL-5). Psilocybin retreats produced greater improvements on seven of eight outcomes, while ayahuasca retreats yielded slightly larger PTSD reductions (26.4% vs. 24.8%). Male participants improved more on all outcomes except PTSD, where females showed a larger reduction (32.1% vs. 24.1%). Veterans with worse initial symptoms benefited most. The findings suggest psychedelic retreats could offer a holistic treatment framework addressing psychological well-being, community factors, and civilian reintegration.
Molecular Psychiatry
April 26, 2025
Rebecca Harding, Neomi Singer, Talma Hendler et al.
4 citations
Psilocybin therapy reduces anhedonia more than the SSRI escitalopram in major depressive disorder, yet escitalopram dampens emotional responses to musical surprises while psilocybin therapy preserves them. Escitalopram increases brain activity in memory and emotion regions during musical surprises, whereas psilocybin therapy decreases activity in the ventromedial prefrontal cortex and angular gyrus and increases sensory region activation. These contrasting neural and behavioral effects suggest fundamentally different treatment mechanisms: psilocybin may maintain subjective responses by reducing the salience of prediction errors or strengthening hedonic expectations, while escitalopram may weaken hedonic priors.
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.
December 25, 2021
Aaron D. Cherniak, Joel Gruneau Brulin, Mario Mikulincer et al.
4 citations
preprint
Combining attachment theory with the REBUS model offers a framework for understanding how psychedelic experiences can reshape spiritual and religious beliefs. Attachment theory holds that early caregiving relationships create internal working models that act as mental templates for later interpersonal and divine relationships. Psychedelic therapy may work by loosening rigid, defensive mental patterns—such as insecure attachment to others or God—while corrective relational experiences with a therapist or others amplify this effect. Three research proposals are outlined: individual attachment security predicts how people experience and integrate psychedelic sessions; effective psychedelic therapy should increase attachment security as a measurable outcome; and attachment-related processes—like feeling connected to others or God and reducing attachment-related anxieties—are key mechanisms in psychedelic treatment's clinical benefits.