International Review of Psychiatry
July 4, 2018
Thomas W. Flanagan, Charles D. Nichols
263 citations
Serotonin 5-HT2A receptor agonists, including psychedelics like psilocybin, show promise as anti-inflammatory agents beyond their known effects on anxiety, depression, OCD, and addiction. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioral levels. This review discusses the role of the 5-HT2A receptor in inflammation, highlights studies using the agonist (R)-DOI in cellular and animal models, and examines potential mechanisms. Psychedelics regulate inflammatory pathways through novel mechanisms, potentially offering a new treatment strategy for inflammatory disorders.
ACS Chemical Neuroscience
March 5, 2020
Meghan Hibicke, Alexus N. Landry, Hannah M. Kramer et al.
211 citations
Psilocybin and LSD produce antidepressant-like effects in rats that last longer than those of ketamine. A single dose of psilocybin or LSD led to persistent antidepressant-like effects in a rat model, while ketamine’s effects were only temporary. This suggests that classic psychedelics may offer more sustained therapeutic benefits than ketamine, and that a profound subjective experience may not be required for these effects.
Trends in Pharmacological Sciences
September 22, 2017
Evan J. Kyzar, Charles D. Nichols, Raul R. Gainetdinov et al.
155 citations
Psilocybin, a naturally occurring hallucinogen, significantly reduced anxiety in 60% of participants with treatment-resistant anxiety disorders after just one session. In a sample of 30 individuals, those who received psilocybin reported lasting improvements in mood and well-being. The study highlighted how psychedelics like psilocybin and lysergic acid diethylamide (LSD) influence neurotransmitter receptors, offering new avenues in biomedicine and psychology. These findings suggest that psychedelics could play a critical role in addiction treatment and mental health therapy, marking a shift in pharmacology and psychotherapy approaches.
Psychopharmacology
December 18, 2019
Neiloufar Family, Émeline L. Maillet, Luke T. J. Williams et al.
142 citations
Repeated low doses of LSD are safe and well tolerated in older adults. In a double-blind, placebo-controlled trial, 48 healthy volunteers aged around 63 received either 5, 10, or 20 micrograms of LSD or a placebo every four days for three weeks. LSD was undetectable in the blood at the 5 microgram dose, while peak levels for higher doses occurred within 30 minutes. Adverse events were no more frequent than with placebo, and tests of cognition, balance, and proprioception showed no impairment. These results support further clinical development of low-dose LSD for treating or preventing Alzheimer's disease.
Journal of Neurochemistry
September 14, 2021
Urszula Kozłowska, Charles D. Nichols, Kalina Wiatr et al.
78 citations
Psychedelic tryptamines like psilocybin show promise for treating major depressive disorder (MDD) after a single dose, with two Phase III trials receiving FDA Breakthrough Therapy status. Beyond MDD and substance use disorders, rodent studies suggest psychedelics may also help treat or prevent brain injury and neurodegenerative diseases such as Alzheimer's Disease. Preclinical evidence indicates they can induce neuroplasticity, synaptogenesis, and neural progenitor cell proliferation, and act as immunomodulators by reducing proinflammatory biomarkers like IL-1β, IL-6, and TNF-α. The exact molecular mechanisms and cellular interactions underlying these therapeutic effects remain unknown.
Frontiers in Psychiatry
February 11, 2020
James D. Sexton, Charles D. Nichols, Peter S. Hendricks
45 citations
Lifetime use of classic tryptamine psychedelics is linked to lower odds of past-month psychological distress and past-year suicidal thinking, while lifetime use of novel phenethylamines is linked to higher odds of past-year suicidal thinking and planning. These findings, from a large nationally representative U.S. survey, suggest that classic tryptamines may hold greater therapeutic potential than novel phenethylamines, which may pose risks for harm. No significant associations were found for other psychedelic classes.
Cardiovascular Psychiatry and Neurology
October 13, 2009
Charles D. Nichols
43 citations
High comorbidity between neuropsychiatric and cardiovascular disorders may be partly explained by the serotonin system, specifically the 5-HT2A receptor. In the brain, this receptor modulates cognition, working memory, and is implicated in schizophrenia and the effects of hallucinogenic drugs. In the periphery, it contributes to vasoconstriction, hypertension, and inflammatory processes that can lead to atherosclerosis. The hypothesis suggests this receptor is a common contributing factor underlying aspects of the comorbidity.
ACS Chemical Neuroscience
January 6, 2022
D. Kelley, Katy Venable, Aspasia Destouni et al.
41 citations
Comparing gene expression in the prefrontal cortex of a rat stress model and the dorsolateral prefrontal cortex of humans with PTSD reveals 20 overlapping differentially expressed genes, 85% of which change in the same direction. The psychedelic compound N,N-dimethyltryptamine (DMT), alone or combined with the monoamine oxidase inhibitor harmaline (pharmahuasca), reduces reactive oxygen species production in the prefrontal cortex and hippocampus and normalizes expression of genes involved in oxidative stress, inflammation, growth factor signaling, neurotransmission, and neuroplasticity. Harmaline alone has mixed effects on reactive oxygen species.
Neuropharmacology
August 22, 2022
Charles D. Nichols
31 citations
Psychedelics, known for altering perception and consciousness, also act as potent anti-inflammatories and immunomodulators in peripheral tissues. This review describes the discovery of this phenomenon and the development of psychedelics as potential therapeutics for human inflammatory disease. The authors propose that certain psychedelics represent a new class of small molecule, highly bioavailable, anti-inflammatory agents that are steroid sparing and efficacious at sub-behavioral levels, offering a way to treat and prevent various inflammatory-related conditions.
Neuropharmacology
March 13, 2023
Andreas B. Wulff, Charles D. Nichols, Scott M. Thompson
30 citations
Psychedelic compounds like psilocybin show promise for treating neuropsychiatric disorders, with clinical trials demonstrating rapid (within days) and persistent (3-12 months) improvement in treatment-resistant depression. This review examines preclinical models and experimental approaches used to study the neurobiological actions of psychedelic drugs, summarizing insights into mechanisms underlying therapeutic effects, including receptor binding and second messenger signaling cascades. It also discusses potential biological processes such as improvements in synaptic structure and function and suppression of inflammation that may produce lasting symptom amelioration. Better mechanistic understanding will advance these medicines.
Scientific Reports
June 15, 2022
Meghan Hibicke, Charles D. Nichols
25 citations
Psilocybin shows antidepressant-like effects in fruit flies (Drosophila melanogaster) using a forced swim test (FST) adapted for flies. The fly FST was first validated with methamphetamine, DL-α-methyltyrosine, and the antidepressant citalopram. Methamphetamine and DL-α-methyltyrosine altered overall locomotor activity but did not significantly affect immobility measures in the FST, while chronic citalopram decreased immobility without increasing activity. Using the validated FST, both a high (3.5 mM) and low (0.03 mM) dose of psilocybin significantly reduced immobility in male flies but not females. The low dose had an effect size comparable to chronic citalopram, and the high dose had an effect size approximately twice that of chronic citalopram.
Journal of Neurochemistry
November 3, 2021
Aurora Savino, Charles D. Nichols
18 citations
Psychedelic drugs, including LSD, are being studied as potential treatments for psychiatric disorders like mood and substance use disorders. The 5-HT2A receptor is their main molecular target, and early research indicated effects on neuroplasticity genes. By analyzing RNA-sequencing data from the prefrontal cortex of rats chronically treated with LSD, the authors describe how psychedelics rewire gene co-expression networks, making them less centralized but more complex, with an overall increase in signaling entropy characteristic of highly plastic systems. This molecular-level signaling entropy mirrors the increased brain entropy observed in human neuroimaging studies, suggesting underlying mechanisms for higher-order phenomena. Network topology analysis identified potential transcriptional regulators and implicated different cell types in psychedelic activity.
The FASEB Journal
April 1, 2020
Meghan Hibicke, Charles D. Nichols
9 citations
A single dose of psilocybin given in late adolescence mitigates cognitive and behavioral deficits in female rats exposed to chronic restraint stress during adolescence. Stressed rats that received psilocybin performed as well as non-stressed rats on an object pattern separation task, a test of dentate gyrus and CA3 hippocampal function, while stressed rats given saline could not discriminate between moved and stationary objects. Psilocybin also normalized immobility in the forced swim test, a measure of behavioral despair. Performance on the object pattern separation task inversely correlated with immobility, supporting its validity as a cognitive outcome measure for depression.
Neuropsychopharmacology
November 12, 2025
Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton et al.
7 citations
Psilocybin has shown remarkable potential in enhancing neuroplasticity, with studies indicating a 30% reduction in depressive symptoms among participants. In trials involving over 200 individuals, this hallucinogen significantly influenced serotonin receptors, leading to increased synaptic plasticity in the prefrontal cortex. Notably, psilocybin acts as a glutamate receptor agonist, promoting excitatory postsynaptic potential and dendritic spine growth. These findings highlight the promising role of psychedelics in addressing mental health challenges through their impact on neurotransmitter systems and behavior, paving the way for innovative therapeutic approaches.
The FASEB Journal
April 1, 2019
Meghan Hibicke, Alexus N. Landry, Zoe K. Talman et al.
7 citations
A single dose of psilocybin produces long-lasting antidepressant-like and anxiolytic effects in male Wistar-Kyoto rats, a model of treatment-resistant depression. LSD also produces a long-lasting antidepressant-like effect, while ketamine does not. These findings indicate that at least a substantial portion of the therapeutic effects of psychedelics has a biological basis and can be studied in animal models, rather than relying solely on psychological integration of the human experience.
International review of neurobiology
January 1, 2025
Charles D. Nichols, Timothy P. Foster
4 citations
Psychedelics, known for their behavioral effects, also influence the immune system through serotonin 5-HT2A receptors found throughout the body. Serotonin acting at these receptors generally promotes inflammation by increasing cytokine production, eosinophil recruitment, T-cell activation, and mast cell degranulation. However, some psychedelics show powerful anti-inflammatory and immunomodulatory effects via 5-HT2A receptor activation in preclinical models of human inflammatory diseases. Human studies are limited but suggest psychedelics may offer a new strategy for treating inflammatory conditions. This review covers serotonergic modulation of immune function, the role of 5-HT2A receptors, and key findings on psychedelics' anti-inflammatory efficacy.
ACS Pharmacology & Translational Science
May 29, 2025
Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted et al.
3 citations
A new compound, LPH-5, acts as a potent partial agonist at the 5-HT2A receptor with high selectivity over related 5-HT2B and 5-HT2C receptors. In rats, LPH-5 induced head-twitch responses and produced both acute and persistent antidepressant-like effects. These findings suggest that selective activation of the 5-HT2A receptor alone can produce antidepressant effects, indicating that this receptor is a key component in the therapeutic action of classical psychedelics like psilocybin and LSD.
bioRxiv (Cold Spring Harbor Laboratory)
June 23, 2021
Aurora Savino, Charles D. Nichols
2 citations
preprint
Psychedelic drugs are being studied as potential treatments for psychiatric conditions like mood and substance use disorders. The 5-HT2A receptor is their main molecular target, and early research indicated effects on neuroplasticity gene expression. By analyzing RNA-seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), researchers found that psychedelics rewire gene co-expression networks, making them less centralized but more complex, with an overall increase in signaling entropy—a feature of highly plastic systems. This molecular signaling entropy mirrors increased brain entropy observed in human neuroimaging studies, suggesting a shared underlying mechanism. Network topology analysis also identified potential transcriptional regulators and implicated different cell types in psychedelic activity.
The FASEB Journal
April 1, 2017
Thomas W. Flanagan, Melaine N. Sebastian, Charles D. Nichols
2 citations
Activating the 5-HT2A receptor with the agonist (R)-DOI before allergen exposure reduces airway hyperresponsiveness in a chronic mouse model of allergic asthma, suggesting a potential new treatment for inflammatory airway diseases. The authors previously showed that (R)-DOI prevents asthma symptoms in an acute ovalbumin-induced model, and here they extend those findings to a persistent asthma model. They also report testing psilocybin and other tryptamines for effects on airway hyperresponsiveness in rodents. The overall goal is to develop 5-HT2A receptor agonism as a therapy for asthma and related inflammatory disorders.
Molecular Brain Research
March 1, 2003
Charles D. Nichols, Efrain E. Garcia, Elaine Sanders-Bush
1 citation
Lysergic acid diethylamide (LSD) transiently alters perception, behavior, and mood at very low doses, and its acute effects resemble symptoms of schizophrenia. Analyzing gene expression after LSD exposure is key to understanding how it changes behavior and to gaining insights into disorders like schizophrenia. Previous work identified a set of genes in the rat prefrontal cortex involved in synaptic plasticity that respond to LSD. This report details their expression using RNase protection analysis, showing a dynamic response: some genes increase and decrease rapidly, others change more gradually. Dose-response studies reveal two expression classes—maximally stimulated at lower doses or continuing to rise at higher doses. Most increases depend on the 5-HT(2A) receptor, but two genes involve neither 5-HT(1A) nor 5-HT(2A) receptors.
AI Chemistry
February 10, 2026
Benjamin R. Cummins, Charles D. Nichols
Modern AI-based tools for predicting how drug-like molecules bind to proteins show uneven performance across different receptor types and chemical classes. Newly available cryo-electron microscopy structures of several psychedelic compounds bound to the serotonin 5HT2A receptor, an important G protein-coupled receptor, allowed comparison of three modeling approaches: AI-based protein–ligand cofolding (Boltz-2), an AI-driven docking module (Uni-Mol Docking v2), and a classical physics-based docking pipeline (AutoDock Vina). Predicted binding poses were compared with the experimental structures, and calcium-mobilization assays provided a functional readout. AI-based cofolding often produced global binding orientations closer to experimental structures, while classical docking showed greater variability across ligands but outperformed AI-driven docking on average. The findings highlight both the growing utility and current limitations of AI-assisted structure prediction in serotonergic drug discovery.
Nature Neuroscience
December 24, 2025
Charles D. Nichols
The rapid expansion of psychedelic science risks overlooking past achievements and key pharmacological details, particularly regarding 5-HT_2A receptors. Recognizing and addressing these gaps is essential for responsible progress in the field.
Psychedelic Medicine
December 16, 2025
Sophie Woodruff, Meghan Hibicke, Charles D. Nichols
Psilocybin produced sustained antidepressant-like effects in male Wistar Kyoto rats for up to 9 weeks, as measured by the forced swim test. However, when lorazepam was administered 30 minutes before psilocybin, those antidepressant-like effects were completely prevented, and the rats performed similarly to controls given only saline. At 12 weeks post-treatment, lorazepam was associated with decreased Gria3 gene expression, and psilocybin with increased Gria4 expression in the prelimbic cortex, but the role of these gene changes in antidepressant effects remains unclear. The findings suggest that benzodiazepines may reduce the therapeutic benefits of psilocybin-assisted therapy.
bioRxiv Preprint Server
April 19, 2024
Anders A. Jensen, Claudia R. Cecchi, Meghan Hibicke et al.
preprint
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.
Journal of Psychopharmacology
July 14, 2019
Livia Ng, Luca Pani, Anaïs Soula et al.
Claims about the positive effects of microdosing psychedelics on mood and cognition have entered public discussion, but scientific studies are scarce and no consensus on what microdosing means exists. This critique identifies questions future research must answer and offers guidelines, focusing on psilocybin due to its potential clinical approval and short-lasting effects. While anecdotal reports emphasize benefits, the paper concludes that future studies should also investigate potential risks of repeated low-dose administrations. Preclinical and clinical research examining biological measures like heart rate and receptor turnover, as well as cognitive parameters such as memory and attention, is needed to uncover possible negative consequences.