The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(2), С. 1329 - 1329

Опубликована: Янв. 10, 2023

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties finding new drugs have led pharmacologists review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists psilocybin or lysergic acid diethylamide obsessive-compulsive disorder, depression, post-traumatic stress although results are not always clear definitive. fact, mechanisms action psychedelics yet fully understood molecular aspects be well defined. Thus, this aims summarize ethnobotanical uses best-known psychedelic plants pharmacological main active ingredients they contain. Furthermore, an up-to-date overview structural computational studies performed evaluate affinity binding modes biologically relevant receptors ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, presented. Finally, most recent clinical evaluating efficacy molecules discussed compared with already used therapy.

Язык: Английский

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UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice

Neuropsychopharmacology, Год журнала: 2023, Номер 48(12), С. 1798 - 1807

Опубликована: Май 29, 2023

Язык: Английский

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Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain

Molecular Psychiatry, Год журнала: 2024, Номер 29(7), С. 2059 - 2073

Опубликована: Фев. 20, 2024

Psilocybin, a naturally occurring, tryptamine alkaloid prodrug, is currently being investigated for the treatment of range psychiatric disorders. Preclinical reports suggest that biological effects psilocybin-containing mushroom extract or "full spectrum" (psychedelic) (PME), may differ from those chemically synthesized psilocybin (PSIL). We compared PME to PSIL on head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar over 20 min. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed proteins, GAP43, PSD95, synaptophysin SV2A, using western blots. These serve as indicators plasticity. Three days after treatment, there was minimal increase proteins. After 11 days, significantly increased GAP43 (p = 0.019; p 0.039 respectively) hippocampus 0.015; 0.027) 0.041; 0.05) amygdala 0.035; 0.004). SV2A 0.036) did so 0.014). In striatum, by only 0.023). There no significant PSD95 any brain area when these analyzed separately. Nested analysis variance (ANOVA) each 4 all areas versus vehicle control, while observed limited SV2A. Metabolomic analyses pre-frontal performed untargeted polar metabolomics utilizing capillary electrophoresis - Fourier transform mass spectrometry (CE-FTMS) differential metabolic separation between groups. The purines guanosine, hypoxanthine inosine, associated with oxidative stress energy production pathways, progressive decline VEH PME. conclusion, our protein findings has more potent prolonged effect plasticity than PSIL. Our data support gradient inert via chemical further supporting effects. Further studies are needed confirm extend identify molecules be responsible enhanced alone.

Язык: Английский

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Psychedelic-like Activity of Norpsilocin Analogues

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(2), С. 315 - 327

Опубликована: Янв. 8, 2024

Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT2A) in vitro but differ their 5-HT2A-mediated effects vivo. In particular, produces centrally mediated psychedelic vivo, whereas norpsilocin, differing only by loss an N-methyl group, is devoid psychedelic-like effects. These observations suggest that secondary methylamine group norpsilocin impacts its central nervous system (CNS) bioavailability not pharmacodynamics. To test this hypothesis, eight derivatives were synthesized with varied alkyl-, allyl-, benzylamine groups, primarily aiming to increase lipophilicity brain permeability. Structure–activity relationships for analogues evaluated using mouse head-twitch response (HTR) as a proxy CNS-mediated HTR studies revealed extending single methyl give corresponding N-ethyl analogue (4-HO-NET), was sufficient produce psilocin-like (median effective dose or ED50 = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, N-benzyl also induced (ED50 1.1–3.2 mg/kg), variable maximum (26–77 total events). By contrast, adding bulkier tert-butyl cyclohexyl groups same position did elicit HTRs. Pharmacological assessments tryptamine series demonstrated interactions multiple subtypes, including 5-HT2A, other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements analogues.

Язык: Английский

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Psychedelic Therapy: A Primer for Primary Care Clinicians—Psilocybin

American Journal of Therapeutics, Год журнала: 2024, Номер 31(2), С. e121 - e132

Опубликована: Март 1, 2024

Background: The primary psychoactive drug in magic mushrooms, psilocybin, induces profound alterations consciousness through the 5-HT 2A receptor. This review consolidates current research findings to elucidate pharmacology, safety profile, and clinical applications of psilocybin. Areas Uncertainty: Despite initial concerns that psilocybin could cause psychosis, contemporary has demonstrated is generally safe. most common adverse effects are nausea headache, yet both tend be transient. Serious events can avoided controlled settings such as trials. However, largest trial date, there were a total 7 reported cases suicidal ideation, up 12 weeks after receiving single 25 mg dose That being said, all did not respond treatment. Although selective serotonin reuptake inhibitors may blunt hallucinogenic qualities preliminary suggests they enhance its antidepressant effects. Therapeutic Advances: In trials, shown promise for treating major depressive disorder treatment-resistant depression. Initial studies indicated 42%–57% patients underwent remission psilocybin-assisted therapy, which more effective than existing medications. Clinical data have also manage substance use disorders end-of-life anxiety with outcomes sustained months sometimes years 1 or 2 doses. Limitations: larger Phase II trials 100 depressed participants much smaller rate 25%–29%, though these still observed causes significant reduction symptoms. Conclusions: Aside from ketamine, clinically well-researched psychedelic drug, enrolled hundreds multiple therapeutic applications. III will determine whether lives it showed previous

Язык: Английский

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Molecular insights into the modulation of the 5HT_2A receptor by serotonin, psilocin, and the G protein subunit Gqα

FEBS Letters, Год журнала: 2025, Номер unknown

Опубликована: Янв. 26, 2025

5HT 2A R is a G‐protein‐coupled receptor that drives many neuronal functions and target for psychedelic drugs. Understanding ligand interactions conformational transitions essential developing effective pharmaceuticals, but mechanistic details of activation remain poorly understood. We utilized all‐atom molecular dynamics simulations free‐energy calculations to investigate R's upon binding serotonin psilocin. show the active state collapses closed in absence Gqα, underscoring importance G‐protein coupling. discover an intermediate “partially‐open” conformation. Both ligands have higher affinities orthosteric than extended pocket. These findings enhance our understanding may aid novel therapeutics. Impact statement This study sheds light on activation, revealing conformations dynamics. insights could drug development neurological psychiatric disorders, benefiting researchers clinicians pharmacology neuroscience.

Язык: Английский

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The risk of chronic psychedelic and MDMA microdosing for valvular heart disease

Journal of Psychopharmacology, Год журнала: 2023, Номер 37(9), С. 876 - 890

Опубликована: Авг. 12, 2023

Psychedelic microdosing is the practice of taking very low doses psychedelic substances, typically over a longer period time. The long-term safety chronic relatively uncharacterized, but valvular heart disease (VHD) has been proposed as potential risk due to activation serotonin 5-HT 2B receptor. However, this not yet comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related VHD lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds some metabolites could bind receptor with potency equal or greater than that 2A receptor, primary target psychedelics. were partial agonists at exception which be adequately assessed potency. Safety margins relative maximum plasma concentrations from typical microdoses known valvulopathogens, without risk. No animal appropriately designed evaluate found four there evidence ingestion full MDMA associated VHD. We conclude microdosing, further are necessary better define

Язык: Английский

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Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs

Neuropharmacology, Год журнала: 2023, Номер 233, С. 109528 - 109528

Опубликована: Апрель 2, 2023

Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and contributor to opioid overdose in the United States. For many people, can be satisfactorily managed by existing medicines comprehensive psychosocial treatments. others, available treatments are either ineffective or not acceptable, due side effects concerns about risks. Preliminary evidence suggests that some psychedelics may effective for certain types and/or improved quality life with increased functionality disability distress people whose never completely relieved. Efficacy these quality-of-life related outcomes would consistent 'reset thinking' chronic management being increasingly called as more realistic goal compared complete elimination pain. This commentary summarizes rationale conducting basic research clinical trials further explore potential management. Additionally, if shown effective, then determine whether primarily direct antinociceptive anti-inflammatory mechanisms, via tolerability, acceptance, sense spirituality, appear at least partially mediate therapeutic observed psychiatric disorders such major depression. represents collaboration scientists examining issues developing recommendations ranging from neuropharmacology biopsychosocial treatment factors important depression other which psychedelic under development. article part Special Issue on "National Institutes Health Psilocybin Research Speaker Series".

Язык: Английский

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Alkoxy chain length governs the potency of 2-benzylbenzimidazole ‘nitazene’ opioids associated with human overdose

Psychopharmacology, Год журнала: 2023, Номер 240(12), С. 2573 - 2584

Опубликована: Сен. 2, 2023

Язык: Английский

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Cardiovascular safety of psychedelic medicine: current status and future directions

Pharmacological Reports, Год журнала: 2023, Номер 75(6), С. 1362 - 1380

Опубликована: Окт. 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.

Язык: Английский

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