Arketamine, a new rapid-acting antidepressant: A historical review and future directions

Neuropharmacology, Journal Year: 2022, Volume and Issue: 218, P. 109219 - 109219

Published: Aug. 14, 2022

The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine causes rapid onset and sustained antidepressant actions in treatment-resistant patients with major depressive disorder (MDD) other psychiatric disorders, such as bipolar post-traumatic stress disorder. is a racemic mixture consisting of (R)-ketamine (or arketamine) (S)-ketamine esketamine), (S)-enantiomer having greater affinity for the NMDAR. In 2019, an esketamine nasal spray by Johnson & was approved USA Europe depression. contrast, increasing number preclinical studies show that arketamine has potency longer-lasting antidepressant-like effects than rodents, despite lower binding Importantly, side effects, i.e., psychotomimetic dissociative abuse liability, are less those animals humans. An open-label study demonstrated MDD. A phase 2 clinical trial MDD underway. This designed to review brief history novel arketamine, molecular mechanisms underlying its actions, future directions. article part Special Issue on 'Ketamine Metabolites'.

Language: Английский

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Functional neuroimaging in psychiatry and the case for failing better

Neuron, Journal Year: 2022, Volume and Issue: 110(16), P. 2524 - 2544

Published: Aug. 1, 2022

Language: Английский

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Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice

ACS Pharmacology & Translational Science, Journal Year: 2022, Volume and Issue: 5(11), P. 1181 - 1196

Published: Nov. 2, 2022

4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present psilocybin-containing mushrooms, including secondary 4-phosphoryloxy-N-methyltryptamine (baeocystin) and quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds not well studied. Here, we investigated structure-activity relationships psilocybin, baeocystin, aeruginascin, as compared to their 4-acetoxy 4-hydroxy analogues, using vitro vivo methods. Broad screening radioligand binding assays transfected cells revealed that with either or substitutions display nanomolar affinity most human 5-HT subtypes tested, 5-HT2A 1A (5-HT1A). The same displayed 5-HT1A mouse brain tissue exhibited efficacy examining 5-HT2A-mediated calcium mobilization β-arrestin 2 recruitment. In experiments, only amines psilocin, 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by antagonist pretreatment, supporting involvement. Both decreased body temperature locomotor higher doses, pretreatment. Across all assays, pharmacological similar, more potent than 4-phosphoryloxy counterparts. Importantly, psilacetin appears be psilocin displays substantial activities its own.

Language: Английский

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Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 154, P. 113612 - 113612

Published: Aug. 30, 2022

The psychedelic 5-HT2A receptor (5HT2AR) agonist psilocybin (or the active metabolite psilocin) has emerged as potential useful drug for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. However, mechanisms responsible such effects remain incompletely characterized. We aimed to study in vitro pharmacological profile and vivo acute mechanism psilocin/psilocybin. Competition binding studies psilocin were performed brain cell cultures. role 5HT2AR, 5-HT2C receptors (5HT2CR) 5-HT1A (5HT1AR) on psychosis-like head-twitch response (HTR) body temperature mice after administration evaluated. Psilocin showed similar affinities 5HT2AR (Ki: 120-173 nM), 5HT2CR 79-311 nM) 5-HT1AR 152-146 human brain. Psilocybin induced dose-dependent HTR (maximal effect 17.07 ± 1.31 at 1 mg/kg i.p.) that was completely suppressed by antagonist MDL11939 (1 mg/kg). Higher doses (3 mg/kg) lower (9.00 0.53). SB242084 (0.1 increased exerted significantly raised core low dose (0.125 (Emax=0.67 0.15 °C), whereas significant decrease over (Emax = -1.31 0.16 °C). Pre-treatment 5HT1AR WAY100635 reversed mg/kg), causing hyperthermia 0.94 0.26 present work provides key findings 5-HT2CR involvement central psilocybin. results may be relevant understanding action underlying side this drug.

Language: Английский

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The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder

The Canadian Journal of Psychiatry, Journal Year: 2022, Volume and Issue: 68(1), P. 5 - 21

Published: Aug. 17, 2022

Objective Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence provide consensus recommendation clinical use of psychedelic Methods A systematic was conducted identify contemporary trials serotonergic treatment disorder cancer-related depression. Studies published between January 1990 July 2021 were identified using combinations search terms, inspection bibliographies other reviews statements. levels efficacy graded according criteria. Results Only psilocybin ayahuasca have evaluating antidepressant effects. Two pilot studies showed preliminary positive effects single-dose treatment-resistant depression (Level 3 evidence). Small randomized controlled combined with psychotherapy superiority waitlist controls comparable safety an active comparator (escitalopram supportive psychotherapy) in disorder, additional showing specifically There only one open-label trial unipolar 4 sample sizes functional unblinding limitations all studies. Adverse events associated psychedelics, psychological (e.g., psychotomimetic effects) physical nausea, emesis headaches) effects, generally transient. Conclusions is currently low-level support In Canada, 2022, remains experimental option that available through or special access program. As such, considers recommends its primarily within trials, or, less commonly, program rare, circumstances.

Language: Английский

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Sustained effects of single doses of classical psychedelics in humans

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 48(1), P. 145 - 150

Published: June 21, 2022

Abstract The serotonergic classical psychedelics include compounds that primarily activate the brain’s serotonin 2 A receptor (5-HT2AR), such as LSD, psilocybin, and DMT (ayahuasca). acute effects of these are well-known their ability to increase emotional state both in healthy people those with neuropsychiatric disorders. In particular psychoactive constituent “magic mushrooms”, has shown great potential for treatment anxiety depression. unique compelling feature is intake just a single psychedelic dose associated long-lasting effects. This includes on personality, e.g., higher openness, amelioration depressive symptoms. review focuses stunning summarizes our current knowledge which behavioral, biochemical, neuroimaging, electrophysiological data support intriguing human brain mind based neural plasticity. also points so far understudied areas suggests research questions be addressed future studies potentially can help understand long-term after (or few) doses.

Language: Английский

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Psychedelics as Transformative Therapeutics

American Journal of Psychiatry, Journal Year: 2023, Volume and Issue: 180(5), P. 340 - 347

Published: May 1, 2023

Over the past decade, psychedelic compounds have emerged as potentially transformative therapeutics for a variety of intractable neuropsychiatric conditions. However, historically most basic science has utilized these probes to interrogate various endogenous neurotransmitter systems-mainly serotonin 5-HT2A receptor. With renewed interest in utilizing and explosion clinical trials, psychedelics been purported treat many disorders, including depression, cluster headaches, migraines, anxiety, obsessive-compulsive disorder. It is therefore imperative understand biology pharmacology behind their therapeutic mechanisms well expose any potential pitfalls widespread use treatments. This review covers latest advances understanding biological mechanisms, newest efforts drug discovery, when it comes this class emerging therapeutics.

Language: Английский

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Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Neuropharmacology, Journal Year: 2023, Volume and Issue: 226, P. 109418 - 109418

Published: Jan. 6, 2023

Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, effective in alleviating symptoms posttraumatic disorder (PTSD), at least some individuals, but have unwanted side-effects do not resolve underlying pathophysiology. After period stagnation, there is renewed enthusiasm from public, academic commercial parties designing developing drug treatments for these disorders. Here, we aim to provide snapshot the current state this field that written neuropharmacologists, also practicing clinicians interested lay-reader. introducing currently available treatments, summarize recent/ongoing clinical assessment novel medicines PTSD, grouped according primary neurochemical targets their potential produce acute and/or enduring effects. The evaluation putative targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic neuropeptide systems, amongst others, discussed. We emphasize importance clinically assessing new medications based on firm understanding neurobiology stemming rapid advances being made neuroscience. This includes harnessing neuroplasticity bring about lasting beneficial changes brain rather than – as many transient attenuation symptoms, exemplified by combining psychotropic/cognitive enhancing drugs psychotherapeutic approaches. conclude noting other emerging trends promising phase development.

Language: Английский

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Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment

Neuropharmacology, Journal Year: 2023, Volume and Issue: 226, P. 109422 - 109422

Published: Jan. 13, 2023

Language: Английский

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Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants

Chemical Reviews, Journal Year: 2023, Volume and Issue: 124(1), P. 124 - 163

Published: Nov. 30, 2023

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated traditional psychedelic substances like psilocybin as class rapid-acting and long-lasting antidepressants. However, there is pressing need for rationally designed 5-HT2AR agonists possess optimal pharmacological profiles in order to fully reveal therapeutic potential these identify safer drug candidates devoid effects. This Perspective provides an overview structure–activity relationships existing based on their chemical classifications discusses recent advancements understanding molecular pharmacology at structural level. The encouraging clinical outcomes psychedelics depression treatment sparked discovery endeavors aimed developing novel with improved subtype selectivity signaling bias properties, which could serve potentially nonhallucinogenic These efforts can be significantly expedited through utilization structure-based methods functional selectivity-directed screening.

Language: Английский

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