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.
Psychedelic Med (New Rochelle)
December 13, 2023
David E. Nichols, Peter S. Hendricks, Charles D. Nichols
1 citation
The authors argue that the term 'psychedelic' is being applied so broadly in recent scientific literature that it risks losing its meaning. They respond to two other articles, contending that not all altered states of consciousness or therapeutic experiences qualify as psychedelic. The piece calls for more precise terminology to preserve the distinctiveness of classic psychedelics and their effects, warning that overextension could dilute scientific classification and hinder research into specific mechanisms and therapeutic applications.
Research Square
June 15, 2021
D. Parker Kelley, Katy Venable, Gerald Billac et al.
1 citation
In a rat model of post-traumatic stress disorder (PTSD), N,N-dimethyltryptamine (DMT) and the combination of DMT with the monoamine oxidase inhibitor harmaline (pharmahuasca) reduced reactive oxygen species (ROS) production in the prefrontal cortex and hippocampus, while harmaline alone had mixed effects. RNA sequencing of the prefrontal cortex showed that DMT and pharmahuasca altered expression of genes related to ROS production, inflammation, neurotransmission, and neuroplasticity. DMT, but not harmaline, showed both affinity and efficacy at the human 5HT2A receptor. The findings suggest DMT and pharmahuasca may help treat PTSD by reducing oxidative stress and inflammation and promoting neuroplasticity.
The FASEB Journal
April 1, 2019
Gerald Billac, Charles D. Nichols
1 citation
Classical serotonergic psychedelics are being re-examined as treatments for various diseases. While most research focuses on their central nervous system effects, previous work suggests that serotonin 2A receptor (5-HT2AR) agonists can modulate TNF-alpha-mediated inflammatory responses in the periphery. This study characterizes signaling pathway activation for a panel of 5-HT2AR ligands from three chemical classes: tryptamines, ergolines, and phenethylamines. Initial results examining the canonical Gαq pathway and β-arrestin2 recruitment showed no significant correlation between potency or efficacy and anti-inflammatory activity in vivo. Ongoing studies are examining additional GPCR-mediated signaling via cAMP accumulation to understand the structural basis for biased signaling and inform drug design.
The FASEB Journal
April 1, 2016
David Martin, Connie Porretta, Charles D. Nichols
1 citation
The classic psychedelic (R)-DOI, a selective 5-HT2 receptor agonist, activates a diverse set of brain cells beyond just neurons. In the medial prefrontal and somatosensory cortex of mice, (R)-DOI induced immediate early genes like cfos in parvalbumin- and somatostatin-expressing interneurons, HTR2A-expressing neurons, and astrocytes. A new flow cytometry method that preserves intact cytoplasm and extracellular membranes allowed isolation of pure populations of somatostatin and parvalbumin interneurons from whole cortex. Further sorting by cFos activation revealed that different immediate early genes, such as egr2, are not uniformly induced across all activated cells. The technique is broadly applicable for studying cell-type-specific transcriptional and translational effects of any manipulation in the brain.
The FASEB Journal
April 1, 2015
David Martin, Connie Porretta, Charles D. Nichols
1 citation
Serotonin hallucinogens such as LSD and DOI primarily act through the 5-HT2A receptor, but their effects on brain function at the cellular and network levels remain incompletely understood. In adult rats treated with LSD, DOI, or saline, the somatosensory and medial prefrontal cortices were collected and dissociated into single cells. Using fluorescence-activated flow cytometry to separate neurons from glia and activated from non-activated neurons, qPCR analysis revealed an enrichment of immediate early genes (including c-fos, fosb, arc, krox-20/egr-2) in a small population of activated cortical neurons. Differences in gene abundance (htr2a, slc17a7, gad67) between activated and non-activated cells indicate which specific cell types are directly activated. Further research is needed to determine how this transcriptional program contributes to long-term psychological changes.
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, Cláudia 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.
The FASEB Journal
April 1, 2017
Gerald Billac, Charles D. Nichols
A panel of 5-HT2A receptor ligands, including the psychedelic drug (R)-DOI, shows superpotent anti-inflammatory effects in mouse models of asthma and atherosclerosis. The ligands exhibit differential activation of signaling pathways, with (R)-2C-BCB strongly biased toward the Gq pathway as measured by calcium mobilization. Ongoing studies examine β-arrestin signaling, receptor internalization, and other GPCR pathways. The goal is to use structure-activity relationships to develop novel therapies targeting specific effector pathways for inflammation-based diseases.
The FASEB Journal
April 1, 2016
Kelly Jean Sherman, Charles D. Nichols
Lysergic acid diethylamide (LSD), a mixed serotonin receptor agonist, alters circadian activity in Drosophila melanogaster in a dose-dependent manner, with a more robust effect in females. Five concentrations (0.01, 0.1, 1.0, 3.0, and 10.0 mM) were administered for seven days in a light/dark environment, and activity was monitored using the Drosophila Activity Monitor. LSD disrupted endogenous circadian rhythms in free run (dark/dark) conditions at doses of 1.0 and 3.0 mM in both sexes. Changes in RNA levels of circadian and P450 genes in fly heads were measured. The findings suggest LSD affects circadian activity potentially through modulating expression of circadian genes downstream of serotonin receptor activation.
The FASEB Journal
April 1, 2012
David Martin, David E. Nichols, Charles D. Nichols
A novel rat model of schizophrenia was developed by treating rats with low doses of LSD for three months. This treatment caused persistent behavioral abnormalities including social deficits, hyperactivity, and anhedonia that continued after the drug was stopped. Protein analysis of the medial prefrontal cortex identified 12 differentially expressed proteins, 9 of which are also dysregulated in post-mortem brain tissue from people with schizophrenia. RNA sequencing showed that chronic LSD alters genes across all major neurotransmitter systems linked to schizophrenia, with many changes involving synaptic plasticity. The findings support chronic LSD treatment as a valid model for studying schizophrenia and may provide insights into the disease's underlying mechanisms.