Neuroscience Newsletter - 2024 November

psylo_newsletters

2 Dec

The Psylo Newsletter 2024 Wrap-up

It’s time to say goodbye to Psylo as you know it

We're rebranding!

The therapeutic potential of psychedelics is clear, but recent challenges in the field highlight significant hurdles, from regulatory delays to accessibility barriers. These obstacles emphasize the importance of developing innovative solutions that overcome these obstacles and reach more people in need.

To meet this need, we are dedicating our efforts exclusively to expanding our non-hallucinogenic “neuroplastogen” pipeline – treatments designed to be accessible, scalable, and truly transformative.

While Psylo has served us well, it no longer fully reflect our vision or strategy. We are rebranding to better align with our focus, expertise in neuroscience, and commitment to pioneering innovative treatments.

Stay tuned as we prepare to announce our new identity and embark on this exciting next chapter!

Thank you for an incredible year!

What a fantastic way to wrap up 2024! Thank you to everyone who joined Psylo’s end-of-year celebration. It was wonderful to see so many faces and reflect on the achievements we’ve made together this year.

A special thanks to our amazing investors, including Tenmile, Main Sequence, UNSW Founders and M8 Ventures, whose belief in our vision continues to drive us forward.

A heartfelt thanks to Village – Wildflower Brewing & Blending for hosting us in such a beautiful space and to Melody Heart for perfectly capturing the evening. 📷 Check out the photo gallery here!

RESEARCH UPDATES

Clinical Research

Psilocybin improves depression and sleep disturbances | Psilocybin reduced depressive symptoms and sleep disturbances, with baseline sleep issues predicting lower chances of remission – a naturalistic survey of participants who took part in facilitated psilocybin sessions within retreat settings, or guided psilocybin experiences (n = 653). Curr Psychiatry Rep

Ketamine reduces attentional bias in depression | Ketamine rapidly reduced attentional bias toward negative emotional information, correlating with improved depressive symptoms. The study validated a novel psychometric measure of attentional bias using a dual probe video task in 83 adults with depression. Biol Psychiatry

Hallucinogen use linked to psychosis risk | Individuals with emergency department (ED) visits involving psychedelic use had a significantly higher risk of developing schizophrenia spectrum disorders within three years compared to both the general population and individuals with ED visits for alcohol or cannabis – a population-based retrospective cohort study of 9,244,292 individuals with median follow-up of 5.1 years. JAMA Psychiatry

Adverse psychiatric effects of psychedelics | Case reports of schizophrenia-spectrum and major affective disorders after psychedelic use are documented but relatively uncommon, while flashbacks sometimes result in persistent psychiatric symptoms, including anxiety and depression – a systematic review of 39 case reports. Psychol Med

Psychedelics and self-related thought processing | Psychedelic users exhibited weaker alpha and beta power increases in self-related brain regions during self-related thoughts compared to non-users in one dataset, but these effects were not replicated in another dataset - Observational study using EEG source localization with two datasets (N=70 and N=38). Prog Neuropsychopharmacol Biol Psychiatry

Psychedelic use linked to cannabis disorder risk | Past year LSD use and lifetime psilocybin use were associated with significantly higher risks of DSM-5 CUD and its symptoms, even after controlling for sociodemographic factors - in a nationally representative US sample, NSDUH data from 2015 – 2019 (N = 214,505) and 2021 – 2022 (N = 94,391). Drug Alcohol Depend

DMT enhances brain connectivity for social cognition | DMT increased connectivity between key brain regions (e.g., supramarginal gyrus, amygdala, and orbitofrontal cortex) associated with social and emotional processing - pharmacoimaging study with 11 experienced DMT users. Front Pharmacol

Mescaline safety and effects in healthy adults | Single oral doses of mescaline (100-800 mg) were well-tolerated in healthy participants, showing dose-dependent increases in positive subjective effects and mild, manageable adverse effects, with nausea as the dose-limiting factor – a pooled analysis from two double-blind, randomized, placebo-controlled studies involving 48 participants and 96 mescaline administrations. Br J Clin Pharmacol

Strategies for managing challenging psychedelic experiences | Acceptance and reappraisal, and social support, were positively associated with emotional breakthroughs during challenging psychedelic experiences, while fear-related challenges were less adaptive – study included qualitative analysis of psilocybin retreat participants (n=16) and an online survey (n=529) that developed and validated the ReCiPE (Responses to Challenging Psychedelic Experiences Inventory). Sci Rep

Healthcare professionals’ views on psilocybin and MDMA | Healthcare professionals generally endorsed the therapeutic potential of psilocybin and MDMA but reported low knowledge levels, with concerns about training, cost, and contraindications influencing openness to their clinical use. Cross-sectional survey of 879 US healthcare professionals. Sci Rep

Psychologists' views on psychedelic-assisted therapy | Australian psychologists showed optimism about the potential of psilocybin- and MDMA-assisted therapy but emphasized the need for robust training, citing concerns about evidence gaps and psychiatric risks. Qualitative study of 20 participants using semi-structured interviews. Drug Alcohol Rev

Peer coaches’ views on psychedelics for addiction | Most Massachusetts peer recovery coaches supported psychedelics for SUD treatment but emphasized concerns about risks, particularly among 12-step program users – a survey of 146 coaches highlighted the influence of personal psychedelic use on attitudes. Addict Sci Clin Pract

Increased 5HT2A receptor expression in SUDC linked to seizures | The study identified significant brainstem protein alterations, including increased 5HT2A receptor expression, in sudden unexplained death in childhood (SUDC) cases with febrile seizure history, suggesting links between seizures, brainstem dysfunction, and serotonergic signaling. Proteomics analysis of 19 cases (8 no-FS, 11 FS). Acta Neuropathol

Psilocybin reduces depression symptoms significantly | Psilocybin-assisted therapy led to significant and clinically observable reductions in depressive symptoms compared to baseline and placebo treatments, found a systematic review and meta-analysis of 6 randomized clinical trials including 432 participants. J Psychopharmacol

Preclinical Research

Psychedelic-responsive neurons reduce anxiety-like behaviors | Psychedelic-responsive neurons in the mPFC reduce anxiety-like behaviors when reactivated, without inducing hallucinogenic-like effects in mice, involving multiple cell types, including those expressing 5-HT2A receptors. Science

Ventral hippocampus mediates psychedelic anxiolytic effects | DOI induced anxiolytic effects in mice by activating 5-HT2A receptors on parvalbumin interneurons in the ventral hippocampus, suggesting the cellular mechanism underlying psychedelic anxiety relief. Neuron

Serotonergic role in ketamine’s antidepressant effects | Ketamine's sustained but not rapid antidepressant effects depend on serotonergic neurotransmission and AMPA receptor activation in mice. Br J Pharmacol

Hydroxyl group effects on psilocin activity | Psilocin and bufotenine, with hydroxyl groups at the 4th and 5th positions, demonstrated higher 5-HT2A receptor activity and stronger psychedelic-like effects compared to 6-OH-DMT and 7-OH-DMT. Eur J Med Chem

Neurochemical effects of 5-HT2AR partial agonists | Psilocybin, lisuride, and 25CN-NBOH showed varying receptor occupancy and hemodynamic responses, with 25CN-NBOH producing significant cerebral blood volume changes despite low occupancy – a peclinical PET-MRI study with N = 3 nonhuman primates. J Cereb Blood Flow Metab

Sex differences in serotonergic vascular modulation | In female rats, 5-HT1D receptors mediate sympatholytic effects, while 5-HT2A and 5-HT3 receptors enhance vascular sympathetic neurotransmission, showing distinct sex-based serotonergic regulatory mechanisms. Br J Pharmacol

Role of 5-HT receptors in DOM effects | 5-HT2A receptors mediate both HTR and locomotor hyperactivity across all doses of DOM, while 5-HT2C and 5-HT1A receptors modulate these responses differently at specific doses, contributing to the biphasic dose-response curve. Psychopharmacology (Berl)

Detecting head-twitch using deep learning | DOI-induced head-twitch responses were accurately detected using marker-less deep learning. Additionally, DOI-induced head-twitch responses were selectively attenuated by 5-HT2A receptor antagonist ketanserin but not by 5-HT5A antagonists, confirming the specificity of HTR to 5-HT2A activation. Pharmacol Rep

Psilocin reduces microglial activity via 5-HT2Rs | Psilocin reduced microglial activity, including ROS production and NO release, via 5-HT2 receptors, indicating potential therapeutic applications for neuroimmune and neurodegenerative disorders. This preclinical study used microglia-like cell lines to examine receptor-mediated effects. Molecules

Mescaline effects mediated by 5-HT2A/2C receptors | Mescaline-induced hyperlocomotion and sensorimotor gating deficits in rats were primarily mediated by the 5-HT2A receptor, with partial contributions from 5-HT2C. Preclinical animal study using behavioral pharmacology in adult Wistar rats. Pharmacol Biochem Behav

5-HT2C receptor regulates hippocampal E/I balance | Inhibition of 5-HT2CR shifted hippocampal excitation-inhibition balance towards excitation, reduced GABA release, and induced depressive-like behaviors in mice. Brain

5-HT7R stimulation rescues deficits in Angelman mice | Stimulation of 5-HT7 receptors restored synaptic plasticity, dendritic spine density, and cognitive performance in a mouse model of Angelman syndrome, a severe neurodevelopmental disorder. Prog Neurobiol
[Preprint] Psilocybin effects depend on 5-HT2A receptors | Psilocybin increased dendritic spine density in two pyramidal cell types, with the effects on stress-related behaviors and plasticity dependent on 5-HT2A receptor activity in subcortical-projecting pyramidal tract neurons. bioRxiv
[Preprint] Neurovascular changes under psychedelic 5-HT2A agonism | DOI altered neurovascular coupling, especially during resting-state conditions in mice, leading to discrepancies between neuronal and hemodynamic signals, and these effects were reversed by the 5-HT2A antagonist MDL100907. bioRxiv
[Preprint] 5-HT2C receptors reduce MDMA’s reward potential | 5-HT2C receptors in the NAc constrain MDMA-induced dopamine release in rodents, reducing its rewarding effects, while serotonergic mechanisms facilitate prosocial behaviors without enhancing abuse potential - highlighting separate mechanisms for MDMA's low abuse potential and prosocial effects. bioRxiv

Reviews and Commentaries

Deepening Psychedelic Integration: Exploring Complex Settings, Understanding User's Struggles, and Implementing Safe Interventions | This chapter explores the concept and practices of psychedelic integration across various settings, highlighting clinical methods for addressing challenges like unresolved experiences, adverse reactions, and repeated psychedelic use without proper integration. Curr Top Behav Neurosci

Epistemic Risk Reduction in Psychedelic-Assisted Therapy | This article examines the unique epistemic challenges in psychedelic-assisted therapy, proposing strategies to mitigate risks associated with belief changes while preserving patient autonomy and adapting interventions to individual needs. Curr Top Behav Neurosci

Editorial: Current Progress and Challenges in Psychopharmacology Research | This editorial highlights recent advancements in psychopharmacology, including studies on psychedelics, plant-based medicines, and newly approved treatments, while addressing the challenges of ensuring safe and accessible therapies for mental health and neurological disorders. Front Pharmacol

Innovative Psychedelic Therapies: Harnessing 5-MeO-DMT and DMT for Mental Health Treatment | This editorial evaluates recent patents exploring the therapeutic potential of 5-MeO-DMT and DMT in mental health treatment, highlighting innovations such as mood preparation agents, prodrugs for enhanced pharmacokinetics, and tailored therapies for specific populations, offering hope for treatment-resistant disorders. ACS Med Chem Lett

Expanding the Therapeutic Horizons of Psilocybin in Mental Health | This editorial highlights innovative applications of psilocybin, including clinical trials for severe psychiatric conditions, incorporation into dietary products for mental wellness, and personalized dosing strategies to optimize treatment outcomes for depression and anxiety, showcasing its transformative potential in mental health care. ACS Med Chem Lett

The Immunomodulatory Effects of Psychedelics in Alzheimer's Disease-Related Dementia | This review explores how psychedelics, through 5-HT2AR and Sigma-1R activation, can reduce neuroinflammation and promote neuroplasticity, highlighting their potential therapeutic role in managing Alzheimer’s disease-related dementia. Neuroscience

Impact of Substance Use Disorder on Tryptophan Metabolism Through the Kynurenine Pathway: A Narrative Review | This review examines how substance use disorders disrupt tryptophan metabolism via the kynurenine pathway, contributing to imbalances that affect the dopamine reward system and exploring potential therapeutic interventions to restore homeostasis. Metabolites

Pharmacotherapeutic strategies for the treatment of anorexia nervosa - novel targets to break a vicious cycle | This review discusses the neurobiological underpinnings of anorexia nervosa and evaluates novel pharmacotherapeutic approaches, including psychedelics, cannabinoids, and neurosteroids, aimed at enhancing cognitive flexibility, mood, and illness insight while addressing comorbid conditions. Expert Opin Pharmacother

New Role of the Serotonin as a Biomarker of Gut-Brain Interaction | This review explores serotonin's role as a biomarker for gut-brain communication, highlighting its potential in diagnosing and treating gut-brain disorders, with implications for mental health and gastrointestinal diseases. Life (Basel)

Serotonergic underpinnings of obsessive-compulsive disorder: A systematic review and meta-analysis of neuroimaging findings | This review and meta-analysis reveal reduced serotonin transporter (SERT) binding potential in specific brain regions of unmedicated OCD patients, highlighting serotonergic dysfunction as a key feature of the disorder while emphasizing the need for further research to clarify underlying mechanisms. Psychiatry Clin Neurosci.

Current and Novel Therapies for Cluster Headache: A Narrative Review | This review highlights the multifaceted approaches to managing cluster headache, including current pharmacological and nonpharmacological treatments, emerging interventional procedures, and the potential role of psychedelics, emphasizing the need for comprehensive strategies to enhance patient outcomes. Pain Ther

The historical opposition to psychedelic research and implications for credibility in psychiatry | This perspective article examines the historical resistance to psychedelic research, shaped by counterculture affiliations, media sensationalism, and scientific critiques, and discusses its implications for the credibility and progress of psychedelic-assisted therapy in psychiatry amidst ongoing drug policy reform. CNS Spectr

Clinical Trials Update

A round-up of the latest registered clinical trials investigating psychedelics:

Psilocybin (25 mg, 1 mg) combined with midazolam or placebo | Suboptimal Wellbeing (N=60) | Role of Experience, Conscious Awareness, and Plasticity in Psilocybin's Behavioral Effects - Follow-Up Study (The RECAP 2 Study) | Sponsor: University of Wisconsin, Madison | NCT06692192

Psilocybin (2 x 25 mg doses) paired with psychotherapy (mindfulness-based CBT) | Bipolar II Depression (N=10) | Acceptability & Safety of Two Sequential Doses of Psilocybin in Bipolar Disorder II Depression | Sponsor: The University of Texas Health Science Center, Houston | NCT06706232

MDMA | Borderline Personality Disorder (N=10) | The Effects of MDMA (3,4-methylenedioxymethamphetamine) in Social Cognition in Borderline Personality Disorder | Sponsor: Yale University | NCT06683014

Ketamine | Depression: KET's effects on the molecular/ gene expression pathways (N=120) | Integrating Ketamine Effects on Neuronal Molecular Signatures and the Brain Functional and Structural Connectome | Sponsor: Massachusetts General Hospital | NCT06698848

PSYLO UPDATES

Season’s Greetings from Psylo

As the year draws to a close, we at Psylo want to thank you for being part of our journey. Your support and collaboration have been instrumental in advancing our mission to develop innovative treatments.

We’re excited about what lies ahead in 2025 and can’t wait to share it with you! Until then, we wish you a joyful and restful holiday season.