Psychedelic Science Newsletter - 2024 April

psylo_newsletters

6 May

Welcome to Psylo's Neuroscience Newsletter - April Edition!
Every month, we bring you a curated selection of the latest research and developments in the world of psychedelics, 5-HT2A, serotonin, and brain and mental health.

In our newsletters you will find:

Science in Sixty Seconds: Quick and digestible insights into key scientific concepts.
Clinical Research Updates: Findings from clinical trials and human studies.
Preclinical Research Highlights: Early-stage research and its implications.
Psychedelic Reviews and Commentaries: Expert opinions and analysis on current trends.
Psychedelic Clinical Trials Update: The latest clinical trials.
Psylo Updates: News about our team and community events.

Whether you're a professional in the field or simply someone interested in psychedelic science, our newsletter is designed to keep you informed and engaged with the most recent and relevant information. Enjoy!

Science in Sixty Seconds

The Journey from Molecule to Medicine

Did you know that bringing a new drug to market can take 10 to 15 years and cost an average of $1.3 billion? This complex process involves several distinct phases to ensure that only the safest and most effective treatments reach the public. The steps that a drug takes on its way from the lab bench to your medicine cabinet are described below.

1. Discovery and Screening

Scientists identify a biological target linked to a disease that could be influenced by a drug to produce beneficial effects. Using natural product libraries or synthetic chemistry, researchers then sift through thousands, sometimes millions, of compounds to identify candidates that potentially interact with the target.

2. Preclinical Testing

Before human testing, a drug must show safety and efficacy in the lab. This is achieved with experiments conducted in cells (in vitro) and animals (in vivo). This stage evaluates the drug's toxicity, pharmacokinetics (how it's processed by the body), and pharmacodynamics (its effects on the body).

3. Investigational New Drug Application

If preclinical results are promising, developers submit an Investigational New Drug (IND) application to regulatory bodies like the US FDA. This includes detailed information on the drug's chemistry, manufacturing, and safety data, along with plans for human clinical trials.

4. Clinical Trials

Drugs that clear IND move to human testing, which is conducted in three phases:

Phase I: A small group of healthy volunteers tests the drug, helping researchers assess its safety, optimal dosage, and side effects.
Phase II: The drug is given to a larger group of patients with the disease of interest to evaluate its efficacy and further assess its safety.
Phase III: Conducted with hundreds to thousands of patients, these trials confirm the drug’s effectiveness, monitor side effects, compare it to existing treatments, and collect data needed for regulatory approval.

5. New Drug Application (NDA)

After successful clinical trials, a New Drug Application is submitted to regulatory authorities. This comprehensive document includes all data from the drug’s development, including clinical trial results and manufacturing specifics.

6. Regulatory Review and Approval

Regulatory agencies meticulously review the NDA, examining trial data, drug formulation, and proposed labeling to ensure the drug is safe, effective, and manufactured to the highest quality standards. If approved, the drug can be marketed and sold.

7. Post-Marketing Surveillance

The drug’s journey doesn’t end with market entry. Regulators continue to monitor its performance in the broader population, tracking any rare or long-term adverse effects. This ongoing evaluation can lead to updates in usage guidelines and, rarely, withdrawal from the market.

A Case Study in Drug Safety and Regulation: Thalidomide

Initially marketed in the 1950s as a sedative and treatment for morning sickness, thalidomide led to tragic results when it was found to cause severe birth defects. This incident had a profound impact on drug regulations worldwide, leading to stricter controls on drug testing and approval processes. Thalidomide’s story highlighted the critical importance of rigorous clinical trials and post-marketing surveillance. It also led to the drug’s later redemption when, after thorough research and strict regulation, it was approved for use in treating leprosy and multiple myeloma under carefully controlled conditions.

The cautionary tale of thalidomide underscores the critical importance of rigorous testing and regulatory oversight in drug development. While long and complex, the path from discovery to market is meticulously designed to ensure the safety and efficacy of medications before they reach our hands.

RESEARCH UPDATES

Clinical Research

🤸‍♀️ Psychological Flexibility May Mediate Effects of Psilocybin Therapy | Psychological flexibility, mindfulness, and values-congruent living improved significantly after psilocybin treatment and were maintained through week 16, with enhancements in psychological flexibility and experiential acceptance strongly associated with reductions in depression severity; results from an exploratory placebo-controlled trial (N=34). Scientific Reports

😴 LSD Microdosing and Sleep Duration | Microdosing LSD (10 µg, every third day for 6 weeks) extended sleep duration by 24.3 minutes the night after dosing, without affecting the distribution of sleep stages or physical activity levels; a randomized controlled trial with 80 healthy males. Translational Psychiatry

🤕 Psilocybin for Cluster Headaches | In a survey of 479 Swedish cluster headache patients (most dissatisfied with current treatments), a small number (3.8%) reported using psilocybin with high effectiveness, suggesting the need for revised treatment approaches and further exploration of psilocybin's potential benefits. Brain Sciences
- Find details about a survey for individuals with cluster headaches below.

💊 Self-reported Coadministration of SSRIs and Psilocybin | Analysis of Reddit discussions revealed that 54% of the analyzed posts reported a diminished psychedelic experience when combining SSRIs with psilocybin, while 8% reported negative effects, including potential serotonin toxicity. Psychopharmacology

❓ Palliative Care Patients' Attitudes Towards Psilocybin Therapy | Over half of the surveyed palliative care patients (N=32) are open to psilocybin therapy for existential distress, indicating both interest and concerns about safety. Front Psychiatry

🧠 Prediction Brian Age with MRI and 5-HT2A PET | Machine learning models using 5-HT2A receptor PET imaging and MRI data of gray matter volume could predict chronological age with high accuracy in a cohort of 209 individuals, suggesting the potential of 5-HT2A receptor as a biomarker for brain aging. Mol Psychiatry

🔺🔻 Gender Differences in Mental Health Burden | Females face a higher burden of mental health disorders like depression and anxiety compared to males globally, systematic analysis using the Global Burden of Disease Study 2021 data. There is an urgent need for sex-specific policies, gender-sensitive research and interventions that promote health equality. Lancet Public Health

📉 SSRI and 5-HT1B Binding in Depression | A PET study shows that SSRI treatment reduces 5-HT1B receptor binding in the raphe nuclei of patients with depression, correlating with reduced depression severity. Int J Neuropsychopharmacol

Seeking Participants for a Cluster Headache Study in Australia.
Adults in Australia living with cluster headache are invited to join an important survey led by The George Institute for Global Health, UNSW. The survey will take ~10-15 minutes, and your participation will help shape the future of cluster headache research. 💡 Learn more or participate here

Preclinical Research

Psilocybin Enhances Cognitive Flexibility in Anorexia | Psilocybin was shown to improve body weight maintenance and cognitive flexibility in a rat model of anorexia. The effects were mediated through 5-HT1A and 5-HT2A receptor pathways. Mol Psychiatry

Serotonin Receptors and Learning Flexibility | The study found that 5-HT2A receptor antagonism specifically affects learning from negative feedback, while 5-HT2C receptor antagonism impacts learning from positive feedback; demonstrating differential roles in reinforcement learning and cognitive flexibility in rats. Psychopharmacology (Berl)

1DD-LSD, a novel 5-HT2A receptor agonist | 1DD-LSD shows similar psychedelic effects to LSD in mice but with significantly lower potency, and may be a long-acting prodrug. Drug Test Anal

LPH-5, a novel 5-HT2A receptor agonist | LPH-5 was identified as a selective and potent agonist at the 5-HT2A receptor with desirable drug-like properties. J Med Chem

CYB210010, a novel 5-HT2A receptor agonist | CYB210010 showed potent activity at 5-HT2A (long-acting) and 5-HT2C receptors, was orally bioavailable, brain-penetrant, and influenced neuroplasticity-related gene expression without causing behavioral tolerance. J Med Chem

Non-Hallucinogenic 2A Agonists for Alzheimer's Treatment | Hybridization of DYRK1A and psychoplastogen pharmacophores effectively promoted cortical neuron growth and reduced tau hyperphosphorylation without hallucinogenic effects in rodents. J Med Chem

Psilocybin-Induced Anxiety Independent of 5-HT2A | Psilocybin causes acute increases in anxiety in mice and alters amygdalar phosphopeptides through mechanisms that do not involve the 5-HT2A receptor. iScience

5-HT2A activation and Respiratory Response in Parkinson's Disease | Activation of 5-HT1A and 5-HT2A receptors improves breathing responsiveness to hypercapnia (excess carbon dioxide in the blood) in a Parkinson’s disease rat model. Int J Mol Sci

Early-Life Stress Affects Serotonin Receptors in Primates | Early-life adversity significantly decreases the binding potentials for 5-HT1A, 5-HT2A, and D2 receptors in adolescent primate brains. Neuropsychopharmacology

Psilocybin's Antidepressant and Neuroplastic Effects | Psilocybin demonstrated rapid and sustained antidepressant effects in mice that were accompanied by significant enhancements in neuroplasticity within the prefrontal cortex and hippocampus. J Psychopharmacol

DMT's Protective Role in Alzheimer's | Chronic DMT restores neuronal functions and reduces Alzheimer's symptoms in a transgenic mouse model by enhancing ER-mitochondria interactions. Alzheimers Res Ther

SERTlight: Innovative Serotonin Brain Probe | A newly developed fluorescent molecule, SERTlight, selectively labels serotonergic neurons by exploiting the serotonin transporter, offering insights into serotonin dynamics without pharmacologically altering its activity. J Am Chem Soc

[PRE-PRINT] 5-HT2A Receptor Agonist, LPH-5's Antidepressant Potential | LPH-5, a selective 5-HT2A receptor agonist, dose-dependently induced antidepressant-like effects in different rodent models. bioRxiv

Psychedelic Reviews and Commentaries

Psilocybin for Dementia Prevention? The Potential Role of Psilocybin to Alter Mechanisms Associated with Major Depression and Neurodegenerative Diseases | This review explores the potential of psilocybin to modulate mechanisms associated with both major depression and neurodegenerative diseases, suggesting a role in altering the progression from depression to dementia. Pharmacol Ther

New Perspective on Sustained Antidepressant Effect: Focus on Neurexins Regulating Synaptic Plasticity | This review explores the role of synaptic plasticity, particularly regulated by neurexins, in sustaining antidepressant effects, providing insights into potential new drug development for long-term management of depression. Cell Death Discov

Visual Hallucinations Originating in the Retinofugal Pathway under Clinical and Psychedelic Conditions | This review explores the role of the retinofugal pathway in generating visual hallucinations under both clinical conditions, such as Charles Bonnet syndrome, and psychedelic experiences induced by substances like LSD and psilocybin, suggesting a potential new theory of psychedelic modulation. Eur Neuropsychopharmacol

Spectral Signatures of Psilocybin, Lysergic Acid Diethylamide (LSD) and Ketamine in Healthy Volunteers and Persons with Major Depressive Disorder and Treatment-Resistant Depression: A Systematic Review | This systematic review explores the spectral signatures of psilocybin, LSD, and ketamine in individuals with major depressive disorder and treatment-resistant depression, suggesting reproducible effects aligning with disease models of network connectivity and indicating potential for further therapeutic discovery within these classes of agents. Journal of Affective Disorders

In the New Era of Psychedelic Assisted Therapy: A Systematic Review of Study Methodology in Randomized Controlled Trials | This review evaluates the methodology of randomized controlled trials (RCTs) utilizing psychedelics for psychiatric disorders, highlighting the challenges of blinding procedures and the importance of innovative experimental designs to minimize bias. Psychopharmacology (Berl)

Investigating Resistance to Antidepressants in Animal Models | This review explores current preclinical approaches to investigating treatment-resistant depression in animal models, aiming to provide insights into the neurobiological mechanisms underlying this condition and suggesting potential paths for improving therapeutic outcomes. Neuroscience

A Critical View on New and Future Antidepressants | This review critically evaluates various new and upcoming antidepressants, discussing their mechanisms of action, efficacy, tolerability, and potential clinical applications, highlighting the need for clinicians to stay updated with emerging evidence for translating benefits into routine clinical care. Clinical Psychopharmacology and Neuroscience

Psychedelic Clinical Trials Update

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

MDMA-Assisted Psychotherapy | Adolescents with Treatment-resistant PTSD (n=10) | MDMA-Assisted Psychotherapy for Treatment Resistant PTSD in Adolescents - NCT06353282

MDMA | PTSD and Moral Injury (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

Psilocybin | Alcohol Use Disorder (n=200) | Neurobehavioral Mechanisms of Psilocybin-assisted Treatment for Alcohol Use Disorder - NCT06349083

Psilocybin | Chronic PTSD (n=15) | Psilocybin-Assisted Massed Cognitive Processing Therapy for Chronic Posttraumatic Stress Disorder: An Open-label Trial - NCT06386003

Psilocybin | Chronic Low-back Pain and Depression (n=40) | Psilocybin and Affective Function in Chronic Lower Back Pain Depression (PsiloCLBP) - NCT06355414

Psilocybin | Fibromyalgia (n=35) | The Impact of Psilocybin on Pain in Fibromyalgia Patients (PsiloFM) - NCT06368492

Psilocybin | Treatment-Resistant Depression (n=24) | Low-Income Group Psilocybin Assisted Therapy for Depression (LIGPATD) - NCT06372197

Psilocybin | Treatment-Resistant Depression in a low-income population (n=92) | Psilocybin-Assisted Psychotherapy for Treatment-Resistant Depression: Comparing One Versus Two Doses of Psilocybin (PSI-1V2) - NCT06341426

Psilocybin | Treatment-Resistant Depression (n=100) | Psilocybin for Hospitalized Patients With Treatment-resistant Depression (PSIHOS-D) - NCT06378229

Psilocybin | Young Adults with Anorexia Nervosa (n=40) | Study of Psilocybin for Anorexia in Young Adults (SPANYA) - NCT06399263

PSYLO UPDATES

CEO Joshua Ismin will be appearing on a panel at the Digital Health Festival in Melbourne, 7-8 May. 🎫 Tickets.

Sam and Dilara will be visiting Australia (Sydney and Melbourne) in May for some quality facetime with the Australian team. Reach out if you'd like to connect.