bioRxiv Preprint Server
May 1, 2025
Claudio Agnorelli, Joseph Peill, Gabriela Sawicka et al.
preprint
A single psychedelic dose of ketamine (1 mg/kg, intravenous) alters brain chemistry and connectivity in healthy people for at least one to eight days. After the dose, glutamate levels in the anterior cingulate cortex rose significantly. Functional connectivity decreased within high-order networks such as the default mode network, while integration between low- and high-order networks increased. Increases in a PET marker of synaptic plasticity correlated with reduced intrinsic activity in default mode network regions and a diminished influence of the posterior cingulate cortex on global network dynamics. The posterior cingulate cortex appears to be a central hub through which ketamine may reshape brain hierarchies over the long term.
bioRxiv Preprint Server
April 12, 2025
Alina T. He, Wenbo Zhang, Hongbin Li et al.
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Ketamine is a fast-acting antidepressant, but how it works is unclear. A key question is whether NMDA receptors (NMDARs), which ketamine blocks, are responsible. Alternative splicing of the GluN1 subunit produces two versions: GluN1a (without exon 5) and GluN1b (with exon 5). In mice, ketamine blocked long-term potentiation (LTP) in the hippocampus only in GluN1a mice, not GluN1b mice. Although ketamine inhibited synaptic NMDARs in both types, GluN1a receptors remained blocked during neuronal firing while GluN1b receptors escaped blockade. Ketamine produced an antidepressant effect in GluN1a mice but not in GluN1b mice. GluN1a-containing NMDARs are selectively responsible for ketamine's antidepressant effect.
bioRxiv Preprint Server
March 27, 2025
Jordy Peeters, Dimitri de Bundel, Kenno Vanommeslaeghe
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Activating the serotonin-2A receptor can produce antidepressant effects, but also risks hallucinations. Recent work suggests that using weak partial agonists or very low doses might separate these effects. Computer simulations of the receptor bound to different drugs show that modest activation may yield only antidepressant benefits, while excessive activation causes hallucinations. This finding points to a possible drug development strategy: administering a sufficiently weak partial agonist could provide therapeutic effects without hallucinogenic side effects, avoiding the abuse and narrow dosing problems of microdosing.
bioRxiv Preprint Server
October 20, 2024
Peter Coppola, Adrian M. Owen, David K. Menon et al.
preprint
A new method captures the brain dynamics unique to each person's subjective experience. Using fMRI while people listened to a story awake and under different levels of anaesthesia, the approach tracks moment-to-moment changes in functional connectivity without assuming common brain states across individuals. The default mode network's dynamics were more dissimilar between conscious participants, reflecting personal engagement with the story. In contrast, the auditory and posterior dorsal attention networks showed higher similarity across conscious individuals, supporting more generalizable experiences. Conscious brain dynamics were more complex for individual-specific patterns but less complex for shared patterns.
bioRxiv Preprint Server
August 28, 2024
Lucie Olejníková-Ladislavová, Michaela Fujáková-Lipski, Klára Šíchová et al.
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Mescaline, a classical psychedelic with a phenylethylamine structure, primarily acts on serotonin 5-HT2A/C receptors but also binds to 5-HT1A and 5-HT2B receptors. Although it was the first psychedelic ever isolated and synthesized, the precise role of these different serotonin receptor subtypes in its behavioral pharmacology remains not fully understood.
bioRxiv Preprint Server
May 7, 2024
Victor Distefano Wiltenburg, Gabriela Morales-Lima, Aline Valéria Sousa Santos et al.
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Oral lyophilized ayahuasca, at doses equivalent to those used in traditional ceremonies, blocked the conditioned place preference (CPP) that mice normally develop for ethanol. In a CPP paradigm, mice pretreated with ayahuasca showed no preference for the ethanol-paired compartment (time difference within ±7 seconds), while controls showed a moderate preference (about +60 seconds). The effect was significant at all tested doses, and no differences were observed among ayahuasca groups. Ayahuasca was well tolerated at ceremony-equivalent doses, though the highest dose (5000 mg/kg) produced transient serotonergic-syndrome-like signs and locomotor deficits. ΔFosB expression in the nucleus accumbens did not differ among groups 24 hours after the post-test. The findings suggest ayahuasca may blunt ethanol-context preference, warranting replication with stronger reward baselines and additional molecular markers.
bioRxiv Preprint Server
April 19, 2024
Anders A. Jensen, Claudia R. Cecchi, Meghan Hibicke et al.
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A new compound called LPH-5 selectively activates the 5-HT2A receptor, unlike classical psychedelics which also affect related receptors. In rats, LPH-5 produced head-twitch responses (a behavioral marker of 5-HT2A activation) at doses of 0.5-1.0 mg/kg and showed antidepressant-like effects in three different rat models: Flinders Sensitive Line rats, adrenocorticotropic hormone-treated Sprague Dawley rats, and a Wistar Kyoto rat model designed to capture long-term antidepressant effects. The findings suggest that selective 5-HT2A receptor activation is sufficient for antidepressant potential, and that LPH-5 or similar selective compounds could represent a new generation of antidepressant drugs derived from psychedelics.
bioRxiv Preprint Server
April 3, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
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Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.
bioRxiv Preprint Server
February 14, 2024
Anne S. Fleiner, Daniel Kolnier, Nicholas Hagger-Vaughan et al.
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Propofol and ketamine are both general anaesthetics but produce markedly different states of consciousness. Propofol induces a deeply unconscious state with few or no dream reports, whereas ketamine anaesthesia is frequently followed by reports of vivid dreams. The abstract contrasts these two drugs' effects on awareness and dreaming, highlighting that different anaesthetics can produce distinct subjective experiences even when both cause loss of consciousness.
bioRxiv Preprint Server
January 16, 2024
Raquel Aparicio-Terrés, Samantha López-Mochales, Margarita Díaz-Andreu et al.
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Listening to electronic music at a tempo of 1.65 Hz (about 99 beats per minute) produces stronger brainwave synchronization than faster tempos of 2.25 Hz or 2.85 Hz. In 20 participants, this slower tempo also increased feelings of unity, a component of altered states of consciousness, though this subjective experience was not directly linked to the brain entrainment itself. However, a correlation emerged between entrainment and faster reaction times on cognitive tasks. The findings suggest tempo modulates neural entrainment and may influence certain aspects of consciousness, but the relationship between entrainment and altered states remains unclear.
bioRxiv Preprint Server
November 7, 2023
Kelly E. Dunham, Kani H. Khaled, Leah Weizman et al.
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Ketamine, recently FDA-approved for treatment-resistant depression, does not work like traditional SSRIs at low doses. In fruit fly larvae, which have a serotonin system similar to mammals, 1 mM ketamine did not affect serotonin reuptake but increased locomotion and feeding. Low doses of SSRIs (escitalopram and fluoxetine) inhibited serotonin reuptake and also increased feeding and locomotion. At a high dose (100 mM), ketamine inhibited serotonin reuptake and increased serotonin concentrations but decreased locomotion and feeding due to anesthetic effects. Low doses of other NMDA receptor antagonists increased feeding, while serotonin receptor agonists increased locomotion, suggesting ketamine affects behavior through multiple mechanisms, not by blocking serotonin reuptake like SSRIs.
bioRxiv Preprint Server
June 19, 2023
Christiane Martins de Vasconcellos Silveira, Vanessa Farelo Dos Santos, Isis Moraes Ornelas et al.
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LSD is metabolized into several compounds in the roundworm Caenorhabditis elegans, as shown by ultra-high performance liquid chromatography coupled with high-resolution tandem mass spectrometry. The identified metabolites reveal specific metabolic pathways and offer insights into LSD's pharmacokinetics. The work demonstrates that C. elegans is a suitable model for studying psychedelic compound metabolism, providing a foundation for further research on LSD's therapeutic potential.
bioRxiv Preprint Server
May 16, 2023
Liya Ma, Nupur Katyare, Kevin Johnston et al.
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Schizophrenia involves disrupted communication between brain regions. Low doses of the NMDA receptor antagonist ketamine produce schizophrenia-like symptoms and cognitive deficits, including impaired working memory. This study recorded neural activity in the lateral prefrontal cortex and posterior parietal cortex of macaque monkeys performing a working memory task. Ketamine impaired rule coding in single neurons during the delay period, reduced low-frequency oscillations in the parietal cortex, and weakened task-related connectivity between frontal and parietal regions in both directions. It also reduced interareal coherence between spiking and low-frequency oscillations. The findings support the use of acute NMDA receptor antagonists to model dysconnection and explore new treatments for schizophrenia.
bioRxiv Preprint Server
September 19, 2022
Stanislav Rozov, Roosa Saarreharju, Stanislav Khirug et al.
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Inhaling 50% nitrous oxide (laughing gas) for one hour and a single low dose of ketamine both alter gene expression in the medial prefrontal cortex of adult mice, particularly affecting regulators of MAPK signaling pathways in pyramidal cells. Nitrous oxide produced much broader and more widespread changes in mRNA expression than ketamine. However, unlike ketamine, nitrous oxide did not increase the firing rate of putative pyramidal neurons or boost gamma brain wave activity. The findings suggest that while both substances share some molecular effects, their neural activity patterns differ markedly.
bioRxiv Preprint Server
August 12, 2022
Daniel C. Javitt, Jonathan C. Javitt
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D-cycloserine (DCS) did not substitute for ketamine in ketamine-dependent rats, suggesting low abuse potential. The study used a self-administration paradigm to evaluate whether DCS would be self-administered by rats trained to self-administer ketamine. DCS failed to maintain ketamine-reinforced behavior, indicating it lacks the reinforcing properties associated with abuse liability. This finding contrasts with NMDAR antagonist antidepressants, which have known potential for abuse. The results suggest DCS may have a lower risk of addiction compared to other drugs in its class.
bioRxiv Preprint Server
July 25, 2022
Mariann Oemisch, Hyojung Seo
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Ketamine reduces the unpleasantness of negative outcomes without changing how gains are evaluated, according to a computational analysis of rhesus macaques making token-based decisions. The drug's effect on aversion was separable from side effects like fixation errors, which could be overcome with strong motivation to avoid mistakes. The authors propose that ketamine's acute dampening of negative events' impact might produce longer-term antidepressant effects by reducing the cumulative burden of slowly decaying memories of those events. They note that disruption-resistant affective memory could pose challenges in treating depression and call for further research on ketamine's action across diverse mood states and time scales.
bioRxiv Preprint Server
June 12, 2022
Luciana López-Jury, Francisco García-Rosales, Eugenia González-Palomares et al.
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Ketamine anesthesia does not uniformly suppress auditory cortex responses to all sounds. In bats, multifunctional neurons that process both echolocation and communication sounds are affected asymmetrically: under anesthesia, communication contexts cause global suppression of responses to lagging sounds, while echolocation contexts do not. This asymmetry depends on the frequency composition of sounds, not their temporal patterns. A computational model shows that anesthesia modulates spiking activity in a channel-specific way, decreasing responses to high-frequency sounds and increasing adaptation in corresponding cortical synapses. These findings indicate that ketamine anesthesia unbalances cortical inputs, altering how neurons respond to natural vocalizations in ways not predictable from known anesthetic effects.
bioRxiv Preprint Server
May 2, 2022
Fangyun Tian, Laura D. Lewis, David W. Zhou et al.
preprint
A subanesthetic dose of ketamine increases gamma oscillations in the prefrontal cortex and hippocampus, brain areas linked to its rapid antidepressant effects, and produces a 3 Hz oscillation in the posteromedial cortex that may underlie its dissociative effects. By adding propofol, which blocks NMDA-mediated disinhibition and shares HCN1 inhibition with ketamine, the study distinguished brain dynamics caused by NMDA-mediated disinhibition from those caused by HCN1 inhibition. The results suggest ketamine engages distinct neural circuits in frequency-dependent patterns to produce antidepressant and dissociative effects, potentially guiding development of new depression therapies with fewer side effects.
bioRxiv Preprint Server
February 21, 2022
Yi Qin, Ali Mahdavi, Marine Bertschy et al.
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In early schizophrenia, attention and perception problems are linked to brain structure and chemistry abnormalities, as well as disrupted brain rhythms in corticothalamic networks. The drug ketamine, which blocks NMDA receptors, mimics these symptoms. In lightly anesthetized rats, a single psychotomimetic dose of ketamine (2.5 mg/kg, subcutaneous) transiently increased baseline beta/gamma oscillations but decreased sensory-induced beta/gamma oscillations. It also disrupted information transfer in the somatosensory thalamus and cortex and reduced sensory-induced thalamocortical connectivity in the broadband gamma range. These findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system.
bioRxiv Preprint Server
December 9, 2021
Gavin P. Schmitz, Manish K. Jain, Samuel T. Slocum et al.
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Random genetic variations in the serotonin 2A receptor can modestly alter how four commonly used psychedelic drugs activate this receptor, with effects that differ depending on the specific drug. Seven naturally occurring receptor variants were tested in the lab; each showed small but statistically significant changes in drug potency and efficacy. These findings suggest that individual genetic differences may influence responses to psychedelic medications.
bioRxiv Preprint Server
September 24, 2021
Sophia Khom, Jacques D. Nguyen, Sophia A. Vandewater et al.
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Female rats that self-administered the entactogen psychostimulants methylone, pentylone, or MDMA under extended-access conditions escalated their drug intake, with methylone and pentylone producing more infusions than MDMA. Pentylone also led to higher breakpoints in progressive-ratio testing, indicating greater motivation. At the cellular level, both pentylone and MDMA increased baseline GABA transmission in the central nucleus of the amygdala (CeA): pentylone raised both the frequency and amplitude of miniature inhibitory postsynaptic currents, while MDMA increased only amplitude. Both drugs disrupted kappa opioid receptor (KOR) signaling in the CeA, with both KOR agonism and antagonism reducing GABA release, suggesting recruitment of non-canonical pathways. These findings indicate that CeA GABA and KOR mechanisms are critically involved in entactogen self-administration, similar to patterns seen with alcohol and cocaine.
bioRxiv Preprint Server
July 6, 2021
Julio Rodriguez-Larios, Eduardo A. Bracho Montes de Oca, Kaat Alaerts
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Experienced meditators report greater focus and less mind wandering during meditation than non-meditators, and these differences are reflected in their brain activity. In a study of 29 experienced meditators and 29 non-meditators, EEG recordings during rest and breath-focus meditations showed that meditators, but not controls, had a significant decrease in individual alpha frequency and amplitude and a steeper 1/f slope during meditation compared to rest. Controls, but not meditators, showed increased alpha amplitude during mind wandering relative to breath focus. The findings indicate that meditation training alters both the subjective experience and the oscillatory and non-oscillatory components of brain activity.
bioRxiv Preprint Server
May 30, 2021
Calvin K. Young, Kachina G. Kinley, Neil McNaughton
preprint
Depression is the leading cause of disability worldwide, yet its biological mechanisms remain poorly understood. This study investigated whether scaffolding proteins in the medial frontal cortex contribute to antidepressant effects. The researchers injected chABC into the infralimbic cortex of animals to remove perineuronal nets and then tested for antidepressant effects using the forced swim test. They also tested whether systemic ketamine injections added to the effect. Preliminary data indicate that neither removing the scaffolding proteins nor ketamine alone decreased depression-like behavior, but the two treatments may interact synergistically to decrease immobility time in the forced swim test.
bioRxiv Preprint Server
April 15, 2021
Moritz Haaf, Stjepan Curic, Saskia Steinmann et al.
preprint
A reduction in the early auditory evoked gamma-band response (aeGBR), a type of brain wave, is seen in both schizophrenia patients and healthy people given ketamine, which mimics the brain's excitation/inhibition imbalance thought to underlie the disorder. This change in brain activity is linked to negative symptoms. In a study of 24 healthy men, ketamine alone reduced the aeGBR amplitude and increased negative symptoms as measured by the PANSS scale. Pretreatment with the amino acid glycine lessened both the brain-wave alteration and the symptom increase in those who responded to glycine. The aeGBR may serve as a biomarker to identify schizophrenia patients with negative symptoms who could benefit from glutamatergic treatments.
bioRxiv Preprint Server
April 12, 2021
Peter Coppola, Lennart R.b. Spindler, Andrea I. Luppi et al.
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The diversity of brain dynamics within small-world network topology, measured as sample entropy (dSW-E), consistently predicts levels of awareness across sedation and disorders of consciousness, even after accounting for underlying functional connectivity dynamics. Both subcortical and cortical areas show predictive value, but subcortical regions exhibit higher and more robust effect sizes. The dynamic reorganization of the functional information architecture, especially in the subcortex, emerges with awareness and offers explanatory power beyond the complexity of dynamic functional connectivity alone.