Neurobiology of psilocybin: a comprehensive overview and comparative analysis of experimental models

Abstract

Psilocybin, a compound found in Psilocybe mushrooms, is emerging as a promising treatment for neurodegenerative and psychiatric disorders, including major depressive disorder. Its potential therapeutic effects stem from promoting neuroprotection, neurogenesis, and neuroplasticity, key factors in brain health. Psilocybin could help combat mild neurodegeneration by increasing synaptic density and supporting neuronal growth. With low risk for addiction and adverse effects, it presents a safe option for long-term use, setting it apart from traditional treatments. Despite their relatively simpler neuronal networks, studies using animal models, such as Drosophila and fish, have provided essential insights on the efficacy and mechanism of action of psilocybin. These models provide foundational information that guides more focused investigations, facilitating high-throughput screening, enabling researchers to quickly explore the compound's effects on neural development, behavior, and underlying genetic pathways. While mammalian models are indispensable for comprehensive studies on psilocybin's pharmacokinetics and its nuanced interactions within the complex nervous systems, small non-mammalian models remain valuable for identifying promising targets and mechanisms at early research stages. Together, these animal systems offer a complementary approach to drive rapid hypothesis generation to refine our understanding of psilocybin as a candidate for not only halting but potentially reversing neurodegenerative processes. This integrative strategy highlights the transformative potential of psilocybin in addressing neurodegenerative disorders, leveraging both small and mammalian models to achieve translational research success.

Keywords: animal models; psilocin; psilocybin; psychedelics; serotonin; therapeutics; translational neuroscience.

FIGURE 1

When psilocybin is ingested, it is metabolized to psilocin, which interacts with serotonin (5-HT) receptors, especially the 5-HT2A subtype. These receptors are concentrated in key brain regions, such as the prefrontal cortex, playing a major role in regulating mood, anxiety, and emotional states. While the general effects of psilocin on these receptors are known to influence perception and emotional processing, the detailed molecular mechanisms behind these changes are still not fully understood. Further research is needed to clarify how these interactions contribute to the therapeutic potential of psilocybin for mental health disorders. Figure adapted from Lowe et al. (2021).

FIGURE 2

Schematic diagram showing the three types of validity (i.e., face, mechanistic, and predictive) used to assess the suitability of animal models for testing new drugs in relation to human responses. Evidence supporting the use of mouse, fish, and Drosophila for each criterion is based on peer-reviewed literature.

FIGURE 3

In Drosophila, the GAL4/UAS system is widely used to control gene expression in specific tissues. This method works by linking the expression of the GAL4 transcription factor to a tissue-specific enhancer. In a separate line of flies, the gene of interest is placed under the control of a UAS (Upstream Activation Sequence). When these two lines are crossed, the offspring express the target gene only in cells where the GAL4 transcription factor is active. This allows for precise spatial and temporal control of gene expression. The GAL4/UAS system is incredibly versatile and has been applied in many experiments. It can be used to label specific cells, activate or silence genes, and even study protein-DNA interactions on a genome-wide scale. This flexibility makes it a powerful tool for studying gene function, neural circuits, and developmental processes in a controlled and targeted way. Figure adapted from Caygill and Brand (2016).