ACS Chemical Neuroscience - The Consciousness Library

Next-Generation Psychedelic Drug Development

ACS Chemical Neuroscience September 15, 2026 Lindsay P. Cameron, Matthew W. Johnson, Kevin S. Murnane et al.

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...

DOI: 10.1021/acschemneuro.6c00492 Full text

Proliferative Effects of the Psychedelic N,N-Dimethyltryptamine (DMT) in Human Neural Stem Cells.

ACS Chemical Neuroscience July 9, 2026 José Alexandre Salerno, Elizabeth R. Dominguez, Karina Karmirian et al.

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...

DOI: 10.1021/acschemneuro.6c00209 Full text Bdnf N,N-Dimethyltryptamine DMT Cell cycle Neurosphere

Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics.

ACS Chemical Neuroscience June 17, 2026 Anoushka Bhat, Elmira Zolali, Mahfuz A Sakib et al.

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...

DOI: 10.1021/acschemneuro.6c00202 Full text Psilocybin 5-ht2a Long-acting Psychedelics +1

Serotonin Transporter Blockade Reduces the Psychedelic-Like Effects of 4-Methoxy- N -methyl- N -isopropyltryptamine and Related Analogs

ACS Chemical Neuroscience May 27, 2026 Grant C. Glatfelter, Serena S. Schalk, Donna Walther et al.

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....

DOI: 10.1021/acschemneuro.6c00083 Serotonin transporter Tryptamine Partial agonist Blockade +8

R-MDDMA is a Safer Analogue of MDMA with Therapeutic Potential.

ACS Chemical Neuroscience May 6, 2026 Maxemiliano V. Vargas, Cassandra J. Hatzipantelis, Lee E. Dunlap et al.

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...

DOI: 10.1021/acschemneuro.5c00891 Full text MDMA PTSD Depression Mddma +3

N-Benzyl-tryptamine Derivatives as Serotonin 5-HT2A Receptor (5-HT2AR) Agonists: Focus on Different In Vitro 5-HT2AR Activity Profiles.

ACS Chemical Neuroscience March 20, 2026 E. Pottie, Emma Vertriest, Darío Martínez-afani et al.

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...

DOI: 10.1021/acschemneuro.5c00352

Synthesis and Characterization of Psilocybin Metabolites and Deuterated Analogs

ACS Chemical Neuroscience March 3, 2026 Samuel E. Williamson, Elise K. Burkhartzmeyer, Michael T. Faley et al.

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...

DOI: 10.1021/acschemneuro.5c00879 Psilocybin Serotonin Hallucinogen Metabolite +7

Rewiring Receptor Activation: Mechanistic Insights into Toggle Switch Modulation by 25CN-NBx Compounds

ACS Chemical Neuroscience February 18, 2026 Vito F. Palmisano, Micaela Vidal−sánchez, Juan J. Nogueira

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...

DOI: 10.1021/acschemneuro.6c00023 Dihedral angle Molecular dynamics Receptor Molecular mechanics +4

Adult Rat Offspring Exposed to THC during Gestation Exhibit Distinct Biomolecular Changes Identified by X-ray Fluorescence Imaging and Fourier Transform Infrared Spectroscopy in Cortico-Limbic Circuits.

ACS Chemical Neuroscience February 18, 2026 Tallan Black, Rhiannon E Boseley, Amanda Quirk et al.

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...

DOI: 10.1021/acschemneuro.5c00752 Full text Cannabis Gestational Neurodevelopment Phytocannabinoids +2

Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics.

ACS Chemical Neuroscience January 21, 2026 Miguel Salfiti, Marios Kyriazis, Georgios Mikellides 2 citations

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...

DOI: 10.1021/acschemneuro.5c00707 Full text Neuroplasticity 5-ht2a Aaz-a-154 Dlx-001 +4

Snapshot IP 1 Detection Following 5-HT 2 A Receptor Stimulation in the Mouse Brain

ACS Chemical Neuroscience January 2, 2026 Mario de la Fuente Revenga, Javier González-Maeso 1 citation

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...

DOI: 10.1021/acschemneuro.5c00932

Dual Modulation of 5-HT2A Receptors and SERT by α-Ethyltryptamine and Its Optical Isomers.

ACS Chemical Neuroscience December 17, 2025 Justin M Silverman, Michael Fiorillo, Jason Younkin et al. 1 citation

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...

DOI: 10.1021/acschemneuro.5c00468 Full text 5-ht2a receptor G protein-coupled receptor Head-twitch response Psychedelics +3

Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights

ACS Chemical Neuroscience December 2, 2025 Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.

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...

DOI: 10.1021/acschemneuro.5c00782 MDMA Norepinephrine transporter Monoamine neurotransmitter Dopamine transporter +8

Indolethylamine N-Methyltransferase Deletion Impacts Mouse Behavior without Disrupting Endogenous Psychedelic Tryptamine Production.

ACS Chemical Neuroscience October 15, 2025 Cassandra J. Hatzipantelis, Lindsay P. Cameron, Min Liu et al.

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...

DOI: 10.1021/acschemneuro.5c00384 Full text DMT Inmt N,N-Dimethyltryptamine Temt +4

Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics

ACS Chemical Neuroscience October 13, 2025 Rajiv 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...

DOI: 10.1021/acschemneuro.5c00667

Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter.

ACS Chemical Neuroscience September 3, 2025 Arabo A. Avanes, Hunter T Warren, Abinaya Senthil et al. 2 citations

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,...

DOI: 10.1021/acschemneuro.5c00443 Full text MDMA Noribogaine Sert Ssri +3

Exploring Esketamine's Therapeutic Role for Perinatal Depression via TASK-1 Tandem Pore Potassium Channels.

ACS Chemical Neuroscience July 29, 2025 Lin Zhu, Ji Chen, Yuan Liu et al. 1 citation

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...

DOI: 10.1021/acschemneuro.5c00535 Full text Synaptic plasticity Neuroinflammation New approach Lowers depression scores +8

Psychedelics, Spirituality, and Fundamentalism: A Brain Network Approach to Cognitive Flexibility and Rigidity

ACS Chemical Neuroscience July 24, 2025 Anjian Yang, Xinyou Lv, Hongshuang Wang et al. 1 citation

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...

DOI: 10.1021/acschemneuro.5c00509 Extremism Fundamentalism Terrorism Rigid thinking +10

Psychedelics and the Gut Microbiome: Unraveling the Interplay and Therapeutic Implications.

ACS Chemical Neuroscience July 9, 2025 Xue Wang, Fan Jun, Cong Lin et al. 4 citations

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...

DOI: 10.1021/acschemneuro.5c00418 Full text Psilocybin Gut microbiome Gut−brain axis Inflammation +11

Neurochemical, Neurocircuitry, and Psychopathological Mechanisms of PTSD: Emerging Pharmacotherapies and Clinical Perspectives.

ACS Chemical Neuroscience June 10, 2025 Santosh Kumar Prajapati, Shreyasi Majumdar, Snehapriya Murari et al. 14 citations

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition triggered by exposure to traumatic events, with complex neurobiological anomalies that remain incompletely understood. This review aims to comprehensively explore the neurocircuitry, neurochemical dysregulation, and emerging pharmacological targets associated with PTSD, offering a consolidated framework for developing...

DOI: 10.1021/acschemneuro.5c00335 Full text Post-traumatic stress disorder Serotonin Glutamatergic system Hypothalamic–pituitary–adrenal-axis +4

Classic Psychedelics in Pain Modulation: Mechanisms, Clinical Evidence, and Future Perspectives

ACS Chemical Neuroscience June 6, 2025 Anna Czopek, Jakub Jończyk, Monika Fryc et al. 9 citations

Millions worldwide suffer from chronic pain, a complex condition often accompanied by depression and anxiety, highlighting the urgent need for innovative treatments. Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), primarily act on serotonin 5-HT2A receptors and have emerged as potential modulators of pain perception and mood...

DOI: 10.1021/acschemneuro.5c00152 Psychotherapist

Exploring the Role of Psychedelics in Modulating Ego and Treating Neuropsychiatric Disorders.

ACS Chemical Neuroscience May 7, 2025 Hongshuang Wang, Xiaohui Wang 5 citations

This viewpoint explores the therapeutic potential of psychedelics in treating neuropsychiatric disorders, particularly through the modulation of brain entropy and the experience of ego dissolution. Psychedelics disrupt rigid neural patterns, facilitating enhanced connectivity and fostering profound emotional breakthroughs that may alleviate symptoms of disorders like depression, anxiety, PTSD,...

DOI: 10.1021/acschemneuro.5c00247 Full text Default mode network Lysergic acid diethylamide Psilocybin LSD +9

Discovery of a Novel Orally Active Ketamine Derivative with Dual Analgesic and Antidepressant Activities, Lacking Psychomimetic Effects.

ACS Chemical Neuroscience March 5, 2025 Syed Muzzammil Masaud, Humaira Nadeem, Babar Murtaza et al. 3 citations

This study investigated the synthesis, characterization, and in silico analysis of novel N-acetamide ketamine derivatives aimed at evaluating their analgesic, anesthetic, and antidepressant properties. The synthesis commenced with the preparation of chloroacetylamide derivatives, which were subsequently reacted with ketamine hydrochloride, yielding 16 derivatives k1 to k16. These compounds were...

DOI: 10.1021/acschemneuro.4c00887 Full text Anesthetic Psychomimetic Pain-relief analgesic Pain management +6

Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice.

ACS Chemical Neuroscience December 18, 2024 Grant C. Glatfelter, Allison A Clark, Natalie G. Cavalco et al. 14 citations

5-methoxy-N,N-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its N-alkyl, N-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the...

DOI: 10.1021/acschemneuro.4c00513 Full text 5-MEO-DMT Brain chemistry 5-ht1a 5-ht2a +6

Effects of a Serotonergic Psychedelic on the Lipid Bilayer.

ACS Chemical Neuroscience October 21, 2024 Debsankar S. Saha Roy, Ankit Singh, V. Vaidya et al.

Serotonergic psychedelics, known for their hallucinogenic effects, have attracted interest due to their ability to enhance neuronal plasticity and potential therapeutic benefits. Although psychedelic-enhanced neuroplasticity is believed to require activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs), serotonin itself is less effective in promoting such plasticity. Also, the...

DOI: 10.1021/acschemneuro.4c00484

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