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 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
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
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
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
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
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
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.