Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 15, 2023

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 recruitment efficacy predicts potential, assessed using head-twitch response (HTR) magnitude in male mice. further disrupting Gq-PLC signaling attenuates the HTR threshold level is required to induce psychedelic-like consistent fact certain partial agonists (e.g., lisuride) are non-psychedelic. Understanding role Gq-efficacy psychopharmacology permits rational development non-psychedelic agonists. also demonstrate block effects downregulation tachyphylaxis. Overall, Gq-signaling can be fine-tuned generate distinct from classical psychedelics.

Language: Английский

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Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis

Psychiatry Research, Journal Year: 2024, Volume and Issue: 335, P. 115886 - 115886

Published: March 28, 2024

Language: Английский

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Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102211 - 102211

Published: Feb. 1, 2024

Language: Английский

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Cardiovascular safety of psychedelic medicine: current status and future directions

Pharmacological Reports, Journal Year: 2023, Volume and Issue: 75(6), P. 1362 - 1380

Published: Oct. 24, 2023

Abstract Psychedelics are powerful psychoactive substances that alter perception and mood processes. Their effectiveness in the treatment of psychiatric diseases was known before their prohibition. An increasing number recent studies, due to indisputable resurgence serotonergic hallucinogens, have shown efficacy alleviating depression, anxiety, substance abuse therapies, existential distress patients facing life-threatening illness. generally considered be physiologically safe with low toxicity addictive potential. However, agonism at receptors should context possible serotonin-related cardiotoxicity (5-HT2A/2B 5-HT4 receptors), influence on platelet aggregation (5-HT2A receptor), proarrhythmic The use psychedelics has also been associated significant sympathomimetic effects both experimental clinical studies. Therefore, present review aims provide a critical discussion cardiovascular safety psilocybin, d-lysergic acid diethylamide (LSD), N,N-dimethyltryptamine, ayahuasca, mescaline, based results research trials humans. Experimental studies inconsistent information potential psychedelics. Data from point relative psychedelic-assisted therapies population “healthy” volunteers. there is insufficient evidence carried out microdoses psychedelics, still lack data disease. exact determination psychedelic (especially long-term therapies) requires further research.

Language: Английский

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Stimulant and hallucinogenic novel psychoactive substances; an update

Expert Review of Clinical Pharmacology, Journal Year: 2023, Volume and Issue: 16(11), P. 1109 - 1123

Published: Nov. 2, 2023

Introduction The renewed interest in considering a range of stimulants, psychedelics and dissociatives as therapeutics emphasizes the need to draft an updated overview these drugs' clinical pharmacological issues.

Language: Английский

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Anxiolytic-like effect of succinic acid: A possible GABAergic intervention

Food Bioscience, Journal Year: 2023, Volume and Issue: 55, P. 103044 - 103044

Published: Aug. 12, 2023

Language: Английский

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Pharmacokinetics and Pharmacodynamics of an Innovative Psychedelic N,N-Dimethyltryptamine/Harmine Formulation in Healthy Participants: A Randomized Controlled Trial

The International Journal of Neuropsychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Background Recent interest in the clinical use of psychedelics has highlighted plant-derived medicines like ayahuasca showing rapid-acting and sustainable therapeutic effects various psychiatric conditions. This traditional Amazonian plant decoction contains N,N-dimethyltryptamine (DMT) β-carboline alkaloids such as harmine. However, its is often accompanied by distressing nausea, vomiting, intense hallucinations, possibly due to complex pharmacokinetic/pharmacodynamic (PK-PD) interactions lack dose standardization. Methods study addresses these limitations testing a novel pharmaceutical formulation containing pure forms DMT harmine double-blind, randomized, placebo-controlled trial with 31 healthy male volunteers. We evaluated PK-PD monitoring drug metabolite plasma levels, subjective effects, adverse events, cardiovascular parameters. Each participant received three randomized treatments: 1) 100 mg buccal intranasal DMT, 2) placebo, 3) full placebo; using repeated-intermittent dosing scheme, that 10 (or placebo) was administered every 15 minutes. Results produced consistent PK profiles Cmax values 22.1 ng/ml acute resembling psychological duration 2–3 hours. Likewise, sustained-release 32.5 ng/ml, but lacked distinguishable compared placebo. All conditions were safe well tolerated, indicating formulation's suitability for applications. Conclusion underscores potential patient-oriented reduce risks improve outcomes treating mental health disorders.

Language: Английский

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N, N-dimethyltryptamine (DMT) in rodent brain: Concentrations, distribution, and recent pharmacological data

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown, P. 111259 - 111259

Published: Jan. 1, 2025

Language: Английский

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Effects of psychedelics on opioid use disorder: a scoping review of preclinical studies

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: Jan. 21, 2025

The current opioid crisis has had an unprecedented public health impact. Approved medications for use disorder (OUD) exist, yet their limitations indicate a need innovative treatments. Limited preliminary clinical studies suggest specific psychedelics might aid OUD treatment, though most evidence remains observational, with few controlled trials. This review aims to bridge the gap between preclinical findings and potential applications, following PRISMA-ScR guidelines. Searches included MEDLINE, Embase, Scopus, Web of Science, focusing on in vivo involving opioids animals, excluding pain those lacking control groups. Forty met criteria, covering both classic non-classic psychedelics. Most showed that 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, ketamine could reduce self-administration, alleviate withdrawal symptoms, change conditioned place preference. However, seven (two 2,5-dimethoxy-4-methylamphetamine (DOM), three one 18-MC, ketamine) no improvement over controls. A methodological quality assessment rated as having unclear quality. Interestingly, are limited iboga derivatives, which were effective, but these agents may have higher cardiovascular risk than other under-explored date. strengthens support translational testing targets OUD. It also suggests include broader range beyond derivatives can explore several ongoing questions field, such mechanism action behind therapeutic effect, safety profiles, doses, frequency administrations needed.

Language: Английский

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Exploring psilocybin’s role in mental health and palliative medicine: a path to improved well-being

Expert Opinion on Emerging Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Although long known for their psychoactive effects, psychedelic drugs have only recently been investigated medicinal use. Psilocybin has attracted the greatest interest with studies suggesting that it may be a useful agent in psychiatry and palliative care. Clinical trials included psilocybin were searched PubMed, Embase, ClinicalTrials.gov, demonstrating adult care are medical fields show treatment. is powerful drug needs to used caution but benefit some patients, including when other options failed. It best evidenced treatment resistant depression care, where patients usually treated specialist centers. novel mechanism of action, targeting 5HT2A receptor, can rapid onset action. There many questions regarding its use remain clarified, efficacy indications role as adjunctive psychotherapy. The psychoactive, or effects well documented, clinical importance disputed.

Language: Английский

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