Psylo Newsletter - March 2023

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5 Apr

But first, vote here to put psychedelics on the stage at SXSW Sydney

The future of psychedelic drug development

Want to learn about the future of drug development of psychedelics? Want to learn about how psychedelics can help address the world's mental health crisis? Want to hear from Scott Riddle, a participant in Australia's first psychedelic assisted therapy clinical trial? If so, please vote for our #sxswsydney session.

Science in Sixty Seconds: Why is 5-HT2A so psychedelic?

Why do psychedelics have the effects like visual hallucinations, altered perception of time, or ego-dissolution? Psychedelics activate serotonin 5-HT2A receptors, and their effects are largely determined by the where 5-HT2A receptors are located in the brain and body.

Research has shown that a relatively high dose of psilocybin led to 72% of the brain’s 5-HT2A receptors being occupied and that the intensity of the psychedelic experience strongly correlated with how many of these receptors were occupied [1].

Serotonin (5-HT) 2A receptors are:

The most abundant serotonin receptor in the brain.
The most important excitatory serotonergic receptor.
Widely distributed in the human brain but not equally.
Most abundant in cortical areas, especially medial frontal cortex, temporo-occipital cortex, as well as piriform and entorhinal cortex and insular cingulate [2, 3].
- These brain regions are important for sensory processing, cognition, self-awareness, semantics, language processing, emotion and memory.
While 2A receptors are found in different locations on different cell-types, their activation generally increases the activity of the neuron they are located on.
- Activation of 2A ➡ Increased neuronal activity

Abnormal or dysfunctional activity of the 5-HT2A receptor has been linked to several psychiatric and substance use (addiction) disorders [4].

The effects of psychedelics on the brain can be evaluated using functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and electroencephalography (EEG).

For example, psilocybin, LSD and DMT have been shown to disrupt connectivity and coordination in regions that make up the default mode network and increases cross-talk between unfamiliar regions.

The default mode network (DMN) 👿 is a set of brain regions that are associated with internally-directed cognition, for example with rumination, recalling autobiographical memory, self-judgement. The DMN is active when people are in a stat of wakeful rest and quiet when people are engaged in tasks or the external world. Altered connectivity in the DMN has been indicated in the pathophysiology of depression.
Interestingly, the size of the disruption in the DMN was correlated with participants’ experience of ego-dissolution (or losing the sense of self), suggesting that this network underlies a stable sense of self.

RESEARCH UPDATES

Psychedelic Clinical Research

🧠 The effects of DMT on the human brain provide insight on consciousness - PNAS | The recordings (N=20) show global hyperconnectivity and breakdown of the brain's normal organization (fMRI) that correlated with increased entropy (EEG). Regions with the densest expression of serotonin 2A receptors were most affected by DMT, and overlapped with regions related to evolved cognitive functions such as language and semantic processing.

😊 Microdosed LSD temporarily improved mood in healthy volunteers - Biol Psychiatry | This long-anticipated microdosing study assessed the effects of taking low doses of LSD (or placebo) every three days for six weeks. it used an interesting design (home-administered randomised controlled trial) where first doses were given in a supervised laboratory setting, with other doses self-administered at home. Microdosing LSD in healthy adult males appears relatively safe, although may induce anxiety. Microdosing was associated with improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness, but the effects were not long-lasting.

🌈 Self-treatment with LSD and psilocybin mushrooms - J Psychopharmacol | In the Global Drug Survey 2020, 3364 respondents reported their self-treatment experiences with LSD (N = 1996) or psilocybin mushrooms (N = 1368). Overall, positive changes were reported across 17-items of well-being, psychiatric symptoms, social-emotional skills, and health behaviours, with the strongest benefits on items related to insight and mood. Negative effects were reported by 22.5% of respondents. High intensity of psychedelic experience, seeking advice before treatment, treating with psilocybin mushrooms and treating post-traumatic stress disorder were associated with more positive outcomes. Younger age, high intensity of experience and treating with LSD were associated with increased number of negative outcomes.

🍄 Psilocybin-assisted therapy for major depressive disorder - J Psychopharmacol | A small study (N=19) found psilocybin-assisted therapy to have anti-depressant effects. This study tried an interesting design (placebo-controlled, fixed-order trial) to overcome the challenge of trying to placebo-control psychedelics but was ultimately unsuccessful.

💡 People who microdose say they benefit from microdosing - BMC Psychiatry | A small survey study interviewed participants about microdosing psychedelic drugs (N=13). Participants reported that they had experienced beneficial effects of microdosing on their mental health, alongside cognitive, physical and social changes. Microdosing was described as a catalyst to achieving their aims in this area.

[case study] Antidepressant Effects of Psilocybin in the Absence of Psychedelic Effects - Am J Psychiatry

Psychedelic Preclinical Research

🐸 5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice - Neuropsychopharmacol
Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that
5-MeO-DMT altered head-twitch response (psychedelic indicator in rodents) and suppressed social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases neuronal growth indicative of neuroplasticity.

🔬 Receptor Binding Profiles for Tryptamine Psychedelics and Effects of DMT analogues in Mice - ACS Pharmacol. Transl. Sci. | The findings suggest that activating the 5-HT_1A receptor attenuates psychedelic-proxy behaviour seen in mice.

🧪 A non-hallucinogenic LSD analog with therapeutic potential for mood disorders - Cell Reports | 2-Br-LSD is a non-hallucinogenic psychedelic. Here, it promoted neuroplasticity, produced active coping behavior and reversed chronic stress deficits in rodents.

🐀 A Single Administration of Psilocybin Persistently Rescues Cognitive Deficits Caused by Adolescent Chronic Restraint Stress Without Long-Term Changes in Synaptic Protein Gene Expression in a Rat Experimental System with Translational Relevance to Depression - Psychedelic Medicine

⚗ [Patent Highlight] Orally Active Forms of DMT, 5-MeO-DMT, and Long-Acting MDMA for the Treatment of Neuropsychiatric Disorders - ACS Med Chem Letters

Psychedelic Research Reviews

Psychedelics: preclinical insights provide directions for future research - Neuropsychopharmacology
Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs - Neuropharmacology
Exploring psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder - Front. Psychiatry
Examining the Rationale for Studying Psychedelic-Assisted Psychotherapy for the Treatment of Caregiver Distress - Psychedelic Medicine
Psychedelic Targeting of Metabotropic Glutamate Receptor 2 and Its Implications for the Treatment of Alcoholism - Cells
The need for establishing best practices and gold standards in psychedelic medicine - J Affect Disord

Psychedelic Clinical Trials Update

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

MDMA-Assisted CBT for OCD (MDMA-CBT4OCD Study) (MDMA-CBT4OCD) - NCT05783817
Mindfulness and Psychedelics - NCT05780216
Safety and Pharmacokinetics of GH002 [5-MeO-DMT] in Healthy Volunteers - NCT05753956
Tolerability of MDMA in Schizophrenia (TMS) - NCT05770375
MDMA-Assisted Therapy for Veterans With Moderate to Severe Post Traumatic Stress Disorder - NCT05790239

Other News

👨‍🚀 A Psychedelics Pioneer Takes the Ultimate Trip
- New York Times, 2 April
🧠 The psychedelic DMT causes the brain to become hyperconnected, scans reveal - Big Think, 31 March
💡 The Cognitive Benefits of Psychedelics - Neuroscience News, 31 March
💟 Can Psychedelics Save a Failing Relationship? - VICE, 28 March
Inside the scientific debate that’s shaping the future of psychedelic therapy: To trip or not to trip - Grid News, 22 March
💰 'It’s going to be for people with money’: Psychedelic treatments tipped to cost at least $25,000 - Sydney Morning Herald, 21 March
🌱 Psychedelic brew ayahuasca’s profound impact revealed in brain scans - The Guardian, 21 Mar
🥼 Government tips $50m into biotech grants - Australian Financial Review, 20 March
🍄 The Psychedelic Rush - ABC Radio National, 18 March
💕 Psychedelics Could Revolutionize Couples Therapy - Time Magazine, 14 March
🎭 How psychedelic drugs may help with depression - NIH Research Matters, 14 March
⚖ Australia is about to legalise MDMA and psilocybin for medicinal use. So how will it work? - ABC News, 3 March
💜 Anorexia is the deadliest psychiatric disorder. Could psychedelics help? - Financial Times, 2 March
🗣 [Listen 39 min] Psychedelic therapy: Will it be a game changer for mental health treatment? With Albert Garcia-Romeu, PhD - Speaking of Psychology podcast, American Psychological Association, March
🏥 I Got a Tour of the First Psychedelic Therapy Clinic in Britain - VICE, 28 Feb
🤞 [Listen, 28 min] The Veterans Fighting to Legalize Psychedelics - The Daily podcast, New York Times Podcast, 22 Feb
👩‍⚕️ Can you get psychedelics from your doctor? - ABC Radio National, 7 Feb [Listen, 22 min]

PSYLO UPDATES

A Sponsored Computational Chemistry PhD Opportunity in Psychedelics
Psylo is co-supervising a PhD candidate at RMIT University with Jessica Holien's lab. The selected applicant will use molecular modelling to predict hallucinogenic properties of novel compounds, contributing to the company's In-Psylico platform development. This project will deliver better psychedelic-inspired medicines, faster! The position has a stipend and a top-up scholarship.
Contact Jessica Holien for more info jessica.holien@rmit.edu.au

It was an absolute pleasure having Lawrence (Larry) Wennogle, our new VP of Translational Research, visit Sydney from Colorado, USA. Very excited to be working together to take Psylo to the next level 🚀

Sam Banister (CSO) interviewed psychedelic research legends, Prof David E. Nichols and Prof Charles Nichols, in a webinar kindly hosted by CDD Vault. Watch the recording here.

Here is an amazing photo that Dr. Dave provided of him, Albert Hoffmann (the chemist who synthesized and discovered the psychedelic effects of LSD) and Alexander (Sasha) Shulgin (godfather of MDMA and creator of hundreds of new psychedelics). Iconic!

📣 We have two amazing paid PhD internship opportunities available:

🧪 One will be based in our labs at UNSW (Sydney) and focus on "design and synthesis of small molecules targeting the serotonin (5-HT) system."
💻 The other can be undertaken remotely, and will involve a "detailed market analysis into possible medical indications and the competitor space in clinical trials for therapeutics being developed by Psylo."

These 3-6 month industry placements are available through APR.Intern and are an unmissable opportunity for research students to gain invaluable experience in biotech, and psychedelic drug discovery, build networks and enhance their CVs.

Psylo in the Media

CEO Josh Ismin presented at World Science Festival in Brisbane, 24 – 25 March 2023
CSO Sam Banister hosted a webinar with psychedelic pharmacologists, Charles and David E. Nichols, as part of the Collaborative Drug Discovery Scientific Webinar Series.

Upcoming

[SOLD OUT] Josh will interviewing Scott Riddle, a participant from the psilocybin-assisted psychotherapy for end-of-life anxiety trial at St Vincent's Hospital Melbourne, and presenting as part Raising the Bar, Sydney

The Clinical Psychedelic Lab at Monash University has teamed up with the Multidisciplinary Association for Psychedelic Studies (MAPS) to bring their 100-hour Therapist Training program down under.
More information here.