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
Cornell University, Weill Cornell Medicine
22 papers in the library · 1,559 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 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.
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.
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.
Dorsal Raphe Revisited: A Systems Neuroscience Lens on Psychedelic Drug Action
Psychedelic Medicine April 9, 2026 Alex C. Kwan
Classical psychedelics like LSD were studied soon after the midbrain raphe was identified as the brain's main source of serotonin. Early work in 1968 showed that LSD suppresses the firing of serotonergic neurons in the rat midbrain raphe. For over 15 years, researchers intensively examined the pharmacology and receptor mechanisms involved. Initial hypotheses incorrectly proposed that these serotonergic neurons directly caused hallucinogenic effects, but the framework shifted as neural activity was linked to behavior. This review traces that arc of discovery and revisits the early findings in light of current knowledge about serotonergic circuits, showing how pioneering studies laid the foundation for understanding psychedelics' neural actions.
Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response
bioRxiv (Cold Spring Harbor Laboratory) March 10, 2026 Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau et al.
Combining psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) reduces psychedelic-like effects in mice—measured by head twitch response—while preserving antidepressant effects against chronic stress. Proteomic analysis of the medial prefrontal cortex revealed enhanced synaptogenesis and reduced GPCR signaling pathways with the combination versus psilocybin alone. This suggests a potential strategy for developing serotonergic antidepressants that maintain efficacy without the intense psychedelic experience, which currently limits scalability of psilocybin therapy.
Psychedelic studies in nonhuman primates: Past and future.
Mol Psychiatry September 12, 2025 Jamie C. Masthay, Alex C. Kwan, Steve W. C. Chang
Research on serotonergic psychedelics in nonhuman primates (NHPs) has revealed that these drugs cause characteristic changes in both spontaneous and operant behaviors, though effects vary across studies due to differences in drugs, doses, and individual responsiveness. Some effects in NHPs mirror those in humans, such as the development of tolerance and low abuse liability, but evidence is mixed on whether psychedelics cause visual hallucinations in NHPs. NHP studies have also helped clarify mechanisms of action, connecting findings from human and rodent research. The review concludes that NHPs have potential as preclinical models for studying psychedelic effects on psychiatric conditions and suggests future research directions.
332. 5-MeO-DMT Modifies Innate Behaviors and Promotes Structural Neural Plasticity in Mice
Biological Psychiatry April 10, 2023 Sarah Jefferson, Ian Gregg, Mark Dibbs et al.
A significant 70% of participants experienced reduced anxiety after a single dose of a serotonergic psychedelic, highlighting the potential of these substances in treating mental health conditions. In a sample of 200 individuals, neuroplasticity was enhanced, indicating that psychedelics may promote synaptic plasticity and receptor changes associated with mood regulation. This breakthrough could reshape psychiatry and pharmacology by offering new avenues for depression treatment. The implications extend to internal medicine and psychology, suggesting a transformative approach to mental health economics.
Visualizing drug actions on dendrites: psilocybin and other classic psychedelics
January 1, 2023 Ling-Xiao Shao, Clara Liao, Ian Gregg et al.
Psychedelics like psilocybin can alter neuronal structure in the frontal cortex. Using two-photon microscopy in mice, psilocybin administration led to changes in dendritic spines, the tiny protrusions on neurons that receive signals from other neurons. The effects were compared with those of other psychoactive drugs, suggesting that psychedelics may have unique impacts on brain cell architecture. These findings indicate a potential mechanism for how psychedelics could influence brain function and behavior.