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)
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)
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)
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)
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.
bioRxiv (Cold Spring Harbor Laboratory)
January 3, 2023
Saampras Ganesan, Bradford A. Moffat, Nicholas T. van Dam et al.
1 citation
preprint
Using ultra-high strength 7 Tesla fMRI, a pilot study scanned 10 beginner meditators during focused attention meditation and rest. Meditation significantly reduced activity in Default-mode network hubs—antero-medial prefrontal cortex, posterior cingulate cortex, precuneus—and in visual and thalamic regions, even after adjusting for physiological differences between conditions. State Mindfulness Scale scores significantly increased after the meditation session and remained elevated at a two-week follow-up. The findings support that focused attention meditation attenuates default-mode activity linked to self-referential processing, establishing the feasibility of 7 Tesla fMRI for meditation research.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2022
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
1 citation
preprint
In mice, psilocybin reduced marble-burying, a behavior linked to obsessive-compulsive disorder, as effectively as the antidepressant escitalopram. This effect was not blocked by a 5-HT2A antagonist or a 5-HT1A antagonist, indicating neither receptor is essential for psilocybin's anti-obsessional action. The 5-HT1A partial agonist buspirone also reduced marble-burying, but combining buspirone with psilocybin did not enhance the effect. Staggered doses of psilocybin over 3.5 hours had no effect, and the effect of a single injection was not persistent. Importantly, buspirone blocked psilocybin's head-twitch response, a rodent correlate of psychedelic effects, suggesting buspirone could prevent psychedelic effects without interfering with anti-obsessional benefits.
bioRxiv (Cold Spring Harbor Laboratory)
July 3, 2022
Mohamed Sherif, Mostafa Z. Khalil, Rammohan Shukla et al.
1 citation
preprint
Synaptic atrophy in major depressive disorder may impair the brain's ability to confidently predict future affective states, even when predictions remain accurate. Using a temporal memory algorithm that mimics a single neocortical layer with Hebbian learning, researchers simulated depression by progressively destroying synapses. Destroying 50% of synapses slightly reduced the number of predictions, but a 25% reduction distinctly lowered prediction confidence. This suggests that in depression, interoceptive cortices become stuck in limited affective states with high prediction error. Treatments like ketamine and psilocybin may help by growing new synapses, enabling more confident and futuristic predictions.
bioRxiv (Cold Spring Harbor Laboratory)
February 22, 2022
Camila Sanz, Federico Cavanna, Stephanie Müller et al.
1 citation
preprint
Low doses of psilocybin (microdoses) can be detected in natural speech. In a double-blind, placebo-controlled experiment, participants given 0.5 g of psilocybin mushrooms showed significant differences in verbosity and sentiment scores compared to placebo, though semantic variability did not differ. Machine learning classifiers using these speech metrics distinguished between the psilocybin and placebo conditions with high accuracy (AUC≈0.8). These findings suggest that unconstrained natural language may serve as a practical, low-cost tool for monitoring microdosing effects, addressing limitations of existing questionnaires designed for larger psychedelic doses.
bioRxiv (Cold Spring Harbor Laboratory)
June 17, 2021
Karina Karmirian, Livia Goto‐silva, Juliana Nascimento et al.
1 citation
preprint
Harmine, a β-carboline found in the ayahuasca vine Banisteriopsis caapi, upregulates proteins in human brain organoids that are involved in synaptic vesicle cycling, cytoskeleton-dependent transport, cell cycle, glucose transporter-4 translocation, and neurotrophin signaling. Treatment with harmine also increased levels of Akt and phosphorylated CREB after 24 hours. These findings point to cellular and molecular pathways that may explain harmine's potential neuroprotective effects, which have been suggested by previous animal studies to include anti-inflammatory and antioxidant activities. The work advances understanding of how harmine might contribute to the antidepressant effects observed with ayahuasca.
bioRxiv (Cold Spring Harbor Laboratory)
July 24, 2018
Greg R. Boyce, Emile Gluck-Thaler, Jason C. Slot et al.
1 citation
preprint
Some entomopathogenic fungi keep their insect hosts alive while releasing spores, a behavior that improves spore dispersal. Metabolomics of four populations of periodical cicadas infected with Massospora cicadina revealed the plant-associated amphetamine cathinone, while annual cicadas infected with Massospora platypediae or Massospora levispora contained the mushroom-associated tryptamine psilocybin; the latter two fungi appear to be a single species. The absence of certain fungal enzymes needed to produce cathinone and psilocybin, along with undetectable intermediate metabolites or gene orthologs, suggests novel biosynthesis pathways in Massospora. The neurogenic activity of these compounds indicates that the extended phenotype of Massospora, which alters cicada behavior to maximize spore dissemination, is chemically induced.
bioRxiv (Cold Spring Harbor Laboratory)
Shawn. M. Aarde, Pai-Kai Huang, Michael A. Taffe
1 citation
preprint
In rats, high ambient temperature (30°C) increases the acquisition of intravenous self-administration of MDMA more than low temperature (20°C). Initially, MDMA caused similar hypothermia in both temperature groups, but this effect diminished over training in the hot group. Activity levels, initially lower in the hot group, became similar by the end of training. When temperature conditions were swapped, rats trained in the hot condition increased MDMA intake under cold, while those trained in the cold modestly decreased intake under hot. Rats with higher MDMA intake showed blunted hypothermia after non-contingent MDMA. High temperature alone raised brain reward thresholds, and MDMA lowered thresholds below baseline only at low temperature. The findings suggest that high temperature enhances MDMA self-administration acquisition through an aversive effect rather than thermoregulatory motivation.
bioRxiv (Cold Spring Harbor Laboratory)
Lucas Dwiel, Angela Henricks, Elise Bragg et al.
1 citation
preprint
Lysergic acid diethylamide (LSD) acutely reduces low-frequency electrical activity across the brain in rats, an effect that returns to normal after 24 hours. However, brain stimulation applied during a window of heightened neuroplasticity 24 hours after LSD produces larger and distinct changes in brain activity compared to stimulation after a placebo. This proof-of-concept finding suggests that psychedelic drugs may work in combination with brain stimulation to achieve enhanced effects on brain activity, with future work needed to assess impacts on behavior.
bioRxiv (Cold Spring Harbor Laboratory)
Kathleen A. Trychta, Brandon K. Harvey
1 citation
preprint
Hyperthermia—elevated body temperature—triggers the abnormal secretion of proteins normally retained inside the endoplasmic reticulum (ER), a process called ER exodosis. The club drugs MDMA (ecstasy) and caffeine, alone or combined, worsen this protein leakage in a cellular model. Hyperthermia also activates the unfolded protein response (UPR), a cellular stress pathway, but the drugs do not alter most UPR-related gene expression despite increasing ER exodosis of UPR proteins. One exception: MDMA raised BiP/Grp78 mRNA levels under hyperthermia. These results suggest that using club drugs in hot environments disrupts ER protein balance, potentially increasing cell toxicity.
bioRxiv (Cold Spring Harbor Laboratory)
Matthew J. Baggott, Kathleen J. Garrison
1 citation
preprint
MDMA (ecstasy) use can cause dangerously low blood sodium levels (hyponatremia), especially when people drink too much water. In two double-blind, placebo-controlled studies, healthy volunteers who took MDMA did not show increased levels of the hormone that normally regulates water balance (ADH or copeptin), but their blood sodium dropped more than with placebo when they drank standardized amounts of water. Women tended to have lower baseline sodium, but this did not significantly interact with MDMA. The findings indicate that consuming hypotonic fluids during MDMA use poses a significant risk of hyponatremia, which should be anticipated and managed in clinical and recreational settings.
bioRxiv (Cold Spring Harbor Laboratory)
Iga Adamska, Karolina Finc
1 citation
preprint
Listening to music while under the influence of LSD alters the brain's moment-to-moment patterns of activity, particularly in networks linked to attention and task performance. In a study of 15 participants who underwent functional MRI scans after taking LSD or a placebo, the combination of music and LSD changed how long the brain stayed in a task-positive state. LSD alone, regardless of music, affected the dynamics of a state involving the default mode, somatomotor, and visual networks. Music itself appeared to have a lingering effect on resting-state brain activity, especially on networks associated with tasks. These findings suggest that music, as part of the setting, can shape the psychedelic experience at a neural level.