Neuroscience Newsletter - 2024 May

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2 June

Welcome to Psylo's Neuroscience Newsletter - May Edition!

Science in Sixty Seconds

Update on the Clinical Trial Landscape

As of May 2024, 278 clinical trials have been registered for classic psychedelics, MDMA, and related compounds. There have been 33 new trials registered since October 2023 (13.5% increase)*.

*Current analyses excluded trials categorised as 'no_longer_available', 'terminated' and 'withdrawn'.

Overview of Interventions

Here’s an updated breakdown of the number of trials for each intervention (analogues and patented formulations are grouped with the parent compound):

Psilocybin: 147 (52.9%)
MDMA: 59 (21.2%)
LSD: 23 (8.3%)
DMT: 19 (6.8%)
5-MeO-DMT: 11 (4.0%)
Multiple#: 10 (3.6%)
Salvinorin A: 4 (1.4%)
Ibogaine: 3 (1.1%)
Mescaline: 1 (0.4%)
2C-B: 1 (0.4%)

Phases of Clinical Trials

The distribution of trials across different phases shows a more detailed progression compared to last year. Phase 2 trials, which focus on assessing efficacy and side effects, are the most numerous at 114 (41%). Phase 3 trials have increased to 12 (doubled from six last year), signaling a move towards finalizing research before potential regulatory approval. There is also one trial in Phase 4, which examines long-term effects post-approval.

Current Status of Trials

Most registered trials are completed (32%), with increases in actively recruiting (30%) and not yet recruiting trials (24%). This suggests that more trials are being set up and progressing, reflecting a robust and expanding field of research.

Funding

Most registered trials list their funding source as "Other" (83%). The majority of the remaining trials are industry-sponsored (14%), while federal and other government sources, including the National Institutes of Health (NIH), each account for 1% of the funding.

Conditions under investigation

This year, the distribution of conditions being investigated shows some shifts:

Basic science: 85 (30.6%) - still the majority of studies
Depression: 58 (20.9%) - up from 48
Post-traumatic stress disorder (PTSD): 35 (12.6%)
Substance use disorders: 35 (12.6%) - up from 29
Demoralization or health-related psychological distress: 17 (6.1%)
Chronic Pain: 11 (4.0%)
Obsessive-compulsive disorder (OCD): 9 (2.9%)
Anxiety: 7 (2.5%)
Eating disorders: 7 (2.5%)

Other conditions being investigated include ADHD, autism, bipolar II disorder, body dysmorphic disorders, borderline personality disorder, burnout, cognition, diabetes, fragile X syndrome, irritable bowel syndrome, Lyme disease, neurological conditions, schizophrenia, and stroke.

Commentary

The field of psychedelic research is rapidly evolving with trials in this area progressing, diversifying and maturing.

Advancing: There has been a significant move towards more advanced research stages, with an increase in Phase 3 trials indicating substances are nearing later stages of clinical testing.

Interventions: Psilocybin continues to be the most studied substance, particularly in the context of depression. It saw the largest absolute and relative increase in trials, with 29 new studies (24.6% growth). MDMA also experienced a notable rise with 5 new trials (9.3% increase).

Emerging conditions: The largest increase in trials, in absolute numbers, is depression, with an addition of 10 new trials, suggesting it is a continued area of interest. OCD experienced the largest relative increase in trials (60%). Other notable increases include PTSD and substance use disorders (both increased by 25%), followed by health-related psychological distress (21.4%). This data points to an expanding scope of conditions being targeted.

New conditions: There has also been an expansion into new areas like IBS, cognition and neurological conditions.

New applications: Notably, there are at least two trials registered for psilocybin in combination with a neuromodulation device. One with repetitive transcranial magnetic stimulation (rTMS) and another with transauricular vagus nerve stimulation (tVNS).

#Multiple interventions: These trials are mostly basic science investigations, trying to better understand how these substances work. However, at least four trials are comparing the efficacy of psilocybin with ketamine in depression or substance use.

Therapeutic focus areas for specific interventions:

Psilocybin is primarily researched for its potential in treating depression, substance use disorders, and health-related psychological distress.
MDMA's focus continues to be PTSD.
LSD research is broad, with a modest emphasis on anxiety and chronic pain, but these studies remain limited.
Both DMT and 5-MeO-DMT are mainly being investigated for depression, while Ibogaine is targeted towards substance use disorders.
Other substances, including Salvinorin A, 2C-B, and Mescaline, are largely in the basic science phase as they are still in the early stages of development.

The expanding scope of clinical trials focusing on the 5-HT2A receptor is refining treatment options and broadening our understanding of its therapeutic potential.

RESEARCH UPDATES

Clinical Research

DMT Alters Brain's Spacetime Hierarchy |DMT induces significant changes in the spacetime hierarchical organization of brain activity found a study using the Harmonic Decomposition of Spacetime (HADES) framework to analyse data from DMT-induced resting-state fMRI in healthy participants. National Science Review

Australian Poison Center Calls on Psychedelics | Psychedelic-related calls more than doubled from 45 in 2014 to 105 in 2022, with common clinical features being hallucinations, gastrointestinal symptoms, and tachycardia; seizures occurred in 2.9% of single substance exposures. This increase reflects growing community use and highlights the need for education on safe use to prevent significant toxicity. Clinical Toxicology (Phila)

First-Time LSD User Experiences | First-time LSD experiences generally exceeded expectations, with 97.7% expressing excitement and low reports of adverse effects found the 2018 Global Drug Survey (N=3340). Continued harm-reduction education is crucial to prevent potential associated risks. Journal of Psychopharmacology

SSRI Impact on 5-HT1B Receptors in Depression| There was a significant reduction in 5-HT1B receptor binding in the dorsal brainstem region after escitalopram treatment, which correlated with improvements in depression severity, reports a PET imaging study of eight unmedicated patients with moderate-to-severe depression. Int J Neuropsychopharmacol

Blood Flow Predicts Antidepressant Outcome | Changes in cerebral blood flow, measured using arterial spin labeling MRI, one week after treatment initiation could predict the 8-week treatment outcomes in patients with major depressive disorder (N=199) who were in the placebo group but not for those in the SSRI group; results from the multicenter, double-blind, randomized, placebo-controlled EMBARC clinical trial. Psychol Med

Psychedelics Linked to Lower Depression | Psychedelic users reported less depression in a survey of 800 participants, and this effect was associated with specific personality traits, particularly lower neuroticism and higher openness. Sci Rep

Telehealth Ketamine for Depression | At-home ketamine, supported by telehealth, was largely safe, well-tolerated, and significantly improved depression symptoms, reports a longitudinal study involving 11,441 patients with moderate-to-severe depression who received four doses of sublingual ketamine at home over four weeks, supported by telehealth. This study used machine learning and symptom network analyses to investigate outcomes. Journal of Affective Disorders

Ethical Guidelines for Medical Psychedelics | The Hopkins-Oxford Psychedelics Ethics (HOPE) Working Group developed consensus ethical guidelines for the use, research, and policy of psychedelics. Recommendations emphasize inclusivity, equity, and informed practices in the context of mental health treatments involving psychedelics. The American Journal of Bioethics

Measuring Psychotherapy Processes in Psychedelic Experiences | The study validates the General Change Mechanisms Questionnaire (GCMQ) for assessing psychotherapeutic processes during psychedelic experiences, demonstrating good internal consistency and convergent validity; online survey of 1,153 English-speaking and 714 German-speaking users. Journal of Psychopharmacology.

[Case study] Psychedelics Alleviate SUNCT Headache Symptoms | A case study showed that ayahuasca, DMT, and LSD effectively alleviated symptoms of Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) in a suicidal patient with excruciating SUNCT. Headache

Preclinical Research

Validating AlphaFold2 ligand discovery | Docking against AlphaFold2 models of the σ2 and 5-HT2A receptors yielded high hit rates and affinities comparable to those obtained using experimental structures, indicating the utility of AF2 in ligand discovery. Science

5-MeO-DMT and Its Therapeutic Potential | A 5-HT1A-selective 5-MeO-DMT analogue was found to exert anxiolytic and antidepressant effects without causing hallucinations, in mice. Nature

5-MeO-DMT Brain Activity Mimics Sleep | 5-MeO-DMT alters hippocampal and prefrontal cortex activity to resemble sleep states in awake rats, offering insights into how classical psychedelics may influence brain states. Sci Rep

Serotonin Dysregulation Drives Alzheimer's Symptoms | Dysregulation of 5-HT1A and 5-HT2A receptors in the amygdala exacerbates mood and cognitive defects in Alzheimer’s mouse models, which can be mitigated by downregulating these receptors. Aging Cell

Serotonin Receptors' Impact on Memory | Activation of 5-HT2A and inhibition of 5-HT1A receptors altered memory, motor behavior, emotional responses and regional dopamine availability in rats. Behav Brain Res

Distinct 5-HT2A-G Protein Mechanisms in Schizophrenia | Specific G protein pathways linked to the 5-HT2A receptor differentially regulate memory deficits and psychosis-related behaviors in schizophrenia models, suggesting possible separation of desirable therapeutic effects from unwanted side effects. Nat Commun

Psilocin Metabolism | CYP2D6 and CYP3A4 are significant enzymes in psilocin metabolism, transforming it into various metabolites, including an identified metabolite norpsilocin in mice and an oxidized metabolite in human plasma samples. Front Pharmacol

Psilocybin for Alcohol Addiction | Psilocybin significantly reduced ethanol self-administration in rats by 50% when injected into the left nucleus accumbens, highlighting the role of this brain region and the 5-HT2A receptor in mediating psilocybin’s effects on alcohol consumption. Brain

DMT: Potential Alzheimer's Treatment | DMT improved cognitive functions and reduced Aβ accumulation in a mouse model of Alzheimer's disease by restoring Sigma-1 receptor-mediated neuronal functions. Alzheimers Res Ther

Transdermal DMT Patch Development | A novel extended-release transdermal DMT patch provided consistent, extended drug release at non-hallucinogenic doses in mice, showing 77% bioavailability compared to IV administration. European Journal of Pharmaceutical Sciences

Novel Short-Acting Psychedelic Prodrug for Depression | RE104, a prodrug of 4-OH-DiPT, shows potential as a short-duration antidepressant in rat models of depression. ACS Chem Neurosci

Ketamine Counters Depression via Serotonin Neurons | Induced stress in the endoplasmic reticulum of serotonin neurons leads to depressive-like behaviors in mice, which can be alleviated by ketamine through its action eIF2α signaling. This study provides insight into ketamine’s antidepressant mechanisms. iScience

[Preprint] Psilocybin Boosts Fear Extinction in Mice | Psilocybin significantly enhanced fear extinction when administered before testing, improved extinction retention, and reduced fear renewal in mice, with these effects being dose-dependent and influenced by serotonin receptor activity. BioRxiv

[Preprint] DMT Study in Rats: Neurochemical and EEG Insights | DMT caused dose-dependent increases in serotonin and dopamine levels, modified EEG spectral power, and altered functional connectivity in mouse brains. BioRxiv

Reviews and Commentaries

New Perspective on Sustained Antidepressant Effect: Focus on Neurexins Regulating Synaptic Plasticity | The editorial highlights the role of synaptic plasticity in sustaining antidepressant effects, with a focus on neurexins as key regulators, offering insights into potential future antidepressant drug development. Cell Death Discov

Is it Now Time to Prepare Psychiatry for a Psychedelic Future? | This article examines the recent rescheduling of psilocybin and MDMA in Australia for the treatment of treatment-resistant depression and post-traumatic stress disorder (PTSD), discussing the implications and challenges this presents to psychiatry and healthcare systems. Br J Psychiatry

What is Needed for the Roll-Out of Psychedelic Treatments? | The review discusses the increasing pace of psychedelic treatments and the urgent need for clinical guidelines and coherent regulation, highlighting the philosophical divide between viewing psychedelics primarily as pharmacological or psychotherapeutic interventions. Curr Opin Psychiatry

The Long Road Toward Equitable MDMA Treatment in the United States | The commentary discusses the regulatory process and potential challenges associated with MDMA-assisted therapy for PTSD in the United States, emphasizing the need for equitable access, lobbying efforts for insurance coverage, and addressing cultural barriers to ensure marginalized communities benefit from this treatment. J Clin Psychiatry

In the New Era of Psychedelic Assisted Therapy: A Systematic Review of Study Methodology in Randomized Controlled Trials | The review examines the challenges of blinding procedures in randomized controlled trials involving psychedelics for psychiatric disorders, highlighting the importance of experimental methodology to address expectancy confounds and ensure internal validity. Psychopharmacology (Berl).

Disentangling the Acute Subjective Effects of Classic Psychedelics from their Enduring Therapeutic Properties | The review explores the correlation between the acute subjective effects of classic psychedelics and their lasting therapeutic benefits, discussing ongoing efforts to dissociate acute subjective effects from therapeutic effects to facilitate widespread clinical implementation. Psychopharmacology (Berl)

Alterations in Brain Network Connectivity and Subjective Experience Induced by Psychedelics: A Scoping Review | This review explores the relationship between psychedelics and alterations in brain functional connectivity, suggesting a potential neural mechanism underlying the subjective effects of psychedelics and their therapeutic potential, while emphasizing the need for further clinical evidence. Front Psychiatry

Perspectives and Preliminary Experiences of Psychedelics for the Treatment of Eating Disorders: A Systematic Scoping Review | This review outlines participant-reported efficacy and perspectives regarding the use of psychedelics in treating eating disorders, suggesting potential benefits but highlighting the need for further robust research to establish efficacy, generalizability, and safety. Eur Eat Disord Rev

The Utility of PET Imaging in Depression | The review explores the role of PET imaging in understanding the neurobiology of depression, discussing its utility in investigating neurotransmitter systems, treatment mechanisms, and potential future applications, despite current limitations in translating findings into clinical practice. Front Psychiatry

Investigating Resistance to Antidepressants in Animal Models | The review systematically examines current preclinical approaches to investigating treatment-resistant depression in animal models, aiming to provide insights for improving our understanding of this condition and developing more effective therapies. Neuroscience

Altered States and Social Bonds: Effects of MDMA and Serotonergic Psychedelics on Social Behavior as a Mechanism Underlying Substance-Assisted Therapy | The review compares the prosocial effects of MDMA and serotonergic psychedelics, highlighting differences in mechanisms that may impact the therapeutic process, with implications for psychosocial interventions. Biol Psychiatry Cogn Neurosci Neuroimaging

Integrating Psychedelics into Digital Health: A New Horizon in Mental Wellness | This review discusses the history, current status, and potential future of integrating psychedelics into mental health care and the role of technology, such as virtual reality, in enhancing psychedelic treatments. Cyberpsychology, Behavior, and Social Networking

Clinical Trials Update

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

MDMA-assisted therapy | Post-traumatic stress disorder (PTSD) and moral injury in veterans (N=60) | Examining 3,4-methylenedioxymethamphetamine (MDMA) effects on psychological, relational and hyperarousal-related neural reactivity mechanisms in veterans with PTSD and moral injury - NCT06394284

Esketamine and behavioral activation therapy | Resistant depression (N=40) | Behavioral activation therapy and esketamine for resistant depression - NCT06431386

Ketamine and CBASP therapy | Chronic treatment-resistant depression (N=60) | Pharmacologic treatment augmentation in chronic depression, investigating the effects of combining ketamine with Cognitive Behavioral Analysis System of Psychotherapy (CBASP) - NCT06410599

MDMA-assisted therapy | PTSD in U.S. veterans (N=60) | Dose optimization of MDMA-assisted therapy for PTSD to determine the optimal number of treatment cycles of MDMA-AT for significant improvement - NCT06418178

Psilocybin therapy | Anorexia nervosa (N=40) | Study of psilocybin for anorexia in young adults - NCT06399263

Psilocybin therapy | PTSD (N=20) | A study of psilocybin for PTSD in adult patients with chronic PTSD who are currently taking a serotonin reuptake inhibitor - NCT06407635

Psilocybin vs ketamine | Alcohol use disorder (N=80) | Psilocybin vs ketamine for alcohol use disorder - NCT06405607

Psilocybin-assisted psychotherapy | Fear of cancer recurrence (N=20) | A phase 1b study of psilocybin assisted psychotherapy to address fear of recurrence in early-stage breast cancer and ovarian cancer patients - NCT06430541

Psilocybin-assisted therapy | Advanced cancer (N=15) | Psilocybin-assisted existential, attachment and relational (PEARL) therapy for patients with advanced cancer - NCT06416085

PSYLO UPDATES

Psylo has successfully completed the first close of our $8M Series Seed financing round, led by Tenmile and supported by Palo Santo, Focalpoint Partners, Mystic Ventures, and others. This funding will accelerate our non-hallucinogenic lead asset development and enhance our neuroplastogen platform. Connect with us to learn more.

CEO Joshua Ismin discussed the future of mental health startups on a panel at the Digital Health Festival, Melbourne, 7-8 May.

Sam and Dilara visited Sydney and Melbourne this month, enjoying valuable face time with colleagues and friends.

Many thanks to Garry Williams for organizing a fantastic event at the Science Gallery Melbourne. I met many brilliant people and look forward to seeing them again. Garry excels at creating engaging events and connecting innovative minds, and is always working on something interesting. Be sure to connect with him and check out his work.

Upcoming

Joshua Ismin (CEO), Dr Sam Banister (CSO) and Dr Mario de la Fuente (Senior Director of Translational Pharmacology) will be at the Biotechnology Innovation Organization (BIO) meeting in San Diego next week. Reach out if you'd like to connect.

Dr Dilara Bahceci, Head of Communications at Psylo (and Research Fellow at The George Institute) will speak on a panel titled, "Lessons Learned from Ketamine" at the Pathways to Access Summit, ICPR, in Amsterdam next week.