ACS chemical neuroscience
March 19, 2014
Martin Hansen, Karina Phonekeo, James S Paine et al.
125 citations
Adding a benzyl group to the nitrogen atom of phenethylamine psychedelics like 2C-B greatly increases their binding and activity at serotonin 5-HT2A receptors. A library of 48 compounds with varied phenethylamine and N-benzyl structures was tested. Most had high 5-HT2A affinity; compound 8b showed the highest affinity at 0.29 nM, while 1b was the most functionally potent at 0.074 nM. Selectivity over the related 5-HT2C receptor ranged from 1- to 40-fold in binding, though 6b achieved 100-fold selectivity. Functional selectivity was higher, with 1b exceeding 400-fold selectivity for 5-HT2A.
ACS chemical neuroscience
February 1, 2023
Lindsay P Cameron, Seona D Patel, Maxemiliano V Vargas et al.
113 citations
Activation of serotonin 2A receptors (5-HT2ARs) is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. While hallucinogenic properties are generally attributed to 5-HT2AR activation, it was unclear whether these receptors also mediate antidepressant effects, especially because some nonhallucinogenic analogues show antidepressant-like properties. Using pharmacological and genetic tools, the authors demonstrate that 5-HT2AR activation is required for the antidepressant-like effects of tryptamine psychedelics, suggesting that hallucinogenic and therapeutic effects can arise through the same receptor.
ACS chemical neuroscience
July 15, 2015
David E Nichols, M Flori Sassano, Adam L Halberstadt et al.
81 citations
A series of N-benzylated-5-methoxytryptamine analogues and a parallel series of N-benzylated 2C-I analogues were synthesized and tested. Most compounds showed highest affinity for 5-HT2 family receptors. Para substitution on the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional testing at human and rat 5-HT2A, 5-HT2B, and 5-HT2C receptors revealed no general correlation between affinity and function. Several tryptamine congeners were potent functional agonists (EC50 values from 7.6 to 63 nM) but mostly partial agonists. In the mouse head twitch assay, many compounds induced head twitches, and this behavior correlated significantly with functional potency at the rat 5-HT2A receptor.
ACS chemical neuroscience
February 7, 2024
Pedro A M Mediano, Fernando E Rosas, Christopher Timmermann et al.
60 citations
LSD increases brain entropy (neural signal diversity) across all conditions, but the effect is strongest when eyes are closed. Brain entropy changes correlate with subjective psychedelic experience ratings, except when viewing a video, possibly because external stimuli compete with LSD-induced imagery. This shows context modulates neural dynamics during psychedelic experiences, highlighting the importance of environment in psychedelic psychotherapy.
ACS chemical neuroscience
June 3, 2020
Paola Rodrı Guez, Jessika Urbanavicius, José Pedro Prieto et al.
44 citations
Ibogaine and its main metabolite noribogaine produce antidepressant-like effects in rats, as measured by the forced swim test. Both compounds induced a dose- and time-dependent reduction in immobility without altering locomotor activity. Noribogaine's effect was short-lived (30 minutes) and correlated with high brain concentrations (estimated >8 μM free drug), while ibogaine's effect was significant at 3 hours, when both ibogaine (~0.5 μM) and noribogaine (~2.5 μM) were present at concentrations that alone could not produce the same outcome. The findings suggest a polypharmacological mechanism underlies the antidepressant-like effects.
ACS chemical neuroscience
December 2, 2020
R Bruno Hernández-alvarado, Abraham Madariaga-Mazón, Alfredo Ortega et al.
29 citations
Salvinorin A, the main psychoactive compound in the plant Salvia divinorum, is the first known nonalkaloidal opioid that acts through the kappa-opioid receptor, producing rapid and short-lived hallucinogenic effects. Its unique chemical structure lacks a protonated amine group, leading to fast metabolism and swift loss of activity. The compound has been used ancestrally in spiritual rites by the Mazatec people of Oaxaca, Mexico, but its psychotropic effects have led to misuse and bans in many countries. This review covers its history, natural isolation, total synthesis, hundreds of synthetic analogues, and pharmacological and safety profiles, highlighting its impact on neuroscience and drug development.
ACS chemical neuroscience
July 3, 2024
Yue Zhang, Hui Ma, Yafan Bai et al.
25 citations
Chronic neuropathic pain and comorbid depression syndrome (CDS) is a major global health problem affecting quality of life and imposing a large socioeconomic burden. More than half of patients with chronic neuropathic pain also suffer from moderate or severe depression. The complex causes of CDS and limited research on its neural circuit mechanisms hinder effective treatments. Activating some neural circuits can alleviate pain or depression, while activating others worsens these conditions. Current and emerging pharmacotherapies, such as ketamine, are discussed. Understanding the circuit mechanisms may guide development of new drugs for better CDS management.
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
May 6, 2020
Emil Marcher-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
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
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
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 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.
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
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 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.