Disorders of consciousness (DoC) are a challenging and complex group of neurological conditions characterised by absent or impaired awareness. The current range of therapeutic options for DoC patients is limited, offering few non-invasive pharmacological alternatives. This situation has sprung a growing interest in the development of novel treatments, such as the proposal to study the efficacy...
Abstract Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. One lesser studied psychedelic, the 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), is suggested to have anxiolytic effects yet a comprehensive mechanism of action is still lacking. Here, we investigated the...
Abstract Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased...
Abstract Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could...
Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal...
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in...
bioRxiv Preprint ServerNovember 7, 2023Kelly E. Dunham, Kani H. Khaled, Leah Weizman et al.
preprint
Recently, the FDA approved microdosing ketamine for treatment resistant depression. Traditional antidepressants, like serotonin selective reuptake inhibitors (SSRIs), block serotonin reuptake, but it is not clear if ketamine blocks serotonin reuptake. Here, we tested the effects of feeding ketamine and SSRIs to Drosophila melanogaster larvae, which has a similar serotonin system to mammals, and...
CureusNovember 1, 2023Maninder Sohi, Lakshit Jain, Michael Ang-Rabanes et al.
Major depressive disorder (MDD) is associated with both insomnia and hypersomnia, but it predominantly decreases sleep continuity and leads to a decrease in rapid eye movement (REM) latency, an increase in REM sleep duration, and an increase in REM density. Some of these changes persist even when MDD is treated and can be associated with a recurrence of MDD. Antidepressants can potentially...
Most of the recent work in psychedelic neuroscience has been done using non-invasive neuroimaging, with data recorded from the brains of adult volunteers under the influence of a variety of drugs. While this data provides holistic insights into the effects of psychedelics on whole-brain dynamics, the effects of psychedelics on the meso-scale dynamics of cortical circuits remains much less...
ABSTRACT Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2 A receptors (5-HT2 A Rs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than...
Addressing the significant challenges of treating depression, anxiety, and substance abuse, this Patent Highlight explores the development of innovative small-molecule heterocyclic compounds as Gq-biased agonists of the 5-HT2A receptor. Unlike traditional treatments, these compounds selectively activate 5-HT2A-mediated Gq signaling, excluding related receptors like 5-HT2B and 5-HT2C. This...
PsychopharmacologyOctober 19, 2023Arya Rahbarnia, Zhaoxia Li, Paul J Fletcher9 citations
Neuropsychiatric disorders such as depression are characterized in part by attention deficits. Attention is modulated by the serotonin (5-HT) neurotransmitter system. The 5-HT2A agonist and hallucinogen psilocybin (PSI) is a promising treatment for disorders characterized by attention changes. However, few studies have investigated PSI's direct effect on attention. Using the rodent continuous...
Psychedelics could have revolutionary potential in psychiatry, although, until recently, the pharmacodynamic properties of such compounds have not seemed to differ much from those of serotonin, whose levels are raised by Serotonin Reuptake Inhibitors (SSRI). The cardinal point is that serotonergic compounds, such as antidepressive drugs, do not have the potential to induce long-lasting...
Introduction Serotonergic psychedelics such as ayahuasca are reported to promote both structural and functional neural plasticity via partial 5-HT 2A agonism. However, little is known about how these molecular mechanisms may extend to repeated psychedelic administration in humans, let alone neuroanatomy. While early evidence suggests localised changes to cortical thickness in long-term...
Psilocybin is a 5-HT2AR agonist, responsible for the psychoactive effects of psychedelic mushrooms, which has recently shown therapeutic potential for several conditions, including major depressive disorder. However, the mechanisms underlying this effect, and the possibility of dissociating the psychedelic and antidepressant actions of psilocybin, remain undetermined, with preclinical research...
Serotonergic psychedelics (SP) such as psilocybin, LSD or DMT pose significant potential for development of new strategies in treating neuropsychiatric disorders including major depression disorder, post-traumatic stress disorder and addiction. To bring these substances to clinical application, however, better understanding of the mechanisms behind their effects on many levels, including...
The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic...
The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or...
Interest in the use of serotonergic agonists such as psilocybin in treatment-resistant depression (TRD) has grown more quickly than the evidence on which to base a final opinion, as emphasized by McIntyre et al1 in their review. Psilocybin, once metabolized to psilocin, activates 5-HT2A receptors, enhancing GABA function in local circuits in the cortex and increasing connectivity between...
Tryptamines, a class of 3-aminoethyl-indoles that activate the serotonin receptor, show potential for novel mental health treatments. The FDA has granted "breakthrough therapy designation" to psilocybin and MDMA for treatment-resistant depression, major depressive disorder, and post-traumatic stress disorder, sparking global research efforts. Various clinical trials are currently investigating...