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
No Summary
Pasha A. Davoudian
16 papers in the library · 983 citations · publishing 2021-2026
Papers
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.
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.
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.
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.
Psychedelic renaissance: Revitalized potential therapies for psychiatric disorders.
Drug Discovery Today December 1, 2023 Taeho Greg Rhee, Pasha A. Davoudian, Gerard Sanacora et al. 20 citations
Psychiatric disorders are the leading cause of disability globally, and interest in psychedelic substances as potential treatments has recently revived. This review examines the therapeutic potential and safety concerns of psilocybin, DMT, LSD, and MDMA, including their possible interactions with psychotherapy. It covers active and recently completed clinical trials drawn from published literature, conference abstracts, clinical trial registries, and press releases. The review suggests that these compounds may offer new avenues for treating psychiatric disorders, though safety considerations remain important.
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.
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.
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 reshapes cortical inhibition through selective interneuron recruitment.
bioRxiv : the preprint server for biology April 17, 2026 Pasha A. Davoudian, Quan Jiang, Cory A. Knox et al.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
Pyramidal cell types and 5-HT 2A receptors are essential for psilocybin’s lasting drug action
bioRxiv (Cold Spring Harbor Laboratory) November 3, 2024 Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian et al. preprint
A single dose of psilocybin increased the density of dendritic spines in both subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) cell types in the mouse medial frontal cortex. Silencing PT neurons eliminated psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons had no detectable effect. In PT neurons only, psilocybin boosted synaptic calcium transients and elevated firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolished psilocybin's effects on stress-related behavior and structural plasticity. These results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential for psilocybin's long-term drug action.
332. 5-MeO-DMT Modifies Innate Behaviors and Promotes Structural Neural Plasticity in Mice
Biological Psychiatry April 10, 2023 Sarah J. 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.