In this issue, we’ll explore how scientists are harnessing plasticity’s power — tipping the balance toward healing instead of harm, and turning “use it or lose it” into a guiding principle for next-generation therapies. You’ll also find highlights from recent studies in Research Updates and the latest company milestones in Xylo Bio Updates.

Science in Sixty Seconds

Use it or Lose it!

The brain is considered plastic, meaning it can reorganize, regenerate, and create new connections as humans learn and adapt. Plasticity begins before birth and continues into adulthood, although at a much lower rate. The stages of brain development follow 6 steps outlined in the figure below (made with BioRender; Kolb & Gibb, 2011).

Neurons can form synapses in hours or even minutes following an experience. One important time point for plasticity is the critical (or sensitive) period — a limited window when a child’s brain is shaped by the environment (Gorzek & Trachtenberg, 2025). During these periods, vision, language, and social behaviors develop. Recent work has aimed to reproduce and leverage brain states during critical periods for neurotherapeutics (Nardou et al., 2023; Lepow et al., 2021).

It’s important to remember plasticity works through both pruning and growth (Kolb & Gibb, 2011). Repeated neural signaling strengthens connections. For instance, motor neurons used while learning to walk are reinforced, enabling lifelong walking ability. Unused connections get pruned—like calculus knowledge fading after high school without practice (use it or lose it!).

What about ill-timed plasticity? In neuropsychiatric disorders like depression, anxiety and post-traumatic stress disorder, plasticity can become maladaptive. Studies have linked increases in neuroplasticity with fear responses related to traumatic events and fear (Mahan & Ressler, 2012) whereas decreases in neuroplasticity are tied to anhedonia (Liang et al., 2025). Stress can push the brain toward wiring patterns that work against us.

Our adaptable brain sometimes needs assistance. Neuronal growth is facilitated by cellular signaling cascades, including serotonergic activation and growth factors (Beretta et al., 2025; Casarotto et al., 2022). Harnessing these pathways is key to promoting adaptive plasticity. That’s why it’s important to develop new therapies that specifically target brain regions implicated in the pathology of neuropsychiatric disorders.

By creating novel compounds that induce neuroplasticity, we can help patients strengthen positive behavioral connections while weakening symptom-reinforcing pathways.

Xylo Bio Updates

• One Mind Accelerator Program comes to an end (Napa Valley, CA) – CEO, Josh Ismin and CSO, Dr. Sam Banister recently completed the program through One Mind which aims to foster collaboration across start-ups, researchers and mental health advocates. View their founder’s video here.

• We’re thrilled to have Dr. Alaina Jaster join the team as Head of Communications. She brings extensive knowledge on collaborative communications and translational neuropharmacology.
• Director of Business Development, Samantha Tabone was nominated and recognized as one of BioSpace’s 40 under 40. This list highlights exemplary biotech and pharma professionals who have distinguished themselves in their companies and their field.
• CSO, Dr. Sam Banister was featured on Alexandre Stipanovich of Cascade Analytics LinkedIn Live to discuss Xylo’s lead compound, XYL-1001, and broader implications of serotonergic therapeutics. Watch the video here.
• If you missed it, CSO, Dr. Sam Banister did a Targeted Neuro Talk with Dr. Devin Effinger on the potential cardiac risk of 5-HT2B receptor agonism. Watch the discussion here.

Coming up:

• HLTH (Las Vegas, NV) – Director of Business Development, Samantha Tabone attending
• Brain Mind Centre Symposium (Sydney, October 20) – Dr. Will Jorgensen and Dr. Nick Everett will be presenting on the Accelerating Discovery panel
• AusBiotech International Conference (Melbourne, October 21-24) – CEO, Josh Ismin and CSO, Dr. Sam Banister attending
• Biological Psychiatry Australia (Melbourne, October 26-28) – Xylo attending
• UNSW Pioneering Investor Series (Singapore, October 27) - CEO, Josh Ismin attending
• SWITCH Conference (Singapore, October 29) - CEO, Josh Ismin attending

🤝Join the Team:

We are currently hiring for:

• Chief Medical Officer (flexible)
• Clinical Advisory Board Member – CNS Drug Development

Photos

Research Updates

Preclinical Research

• Neurons found to communicate through nanotubes | Using advanced super resolution microscopy, dendrite protrusions were found to have direct non-chemical connections with other dendrites through membrane bridges called nanotubes. These nanotube connections were able to transport calcium signals and other molecules similar to traditional chemical synapses. Neuroscience.
• Activation of pre-synaptic 5-HT2A receptors involved in neuroplasticity | Using genetically engineered 5-HT2A receptor conditional knockout mice and measures of functional and structural neuroplasticity authors report psychedelic 25CN-NBOH was found to induce synaptic connectivity in regions that do not express 5-HT2A receptors through projections of presynaptic neurons expressing the receptor. Mol Psychiatry.
• Chronic psilocybin produces a potential gut microbiome feedback mechanism | Administration of 1 mg/kg oral psilocybin produced reductions in three types of gut bacteria in male but not female mice. These changes in gut microbiome were correlated with locomotion, head twitch response and gut motility. Separate microbial clusters were linked to other behaviors such as startle response and sociability. Neuropharmacology.
• Psilocin partial agonism at serotonergic receptors modulates pain and mood circuits | Single administration of 0.5 mg/kg psilocin reverses mechanical hypersensitivity and anxiodepressive-like behaviors in two chronic pain models. Chronic pain associated hyperactivity in cortical pyramidal neurons was normalized following psilocin through mechanisms related to the compounds partial agonism at 5-HT2A and 5-HT1A receptors. Nat Neurosci.Clinical Research

Clinical Research

• Unique G-protein coupling patterns of commonly used 5-HT2A receptor ligands | Ketanserin and altanserin are considered 5-HT2A receptor antagonists but when tested in human post-mortem tissue were found to have distinct signaling profiles. Ketanserin was found to have partial agonist activity at G_q/11, whereas altanserin has inverse agonist properties on G_i1 proteins, suggesting possible limits to interpreting antagonistic activity. Mol Pharm.
• Genetic predisposition for treatment resistant depression across global populations | Genetic liability for nervous-related personality traits was associated with development of treatment resistant depression among those with major depressive disorder in East Asian populations. While some psychosocial factors and personality traits contributed to incidence and depression severity trans-ancestrally, there non-generalizable traits related to education and cognition. This was a cohort study (n=106,796). Neuropsychopharmacol.
• Lysergide for generalized anxiety disorder | MM120, or lysergide D-tartrate, had favorable dose-dependent changes in primary outcomes of anxiety score. These phase IIb findings support dose selection of 100 μg of MM120 for continuing clinical trials evaluating treatment for moderate to severe GAD. JAMA.
• MDMA, MDA, and lysine-conjugated prodrugs in healthy volunteers | MDA produced stronger, longer-lasting, more psychedelic-like perceptual effects and had more reported adverse effects compared with MDMA. The Lys-MDA acted as a slow-release drug, delaying onset and peak effects, while Lys-MDMA did not release MDMA. This was a randomized, double-blind, placebo-controlled crossover trial (n=23). Neuropsychopharmacol.

Reviews and Editorials

• Cortical 5-HT_2A receptors in depression and suicide: a systematic review and meta-analysis of in vivo and post-mortem imaging studies | Distinct patterns of 5-HT2A receptor binding in various brain regions across 31 PET and post-mortem studies (n=1082) of those with major depressive disorder (MDD) were found. Lower levels of 5-HT2A receptors were more noticeable in those with more severe depression, suggesting changes in serotonin may play a key role in MDD and suicide risk. Mol Psychiatry.
• Sertraline and inflammatory markers in major depression: a systematic review and meta-analysis | There has been increased interest in the role of inflammatory pathways in the pathophysiology of major depressive disorder. This systemic review analyzed 11 studies (n=406) and found changes in inflammatory biomarkers, IL-6 and TNF-α, after sertraline treatment. This suggests a potential role of the inflammatory pathway in depression. Ann Gen Psychiatry.
• Biased signaling via serotonin 5-HT_2A receptor: From structural aspects to in vitro and in vivo pharmacology | G protein-coupled receptors are molecular targets for 30-40% of all medications. Medications that can activate certain receptor signaling profiles through biased agonism may improve mental health outcomes. 5-HT2A receptor-biased signaling is of specific interest for developing targeted antidepressants without psychedelic effects. Acta Pharm Sin B.
• Psychedelic studies in nonhuman primates: Past and future | Non-human primates (NHP) have served as a valuable model for understanding psychedelics’ effects on spontaneous and operant behavior. Utilizing NHPs could provide a critical opportunity to further understand mechanisms of psychedelics with better translational value to human conditions. Mol Psychiatry.
• The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine | Psilocybin and ketamine have been found to act as rapid-acting antidepressants. Understanding the molecular targets, including biased agonism at 5-HT2A receptors, and shared mechanisms of these compounds, such as the BDNF-TrkB pathway, may help better inform drug discover. Mol Psychiatry.

‍New Clinical Trial Registrations

• 0.5 or 0.1 mg/kg Ketamine | Treatment Resistant Depression (N=100) | Neuropharmacologic Imaging and Biomarker Assessments of Response to Acute and Repeated-Dosed Ketamine Infusions in Major Depressive Disorder | Sponsor: National Institute of Mental Health | NCT03065335
• Psilocybin + MDMA | Post-Traumatic Stress Disorder (N=40) | Psilocybin and Methylenedioxymethamphetamine (MDMA) for Post-traumatic Stress Disorder (PTSD) (PAM-VET) | Sponsor: Brandon Weiss | NCT06989957
• 10 μg LSD | Premenstrual Disorders (N=150) |Microdosing LSD in women with premenstrual disorders (L4Her) | Sponsor: Friederike Holze | NCT07189299
• 25 mg Psilocybin | Anorexia Nervosa (N=40) | Safety, Therapeutic Potential, and Mechanisms of Two Psilocybin Doses, Administered With Psychological Support in Young Adults With Anorexia Nervosa (psiAN) | Sponsor: Region Skane | NCT07169747
• 25 mg Psilocybin | Chronic Stroke (N=20) |Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability (PHATHOM) | Sponsor: Johns Hopkins University | NCT07053917

Jump back to:

• Science in Sixty Seconds – Exploring our adaptable brains
• Xylo Bio Updates – Company news, progress, and highlights.
• Research Updates – Summaries of recent studies shaping the field

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