Psychedelic medicine has gained rapid popularity for the treatment of a variety of neuropsychiatric disorders, including depression, anxiety, and post-traumatic stress disorder. As novel psychedelic analogues and treatment regimes emerge, increasing numbers of variables are being tested. Here, we review various approaches and considerations for novel psychedelic therapies, including the...
The serotonergic psychedelic N,N-dimethyltryptamine (DMT) produces rapid antidepressant effects in preclinical and early clinical studies. Therapeutic benefits have been linked to sustained neural plasticity, including adult neurogenesis in rodents. Whether brief DMT exposure engages proliferative responses in human neural stem cells (NSCs) remains unresolved. Using human iPSC-derived NSCs, we...
Psychedelics have re-emerged as promising therapeutics for neuropsychiatric disorders, including depression, anxiety, post-traumatic stress disorder, and substance use disorders. While their beneficial effects are largely attributed to serotonin 2A (5-HT2A) receptor activation, psychedelics exhibit substantial diversity in chemical structure, receptor binding kinetics, metabolism, and duration...
High Resolution Image Download MS PowerPoint Slide Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT 2A ), but the compounds are generally nonselective. 4-Methoxy- N -methyl- N -isopropyltryptamine (4-MeO-MiPT) is a 5-HT 2A agonist which also blocks the 5-HT transporter (SERT) and has blunted visual and other psychedelic effects in humans....
Neuroplastogens, small molecules that induce beneficial neuronal growth and plasticity, are a class of compounds emerging as new drugs for treating a range of central nervous system conditions. Clausenamide is a plasticity-promoting natural product isolated from the leaves of Clausena lansium, an evergreen native to Southeast Asia and southern China. Herein, we report an efficient synthesis of...
Recent clinical evidence suggests that racemic 3,4-methylenedioxymethamphetamine (MDMA) might be useful for treating a range of neuropsychiatric diseases including post-traumatic stress disorder (PTSD) and depression. However, concerns about its abuse potential stemming from its monoamine releasing properties have hampered its clinical development. Thus, safer analogues of racemic MDMA with...
N-Benzyl-derived phenethylamines are highly active (psychedelic) 5-HT2AR (serotonin 2A receptor) agonists used as biochemical tools and on the drug market. The impact of adding an N-benzyl substituent to the tryptamine core structure has scarcely been studied. A recent systematic exploration of N-benzyl-substituted (5-MeO-)tryptamines revealed a surprisingly low activity in a Ca2+ mobilization...
Correction 1: Table 1.The analyses were conducted using the correct data, and all results, interpretations, and conclusions in the paper remain fully accurate.The issue is limited to the presentation of values in the table.Correction 2: p 4733, second paragraph, 1 st sentence.Thigmotaxis was evaluated to assess potential anxiety-like effects induced by the compounds.When comparing the tested...
To support ongoing clinical trials, the major human metabolites of psilocybin were synthesized on a preparative scale, specifically psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA), along with putative minor metabolites and several deuterium-labeled derivatives. Psilocybin, psilocin, psilocin-O-glucuronide, and 4-HIAA were assayed for engagement at seven serotonin receptor...
High Resolution Image Download MS PowerPoint Slide The development of new treatments for neuropsychiatric disorders relies on a deeper understanding of the molecular mechanisms behind psychedelic compounds, particularly how they differentiate between hallucinogenic and antidepressant effects. In this study, we explore by molecular dynamics simulations a series of 25CN-NBx compounds bound to the...
Perspectives surrounding Cannabis use have transformed over the past decade. This shift in perspective has been noted in pregnant populations in Canada and the US, where various investigations report that the use of Cannabis in pregnancy is increasingly commonplace. There is some evidence indicating that Δ9-tetrahydrocannabinol (THC), the main intoxicating phytocannabinoid found within Cannabis...
This review aims to evaluate the pharmacological properties, mechanistic selectivity, and early clinical development of zalsupindole, highlighting its potential as a next-generation psychiatric therapeutic. This review was conducted using a structured literature search strategy across PubMed, Google Scholar, ClinicalTrials.gov, and the official Web sites of regulatory bodies and pharmaceutical...
Psychedelics are a diverse class of psychoactive compounds that profoundly alter perception, cognition, and emotional states. Recently, classical serotonergic agents, such as psilocybin and lysergic acid diethylamide (LSD), along with atypical agents such as methylenedioxymethamphetamine (MDMA, ecstasy) and ibogaine, have attracted renewed attention due to their rapid and sustained clinical...
The distinct subjective effects that define psychedelics such as lysergic acid diethylamide (LSD), psilocybin, or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) as drug class are causally linked to the activation of the serotonin 2A receptor (5-HT 2A R). However, some aspects of 5-HT 2A R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from...
α-Ethyltryptamine (AET), a synthetic tryptamine formerly used as an antidepressant, has resurfaced as a compound of interest due to its structural and functional overlap with serotonergic psychedelics and entactogens. Here, we characterized the pharmacological properties of racemic AET and its optical isomers, R(-)-AET and S(+)-AET, focusing on their interactions with the serotonin (or...
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, shows promise in treating depression and post-traumatic stress disorder (PTSD), resulting in breakthrough status. However, concerns regarding MDMA's abuse potential and cytotoxicity have sparked interest in developing safer analogues with similar therapeutic benefits. This study investigated the pharmacological properties of...
Psychedelic drugs have begun to show therapeutic promise. However, there is a growing research effort focused on creating nonhallucinogenic analogs of these substances. The goal is to develop new treatments for an expanding list of psychiatric and neurodegenerative disorders, while eliminating the complications and costs of treatment engendered by the subjective psychedelic experience....
Exogenously administered psychedelics produce both rapid and long-lasting effects on neuroplasticity and behavior, but it is currently unclear if endogenously produced psychedelics can elicit similar effects. There have been relatively few studies on the role of endogenous psychedelics in health and disease, perhaps owing to the difficulty in quantifying their levels and manipulating their...
ACS Chemical NeuroscienceOctober 13, 2025Rajiv Agrawal, Daniel J. Gillie, Alison E. Mungenast et al.8 citations
Many neuropsychiatric conditions, including depression, involve synaptic loss and atrophy of the prefrontal cortex. The rapid regrowth of cortical neurons has been hypothesized to explain the rapid and enduring therapeutic effects of psychedelics and the dissociative anesthetic ketamine. However, safety concerns related to hallucinogenic/dissociative properties have limited the addressable...
The serotonin 2C receptor (5-HT 2C ) is a G protein-coupled receptor implicated in multiple physiological and psychological processes and has been investigated as a therapeutic target for neuropsychiatric conditions such as obesity, drug abuse, and depression. With renewed interest in serotonergic psychedelics for treating depression, 5-HT 2C may contribute to psychedelic-induced therapeutic...
Tropane alkaloids and their derivatives represent a diverse class of small molecules with a broad range of therapeutic applications. Many tropanes regulate synaptic levels of neuromodulators by interacting with monoamine transporters such as dopamine (DAT) and serotonin (SERT) transporters. While DAT inhibition plays an important role in the addictive potential of tropanes such as cocaine,...
This research focuses on the promising use of esketamine in perinatal depression, a widespread disorder impacting postpartum women's mental health. Despite esketamine's known rapid antidepressant effects, its precise mechanisms are not fully understood. This study integrates clinical and preclinical approaches to explore esketamine's efficacy in treating perinatal depression and its actions...
This viewpoint reconceptualizes mysticism and fundamentalism as brain network disorders, with psychedelics like psilocybin, lysergic acid diethylamide, and N,N-dimethyltryptamine offering potential to modulate these states. By disrupting rigid neural patterns, psychedelics may foster cognitive flexibility, challenge inflexible belief systems, and offer therapeutic value for extremism and mental...
Classic psychedelics and the gut microbiome interact bidirectionally through mechanisms involving 5-HT2A receptor signaling, neuroplasticity, and microbial metabolism. This viewpoint highlights how psychedelics may reshape microbiota and how microbes influence psychedelic efficacy, proposing microbiome-informed strategies─such as probiotics or dietary interventions─to personalize and enhance...