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
Psychedelic drugs like LSD, mescaline, and psilocybin produce strong effects on the brain and behavior. After decades of research difficulties, they are being tested again as possible treatments for hard-to-treat medical conditions. Preclinical research, human brain imaging, and early clinical trials suggest these compounds may help with addiction, depression, anxiety, and other disorders. However, many questions about how they work, their safety, and their effectiveness remain. This review summarizes recent preclinical and clinical data, discusses their pharmacological mechanisms, and outlines key areas for future research to maximize the potential benefits of psychedelic medicine for patients.
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.
EBioMedicine
September 1, 2016
David Martin, Charles D. Nichols
88 citations
Psychedelics directly activate a small subset of serotonin 5-HT2A receptor-expressing excitatory neurons in the cortex, which then recruit inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, producing distinct regional responses. This finding clarifies the cellular mechanisms underlying psychedelics' effects on perception and cognition, and their therapeutic potential for anxiety, depression, and addiction. The study also introduces a fluorescence-activated cell sorting (FACS) method for isolating specific brain cell subtypes based on cytoplasmic epitopes, enabling downstream nucleic acid analysis and expanding FACS applications in neuroscience.
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.
Journal of Neurochemistry
June 18, 2004
Charles D. Nichols, Elaine Sanders‐bush
62 citations
Lysergic acid diethylamide (LSD) increases the expression of three specific genes in the mammalian prefrontal cortex: C/EBP-beta, a transcription factor; MKP-1, indicating activation of the MAP kinase pathway; and ILAD-1, which shows sequence similarity to arrestins. These expression changes are partially mediated through LSD interactions at 5-HT2A serotonin receptors. Evidence suggests alternative splicing at the ILAD-1 locus, with different splice isoforms responding differently at the transcriptional level to LSD. These findings help build a more complete picture of the complex intracellular events initiated by hallucinogens.
Psychedelic Med (New Rochelle)
September 13, 2023
Jacob S. Aday, Brian S. Barnett, Dan Grossman et al.
56 citations
The psychedelic industry has grown into a multibillion dollar sector, with hundreds of companies formed in recent years to commercialize psychedelic-assisted therapies. Investment surged in the late 2010s and early 2020s, focusing on drug discovery, novel formulations, manufacturing, treatment centers, consumer goods, and adjunct technologies. Key challenges include regulatory barriers, high treatment costs, and intellectual property issues. Ethical concerns involve potential adverse effects, cost-cutting, ensuring access for marginalized communities, and reciprocity with Indigenous peoples. Lessons from the ketamine and cannabis industries offer guidance on regulatory approval, clinical implementation, and insurance reimbursement.
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.
Psychedelic Med (New Rochelle)
March 13, 2023
David E. Nichols, Charles D. Nichols, Peter S. Hendricks
39 citations
A proposed consensus statement defines psychedelic drugs as substances that reliably produce profound alterations in consciousness, perception, and mood through agonist activity at the serotonin 2A receptor. The definition emphasizes pharmacological mechanism over subjective effects, distinguishing psychedelics from other psychoactive compounds. The authors argue that a standardized definition is essential for advancing medical research, drug development, and clinical applications by providing a clear framework for classification and nomenclature. This consensus aims to reduce ambiguity in scientific and therapeutic contexts, supporting more precise communication and regulatory clarity in psychedelic research.
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.
ACS Pharmacology & Translational Science
January 25, 2024
Thomas W. Flanagan, Timothy P. Foster, Thomas E. Galbato et al.
18 citations
Two psychedelic compounds, (R)-DOI and (R)-DOTFM, both activate the serotonin 2A receptor with comparable in vitro activity and behavioral potency, yet only (R)-DOI prevents inflammation and airway hyperresponsiveness in a mouse model of asthma. The compounds produce distinct differences in protein expression and inflammatory-related gene expression in lung tissue. The anti-inflammatory effects of certain psychedelics involve suppression of arginase 1 expression, revealing key mechanistic components of their anti-inflammatory action.
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
A single dose of psilocybin or the selective 5-HT2A receptor agonist 25CN-NBOH reduces immobility in the forced swim test in rats for at least three months, with no decrease in effect size over that period. Both drugs produced similar behavioral effects, indicating that 5-HT2A receptor activation alone is sufficient for long-lasting changes. In the medial prefrontal cortex, layer 5 excitatory pyramidal neurons showed altered resting membrane potential, firing rates, and synaptic excitation months after treatment. However, no changes were found in synaptic density, spine classification, or expression of presynaptic and postsynaptic markers. The results suggest that enduring functional plasticity, rather than structural plasticity, underlies the long-term behavioral effects of psychedelics.
Psychedelic Med (New Rochelle)
March 13, 2023
Peter S. Hendricks, Charles D. Nichols, Kathryn A. Cunningham et al.
7 citations
A roundtable discussion among experts traces the history, current state, and future directions of psychedelic medicine. Participants review the early research era of the mid-20th century, the subsequent decades of prohibition, and the recent resurgence of clinical trials exploring psychedelics for mental health conditions. The conversation highlights therapeutic applications of substances such as psilocybin and MDMA, emphasizing their potential to treat depression, PTSD, and addiction. Experts also address challenges including regulatory hurdles, the need for trained therapists, and the importance of integrating these treatments into mainstream healthcare. The discussion concludes with cautious optimism about the field's trajectory.
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.
Psychedelic Med (New Rochelle)
September 13, 2023
Peter S. Hendricks, Charles D. Nichols
6 citations
A survey of psychedelic researchers found that a substantial majority have personal experience with psychedelics, and many report that this experience positively influences their professional work, including enhancing empathy and insight. The study highlights that personal use is common in the field, yet often remains an unspoken topic, suggesting it may shape research perspectives and practices.
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.