bioRxiv (Cold Spring Harbor Laboratory)
September 23, 2019
Kirsten C. S. Adam, Manoj K. Doss, Elisa Pabon et al.
2 citations
preprint
THC, the main psychoactive component in cannabis, impairs visual working memory—the ability to temporarily hold visual information in mind. Two double-blind, randomized crossover experiments with 23 healthy adults each found that oral THC (7.5 or 15 mg) reduced working memory performance, increased self-reported mind wandering, and decreased metacognitive accuracy about ongoing task performance. The authors also showed that short task durations and small sample sizes reduce the likelihood of detecting such drug effects.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Gorka Zamora‐lópez et al.
1 citation
Psilocybin and the conventional antidepressant escitalopram produce opposite changes in the brain's hierarchical non-equilibrium dynamics when treating major depressive disorder. Using resting-state fMRI before and after treatment, researchers built whole-brain models and measured how much each patient's brain activity deviated from the fluctuation-dissipation theorem. Baseline measures distinguished treatment responders from non-responders within each group. The deviation from the fluctuation-dissipation theorem may serve as a marker to differentiate the brain effects of psilocybin and escitalopram, contributing to understanding how these treatments work for depression.
bioRxiv (Cold Spring Harbor Laboratory)
March 24, 2026
Kenneth Shinozuka, Mattia Rosso, Anna Chaiken et al.
1 citation
A single dose of the atypical psychedelic ibogaine can be highly effective at treating PTSD in veterans up to twelve months later, according to an observational study of 30 veterans. Using a novel EEG analysis method, researchers found that ibogaine shifted high-beta (24 and 25 Hz) brain networks from frontal areas toward posterior regions, an effect seen both three to four days and one month after treatment. This posterior shift correlated with improvements in PTSD symptoms and was replicated in an independent dataset on ibogaine for opioid use disorder. Neural modeling suggested the shift reflects increased corticocortical, not corticothalamic, connectivity. The reconfiguration of high-beta networks may be a robust biomarker for ibogaine's therapeutic effects.
bioRxiv (Cold Spring Harbor Laboratory)
February 18, 2026
Ethan Grove, Trevor Hewitt, Anil K. Seth et al.
1 citation
Visual hallucinations (VHs) occur in psychedelic states and various psychiatric and neurological conditions, but their phenomenology is hard to characterize due to a lack of large-scale datasets. Stroboscopic light stimulation (SLS) with closed eyes reliably induces VHs in healthy people, producing vivid colors and dynamic geometric patterns similar to simple VHs in other contexts. Researchers developed an unsupervised computer-vision pipeline to analyze 10,598 drawings made after hallucination-inducing SLS at a public installation. Most drawings contained geometric forms, consistent with prior observations, but novel patterns like concentric squares, crosses, and hyperbolic shapes also appeared. The pipeline organized the drawings into interpretable classes, mapping the diversity of simple geometric VHs and placing new constraints on theoretical accounts.
bioRxiv (Cold Spring Harbor Laboratory)
January 29, 2026
Venkatesh Subramani, Timothy Nest, Annalisa Pascarella et al.
1 citation
LSD alters brain activity by increasing alpha and beta brain-wave frequencies while genuinely reducing oscillatory power, with these effects showing distinct cortical patterns. The drug also flattens the aperiodic 1/f spectral slope and increases neural signal fractality and complexity, particularly in sensory, language, emotion, and imagery-related networks, while sparing motor cortex. Machine learning identified peak-frequency shifts, aperiodic parameters, and complexity measures as key discriminators of the psychedelic state. Music did not amplify these neural signatures and showed a trend toward attenuation. These findings provide a comprehensive account of how LSD reorganizes large-scale human brain dynamics.
bioRxiv (Cold Spring Harbor Laboratory)
December 9, 2025
Maria Niedernhuber, Dila Suay, Michael J. Mueller et al.
1 citation
Classic serotonergic psychedelics strongly alter conscious awareness, but how they change the temporal structure of brain activity has been unclear. In a double-blind, placebo-controlled study with 25 participants using high-density EEG, an ayahuasca-inspired formulation (intranasal N,N-DMT and buccal harmine) accelerated neural dynamics: microstate duration decreased and state transitions became more frequent. Surprisingly, the sequence of microstates became less random, showing higher first-order Markov structure. This restructuring involved reduced transitions into one state (M2) and increased prevalence and accessibility of two others (M3 and M5). The psychedelic state thus produces a syntactically reconfigured, highly metastable neural dynamic, not mere randomization.
bioRxiv (Cold Spring Harbor Laboratory)
November 1, 2025
Dasha Anderson, Justyna Hinchcliffe, Megan Jackson et al.
1 citation
preprint
Antidepressant doses used in conventional rodent models of depression often exceed those used in clinical practice by 1.5 to 25 times, potentially engaging mechanisms irrelevant to human therapeutic effects. A review of forced swim test studies found median doses of 10 mg/kg across antidepressants, while the more recently developed affective bias test showed doses closer to clinical levels. In a separate analysis of 232 ketamine and 202 fluoxetine rodent studies, median doses were also 10 mg/kg, exceeding animal equivalent doses by 1.6–6.5 times. This mismatch may explain why positive preclinical results often fail to translate into clinical efficacy.
bioRxiv (Cold Spring Harbor Laboratory)
October 14, 2025
Nicholas Kolbman, Amanda Nelson, Rachel Summerfield et al.
1 citation
preprint
Psilocybin and DMT, two serotonergic psychedelics, delay the onset of slow-wave sleep and REM sleep, and cause a short-lasting increase in wakefulness and decrease in slow-wave sleep in rats. Psilocybin also reduces REM sleep, decreases theta power and coherence, and increases high gamma power and coherence during wake and slow-wave sleep, as well as increasing high gamma coherence during REM sleep. DMT increases gamma coherence only during wakefulness. The enhanced high gamma functional connectivity suggests that psychedelic-induced changes in neural dynamics can occur independently of arousal states.
bioRxiv (Cold Spring Harbor Laboratory)
October 3, 2025
Marian Martínez-Marín, Jakub Vohryzek, Anira Escrichs et al.
1 citation
preprint
Consciousness levels after coma can be assessed by measuring how far the brain's dynamics are from equilibrium. Using fMRI data and individualized whole-brain models, researchers found that patients with disorders of consciousness—those in a minimally conscious state or unresponsive wakefulness syndrome—show brain activity closer to equilibrium than healthy controls, with the shift increasing as consciousness decreases. Disruptions in hierarchical drive were identified in default-mode network regions and subcortical hubs like the thalamus. Recovery of near-control hierarchy in the visual network distinguished minimally conscious from unresponsive patients, while limbic areas showed similar abnormalities in both groups. Deviation from the fluctuation-dissipation theorem offers a model-based biomarker for clinical stratification.
bioRxiv (Cold Spring Harbor Laboratory)
June 26, 2025
Prakash Shrimali, Arun Sasidharan, Saketh Malipeddi et al.
1 citation
preprint
Meditation involves training attention inward, but the brain activity that distinguishes meditative from non-meditative states across different traditions is not well understood. Analyzing high-density EEG data from 170 participants—121 advanced meditators and 49 controls—across Vipassana, Brahma Kumaris Raja Yoga, Heartfulness, and Isha Yoga traditions, researchers used random forest classifiers to distinguish meditative from non-meditative states with 91% accuracy. Nonlinear features contributed most, indicating a core neurodynamic profile. Classification was higher in advanced meditators (92%) than controls (85%), with different feature importance: nonlinear and aperiodic features dominated in meditators, while oscillatory and timescale features dominated in controls. Each tradition showed distinct neurodynamic profiles, suggesting multiple pathways lead to meditative states.
bioRxiv (Cold Spring Harbor Laboratory)
June 5, 2025
Ekaterina Shatalina, Natalie Ertl, Kat Petrilli et al.
1 citation
preprint
Inhaling cannabis with THC alone or THC plus CBD reduces resting-state functional connectivity in brain networks that are rich in CB1 and CB2 cannabinoid receptors. Co-administering CBD with THC produced more widespread reductions than THC alone, affecting regions involved in cognition and emotion such as the prefrontal cortex, cingulate cortex, insula, hippocampus, amygdala, and putamen. Higher THC levels in the blood were linked to greater connectivity decreases when CBD was also present. Subjective drug effects correlated with connectivity changes in a region-specific way. The findings suggest that CBD may enhance rather than dampen THC's effects on brain connectivity, contrary to some earlier expectations.
bioRxiv (Cold Spring Harbor Laboratory)
February 8, 2025
Marco Aqil, Gilles de Hollander, Nina Vreugdenhil et al.
1 citation
preprint
Psilocybin changes how the brain processes visual context, altering perception of the Ebbinghaus illusion and reducing contextual modulation in cortical responses. A computational model links these perceptual and neural changes, suggesting that psychedelics may act by disrupting contextual computations throughout the brain.
bioRxiv (Cold Spring Harbor Laboratory)
December 22, 2024
Jakub Vohryzek, Morten L. Kringelbach, Edmundo Lopez-Sola et al.
1 citation
preprint
Both psychedelic states and reduced states of consciousness flatten the brain's functional hierarchy, yet their behavioral and phenomenological profiles differ. To resolve this paradox, researchers defined hierarchy by the brain's proximity to thermodynamic equilibrium and examined changes induced by three serotonergic psychedelics: psilocybin, LSD, and DMT. All three consistently reduced the functional hierarchy globally. Unlike loss of consciousness, psychedelics moved the brain toward equilibrium while increasing neural activity complexity, indicating a distinct mechanism involving altered configuration and differentiation of resting-state networks. This work demonstrates how statistical mechanics metrics can characterize different global brain states, advancing understanding of consciousness as an emergent collective process.
bioRxiv (Cold Spring Harbor Laboratory)
December 17, 2024
J. Hudson Barnett, Kennedi T. Todd, Joseph Benetatos et al.
1 citation
preprint
Psilocybin, a psychedelic tryptamine, shows promise for treating conditions like treatment-resistant depression and PTSD by rapidly improving depression scores. Its primary mechanism involves activating the serotonin 2A receptor, but downstream therapeutic effects remain unclear. This study analyzed dose- and sex-dependent transcriptional changes in mouse forebrains at 8 hours, 24 hours, and 7 days after a single low (0.25 mg/kg) or high (1 mg/kg) dose. Females showed faster transcriptional changes and attenuation at low doses compared to males, and more robust responses to high doses at early timepoints. Low-dose effects persisted at 7 days, outlasting high-dose changes, and involved pathways related to neuronal differentiation and neurogenesis. These sexually divergent and temporal molecular effects should inform treatment strategies and timing with cognitive behavioral therapy.
bioRxiv (Cold Spring Harbor Laboratory)
December 13, 2024
Ross J. Purple, Rekha Gupta, Christopher W. Thomas et al.
1 citation
preprint
Psilocybin at therapeutically relevant doses (0.3 or 1 mg/kg) in rats unmasked 100 Hz high frequency oscillations in the infralimbic cortex that persisted for about an hour, accompanied by decreased pyramidal cell firing rates and reduced signal complexity. These acute effects were more pronounced during rest than during a sustained attention task. Over the following days, gradually emerging increases in beta and low-gamma (20-60 Hz) power appeared specifically in the infralimbic cortex, suggesting network plasticity on multi-day timescales. The findings implicate infralimbic network oscillations as potential biomarkers of psychedelic action not readily detectable in human brain imaging.
bioRxiv (Cold Spring Harbor Laboratory)
October 24, 2024
James J Gattuso, Carey Wilson, Anthony J. Hannan et al.
1 citation
preprint
Acute psilocybin administration reduced compulsive grooming behavior in male SAPAP3 knockout mice, a model of obsessive-compulsive disorder, for up to eight days after a single injection. The compound did not affect anxiety-like behaviors. Psilocybin increased locomotion in wild-type mice but not in knockouts, suggesting underlying serotonergic differences. Both genotypes showed the typical head-twitch response, confirming the drug's hallucinogenic effect at the 1 mg/kg dose. The findings indicate psilocybin may have enduring anti-compulsive potential.
bioRxiv (Cold Spring Harbor Laboratory)
September 30, 2024
Conor P. Lane, Veronica Tarka, Olivier Valentin et al.
1 citation
preprint
Psilocybin, a psychoactive substance from fungi, prevents the normal habituation of sound-evoked responses in the primary auditory cortex of mice. After administration of 1 mg/kg psilocybin, neurons maintained their responsiveness, bandwidth, and sound-level response thresholds to repeated stimuli, whereas control mice showed marked habituation and narrowing of tuning. Psilocybin did not alter the overall distribution of best frequencies, indicating it disrupts normal sensory gating rather than tonotopic organization. This supports models where psychedelics cause perceptual disturbances by disrupting hierarchical sensory gating. These findings may inform future treatments for conditions involving maladaptive sensory processing, such as tinnitus.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2024
Isaac N. Treves, Aaron Kucyi, Madelynn Park et al.
1 citation
preprint
Trait mindfulness—the tendency to attend to present-moment experience non-judgmentally—is linked to better mental health, but its neural basis remains unclear. In the largest resting-state fMRI study of trait mindfulness to date, involving 367 adults across three samples, researchers used connectome predictive modeling to test whether brain connectivity patterns could predict mindfulness scores. No connections predicted overall trait mindfulness, but models for two subscales—Acting with Awareness and Non-judging—were identified. Positive networks for these subscales involved fronto-parietal and default-mode networks, respectively. Negative networks, which overlapped across subscales, included somatomotor, visual, and default-mode connections. Only negative networks generalized to predict subscale scores in some out-of-sample datasets, and predictions correlated negatively with a mind-wandering model. The incomplete generalization and model overlap highlight the challenge of identifying robust brain markers for mindfulness facets.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2024
Aurelija Ippolito, Sridhar R. Vasudevan, Shaun Hurley et al.
1 citation
preprint
All psychedelic drugs tested were unbiased, partial agonists at the 5-HT2A receptor, activating G-protein and β-arrestin2 pathways equally. Non-psychedelic drugs lisuride and TBG were not biased either, but they showed the lowest signalling efficacy among all compounds. Low efficacy at the 5-HT2A receptor, not biased signalling, may explain why some 5-HT2A agonists are not psychedelic.
bioRxiv (Cold Spring Harbor Laboratory)
April 15, 2024
Maricela X. Martinez, Vanessa Alizo Vera, Christina M. Ruiz et al.
1 citation
preprint
Adolescent exposure to THC, the main psychoactive component of cannabis, persistently alters dopamine-dependent cognitive functions in a sex-specific manner in rats. Adult rats treated with THC during adolescence showed reduced acquisition of cue-guided reward seeking, but minimal changes in set-shifting or decision-making under uncertainty. When given amphetamine, these rats were more sensitive to its effects on reducing preference for improbable rewards compared to controls. Directly stimulating dopamine neurons in the ventral tegmental area or their projections to the medial prefrontal cortex did not affect decision-making in control rats, but slightly disrupted choices in THC-exposed rats. These results indicate that adolescent THC exposure has specific, lasting effects on cognition and amphetamine sensitivity that may not involve direct dopamine pathway changes.
bioRxiv (Cold Spring Harbor Laboratory)
January 20, 2024
Adam T. Brockett, Nikolas A. Francis
1 citation
preprint
Psilocybin, a serotonergic psychedelic, alters sensory cortex activity in awake mice in a biphasic manner. A 2 mg/kg dose initially increased both behavioral activity and neural responses to sound. Thirty minutes later, mice became behaviorally hypoactive and cortical responses to sound decreased, while neural response variance and noise correlations increased. Neuronal selectivity for auditory stimuli remained stable. The results suggest psilocybin modulates the balance between intrinsic and stimulus-driven neural activity in sensory cortex, preserving fundamental sensory processing while potentially providing a basis for auditory hallucinations at the level of neuronal micro-circuits.
bioRxiv (Cold Spring Harbor Laboratory)
September 22, 2023
Suvarnalata Xanthate Duggirala, Hanna Honcamp, Michael Schwartze et al.
1 citation
preprint
Auditory verbal hallucinations occur along a continuum from the general population to patients with psychosis, yet how sensory feedback processing and attention control interact along this continuum is unclear. By manipulating self-voice quality (from neutral to angry) and measuring brain activity with electroencephalography, the study found that hallucination proneness (HP) modulated the N100 and P200 suppression effects regardless of voice quality. Individuals with high HP showed an increased N100 response to self-generated voices and an increased P200 response to externally-generated voices, suggesting heightened error awareness and attention allocation during self-voice production due to altered sensory feedback processing and attentional control. These findings indicate that altered sensory feedback processing in self-voice production is a fundamental characteristic of the HP continuum, independent of clinical status.
bioRxiv (Cold Spring Harbor Laboratory)
July 28, 2023
Juan Pedro Castro‐nin, Diego Serantes, Paola Rodrı́guez et al.
1 citation
preprint
Noribogaine, the main metabolite of the psychedelic ibogaine, promotes wakefulness and reduces slow-wave sleep while completely blocking REM sleep in rats. These sleep-wake alterations mirror those caused by ibogaine itself, suggesting that noribogaine is responsible for the sleep-suppressing effects previously attributed to ibogaine. The findings point to serotonin reuptake inhibition as a likely mechanism underlying the wake-promoting and REM sleep-suppressing actions of both compounds.
bioRxiv (Cold Spring Harbor Laboratory)
May 18, 2023
Sheetal A. Raithatha, Jillian M. Hagel, Kaveh Matinkhoo et al.
1 citation
preprint
Psilocybin, the prodrug of psilocin found in magic mushrooms, shows therapeutic promise for depression and anxiety but produces a psychoactive episode lasting up to 6 hours, which limits clinical use. Researchers engineered a library of 28 novel prodrug derivatives of psilocin by modifying the 4-carbon position of the indole ring. In vitro screening in human serum and cellular fractions identified 15 prodrugs that produced psilocin, notably ester and thiocarbonate-based compounds. Pharmacokinetic studies in mice showed these prodrugs yielded psilocin levels comparable to psilocybin but with reduced overall exposure and no detectable psilocin at 24 hours. Five prodrugs induced head twitch responses approaching or exceeding psilocybin, and two provided long-term anxiety relief in stressed mice. These candidates may shorten the psychedelic experience while retaining therapeutic benefits.
bioRxiv (Cold Spring Harbor Laboratory)
March 21, 2023
Hanna M. Tolle, Juan Carlos Farah, Pablo Mallaroni et al.
1 citation
preprint
Functional connectomes (FCs) become more idiosyncratic under the psychedelic psilocybin than under placebo, with idiosyncratic features concentrating in the default-mode network (DMN). An FC pattern predicting subjective psilocybin experience shows reduced within-DMN and DMN-limbic connectivity, alongside increased DMN-attentional system connectivity. These results bridge psilocybin's brain effects and behavior, demonstrating the value of brain-fingerprinting in pharmacological neuroimaging.