ACS Chemical Neuroscience
August 2, 2023
Eline Pottie, Christian B M Poulie, Icaro A Simon et al.
25 citations
Serotonergic psychedelics primarily activate the serotonin 2A receptor (5-HT2A), but the molecular basis for their psychedelic effects is not fully understood. A leading hypothesis is biased agonism, where certain signaling pathways are preferentially activated. This study tested a series of 4-position-substituted phenylalkylamines for their ability to recruit β-arrestin2 or miniGαq to the 5-HT2A receptor. All compounds acted as agonists with varying potency and efficacy. Lipophilicity of the 2C-X phenethylamines correlated more strongly with efficacy in the miniGαq assay than the β-arrestin2 assay. Molecular docking suggested that the 4-substituent fits into a hydrophobic pocket between transmembrane helices 4 and 5, potentially explaining this differential effect. Using serotonin and LSD as reference agonists, both benchmark and physiology bias were estimated, and qualitative structure-activity relationships remained consistent across different activation profiles.
ACS Chemical Neuroscience
August 24, 2022
Manoj K. Doss, Frederick S. Barrett, Philip R. Corlett
21 citations
A critique of a Nature Medicine paper claiming psilocybin therapy reduces brain network modularity in depressed patients, an effect not seen with the SSRI S-citalopram. The authors identify multiple problems: inconsistent reporting of the primary clinical outcome, statistical flaws including a one-tailed test and a nonsignificant interaction, regression to the mean, ambiguous interpretation of resting-state fMRI data, and a missing reference to a similar study that undermines the justification for a one-tailed test. These issues cast doubt on the uniqueness and impact of the original findings and the media hype they generated.
ACS Chemical Neuroscience
June 7, 2022
Konstantin A. Demin, Olga V. Kupriyanova, Вадим А. Шевырин et al.
20 citations
Novel N-benzyl-2-phenylethylamine (NBPEA) derivatives, with specific substitutions in the N-benzyl and phenethylamine moieties, alter locomotion and anxiety-like behavior in adult zebrafish. Substitutions in the N-benzyl moiety modulate locomotion, while those in the phenethylamine moiety affect anxiety-like behavior and brain serotonin or dopamine turnover. The 24H–NBOMe(F) and 34H–NBOMe(F) treatments reduced despair-like behavior. Computational analyses classified the agents into anxiogenic/hypolocomotor, behaviorally inert, anxiogenic/hallucinogenic-like, and anxiolytic/hallucinogenic-like clusters, with some NBPEAs showing behavioral similarity to conventional serotonergic and antiglutamatergic hallucinogens. These findings suggest potent neuroactive properties of several NBPEAs, indicating potential clinical use or abuse.
ACS Chemical Neuroscience
May 6, 2020
Emil Märcher-Rørsted, Adam L. Halberstadt, Adam K. Klein et al.
20 citations
The 2,5-dimethoxy motif found in many phenethylamine psychedelics has been considered essential for activating the serotonin 2A receptor (5-HT2AR). This study synthesized derivatives of 2C-B and DOB lacking either the 2- or 5-methoxy group and tested them in binding and functional assays at 5-HT2AR and 5-HT2CR, as well as in mice for head-twitch response, a behavioral proxy for psychedelic activity. Removing either methoxy group caused a modest drop in binding affinity and functional potency at both receptors, with larger effects from removing the 2-methoxy group. However, in mice, removal of either group drastically reduced head-twitch response. Thus, the 2,5-dimethoxy motif is important for in vivo potency, but this does not correlate with in vitro receptor affinity or potency.
ACS Chemical Neuroscience
January 8, 2024
Alexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson et al.
18 citations
Psilocin, a metabolite of psilocybin, produces psychedelic effects in vivo, while norpsilocin, which differs by a single N-methyl group, does not. To explore this, eight norpsilocin derivatives with varied secondary amine groups were synthesized to increase lipophilicity and brain permeability. In mouse head-twitch response (HTR) studies, extending norpsilocin's N-methyl group to an N-ethyl group (4-HO-NET) produced psilocin-like activity (ED50 = 1.4 mg/kg). N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced HTRs (ED50 = 1.1–3.2 mg/kg), with variable maximum effects (26–77 total HTR events). Bulky tert-butyl or cyclohexyl groups did not elicit psilocin-like HTRs. In vitro, these tryptamines interacted with multiple serotonin receptor subtypes and other CNS proteins.
ACS Chemical Neuroscience
September 18, 2024
Diego Rivera-Illanes, Gonzalo Recabarren-Gajardo
17 citations
Muscimol is a psychoactive compound found in Amanita mushrooms, including the fly agaric, and is structurally similar to the neurotransmitter GABA. It acts as a potent agonist at GABAA receptors and has been used historically as an entheogen in Siberian shamanic cultures. Although not approved for clinical use, muscimol is a valuable research tool in neuroscience, with its radiolabeled form, 3H-muscimol, employed as a radioligand in GABA receptor studies. Recent research explores its potential for neuropathic pain relief. This review covers the history, chemistry, pharmacology, and overall importance of muscimol.
ACS Chemical Neuroscience
March 1, 2023
Robert J Tombari, Paige C Mundy, Kelly M Morales et al.
15 citations
Thirteen psychoactive compounds from different chemical classes were screened in larval zebrafish for developmental toxicity. Psychedelic tryptamines and ketamine were less neurotoxic than LSD and psychostimulants. The results provide a reference database for comparing neurotoxicity profiles of novel psychedelics being developed as therapeutics.
ACS Chemical Neuroscience
September 30, 2018
Julian Maier, Felix P. Mayer, Simon D. Brandt et al.
15 citations
Aminorex and its analogues are psychostimulants that interact with monoamine transporters, sharing pharmacological similarities with amphetamines and cocaine. Some of these substances, originally failed pharmaceuticals, have reemerged as new psychoactive substances (NPS) for recreational use. Consumption of certain analogues, such as 4-methylaminorex and 4,4'-dimethylaminorex, has been linked to adverse events including death. This review covers the historical background, pharmacodynamic and pharmacokinetic properties, and misuse of these drugs as adulterants. It highlights the dangers of the NPS market, where users often lack knowledge of the pharmacology, potency, or identity of active ingredients.
ACS Chemical Neuroscience
June 10, 2025
Santosh Kumar Prajapati, Shreyasi Majumdar, Snehapriya Murari et al.
14 citations
PTSD involves complex disruptions in brain circuits, stress hormone regulation, and multiple neurotransmitter systems including serotonin, glutamate, and GABA. This review describes how the hypothalamic-pituitary-adrenal axis, monoamines, and orexinergic system contribute to the disorder. Emerging treatments discussed include MDMA, ketamine, suvorexant, and cannabinoid modulators, alongside established psychotherapies like cognitive-behavioral therapy. By integrating findings from original research, clinical trials, and reviews published between 1950 and 2025, the authors provide a consolidated framework for understanding PTSD pathophysiology and highlight potential targets for personalized therapies.
ACS Chemical Neuroscience
December 18, 2024
Grant C. Glatfelter, Allison A Clark, Natalie G. Cavalco et al.
14 citations
5-MeO-DMT and its analogs bind to multiple serotonin and adrenergic receptors, with potent activity at 5-HT2A and 5-HT1A receptors. In mice, these compounds induce head twitch responses (a proxy for psychedelic-like effects) with varying potencies (ED50 0.2–1.8 mg/kg) and maximal effects (20–60 head twitches per 30 minutes), while higher doses cause hypothermia and reduced movement (ED50 3.2–20.6 mg/kg). Blocking 5-HT1A receptors enhances head twitch responses, unmasking activity in some analogs and increasing maximal responses to 40–90 head twitches per 30 minutes, indicating that 5-HT1A activation dampens 5-HT2A-mediated psychedelic-like effects. Suppression of head twitch responses by 5-HT1A only occurred at high 5-MeO-DMT doses, suggesting other receptors also modulate these effects.
ACS Chemical Neuroscience
June 4, 2018
Marc Aixalà, Rafael G. Dos Santos, Jaime E. C. Hallak et al.
14 citations
Clinical trials increasingly report that psychedelics like LSD, psilocybin, and ayahuasca may help treat mood, anxiety, and substance use disorders. The mechanisms remain unclear but appear to involve altered brain dynamics in regions dense with serotonergic 5-HT2A receptors and changes in personality. This text offers a brief, critical overview of current research, highlighting both the promise and limitations of these studies.
ACS Chemical Neuroscience
December 27, 2018
Patrick Vizeli, Henriette E. Meyer zu Schwabedissen, Matthias E. Liechti
13 citations
A pooled analysis of eight placebo-controlled studies in 124 healthy subjects tested whether common genetic variants in serotonin-system genes influence the physiological and subjective effects of 125 mg of MDMA. Variants in TPH2, HTR2A, and the serotonin-transporter gene showed only modest, non-significant associations after correction for multiple comparisons. No tested genetic polymorphism significantly altered the response to MDMA. The results suggest that interindividual differences in serotonin-system genes play a marginal role in MDMA's effects, whether used recreationally or therapeutically.
ACS Chemical Neuroscience
October 17, 2023
Hideaki Yano, Rezvan Chitsazi, Christopher Lucaj et al.
12 citations
Minor chemical changes in synthetic cannabinoid receptor agonists (SCRAs) can dramatically increase their potency and efficacy at the CB1 receptor, making them far more toxic than THC. Using bioluminescence assays and hippocampal slice recordings, the authors found that adding a single methyl group to the head moiety of 5F-MMB-PICA (producing 5F-MDMB-PICA) greatly enhanced G protein signaling and β-arrestin recruitment. Molecular modeling showed how this small structural difference propagated to the receptor-G protein interface, explaining the heightened activity. These findings underscore the need for close surveillance of structural modifications in newly emerging SCRAs due to their potential for severe toxicity in humans.
ACS Chemical Neuroscience
October 6, 2020
Genís Ona, Rafael G. Dos Santos, Jaime E. C. Hallak et al.
12 citations
Research on psychedelic drugs typically examines isolated compounds, but this approach may overlook important effects because these substances contain multiple active ingredients. This viewpoint argues that studying whole products like ayahuasca or Psilocybe mushrooms, rather than just single compounds, could reveal additional therapeutic or experiential properties. The authors describe how psychedelic research can incorporate a polypharmacology framework, which considers the combined actions of multiple chemicals. Ethical considerations of this broader approach are also briefly discussed.
ACS Chemical Neuroscience
June 25, 2024
Jingyuan Chen, Frederick A. Bagdasarian, Hanne D. Hansen et al.
11 citations
Using fMRI in nonhuman primates, this work compared how two different hallucinogens—psilocybin, a serotonergic psychedelic, and salvinorin-A, a kappa-opioid receptor agonist—alter resting-state functional connectivity. Both drugs acutely desynchronized the default mode network and affected a network involving the claustrum, prefrontal cortex, anterior cingulate cortices, and angular gyrus, supporting a cortico-claustro-cortical model for probing hallucinogen effects regardless of serotonergic activity. Thalamo-cortical changes appeared dependent on 5-HT2AR activation. The findings offer a framework for understanding mechanisms common across hallucinogenic drug classes.
ACS Chemical Neuroscience
June 6, 2025
Anna Czopek, Jakub Jończyk, Monika Fryc et al.
9 citations
Classic psychedelics such as psilocybin, LSD, and DMT, which primarily act on serotonin 5-HT2A receptors, may offer an alternative to conventional pain medications like opioids and NSAIDs for chronic pain—a condition often accompanied by depression and anxiety. Evidence from case studies, preclinical research, and early clinical trials suggests these substances can alleviate pain in cluster headaches, migraines, fibromyalgia, and other chronic pain syndromes by influencing neuroplasticity, descending pain modulation pathways, and inflammatory processes. However, the exact mechanisms remain unclear, and rigorous randomized controlled trials are needed to establish safety, efficacy, and optimal dosing.
ACS Chemical Neuroscience
August 2, 2024
Fabio Urbina, Thane Jones, Joshua S. Harris et al.
9 citations
New drugs for serious mental health disorders should avoid causing psychedelic experiences. Analogs of psychedelic drugs called psychoplastogens show promise for treating opioid use disorder by reducing drug dependence, with rare serious side effects. This effect is linked to increased neuritogenesis and neuroplasticity. Some psychoplastogens act through the 5HT 2A receptor, but others have different pharmacology, making prediction of hallucinogenic potential difficult. Researchers developed machine learning classification models to predict psychedelic effects using in vitro PsychLight data (support vector classification, AUC 0.74) and in vivo human data from Shulgin and Shulgin (SVC, AUC 0.72). The models predicted known 5HT 2A agonists' psychedelic potential with AUCs of 0.97 and 0.71, respectively, aiding design of non-hallucinogenic psychoplastogens.
ACS Chemical Neuroscience
May 17, 2024
Nathan Bryson, Robert Alexander, Aviva Asnis-Alibozek et al.
9 citations
A prodrug called RE104, which releases the short-acting psychedelic 4-OH-DiPT (structurally similar to psilocin), was characterized in rats. 4-OH-DiPT is a synthetic serotonin 2A receptor agonist with a reported 2-3 hour duration of psychedelic effects, shorter than psilocybin. RE104 incorporates a glutarate moiety that cleaves rapidly in the body to provide the active drug. In rats, plasma concentrations of 4-OH-DiPT correlated with head-twitch intensity, and its half-life was 40 minutes after subcutaneous RE104 administration. A single 1 mg/kg dose of RE104 significantly reduced immobility time in the forced swim test one week later, indicating potential antidepressant activity.
ACS Chemical Neuroscience
October 13, 2025
Rajiv Agrawal, Daniel J. Gillie, Alison E. Mungenast et al.
8 citations
A new compound called zalsupindole, designed to promote brain cell regrowth without causing hallucinations or dissociation, shows promise for treating depression. In rats, it produced robust structural and functional neuroplasticity in the prefrontal cortex and sustained antidepressant-like effects, comparable to or greater than ketamine, psilocybin, and DMT. Unlike these other compounds, zalsupindole lacked hallucinogenic or dissociative properties, suggesting it could be a safer and more scalable treatment for depression. This work addresses the need for neuroplastogens that promote cortical neuron regrowth without the safety concerns of psychedelics and dissociative anesthetics.
ACS Chemical Neuroscience
May 1, 2024
Benjamin M Williams, Nathan D Steed, Joel T Woolley et al.
7 citations
Catharanthine and 18-methoxycoronaridine (18-MC), iboga alkaloids, reduce nicotine's effects on dopamine transmission and behavior. In male mice, both compounds inhibited evoked dopamine release in the nucleus accumbens core, with catharanthine's effect depending on α4 and α6 nicotinic receptors. Catharanthine slowed dopamine reuptake ex vivo but increased extracellular dopamine in vivo. Both compounds suppressed firing of striatal cholinergic interneurons and acetylcholine currents in oocytes. In male rats, catharanthine and 18-MC blocked nicotine-enhanced locomotor activity, and catharanthine dose-dependently reduced nicotine self-administration without affecting food reinforcement. Combining catharanthine with nicotine increased head twitch responses, suggesting a potential synergistic hallucinogenic effect.
ACS Chemical Neuroscience
May 12, 2020
Kodye L. Abbott, Kristina Gill, Patrick Flannery et al.
7 citations
Regulations intended to prevent harm and addiction from substances like cannabis, MDMA, LSD, and psilocybin also create major barriers for scientists trying to study these drugs. The authors argue that modifying current drug scheduling to reclassify illicit substances would allow extensive testing in research settings, potentially advancing life-saving research.
ACS Chemical Neuroscience
May 7, 2025
Hongshuang Wang, Xiaohui Wang
5 citations
Psychedelics may help treat neuropsychiatric disorders by increasing brain entropy and disrupting rigid neural patterns, which can lead to ego dissolution and profound emotional breakthroughs. This process potentially alleviates symptoms of depression, anxiety, PTSD, and addiction. However, clinical use faces challenges such as careful patient screening, managing adverse experiences, and ethical considerations, all essential for safe therapeutic integration.
ACS Chemical Neuroscience
July 9, 2025
Xue Wang, Fan Jun, Cong Lin et al.
4 citations
Classic psychedelics and the gut microbiome influence each other through 5-HT2A receptor signaling, neuroplasticity, and microbial metabolism. Psychedelics may alter the composition of gut bacteria, while the microbiome can affect how well these compounds work. The authors propose using microbiome-informed approaches, such as probiotics or dietary changes, to tailor and improve psychedelic treatments for mental health conditions.
ACS Chemical Neuroscience
February 7, 2024
Breno A. Soares, Thirumal Yempala, Darío Martínez-afani et al.
4 citations
Adding a very large chemical group (dibenzo[b,d]furylmethyl, or DBFM) to the nitrogen atom of the psychedelic phenethylamine 2C-B can either decrease or increase its binding to serotonin 5-HT2 receptors, depending on which position of the DBFM group is attached. Attaching through the 4-position generally improved affinity, with one compound showing 10-fold higher affinity at 5-HT2A receptors and 40-fold higher at 5-HT2C receptors, though selectivity among receptor subtypes was low. All compounds were weak partial agonists at 5-HT2A receptors but full or nearly full agonists at 5-HT2C receptors. Molecular docking simulations indicated the dibenzofuryl part inserts deeper into the 5-HT2A receptor's binding site than into 5-HT2C's, interacting with a key activation switch.
ACS Chemical Neuroscience
March 5, 2025
Syed Muzzammil Masaud, Humaira Nadeem, Babar Murtaza et al.
3 citations
Sixteen novel N-acetamide ketamine derivatives (k1 to k16) were synthesized and characterized. In mouse models, derivative k1 showed analgesic activity comparable to ketamine and the highest antidepressant potential among all derivatives, performing similarly to ketamine in forced swimming, open field, sucrose preference, and tail suspension tests. Notably, k1 exhibited almost no psychomimetic activity—assessed via loss of righting reflex and Y-maze tests—unlike ketamine. Molecular docking against the NMDA receptor (PDB ID: 7EU7) indicated all derivatives had significant binding affinities relative to ketamine. These results suggest k1 has a promising pharmacological profile with reduced psychomimetic side effects.