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Are classic psychedelics cardiotoxic?
"2B or not 2B?" is the critical question being asked by psychedelics researchers, the FDA and psychedelic users. Does chronic use lead to cardiotoxic effects via activation of 5-HT2B receptors?
Psychedelic 5-HT2A receptors
Serotonin 5-HT2A receptors are integral to the signature psychedelic experience. These receptors are predominantly located in the brain’s regions associated with cognition and perception, including the prefrontal cortex. Activation of these receptors induces alterations in perception, mood, and cognition, sympathetic effects, and enhances neuroplasticity and cognitive flexibility. These receptors are believed to mediate the proposed benefits of psychedelics in treating conditions like depression and substance use disorders. However, classic psychedelics also interact with other receptor targets that could have beneficial or detrimental outcomes.
Risky 5-HT2B receptors
In contrast, 5-HT2B receptors are mainly found in the cardiovascular system, gastrointestinal tract, and lungs, rather than the brain. Thus, its stimulation is more associated with physiological responses than perception. Their activation is linked to physiological rather than perceptual effects, raising significant health concerns, notably cardiotoxicity, valvular heart disease, and potential heart failure.
- Fenphen as a warning case - Fen-Phen, a combination of fenfluramine and phentermine, was a popular weight loss drug in the 1990's but was pulled from the market after the severe side effects of valvular heart disease and pulmonary hypertension were linked to the drug. Fenfluramine's potent activation of 5-HT2B receptors was found to be responsible for the adverse cardiac effects.
Cardiotoxicity Risk and Chronic Psychedelic Use
While the current model of administering a few high doses under clinical supervision poses a low, manageable cardiac risk, the full extent of psychedelics' cardiac impact remains uncertain. Uncertainties compound by the durability of benefits and the potential need for repeated dosing being unknown. The increasing popularity of psychedelics for therapeutic use raises concerns about the chronic activation of 5-HT2B receptors. The recent FDA guidance for research and development of psychedelics recommended comprehensive safety evaluations in psychedelic research to assess the risk of valvular heart disease associated with 5-HT2B receptor activation.
The Need for Selective 5-HT2A Agonist and Safer Psychedelics
Psylo is at the cutting edge, innovating next-generation 5-HT2A agonists inspired by natural psychedelics. Utilizing iterative design and computational chemistry, Psylo is optimizing compounds for human use, ensuring they are selective for the 5-HT2A receptor and paving the way for safer chronic dosing. Evolving towards selective 5-HT2A agonists will reduce the risk of cardiotoxicity, provide a safer psychedelic experience and support broader therapeutic application.
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Psychedelic Clinical Research
- 💜 MDMA Breakthrough for PTSD Relief | MDMA-assisted therapy significantly reduced PTSD symptoms and functional impairment in patients with moderate to severe PTSD, in MAPS second Phase 3 randomized, placebo-controlled design with 104 participants. Nature Medicine
- 🍄 Psilocybin Shows Sustained Antidepressant Effect | A single 25-mg dose of psilocybin, administered with psychological support in a 6-week trial with 104 adults, resulted in a rapid and sustained antidepressant effect with no serious adverse events, offering a potential new treatment avenue for major depressive disorder. JAMA
- 🤝 MDMA and Methamphetamine Increase Feelings of Connectedness | MDMA (100 mg) and methamphetamine (20 mg) both increased feelings of connectedness during semi-structured casual conversations with unfamiliar partners, with oxytocin levels correlating with increased closeness only after MDMA administration; clinical trial with 18 participants for MDMA and 19 participants for methamphetamine. Scientific Reports
- 🧠 Biomarkers for Antidepressant Response to Ketamine | A consistent neuroimaging biomarker for ketamine response wasn't found in a systematic review of 69 neuroimaging studies and 1,751 participants. However, promising signals include increased gamma power in frontoparietal regions, enhanced functional connectivity within the prefrontal cortex, and heightened functional activation of the striatum. Lancet Psychiatry
- 🩹 MDMA Co-use: A Soother for Psychedelic Challenges | Co-use of MDMA with psilocybin/LSD was associated with reduced challenging experiences and enhanced positive emotions; data from self-reports in a prospective convenience sample of 698 individuals. Scientific Reports
- 🔎 Potential Causal Factors for Negative Psychological Responses to Psychedelics | A small study found that negative psychological responses to psychedelics (predominantly anxiety symptoms) were associated with adverse environments, high drug doses, prior psychological vulnerabilities, and young age; an online questionnaire and in-depth interviews of 20 people. Scientific Reports
- 🤔 Psychedelic Use Associated With Non-Conformist Thinking | Recent use of classical psychedelics correlates with an increased tendency to believe in alternative facts, particularly the perception that facts are politically driven; analysis of survey data from 392 participants. Scientific Reports
- ❓ [Case Report] Potential Link Between MDMA and Early-Onset Parkinson's Disease | This case report suggests that MDMA use may have precipitated the early onset of Parkinson's disease in a genetically vulnerable individual. Journal of Medical Case Reports
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Psychedelic Preclinical Research
- 🐭 Psilocybin Analog Enhances Fear Extinction in Mice | In mice, 4-OH-DiPT, a psilocybin analog, demonstrated strong agonist activity at 5-HT2A receptors, reducing fear responses, especially in female mice, and enhancing GABAergic inhibition in basolateral amygdala neurons. Neuropsychopharmacology
- 🐁 Prolonged Ketamine Treatment: Beneficial for Anxiety but Not Depression | The study unveils that in stressed mice, prolonged ketamine administration ameliorated anxiety-like behaviors, short-term memory, and social interaction deficits, but did not rescue depressive-like behavior, illuminating its distinct neurobehavioral impacts. Psychoneuroendocrinology
- 🐭 GluN2A Mediates Ketamine-Triggered Rapid Antidepressant-Like Responses | This study reveals that in adult mouse brains, the suppression of NMDAR subunit GluN2A, rather than GluN2B, mediates the rapid antidepressant-like effects of ketamine and MK-801, challenging previous assumptions and opening new avenues for antidepressant development. Nature Neuroscience
- 🐁 A Validated Model Of Microdosing In Mice Increased Resilience To Stress And Lowered Compulsivity | Repeated low doses of psilocybin in rats increased resilience to stress, lowered compulsive actions (self-grooming), and enhanced synaptic density in the paraventricular nucleus of the thalamus. The treatment did not induce anhedonia, anxiety, or altered locomotor activity, and 5-HT2A receptors were not downregulated. Molecular Psychiatry
- 🧪 New Synthetic Strategies for LSD's Core Structure | The study presents novel strategies for efficiently synthesizing the tetracyclic core structure of ergoline alkaloids, including LSD, and demonstrates the first methods for introducing substitutions on the C-ring. The Journal of Organic Chemistry
- 📈 Refined Analysis of Concentration–Response Curves | This study introduces a nonlinear regression procedure improving the precision in analyzing concentration–response curves, demonstrated using enzymatic inhibition data from the COVID Moonshot project. Journal of Medicinal Chemistry
- 🐀 Chronic Administration of 25B-NBOMe Alters Neurotransmitter Release and Behavior in Rats | This study, conducted on rats, assesses the effects of a 7-day treatment with the psychoactive compound 25B-NBOMe on neurotransmitter release, hallucinogenic activity, anxiety levels, and genotoxicity, concluding that chronic administration of 25B-NBOMe leads to tolerance in neurotransmitter release and hallucinogenic activity and exerts anxiogenic effects after single and repeated treatment. Neuropharmacology
- 💻 Exploring Cathinones as Ligands for the 5-HT2AR Receptor | This study employs molecular docking assessment to investigate cathinones as potential ligands for the 5-HT2AR receptor, with the aim of creating predictive models for improved drug abuse recognition. Molecules
- 🐭 [Preprint] Neural and Vascular Effects of Psychedelic 5-HT2A Receptor Activation | DOI administration in mice led to narrowed hemodynamic response functions and increased transduction of neuronal activity in the delta band, with region-specific effects. BioRxiv
- 🐁 [Preprint] Engineered Mice for Studying Psychedelic Drug Effects | The study generated engineered mice lines, including a humanized Htr2a mouse line and a constitutive Htr2A-Cre mouse line, which exhibited known behavioral responses to psychedelics. Electrophysiology studies indicated that HTR2A activation increased firing of genetically-identified pyramidal neurons. BioRxiv
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Psychedelic Reviews and Commentaries
- 🔍 Treatment-Resistant Depression: Definition, Prevalence, Detection, Management, and Investigational Interventions | This paper provides a synthesis of current definitions of TRD, emphasising their limitations, and highlights the need for an improved consensus definition. World Psychiatry
- 🐟 The Zebrafish For Preclinical Psilocybin Research | The review suggests that zebrafish could be a valuable tool for preclinical research on psychedelic drugs, including psilocybin, by assessing behavioral effects, genetic manipulations, and treatment efficacy in affective disorders. Neuroscience & Biobehavioral Reviews
- 🎯 Mechanisms And Molecular Targets Surrounding The Potential Therapeutic Effects Of Psychedelics | This review comprehensively explores the chemistry, pharmacology, acute and post-acute effects, potential therapeutic applications, molecular targets, and future directions of psychedelics in both preclinical and clinical research. Molecular Psychiatry
- 🧠 Neuroimaging In Psychedelic Drug Development: Past, Present, And Future | This review explores the historical context and current use of neuroimaging techniques in understanding the therapeutic potential of psychedelic drugs for psychiatric disorders, highlighting the gaps in knowledge and proposing future research directions. Molecular Psychiatry
- 🤰 A Perspective On Psychedelic Teratogenicity: The Utility Of Zebrafish Models | This opinion piece highlights the underexplored risks of psychedelic use in pregnant and breastfeeding women, proposing the zebrafish as a reliable model for studying potential teratogenic effects due to its practicality and translational relevance. Trends in Pharmacological Sciences
- 🧠 A Role For The Serotonin 2A Receptor In The Expansion And Functioning Of Human Transmodal Cortex | This review propose that serotonin 2A receptor (5-HT2AR) signaling plays a significant role in the expansion and functioning of the human transmodal cortex, contributing to cognitive and psychological flexibility. Brain
- 🎭 The Psychedelic Experience And Treatment-Resistant Depression | This commentary discusses the use of psilocybin in treatment-resistant depression, emphasizing that challenges related to blinding and the role of psychotherapy need to be addressed for it to gain approval as a medicine. World Psychiatry
- 🍺 Molecular And Structural Insights Into The 5-HT2C Receptor As A Therapeutic Target For Substance Use Disorders | This review explores the potential therapeutic role of the 5-HT2C receptor in substance use disorder treatment, focusing on its molecular and structural aspects. British Journal of Pharmacology.
- 🛠 Neuroplasticity: The Continuum of Change | This viewpoint article delves into the concept of neuroplasticity, describing its multifaceted nature in connecting molecular, cellular, and circuit-level changes in response to stimuli, emphasizing its relevance in both health and disease. ACS Chemical Neuroscience.
- 🟢 Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics | This review explores ligand-free signaling in GPCRs, and suggest that ligand-free signaling of 5-HT2A receptors may mediate the therapeutic effects of psychedelics. Molecules
- 🤕 Adapting Psychedelic Medicine For Headache And Chronic Pain Disorders| This review discusses the potential therapeutic effects of psychedelics, particularly psilocybin, in headache disorders and chronic pain, including insights from clinical trials and case reports. Expert Review of Neurotherapeutics
- 🤝 Psychedelic Science, Contemplative Practices, and Indigenous and Other Traditional Knowledge Systems: Towards Integrative Community-Based Approaches in Global Health | This paper reviews literature on psychedelic science, contemplative practices, and Indigenous and other traditional knowledge systems to make the case that combining them in integrative models of care delivered through community-based approaches backed by strong and accountable health systems could prove transformative for global health. Journal of Psychoactive Drugs
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Dr Will Jorgensen, Psylo's Lead Medicinal Chemist, took first place in the Hello Tomorrow APAC challenge in Singapore this month. Congratulations Will!
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Psychedelic Clinical Trials Update
A round-up of the latest registered clinical trials investigating psychedelics:
Australia
- MDMA | PTSD in Military Veterans and First Responders | MDMA-assisted therapy for Post-Traumatic Stress Disorder in Military Veterans and First Responders - ACTRN12623000971639
- Psilocybin | Treatment-Resistant Depression | Evaluating the management of treatment resistant depression with psychedelic (psilocybin) assisted psychotherapy (EMPACT) - ACTRN12623001004651
Canada
- MDMA | PTSD | MDMA-Assisted CBCT for PTSD vs CBCT RCT - NCT06044675
- Psilocybin | Alcohol Use Disorder | Mechanisms supporting psilocybin-assisted psychotherapy for alcohol use disorder: A randomized, controlled clinical trial - 278421
- Psilocybin | Amnestic Mild Cognitive Impairment | Does Psilocybin Change Synaptic Density in Amnestic Mild Cognitive Impairment - NCT06041152
- Psilocybin | Depression | Does psilocybin require psychedelic effects to treat depression? An open-label clinical trial - 278284
Jordan
- Psilocin | Safety and Absorption | Evaluation of Safety, Rate and Extent of Absorption of Psilocin Mucate (Psilocin-1) - NCT06035900
USA
- Ketamine | Levodopa-Induced Dyskinesia in Parkinson's Disease | Phase I Open-label Study of Low-dose Ketamine Infusion Treatment in Levodopa-Induced Dyskinesia in Parkinson's Disease - NCT06021756
- Ketamine | PTSD | Connectivity Changes Associated With Ketamine Assisted Psychotherapy for PTSD (CONCHKAP) - NCT06036511
- Ketamine | Depression | Comparative Effectiveness of ECT vs. KETAMINE Over the Lifespan (REaKT-SD) - NCT06034821
- N, N-dimethyltryptamine (DMT) Analog (CYB004) | Generalized Anxiety Disorder (GAD) with Depressive Symptoms | A Study of a N, N-dimethyltryptamine (DMT) Analog (CYB004) in Participants With Generalized Anxiety Disorder (GAD) With Depressive Symptoms - NCT06051721
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Other News
- The Psychedelic Paradigm Shift: Revolutionary Treatment or a Slippery Slope for Mental Health? - SciTechDaily, Sep 27 | This article discusses the ongoing shift in mental health treatment toward psychedelics, raising questions about the risks and benefits of this emerging therapeutic approach.
- Psychedelic Bulletin #145: MAPS' Second Phase 3 Study Published, EMA's New Draft Guideline on Depression Drug Dev Includes Psychedelics, California's Decrim Bill Goes to Governor - Psychedelic Alpha, Sep 26 | This bulletin highlights various developments in the field of psychedelics, including MAPS' Phase 3 study, regulatory guidelines, and legislative efforts related to decriminalization.
- [Podcast] Finding Happiness - NPR, Sep 8, 202 | “On this episode, we'll explore happiness - and how we can find more of it. We'll hear about the longest-running study on the subject, find out if money is really a game-changer, and talk to a therapist who says we need to stop obsessing over happiness.”
- Biomarker Tracks Recovery in Depression – NIH Research Matters, Sep 26 | Researchers identified a unique pattern of brain activity, a “biomarker,” that can detect a patent’s response to deep-brain stimulation for treating severe depression.
- Psychedelic Drug Market Set to Reach $7.2 Billion in 2029: Report - Economic Times, Sep 25 | A new report predicts growth projections for the psychedelic drug market, estimating it to reach $7.2 billion by 2029.
- [Podcast] Exploring Psychedelic-Assisted Psychotherapy for Veterans with PTSD – VA News, Sep 26, 2023
- Drug discovery on an unprecedented scale – ScienceDaily, Sep 26 | Researchers use supercomputers and machine learning to accelerate virtual screening, reducing the time required to process 1.56 billion drug-like molecules by tenfold.
- In depression treatment trials, placebo effect is growing stronger - Ars Technica, Sep 26 | The placebo effect for antidepressant treatments appears to be growing stronger over time. This has been known for placebo medications and has now been seen with placebo transcranial magnetic stimulation.
- Psychedelics for Depression: Unpacking the Research - Neuroscience News, Sep 25, | This article delves into recent research on the use of psychedelics, such as psilocybin and MDMA, in the treatment of depression, highlighting their potential as novel therapeutic approaches.
- Psychedelics Research Roundup - Psychiatric Times, Sep 22 | The article provides an overview of recent developments in psychedelic research, including studies on psilocybin, MDMA, and ketamine, as well as their potential applications in mental health treatment.
- U.S. Adults, Especially Millennials, Are Interested in Psychedelics as Mental Health Treatment - Morning Consult, Sep 21 | Survey shows that 1 in 3 U.S. adults are interested in trying psychedelics to treat mental health issues: more than half of millennials expressed interest while 70% of baby boomers said they were “not interested at all.”
- Target Based Drug Discovery - A Waste of Time? - Science, Sep 21 | New study analysing 1144 approved small-molecule drugs reports that only 123 of them were discovered by purely target-based assay methods, and that the rest have to be described as discovered through phenotypic means.
- What Psychedelics Can Teach Us About Play - Time, Sep 20 | This article highlights the capacity for psychedelics to promote playfulness and a flexible mindset, and foster collaboration.
- These habits can cut the risk of depression in half, a new study finds - NPR, Sep 19 | Researchers identified seven healthy habits and found that people who maintained most of them — five or more— had a 57% lower risk of depression.
- Heart risks, serotonin, and fen-phen: 5 Questions for 5-HT receptor researcher Bryan Roth – The Microdose, Sep 18 | Dr. Bryan Roth discusses the potential heart risks associated with drugs that stimulate 5-HT receptors, including psychedelics
- AI can help to speed up drug discovery — but only if we give it the right data - Nature, Sep 19 | Artificial-intelligence tools that enable companies to share data about drug candidates while keeping sensitive information safe can unleash the potential of machine learning and cutting-edge lab techniques, for the common good.
- Chasing Hobbies Over Achievement Boosts Happiness - Neuroscience News, Sep 14 |“Individuals emphasizing freedom and hobbies experienced a boost in well-being, whereas those prioritizing achievement felt less happy.”
- The science behind lifestyle's role in preventing depression - News-Medical, Sep 13, Lifestyle factors such as diet, exercise, sleep, smoking, and social interactions play a significant role in reducing the risk of depression, with a favorable lifestyle reducing the risk by up to 72%, according to a study involving nearly 290,000 participants.
- Scientists Transform Yeast into Psychedelics - Health News, Sep 12 | Producing psilocybin through the biological process of yeast fermentation is a promising way to mass-produce the drug more sustainably.
- Psychedelic Treatment in Mental Health Lacks Evidence, Australian Experts Say - The Guardian, Sep 12 | Researchers from Monash University in Melbourne conducted in-depth interviews with senior experts from a range of organisations involved in psychedelic drug law reform, clinical use or regulation; the interviewees were hesitant to support the widespread clinical implementation of psychedelics due to concern about this poor quality of evidence.
- Coverage of the Usona psilocybin trial
- Using psychedelics to treat mental illnesses ‘not hippy movement,’ expert says - The Independent, Sep 1, 2023 | Professor David Nutt, a neuropsychopharmacology expert, advocates for a more rational drugs policy and the use of psychedelic drugs like magic mushrooms and MDMA as potential treatments for mental health conditions, asserting that they have the potential to positively impact people's lives and should not be dismissed as a fringe or hippy movement.
- Nitrous Oxide (“Laughing Gas”) May Have Rapid-Acting Anti-Suicidal Effects - Brain & Behavior Research Foundation, Aug 31 | Results of 3 small clinical trials suggest that 1-hour inhalation of the anesthetic nitrous oxide (N₂O, or “laughing gas”) may have rapid-acting anti-suicidal effects, in addition to antidepressant effects.
- AI Is Game Changer for Toughest Areas of Drug Discovery - Forbes, Aug 31 | AI is revolutionizing drug discovery, particularly in large molecules like antibodies, proteins, gene therapies, and RNA-based treatments.
- Psychedelic Drug Trial Guidance: Commenters See Vital Role for Psychotherapy - Regulatory Affairs Professionals Society, Aug 29 | Comments on the FDA's guidance for psychedelic drug trials express concerns about the decoupling of drug administration from psychotherapy support, the proposed credentials for lead safety monitors, and the FDA's characterization of the abuse potential of psychedelic drugs.
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| Josh took to the stage at TEDxSydney to share that psychedelics are not just at a tipping point - they are the starting point! Check out the live drawing of his talk by Gavin Blake. |
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We spent the day with the Daiichi Sankyo team at our new B+labs location in Philadelphia. It was wonderful to have some face-time planning out our activities for the rest of the year.
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Dilara appeared as a guest on The Scan podcast to discuss how psychedelic drugs are being used to treat mental illness and why Australia is a world leader in this space.
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Psylo and Will feature in the Hello Tomorrow 2023 Recap episode by One North Stories. Listen here.
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- Josh will be speaking on a SXSW Sydney panel on ‘Psychedelics and the Future of Mental Health Treatments’, 18 October
- Sam will also be participating in a SXSW Sydney session called “Reimagined Futures” alongside Hon Weng Chong from Cortical Labs, organized by AWS, 19 October
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