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Welcome to Psylo's Psychedelic Science Newsletter - March Edition!
Every month, we bring you a curated selection of the latest research and developments in the world of psychedelics, 5-HT2A, serotonin 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!
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Serotonin Receptors as Drug Targets
Serotonin, or 5-hydroxytryptamine (5-HT), is a hormone and neurotransmitter that is crucial for various physiological functions and behaviours. Serotonin operates through 14 receptor subtypes in humans, which are categorized into seven main families: 5-HT1 through 5-HT7
These receptors are widely distributed across the nervous system and peripheral tissues, making them key therapeutic targets for an array of conditions including migraines, anxiety, obesity, cancer therapy-induced vomiting, irritable bowel syndrome, depression, and schizophrenia.
This broad distribution and versatility underline the significance of serotonin receptors in both understanding human biology and in the development of effective treatments for various diseases.
Types of Serotonin Receptors
5-HT1 RECEPTORS
5-HT1A:
- Distribution: CNS: raphe nuclei, hippocampus, cortex, and amygdala; Periphery: vascular smooth muscle, spleen.
- Function: Regulates mood, anxiety, appetite, cardiovascular function, vascular tone, and immune function.
- Drug Examples: Buspirone (non-selective agonist; anxiolytic), Befiradol (agonist; levodopa-induced dyskinesia).
5-HT1B:
- Distribution: CNS: basal ganglia, hippocampus, cortex, and substantia nigra; blood vessels
- Function: inhibition of neurotransmitter release, aggression, feeding, and sexual behavior.
- Drug Examples: Triptans (agonists, also act on 1D; migraine treatment)
5-HT1D:
- Distribution: CNS: basal ganglia, hippocampus, and cortex; blood vessels.
- Function: Vasoconstriction, locomotion and anxiety
- Drug Examples: Triptans (agonists, also act on 1B; migraine treatment)
5-HT1E:
- Distribution: CNS: cortex, striatum.
- Function: Unknown.
- Drug Examples: Not specifically targeted by current drugs.
5-HT1F:
- Distribution: CNS: hippocampus, cortex, and trigeminal ganglia; PNS, uterus, mesentery, vascular smooth muscle
- Function: Role in pain modulation, particularly migraine.
- Drug Examples: Lasmiditan (agonist; migraine treatment).
5-HT2 RECEPTORS
5-HT2A:
- Distribution: CNS: cortex; platelets, smooth muscle
- Function: Involved in mood and perception, endocrine response, platelet aggregation, bronchoconstriction, and vasoconstriction.
- Drug Examples: Antipsychotics like Clozapine (antagonist); psychedelics (agonists; mood disorders, addiction).
5-HT2B:
- Distribution: Heart, liver, intestine, stomach, and pulmonary smooth muscles, ear. Weak expression in brain.
- Function: Heart development and function, gastrointestinal motility, and lung function.
- Drug Examples: Not typically targeted due to risk of cardiac issues.
5-HT2C:
- Distribution: CNS: choroid plexus, cortex, hippocampus, amygdala, substantia nigra, and ventral tegmental area.
- Function: Appetite suppression, mood regulation and seizure susceptibility.
- Drug Examples: Lorcaserin (agonist; weight loss). Agomelatine (antagonist, also melatonin receptor agonist; depression).
5-HT3-7 RECEPTORS
5-HT3:
- Distribution: CNS (brainstem) and peripheral nervous system (enteric nerves).
- Function: Involved in nausea/vomiting reflex, pain pathways; anxiety and depression.
- Drug Examples: Ondansetron, Granisetron, Palonosetron (antagonist; antiemetics).
5-HT4:
- Distribution: Gastrointestinal tract, CNS: hippocampus and basal ganglia.
- Function: Promotes gastrointestinal motility, involved in learning and memory.
- Drug Examples: Tegaserod, Prucalopride (agonist; gastrointestinal motility disorders).
- 5-HT5 Receptors:
5-HT5A:
- Distribution: CNS: cerebral cortex, hippocampus.
- Function: Role unclear, potentially involved in circadian rhythm and cognition.
- Drug Examples: Not specifically targeted by current drugs.
5-HT6:
- Distribution: CNS: striatum, hippocampus and olfactory tubercle.
- Function: Modulates neurotransmitter release, learning, memory, and neuroplasticity.
- Drug Examples: No specific drugs but antagonists are in trials for Alzheimer's Disease, e.g. Masupirdine.
5-HT7:
- Distribution: CNS: thalamus, hypothalamus, hippocampus, cortex
- Function: Involved in circadian rhythms, mood regulation, and thermoregulation.
- Drug Examples: No specific drugs but some newer antidepressant and antipsychotic drugs are antagonists.
In summary, serotonin receptors are central to our understanding of a wide range of physiological processes and complex behaviors. They represent a frontier in medical research, offering vast potential as drug targets for a variety of central nervous system and peripheral conditions.
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Clinical Research
- Antidepressants may reduce the effectiveness of psilocybin Therapy | Participants in a psilocybin therapy trial for depression who stopped taking SSRIs/SNRIs beforehand showed a lesser antidepressant response than those not on medication at the start, posthoc analysis from a trial. The intensity of the psychedelic experience was unaffected. Authors highlight the need for a controlled study. Journal of Psychopharmacology
- Psychedelics Linked to Lower Psychosis but Higher Mania in At-Risk Youth | Adolescents using psychedelics showed reduced psychotic symptoms but increased manic symptoms if genetically prone to schizophrenia or bipolar disorder. This large twin study (N= 16,255) suggests a nuanced impact of psychedelics on adolescent mental health. JAMA Psychiatry
- Psychedelics Impact on Substance Use Patterns | This global survey of over 5,000 adults found that 70.9% reported a reduction or cessation in using other substances like alcohol, antidepressants, and cocaine after psychedelic use. However, 19.8% also reported an increase or initiation substance use, like opioids and cannabis. Front Psychiatry
- Personality Disorders Worsen Risk for Negative Effects After Psychedelic Use | In a study of 807 individuals who had taken psychedelics, 16% experienced adverse effects. Individuals with a history of personality disorders had a higher risk of adverse effects, suggesting the need for increased psychological support for this group when using psychedelics. Journal of Psychopharmacology
- Therapeutic Alliance in Psychedelic Therapy | A stronger therapeutic alliance between study participants and facilitators was associated with stronger mystical experiences and psychological insight, and correlated with improved depression outcomes; secondary analysis from a randomized, waiting list-controlled clinical trial of psilocybin-assisted therapy for major depressive disorder (N=24). PLoS One
- Case Study of Encephalopathy After Psilocybin in an Adolescent | A case study about an adolescent who presented with sudden altered mental status and erratic behavior afer consuming psilocybin-infused chocolate. MRI revealed cytotoxic lesions and led to a diagnosis of toxic-metabolic encephalopathy. The patient recovered after six days of treatment. BMJ Case Reports
- Serotonin and Fatigue | In chronic fatigue syndrome and hypothyroidism, supplementation with L-carnitine for 7 weeks significantly increased serotonin levels and reduced fatigue in both groups; a retrospective study of 12 CFS patients and 40 hypothyroidism patients. Front Endocrinol (Lausanne)
- [Preprint] Therapeutic Effects of Psychedelics in Older Adults | Guided psychedelic group sessions in a retreat setting improved well-being among younger and older (>60) adults, especially in older adults with history of psychiatric diagnoses, found a survey collecting data before, immediately after, and up to six months post-experience (N-=124). Interestingly, acute subjective psychedelic effects were attenuated in older adults. Research Square
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Preclinical Research
- Effects of 5-MeO-DMT Derivates | Amino-substituted 5-MeO-tryptamines show selectivity for 5-HT1AR over 5-HT2AR, influence serotonin release, and produce varying degrees of the hallucinogenic head twitch response in mice. Molecular Psychiatry
- Knocking Down 5HT-2A Enhances Memory and Alleviates Anxiety | Knocking down the gene for the 5-HT2A receptor (HTR2A), using intranasal delivery of shRNA, decreased anxiety and improved memory in mice and rats. Translational Psychiatry
- Psilocybin Derivative Aids Fear Extinction | 4-OH-DiPT, a psilocybin analog, was found to enhance fear extinction learning and increase GABAergic inhibition in the amygdala through 5-HT2A receptor activity, especially effective in female mice. Neuropsychopharmacology
- Serotonin Changes in Perimenopause | In a perimenopausal mouse model, there was a widespread decrease in serotonin across the brain and altered expression of serotonin 5-HT1AR and 5-HT2AR receptors in regions associated with the occurrence of hot flashes and perimenopausal depression. Heliyon
- Serotonin's Role in Parkinson's Disease | In a mouse model of Parkinson’s Disease (MPTP), mice had reduced serotonin levels in the hippocampus and were less sensitive to an SSRI antidepressant. Post L-DOPA administration, a machine learning analysis suggests a shift from serotonin to dopamine release. Molecular Medicine
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Psychedelic Reviews and Commentaries
- Multimodal Neuroimaging of the Effect of Serotonergic Psychedelics on the Brain | The review explores the functional changes in the brain following the administration of serotonergic psychedelics like psilocybin, LSD, or DMT using fMRI and PET neuroimaging techniques, aiming to enhance understanding of their neurobiological mechanisms and potential for treating neuropsychiatric illnesses. AJNR Am J Neuroradiol
- Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures | The review delves into the structural basis of major depressive disorder (MDD) and explores the potential of novel antidepressants targeting G protein-coupled receptors and key membrane receptors, emphasizing breakthroughs in cryo-electron microscopy and virtual drug screening for the development of rapid-onset and low side-effect antidepressants. Molecules
- Scoping Review: The Role of Psychedelics in the Management of Chronic Pain | The review explores the potential of psychedelics, such as LSD and psilocybin, in alleviating pain symptoms associated with chronic conditions like cluster headaches, phantom limb pain, and fibromyalgia, emphasizing the need for further randomized controlled trials to evaluate their efficacy. J Pain Res
- Serotonin Signaling through Lipid Membranes | The review explores the intricate interplay between serotonin signaling and lipid membranes, emphasizing the importance of lipid-protein interactions in modulating synaptic efficacy and suggesting implications for understanding mental disorders associated with serotonin dysfunction. ACS Chem Neurosci
- Contribution of the Serotonergic System to Developmental Brain Abnormalities in Autism Spectrum Disorder | The review discusses the significant role of the serotonergic system in brain development and its association with developmental abnormalities observed in autism spectrum disorder, emphasizing the need for further research into the contributions of the serotonergic system to the disorder's diagnostic features and behavioral anomalies. Autism Res
- Pioneering Methods in Brain Optimization and Mental Health Treatment | This editorial explores recent groundbreaking advancements in neurostimulation techniques, psychedelic therapy, and brain function optimization, emphasizing their therapeutic potential and contributions to neuroscience and mental health fields. ACS Med Chem Lett
- Role of Serotonergic System in Regulating Brain Tumor-Associated Neuroinflammatory Responses | This review discusses the involvement of the serotonergic system in regulating neuroinflammatory responses associated with brain tumors, highlighting its potential as a target for modulating inflammation-induced brain damages in cancer treatment. Methods Mol Biol
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Psychedelic Clinical Trials Update
A round-up of the latest registered clinical trials investigating psychedelics:
- Psilocybin | Major Depressive Disorder (N=240) | Psilocybin for Major Depressive Disorder (MDD) (uAspire) - NCT06308653
- Psilocybin | Cancer Related Major Depression (N=100) | Cancer Related Major Depression Treated With a Single Dose of Psilocybin (CAPSI) - NCT06319378
- Psilocybin | Treatment-resistant OCD (N=10) | Feasibility, Clinical Effects, and Safety of Psilocybin-assisted Psychotherapy for Treatment-resistant OCD (PAP-OCD) - NCT06299319
- Psilocybin | Treatment-Resistant Depression (N=20) | Psilocybin-Assisted Therapy in Treatment-Resistant Depression - NCT06303739
- MLS101 [low dose psilocybin] | Healthy Participants (N=80) | A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MLS101 [low dose psilocybin] in Healthy Participants - NCT06326606
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Exciting new career opportunities at Psylo!
We're growing and seeking passionate, skilled individuals for three key roles:
- Vice President of Drug Development: Clinical Readiness
- Lead the charge in advancing our novel drug candidates from the lab to clinical trials.
- Location: Boulder, Colorado or Sydney, Australia.
- Chemistry, Manufacturing, and Controls (CMC) Consultant
- Collaborate globally to optimize lead compounds in our small molecule drug discovery programs.
- Location: Remote
- Regulatory Affairs Consultant
- Guide and execute regulatory strategies for our drug development pipeline.
- Location: Remote
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Sam, Josh and Krista had a great meeting with the Daiichi Sankyo team in New Jersey.
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Psychedelics Today, PT491 – Dr. Sam Banister – Drug Development, Biotech, and Exploring Non-Hallucinogenic Compounds.
Dr. Sam Banister, co-founder and chief scientific officer of Psylo, discusses how he got involved in drug development, how Psylo came about, and the hallucinogenic and non-hallucinogenic 5-HT2A agonists Psylo is working on. Listen here
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Upcoming
- Sam and Dilara will be visiting Australia (Sydney and Melbourne) in May for some quality facetime with the Sydney team. Reach out if you'd like to connect.
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CEO Joshua Ismin will be appearing on a panel at the Digital Health Festival in Melbourne, 1-8 May. 🎫 Tickets.
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