Neuroscience Newsletter - 2024 October

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5 Nov

Welcome to Psylo's Neuroscience Newsletter

Science in Sixty Seconds

The Global Burden of Mental and Neurological Disorders

Mental and neurological disorders are major global health challenges, affecting billions of people worldwide and contributing significantly to the global disease burden. Despite their profound impact on individuals, families, and societies, these conditions remain under-recognized, underfunded, and under-treated.

Global Prevalence and Burden

The impact of mental and neurological disorders is profound and far-reaching. Together, these conditions contribute to nearly 10% of the global disease burden, measured in disability-adjusted life years (DALYs), which represents the years of healthy life lost to illness and disability.

Neurological Disorders: Neurological disorders have become the leading cause of disability and the second leading cause of death worldwide. In 2021, 3.4 billion people experienced some form of health loss due to nervous system disorders, with over 11 million deaths from conditions like stroke, Alzheimer’s, and epilepsy. Stroke alone is the third leading cause of DALYs worldwide, reflecting the significant burden of these disorders on quality of life and mortality.

Mental Disorders: Mental health conditions are increasingly recognized as major contributors to global disease burden, accounting for around 125.3 million DALYs in 2019 - nearly 5% of the global total. Depressive disorders, the 13th leading cause of global disability, are the largest contributors (37.3% of mental health DALYs), followed by anxiety disorders (22.9%) and schizophrenia (12.2%). Suicide, often linked to untreated mental health conditions, claims over 700,000 lives annually, ranking as the 18th leading cause of death globally and the 4th among young people aged 15-29.

Economic Impact

The economic toll of untreated mental and neurological conditions is enormous. The WHO estimates that depression and anxiety alone cost the global economy about $1 trillion annually due to lost productivity. While, in the USA and Europe alone, the annual cost of neurological disorders is USD $1.7 trillion – almost double the estimated global cost of cardiovascular disease. These impacts extend beyond healthcare to workplace productivity and economic stability, with depression and anxiety as leading contributors to workplace absenteeism.

The Treatment Gap

Despite their widespread impact, mental and neurological disorders face a significant treatment gap, with many affected individuals lacking adequate care. Up to 78% of people with mental health disorders go untreated, rising to 96% in low- and middle-income countries. For neurological disorders, the treatment gap exceeds 75% in most low-income countries and 50% in middle-income countries. This gap stems from factors such as stigma, high costs, and limited healthcare infrastructure. A critical shortage of mental health professionals compounds the issue, with less than 1 psychiatrist per 100,000 people in low-income regions compared to 50 per 100,000 in high-income areas.

Disproportionate Investment

A major factor behind the treatment gap is inadequate funding. Despite their high burden, these conditions receive disproportionately low funding. In many countries, mental health receives less than 2% of national health budgets, with most funds going to psychiatric hospitals, while neurological conditions often receive even less. This underinvestment limits the development of new treatments and perpetuates the treatment gap.

Conclusion: A Path Forward

The burden of mental and neurological disorders is growing alongside our aging and expanding global population, underscoring the need for greater investment. One path forward is accelerating drug development, particularly for therapies that target the underlying biology of these complex conditions. Neuroplastogens, for example, have the potential to stimulate neuroplasticity, offering a new avenue to treat conditions like depression, substance use disorders and neurodegenerative diseases. The World Health Organization (WHO) reports that every $1 invested in mental health treatment yields a $4 return in health and productivity gains. By prioritizing mental and neurological health in drug development, we can make meaningful strides toward improving outcomes and quality of life for millions worldwide.

RESEARCH UPDATES

Clinical Research

Psilocybin efficacy unaffected by antidepressant discontinuation | Discontinuing antidepressants before psilocybin treatment did not impact the efficacy or subjective experience in patients with treatment-resistant depression. This analysis included 233 participants from a randomized controlled trial. J Psychiatr Res

Ketanserin's dose-occupancy at the 5-HT2A receptor | Ketanserin showed dose-dependent 5-HT2A receptor occupancy, indicating its potential for mitigating psychedelic effects. This PET study involved oral doses of 10, 20, and 40 mg in healthy individuals (N=5), measuring receptor occupancy via [11C]Cimbi-36 radiotracer and finding significant occupancy levels at 10 mg. Eur Neuropsychopharmacol

Psilocybin-assisted neurofeedback for executive function | Psilocybin-assisted neurofeedback was feasible and showed potential for enhancing self-reported executive functions, though objective task-based gains were not observed. In this study, 37 participants were randomized in a semi-naturalistic design. The experimental group self-administered psilocybin microdoses (0.3–2 grams of fresh Psilocybe mexicana truffles) before neurofeedback sessions after adjusting their dose over a week. A passive control group was unaware of the experimental neurofeedback condition. Philos Trans R Soc Lond B Biol Sci

Study design and psychedelic treatment response | Studies using pre-post single-arm, non-active placebo controls, and waitlist control designs likely inflated the reported effects of psychedelics, whereas active-drug placebo designs yielded more conservative estimates; additionally, psilocybin demonstrated a dose-response trend. This meta-analysis primarily focused on psilocybin's effects on depression, supported by 11 studies, and included limited data on MDMA, ayahuasca, and LSD, which were analyzed cautiously due to fewer studies and varied therapeutic indications. J Affect Disord

Psychedelic-related deaths in the UK (1997-2022) | An analysis of coroner reports submitted to the National Programme on Substance Use Mortality, where psychedelic serotonergic agonist drugs were involved in the death, identified 28 cases from 1997 to 2022. Psychedelic-related deaths were rare, often accidental, and typically involved polydrug use and environmental factors. Prog Neuropsychopharmacol Biol Psychiatry

Psychedelics and mental health in autistic adults | Most autistic adults reported reductions in psychological distress and social anxiety and increases in social engagement after a single impactful psychedelic experience; an online survey study involving 233 self-selected autistic adults, assessing perceived changes after their most impactful psychedelic experience. Psychopharmacology (Berl)

Co-use of psychedelics with other substances | The 2023 Global Psychedelic Survey, encompassing responses from 5,370 participants, identified high rates of co-use of psychedelics with substances such as cannabis and alcohol, particularly among recreational users. J Psychopharmacol

Psychedelic use in Latin America analyzed | Regular macrodose use of psychedelics among Latin American adults was primarily for psychological and spiritual well-being, with psilocybin mushrooms being the most common; a cross-sectional survey study with 4,270 participants. Sci Rep

Psilocybin effects differ by race/ethnicity | Race/ethnicity moderated psilocybin’s effects on spiritual wellbeing, cognitive flexibility, and emotion regulation, with differences in outcomes observed for White participants and Participants of Color; data from a longitudinal online survey study involving 2,833 individuals planning to use psilocybin. J Affect Disord

Insightful psychedelic experiences linked to well-being| Psychological insights gained from past psychedelic experiences, rather than frequency of use, were linked to greater psychological flexibility (particularly Acceptance), which mediated the effects on well-being. Cross-sectional survey with 629 participants using network and mediation analyses; cross-sectional survey study with 629 participants. Sci Rep

BDNF levels predict antidepressant treatment response | Higher baseline BDNF levels were linked to a better response to SSRIs in depressed patients, while lower levels were associated with elevated anxiety post-treatment. Clinical study with 40 participants over an 8-week SSRI treatment. Int J Mol Sci

MDMA's Rapid Impact on Self-reported Personality and Mood | MDMA administration was associated with increased openness and positive affect, though results were not statistically significant; a randomized, placebo-controlled trial in healthy adults (N = 34). J Psychoactive Drugs

[Preprint] Brain changes after first psilocybin dose | Psilocybin administration led to enduring brain changes, including decreased tract diffusivity and enhanced psychological well-being one month after dosing, based on data from a placebo-controlled neuroimaging study involving 28 psychedelic-naive adults. bioRxiv

[Preprint] Brain dynamics under 5-MeO-DMT | 5-MeO-DMT reorganizes low-frequency brain waves, creating incoherent, fragmented flow patterns that disrupt cortical communication; an EEG-based experimental study on 29 participants, with 19 included post-dosing. bioRxiv

Preclinical Research

Molecular mechanisms of working memory | Working memory performance was associated with specific functional connectivity patterns and gene expression related to cortical and neurotransmitter pathways; an fMRI and gene expression study in 502 healthy adults. BMC Biol

Psilocybin analog enhances fear extinction | 4-OH-DiPT reduced fear responses and improved GABAergic inhibition in the basolateral amygdala of mice, demonstrating dose-dependent effects, and greater efficacy in females; and 5-HT2A receptor activation was identified as the underlying mechanism. Neuropsychopharmacology

Serotonin’s role in glial synapse pruning | Serotonin signaling through 5-HT2A receptors in glial cells was crucial for experience-dependent synaptic pruning during critical periods in Drosophila, with adult reactivation of these receptors restoring pruning effects. PLoS Biol

Rapid antidepressant effects of 5-HT1A-biased agonist, NLX-101 | NLX-101 reduced depressive behaviors and increased serotonin innervation in fluoxetine-resistant cF1ko mice, suggesting its potential for SSRI-resistant depression. Neuropharmacology

5-HT2C receptors regulate exercise motivation | Activation of 5-HT2C receptors in the nucleus accumbens modulated motivation for wheel running in mice by influencing ventral pallidum-projecting neurons. Neuropharmacology

Human neuron model for Alzheimer's research | A human iPSC-derived cortical neuron model for Alzheimer's research was developed, demonstrating Alzheimer's-related neurodegeneration and senescence, but showed limited therapeutic efficacy against Aβ-induced damage. Alzheimers Dement

Serotonin’s role in pain modulation in rats | Blocking serotonin receptors (5-HT1A, 5-HT2A, 5-HT3) in the insular cortex of carrageenan-treated rats reduced long-lasting inflammatory pain, highlighting serotonin's role in modulating pain. Cells

Psychedelic effects on lipid bilayers | DOI was shown to disrupt lipid bilayer order, enhance vesicle fusion, and reduce membrane stability in artificial lipid bilayers, indicating potential receptor-independent mechanisms for its neuroplastic effects. ACS Chem Neurosci

Activation mechanisms of 5-HT2A receptors | Molecular dynamics simulations showed that the agonist DOI induces specific conformational changes in 5-HT2A receptors, triggering activation through ionic lock breakage, while antagonists maintain the lock to inhibit activation. Molecules

5-HT1A receptor role in stress resilience | Early life adversity led to long-lasting, sex-specific increases in stress reactivity, neuroinflammation, and decreased neurogenesis in females; postnatal knockdown of 5-HT1A autoreceptors mitigated these effects in adult female mice. Neuropsychopharmacology

Psilocybin reduces OCD-like behaviors in mice | A single dose of psilocybin and psychedelic mushroom extract significantly reduced self-grooming, anxiety, and twitch behaviors in SAPAP3 knockout mouse model of obsessive compulsive disorder (OCD), with effects lasting up to seven weeks. Mol Psychiatry

Psilocybin affects spatial encoding in mice | Psilocybin reduced spatial encoding and neural correlation in the retrosplenial cortex of mice, an effect blocked by the 5-HT2A receptor antagonist ketanserin, suggesting increased neural entropy as a potential mechanism for disorientation. Eur J Neurosci

5-HT2B receptor changes in Alzheimer's disease | Increased 5-HT2B receptor mRNA levels and reduced receptor binding were found in amyloid-β plaque regions of post-mortem Alzheimer's disease brains and a transgenic mouse model, suggesting a role for 5-HT2BR in Alzheimer's disease pathology. Neurosci Lett

Psilocybin reduces brain damage after stroke | Psilocybin reduced neuronal loss, brain infarction, and improved motor function in stroke-affected rats (middle cerebral artery occlusion model), with effects linked to BDNF regulation. BMC Neurosci

[Preprint] Psilocybin enhances neural plasticity and resilience to stress | Psilocybin treatment increased dendritic spine density in specific pyramidal neurons in mice, correlating with improved stress resilience. These effects were mediated through 5-HT2A receptors in the medial frontal cortex. bioRxiv

[Preprint] Snapshot of 5-HT2A activation in mice | IP1 levels in mouse brain tissue correlated with 5-HT2A activation and psychedelic effects, supporting IP1 as a biomarker for 5-HT2A-driven actions; an ex vivo study in mouse brain tissue using DOI, LSD, and other serotonergic drugs. bioRxiv

Reviews and Commentaries

A Perspective on Alzheimer’s Disease: Exploring the Potential of Terminal/Paradoxical Lucidity and Psychedelics | This perspective examines how terminal/paradoxical lucidity and psychedelics could inform new therapeutic approaches for Alzheimer’s disease by promoting neuroplasticity and enhancing cognitive function, especially in late stages. Mol Neurodegener

Preclinical Models for Evaluating Psychedelics in the Treatment of Major Depressive Disorder | This review discusses the use of preclinical animal models to explore the pharmacology and antidepressant mechanisms of psychedelics, emphasizing the need for clinically relevant dosing, consideration of sex differences, and methodological improvements to better understand these drugs' therapeutic potential. Br J Pharmacol

Psychedelics and the Treatment of Eating Disorders: Considerations for Future Research and Practice | This article outlines critical ethical, methodological, and safety considerations for future clinical trials on psychedelic-assisted therapy for eating disorders, offering provisional guidelines to ensure participant protection and scientific rigor. J Eat Disord

Anxiety and Affective Symptoms Related to the Use of Classic Psychedelics: A Systematic Review | This systematic review explores the potential for classic psychedelics to induce anxiety and affective symptoms, finding that persistent disorders are rare and primarily occur in individuals with specific risk factors, while clinically administered psychedelics in therapeutic settings show low incidence of enduring anxiety. Curr Top Behav Neurosci

Is the Stereoisomer R-MDMA a Safer Version of MDMA? | This article highlights a study comparing R-MDMA, S-MDMA, and racemic MDMA, suggesting that R-MDMA may reduce certain adverse effects while retaining some prosocial effects but not supporting it as a safer alternative for clinical use. Neuropsychopharmacol

Classical Psychedelics' Action on Brain Monoaminergic Systems | This review examines the effects of classical psychedelics on brain monoaminergic systems, specifically serotonin, dopamine, and noradrenaline pathways, highlighting the complex and region-dependent responses that challenge the identification of a definitive monoamine signature for these compounds. Int J Biochem Cell Biol

Editorial: New Players on the Monoaminergic Field: Relevance to the Mental Disorders | This editorial introduces a collection of studies focused on the complex interactions between classical monoamines and various bioactive molecules, highlighting their significance for mental health and the potential for innovative treatments. Front Pharmacol

Into the Wild Frontier: Mapping the Terrain of Adverse Events in Psychedelic-Assisted Therapies | This commentary explores the unique risks and potential adverse events associated with psychedelic-assisted therapies, calling for standardized assessment frameworks to improve the safety and consistency of these treatments. J Psychopharmacol

From Antidepressants and Psychotherapy to Oxytocin, Vagus Nerve Stimulation, Ketamine and Psychedelics: How Established and Novel Treatments Can Improve Social Functioning in Major Depression | This review examines how various treatments, both conventional and emerging, impact social functioning in major depressive disorder and explores the potential benefits of combining therapies to enhance social cognition and behavior. Front Psychiatry

Psilocybin and the Glutamatergic Pathway: Implications for the Treatment of Neuropsychiatric Diseases | This review explores psilocybin’s influence on the glutamatergic pathway, highlighting its potential to enhance neuroplasticity and act as a rapid antidepressant by modulating glutamate and GABA neurotransmission, with implications for treating depression and other neuropsychiatric disorders. Pharmacol Rep

Beyond Psilocybin: Reviewing the Therapeutic Potential of Other Serotonergic Psychedelics in Mental and Substance Use Disorders | This review evaluates the limited evidence on the safety and efficacy of non-psilocybin serotonergic psychedelics, such as LSD, ayahuasca, DMT, ibogaine, and mescaline, in treating mental health and substance use disorders, highlighting both benefits and potential adverse effects. J Psychoactive Drugs

Clinical Trials Update

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

DMT vs THC active control | Major Depression Disorder (N=60) | Study of the Safety, Tolerability, Electrophysiological Effects and Efficacy of DMT in Humans | Sponsor: Deepak C. D'Souza | NCT06671977
- Interesting to see THC being used as an active control for psilocybin

MLS101 (Psilocybin) | Healthy Volunteers (N=24) | A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of MLS101 (Psilocybin) in Healthy Participants | NCT06643637

PEX010 [psilocybin]-Assisted Therapy | Stimulant Use Disorder (N=86) | PEX010-Assisted Therapy for Stimulant Use Disorder: A Safety, Feasibility and Efficacy Study (PATSUD) | Sponsor: Filament Health Corp. | NCT06666010

Psilocybin | Amyotrophic Lateral Sclerosis with Depressed Mood (N=24) | Effects of Psilocybin in Patients With Amyotrophic Lateral Sclerosis | Sponsor: Johns Hopkins University | NCT06656702
- This is the first trial of psilocybin in ALS

Psilocybin | Anxiety Associated with Metastatic Cancer (N=16) | A Phase 1 Study of a Second Psilocybin Group Retreat for Partial Responders With Anxiety Associated With Metastatic Cancer | Sponsor: University of Washington | NCT06644170

Psilocybin | Cannabis Use Disorder (N=12) | Psilocybin-assisted Treatment for Cannabis Use Disorder | Sponsor: Johns Hopkins University | NCT06660381

Psilocybin | Healthy Participants with Lower-than-average Mental Well-being (N=120) | 2 X 2 Factorial, Double-blind, Randomized Trial of 'set and Setting': a Translational Study in Healthy Volunteers | Sponsor: Robin Carhart-Harris, PhD, MA | NCT06626139

Psilocybin | Cognitive Control in Psychogenic Nonepileptic Seizures (N=10) | Evaluation of the Effect of a Single Dose of Psilocybin on Neural Correlates of Cognitive Control in Patients with Psychogenic Nonepileptic Seizures | Sponsor: Centre Hospitalier Universitaire de Nīmes | NCT06647056
- This is the first study of psilocybin in seizures

Psilocybin | Treatment-resistant Depression + Neuroimaging (N=12) | Effect of Psilocybin on the Positive Valence System in Treatment-resistant Depression: a Pilot Clinical Neuroimaging Study | Sponsor: Centre Hospitalier Universitaire de Nîmes | NCT06650800

PSYLO UPDATES

We’re excited to share that Psylo, Tessara Therapeutics, and the Brain and Mind Centre, University of Sydney have been awarded a $3 million CRC-P grant to advance neuroplastogens for treating substance use disorders, focusing on methamphetamine addiction. Read more about this exciting project here.

It was wonderful to have CEO Josh Ismin visit the Colorado team for valuable face-to-face time.

We had a productive meeting with Prof. Scott Thompson, Director of the Center for Novel Therapeutics, and his team at the University of Colorado Anschutz. We enjoyed learning about the work underway at the Laboratory of Translational Psychiatry on depression mechanisms, translating psychedelic research into novel therapeutic compounds, and our shared goal of advancing therapeutic approaches for mental illness.