Xylo Bio's Neurocience Newsletter, April 2025

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Science in Sixty Seconds

An Update on 5-HT2A Clinical Trials

As of April 2025, 281 trials investigating 5-HT2A receptor agonists have been registered on ClinicalTrials.gov since 2016 – a 27% increase since our last update in May 2024 (up from 220). 2024 marked a peak year for new registrations. This growth reflects continued momentum in clinical development across a widening range of therapeutic areas.

📊 See figures for year-on-year growth, compound distribution, therapeutic areas, and condition-specific trends. Note: Analyses exclude trials categorised as ‘suspended’, ‘terminated’, or ‘withdrawn’.

By compound

Psilocybin remains the most studied agent, featured in 70% of trials, followed by LSD (7.6%). Notably, there is a small but growing number of trials investigating novel compounds (NCEs, 19 trials, 7.2%) – signalling early investment in next-generation agents that may offer differentiated profiles or improved practicality over legacy compounds.

By condition

Most studies continue to target depression (25.4%), followed by substance use disorders (13.2%) and health-related psychological distress (7%), including existential distress in patients with advanced illness, fear of cancer recurrence and demoralisation in palliative care settings.

There’s also growing activity in trials addressing chronic pain, PTSD, neurological conditions, obsessive-compulsive disorder (OCD), and anxiety. Less common focus areas include: burnout, irritable bowel syndrome (IBS), ADHD, autism spectrum disorder (ASD), body dysmorphic disorder, borderline personality disorder, cognitive resilience, diabetes, Lyme disease, prolonged grief disorder, and self-harm.

By phase and status

Phase 2 trials dominate the pipeline (38.6%), followed by Phase 1 (34.1%). There are now 11 Phase 3 trials (4%) of 5-HT2A agonists, indicating a small but advancing late-stage cohort. Regarding status, 99 trials have been completed, with 88 currently recruiting, and another 47 preparing to recruit – underscoring sustained momentum and an active landscape of ongoing investigation.

❓ Want to explore the data further or have a question? Reach out - we’re always keen to exchange ideas, insights, and collaborations.

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Research Updates

Clinical Research

• Low-dose LSD trial for adult ADHD | Repeated administration of low-dose LSD was safe but no more effective than placebo in reducing ADHD symptoms in adults. This phase 2A double-blind, placebo-controlled trial enrolled 53 participants and administered 20 μg LSD or placebo twice weekly over 6 weeks. JAMA Psychiatry
• Mapping brain changes in depression | Researchers identified three continuous and stable patterns of brain structural changes in major depressive disorder, each associated with distinct serotonin and norepinephrine receptor distributions and clinical symptom improvement. Using Bayesian decomposition of structural MRI data from multisite cohorts, they linked cortical thickness variations to 5-HT2A and 5-HTT density, supporting a dimensional approach to understanding depression. Nat Commun
• Brain network markers predict depression treatment | Multimodal neuroimaging biomarkers (brain connectivity patterns from fMRI and EEG) identified through deep learning could predict individual responses to sertraline and placebo in major depressive disorder, identifying distinct regional signatures for each; data from 265 participants. Mol Psychiatry
• Psilocybin therapy for alcohol relapse prevention | Psilocybin-assisted therapy (single 25 mg dose) did not significantly outperform placebo in reducing relapse or alcohol use in recently detoxified individuals with alcohol use disorder in a phase 2 RCT (N=37). EClinicalMedicine
• Serotonin receptor linked to neuroticism traits | Higher brain 5-HT2AR binding was positively associated with neuroticism traits linked to depression risk, such as anxiety and vulnerability to stress, and this association was not influenced by cortisol levels – a PET imaging study with 80 healthy volunteers. Br J Psychiatry
• Psilocybin therapy for mood issues in Parkinson's | In adults with Parkinson’s disease, psilocybin-assisted therapy (two doses: 10 mg and 25 mg) was safe and led to clinically meaningful improvements in depression, anxiety, motor and non-motor symptoms, and select cognitive domains in an open-label pilot study (N = 12), with benefits persisting for up to three months. Neuropsychopharmacology
• Serotonin-related neuroplasticity after ECT | ECT-induced brain activity changes were linked to improved depression symptoms and correlated with serotonin and dopamine receptor/transporter density, highlighting serotonin-related neuroplasticity in the default mode network in two MDD cohorts (n=84 and n=35). Transl Psychiatry
• DMT temporarily destabilizes brain dynamics | DMT caused a transient increase in brain reactivity that was strongly associated with serotonin 5-HT2A receptor density, suggesting a mechanism for its powerful and lasting psychological effects; N=15 healthy volunteers given intravenous DMT (20 mg). Commun Biol
• Psychedelics and headache prevalence | Lifetime use of classic psychedelics was associated with a 25% lower likelihood of experiencing frequent bad headaches in a large cross-sectional analysis of a British sample (N=11,419). J Psychopharmacol
• Cognitive effects of sporadic psychedelic use | A cross-sectional analysis (N = 136) found that sporadic lifetime use of classic psychedelics was not associated with cognitive impairment or negative neuropsychological effects, and was moderately linked to enhanced executive function, particularly on the Wisconsin Card Sorting Test. Prog Neuropsychopharmacol Biol Psychiatry

Preclinical Research

• Psilocybin’s effects depend on 5-HT2A and PT neurons | Psilocybin’s long-lasting effects on stress-related behavior and neural plasticity depended on 5-HT2A receptors and pyramidal tract neurons in the medial frontal cortex. The study used optical imaging, electrophysiology, and chemogenetic silencing to identify a critical role for cell-type-specific 5-HT2A signalling in mediating psilocybin’s long-term neural and behavioural effects. Nature
• How psychedelics bind to 5-HT2A receptors | The study revealed distinct and overlapping structural interactions between various psychedelic and non-psychedelic compounds and the 5-HT2A serotonin receptor. Using cryo-EM, researchers solved seven receptor-ligand complex structures, offering insights into biased signaling and aiding future drug development. Nat Commun
• Targeting 5-HT2B receptors for cognitive symptoms | Selective inhibition of the serotonin 5-HT2B receptor improved behavioral and synaptic function in animal models of Alzheimer’s and related neuropsychiatric syndromes. The study also identified risperidone as a dose-dependent 5-HT2B inhibitor. Alzheimers Dement
• Psilocybin reduces chronic pain in mice | Psilocybin and DOI reduced pain-like behaviors in mice in a dose-dependent manner, and these effects were mediated by 5-HT2A receptor activation. Pharmacol Res
• Psilocybin alters brain network activity | Psilocybin dose-dependently altered rat cortical network organization by increasing high gamma and theta connectivity and disrupting theta-gamma coupling, highlighting high-frequency network reorganization as a possible neural signature of the psychedelic state. Transl Psychiatry
• Low doses of psilocybin offer benefits without hallucinogenic effects | Low-dose psilocybin altered neurotransmitter release in the frontal cortex, reduced anxiety-like behavior, and modulated the stress axis in rats without causing hallucinogenic effects or DNA damage. The animal study used subcutaneous psilocybin doses (0.1–0.6 mg/kg) and found non-linear neurochemical responses. Prog Neuropsychopharmacol Biol Psychiatry
• Blocking serotonin-dopamine receptor pairing reduces PTSD symptoms | Disrupting the interaction between serotonin 5-HT2C and dopamine D2 receptors reduced PTSD-like behaviors and improved cognitive function in stressed mice by restoring PI3K/AKT signaling. This animal study used a targeted interfering peptide (TAT-D2R-KL) in a single prolonged stress model of PTSD. J Affect Disord
• Effects of new synthetic tryptamines in rodents | Only 4-OH-MiPT produced effects similar to the known hallucinogen DOM in locomotor and drug discrimination assays in rats, while 5-MeO-DBT and 5-Cl-DMT showed weaker or partial effects. J Psychopharmacol
• Psilocybin in juvenile OCD mice | In this follow-up to a study where psilocybin reduced self-grooming and anxiety in adult OCD-model mice, juvenile SAPAP3-knockouts showed early anxiety-like behavior before developing OCD-like grooming, but did not respond to psilocybin. Synaptic changes appeared only in adults, suggesting age-dependent effects. Int J Neuropsychopharmacol
• Serotonin deficiency hinders spinal injury recovery | Rats lacking central serotonin exhibited impaired sensorimotor recovery after spinal cord injury in a TPH2 knockout rat model, highlighting serotonin’s key role in neuroplasticity. Int J Mol Sci
• Coumarins targeting serotonin receptors | Coumarin–piperazine compounds were found to bind selectively to 5-HT1A and 5-HT2A receptors, with binding strength influenced by structural modifications like methoxy and acetyl substituent positions. Int J Mol Sci
• Psilocybin produced in E. coli bacteria | Researchers successfully engineered E. coli to produce psilocybin through de novo biosynthesis, overcoming limitations of fungal enzyme activity and achieving a 100-fold yield improvement through pathway optimization and fermentation tuning. Microb Biotechnol
• [Preprint] Antidepressants reactivation of developmental plasticity | Chronic SSRI treatment reactivated juvenile-like plasticity in the dentate gyrus by remodeling the extracellular matrix and increasing SOX11 and BDNF expression, which reduced stress-induced fear generalization in mice. These effects were replicated by enzymatic ECM degradation, indicating that structural plasticity underlies some antidepressant actions. bioRxiv (preprint)

Reviews and Editorials

• The neurons that mediate a psychedelic's long-term antidepressive effects | Psilocybin’s lasting antidepressant effects in mice are driven by serotonin 2A receptor-mediated plasticity in prefrontal pyramidal tract neurons, highlighting a distinct neural circuit responsible for its therapeutic benefits. Nature
• Expectancy effects, failure of blinding integrity, and placebo response in trials of treatments for psychiatric disorders | This narrative review explores how expectancy effects and compromised blinding undermine the reliability of psychiatric RCTs, and proposes strategies to mitigate these confounds, such as monitoring blinding integrity, collecting expectancy data, and developing objective outcome measures. JAMA Psychiatry
• Psychedelic drugs in mental disorders: Current clinical scope and deep learning-based advanced perspectives | This review highlights the therapeutic potential of psychedelics for mental disorders and proposes deep learning as a powerful tool to optimize psychedelic drug development through precision medicine approaches. Adv Sci (Weinh)
• Classic psychedelics for the treatment of depression: Potential benefits and challenges | This review explores the emerging evidence for classic psychedelics like psilocybin, DMT, ayahuasca, and 5-MeO-DMT in treating treatment-resistant and major depression, highlighting promising early results alongside significant limitations such as short follow-up, functional unblinding, and high patient expectations. Drugs
• Hype or hope? The developing evidence base for psychedelic treatment of addiction disorders | This editorial reviews current randomized trial evidence on psychedelics for addiction treatment, highlighting promising early efficacy findings but cautioning that methodological limitations, lack of regulatory approval, and infrastructure challenges mean further rigorous research is essential. Br J Psychiatry
• Neuroplasticity and psychedelics: A comprehensive examination of classic and non-classic compounds in pre and clinical models | This review synthesizes evidence from preclinical and clinical studies showing that both classic and non-classic psychedelics promote neuroplasticity, potentially underpinning their rapid and lasting therapeutic effects in neuropsychiatric disorders. Neurosci Biobehav Rev
• Insights on psychedelics: A systematic review of therapeutic effects | This systematic review found that psychedelic-induced insight is commonly reported, dose-dependent, and strongly associated with therapeutic improvements, suggesting it may be a key mechanism of action in psychedelic therapy. Neurosci Biobehav Rev
• Exploring serotonergic psychedelics as a treatment for personality disorders | This review explores the emerging potential of serotonergic psychedelics to treat personality disorders like borderline, avoidant, and obsessive-compulsive personality disorders. Neuropharmacology
• Addressing blinding in classic psychedelic studies with innovative active placebos | This review outlines the limitations of current placebo strategies in psychedelic trials and proposes criteria and candidate agents for more effective active placebos to improve blinding integrity. Int J Neuropsychopharmacol
• [Patent Highlight] Novel compounds as 5-HT2A agonists for treating mental illness or CNS disorders | This Patent Highlight highlights newly developed 5-HT2A agonists with potential for treating psychiatric and central nervous system disorders, detailing their pharmacological activity and relevance to psychedelic drug development. ACS Med Chem Lett
• [Patent Highlight] Novel tryptamine compounds as 5-HT2A agonists for treating mood disorders such as depressive disorders and bipolar disorders | This editorial presents a series of newly developed tryptamine compounds that act as 5-HT2A receptor agonists, with potential therapeutic applications in depressive and bipolar disorders. ACS Med Chem Lett

‍New Clinical Trial Registrations

• DMT (2 mg/min infusion) +/- Propofol | Major Depressive Disorder (N=112) | Investigating the Role of the Psychedelic Experience in the Antidepressant Response in Patients With Major Depression: a Placebo-controlled Factorial Trial With DMT Masked With Propofol (DMT4D-Study) | Sponsor: University Hospital, Basel, Switzerland | NCT06927076
• LSD (150 µg), Psilocybin (30 mg), DMT (2 mg/min infusion); with effect durations standardized with ketanserin | Altered states of consciousness in healthy participants (N=24) | Direct Comparison of Altered States of Consciousness Induced by LSD, Psilocybin, and DMT in a Randomized, Placebo-controlled, Cross-over Trial in Healthy Participants (LPD-Study) | Sponsor: University Hospital, Basel, Switzerland | NCT06899334
• Psilocybe cubensis (30 mg psilocybin) +/- Fluoxetine (20 mg/day for 4 weeks) | Treatment-Resistant Depression (N=50) | Administration of Psilocybe Cubensis Mushrooms with or Without Fluoxetine for Refractory Depression: a Randomized Double-blind Controlled Trial (COGUNILA) | Sponsor: Federal University of Latin American Integration | NCT06898606
• Psilocybin (10 mg ) | Chronic Pain with implanted sensing-capable deep brain stimulation (DBS) devices (N=20) | Psilocybin With Intracranial Neural Sensing (PINS) (Open label) | Sponsor: Joshua Woolley, MD, PhD | NCT06919640
• Psilocybin (2 doses: 15 mg then 25 mg) + Psychotherapy | Post-Traumatic Stress Disorder (PTSD) (N=15) | The STARLIGHT Protocol: State-Funded Trial Assessing Recovery and Long-Term Impact of Guided Psilocybin for Healing Trauma | Sponsor: Baylor College of Medicine (Open Label) | NCT06888128
• Psilocybin (20 mg) +/- MDMA (100 mg) | Healthy Volunteers (N=24) | Acute Effects of MDMA Co-administration on the Response to Psilocybin in Healthy Subjects | Sponsor: University Hospital, Basel, Switzerland | NCT06884514
• Psilocybin (25 mg vs 1 mg) + ACT | PTSD in survivors of intimate partner violence (N=76) | Psilocybin-assisted Therapy for Post-Traumatic Stress Disorder in Survivors of Intimate Partner Violence | Sponsor: University of Calgary | NCT06885996
• Psilocybin (25 mg) + Therapy | Intergenerational Trauma (N=100) | Processing Intergenerational Trauma with Psilocybin-Assisted Therapy (Open Label) | Sponsor: Rachel Yehuda | NCT06899165
• Psilocybin (25 mg) + Therapy | Methamphetamine Use Disorder (N=20) | A Pilot Study in North Louisiana to Assess the Tolerability of Psilocybin As Well As Its Capacity to Promote Abstinence from Methamphetamine (Open Label) | Sponsor: Kevin Murnane | NCT06899594
• Psilocybin (25 mg) + Therapy | PTSD secondary to sexual assault (N=35) | A Phase 2, Open-Label Study Investigating the Safety and Efficacy of Psilocybin-Assisted Therapy for Sexual Assault-Related Posttraumatic Stress Disorder (PTSD) (Open Label) | Sponsor: Sunstone Medical | NCT06902974
• R-MDMA (300 mg) vs S-MDMA (100 mg oral) | Healthy Volunteers (N=24) | Comparative Acute Effects of R-MDMA and S-MDMA in Healthy Participants | Sponsor: University Hospital, Basel, Switzerland | NCT06905652

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Xylo Bio Updates

• We are thrilled to welcome Samantha Tabone to the team as Director of Business Development. With a decade of experience spanning biotech, neurotherapeutics, and venture investing, Samantha brings deep domain expertise and a passion for translating scientific innovation into real-world impact – an ideal match for our mission at Xylo.
• We launched our Targeted Neuro Talks video series to spotlight expert conversations on the latest breakthroughs and emerging ideas shaping the future of neurotherapeutics.
• Congratulations to Xylo advisor Dr. Alex Kwan and team on their recent Nature publication, which reveals how 5-HT2A receptors mediate psilocybin’s lasting neural and behavioral effects – also the focus of our latest Targeted Neuro Talks episode that you can watch below.
• Sam and Dilara enjoyed valuable in-person time with the Australian team during their recent visit.

🤝Join the Team:

We are currently hiring for:

• Vice President of Research and Development (San Francisco, CA, or Boulder, CO)
• Chief Development Officer (San Francisco, CA, flexible)
• Clinical Advisory Board Member – CNS Drug Development

Coming up:

• The Xylo team will be in CA later this month to reconnect with the 2025 One Mind Accelerator cohort and attend the Stanford Drug Discovery Symposium 2025.
• Xylo team members will be heading to Melbourne in mid-May to kick-off the CRC-P project to develop targeted neurotherapeutics for substance use disorders, in partnership with Tessara Therapeutics, and the University of Sydney.
• Dr Sam Banister will be presenting Xylo’s latest research at the 5th Annual Psychedelic Therapeutics & Drug Development Conference in San Diego, CA, May 19-20.

Photos

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