bioRxiv (Cold Spring Harbor Laboratory)
November 2, 2020
Pedro A. M. Mediano, Fernando E. Rosas, Christopher Timmermann et al.
39 citations
preprint
Psychedelics reliably increase brain entropy (neural signal diversity), an effect linked to psychological changes and opposite to the decrease seen during loss of consciousness. This study investigated how context—specifically stimulus manipulation—modulates that entropy increase. Participants under LSD or placebo experienced eyes-closed versus eyes-open conditions, or no stimulus, music, or video. Brain entropy rose with LSD across all conditions but was largest with eyes closed. Entropy changes consistently matched subjective ratings of the psychedelic experience, except during video viewing, suggesting competition between external stimuli and internal LSD-induced imagery. The findings provide quantitative evidence that context shapes neural dynamics during psychedelic experiences, supporting the practice of eyes-closed psychedelic psychotherapy, and challenge simplistic views of brain entropy as a direct measure of conscious level.
bioRxiv (Cold Spring Harbor Laboratory)
January 4, 2019
David J. Schwartzman, Michael Schartner, Benjamin B. Ador et al.
31 citations
preprint
Stroboscopic stimulation—flashing light—can induce altered states of consciousness without drugs, increasing the intensity and range of subjective experiences, including simple and complex visual hallucinations. These experiences were accompanied by rises in EEG signal diversity, measured by Lempel-Ziv complexity, that exceeded levels seen during wakeful rest. The results align with previous findings from psychedelic studies and support the idea that neural signal diversity reflects the richness of subjective experience across different states of consciousness.
bioRxiv (Cold Spring Harbor Laboratory)
September 23, 2021
Pedro A. M. Mediano, Aleksi Ikkala, Rogier Kievit et al.
30 citations
preprint
Neural complexity measures, which can distinguish conscious from unconscious states, also detect meaningful fluctuations in conscious level during normal wakefulness. Using MEG and fMRI data from healthy adults, complexity decreased as participants became drowsy, validating the approach. Complexity changed within and between tasks, and higher complexity was associated with better performance and faster reaction times on an executive task. This offers a new way to explore the cognitive and neural basis of consciousness.
bioRxiv (Cold Spring Harbor Laboratory)
May 17, 2021
S. Parker Singleton, Andrea I. Luppi, Robin L. Carhart-Harris et al.
30 citations
preprint
LSD and psilocybin reduce the amount of energy the brain needs to transition between different activity states, as measured by functional MRI. This flattening of the brain's control energy landscape allows for more frequent state transitions and more diverse (entropic) brain activity. The effects are linked to the spatial distribution of serotonin 2a receptors, the main target of these psychedelics. The findings suggest that these compounds make brain state transitions more facile and temporally diverse, offering a mechanistic explanation for the altered subjective experience induced by psychedelics.
bioRxiv (Cold Spring Harbor Laboratory)
February 5, 2021
M. Madsen, Dea Siggaard Stenbæk, Albin Arvidsson et al.
27 citations
preprint
Psilocybin, a psychedelic drug, produces its effects through its active metabolite psilocin, which activates serotonin 2A receptors in the brain. In fifteen healthy individuals given a moderate oral dose (0.2–0.3 mg/kg), higher plasma psilocin levels and stronger subjective drug intensity correlated with reduced integrity and segregation of brain networks, particularly the default mode network, and with increased connectivity between networks such as the executive control and dorsal attention networks. These changes in functional brain architecture tracked the time course and magnitude of the psychedelic experience, linking network desegregation to altered consciousness.
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.
bioRxiv (Cold Spring Harbor Laboratory)
February 17, 2021
Ling-Xiao Shao, Clara Liao, Ian Gregg et al.
26 citations
preprint
A single dose of psilocybin, a serotonergic psychedelic, caused a roughly 10% increase in the size and density of dendritic spines on layer 5 pyramidal neurons in the mouse medial frontal cortex. This structural remodeling began within 24 hours and persisted for at least one month, driven by an elevated rate of new spine formation. The drug also reduced stress-related behavioral deficits and increased excitatory neurotransmission. The findings demonstrate that psilocybin induces fast and enduring synaptic rewiring in the cortex, which may provide a structural basis for long-term integration of experiences and lasting therapeutic benefits.
bioRxiv (Cold Spring Harbor Laboratory)
August 10, 2020
Andrea I. Luppi, Jakub Vohryzek, Morten L. Kringelbach et al.
26 citations
preprint
Consciousness arises from how the brain's structural wiring shapes its dynamic activity. By decomposing resting-state fMRI data into harmonic modes of the human structural connectome, a generalizable signature of lost consciousness emerges—whether from anesthesia or brain injury—while a reversed signature characterizes psychedelic states induced by LSD or ketamine, reflecting decoupling of function from structure. This connectome harmonic approach discriminates between behaviorally indistinguishable brain-injured patients and tracks covert consciousness, linking neurobiology to conscious experience.
bioRxiv (Cold Spring Harbor Laboratory)
July 25, 2018
Ali R. Awan, Jaclyn M. Winter, Daniel J. Turner et al.
26 citations
preprint
Psilocybin, the psychoactive compound found in dozens of mushroom species, is being studied for treating addiction, depression, and end-of-life suffering. New genome analyses of the hallucinogenic mushrooms Psilocybe cyanescens and Pluteus salicinus confirm and refine the genes responsible for psilocybin biosynthesis, showing that a previously implicated transcription factor is not part of that gene cluster. The mushroom Inocybe corydalina produces psilocybin but lacks the established cluster, and an alternative cluster is described. Meta-transcriptome analysis of wild mushrooms reveals gene expression from fly larvae growing inside Psilocybe cyanescens, and these larvae were reared to adulthood. Psilocybin does not fully protect against insect consumption, suggesting its ecological role as a defense compound may need rethinking.
bioRxiv (Cold Spring Harbor Laboratory)
May 8, 2020
Andrea Alamia, Christopher Timmermann, Rufin Vanrullen et al.
25 citations
preprint
The psychedelic drug DMT rapidly induces an immersive conscious state with vivid visual imagery. EEG recordings showed that DMT alters cortical traveling waves: the typical alpha-band backward wave of eyes-closed rest decreased, while a forward wave similar to that seen during visual stimulation increased. This supports a model where psychedelics reduce the precision-weighting of prior expectations, shifting the balance from top-down to bottom-up information flow. The findings suggest that backward traveling waves are correlates of precision weighting and that reduced backward and increased forward waves are a mechanistic principle of psychedelic-induced altered states.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2017
Selen Atasoy, Leor Roseman, Mendel Kaelen et al.
25 citations
preprint
Lysergic acid diethylamide (LSD) alters the energy and power of individual harmonic brain states in a frequency-selective manner, expanding the repertoire of active brain states. This non-random increase in co-activation across frequencies suggests a general re-organization of brain dynamics. The frequency distribution of active brain states under LSD follows power-laws, indicating dynamics at the edge of criticality. These methods offer insights into complex brain dynamics in health and disease.
bioRxiv (Cold Spring Harbor Laboratory)
January 27, 2017
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias et al.
22 citations
preprint
A single dose of ayahuasca produced significant antidepressant effects in patients with treatment-resistant depression compared to placebo. Depression severity, measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), was significantly lower in the ayahuasca group at one, two, and seven days after dosing. Effect sizes increased over time, reaching a Cohen's d of 1.49 at day seven. Response rates were significantly higher in the ayahuasca group at day seven (64% vs. 27%), and remission rates were marginally significant (36% vs. 7%). This controlled trial supports the safety and therapeutic value of ayahuasca in treating depression.
bioRxiv (Cold Spring Harbor Laboratory)
June 23, 2015
Matthew J. Baggott, Jeremy Coyle, Jennifer D. Siegrist et al.
21 citations
preprint
MDMA produces a prosocial syndrome that facilitates emotional disclosure by increasing feelings of authenticity and decreasing concerns about negative evaluation by others. In a within-subjects double-blind placebo controlled study of 1.5 mg/kg oral MDMA, the drug showed both sedative- and stimulant-like effects, including increased self-report anxiety, but positively altered self-evaluation and reduced social anxiety. MDMA also increased how comfortable participants felt describing emotional memories, consistent with the suggestion that it represents a novel pharmacological class.
bioRxiv (Cold Spring Harbor Laboratory)
June 25, 2017
Mendel Kaelen, Romy Lorenz, Frederick S. Barrett et al.
20 citations
preprint
Lysergic acid diethylamide (LSD) alters how the brain processes music, particularly by enhancing activity and connectivity in networks linked to music perception and emotion. Sixteen healthy volunteers listened to a 7-minute music piece during fMRI after taking either 75 mcg of LSD or a placebo. The acoustic feature of timbral complexity—the richness of the music's spectral distribution—drove the most pronounced changes in brain activity and connectivity under LSD. These changes correlated with increased feelings of wonder evoked by the music. The results suggest a neurobiological basis for why music is useful in psychedelic therapy.
bioRxiv (Cold Spring Harbor Laboratory)
April 9, 2025
Odilia D Lu, Katrina White, Kendall Raymond et al.
18 citations
preprint
Psilocybin, the active compound in magic mushrooms, had several clear and repeatable immediate effects on mouse behavior, including increased anxiety and avoidance and reduced fear expression. However, its effects one day later were not consistent across five different laboratories, and no reliable changes were seen in depression-like behavior, fear extinction learning, social preference, or social reward learning. Using about 200 mice per experiment across five independent labs, the findings show that psilocybin's lasting behavioral effects in mice are more modest and less reliable than previously claimed. This coordinated multi-lab approach highlights the importance of replication for producing trustworthy results.
bioRxiv (Cold Spring Harbor Laboratory)
October 23, 2023
Tyler G. Ekins, Isla Brooks, Sameer Kailasa et al.
17 citations
preprint
Classic psychedelic drugs, such as LSD and psilocybin, are thought to boost brain cell activity in the prefrontal cortex by activating serotonin 2A receptors. However, this research shows that these drugs actually suppress the intrinsic excitability of pyramidal neurons in a dose-dependent manner. The suppression is stronger when drugs are applied outside cells than inside, and it occurs through a previously unknown mechanism: enhancement of potassium M-current channels, independent of serotonin 2A receptor activation. Computer models reveal that M-current activation interacts with other mechanisms to reduce excitability and shorten working memory span. This suggests psychedelics may trigger widespread homeostatic adjustments that contribute to therapeutic benefits.
bioRxiv (Cold Spring Harbor Laboratory)
May 12, 2023
Christopher Timmermann, Emma Eckernäs, Leor Roseman et al.
17 citations
preprint
The serotonergic psychedelic DMT rapidly induces a profoundly immersive altered state lasting less than 20 minutes, allowing the entire drug experience to be captured during a single fMRI scan. Using network control theory, which quantifies the input needed to drive transitions between brain states, brain structure and function were integrated to map energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Global control energy was reduced following DMT compared to placebo. Longitudinal trajectories of global control energy correlated with EEG signal diversity and subjective drug intensity ratings. Regional effects correlated with serotonin 2a receptor density. Receptor distribution and pharmacokinetic information successfully recapitulated DMT's effects on global control energy trajectories.
bioRxiv (Cold Spring Harbor Laboratory)
March 20, 2022
Pasha A. Davoudian, Ling-Xiao Shao, Alex C. Kwan
17 citations
preprint
Psilocybin, a psychedelic with therapeutic potential, and ketamine both acutely increased expression of the immediate early gene c-Fos in numerous brain regions of male and female mice, including the anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Some regions showed drug-preferential differences: psilocybin preferentially affected the dorsal raphe and insular cortex, while ketamine preferentially affected the CA1 subfield of the hippocampus. Endogenous levels of the glutamate receptor subunits Grin2a and Grin2b predicted whether a cortical region was sensitive to drug-evoked neural plasticity for both drugs, suggesting glutamatergic receptors as a convergent target for their therapeutic effects.
bioRxiv (Cold Spring Harbor Laboratory)
August 20, 2020
Carla Pallavicini, Federico Cavanna, Federico Zamberlán et al.
17 citations
preprint
Inhaled DMT, a short-acting psychedelic found in plants and animals, was studied in 35 experienced participants in natural settings using wireless EEG and questionnaires. DMT reduced alpha brain waves (8-12 Hz) across the scalp while increasing delta (1-4 Hz) and gamma (30-40 Hz) waves. Increases in gamma power correlated with reports of mystical-type experiences. DMT also altered global synchrony and metastability in gamma and alpha bands and increased signal complexity. These findings align with prior psychedelic research and suggest EEG markers for mystical experiences in natural contexts, underscoring the value of studying these compounds in real-world settings.
bioRxiv (Cold Spring Harbor Laboratory)
September 26, 2023
Yi-Ting Chiu, Wei Wang, Pierre Llorach et al.
15 citations
preprint
Psychedelic drugs such as LSD and psilocybin show promise as treatments for depression, anxiety, PTSD, migraine, and cluster headaches by activating the 5-HT2A receptor (HTR2A). Researchers engineered several new mouse lines to study the role of HTR2A and the neurons that express it. One line allows visualization of the receptor and identification of HTR2A-containing cells, providing a detailed anatomical map. Another line has a humanized version of the receptor, and a third enables targeted genetic manipulation. The mice exhibited expected behavioral responses to psychedelics, confirming their usefulness. Electrophysiology showed that serotonin increases firing of specific pyramidal neurons through HTR2A, consistent with the receptor's location on the cell surface. These tools will help clarify how psychedelics work at molecular, cellular, and behavioral levels.
bioRxiv (Cold Spring Harbor Laboratory)
November 15, 2022
Gavin P. Schmitz, Yi-Ting Chiu, Gabriele M. König et al.
15 citations
preprint
Psilocin, the active compound in psilocybin mushrooms, activates serotonin 2A receptors (5-HT2ARs) in the prefrontal cortex (PFC), but its specific effects on PFC neurons were unclear. Using slice electrophysiology in mice, researchers found that psilocin application onto layer 5 pyramidal neurons in the prelimbic PFC produced variable firing changes (increase, decrease, or no change) in unspecific neurons. However, in neurons identified as expressing 5-HT2ARs, psilocin consistently increased firing without altering synaptic transmission. The results demonstrate that psilocin evokes strong, 5-HT2AR- and Gαq-dependent firing changes in the PFC, offering insights into how psychedelics affect a brain region key to their therapeutic actions.
bioRxiv (Cold Spring Harbor Laboratory)
November 9, 2023
Fernando E. Rosas, Pedro A. M. Mediano, Christopher Timmermann et al.
14 citations
preprint
Autonomic signals can reveal aspects of subjective and neural states. A Bayesian framework estimated heart rate entropy under psychedelics. Across four drugs—LSD, DMT, psilocybin, and ketamine—mean heart rate, high-frequency heart rate variability, and heart rate entropy consistently increased during the psychedelic experience. These changes predicted various dimensions of the experience. Heart rate entropy increases correlated with brain entropy increases, while other autonomic markers did not. Cost-efficient autonomic measures can reveal detail about subjective and brain states, opening new research avenues in neuroscience.
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.
bioRxiv (Cold Spring Harbor Laboratory)
February 4, 2024
Sophie A. Rogers, Elizabeth A. Heller, Gregory Corder
11 citations
preprint
A single dose of the serotonin 2 receptor agonist psilocybin enhances behavioral flexibility by altering neural activity in the retrosplenial cortex. In a five-day trace fear learning and extinction assay using longitudinal single-cell calcium imaging in mice, psilocybin induced ensemble turnover between fear learning and extinction days, oppositely modulating activity in fear- and extinction-active neurons. Acute suppression of fear-active neurons and delayed recruitment of extinction-active neurons predicted enhanced fear extinction. A computational model showed that acute inhibition of fear-active neurons by psilocybin suffices to explain its neural and behavioral effects days later, suggesting a new mechanism involving suppression of fear-active populations.
bioRxiv (Cold Spring Harbor Laboratory)
February 25, 2021
Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara et al.
11 citations
preprint
A single dose of the psychedelic DOI produces rapid and sustained antidepressant-like effects by altering chromatin organization at enhancer regions of genes involved in synaptic assembly in the frontal cortex, an effect mediated by the 5-HT2A receptor. These epigenetic changes drive lasting synaptic plasticity and accelerate fear extinction. The findings suggest that epigenetic-driven synaptic plasticity underlies psychedelics' long-lasting antidepressant action, but also indicate potential risks for individuals with underlying vulnerability to psychosis, as the altered neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.