Psychedelic Science Newsletter - November

psylo_newsletters

1 Dec

Science in Sixty Seconds

Biomarkers of Depression: A Game Changer in Mental Health

Depression is traditionally assessed through subjective methods like clinical interviews and questionnaires. However, the integration of biomarkers is revolutionizing this approach by offering a more precise understanding of depression.

What are Biomarkers?

Biomarkers are characteristics that can be objectively measured and used as an indicator of normal health, disease, or responses to treatment. Biomarkers range from simple physical signs like heart rate and body weight to laboratory tests of blood and urine, complex neuroimaging and genetic tests. They includes:

Genetic Biomarkers: These involve genes that indicate a predisposition to conditions like cancer.
Molecular Biomarkers: Examples include blood glucose levels for diabetes or inflammatory markers to detect infections.
Neuroimaging Biomarkers: Brain MRI scans, for instance, are used to diagnose conditions such as multiple sclerosis.
Cognitive Biomarkers: Memory tests are employed to monitor conditions like dementia.
Behavioral Biomarkers: Changes in speech or movement can indicate the effects of a drug, increased thirst may hint at diabetes, and snoring could suggest sleep apnea.

Biomarkers play a crucial role in diagnosing diseases, monitoring disease progression, predicting susceptibility, predicting treatment response, guiding treatment strategies and in the development of new treatments.

The Complexities and Challenges of Depression

Depression's multifaceted nature, encompassing emotional, physical, and cognitive symptoms, makes diagnosis and management challenging. Traditional subjective assessments are prone to biases, variability, and inaccuracies, leading to inconsistent care and treatment challenges

Despite numerous treatment options, only a third of patients achieve remission, underscoring the need for improved antidepressants. Biomarkers offer more definitive and quantifiable insights that can advance treatment development.

Potential Biomarkers for Depression

Research has identified a multitude of potential biomarkers for depression, including:

Genetic Biomarkers

Gene Variants: Specific gene variants like the serotonin transporter gene (SLC6A4), which plays a role in regulating the levels of serotonin, and the BDNF gene, which is crucial for the survival and growth of neurons, have been linked to depression.
Epigenetic Changes: Studies are exploring how life experiences can cause epigenetic modifications that affect gene expression related to stress response systems, potentially influencing depression risk.

Molecular Biomarkers

Cortisol Levels: Elevated cortisol levels, indicative of heightened stress, have been linked to depression and serve as a significant predictor of future depressive episodes.
Brain-Derived Neurotrophic Factor (BDNF): Lower levels of BDNF, which plays a vital role in neuroplasticity and neuronal survival, have been associated with depression.
Inflammatory Markers: Increased levels of inflammatory cytokines, such as IL-1β, IL-6 and TNF-alpha, have been implicated in the development of depression and have been observed to decrease with treatment.

Neuroimaging Biomarkers

MRI Findings: MRI scans have revealed structural changes in the hippocampus and prefrontal cortex in individuals with depression, areas involved in emotion and stress regulation.
PET Scans: PET scans have shown altered glucose metabolism in specific brain regions in depressed patients, reflecting changes in brain activity.

Physiological Biomarkers

EEG (Electroencephalography): Among the most promising avenues in depression biomarker development is EEG, which measures brain activity. In depression, EEG patterns frequently exhibit heightened theta wave activity and diminished alpha wave activity, reflecting altered brain function.
Heart Rate Variability (HRV): Depressed patients have been shown to exhibit reduced HRV during stress, reflecting a possibly dysregulated autonomic nervous system.

Behavioral Biomarkers

Speech Analysis: Research using AI and machine learning has found that slowed speech rate and decreased tone variability can be indicative of depression.
Facial Expression Analysis: AI technologies are being developed to analyze facial expressions for signs of depression, such as reduced expressiveness or slower smile onset.

Cognitive Biomarkers

Cognitive Tests: Performance deficits in tasks measuring attention, memory, and executive function are being studied as cognitive markers of depression.

The Future of Depression Diagnosis and Treatment

Biomarkers offer to transform mental health care by providing a deeper and more nuanced understanding of depression. Established biomarkers will enable precise diagnoses, personalized treatments, and the development of targeted, effective therapies. While research continues to validate their clinical use, their promise is undeniable. Biomarkers stand poised to catalyze a new era in mental healthcare and support a future where the management of depression is more precise, personalized, and ultimately, more successful.

RESEARCH UPDATES

Psychedelic Clinical Research

LSD's Effects on Thalamic Connectivity | LSD intake increases thalamic connectivity in specific nuclei and alters sensory and associative cortex connections. Placebo-controlled MRI study on healthy volunteer (N=15). NeuroImage

Genetic variation of 5-HT2A in depressed patients | Study finds altered endocannabinoid levels and genetic variations in serotonergic receptors in depression (N=322) | Brain and Behavior

Ayahuasca's Impact on Emotional Regulation | Ayahuasca use reduced amygdala activity and enhanced insular and prefrontal cortex activation in response to aversive stimuli, along with reported reductions in anxiety and mental sedation; within subject-controlled fMRI study of experienced male Ayahuasca users (N=19). Journal of Ethnopharmacology

Intentions for Psychedelic Use in Norway | A survey of 770 Norwegian adults indicates that motivations for using psychedelic substances were primarily recreational or therapeutic. Results show mostly positive mental health outcomes from classic psychedelic use, though a small percentage reported long-term adverse effects. Frontiers in Psychiatry

Psychedelic Preclinical Research

Ketamine's Long-Term Antidepressant Mechanism | Ketamine's antidepressant effects last beyond its plasma presence due to ongoing suppression of burst firing and prolonged NMDAR blockade in the lateral habenula in mice. Nature

Dopamine Crucial for Acute Sleep Deprivation’s Antidepressant Effects | Acute sleep deprivation caused increased hyperactivity and reduced depressive-like behaviors in mice, mediated by increased dopamine release in specific brain regions. Neuron

Novel Psilocin Prodrugs for Anxiety Disorders | Novel prodrug derivatives of psilocin showed similar benefits to psilocybin but shorter psychedelic effects, with two demonstrating long-term anxiolytic benefits in stressed mice. Journal of Medicinal Chemistry

mGluR2's Role in Psychedelic-Induced Responses | mGluR2 agonists inhibited, while inverse agonist enhanced, the DOM-induced head twitch response in mice, indicating the critical role of 5-HT2AR/mGluR2 heterodimers in psychedelic-induced responses. Neurochemical Research

[Preprint] Beyond 5-HT2AR: Psychedelics and Ion Channels| Psychedelics dose-dependently suppressed the intrinsic excitability of pyramidal neurons, primarily through enhancing potassium M-current channels, independently of 5-HT2R activation; a cellular and computational modelling study. BioRxiv

Psychedelic Reviews and Commentaries

Psilocybin and Other Classic Psychedelics in Depression | This chapter reviews the use of psychedelics, particularly psilocybin and DMT, in treating depression, emphasizing their potential for rapid mood improvement and lasting therapeutic effects when combined with psychological support. Current Topics in Behavioral Neurosciences

Synergistic psychedelic - NMDAR modulator treatment for neuropsychiatric disorders | This article discusses the potential benefits of combining serotonergic psychedelics with NMDAR modulators to enhance therapeutic effects and safety in treating neuropsychiatric disorders like depression. Molecular Psychiatry

Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action | This review covers the complex mechanisms of action of serotonergic psychedelics beyond just 5-HT2A receptor activation, discussing their interactions with other receptors and the development of nonhallucinogenic derivatives for safer psychiatric treatments. Journal of Neuroscience

Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review | This review systematically examines preclinical studies on psilocybin, highlighting its potential as a treatment for various neuropsychiatric conditions, particularly depression, and discusses possible mechanisms and future research directions. Journal of Neurochemistry

The Effects of Psychedelics on Neuronal Physiology | This review describes how psychedelics impact neuronal physiology, focusing on their acute and long-lasting effects on neurotransmission and neuroplasticity, and suggests the possibility of engineering compounds with optimized safety and efficacy. Annual Review of Physiology

A Comprehensive Review of the Current Status of the Cellular Neurobiology of Psychedelics | This review delves into the cellular neurobiology of psychedelics, discussing their pharmacological mechanisms, receptor interactions, and potential as therapeutic agents for mental health disorders. Biology

Enabling late-stage drug diversification by high-throughput experimentation with geometric deep learning | This article discusses the development of a late-stage functionalization platform using geometric deep learning and high-throughput reaction screening to optimize drug candidate properties, demonstrating its effectiveness in diversifying commercial drug molecules. Nature Chemistry

A brief historical overview of psychedelic research | This review provides a historical perspective on psychedelic research, tracing its evolution from ancient use to modern investigations into their effects and mechanisms, and highlighting recent interest in their therapeutic potential for psychiatric disorders. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Drug–drug interactions involving classic psychedelics: A systematic review | This review systematically examines the interactions between classic psychedelics and other drugs, revealing various effects including attenuation, potentiation, and instances of no change, with a focus on understanding the underlying molecular pathways. Journal of Psychopharmacology

Editorial: Alternative treatments to classical antidepressants in treatment-resistant depression | This editorial summarizes research on alternative treatments for treatment-resistant depression (TRD), including serotonergic psychedelics, oral esketamine, and combined ketamine and transcranial magnetic stimulation (TMS), highlighting their potential effectiveness and mechanisms. Frontiers in Psychiatry

The effects of Lysergic Acid Diethylamide (LSD) on the Positive Valence Systems: A Research Domain Criteria (RDoC)-Informed Systematic Review | This systematic review analyzes the effects of LSD on the Positive Valence Systems (PVS), revealing dose-dependent mood improvements, mixed findings on reward learning, and potential changes in reward valuation. They suggest that serotonin 2A receptor agonists enhanced reward responsiveness in healthy individuals and patient populations. CNS Drugs

IUPHAR-review: The Integration of Classic Psychedelics into Current Substance Use Disorder Treatment Models | This article discusses the potential integration of classic psychedelic-assisted therapies into existing treatment models for substance use disorders, suggesting their broad compatibility with current evidence-based treatments. Pharmacological Research

Present and future of metabolic and metabolomics studies focused on classical psychedelics in humans | The review focuses on metabolic and metabolomics research on classical psychedelics, noting significant advancements in identifying primary metabolites but a lag in understanding broader metabolic changes and emphasising the need for further exploration. Biomedicine & Pharmacotherapy

Overcoming blinding confounds in psychedelic randomized controlled trials using biomarker driven causal mediation analysis | This perspective article discusses the challenges of blinding in psychedelic randomized controlled trials and proposes using causal mediation analysis with biomarkers to better understand the causal pathways and efficacy of psychedelic therapies. Expert Review of Clinical Pharmacology

Assessment of the acute subjective psychedelic experience: A review of patient-reported outcome measures in clinical research on classical psychedelics | This review evaluates the various outcome measures used in clinical trials on classical psychedelics, highlighting the need for a standardized set of instruments to reliably assess and compare the acute subjective psychedelic experience across different contexts. Journal of Psychopharmacology

[Patent Highligt] Small-Molecule Heterocyclic Compounds: Gq-Biased Agonists for the 5-HT2A Receptor in Neuropsychiatric Treatment | This Patent Highlight explores the development of innovative small-molecule heterocyclic compounds as Gq-biased agonists of the 5-HT2A receptor, offering a more targeted and potentially more effective approach for treating depression, anxiety, and substance abuse. ACS Medicinal Chemistry Letters

Psychedelic Clinical Trials Update

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

Ayahuasca + Therapy | Grief | Ayahuasca Assisted Psychotherapy for Grief (PSICODUELAYA) - NCT06150859

Psilocybin + rTMS | Treatment Resistant Depression | Psilocybin and repetitive transcranial magnetic stimulation (rTMS) for Treatment Resistant Depression (PSILOBSD) - NCT06132178

Psilocybin + Therapy | Severe Depression with PTSD | Evaluation of Psilocybin-Assisted Psychotherapy in Treating Severe Depression in Patients With PTSD (SUMMIT-90) - NCT06141876

MDMA + Therapy | PTSD | MDMA-assisted Massed Prolonged Exposure for PTSD (MDMA-PE) - NCT06117306

Ketamine/Esketamine + Virtual Reality | Safety, Tolerability, Treatment experience | Using Virtual Reality to Control the Audio-visual Inputs During Ketamine/Esketamine Treatment (VR-KET) - NCT06139016

Ketamine + Therapy | Treatment Resistant Depression | Ketamine Plus Radically Open Dialectical Behavior Therapy (RO DBT) for Treatment Resistant Depression (KET-RO) - NCT06138691

PSYLO UPDATES

The Chemistry Team has been busy in our labs at UNSW synthesizing new antidepressants!

Congratulations to Dr Nick Everett, Psylo’s Behavioural Pharmacologist, who received a partnership grant from the University of Sydney’s Brain and Mind Centre, to establish high throughput Head Twitch Response experiments.

Congratulations to Dr Lachlan Whish, one of our star medicinal chemists, on having his Ph.D. in Medicinal and Pharmaceutical Chemistry conferred.

Sam and Dilara visited Australia enabling some quality time between US and AU-based team members in the lab--and out of it!

Farewell to our interns from 2023: Catherine Liu, Catherine Do, Zoe Adam, Rubia Yano Da Silva and Evgenia Konstantinidou. Thank you for all your hard work. You have been instrumental in supporting our lab operations and research.

Psylo in the Media

Josh and Will gave talks at The Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) meeting on preclinical and clinical development and pharmacology.
MDMA & Ketamine: the New Frontiers of Mental Health - Dilara was a guest on the podcast Higher living w/ Chad Walkaden.
Dilara was interviewed for an article in No Filter, that deep-dives into the the psychedelic-assisted therapy sector in Australia.