Charles D. Nichols - The Consciousness Library

Assessing Modern AI-Driven Protein-Ligand Modeling with Phenethylamine and Tryptamine Psychedelics

AI Chemistry February 10, 2026 Benjamin R. Cummins, Charles D. Nichols

Modern advances in artificial intelligence have accelerated the development of computational tools for protein–ligand structure prediction, yet their real-world performance remains uneven across receptor classes and ligand chemotypes. Recently published cryo-EM structures of several different psychedelics bound to the serotonin 5HT2A receptor provide a unique opportunity to explore how modern...

DOI: 10.3390/aichem1010004 Docking animal Tryptamine Drug discovery G protein-coupled receptor +5

Allostatic Recalibration Theory (ART): Serotonergic Psychedelics Exert Transdiagnostic Therapeutic Effects by Recalibrating Allostasis to the Environment

SSRN Electronic Journal 2026 Dennis Parker Kelley, Gabriel Sturm, Katy Venable et al.

Serotonergic psychedelics produce therapeutic effects in clinical trials of diverse neuropsychiatric disorders, and preclinical models of inflammatory, cardiometabolic, and neuropsychiatric diseases. These effects appear largely mediated by the serotonin 5-HT2A receptor (5-HT2AR). How could psychedelics elicit transdiagnostic therapeutic effects through a single receptor across tissues as...

DOI: 10.2139/ssrn.6598058 Serotonergic Neuroplasticity Allostatic load Allostasis +5

Psychedelic research must be grounded in pharmacology

Nature Neuroscience December 24, 2025 Charles D. Nichols

Psychedelic science is growing rapidly and offers great promise for exciting new therapies, but this rapid growth has brought growing pains. These include a lack of appreciation of the history of the field and what has already been accomplished, and a lack of understanding of the pharmacology of psychedelics and 5-HT_2A receptors. These gaps must be recognized, acknowledged and addressed in...

DOI: 10.1038/s41593-025-02186-9 Full text

Preadministration of Lorazepam Negates the Long-Term Antidepressant-Like Effects of Psilocybin in Male Wistar Kyoto Rats

Psychedelic Medicine December 16, 2025 Sophie Woodruff, Meghan Hibicke, Charles D. Nichols

Introduction:Psilocybin, a classical psychedelic, has shown to produce persistent antidepressant effects, including in patients with treatment-resistant depression. In clinical practice, it is common to coprescribe benzodiazepines (BZDs) alongside antidepressants. However, our preliminary study indicated that preadministration of lorazepam diminished the antidepressant-like efficacy and...

DOI: 10.1177/28314425251393186 Psilocybin Lorazepam Pharmacology Prefrontal cortex +6

Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity

Neuropsychopharmacology November 12, 2025 Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton et al. 7 citations

Activation of serotonin 2A (5-HT2A) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well understood. Recent preclinical studies using mice have primarily examined relatively short time points after psychedelic administration, which does not address the long-lasting...

DOI: 10.1038/s41386-025-02272-3 Full text Psilocybin Neuroplasticity Synaptic plasticity Serotonin +11

The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents

ACS Pharmacology & Translational Science May 29, 2025 Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted et al. 3 citations

Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed...

DOI: 10.1021/acsptsci.5c00208 Serotonin Antidepressant Piperidine Agonist +3

5-HT2A receptors: Pharmacology and functional selectivity.

Pharmacological Reviews April 23, 2025 Benjamin R. Cummins, Gerald Billac, David E Nichols et al. 62 citations

Serotonin 5-HT2A receptors were one of the first serotonin receptors to be pharmacologically characterized. In mammals, they are expressed throughout the body in nearly every cell and tissue type, with the highest density in cortical layer V of the brain. They are involved in several aspects of normal physiological processes and behaviors and have been implicated in the etiology of...

DOI: 10.1016/j.pharmr.2025.100059 Full text Serotonin Psychedelics Mental health Brain chemistry

Serotonin, immune function, and psychedelics as potent anti-inflammatories.

International review of neurobiology 2025 Charles D. Nichols, Timothy P. Foster 4 citations

Psychedelics are primarily recognized for their profound behavioral effects, leading most research on psychedelics and their primary target, the 5-HT2A receptor, to focus on brain activity. However, these receptors are not only found within the brain and are present in nearly every tissue and cell type throughout the body, playing a significant role alongside serotonin in modulating various...

DOI: 10.1016/bs.irn.2025.04.011 Full text Immune system Psychedelic therapy psychedelics Therapeutic potential New strategy +8

History of psychedelic drug science and molecular pharmacology.

International review of neurobiology 2025 David E Nichols, Charles D. Nichols 3 citations

Classic psychedelics have been used by various cultures for millennia for healing and religious purposes. The modern era of psychedelic science began with the first empirical experiments by Dr. Arthur Heffter in 1898 to determine just what they are when he discovered the active alkaloid in the peyote cactus responsible for its intoxicating effects and named it mescaline. As with many aspects of...

DOI: 10.1016/bs.irn.2025.02.001 Full text Psychedelic therapy 5-ht2a receptors Classical psychedelics Psychedelic history +12

The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents

bioRxiv Preprint Server April 19, 2024 Anders A. Jensen, Cláudia R. Cecchi, Meghan Hibicke et al. preprint

Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with...

DOI: 10.1101/2024.04.19.590212 Full text

Preadministration of Lorazepam Reduces Efficacy and Longevity of Antidepressant-Like Effect from a Psychedelic.

Psychedelic medicine (New Rochelle, N.Y.) March 1, 2024 Meghan Hibicke, Gerald Billac, Charles D. Nichols 2 citations

Psychedelics such as psilocybin have been shown to have persistent antidepressant effects, but with considerable individual variability in optimal dosing. Intravenous (IV) dosing is rapid onset and quickly titrated, possibly preceded by an anxiolytic for patient comfort. We explored the viability of IV psilocin with and without preadministration of lorazepam for possible future inpatient...

DOI: 10.1089/psymed.2023.0037 Full text Psychedelic therapy Antidepressant efficacy Lorazepam Anxiety medication +3

Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression

ACS Pharmacology & Translational Science January 25, 2024 Thomas W. Flanagan, Timothy P. Foster, Thomas E. Galbato et al. 18 citations

Functional selectivity in the context of serotonin 2A (5-HT 2A ) receptor agonists is often described as differences psychedelic compounds have in the activation of Gq vs β-arrestin signaling in the brain and how that may relate to inducing psychoactive and hallucinatory properties with respect to each other. However, the presence of 5-HT 2A receptors throughout the body in several cell types,...

DOI: 10.1021/acsptsci.3c00297 Full text Serotonin Functional selectivity Agonist 5-HT Receptor +8

If Everything Is Psychedelic, Then Nothing Is: A Response to O'Donnell et al. and Lepow et al.

Psychedelic Med (New Rochelle) December 13, 2023 David E. Nichols, Peter S. Hendricks, Charles D. Nichols 1 citation

If Everything Is Psychedelic, Then Nothing Is: A Response to O'Donnell et al. and Lepow et al.

DOI: 10.1089/psymed.2023.29003.cdn Full text Psychedelics Terminology Scientific-classification Altered-states +1

5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

Psychopharmacology December 11, 2023 Haley Maria Dourron, Charles D. Nichols, Otto Simonsson et al. 23 citations

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity,...

DOI: 10.1007/s00213-023-06517-1 Full text 5-ht1a receptors Flashbacks Seizures Psychedelics hallucinogens +7

Psychedelic Commercialization: A Wide-Spanning Overview of the Emerging Psychedelic Industry.

Psychedelic Med (New Rochelle) September 13, 2023 Jacob S. Aday, Brian S. Barnett, Dan Grossman et al. 56 citations

Background: In the wake of positive clinical trial outcomes of psychedelic-assisted psychotherapy for the treatment of various psychiatric disorders, there has been an influx of financial investment into psychedelic drug development from the pharmaceutical and biotech sectors. Psychedelics are now a multibillion dollar industry, with hundreds of companies that are seeking to commercialize...

DOI: 10.1089/psymed.2023.0013 Full text Psychedelics Pharmaceutical-industry Mental-health-treatment Indigenous-medicine +1

The Elephant in the Room: Personal Use of Psychedelics Among Psychedelic Researchers.

Psychedelic Med (New Rochelle) September 13, 2023 Peter S. Hendricks, Charles D. Nichols 6 citations

The Elephant in the Room: Personal Use of Psychedelics Among Psychedelic Researchers.

DOI: 10.1089/psymed.2023.29002.psh Full text Psychedelic research Psychedelic science Hallucinogen studies Entheogen research +14

Proposed Consensus Statement on Defining Psychedelic Drugs.

Psychedelic Med (New Rochelle) March 13, 2023 David E. Nichols, Charles D. Nichols, Peter S. Hendricks 39 citations

Proposed Consensus Statement on Defining Psychedelic Drugs.

DOI: 10.1089/psymed.2022.0008 Full text Psychedelic drugs Psychedelics Hallucinogens Entheogens +25

Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders

Neuropharmacology March 13, 2023 Andreas B. Wulff, Charles D. Nichols, Scott M. Thompson 30 citations

Psychedelic compounds have shown extraordinary potential in treating a wide range of neuropsychiatric disorders. Psilocybin, for example, has now been shown in several clinical trials to induce a rapid (within days) and persistent (3-12 months) improvement in human treatment-resistant depression and other neuropsychiatric conditions. Here we review the preclinical models and experimental...

DOI: 10.1016/j.neuropharm.2023.109504 Psilocybin Hallucinogen Psychotherapist

Past, Present, and Future of Psychedelics: A Psychedelic Medicine Roundtable Discussion.

Psychedelic Med (New Rochelle) March 13, 2023 Peter S. Hendricks, Charles D. Nichols, Kathryn A. Cunningham et al. 7 citations

Past, Present, and Future of Psychedelics: A Psychedelic Medicine Roundtable Discussion.

DOI: 10.1089/psymed.2022.0003 Full text Psychedelics: powerful compounds Transformative healing Medical applications: medicine Healthcare +3

A Single Administration of Psilocybin Persistently Rescues Cognitive Deficits Caused by Adolescent Chronic Restraint Stress Without Long-Term Changes in Synaptic Protein Gene Expression in a Rat Experimental System with Translational Relevance to Depression.

Psychedelic medicine (New Rochelle, N.Y.) March 1, 2023 Meghan Hibicke, Hannah M. Kramer, Charles D. Nichols 25 citations

Psilocybin has shown long-lasting antidepressant effects in preclinical and clinical trials, but the mechanisms responsible are unclear. As both passive coping strategies and pattern separation deficits are characteristics of major depression, we used adult female rats subjected to adolescent chronic restraint stress (aCRS) to investigate the effects of psilocybin on forced swim test (FST) and...

DOI: 10.1089/psymed.2022.0012 Full text Depression Psilocybin Adolescent stress Pattern separation +8

Psychedelics as potent anti-inflammatory therapeutics

Neuropharmacology August 22, 2022 Charles D. Nichols 31 citations

Psychedelics have seen a resurgence of interest from both the scientific and lay community in recent years. Psychedelics are known for their ability to produce profound perceptual alterations, ego dissolution, and separation from reality in humans. Virtually all research into psychedelics and their mechanism of action has focused on examining effects in the brain, and on consciousness....

DOI: 10.1016/j.neuropharm.2022.109232 Psilocybin Consciousness Hallucinogen Pharmacology

Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling

Neuropharmacology August 17, 2022 Jack E Henningfield, Marion A Coe, Roland R. Griffiths et al. 34 citations

New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled...

DOI: 10.1016/j.neuropharm.2022.109220 Clinical study design Consciousness Controlled substance regulation Drug scheduling +9

Validation of the forced swim test in Drosophila, and its use to demonstrate psilocybin has long-lasting antidepressant-like effects in flies

Scientific Reports June 15, 2022 Meghan Hibicke, Charles D. Nichols 25 citations

Abstract Psilocybin has been shown to be a powerful, long-lasting antidepressant in human clinical trials and in rodent models. Although rodents have commonly been used to model psychiatric disorders, Drosophila have neurotransmitter systems similar to mammals and many comparable brain structures involved in similar behaviors. The forced swim test (FST), which has been used extensively to...

DOI: 10.1038/s41598-022-14165-2 Full text Psilocybin Antidepressant Behavioural despair test Drosophila subgenus +3

Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD.

ACS Chemical Neuroscience January 6, 2022 D. Kelley, Katy Venable, Aspasia Destouni et al. 41 citations

Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress, and inflammation. Animal models have recapitulated features of PTSD, but no comparative RNA sequencing analysis of differentially expressed genes (DEGs) in the brain between PTSD and animal models of traumatic stress has been carried out. We compared DEGs from the prefrontal cortex (PFC) of an...

DOI: 10.1021/acschemneuro.1c00660 Full text

Lysergic acid diethylamide induces increased signalling entropy in rats’ prefrontal cortex

Journal of Neurochemistry November 3, 2021 Aurora Savino, Charles D. Nichols 18 citations

Abstract Psychedelic drugs are gaining attention from the scientific community as potential new compounds for the treatment of psychiatric diseases such as mood and substance use disorders. The 5‐HT 2A receptor has been identified as the main molecular target, and early studies pointed to an effect on the expression of neuroplasticity genes. Analysing RNA‐seq data from the prefrontal cortex of...

DOI: 10.1111/jnc.15534 Lysergic acid diethylamide Prefrontal cortex Signalling

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