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 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)
November 1, 2023
Gregory Humble, Harry Geddes, Oliver Baell et al.
1 citation
preprint
Experienced mindfulness meditators show altered brain reactivity to transcranial magnetic stimulation (TMS) compared to non-meditators. When TMS was applied to the left and right dorsolateral prefrontal cortices, meditators had larger P60/N100 ratios in their brain responses, suggesting differences in cortical reactivity. No differences were seen in the individual P60 or N100 amplitudes. Preliminary evidence also indicated differences in the distribution of neural activity about 300 milliseconds after stimulation, possibly reflecting greater inhibitory activity in frontal regions and differences in cortico-subcortical reverberation. These findings contribute to understanding the neurophysiology of mindfulness.
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)
June 20, 2020
Jacob van Doorn, Mengqi Xing, B. Rael Cahn et al.
1 citation
preprint
Brain connectivity patterns differ between meditation states and instructed mind-wandering, regardless of meditation experience or tradition. Experienced meditators from Isha Yoga, Himalayan Yoga, and Vipassana traditions, along with meditation-naïve individuals, performed breath awareness, autobiographical thinking, and their own meditation practice while 64-electrode EEG recorded brain activity. A new method called Thought Chart mapped each person's dynamic functional connectivity. Both breath awareness and meditation tasks showed consistently different connectivity patterns compared to mind-wandering, measured by Hausdorff distance. The meditation state most closely resembled breath awareness across all groups. These differences were not driven by specific frequency bands, and no significant group differences emerged.
bioRxiv (Cold Spring Harbor Laboratory)
September 8, 2019
Laura Alethia de la Fuente, Federico Zamberlán, Andrés Sánchez Ferrán et al.
1 citation
preprint
Machine learning analysis of a large public dataset where users freely reported their experiences with cannabis strains, combined with chemical composition data, reveals that cannabis strains can be reliably classified into three major clusters corresponding to Cannabis sativa, Cannabis indica, and hybrids based on self-reported effect and flavor tags. Terpene profiles matched users' perceptual characterizations and could predict associations between different psychoactive effects, while cannabinoid content was variable even within individual strains. The findings suggest that flavor perception, reflecting robustly inherited terpene content, could serve as a reliable marker to predict psychoactive effects, offering a data-driven approach to strain classification for the growing medicinal and recreational cannabis market.
bioRxiv (Cold Spring Harbor Laboratory)
March 9, 2019
Andria Pelentritou, Levin Kuhlmann, John Cormack et al.
1 citation
preprint
Equivalent stepwise subanesthetic doses of the NMDA-antagonists nitrous oxide (N2O) and xenon (Xe) produce distinct, frequency-dependent changes in cortical oscillatory source power, measured with simultaneous magnetoencephalography (MEG) and electroencephalography (EEG). At the highest Xe concentration (42%, 1.30 MAC-awake), delta and theta band power significantly increased in both MEG and EEG. N2O administration reduced frontal alpha power more strongly than equivalent Xe doses. N2O alone increased MEG (but not EEG) high-frequency gamma power, with occipital low gamma and widespread high gamma rises. These results demonstrate divergent MEG and EEG signatures of dissociative anesthesia.
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)
October 16, 2017
Suresh Muthukumaraswamy, David T. J. Liley
1 citation
preprint
The arhythmical, scale-free brain activity (1/f β) that dominates neurophysiological recordings is dynamically linked to oscillatory alpha rhythms and is systematically modulated by excitation-inhibition balance. Using IRASA to separate arhythmical from oscillatory activity, the authors show that alpha power correlates over time with the high-frequency power-law exponent βhf, and participants with higher alpha power also have higher βhf. Pharmacological manipulations with tiagabine, perampanel, ketamine, and LSD in MEG, and propofol and ketamine in monkey ECoG, reveal consistent effects of excitation-inhibition balance on both high- and low-frequency β exponents.
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.