🌈 Welcome to the Psychedelic Science Newsletter! In this edition, we delve into extended DMT infusions, real-world evidence of psychedelics transforming substance use patterns, a case study involving cardiac arrest and psilocybin and we revisit the microdosing and the placebo response. Discover research from the cutting-edge, including novel applications, LSD vs ketamine and the future of using bacteria to produce psychedelics.
I am pleased to announce that Sam (CSO) and I (Dilara; Head of Communications) have officially touched down in the United States! We have made our way to Colorado, our beautiful new home state, ready to join forces with Larry and supercharge Psylo's expansion in the US (Why Colorado? See here).
In June, we're eagerly looking forward to attending the 'Psychedelic Science', conference hosted by MAPS, where over 10,000 attendees will come together to explore the latest advancements in psychedelic research.
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The history of antidepressant drugs (AD) began, by chance, in the 1950s.
1950s: The first generation of antidepressants, known as monoamine oxidase inhibitors (MAOIs), were discovered serendipitously after the tuberculosis drug iproniazid was found to improve the mood of patients. MAOIs function by inhibiting the enzyme monoamine oxidase, which leads to increased levels of neurotransmitters like serotonin, norepinephrine, and dopamine in the brain. Although MAOIs can be beneficial, they carry the risk of severe side effects and potentially dangerous interactions with other drugs and foods, resulting in limited usage.
1950s-1960s: Tricyclic antidepressants (TCAs) were introduced. TCAs also elevate the levels of serotonin and norepinephrine in the brain. These medications were effective but had significant side effects. The discovery of TCAs was also serendipitous when compounds being investigated as antihistamines were found to have mood-enhancing effects.
1980s: Selective serotonin reuptake inhibitors (SSRIs) were developed based on the understanding of serotonin's crucial role in mood regulation. Fluoxetine (Prozac®) became the first SSRI approved for clinical use in the United States. Other examples include Citalopram (Celexa®) and Sertraline (Zoloft®). SSRIs primarily target serotonin levels by inhibiting its reuptake, thereby increasing its availability in the brain. SSRIs gained popularity due to their improved safety profile compared to earlier antidepressants.
1990s: Serotonin-norepinephrine reuptake inhibitors (SNRIs) emerged. Medications such as venlafaxine (Effexor®), duloxetine (Cymbalta®) and Desvenlafaxine (Pristiq®) increase levels of both serotonin and norepinephrine (also known as noradrenaline) in the brain.
1990s-2000s: Atypical antidepressants were introduced, encompassing a diverse group of medications with different mechanisms of action that target various neurotransmitters. Examples include bupropion (Wellbutrin®) and trazodone (Desyrel®). Bupropion primarily affects dopamine and norepinephrine.
2000s: Other novel antidepressants were specifically developed based on increased understanding of depression. Examples include serotonin modulators like vortioxetine (Trintellix®) and Vilazodone (Viibryd®), as well as the melatonin analogue agomelatine* (Valdoxan®). The first rapid-acting antidepressant drugs are discovered - Ketamine and esketamine (Spravato®), both NMDA receptor antagonists, are discovered to have antidepressant effects in hours to days, and esketamine is approved.
2020s: In recent years, there has been a resurgence in the research and development of novel antidepressant treatments, including a renaissance of psychedelic research. Psychedelic substances like psilocybin and DMT are being investigated for their potential therapeutic benefits in specific psychiatric disorders, including depression. However, access to psychedelics may be limited to select populations. Consequently, the next generation of psychedelic therapeutics, such as shorter-acting psychedelics and non-hallucinogenic agents that retain the beneficial effects of 5-HT2A agonists, are being developed by Psylo and others to address the limitations of first-generation psychedelics.
*Some of these drugs are not approved by the U.S. Food and Drug Administration (FDA) because they have been discontinued or were never approved.
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Psychedelic Clinical Research
- 🌈 LSD's subjective Effects Peak at 100 μg Dose - Neuropsychopharmacology | A meta-analysis of LSD studies revealed that the effects of the drug increase up to a dose of around 100 μg and then plateau. Changes in perception, imagination, and positive ego-dissolution were the most notable effects. These findings provide important insights into LSD's impact on consciousness and can guide future research and therapeutic use.
- 💉 Acute effects of intravenous DMT - Translational Psychiatry | Researchers tested different administration regimens of DMT in health participants. They found giving DMT all at once produced more negative effects and anxiety compared to gradual infusions. The effects of DMT were short-lived, subsiding within 15 minutes, and participants developed rapid tolerance to continuous administration.
- 🙈 How does psilocybin therapy work? An exploration of experiential avoidance as a putative mechanism of change - J Affect Disord | This study explored the mechanism of action of psilocybin therapy and found that reductions in experiential avoidance, or the tendency to avoid or suppress difficult emotions and experiences, played a key role in the therapeutic effects of psilocybin therapy. By addressing experiential avoidance, psilocybin therapy led to improvements in mental health outcomes, such as well-being, depression severity, and anxiety.
- 🍷 Changed Substance Use After Psychedelic Experiences Among Individuals in Canada - Int J Ment Health Addict | This study surveyed individuals in Canada who had used psychedelics to explore if it was associated with changes in their use of other substances. Many participants reported reducing or stopping their use of alcohol, antidepressants, and cocaine after psychedelic experiences, while cannabis and tobacco use increased. The reasons for substance use changes were related to feeling more connected and experiencing less anxiety or depression. These findings provide real-world evidence of the potential impact of psychedelics on substance use patterns.
- 💊 A review of Control Conditions in Randomized Trials of Psychedelics - J Clin Psychiatry | This systematic review examined control conditions in randomized trials of psychedelics. The study found that many trials used inert placebos as control conditions, while few compared the effects of psychological support to minimally supportive conditions. The findings highlight the need for improved control conditions and assessment of blinding in psychedelic research, which can help ensure the reliability and validity of study results.
- 📞 Reducing the Harms of Nonclinical Psychedelics Use Through a Peer-Support Telephone Helpline - Psychedelic Medicine | This study found that a psychedelic helpline was effective in reducing risks and providing support for individuals using psychedelics outside of clinical settings. The helpline helped de-escalate psychological distress, preventing potential harm and reducing the burden on emergency and medical services.
- 🏢 Lifetime classic psychedelic use is associated with greater psychological distress in unemployed job seekers - J Psychedelic Stud | This study found that unemployed job seekers who had used classic psychedelics in their lifetime experienced higher levels of psychological distress compared to unemployed job seekers who had not used psychedelics. The study suggests that while classic psychedelics have been associated with positive mental health outcomes, they may exacerbate stress in certain life situations like unemployment.
- 👨⚕️ [Preprint] Cardiac Arrest Associated With Psilocybin Use and Hereditary Hemochromatosis - Cureus | This is a case of a 48-year-old man who experienced cardiac arrest after using psilocybin. The man had an underlying genetic condition called hereditary hemochromatosis, and the combination of psilocybin with other medications may have triggered a release of catecholamines, resulting in a dangerous heart rhythm.
- ✂ [Preprint] Microdosing Is More Than Placebo In Some Individuals: A Critical Re-examination of ‘Self-blinding citizen science to explore psychedelic microdosing’ - OFS | In a critical re-examination of a previous study on psychedelic microdosing, researchers found that microdosing had more than just a placebo effect in certain individuals. By analyzing additional variables and exploring drug intensity and within-person variability, they discovered that specific conditions, such as receiving both placebo and treatment, feeling some level of intoxication, correctly identifying placebo from treatment, and having at least mild depression, were associated with positive effects of microdosing. This study contributes to the growing evidence that microdoses of psychedelics may have benefits for certain individuals.
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Psychedelic Preclinical Research
- 🚩 Discovering drugs that selectively block the serotonin transporter - Cell | This study discovered two potent inhibitors of the serotonin transporter (SERT), which is a target for antidepressant medications. Using a structure-based approach, the researchers screened millions of small molecules and synthesized top-ranking compounds. They identified two low nanomolar inhibitors that selectively targeted SERT, demonstrated minimal off-target activity, and exhibited promising anxiolytic, anti-depressant-like effects, and the ability to reverse morphine withdrawal effects in mouse models.
- 🍄 Psilocybin's Impact on Obsessive-Compulsive Behavior - Translational Psychiatry | Psilocybin may be effective in treating obsessive-compulsive disorder. This study OCD behaviour in mice explored with marble burying behaviour and explored the receptor mechanisms implicated in the putative anti-obsessional effect.
- 🌿 Harmine may work as an anxiolytic by reducing inflammation and restoring healthy brain function - Int. Immunopharmacol. | Harmine, a vital component of the ayahuasca brew, shows potential as an anti-anxiety agent. It reduces brain inflammation and restores normal brain activity in the basolateral amygdala, a region associated with anxiety
- 🧠 Exploring the Effects of LSD and Ketamine on the Brain - Front. Neurosci | The effects of LSD and ketamine on brain activity and connectivity were compared using high-resolution electrophysiological measurements in rodents to analyze the local field potential (LFP) and assessed functional connectivity between different brain regions. They found LSD and ketamine to have distinct effects on the brain, with ketamine increasing neuronal activity but reducing connectivity, while LSD also reduced connectivity but without affecting overall brain activity. These findings provide insights into the mechanisms underlying the effects of psychedelics and may contribute to the development of new treatments for psychiatric conditions.
- 🐀 Psilocybin increased brain activity in rats in a similar way as it does in humans - Front. Neurosci. | This study investigated the effects of psilocybin on the brain activity of rats using functional magnetic resonance imaging (fMRI). The study found that psilocybin increased cortical activities in various regions of the brain, including the frontal, temporal, and parietal cortex, hippocampus, and striatum. These findings suggest that the hyperactive state induced by psilocybin in rats resembles the effects observed in humans, providing insights into the pharmacological effects of this compound.
- 🧫 Using bacteria to produce psychedelic tryptamines, DMT, 5-MeO-DMT, and Bufotenine - Metabolic Engineering | This study developed a biosynthetic pathway for these compounds in E. coli bacteria, achieving significant production levels. These findings offer promising prospects for further optimization and scaling of microbial production to meet the demand for ongoing clinical research and potentially provide alternative sources of these therapeutic substances.
- 🧪 [Preprint] Novel psilocin prodrugs with altered pharmacological properties as candidate therapies for treatment-resistant anxiety disorders - BioRxiv
- ❤ [Preprint] LSD stimulates human heart receptors - Research Square | The study found that LSD stimulates specific receptors in the heart (H2 histamine receptors), leading to increased force of contraction and beating rate in human atrial preparations. It is important to understand the potential cardiac side effects of LSD.
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Psychedelic Research Reviews
- Psychedelics as Transformative Therapeutics - Am J Psychiatry
- Pressing regulatory challenges for psychedelic medicine - Science
- "...this is a complicated moment for regulators seeking to impose a traditional regime of clinical trials and pharmaceutical premarket approval to a class of drugs already used outside the medical establishment through a patchwork of state and local regulation, Indigenous use, and “underground” consumption... we focus on pressing regulatory issues that demand attention, creativity, and collaboration to maximize psychedelics’ therapeutic potential.
- Remove barriers to clinical research for schedule 1 drugs with therapeutic potential - BMJ
- Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis - J Palliative medicine
- Psychedelics for treating chronic pain - Pain Practice
- A Systematic Review of MDMA Effects on the Male and Female Sexual Response Cycle - The Journal of Sexual Medicine
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Psychedelic Clinical Trials Update
A round-up of the latest registered clinical trials investigating psychedelics:
- MDMA-assisted Therapy Versus Cognitive Processing Therapy for Veterans With Severe Posttraumatic Stress Disorder - NCT05837845
- Pairing Psilocybin With Transauricular Vagus Nerve Stimulation (ENHANCE) - NCT05866471
- Psilocybin-Assisted Therapy for the Treatment of Cancer-Related Anxiety in Patients With Metastatic Cancer - NCT05847686
- An Investigation of Psilocybin on Behavioural and Cognitive Symptoms of Adults With Fragile X Syndrome - NCT05832255
- BPL-003 [5-MeO-DMT] Efficacy and Safety in Treatment Resistant Depression - NCT05870540
- Phase 2 Clinical Trial of GH001 [5-MeO-DMT] in Bipolar II Disorder [experiencing a current episode of depression] - NCT05839509
- LUCID-201-001: A Double-Blind, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Lucid-201 [psilocybin-related novel psychedelic] in Healthy Male and Female Volunteers and Patients with Depressive Symptoms on a selective-serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) - ACTRN12623000423617
- Assessing the effects of Lysergic acid diethylamide (LSD) microdosing in people experiencing depression (LSDDEP1) - ACTRN12623000486628
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Other News
- ⭐🏆 Lindy has a terminal illness. Psilocybin, the compound found in 'magic mushrooms', is helping her face death - ABC News, 21 May
- This is a really powerful & moving article about the psilocybin end-of-life distress trial that was initiated by one of the best therapists & pioneers in this space, Marg Ross, at St Vincent's Melbourne. It is a potent reminder of why we are working in this space and trying to develop solutions that can be accessed by more people.
- 🎌 It’s Surprisingly Easy to Get ‘Legal’ LSD in Japan - VICE, 24 May. A fascinating article on novel LSD analogues and Japan’s psychedelic grey market.
- 🌏 The Global Psychedelic Survey, sponsored by MAPS, has launched - MAPS Press release, 22 May
- Contribute to psychedelic research by completing the survey: Global Psychedelic Survey 2023
- 🌱 A new start after 60: I had my first psychedelic experience at 68 - The Guardian, 22 May
- 🌈 Harnessing Psychedelics for Mental Health - Neuroscience News, 16 May
- Insight from Prof. Colleen Loo and Dr Adam Bayes, from UNSW, on the prescription of MDMA and psilocybin in Australia
- 🧠 Delix Therapeutics launches phase 1 study for novel neuroplasticity-promoting therapeutic - Drug Discovery & Development, 9 May
- 🌵 The secret world of Sydney's psychoactive cacti growers who tend suburban gardens of peyote and ayahuasca - ABC News, 6 May
- 🎨 Consuming Psychedelics Temporarily Improves Man's Color Blindness - Technology Networks Drug Discovery, 5 May
- ✅ NIDA Partners With The National Institute Of Mental Health To Study Psychedelics Potential - Benzinga, 5 May
- ❓ Psychedelic medicine is coming—but who’s going to guide your trip? - National Geographic, 3 May
- 🎭 Psychedelic Inspires New Treatments for Addiction and Depression - UCSF, 2 May
- 🎯 The tricky economics of subsidising psychedelics for mental health therapy - The Conversation, 30 April
- Meticulous commentary from Prof. Cathy Mihalopoulos, Prof. Chris Langmead, Dr. Mary Lou Chatterton (Monash University) on the reality of accessing psychedelic medicines in their current form.
- 👀 Psychedelics may increase entropy in the brain's vision centre - New Scientist, 28 April
- 🥼 The future of rapid and enduring neuropsychiatric treatments: From psychedelics to non-hallucinatory psychoplastogens - Drug Discovery and Development, 24 April
🎧 Listen
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The Sydney Psylo team at Sam and Dilara's farewell.
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Sam and Larry attended the Psychedelic Therapeutics and Drug Development Conference in San Francisco, on 15-16 May. They also had the fortune of attending an afterparty at Graham Pechenik's place and mingling with some of the lovely people in this space.
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Josh presented at the Mind the Gap seminar hosted by Randwick Health & Innovation Precinct, 15 May
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Psylo CEO Josh Ismin interviewed psychedelic clinical trial participant Scott Riddle for Raising the Bar [Listen here]
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Want to meet up at Psychedelic Science?
- Josh Ismin, Sam Banister, Will Jorgensen, Larry Wennogle, Dilara Bahceci, Jin Tan, Mario de la Fuente, and Jacob Cameron from Team Psylo will be attending Psychedelic Science, 19-23 June, Denver, Colorado. Please reach out if you would like to meet up.
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This is Psylo's Psychedelic Science Newsletter, delivering curated research and news right to your inbox. Join the revolution.
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