Psylo Newsletter - August 2022

psylo_newsletters

31 Aug

Science in Sixty Seconds

Psychedelic Drugs and Tolerance

Tolerance is a person's diminished response to a drug with repeated use. Classic psychedelics, like LSD and psilocybin from psychedelic mushrooms, activate 5-HT2A receptors and induce rapid tolerance. For example, taking the same dose of LSD daily reduces its psychedelic effects almost completely after several days.

"In an early human study from the mid-1950s, psychedelic doses of LSD were given daily for two to three weeks, or even up to three months. By the end of the repeated LSD dosings, tolerance was so profound that when researchers replaced the drug with mere water, subjects did not even recognise that it was not LSD they had received." - Mind Foundation.

However, tolerance is also quickly abolished, and maximal effects return after 3-7 days of abstinence.

Interestingly, cross-tolerance occurs between different psychedelics that are 5-HT2A agonists. For example, taking LSD on day 1 will reduce response to psilocybin on day 2 and visa versa.

Tolerance is thought to occur because “psychedelic” 5-HT2A receptors are down-regulated (transported back into the cell for recycling) after excessive stimulation and there are fewer receptors to stimulate on the cell surface. These receptors are recycled and returned to the surface of the cell after a few days.

For more information, see https://mind-foundation.org/tolerance-to-lsd/

RESEARCH UPDATES

Psychedelic Clinical Research

🍺 Psilocybin-therapy reduces heavy drinking | Psilocybin administered in combination with psychotherapy produced robust decreases in the percentage of heavy drinking days in patients with alcohol use disorder in a double-blind randomized clinical trial (N=95) - JAMA Psychiatry
🔸 Microdosing with psilocybin mushrooms | Microdosing was detectable with low doses of psilocybin mushrooms producing noticeable subjective effects and altered EEG rhythms compared to placebo, but only for participants who correctly identified their experimental condition (psilocybin vs placebo). There was no evidence to support enhanced well-being, creativity and cognitive function. Authors state, “expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.” A small (N=34) double-blind placebo-controlled study - Translational Psychiatry
🚶‍♀️ Restoration of Motor Function Post-Neurological Injury Using Serotonergic Agonist [Patent Highlight] | Novel Psychedelic-based agents, 3-Cyclic Amine-Indole Derivatives (tryptamine analogues), show promise for the treatment of psychosis or psychotic symptoms, mental illness and motor function in subjects diagnosed with a central nervous system injury when administered in combination with motor skill restoration therapy – ACS Med. Chem. Lett.
👨🏾‍🤝‍👨🏻 More people are using psychedelics | Psychedelics use by US adults has increased over time and is now estimated to be used by more than 5.5 million adults aged 18+ years. Data from the US National Survey on Drug Use and Health, 2002–19 (n = 1 006 051) – Addiction
Fatal Intoxications from a Combination of novel psychedelic substances, 4-Fluoroamphetamine (4-FA, PFA, "Flux", "Flits", "R2D2", "Miley") and 25C-NBOMe – Journal of Analytical Toxicology
💉 Psychedelic use is not associated with cancer | While laboratory studies and case reports from the 1960s and 1970s generated concerns about psychedelics’ carcinogenic potential, this analysis of recent epidemiological data does not support an association between psychedelic use and development of cancer. Analysis of data from the National Survey on Drug Use and Health 2015-2019 – J Psychopharmacol.
👩‍⚕️ Inconsistencies between national drug policy and professional beliefs about psychoactive drugs among psychiatrists in the United States | American psychiatrists’ perceptions about safety and abuse/therapeutic potentials of psychoactive drugs were inconsistent the the scheduling of those drugs. Authors state that “these findings add to a growing consensus amongst experts that the current drug policy is not scientifically coherent.” A quasi-experimental online survey of US psychiatrists (N=181) questioned about non-prescribed psychoactive drugs: psilocybin [Schedule 1], methamphetamine [Schedule 2], ketamine [Schedule 3], or alprazolam [Schedule 4]) – International Journal of Drug Policy
🩺 People are hesitant to discuss the use of psychedelics with their practitioners | Only 4.4% of people reported their use of psychedelics to a therapist and 3% in clinical settings, even though 77.8% were very or extremely likely to take psychedelics with a therapist if one were legally available. A survey of 1435 people. Authors state, “Our findings suggest that relevant training and education for healthcare providers is needed, along with more visible options for substance identity testing.” – Journal of Psychoactive Drugs

Psychedelic Preclinical Research

📉 Tolerance and Cross-Tolerance Among Psychedelic And Nonpsychedelic 5-HT2A Receptor Agonists in Mice | See Science in Sixty seconds (at the top of the newsletter) for an explanation of drug tolerance. Tolerance to psychedelics DOI and LSD was observed in mice as reduced head twitch response (HTR), the functional readout of psychedelic activity in rodent models, to the same dose of psychedelics on subsequent days in mice. Dosing with LSD also reduced response levels to DOI (cross-tolerance). Interestingly, the non-hallucinogenic 5-HT2AR agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI reduced 5-HT2A receptors in the mouse frontal cortex. Tolerance was not observed in β-arrestin-2 knockout mice. Therefore, tolerance to HTR induced by psychedelics involves activation of the 5-HT2A receptor and occurs via a signaling mechanism independent of β-arrestin-2 – ACS Chem Neurosci
🚻 Male and Female Mice Respond Differently to Psychedelics | The psychedelic DOI elicited more head twitch response (HTR) in female mice than male mice in the C57BL/6J strain but not the 129S6/SvEv strain. The difference is likely due to the different pharmacokinetic profile that was observed between sexes in in C57BL/6J mice – Neurosci Letters
🧠 Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in 5-HT2A-TrkB Heteroreceptor Complexes | Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. 5-HT2A-TrkB heteroreceptor complexes were found to regulate neural development and to be sensitive to 5HT2A function – Cells
⚗ Semisynthetic Transformations on (+)-Boldine Reveal a 5-HT2A/2C Receptor antagonist – J Nat Prod
💣 Pharmacokinetics, Systemic Toxicity, Thermoregulation and Acute Behavioural Effects Of Synthetic Psychedelic, 25CN-Nbome – Addict Biol
🌾 A Short Synthesis of Ergot Alkaloids and Evaluation of the 5-HT 1/2 Receptor Selectivity of Lysergols and Isolysergols – Org Lett
🔮 New Crystal Structure Of "Psychedelic" Serotonin 5HT2A Receptor | bound to the tetrahydropyridine agonist, (R)-69 – RCSB Protein data bank

Psychedelic Research Reviews

Treating Alcohol Use Disorder with Hallucinogens—Renewed Interest After a 50-Year Hiatus - JAMA Psychiatry editorial
Skepticism about Recent Evidence That Psilocybin “Liberates” Depressed Minds - ACS Chem Neuroscience
Psychedelics as potent anti-inflammatory therapeutics - Neuropharmacology
A review on the potential of psychedelics, ketamine and other drugs with abuse liability in the treatment of substance use disorders - Current Addiction Reports
Policy considerations that support equitable access to responsible, accountable, safe, and ethical uses of psychedelic medicines - Neuropharmacology
The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference - Int J Mol Sci

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

Minidosing Lysergic Acid Diethylamide (LSD) for Chronic Cluster Headache - NCT05477459
An Evaluation of Psilocybin's Effect on Cardiac Repolarization - NCT05478278
Efficacy and Safety of COMP360 Psilocybin Therapy in Anorexia Nervosa: a Proof-of-concept Study - NCT05481736
Psilocybin Combined With Multidisciplinary Palliative Care in Demoralized Cancer Survivors With Chronic Pain - NCT05506982
Abuse Potential and Human Pharmacology of Methylone (METI/FIS/1) - NCT05488171
Ketamine Therapy Experiential Education Study (KTEES1) - NCT05468047
MDMA-Assisted Therapy for Stress Disorders in Healthcare Workers - NCT05455996

How do you get from magic mushrooms to a clinical treatment? Cosmos journalist Ellen Phiddian chats to Joshua Ismin and Dr Samuel Banister, the founders of Australian startup Psylo, to learn how they’re hoping to develop medicinal drugs out of psychedelics, and what they’re expecting to see.

Other News

💪 Dying Patients Are Fighting for Access to Psychedelics – Time, 24 August 2022
🍷 Psilocybin, Psychedelic Compound in Magic Mushrooms, Shown Effective for Alcohol Addiction – Wall Street Journal, 24 August 2022
🧠 Psychedelic drugs take on depression – Nature Outlook, 24 August 2022
⭐ Annual US drug survey finds use of psychedelics at a record high – New Atlas, 22 August 2022
🌈 Does Microdosing Actually Work? The Science Is Still Conflicted – Vice, 22 August 2022
👩‍⚖️ The DEA is Attempting to Ban Two New Psychedelic Drugs (psychedelics that are typically only used for research purposes and with very limited abuse history) – Psychedelic Spotlight, 23 August 2022
👭 Psychedelics are having a moment and women could be the ones to benefit – Technology Review, 10 August 2022. psychedelics are showing promise in mental disorders, which tend to have higher prevalence in women, and also for women’s health matters, like postpartum depression, female sexual dysfunction.
👟 What Do Athletes Get From Ayahuasca, Mushrooms and Ecstasy? – Sports Illustrated, 12 August 2022
⚖ Compass Pathways Sued for Stealing Trade Secrets – Psychedelic Spotlight, 10 August 2022
⚠ Psychedelic Clinical Trials and the Michael Pollan Effect – Psychedelic Spotlight, 9 August 2022
🥼 MDMA for PTSD; Psilocybin for Depression; Ketamine for Alcohol use disorder: Three Phase 3 Clinical Trials that Could Legalize Psychedelics – Psychedelic Spotlight, 8 August 2022
🏉 Famous NFL player, Aaron Rodgers, Opens Up About Use of Psychedelics for Mental Health – Sports Illustrated, 3 August 2022
❓ Over the counter culture: Are psychedelics coming to the corner shop? – Independent UK, 6 August 2022
🥽 VR is as good as psychedelics at helping people reach transcendence – MIT Technology Review, 6 August 2022. A VR experience elicited a response indistinguishable from subjects who took medium doses of LSD or magic mushrooms on some key measures.
🗝 Buried Treasure: How Does Psilocybin Reduce Compulsivity? – Psychedelic Science Review, 08 August 2022
🦺 Issues of Patient Safety and Ethical Violations in Psychedelic Therapy – Psychedelic Science Review, 19 August 2022
❤ Ecstasy for the 21st Century: Designer Drugs to Improve MDMA Therapy - Psychedelic Science Review, 26 July 2022
👁 Does the trip matter? Investigating the role of the subjective effects of psychedelics in persisting therapeutic effects – Neuropsychopharmacology Hot Topics, 18 August 2022
🧪 Non-hallucinogenic Psychedelic Analog Design: A Promising Direction for Depression Treatment - Neuroscience Bulletin

PSYLO UPDATES

Sam and Dilara had the fortune of catching up with legendary psychedelic chemist Dr Paul Daley at The Farm; Sasha and Ann Shulgin’s residence and home laboratory in Lafayette, California, where hundreds of new psychedelic compounds were discovered.
Dr Sam Banister, CSO and co-founder, presented at the Brain and Mind Center (University of Sydney) on drug discovery, 17 August 2022
Why UNSW makes up 25% of The Australian’s Top 100 Innovators for 2022 - UNSW Founders Newsletter, 15 August 2022
Psylo was part of the 25% of The Australian’s Top innovators for 2021 from UNSW - The Australian, 10 August 2022
Psychedelic tech: an interview with Psylo - Cosmos Magazine, 1 August 2022

Check out Josh Ismin's interview with Psychedelic Alpha, 19 August 2022

This month we said farewell to Psylo's first intern from the UNSW Business School; Joanne Chen. Joanne did a huge amount of behind-the-scenes coding to revamp the Psylo website, including linking Psylo's new merch store! All proceeds from the sale of Psylo merch are donated to the Black Dog Institute.