Science in Sixty Seconds

Psychedelic Anti-Depressants Without the Trip

Classic psychedelics, like LSD and psilocybin from psychedelic mushrooms, activate 5-HT2A "psychedelic" serotonin receptors in the brain, which cause psychedelic effects (like hallucinations) and therapeutic effects (e.g. reduced depressive symptoms).

Activation of 5-HT2A receptors stimulates neurons to grow new branches and form new connections with other neurons in a process called 'neuroplasticity'. This rewiring of neural connections can occur within days and the benefits can last for months; it is also thought to underpin the anti-depressant effects that are being observed in clinical trials with psychedelics.

However, activation of 5-HT2A receptors also causes intense perception-distorting effects, which require psychedelic therapies to be administered under clinical supervision (i.e. making treatment prohibitively expensive) and deem them inappropriate for people who are sensitive to hallucinations (e.g. individuals at risk of psychosis). Thus, the therapeutic use of psychedelics is limited by their hallucinatory effects.

Tweaking the chemical structure of existing psychedelic molecules is predicted to yield compounds that activate the 5-HT2A receptor, increase neuroplasticity and treat depression without causing hallucinations. Non-hallucinogenic 5-HT2A anti-depressants will not replace existing classic psychedelic-assisted psychotherapies but will complement them in a suite of personalized treatment options.  

In the hope to develop anti-depressants that can benefit broader populations, biotech companies like Psylo are using innovative strategies to develop novel 5-HT2A antidepressants that don't induce strong hallucinatory effects. These promising compounds are progressing through early R&D and are expected to enter clinical trials in the coming years.

For more information, see Taking the tripping out of psychedelic medicine

RESEARCH UPDATES

Psychedelic Clinical Research

• 🌈 LSD-assisted therapy for anxiety in patients with and without a life-threatening illness | A randomized, double-blind, placebo-controlled Phase II study (N=42) Biol Psychiatry
  • LSD treatment significantly reduced anxiety and depression scores up to 16 weeks after treatment. Feeling positive subjective effects when on LSD and mystical-type experiences correlated with the long-term reductions in anxiety symptoms. Mild adverse effects were reported by eight patients (19%). One treatment-related serious adverse event (acute transient anxiety) occurred (2%).

Psychedelic Preclinical Research

• 🌞 Non-psychedelic 5-HT2A agonists as antidepressants | AI was used to scan 75 million molecules against the psychedelic 5-HT2A receptor to identify potential agonists. 17 of the most-promising hits were synthesized and tested in cells and rodents to identify novel antidepressants without psychedelic effects, Nature.
• 📷 Signaling snapshots of the 5-HT_2B serotonin receptor activated by the prototypical psychedelic LSD - Neuron
• 🔪 Inhibition pf 5-HT2A receptors and Kv7 potassium channels attenuated chronic neuropathic pain in a rat model of nerve injury - Neurosci Lett
• 🎨 Serotonin 5-HT2A, 5-HT2C and 5-HT1A receptor involvement in the acute effects of psilocybin in mice | 5-HT2A and 5-HT2C receptors exert opposite effects in the psilocybin head-twich response, Biomed Pharmacother.
• 🔦 Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists - J Med Chem
• 🧪 A Concise and Malleable Synthesis of (±)-Lysergic Acid - ChemRxiv [preprint]
• ⭐ [Patent Highlight] Potential Treatment for Obsessive-Compulsive Disorder - ACS Med Chem Lett
• ⭐ [Patent Highlight] MDMA and Their Analogs as Therapeutics for Mental Disorder and Response Predictor - ACS Med Chem Lett

Psychedelic Clinical Trials Update A round-up of the latest registered clinical trials investigating psychedelics:

• Acute Effects of 2C-B Compared With MDMA and Psilocybin in Healthy Subjects (2C-B) - NCT05523401
• PAPR: Psilocybin-assisted Psychotherapy (PAP) + Mindfulness-Based Stress Reduction (MBSR) for Front-line Healthcare Provider COVID-19 Related Burnout (PAPR) - NCT05557643
• Psilocybin for the Treatment of Veterans With Post-Traumatic Stress Disorder - NCT05554094
• SPL026 [N,N-dimethyltryptamine; DMT] With or Without antidepressants SSRIs in Participants With Major Depressive Disorder - NCT05553691
• Effects of Psilocybin in Obsessive Compulsive Disorder - NCT05546658
• Psilocybin in Patients With Fibromyalgia: EEG-measured Brain Biomarkers of Action (Psilopain) - NCT05548075

Other News

• 🙌 Nature Outlook released a "Psychedelic medicine" edition with many great articles [all 28 September 2022]:
  • 🌈 Psychedelic medicine faces the acid test
  • 🌞 Taking the tripping out of psychedelic medicine -
    • "The creation of non-hallucinogenic psychedelic analogues that offer the mental health benefits of psychedelics like psilocybin without inducing strong hallucinatory effects remains a top priority for the industry."
  • 🤍 Hope that psychedelic drugs can erase trauma
  • 💡 How MDMA resensitizes the brain
  • 🔑 The psychedelic escape from depression
  • 🌵 Finding medical value in mescaline
  • 🧠 Your brain on psychedelics
  • 🌍 Psychedelic research and the real world
  • 🎭 Psychedelic microdosing hits a rough patch in clinical trials
  • 📣 Research round-up: psychedelic medicine
  • ⚡ The psychedelic remedy for chronic pain
  • 🕵️‍♀️Can psychedelic drugs uncover the secrets of consciousness?
  • ⚖ Why federal agencies say now is the time to explore psychedelics

• 🧪 Innovative chemistry yields potential antidepressant drugs - Nature Research Briefings, 28 September 2022.
  • "Computational simulation of interactions of each of 75 million molecules with a model structure of the 5-HT2A receptor, which mediates the actions of psychedelic drugs, identified molecules that selectively activate the receptor. When tested in mice, two of these compounds had antidepressant-like actions without the side effects of psychedelic drugs.
• 🌞 Scientists Create Non-Psychedelic Compound with Same Anti-depressant Effect - Business Wire, 28 September 2022
• 🎙[Podcast] The psychedelic renaissance in medicine - The Economist, 27 September 2022
• 🍎 Effects of LSD and Psilocybin in Healthy Participants - Psychiatric Times, 27 September 2022.
  • "Psilocybin 20 mg is likely equivalent to LSD 100 µg. There was no evidence for qualitative differences in altered states of consciousness, except for a shorter duration of action for psilocybin."
• 🍏 Two Psychedelics Companies Will Study Effects Of Natural Psilocybin And MDMA In Healthy Volunteers - Bezinga, 22 September 2022
• 🤏 The popularity of microdosing of psychedelics: What does the science say? - Harvard Health, 19 September 2022.
  • "it is important to understand that there isn’t yet definitive proof that microdosing is at all helpful, or even that it is safe in the long term."
• 🍄 Scientists have started to examine whether “magic” mushrooms can help in the fight against obesity - PsyPost, 11 September 2022
• 🍷 Psychedelics take on alcohol dependence - Nature Reviews Drug Discovery News in Brief, 2 September 2022
• 🎈 Preparing for the Bursting of the Psychedelic Hype Bubble - JAMA Psychiatry Viewpoint, 31 August 2022

WE ARE HIRING! There are five new jobs currently available for Psylo: including junior and senior chemist roles, and an operations manager. Explore the opportunities and apply here.

PSYLO UPDATES

Chief Scientist Sam and Science Comms Officer Dilara met Rick Doblin, the founder of MAPS and one of the founding fathers of psychedelic medicines, at Burning Man. They also had the fortune of meeting Dr Carl Hart (author of Drug Use for Grown Ups), Jamie Wheal (author of Stealing Fire) and the legendary mycologist, Paul Stamets. 🍄❤

Psylo is based at UNSW, and is collaborating with Associate Professor Luke Hunter to advance our development of psychedelic-inspired medicines to treat depression and other serious mental illness. We have partnered with Dr Hunter to develop psilocybin-like therapeutics with improved clinical efficacy and reduced side-effect profile. Watch this video to learn more.

Dr Dilara chats psychedelics with Australian national treasure Dr Karl on his podcast, Shirtloads of Science: Listen here

Upcoming

• 19th-20th of October: Purpose Conference. Co-founders Josh and Sam will be presenting at the Purpose Conference in Sydney.
• 26th-28th of October: AusBiotech. Josh, Sam and Dilara will be attending and presenting at the conference in Perth.

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