Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
Neuron July 5, 2021 Ling-Xiao Shao, Clara Liao, Ian Gregg et al. 589 citations
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Alex C. Kwan
Yale University, Cornell University
32 papers in the library · 1,808 citations · publishing 2016-2026
Papers
The neural basis of psychedelic action.
Nat Neurosci October 24, 2022 Alex C. Kwan, David E. Olson, Katrin H. Preller et al. 291 citations
This review synthesizes the neurobiology of psychedelic drugs, which are serotonin 2A receptor agonists that alter perception, cognition, and mood. It covers the chemistry of diverse psychoactive molecules, their potency and pharmacokinetics, and the roles of serotonin receptors and downstream signaling pathways. The review describes effects on neuronal spiking in cortical and subcortical regions, transcriptional changes, and structural plasticity. Neuroimaging findings highlight impacts on association cortices and thalamocortical connectivity, informing theories of psychedelic action. The authors integrate knowledge across chemical, molecular, neuronal, and network levels to explain acute and enduring behavioral effects.
Longitudinal Effects of Ketamine on Dendritic ArchitectureIn Vivoin the Mouse Medial Frontal Cortex
eNeuro March 1, 2016 Victoria Phoumthipphavong, Florent Barthas, Samantha Hassett et al. 142 citations
A single low dose of ketamine, an NMDA receptor antagonist, produces fast-acting antidepressant effects. In mice, a single injection of ketamine increased dendritic spine density in the medial frontal cortex for up to two weeks compared to saline-injected controls. This prolonged increase was driven by a higher rate of new spine formation, not by changes in spine elimination. Some new spines persisted, indicating functional synapses. In a few cases, distal apical tuft branches retracted the day after ketamine administration. These findings suggest that ketamine causes immediate removal of some dendritic inputs and gradual addition of others, consistent with a rebalancing of synaptic inputs onto frontal cortical neurons.
Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin
ACS Chemical Neuroscience January 11, 2023 Ling-Xiao Shao, Pasha A. Davoudian, Alex C. Kwan 131 citations
Psilocybin and ketamine both acutely increase expression of the immediate early gene c-Fos in numerous brain regions of male and female mice, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Some regions showed drug-preferential differences: dorsal raphe and insular cortex for psilocybin, and the CA1 subfield of hippocampus for ketamine. Endogenous levels of the glutamate receptor genes Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both compounds. The findings suggest glutamatergic receptors as a convergent target for the therapeutic effects of psilocybin and ketamine.
Psychedelics.
Curr Biol January 1, 2022 Benjamin Kelmendi, Alfred P. Kaye, Christopher Pittenger et al. 115 citations
Psychedelics are consciousness-altering compounds that act on serotonin receptors in the brain. First called 'psychedelic' in 1956, they are also known as hallucinogens, entheogens, or empathogens, reflecting their diverse subjective effects. Hundreds of such compounds exist with a range of behavioral and neurobiological impacts. Recent evidence that psychedelics can effectively treat mental illnesses has renewed scientific interest in their neural mechanisms. This Primer offers a concise overview of current scientific data for those entering the field.
A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics
Trends in Neurosciences December 21, 2020 Neil K. Savalia, Ling-Xiao Shao, Alex C. Kwan 110 citations
Ketamine and serotonergic psychedelics like psilocybin both relieve depression and promote neural plasticity, despite targeting different molecular receptors. This opinion article proposes a conceptual framework suggesting their actions converge at the dendrites, where they both enhance and suppress membrane excitability. Mismatches in these opposing effects may explain differences in cell-type and region selectivity, the compounds' moderate range of effects and toxicity, and their plasticity-promoting capacities.
Psychedelics and Neural Plasticity: Therapeutic Implications.
J Neurosci November 1, 2022 Steven F. Grieco, Eero Castrén, Gitte M. Knudsen et al. 83 citations
Psychedelic drugs are being reexamined as treatments for brain disorders, with hundreds of clinical trials underway by 2022. Emerging evidence suggests these drugs may produce lasting therapeutic effects by inducing structural and functional neural plasticity. The work reviews basic and clinical research on mechanisms, including receptor binding, gene expression, dendritic changes, and effects on microcircuitry and brain-wide circuits. It also outlines unmet clinical needs and unanswered neuroscience questions for future study.
Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.
Nature June 1, 2025 Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian et al. 75 citations
A single dose of psilocybin increases dendritic spine density in two types of pyramidal cells in the mouse medial frontal cortex: subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) neurons. Silencing PT neurons eliminates psilocybin's ability to reduce stress-related behaviors, while silencing IT neurons has no effect. Psilocybin boosts synaptic calcium transients and firing rates specifically in PT neurons shortly after administration. Knocking out the 5-HT2A receptor blocks psilocybin's effects on both stress-related behavior and structural plasticity. These findings identify PT neurons and the 5-HT2A receptor as essential for psilocybin's long-term actions.
Structural neural plasticity evoked by rapid-acting antidepressant interventions.
Nature reviews. Neuroscience February 1, 2025 Clara Liao, Alisha N Dua, Cassandra Wojtasiewicz et al. 60 citations
A feature of major depressive disorder is impaired excitatory synapses in the prefrontal cortex. Treatments with rapid antidepressant effects—ketamine, electroconvulsive therapy, and non-invasive neurostimulation—appear to enhance neural plasticity, but the specific forms and mechanisms linking these interventions to restoring excitatory synaptic function remain unknown. This review highlights preclinical research from the past 15 years showing that ketamine and psychedelic drugs can trigger growth of dendritic spines in cortical pyramidal neurons.
5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology August 1, 2023 Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al. 57 citations
5-MeO-DMT, a short-acting psychedelic, produces a dose-dependent increase in head-twitch response in mice that is shorter in duration than psilocybin at all doses tested. It also substantially suppresses social ultrasonic vocalizations during mating behavior. The compound causes long-lasting increases in dendritic spine density in the mouse medial frontal cortex, driven by an elevated rate of spine formation, but unlike psilocybin, it does not affect the size of dendritic spines. These findings reveal behavioral and neural mechanisms of 5-MeO-DMT, highlighting similarities and differences with psilocybin.
Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors
ACS Chemical Neuroscience August 1, 2024 Samuel C Woodburn, Caleb M. Levitt, Allison M Koester et al. 28 citations
Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, across all doses tested. It also produces long-term improvements in extinction retention and reduces fear renewal in a novel context, though these effects depend on dose. Females may respond to a narrower dose range than males. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is necessary. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, retention, and renewal, while blocking the 5-HT1A receptor only attenuates the effect on fear renewal. These findings highlight dose, context, and serotonin receptors as key factors in psilocybin's facilitation of fear extinction.
Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI.
Neuron November 20, 2024 Praachi Tiwari, Pasha A. Davoudian, Darshana Kapri et al. 26 citations
The serotonergic psychedelic DOI reduces anxiety-like behavior by activating 5-HT2A receptors on fast-spiking parvalbumin (PV)-positive interneurons in the CA1/subiculum region of the ventral hippocampus. Experiments combining anatomical, pharmacological, and genetic methods showed that these receptors are necessary for the anxiolytic effect. In vivo recordings revealed that DOI increases the firing rate of PV-positive interneurons, most of which express 5-HT2A receptors. Restoring 5-HT2A receptors specifically in PV-positive cells in a loss-of-function background reinstated DOI's anxiety-relieving effects, identifying these interneurons as a cellular trigger for psychedelic-induced relief of anxiety-like behavior.
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
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.
Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression
Nature Communications February 12, 2025 Farid Aboharb, Pasha A. Davoudian, Ling-Xiao Shao et al. 19 citations
A machine-learning pipeline using light sheet fluorescence microscopy to measure immediate early gene expression in mouse brain tissues classified psychoactive drugs with 67% accuracy across eight conditions, significantly above the 12.5% chance level. Psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with over 95% accuracy. Shapley additive explanation identified brain regions driving predictions, suggesting a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.
Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin
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.
Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks
Cell December 5, 2025 Quan Jiang, Ling-Xiao Shao, Shenqin Yao et al. 15 citations
A single dose of psilocybin causes structural remodeling of dendritic spines in the medial frontal cortex of mice. Using monosynaptic rabies tracing, the researchers mapped brain-wide inputs to frontal cortical pyramidal neurons and found that psilocybin's effect on connectivity is network specific: it strengthens routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on drug-evoked spiking activity, as silencing a presynaptic region during psilocybin administration disrupts the rewiring. These results reveal how psilocybin impacts large-scale cortical network connectivity and show that neural activity modulation can sculpt psychedelic-evoked plasticity.
The ABCs of psychedelics: a preclinical roadmap for drug discovery.
Trends Pharmacol Sci August 28, 2025 Alex C. Kwan, John R. Mantsch, John D. Mccorvy 7 citations
Developing psychedelic-inspired drugs for psychiatric disorders requires identifying analogs with ideal receptor selectivity and therapeutic efficacy. Recent advances include determining agonist-induced biased signal transduction, high-content behavioral phenotyping via automated video analysis, drug-evoked structural neural remodeling, and activity-dependent gene expression. This review outlines a framework for evaluating psychedelics and non-hallucinogenic serotonin 2A (5-HT2A) receptor agonists, critically examining methods for assessing agonism, behavior, and cellular plasticity. Emerging techniques that may improve translation to humans are highlighted. An effective discovery pipeline must align with specific experimental goals and incorporate multiple approaches for successful psychedelic drug development.
5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice
bioRxiv (Cold Spring Harbor Laboratory) November 3, 2022 Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al. 5 citations preprint
The short-acting psychedelic 5-MeO-DMT increases head-twitch response in mice in a dose-dependent manner, with a shorter duration than psilocybin. It strongly suppresses social ultrasonic vocalizations during mating behavior and produces long-lasting increases in dendritic spine density in the medial frontal cortex by elevating the rate of spine formation, but unlike psilocybin, it does not affect spine size. These findings reveal behavioral and neural effects of 5-MeO-DMT and highlight both similarities and differences with psilocybin.
Psilocybin Prolongs the Neurovascular Coupling Response in Mouse Visual Cortex
bioRxiv (Cold Spring Harbor Laboratory) July 31, 2025 Rick Zirkel, Matthew Isaacson, Clara Liao et al. 3 citations preprint
Psilocybin prolongs increases in visual stimulus-evoked capillary blood flow in the mouse visual cortex without altering stimulus-evoked neural activity. This effect was reduced by pretreatment with a 5-HT2A receptor antagonist. Multi-modal widefield imaging confirmed extended vascular responses in surface vessels with no observed effect on population neural response. Computational simulations showed that prolonged neurovascular coupling responses can produce spurious increases in BOLD-based measures of functional connectivity. These findings demonstrate that psilocybin broadens neurovascular responses in the brain, highlighting the need to account for these effects when interpreting human neuroimaging data of psychedelic drug action.
Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression
bioRxiv (Cold Spring Harbor Laboratory) January 4, 2025 Clara Liao, Ethan O'Farrell, Yaman Qalieh et al. 3 citations preprint
A single dose of psilocybin triggers time-dependent and cell-type-specific changes in gene expression in the medial frontal cortex of mice. Excitatory neurons showed altered genes involved in synaptic plasticity, while GABAergic neurons showed changes in genes related to mitochondrial function and metabolism. These transcriptional responses occurred in an early phase at 1-2 hours and a late phase at 72 hours after administration. Ketamine produced similar transcriptional changes. These findings suggest that psilocybin's long-term neural and behavioral effects may stem from lasting alterations in gene expression.
Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression.
bioRxiv : the preprint server for biology November 23, 2024 Farid Aboharb, Pasha A. Davoudian, Ling-Xiao Shao et al. 3 citations preprint
A pipeline using light sheet fluorescence microscopy to measure immediate early gene expression in mouse brain tissues, combined with machine learning, can classify psychoactive drugs including psilocybin, ketamine, and MDMA. In one-versus-rest tests, the exact drug was identified with 67% accuracy, far above the 12.5% chance level. Psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with over 95% accuracy in pairwise comparisons. Shapley additive explanation identified brain regions driving the predictions. The approach offers a novel way to characterize and validate psychedelic and related compounds.
Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors
bioRxiv (Cold Spring Harbor Laboratory) May 6, 2024 Samuel C Woodburn, Caleb M. Levitt, A. Koester et al. 3 citations preprint
Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, with effects observed at all doses tested. It also produces long-term improvements in extinction retention and suppression of fear renewal in a novel context, though these effects depend on dose. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is required. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, extinction retention, and fear renewal, while blocking the 5-HT1A receptor only reduces the effect on fear renewal. These results indicate dose, timing, context, and serotonin receptors are critical for psilocybin's facilitation of fear extinction, supporting its potential as an adjunct to extinction-based therapy for PTSD.
Psychedelic drug action at dendrites is gated by behavioral state and serotonin receptors
bioRxiv (Cold Spring Harbor Laboratory) July 20, 2026 Neil K. Savalia, Ling-Xiao Shao, Cory A. Knox et al.
Psilocybin transiently increases calcium event rates in apical dendritic tufts of pyramidal tract neurons in the mouse medial frontal cortex, an effect that parallels the drug's brain pharmacokinetics. This acute effect occurs selectively during quiet wakefulness and depends on the 5-HT2A receptor. Under normal conditions, dendritic calcium signaling predicts subsequent spine formation, but psilocybin disrupts this relationship. The findings suggest that the mechanisms linking acute dendritic activity to long-term structural plasticity differ between physiological and psychedelic-induced plasticity.
α2-Adrenergic receptor modulates 5-HT2A-mediated behavioral effects of MDMA and psilocybin in mice.
Mol Psychiatry July 7, 2026 Axel F. Rosado, Abigail L. Yu, Jen-Hau Yang et al.
Psilocybin and MDMA are both psychedelic drugs but produce different behavioral effects. MDMA, but not psilocybin, raises both serotonin and norepinephrine in the medial prefrontal cortex. Blocking norepinephrine release reveals head-twitch responses (a rodent correlate of psychedelic effects) from MDMA, suggesting that noradrenergic signaling opposes serotonin 2A receptor effects. Artificially raising norepinephrine also reduces psilocybin-induced head-twitch responses. Activating the noradrenergic alpha-2 receptor alone suppresses these responses, even in mice lacking the locus coeruleus, indicating action via heteroreceptors. Importantly, alpha-2 receptor activation does not block psilocybin's antidepressant-like effects in the forced swim test. This suggests that side effects of serotonin 2A activation can be reduced without losing therapeutic benefits.
Structural plasticity and enhanced fear extinction following psilocybin in chronically stressed mice.
bioRxiv : the preprint server for biology April 22, 2026 Cory A. Knox, Samuel C Woodburn, Amelia D. Gilbert et al.
Psilocybin, a classic psychedelic, increases dendritic spine density in frontal cortical neurons and facilitates fear extinction after chronic restraint stress in mice, demonstrating its effects in a translationally relevant animal model. Prior studies had largely examined stress-naive animals, so these findings show that psilocybin can promote neural plasticity and behavioral recovery even after chronic stress.