Credit: Denis Pobytov
Background and Scientific Rationale
For decades, the scientific exploration of psychedelic compounds, such as psilocybin and psilocin, was severely restricted due to their Schedule I classification and historical stigma regarding their hallucinogenic properties. However, a significant paradigm shift is currently underway within modern neuroscience and psychiatry. A rapidly expanding body of preclinical and clinical data highlights their robust antidepressant properties (Horsley et al., 2018; Hibicke et al., 2020) and sustained anxiolytic effects (Gasser et al., 2014; 2015). Furthermore, historical and contemporary investigations indicate therapeutic promise for substance-related conditions, including alcohol use disorder (Abramson, 1967; Bogenschutz et al., 2015) and tobacco cessation (Johnson et al., 2014).
Despite these advances, substance use disorders continue to present a catastrophic public health crisis worldwide, further compounded by an escalating wave of post-relapse opioid overdoses driven by the ongoing opioid and synthetic drug epidemics (National Center for Health Statistics, 2021; Pobytov et al., 2026). Because traditional pharmacotherapies often yield high relapse rates or fail to address the underlying neurocircuitry of compulsive drug-seeking, it is critically urgent to investigate novel, non-traditional therapeutic targets.
Preclinical Investigation and Abuse Liability Assessment
Evaluating these emerging compounds requires a rigorous balance: researchers must determine whether specific psychedelic analogs can successfully suppress or reverse established drug-seeking patterns while simultaneously estimating the inherent risk that these novel therapeutic targets might become abused themselves.
To address these critical questions, this project utilizes sophisticated, well-established rodent behavioral models of substance use disorders. Supported in part through a collaborative partnership with CaaMtech, a biotech company dedicated to pioneering the next generation of psychedelic therapeutics, the project systematically characterizes how specific psychedelic compounds interact with reward circuitry. By tracking behavioral metrics and physiological outcomes across diverse experimental paradigms, this work aims to clarify the translational potential of psychedelics as viable interventions for addiction without introducing new dependencies.
Sex Differences in Response and Behavioral Frameworks
Crucially, behavioral and neurochemical responses to psychedelic compounds can vary significantly across biological sexes, underscoring the necessity of accounting for female hormonal fluctuations in preclinical studies. Because estrous cycle dynamics heavily influence behavioral states and neuroplasticity in female models, integrating rigorous cycle tracking is essential for capturing accurate, unbiased therapeutic efficacy. To evaluate these dynamics, this project employs a comprehensive suite of methodologies, including:
Behavioral Assays: Conditioned place preference (CPP), self-administration (SA) models, and Head Twitch Responses (HTR) to quantify reward-seeking, reinforcement, and psychedelic-typical head twitch behaviors.
Cellular & Anatomical Analysis: Immunohistochemistry (IHC), confocal microscopy, and precise automated or manual cell quantification to measure cellular activation and structural changes.
Cellular Plasticity and Neural Circuit Mechanisms
Beyond broad behavioral outcomes, recent insights emphasize the importance of studying neuroplasticity at the cellular level. Serotonergic psychedelics have been shown to promote structural plasticity, such as increases in dendritic spine density and synaptogenesis in cortical regions heavily implicated in reward processing and cognitive control. Because addictive behaviors are driven by maladaptive, deeply entrenched circuit-level adaptations (such as those between the prefrontal cortex and the nucleus accumbens), investigating how single doses or targeted regimens of non-hallucinogenic or classic psychedelic analogs can structurally remodel these synapses offers a promising avenue for halting relapse-associated behaviors.
