‍Xylo Bio's Neuroscience Newsletter, August 2025

Serotonin as the backbone of many psychiatric and neurological treatments, and the latest in serotonergic neuroscience.

Welcome to the August edition of Xylo Bio’s Neuroscience Newsletter. This month, we explore serotonin’s central role in brain function and psychiatric treatment, spotlight the latest findings in serotonergic neuroscience in Research Updates, and shares the latest Xylo Bio Updates.]

Science in Sixty Seconds

Serotonin: The Master Modulator of the Brain

Serotonin (5-HT) is a neurotransmitter that modulates neural activity and a broad range of neuropsychological processes. Beyond its well-known role in mood regulation, it is critically involved in cognition, sleep, pain perception, memory, appetite, and neurodevelopment. Dysregulation of serotonergic signaling is implicated in nearly all major psychiatric disorders, including depression, anxiety, schizophrenia, and eating disorders.

Nearly all major classes of psychiatric medications—including SSRIs, monoamine oxidase inhibitors, azapirone anxiolytics, atypical antipsychotics—directly or indirectly modulate serotonin pathways. Beyond psychiatry, drugs with serotonergic targets include analgesics, antimigraine drugs, antiemetics, appetite suppressants, and anticonvulsants.

Serotonin is synthesized from tryptophan, stored in presynaptic vesicles, and released into the synapse in response to neuronal firing. Its actions are mediated by 14 serotonin receptor subtypes, grouped into seven families (5-HT1 to 5-HT7), that are located on the pre- and post-synapses throughout the central and peripheral nervous systems. Their distribution and function vary widely, helping to explain the broad clinical relevance of serotonergic drugs.

For example, presynaptic 5-HT1A autoreceptors provide homeostatic feedback by inhibiting further release when serotonin levels are too high. Chronic stress can downregulate 5-HT1A autoreceptor function, potentially impairing serotonin regulation and contributing to mood instability.

After signaling, serotonin is cleared either through reuptake by the serotonin transporter (SERT) or enzymatic degradation by monoamine oxidase (MAO) — key drug targets that underlie the efficacy of many antidepressants.

Understanding the diversity and regulatory mechanisms of the serotonin system is key to developing more targeted and effective neuropsychiatric treatments.

Xylo Bio Updates

• Targeted Neuro Talks with Dr Devin Effinger (University of Colorado Anschutz) explores the first preclinical evidence on whether chronic psychedelic microdosing could pose cardiovascular risks via 5-HT₂B receptor activation. 📺 Watch it here
• First Thursdays at UNSW Founders – CEO Josh Ismin presented on Xylo’s journey developing fast-acting, non-hallucinogenic neurotherapeutics.
• We’re thrilled to have Dr. Jack Nguyen on the team as VP of R&D who brings deep experience in translational neuroscience and CNS drug development – read about it here
• As part of the One Mind Accelerator, CSO Dr. Sam Banister pitched Xylo Bio’s vision to deliver safe, scalable, non-hallucinogenic 5-HT2A-targeting therapies for mental health. 📺 You can watch the pitch here.
• Dilara Bahceci is leaving Xylo Bio after nearly four incredible years as Head of Communications — and we're now hiring for the role.

Coming up:

• 8th Neuropsychiatric Drug Development Summit (Boston, September 9-11) – CSO Sam Banister attending
• One Mind Music Festival for Brain Health (California, September 13) – Xylo attending
• Targeted Neuro Talk with Prof. Bryan Roth (UNC School of Medicine) coming soon

🤝Join the Team:

We are currently hiring for:

• Director of Clinical Operations (Sydney strongly preferred)
• Chief Development Officer (San Francisco, CA, flexible)
• Clinical Advisory Board Member – CNS Drug Development
• Head of Communications (Remote)

Photos

Research Updates

Clinical Research

Psilocybin trial in PTSD patients | A single 25 mg dose of psilocybin with psychological support was safe, well tolerated, and associated with significant reductions in PTSD symptoms sustained over 12 weeks; a nonrandomized open-label clinical trial (N=22). J Psychopharmacol

Psilocybin for anxiety and depression in illness | Psilocybin-assisted psychotherapy significantly reduced depression and anxiety in patients with life-threatening illness compared to active placebo, with effects sustained at 26 weeks; a Phase 2b double-blind RCT (N=35). Gen Hosp Psychiatry

Psilocybin retreats improve mental health in veterans | Participation in psilocybin-assisted retreats significantly reduced PTSD, depression, and anxiety symptoms and normalised EEG activity in veterans with a history of traumatic brain injury; a naturalistic intervention study (N=21). Front Psychiatry

Cost-effectiveness of psilocybin for depression | Psilocybin-assisted therapy added quality-adjusted life years at acceptable cost and was likely to be cost-effective compared to standard care for treatment-resistant depression in the US when priced at or below $5000. Transl Psychiatry

NR2B modulator trial in depression | BI 1569912, a selective NMDA-2B negative allosteric modulator, was well tolerated and reduced depressive symptoms compared to placebo after a single 20 mg dose; a Phase Ib RCT (N=59). Clin Pharmacol Ther

DMT/harmine alters creative thinking patterns | DMT/harmine impaired convergent thinking and altered creative process dynamics, reducing incubation-to-illumination transitions during an artistic task; a placebo-controlled within-subjects study in healthy male participants (N=30). J Psychopharmacol

Preclinical Research

Psilocybin alters rat prefrontal brain activity | Psilocybin induced immediate reductions in neuronal firing and high-frequency oscillations in the rat infralimbic cortex, followed by multi-day increases in beta and gamma power. Mol Psychiatry

Psilocybin suppresses claustrum signaling via 5-HT1B | Psilocybin and serotonin suppressed cortical input to the claustrum by activating 5-HT1B receptors on anterior cingulate cortex terminals, providing a mechanism for network modulation. Nat Commun

How 5-HT1A selects G proteins | Structural and functional analysis revealed how the serotonin receptor 5-HT1A differentially engages G protein subtypes through distinct ligand interactions. Sci Adv

Improved photoswitchable psychedelic compound designed | A novel compound (PQ-azo-N,N-DMT) was computationally designed to show strong 5-HT2A receptor binding, visible-light activation, and enhanced membrane permeability, improving on earlier photoswitchable psychedelics. Phys Chem Chem Phys

TBG promotes plasticity without IEG activation | The nonhallucinogenic psychoplastogen TBG promoted cortical neuroplasticity and antidepressant-like effects via 5-HT2A, TrkB, mTOR, and AMPA receptor pathways without inducing immediate early gene activation or glutamate release.Nat Neurosci

Drug discrimination shows translational value | Psilocybin and 5-MeO-DMT drug cues in rats were mediated by 5-HT2A and 5-HT1A receptors and showed pharmacokinetic and behavioral profiles consistent with human hallucinogenic effects. J Psychopharmacol

Psilocybin effects differ by age and hormones | Psilocybin induced head twitch responses in adult but not adolescent rats, and responses in adult females varied by estrous cycle; no long-term behavioral changes were found following adolescent exposure. Neuropharmacology

Serotonin receptors influence alcohol drinking | 5-HT2A and 5-HT2C receptors were found to play different roles in alcohol consumption: combined antagonism reduced initial drinking, while 5-HT2A antagonism alone reduced relapse-like drinking in mice. Front Neurosci

[Preprint] Psychedelic DOI impairs smell-guided behavior | DOI, a 5-HT2A agonist, impaired olfactory search accuracy, altered movement patterns, and increased sniffing rate in mice. bioRxiv

[Preprint] Psilocybin rewires brain-wide connectivity | Psilocybin triggered activity-dependent reorganization of large-scale input networks to frontal cortical neurons in mice, enhancing connectivity from perceptual and medial regions while weakening cortico-cortical loops. bioRxiv

Reviews and Editorials

The ABCs of psychedelics: a preclinical roadmap for drug discovery | This review proposes a structured framework for evaluating psychedelic-inspired compounds by focusing on agonism, behavior, and cellular plasticity, and highlights emerging tools to improve translational success in drug development. Trends Pharmacol Sci

Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects | This narrative review evaluates the evidence linking 5-HT2A receptor activation to the neuroplastic and antidepressant effects of psychedelics, proposing a mechanistic model while acknowledging ongoing debate over receptor necessity. Mol Psychiatry

Exploring the therapeutic potential of psychedelics in treating substance use disorders | This review highlights the promise of psychedelics, especially psilocybin, in treating substance use disorders by enhancing neuroplasticity, disrupting maladaptive circuits, and promoting psychological insight, while noting the need for further research and regulatory clarity. Mol Psychiatry

Psychedelics meet human brain organoids: insights into proteomics and potential for Alzheimer's disease treatment | This mini review explores how psychedelic compounds induce neuroplastic and anti-inflammatory changes in human brain organoids, highlighting their potential as therapeutic candidates for Alzheimer's disease. Front Dement

Appraisal of the validity of preclinical investigations to predict the efficacy of psychedelic drugs as fast-acting antidepressants | This review critiques the reliability and translational relevance of preclinical models used to assess psychedelics as rapid-acting antidepressants, highlighting issues of reproducibility and model validity. J Psychopharmacol

Psychedelics and the serotonin hypothesis of eating disorders | This review examines the potential of serotonergic psychedelics—especially 5-HT2A agonists like psilocybin—to treat eating disorders by enhancing cognitive flexibility and neuroplasticity, aligning with the broader serotonin dysregulation hypothesis of these conditions. Brain Sci

Biased signaling in psychedelic action | This review explores how biased 5-HT2A receptor signaling may separate therapeutic from hallucinogenic effects of psychedelics, highlighting new tool compounds and structural insights that could guide the development of safer, more targeted treatments. Annu Rev Pharmacol Toxicol

‍New Clinical Trial Registrations

MDMA (120 mg + 40 mg) + therapy | Mental wellbeing (N=30) | A Phase 1, Open-Label Study to Assess Psychological and Biological Effects of MDMA Assisted Therapy When Administered to Mental Health Providers in Training to be MDMA-Assisted Therapists (Open Label) | Sponsor: Rachel Yehuda | NCT07102576

MDMA-Assisted Therapy vs Placebo | Veterans With PTSD and Alcohol Use Disorder (N=80) | MDMA-Assisted Therapy for Veterans With PTSD and Alcohol Use Disorder | Sponsor: VA Office of Research and Development | NCT07118839

Psilocybin (25 mg) + MBCT therapy vs Psilocybin (25 mg) + support | Post-Traumatic Stress Disorder (N=30) | A Pilot Mechanistic RCT of Psilocybin With Mindfulness-based Therapy vs Support for Posttraumatic Stress Disorder (PTSD) | Sponsor: Anthony P King | NCT07104916

Psilocybin | Chronic Pain in Smokers (N=10) | Psilocybin as a Treatment for Chronic Pain in Smokers (Open Label) | Sponsor: Yale University | NCT07118332

Jump back to:

• Science in Sixty Seconds
• Xylo Bio Updates
• Research Updates

‍