PSILOCYBIN AND COGNITIVE REHABILITATION: A TRANSDIAGNOSTIC ANALYSIS OF INFLEXIBILITY IN PSYCHIATRIC RIGIDITY DISORDERS

1. Introduction: The Challenge of Cognitive Inflexibility

The contemporary paradigm of clinical neuropsychology faces a profound challenge in the therapeutic management of psychiatric conditions characterized by pervasive cognitive inflexibility. Traditional pharmacological frameworks, founded predominantly upon the classical monoaminergic hypothesis, frequently fail to generate sustained modifications in the rigid cognitive and behavioral schemas observed in treatment-resistant depression, obsessive-compulsive disorder, and eating disorders (Dos Santos et al., 2016).

Under this transdiagnostic framework, cognitive rigidity ceases to be interpreted as a mere secondary epiphenomenon and is recognized as a primary neuropsychological marker, directly correlated with structural dysfunctions across prefrontal executive control networks and marked refractoriness to first-line psychotherapeutic protocols (Doss et al., 2021).

In this landscape, the re-emergence of research on the tryptamine alkaloid psilocybin represents a fundamental paradigm shift. Unlike conventional psychotropics, whose clinical benefits require weeks of daily administration accompanied by substantial discontinuation rates, psilocybin-assisted therapy demonstrates an ability to induce lasting modifications in neural architecture following only a limited number of controlled exposures (Vargas et al., 2023).

2. Integrative Review Methodology

This investigation was structured as an integrative literature review, covering the period between January 2016 and July 2026, a timeframe encompassing the modern renaissance of assisted psychedelic clinical trials and the consolidation of functional neuroimaging and standardized neuropsychological test batteries.

Systematic searches were conducted across PubMed/MEDLINE, APA PsycINFO, and SciELO, using Boolean operators to cross-reference controlled MeSH and DeCS descriptors (psilocybin, neuroplasticity, default mode network, TrkB, cognitive flexibility, eating disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism). Priority was granted to randomized controlled trials, safety and feasibility studies, systematic reviews, and preclinical investigations of high translational validity.

3. Discussion and Neuropsychological Articulation

3.1. Molecular Mechanisms and Cortical Network Reconfiguration

At the molecular level, our understanding of psychoplastogenic mechanisms has undergone significant refinement. Classic and recent investigations establish that psychedelics passively diffuse across the plasma membrane due to their hydrophobic properties, selectively engaging intracellular 5-HT2A receptors localized within the endoplasmic reticulum and Golgi apparatus of cortical pyramidal neurons (Vargas et al., 2023). This intracellular activation drives the release of brain-derived neurotrophic factor (BDNF) and triggers rapid prefrontal spinogenesis.

Concurrently, psilocin (the active dephosphorylated metabolite of psilocybin) has been identified as a direct positive allosteric modulator of the neurotrophic receptor tyrosine kinase B (TrkB), exhibiting a binding affinity approximately 1,000-fold higher than that of conventional selective serotonin reuptake inhibitors (Moliner et al., 2023). Recent phytochemical profiling further suggests an entourage effect conferred by secondary fungal tryptamines and trace metabolites that modulate systemic bioavailability and receptor kinetics (Cohen et al., 2025).

3.2. The REBUS Model and Objective Metrics of Executive Flexibility

The computational translation of this neural phenomenon is formalized in the REBUS model (RElaxed Beliefs Under pSychedelics), grounded in Bayesian brain theory and hierarchical predictive coding (Carhart-Harris; Friston, 2019). In pathological rigidity, high-level priors situated at the apex of the cortical hierarchy exert excessive, overweighted constraints on reality testing, preventing new environmental feedback from updating entrenched maladaptive cognitions.

This computational model has gained empirical validation through standardized neuropsychological testing. Patients with treatment-resistant depression undergoing psilocybin therapy exhibited statistically significant reductions in perseverative errors on the computerized Penn Conditional Exclusion Test (PCET), sustained for at least 4 weeks post-treatment (Doss et al., 2021). This marked improvement in set-shifting (rapid switching between mental sorting rules) correlated with the normalization of glutamate concentrations in the anterior cingulate cortex (ACC).

The therapeutic efficacy of this plastic state transcends expectancy bias and placebo mechanisms, as demonstrated in rigorous double-blind randomized trials employing active placebos (Palhano-Fontes et al., 2019).

3.3. Transdiagnostic Efficacy Across Rigidity Disorders

The clinical utility of psilocybin operates across multiple diagnostic categories characterized by executive and behavioral rigidity:

• Treatment-Resistant Major Depressive Disorder (TRD): Rapid, high-magnitude antidepressant responses sustained for up to 12 months when paired with structured psychotherapeutic support (Davis et al., 2021; Goodwin et al., 2022; Gukasyan et al., 2022).
• Existential Distress in Life-Threatening Illness: Immediate and enduring reductions in existential anxiety and demoralization among oncology patients, mediated by the subjective intensity of meaningful experiences (Griffiths et al., 2016).
• Anorexia Nervosa: Characterized by compulsive caloric restriction and entrenched body image distortion. A single 25 mg dose demonstrated remarkable physical safety and attenuated rigid cognitive control through functional normalization of fronto-insular circuitry (Peck et al., 2023; Koning; Brietzke, 2024).
• Obsessive-Compulsive Disorder (OCD): Normalization of aberrant signaling across the cortico-striatal-thalamo-cortical (CSTC) loop, temporarily suspending intrusive obsessions and compulsive neutralization rituals (Collins, 2024).

3.4. Perspectives and Methodological Boundaries in Neurodevelopment

In neurodevelopmental conditions, the current empirical evidence demands rigorous discrimination:

• Autism Spectrum Disorder (ASD): Psilocybin selectively enhances implicit and explicit emotional empathy as indexed by the Multifaceted Empathy Test (MET), while preserving intact moral reasoning and executive decision-making (Pokorny et al., 2017). Serotonergic agonists have also been demonstrated to restore joint attention and functional connectivity within social cognition circuits (Preller et al., 2018).
• ADHD and the Empirical Limits of Microdosing: While naturalistic surveys of self-selected microdosers report subjective improvements in focus and mood (Rootman et al., 2021), systematic reviews of rigorous randomized controlled trials confirm that microdosing has failed to demonstrate statistical superiority over active placebo for the cardinal symptoms of ADHD (Chmiel; Malinowska; Kurpas, 2026). Expectancy bias and self-fulfilling belief explain the vast majority of uncontrolled observational claims.

Synthesis of the Analyzed Bibliographic Corpus

4. The Essential Role of Neuropsychology in the Plastic Window

The synthesis of this evidence demonstrates that psilocybin does not accomplish rehabilitation autonomously: it operates strictly as a biological catalyst that opens a temporary window of synaptic malleability.

Long-term therapeutic success fundamentally depends on active clinical neuropsychological intervention to structure, direct, and consolidate this neuroplastic window through:

• Standardized protocols of neuropsychological training and executive stimulation;
• Evidence-based cognitive restructuring targeting dysfunctional core schemas;
• Gradual behavioral exposure experiments that reinforce adaptive neural pathways in the patient’s daily routine.

5. Conclusions and Research Agenda

This integrative analysis confirms that the molecular mechanisms of structural plasticity and cortical network desegregation induced by psilocybin act as powerful catalysts in alleviating cognitive and behavioral rigidity. Through the lens of translational neuropsychology, the compound liberates the brain from hyper-stable pathological attractor states, restoring executive flexibility and adaptive responsiveness to the environment.

Recommendations for Future Investigations:

1. Phase 3 Clinical Trials with Standardized Executive Batteries: Systematic evaluation of standardized psychometric endpoints (e.g., PCET, WCST, Stroop) before, during, and longitudinally after dosing protocols.
2. Integration of Dynamic fMRI and Glutamate Spectroscopy: Longitudinal tracking of cortical neurometabolites and large-scale connectome reorganization.
3. Customized Post-Dosing Cognitive Rehabilitation Protocols: Tailored executive stimulation regimens designed to maximize the peak spinogenesis window in the initial post-acute weeks.

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