Welcome to the first Xylo Bio Neuroscience Newsletter!
This newsletter delivers the latest insights into serotonergic neuroplastogens, covering both psychedelic and non-psychedelic compounds that promote neuroplasticity to advance mental and neurological health.

Each issue follows a structured format:

• Scientific Spotlight – In-depth explorations of key research topics.
• Research Updates – Summaries of recent studies shaping the field.
• Xylo Bio Updates – Company news, progress, and highlights.

We’ve been busy with the rebrand and haven’t published an update in a while, so this edition is extra packed. Enjoy the latest updates!

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Introduction to Neuroplastogens

Targeted therapeutics to repair the brain

For decades, psychiatric drug development has focused on managing symptoms rather than addressing the underlying causes of mental health disorders. Conditions like depression, PTSD, and neurodegenerative diseases continue to burden public health, despite progress with SSRIs, ketamine, and psychedelic-assisted therapy. A key challenge is rapidly and effectively promoting long-term brain rewiring without adverse side effects. Neuroplastogens, a novel class of compounds, offer a breakthrough by enhancing neuroplasticity while overcoming the limitations of existing treatments.

Neuroplasticity and Mental Health

Neuroplasticity is the brain’s ability to adapt by forming new neural connections. It underlies learning, memory, and emotional regulation. In disorders like depression, PTSD, and Alzheimer’s disease, neuroplasticity is impaired, leading to rigid neural networks that reinforce maladaptive thoughts and behaviors.^1,2 Many psychiatric treatments - including SSRIs, electroconvulsive therapy (ECT), psychotherapy, ketamine, and psychedelics - work, at least in part, by enhancing neuroplasticity.^1,3

Neuroplastogens: A New Class of Therapeutics

Serotonergic psychedelics, like psilocybin and LSD, have been shown to rapidly enhance neuroplasticity by inducing structural and functional changes - primarily by activating the 5-HT2A receptor - with effects that persist long after the drug has been metabolized.^3,4 While classic psychedelics show promise in enhancing neuroplasticity, their hallucinogenic effects require controlled settings and extensive supervision and may not be well-tolerated by all patients.

Neuroplastogens, serotonergic compounds designed to enhance neuroplasticity without inducing hallucinations, offer a rapid, scalable, and accessible solution for mental health treatment. By directly addressing underlying neural dysfunctions rather than just symptoms, these next-generation therapeutics hold broad transdiagnostic potential for conditions such as depression, anxiety, PTSD, chronic pain, and neurodegenerative diseases, offer a more effective and sustainable approach to care.

Serotonergic-Driven Neuroplasticity:

• Structural Neuroplasticity: Promote dendritic spine growth and synapse formation, particularly in the prefrontal cortex.³ Serotonergic psychedelics also upregulate genes related to neuroplasticity (Arc, Egr1, Bdnf) ^5,6,7 and induce epigenetic modifications that sustain long-term plasticity.⁸
• Functional Neuroplasticity: Enhance cognitive flexibility, reduce activity in the default mode network (DMN), and increase connectivity across cortical and subcortical regions.^4,9,10 These compounds also reopen critical periods for social learning, enabling better integration of new experiences.¹¹
• Metaplasticity: These compounds prime neural circuits for future adaptation, enhancing the brain’s capacity for long-term synaptic modifications, which could make it more responsive to future therapies.^11,12

Key Mechanisms:

• 5-HT2A Receptor Activation: This receptor is the primary driver of psychedelics' neuroplasticity-promoting effects, therapeutic outcomes, and hallucinogenic experiences.¹³ Activation of 5-HT2A triggers downstream effects that mediate neuroplastic changes.
• Pyramidal Neuron Activation: In regions like the prefrontal cortex, activation of pyramidal neurons expressing 5-HT2A receptors is essential for behavioral effects and structural plasticity, including synaptic remodeling.¹³
• Glutamatergic Activity: Activation of 5-HT2A receptors enhances excitatory glutamatergic activity, strengthening synaptic transmission and promoting long-term potentiation (LTP), which is vital for cognitive function and neural remodeling.⁴
• mTOR Pathway: The mTOR pathway, activated by increased neural activity through 5-HT2A, promotes the synthesis of proteins necessary for dendritic and synaptic growth, thus sustaining the neuroplastic effects of serotonergic neuroplastogens.¹⁴
• Neurotrophic Signaling: Although direct binding of psychedelics to tropomyosin receptor kinase B (TrkB) is still under investigation, activation of 5-HT2A receptors increases the expression of brain-derived neurotrophic factor (BDNF), which activates TrkB.¹⁴ This signaling cascade is critical for synaptic and structural plasticity, supporting long-term neuroplastic changes.

Xylo Bio: Pioneering Neuroplastogens

Xylo Bio, formerly Psylo, is at the forefront of developing next-generation neuroplastogens by leveraging computational drug discovery and structure-based design to optimize both safety and efficacy. The company’s innovations focus on:

• Target pathophysiology: Addressing underlying neural dysfunctions, not just symptoms.
• Broad access: Developing safe, scalable treatments without the drawbacks of existing treatments.
• Transdiagnostic applications: Addressing a wide range of neuropsychiatric and neurological conditions linked to cognitive rigidity and impaired neuroplasticity.
• Chronic treatment potential: Treatments that can be administered repeatedly with minimized risks, offering long-term therapeutic potential.

Xylo Bio’s pipeline includes compound XYL-1001, which is a non-hallucinogenic, 5-HT_2A-selective neuroplastogen that has demonstrated promising preclinical efficacy and is advancing toward clinical trials.

A New Era in Mental and Brain Health

Neuroplastogens represent a paradigm shift in psychiatry. By targeting underlying dysfunctions, these compounds have the potential to transform mental health care, delivering durable, transformative outcomes. Xylo Bio is at the forefront of this innovation and is dedicated to bringing advanced neuroplastogens to those who need them most.

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Research Updates

Follow this link to read the latest published research on serotonergic neuroplastogens, including:

• Clinical Trials and Other Clinical Studies: Key findings from recently published research in psychiatry and neurology
• Preclinical Research: Insights into neuropharmacology and underlying mechanisms
• Reviews and Editorials: Highlighting expert perspectives, meta-analyses, and systematic reviews
• Newly Registered Clinical Trials: Updates on upcoming research initiatives

Each section provides a concise summary with links to original research articles. Whether you're interested in clinical applications, pharmacology, or broader discussions on neurotherapeutics, this newsletter keeps you informed!

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Xylo Bio Updates

• Xylo Bio is excited to be participating in the 2025 One Mind Accelerator program!
• Sam Banister (CSO) and William Jorgensen (Director, Medicinal Chemistry) presented at the International Society for Research on Psychedelics (ISRP) Virtual Conference, March 7, 2025.
• Sam Banister also spoke at the Neuroscience Innovation Pharma Partnering Summit in Boston, MA on February 18-19, 2025.
• Joshua Ismin (CEO), Sam Banister, and Samantha Tabone (Director, Business Development) attended JPM2025 in January, engaging with key industry leaders.
• Psylo Rebrands as Xylo, with Key Board Appointments and Breakthrough Pipeline Progress, Jan 10
• Explore our new website, xylo.bio, designed by the talented team at weboaf

🤝Join the Team:

We are currently hiring for:

• Vice President of Research and Development (San Francisco, CA, or Boulder, CO)
• Medicinal Chemist (Sydney, Australia)

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