ACS Chemical Neuroscience
January 21, 2026
Miguel Salfiti, Marios Kyriazis, Georgios Mikellides
2 citations
Zalsupindole, a non-hallucinogenic psychoplastogen, promotes neuritogenesis and dendritic spine growth via 5-HT2-dependent mechanisms, potentially involving the mTOR pathway. In rats, it shows rapid brain penetration, no 5-HT2B agonism, no glutamate surge, and no head-twitch response. Single doses produce rapid and durable antidepressant-like effects in forced swim test and VMAT2-deficient mouse models. Phase 1 trials (2-360 mg) show good tolerability, no psychotomimetic effects, linear absorption, and dose-dependent EEG changes indicating synaptic potentiation. This biased 5-HT2A agonist may offer a new treatment for mood disorders without hallucinogenic side effects.
ACS Chemical Neuroscience
September 3, 2025
Arabo A. Avanes, Hunter T Warren, Abinaya Senthil et al.
2 citations
Tropane alkaloids and their derivatives are a diverse group of small molecules with many therapeutic uses. Many tropanes affect dopamine and serotonin transporters in the brain. While blocking the dopamine transporter contributes to the addictive potential of tropanes like cocaine, modulating the serotonin transporter may counteract those effects. Serotonin transporter modulators such as MDMA, ibogaine, and SSRIs show promise for treating depression, addiction, and PTSD. This work profiled various tropane subclasses and identified compounds, notably UCD0168 and UCD0820, that potently modulate the serotonin transporter similarly to fluoxetine, MDMA, or noribogaine. UCD0168 acts as a full serotonin releasing agent, and UCD0820 as a partial one. The tropane scaffold can serve as a starting point for developing new serotonin transporter modulators.
ACS Chemical Neuroscience
May 17, 2023
Khalyd J Clay, Ava E Axelrod, Christina M MacLaughlin et al.
2 citations
Several naturally occurring molecules, including entheogens—plant-derived compounds used by Indigenous groups for religious or spiritual purposes—show unique potential for treating psychiatric illnesses and are being pursued in therapeutic development. This viewpoint argues that labeling such compounds as "DARK" in ACS Chemical Neuroscience issues perpetuates harmful stigmas. The authors propose reframing these substances in the light and beauty of their cultural and historical contexts, urging a shift in language surrounding entheogens and psychedelics more broadly.
ACS Chemical Neuroscience
January 2, 2026
Mario de la Fuente Revenga, Javier González-Maeso
1 citation
The subjective effects that define psychedelics like LSD, psilocybin, and DOI are linked to activation of the serotonin 2A receptor (5-HT2AR), but what differentiates psychedelic from nonpsychedelic 5-HT2AR agonists is unclear. A new ex vivo platform was developed to measure drug-mediated activation of the Gq/11 pathway in mouse brain tissue by tracking inositol monophosphate (IP1) levels. In the frontal cortex of mice, DOI produced time-bound, dose-dependent IP1 increases that correlated with head twitch responses. LSD elevated IP1, while lisuride did not, consistent with their respective psychedelic and nonpsychedelic natures. MDMA also increased IP1, attributed to serotonin release, unlike the serotonin precursor 5-HTP or fluoxetine. This method provides mechanistic insights into psychedelic action and Gq/11-coupled receptors.
ACS Chemical Neuroscience
December 17, 2025
Justin M Silverman, Michael Fiorillo, Jason Younkin et al.
1 citation
α-Ethyltryptamine (AET), a synthetic tryptamine once used as an antidepressant, acts through a dual mechanism involving both direct activation of the 5-HT2A receptor and indirect serotonin release via the serotonin transporter (SERT). In vitro, AET and its isomers displaced ketanserin from the 5-HT2A receptor with micromolar affinity, but only the S(+)-AET isomer showed weak partial agonist activity. In mice, all forms of AET produced a head-twitch response that was blocked by a 5-HT2A antagonist and also by fluoxetine, indicating that SERT-mediated serotonin release contributes to its behavioral effects. This dual pharmacology distinguishes AET from classical psychedelics and aligns it with MDMA-like compounds, suggesting potential for modulating mood and cognition.
ACS Chemical Neuroscience
July 29, 2025
Lin Zhu, Ji Chen, Yuan Liu et al.
1 citation
Esketamine significantly lowers depression scores in new mothers with perinatal depression, as shown in a clinical trial with 298 full-term pregnant women. The antidepressant effect is linked to modulation of TASK-1 potassium channels, which reduces neuroinflammation and depressive-like symptoms. Studies in mouse models and cultured neurons confirm that esketamine acts through these channels to alter synaptic plasticity proteins. This work identifies a specific neural pathway for esketamine's rapid action, offering a promising therapeutic avenue for perinatal depression.
ACS Chemical Neuroscience
July 24, 2025
Anjian Yang, Xinyou Lv, Hongshuang Wang et al.
1 citation
This viewpoint proposes that mysticism and fundamentalism can be understood as brain network disorders, where rigid neural patterns underlie inflexible belief systems. Psychedelics such as psilocybin, LSD, and DMT may disrupt these patterns, potentially increasing cognitive flexibility and challenging dogmatic thinking. The authors suggest this modulation could have therapeutic applications for extremism and certain mental health conditions, though the argument remains theoretical and not empirically tested.
ACS Chemical Neuroscience
July 9, 2026
José Alexandre Salerno, Elizabeth R. Dominguez, Karina Karmirian et al.
Brief exposure to the psychedelic N,N-dimethyltryptamine (DMT) increases proliferation of human neural stem cells derived from induced pluripotent stem cells. A 24-hour DMT treatment boosted cell division in a concentration-dependent way, with half-maximal effect at 59.7 nM, and raised levels of G1 cell-cycle regulators. DMT also altered expression of trophic genes, decreasing neurotrophin-3 while increasing nerve growth factor and brain-derived neurotrophic factor (BDNF) transcripts and intracellular BDNF protein. After DMT was removed, treated stem cells formed larger neurospheres, with progenitor and early neuron markers matching controls by day 10. The findings indicate DMT can engage proliferative and neurotrophin-related responses in human neural stem cells at concentrations linked to plasticity in other systems.
ACS Chemical Neuroscience
June 17, 2026
Anoushka Bhat, Elmira Zolali, Mahfuz A Sakib et al.
Psychedelics are being studied again as treatments for depression, anxiety, PTSD, and substance use disorders. Their beneficial effects are mostly due to activating the serotonin 2A (5-HT2A) receptor, but they differ greatly in chemical structure, how they bind to receptors, how they are broken down, and how long they last. Short-acting psychedelics like DMT and 5-methoxy-DMT may be better for brief therapy sessions, while long-acting ones like LSD and mescaline might be more effective for some outcomes. This review covers the chemistry, structure-activity relationships, and pharmacology of both types, and discusses how small chemical changes affect receptor binding and duration. It aims to guide development of next-generation treatments with controlled effects.
ACS Chemical Neuroscience
May 27, 2026
Grant C. Glatfelter, Serena S. Schalk, Donna Walther et al.
Tryptamine psychedelics produce their effects mainly by activating serotonin 2A receptors, but many also affect other targets. 4-MeO-MiPT, a compound that both activates 5-HT2A receptors and blocks the serotonin transporter (SERT), produces blunted psychedelic effects in humans. In mice, 4-MeO-MiPT and its analogs with stronger SERT blockade showed fewer head twitch responses (a proxy for psychedelic-like effects) than their 4-hydroxy counterparts. Pretreating mice with the SERT inhibitor fluoxetine reduced head twitch responses from 4-hydroxy compounds to levels seen with the 4-methoxy analogs. The findings suggest that dual 5-HT2A/SERT ligands may have therapeutic potential with reduced acute psychedelic effects.
ACS Chemical Neuroscience
May 6, 2026
Maxemiliano V. Vargas, Cassandra J. Hatzipantelis, Lee E. Dunlap et al.
A safer analogue of MDMA, called R-MDDMA, shows promise for treating PTSD and depression without the abuse potential of MDMA. Unlike MDMA, R-MDDMA does not activate 5-HT2B receptors, induce serotonin release, cause head-twitch responses, affect body temperature, or increase locomotion at therapeutic doses. However, it still promotes structural neuroplasticity in cortical neurons, facilitates fear extinction learning, and produces sustained antidepressant-like effects. These results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.
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—psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA)—along with putative minor metabolites and several deuterium-labeled derivatives, were synthesized on a preparative scale. When assayed for engagement at seven serotonin receptor subtypes using a BRET-based binding assay, only psilocin exhibited any discernible binding. Given the high cost and challenging preparation of these compounds, the work provides a comprehensive guide for researchers to access these resources, advancing both basic and clinical research with psilocybin and its metabolites.
ACS Chemical Neuroscience
February 18, 2026
Vito F. Palmisano, Micaela Vidal−sánchez, Juan J. Nogueira
Bulky substitutions on the N-benzyl ring of 25CN-NBx compounds cause a significant shift in the position of W336, a key toggle switch residue in the 5-HT2A receptor. This shift influences receptor activation and is thought to play a crucial role in mediating psychedelic signaling. Potential of mean force calculations along the toggle switch's dihedral angle confirm this result. End-state free energy calculations show that 25CN-NB-2-OH-3-Me and 25CN-NB-2-OH-5-MeO have the highest and lowest affinities, respectively, for the receptor. When W336 adopts its negative dihedral state, it establishes stronger van der Waals interactions with residues F332 and I163, key players in receptor activation. This framework can extend to other G protein-coupled receptors where the toggle switch is central to signal activation.
ACS Chemical Neuroscience
February 18, 2026
Tallan Black, Rhiannon E Boseley, Amanda Quirk et al.
Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main intoxicating compound in cannabis, alters brain chemistry in offspring. Using X-ray fluorescence imaging and Fourier transform infrared spectromicroscopy on rat brains, the study found that THC-exposed offspring had decreased copper concentrations in the corpus callosum and changes in lipid structure, including increased methylene, lipid esters, phosphate, protein, and unsaturation levels, particularly in the hippocampus. Biochemical changes were modest, with increased structural lipid changes in the corpus callosum and increased protein in the lateral ventricle. These findings demonstrate that gestational THC induces subtle but measurable biomolecular alterations in the developing brain.
ACS Chemical Neuroscience
December 2, 2025
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.
Replacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.
ACS Chemical Neuroscience
October 15, 2025
Cassandra J. Hatzipantelis, Lindsay P. Cameron, Min Liu et al.
A new genetic mouse model lacking the enzyme indolethylamine N-methyltransferase (INMT) shows that INMT is not required for the production of endogenous psychedelics, suggesting alternative biosynthetic pathways exist in rodents. INMT knockout mice had no major abnormalities in reproduction or growth but did exhibit altered behaviors across several domains. The study also describes highly sensitive mass spectrometry methods for quantifying endogenous psychedelics in mice. These findings challenge the assumption that INMT is the primary enzyme for endogenous psychedelic production and open new questions about the role of these compounds in health and disease.
ACS Chemical Neuroscience
October 21, 2024
Debsankar S. Saha Roy, Ankit Singh, V. Vaidya et al.
The serotonergic psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) alters the physical properties of artificial lipid bilayers in ways that may contribute to its biological effects, such as enhancing neuronal plasticity. Using solid-state NMR, atomic force microscopy, and fluorescence techniques, DOI was found to induce disorder in lipid acyl chains, shrink ordered domains, reduce the force needed to form nanopores, and promote vesicle fusion to lipid bilayers. These receptor-independent effects on membranes are more than two orders of magnitude more potent than those of serotonin. The findings suggest that direct membrane actions of psychedelics, not just serotonin 2A receptor activation, could play a role in processes requiring membrane remodeling.
ACS Chemical Neuroscience
April 17, 2024
Hui Li, Qiong Ye, Da Wang et al.
Suppressing the cannabinoid receptor 1 (CB1) has been proposed as a treatment for conditions like obesity and Parkinson's disease, but a clinical trial produced unanticipated psychological side effects. Using in vivo imaging in mice, the authors show that complete genetic knockout of the CB1 gene (cnr1-/-) alters white matter structure and functional directional uniformity (in male mice) across the brain while largely preserving network activity. In contrast, the CB1 inverse agonist rimonabant alters network activity in cortical regions known to be affected by THC but does not affect directional uniformity. Chronic loss of cnr1 differs substantially from short-term pharmacological suppression, which may explain why pathological CB1 mutations do not predict side effects of CB1-suppressing drugs.
ACS Chemical Neuroscience
June 21, 2023
Elliot W McClure, R Nathan Daniels
Dextromethorphan (DXM), introduced in 1958 as the first non-opioid cough suppressant, has become the most used over-the-counter cough medicine. While its antagonism at NMDA receptors underlies its effectiveness for cough, large doses produce intoxicating and psychedelic effects similar to dissociative hallucinogens like phencyclidine and ketamine. This review covers DXM's synthesis, metabolism, pharmacology, adverse effects, recreational use, abuse potential, and therapeutic history, presenting it as a classic compound in chemical neuroscience.
ACS Chemical Neuroscience
May 8, 2020
Rachel S Crowley, Andrew P Riley, Amy F Alder et al.
A series of analogues of kurkinorin, a non-nitrogenous μ opioid receptor (MOR) agonist derived from salvinorin A, were synthesized and tested in vitro for G-protein activation and β-arrestin-2 recruitment. Some compounds showed biased signaling, either toward β-arrestin-2 or G-protein activation. Compound 25 is a potent MOR-selective agonist with G-protein bias, over 100 times more potent than morphine and over 5 times more potent than fentanyl in vitro, and produces antinociception with limited tolerance development in vivo, despite lacking a basic nitrogen or other ionizable groups typical of opioid ligands.
ACS Chemical Neuroscience
February 3, 2020
Jinghua Zhao, XueJie Liu, Daiyue Chang et al.
Low doses of ketamine produce rapid antidepressant effects by activating the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic anti-inflammatory pathway. In a rat model of depression induced by lipopolysaccharide and in PC12 nerve cells, ketamine reduced neuroinflammation, improved behavior, synaptic plasticity, and Nissl bodies. Blocking α7nAChR with methyllycaconatine or α7nAChR-siRNA reversed these effects, and the degree of reversal correlated with the dose of the blocker. A specific α7nAChR agonist, GTS-21, produced similar protective effects as ketamine, confirming the pathway's role.
ACS Chemical Neuroscience
August 21, 2019
Amelia D Dunn, Brian Reed, Jose Erazo et al.
A set of 21 structurally diverse kappa opioid receptor (KOR) ligands, including the natural product Salvinorin A and the endogenous peptide Dynorphin A(1-17), were tested in parallel to quantify biased signaling. Compounds were assessed for G-protein and β-arrestin recruitment in KOR-expressing U2OS cells, and a subset was tested for sedative properties in mice using the rotarod assay. Sedation significantly correlated with β-arrestin signaling, suggesting this in vitro system can predict this in vivo behavior. Downstream ERK1/2 and mTOR signaling diverged from G-protein and arrestin pathways.
ACS Chemical Neuroscience
November 16, 2016
Sebastian Leth-Petersen, Ida N Petersen, Anders A. Jensen et al.
The toxic hallucinogen 25B-NBOMe is rapidly broken down by human liver enzymes and has low oral bioavailability. New chemical variants were synthesized by modifying the part of the molecule where metabolism normally occurs. While some analogues resisted breakdown longer and still strongly activated 5-HT2 receptors, all had an intrinsic clearance above 1.3 L/kg/h, indicating they would still be extensively metabolized on first pass through the liver.
ACS Chemical Neuroscience
January 16, 2013
Jose I Juncosa, Martin Hansen, Lisa A Bonner et al.
By modifying the structure of a known superpotent 5-HT(2A) receptor agonist, researchers synthesized a set of constrained analogues to determine the best arrangement of the ligand's key chemical features. The compounds included substituted tetrahydroisoquinolines, piperidines, and a benzazepine. One compound, (S,S)-9b, had the highest binding affinity and a 124-fold selectivity for the 5-HT(2A) receptor over the 5-HT(2C) receptor, making it the most selective 5-HT(2A) receptor agonist ligand currently known. An optimal binding conformation is proposed based on this compound.