bioRxiv (Cold Spring Harbor Laboratory)
February 21, 2023
Daniel Ryskamp Rijsketic, Austen B. Casey, Daniel A. N. Barbosa et al.
10 citations
preprint
Psilocybin, given to mice in either their home cage or an enriched environment, increased neural activity in brain regions including the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while decreasing activity in the hypothalamus, cortical amygdala, striatum, and pallidum. The effects of both the drug and the environment were strong and widespread but largely independent, with very few interactions between context and psilocybin treatment. This suggests that the brain's response to psilocybin is not strongly modulated by environmental setting at the level of immediate early gene expression.
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.
bioRxiv (Cold Spring Harbor Laboratory)
September 24, 2023
Xiaodan Wang, Jonah A. Padawer-Curry, Oliver J. Krentzman et al.
9 citations
preprint
Psychedelics show promise for treating mood disorders, but their effects on brain blood vessels have been overlooked. Psilocybin altered hemodynamic response functions in humans, suggesting changes in neurovascular coupling (NVC). Using wide-field optical imaging in awake mice, the psychedelic DOI (a serotonin-2A receptor agonist) partially altered task-based NVC but caused more pronounced NVC changes during rest, especially in association brain regions. Calcium and hemodynamic signals gave different accounts of resting-state functional connectivity under DOI. Co-administration with a 5-HT2A antagonist reversed many effects. The dissociation between neuronal and hemodynamic signals highlights the need to consider neurovascular effects when interpreting fMRI measures in psychedelic studies.
bioRxiv (Cold Spring Harbor Laboratory)
August 14, 2020
N. Jones, Zarmeen Zahid, Sean M. Grady et al.
9 citations
preprint
Acute release of the stress hormone corticosterone modifies the lasting behavioral effects of psilocybin in male mice. Psilocybin caused an initial anxiety-like response and a rise in plasma corticosterone, followed by a later reduction in anxiety in the novelty suppressed feeding test. Both the acute and delayed effects disappeared when mice were first given chronic oral corticosterone to suppress their own stress-axis. One week later, psilocybin-treated mice spent more time in the center of an open field, but this long-term anxiolytic effect was also blocked by prior chronic corticosterone exposure. Brief isoflurane anesthesia after psilocybin eliminated these interactions. The findings identify glucocorticoid release as a biological modifier of psilocybin's post-acute and long-term behavioral effects in mice.
bioRxiv (Cold Spring Harbor Laboratory)
December 6, 2019
Felipe Augusto Cini da Silva, Isis M. Ornelas, Encarni Marcos et al.
9 citations
preprint
A single dose of d-LSD, a potent serotonergic agonist, increased preference for novel objects in young and adult rats several days after treatment, but did not increase preference in old animals unless followed by a 6-day exposure to enriched environment, which rescued novelty preference to young levels. Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions with alterations of long-range synapses, and that better pattern separation within enriched environment explains its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.
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)
October 7, 2024
George Blackburne, Rosalind McAlpine, Marco S. Fabus et al.
8 citations
preprint
A high dose of the psychedelic drug 5-MeO-DMT radically reorganizes low-frequency brain activity in 29 healthy individuals. Inhaling 12 mg of vaporized synthetic 5-MeO-DMT caused neural activity flows to become incoherent, heterogeneous, viscous, fleeting, and nonrecurring, ceasing typical traveling waves across the cortex. This reorganization led to slower, more stable, low-dimensional broadband activity with increased energy barriers to rapid global shifts. The findings provide the first detailed empirical account of how 5-MeO-DMT alters human brain dynamics, revealing novel cortical slow wave behaviors.
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.
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)
December 7, 2021
Federico Cavanna, Stephanie Müller, Laura Alethia de la Fuente et al.
8 citations
preprint
A double-blind placebo-controlled trial tested the effects of a low (0.5 g) sub-hallucinogenic dose of dried psilocybin mushrooms in 34 individuals planning to microdose. Acute subjective effects were significantly stronger with the active dose than with placebo, possibly due to unblinding. For other measures—including creativity, perception, cognition, and brain activity—the results were null or showed a trend toward cognitive impairment and, in electroencephalography, reduced theta band spectral power. These findings suggest that expectation effects may account for some of the anecdotal benefits people report from microdosing psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
June 11, 2020
Tim Hirschfeld, Timo Torsten Schmidt
8 citations
preprint
Psilocybin, the active component of magic mushrooms, produces subjective experiences that vary with dose. A meta-analysis of data from the Altered States Database examined dose-response relationships for three standardized questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire (MEQ30), and the Hallucinogen Rating Scale (HRS). Ratings on most dimensions and subscales correlated positively with psilocybin dose. Because individual differences and environmental factors also influence subjective experiences, these findings from controlled laboratory experiments may not generalize to recreational use. The analysis provides a reference for expected subjective effects in experimental and clinical psilocybin research.
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.
bioRxiv (Cold Spring Harbor Laboratory)
September 18, 2023
Sepehr Mortaheb, Larry D. Fort, Natasha L. Mason et al.
7 citations
preprint
Psilocybin increases functional connectivity across the brain and induces a recurrent hyperconnected pattern with low BOLD signal amplitude, suggesting heightened cortical arousal. These brain dynamics are linked to feelings of oceanic boundlessness and visionary restructuralization, as measured by the 5-Dimensional Altered States of Consciousness Rating Scale. The brain's tendency to enter this hyperconnected-hyperarousal pattern under psilocybin may enable variant mental associations. For the first time, these findings connect brain dynamics with phenomenological alterations, offering new insights into the neurophenomenology and neurophysiology of the psychedelic state.
bioRxiv (Cold Spring Harbor Laboratory)
December 13, 2023
Kyna‐anne Conn, Lk Milton, Kaixin Huang et al.
6 citations
preprint
In a rat model of anorexia nervosa (activity-based anorexia), psilocybin improved body weight maintenance and facilitated cognitive flexibility, particularly by enhancing adaptation when reward contingencies were reversed. The cognitive benefits depended on signaling through the serotonin 5-HT1A receptor, as blocking that receptor negated the effects. Psilocybin also transiently altered cortical expression of serotonin receptor genes, increasing Htr2a and decreasing Htr1a transcripts, with a further reduction in Htr2a in anorexic-model rats. These findings suggest psilocybin could help break cognitive inflexibility in anorexia nervosa and indicate that therapeutic mechanisms may extend beyond 5-HT2A receptor binding.
bioRxiv (Cold Spring Harbor Laboratory)
May 24, 2022
Manoj K. Doss, Jason Samaha, Frederick S. Barrett et al.
6 citations
preprint
Different classes of psychoactive drugs—sedatives, dissociatives, psychedelics, stimulants, and cannabinoids—each produce unique patterns of effects on the conscious processes underlying episodic memory, depending on whether they act during encoding, consolidation, or retrieval. Reanalyzing confidence data from 10 published datasets (28 drug conditions) with signal detection models, the authors found that all drugs except stimulants impaired recollection when given at encoding; sedatives, dissociatives, and cannabinoids also impaired familiarity at encoding. Psychedelics at encoding enhanced familiarity and did not affect metamemory, while dissociatives and cannabinoids tended to enhance metamemory. Stimulants enhanced metamemory at encoding and retrieval but impaired it at consolidation. These distinct profiles may help explain drug-specific subjective phenomena such as sedative-induced blackouts or psychedelic déjà vu.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2021
Galen Ballentine, Sam Friedman, Danilo Bzdok
6 citations
preprint
Psychedelic drugs alter consciousness by disrupting how the brain's higher association cortex processes incoming sensory signals. Analyzing 6,850 free-form testimonials about 27 drugs and linking them to 40 neurotransmitter receptor subtypes via gene transcription maps, a pattern-learning approach revealed that specific changes in awareness—such as dissolving self-world boundaries or fractal visual distortions—correspond to distinct distributions of receptor densities across the cortex. Ego-dissolution-like experiences were tied to 5-HT2A, D2, KOR, and NMDA receptors in both deep hierarchical (associative higher-order cortex) and shallow hierarchical (visual cortex) brain regions. Emotional effects involved 5-HT2A and Imidazoline1 receptors, while auditory and visual sensations involved SERT, 5-HT1A, and 5-HT2A receptors. Each receptor-experience factor spanned between higher-level association and sensory input poles, potentially relating to a collapse of hierarchical order among large-scale brain networks.
bioRxiv (Cold Spring Harbor Laboratory)
September 10, 2020
Irene Mollinedo-Gajate, Chenchen Song, Marcos Sintes-Rodriguez et al.
6 citations
preprint
In a mouse model of autism spectrum disorder (ASD) created by prenatal exposure to valproic acid, the acute response to the serotonergic psychedelic psilocybin was reduced compared to controls. However, psilocybin treatment reversed the social behavior deficits that are characteristic of the ASD model. These findings suggest that psilocybin may have therapeutic potential for improving social interaction in ASD.
bioRxiv (Cold Spring Harbor Laboratory)
June 29, 2024
Michal Brownstien, Michal Lazar, Alexander Botvinnik et al.
5 citations
preprint
In mice with a genetic deletion that causes excessive self-grooming and anxiety—behaviors resembling aspects of obsessive-compulsive disorder (OCD)—a single dose of psilocybin or psychedelic mushroom extract reduced self-grooming over 21 days, while vehicle-treated mice showed a 118.7% increase. Psilocybin and the extract both decreased self-grooming by about 15–19%, and improvements in secondary measures like twitches and anxiety were also significant. In responsive mice, benefits lasted up to 7 weeks. The extract was superior for alleviating head-body twitches and anxiety. These results support clinical trials of psilocybin for OCD.
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.
bioRxiv (Cold Spring Harbor Laboratory)
December 11, 2022
Benjamin J. B. Bréant, José Prius-Mengual, David M. Bannerman et al.
5 citations
preprint
Psychedelics like 5-MeO-DMT induce a dissociated state of arousal that combines features of waking and sleep. In freely moving adult male mice, the drug produced sleep-like slow waves in the cortex alongside marked pupil dilation, even while animals were awake and moving. REM sleep was strongly suppressed, similar to the effect of conventional antidepressants. This mixed brain state may explain psychedelic effects such as dream-like hallucinations and reopening of the critical period for plasticity.
bioRxiv (Cold Spring Harbor Laboratory)
November 3, 2022
Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al.
5 citations
preprint
The short-acting psychedelic 5-MeO-DMT increases head-twitch response in mice in a dose-dependent manner, with a shorter duration than psilocybin. It strongly suppresses social ultrasonic vocalizations during mating behavior and produces long-lasting increases in dendritic spine density in the medial frontal cortex by elevating the rate of spine formation, but unlike psilocybin, it does not affect spine size. These findings reveal behavioral and neural effects of 5-MeO-DMT and highlight both similarities and differences with psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
July 23, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
5 citations
preprint
Psilocybin and the serotonin precursor 5-HTP both cause a characteristic head twitch response in mice, a behavior linked to the human psychedelic experience. The head twitch response depends primarily on the 5-HT2A receptor, as blocking this receptor with volanserin reduced the response. Activating the 5-HT1A receptor also reduced head twitching. In contrast, blocking the 5-HT2C receptor had a bimodal effect, enhancing the response at lower doses but reducing it at higher doses. Blocking the trace amine associated receptor 1 (TAAR1) reduced head twitching caused by 5-HTP but not by psilocybin, indicating a differential role for this receptor. These findings identify multiple receptors that could be targeted to modulate the effects of psychedelic compounds in therapeutic settings.
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.
bioRxiv (Cold Spring Harbor Laboratory)
June 29, 2020
Joaqúın González, Matías Cavelli, Santiago Castro‐zaballa et al.
5 citations
preprint
Ibogaine, a psychedelic alkaloid with anti-addictive properties, produces a waking state that shares brain-wave traits with REM sleep. In rats, ibogaine increased gamma oscillation power in the brain but made those oscillations less coherent and less complex than normal waking levels. This pattern mirrors REM sleep features within the gamma frequency band, providing biological evidence for the long-standing hypothesis that ibogaine induces a dream-like state while awake—a phenomenon called oneirogenesis. The findings offer an empirical basis for understanding how ibogaine's unique subjective effects may contribute to its anti-addictive potential.