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.
Progress in Neuro-psychopharmacology and Biological Psychiatry
January 10, 2012
Evan J. Kyzar, Christopher Collins, Siddharth Gaikwad et al.
122 citations
Mescaline and phencyclidine (PCP) dose-dependently increased top activity in the novel tank test, reduced immobility, and disrupted swimming patterns in zebrafish. PCP, but not mescaline, evoked circling behavior in the open field test. At the highest doses tested, mescaline markedly increased shoaling behavior, while PCP did not affect it. Whole-body cortisol levels were unchanged by 20 mg/l mescaline but elevated by 3 mg/l PCP. These findings indicate that zebrafish models are sensitive to hallucinogenic compounds, producing complex behavioral and physiological effects.
Behavioural Brain Research
January 1, 2013
Jonathan Cachat, Evan J. Kyzar, Christopher Collins et al.
112 citations
Ibogaine, a psychoactive compound from the iboga plant, alters multiple behaviors in adult zebrafish. At doses of 10 and 20 mg/L, it reversed the natural diving response, causing initial top swimming followed by bottom dwelling, and reduced the innate preference for dark environments. It did not change overall locomotion or wall-hugging behavior but altered spatial exploration, promoted mirror interaction, disrupted group cohesion, and induced color changes from melanophore aggregation. Brain c-fos expression and whole-body cortisol levels remained unchanged. These results demonstrate ibogaine's complex pharmacological profile and support the use of zebrafish for studying hallucinogenic drug effects.
Behavioural Pharmacology
April 8, 2011
Adam Stewart, Russell Riehl, Keith Wong et al.
66 citations
Acute exposure to high doses of MDMA (40-120 mg/l) reduces bottom swimming and immobility in zebrafish and impairs intrasession habituation at doses as low as 10 mg/l, while lower doses (0.25-10 mg/l) show no behavioral effects. MDMA also increases brain c-fos expression. These findings support the use of zebrafish as a model for screening hallucinogenic compounds.
Molecular Psychiatry
January 1, 2023
Evan J. Kyzar, George H Denfield
62 citations
Psychiatric diseases alter subjective experience, yet neuroscience mostly studies objective behaviors. Phenomenology, a philosophical tradition examining lived experience, can generate hypotheses about the neurobiological basis of mental illness. Early 20th-century phenomenological psychiatrists made important contributions, but this approach faded with operationalized diagnoses. Recently, clinical-phenomenological research has re-emerged. Using examples from mania and psychosis, the authors show that phenomenological studies can produce fruitful neuroscientific proposals. They advocate integrating phenomenological methods with modern neuroscience, including cross-species research and human subjects work, to move toward a unified understanding of mental illness.
ACS Chemical Neuroscience
September 25, 2018
Andrey D. Volgin, Oleg A. Yakovlev, Konstantin A. Demin et al.
38 citations
Deliriant hallucinogens, such as atropine and scopolamine, are a distinct class of drugs that induce hyperactivity and dream-like hallucinations by blocking muscarinic acetylcholine receptors. Despite their long history of use and being well-studied in cholinergic physiology, they are the least-studied class of hallucinogens regarding their behavioral and neurological effects. This review comprehensively evaluates the preclinical effects of these drugs in various animal models, detailing their mechanisms of action and potential interactions with other signaling pathways. It parallels experimental and clinical findings to outline future directions for translational research, emphasizing the need for novel approaches and new model organisms to investigate their central nervous system effects.
Zebrafish
March 22, 2016
Evan J. Kyzar, Allan V. Kalueff
29 citations
Interest in using hallucinogens to treat brain disorders is reviving. Early studies show classic serotonergic hallucinogens like LSD and psilocybin may help with addiction, PTSD, and anxiety, but basic pharmacological and toxicological questions remain. This paper discusses psychedelic medicine and the behavioral and toxic effects of hallucinogenic drugs in zebrafish, highlighting the fish as a model for screening both toxic and therapeutic effects of known and novel hallucinogenic compounds. Well-designed zebrafish studies could support the reemerging treatment paradigm of psychedelic medicine and open new clinical avenues for psychiatric disorders.
Psychopathology
August 18, 2025
Evan J. Kyzar, George H Denfield, Jasper Feyaerts et al.
1 citation
Integrating methods from phenomenology can strengthen the application of dynamical systems theory (DST) in psychopathology research. Phenomenological psychopathology improves DST-based investigations by specifying core symptoms more precisely through a focus on subjective experiences and by deepening theoretical understanding of how symptoms evolve in severity over time. Using clinical high risk for psychosis as a test case, the article demonstrates the utility of combining phenomenologically informed theory and DST, examining the ipseity-disturbance model of psychosis development. The authors offer a vision for broader integration of DST and phenomenological research methods to better understand and predict psychiatric disorders and transitions in mental health states.
Psychopathology
January 1, 2024
George H Denfield, Evan J. Kyzar
1 citation
Subjective experience is central to mental illness but has been neglected in empirical psychopathology. A framework called the Nested States Model (NSM) describes the dynamic structure of experience as a system of nested states that influence each other across hierarchical layers. The NSM provides a scheme for characterizing patterns of experience in psychopathological processes, aiding clinical practice and research. It advances three aims: centering clinical formulations on subjective experience, organizing findings from clinical-phenomenological research to build broader models, and aligning perspectives on experience with brain dynamics to bridge phenomenological and neurophysiological work.
The FASEB Journal
April 1, 2012
Evan J. Kyzar, Christopher Collins, Jeremy Green et al.
1 citation
Mescaline and phencyclidine (PCP) alter zebrafish behavior in distinct ways, while psilocybin shows no behavioral effects at the doses tested. Mescaline (10–20 mg/L) reduces anxiety-like behavior in the novel tank test, increases shoaling, and changes movement in the open field. PCP (1–3 mg/L) decreases freezing and causes erratic swimming. Both mescaline and PCP disrupt normal exploratory behavior. Psilocybin (0.5–3 mg/L) is inactive in all behavioral tests. Psilocybin and PCP raise whole-body cortisol levels without affecting brain c-fos expression; mescaline does not alter either measure. Zebrafish models are sensitive to hallucinogenic compounds with complex behavioral and physiological effects.
October 16, 2023
George H Denfield, Evan J. Kyzar
preprint
Subjective experience is central to mental illness but has been neglected in empirical psychopathology. The Nested States Model (NSM) offers a framework for constructing detailed phenomenological models by describing subjective experience as a system of nested states. This provides a structured scheme for operationalizing subjectivity, enabling empirical study. The NSM grounds thinking about psychopathological processes around states and their transitions, promising an approach that is close to individual experience, empirically tractable, and aligned with neuroscience research.
Open MIND
January 1, 2015
Jonathan Cachat, Chris Collins, Evan J. Kyzar et al.
Three-dimensional reconstructions of zebrafish swimming paths enable both macro- and micro-level analysis of behavior, offering a more complete picture than traditional 2D traces. Temporal 3D reconstructions plot spatial data across time to reflect activity over testing, while spatial 3D reconstructions use two cameras to depict activity within the actual arena. These reconstructions are highly sensitive to anxiolytic, anxiogenic, and hallucinogenic effects in adult zebrafish. For example, ibogaine reversed natural behaviors, a characterization impossible without 3D reconstructions. Track3D, applied for the first time in adult zebrafish, showed strong significant correlation (R>0.07) of automated endpoints with manual data, providing precise calculation of movement parameters and accurate spatiotemporal integration. These approaches permit advanced movement pattern analysis for screening psychoactive compounds.
Journal of consciousness studies : controversies in science & the humanities
April 1, 2024
George H Denfield, Evan J. Kyzar
A framework called the Nested States Model is proposed to bridge the gap between subjective experience and brain activity. Building on philosophy of mind and phenomenology, the model characterizes both experiential states and brain states as layered, nested systems. Recognizing this structural homology—that both domains share a nested organization—allows for a more systematic approach to formulating hypotheses about how subjective mental states relate to neurophysiological processes. The model aims to guide empirical investigation into the relationship between subjectivity and neurobiology, addressing the lack of principled means currently available.
Behavioural Brain Research
January 1, 2016
Evan J. Kyzar, Adam Michael Stewart, Allan V. Kalueff
The serotonin transporter (SERT) regulates serotonin signaling and is linked to psychiatric disorders like anxiety, autism spectrum disorders (ASD), and obsessive-compulsive disorder (OCD). In mice, removing the Sert gene increases anxiety and grooming behavior. This study examined the effects of the hallucinogen LSD (0.32 mg/kg) on grooming and other behaviors in mice with one copy of the Sert gene (Sert+/-). These mice showed longer self-grooming regardless of LSD treatment. LSD increased serotonin-sensitive behaviors like head twitching and tremors in both normal and Sert+/- mice, with no significant interaction between LSD and Sert gene dosage. The results suggest Sert+/- mice respond to LSD similarly to normal mice.