ACS Chemical Neuroscience
March 5, 2020
Meghan Hibicke, Alexus N. Landry, Hannah M. Kramer et al.
211 citations
Psilocybin and LSD produce antidepressant-like effects in rats that last longer than those of ketamine. A single dose of psilocybin or LSD led to persistent antidepressant-like effects in a rat model, while ketamine’s effects were only temporary. This suggests that classic psychedelics may offer more sustained therapeutic benefits than ketamine, and that a profound subjective experience may not be required for these effects.
ACS Chemical Neuroscience
April 17, 2018
Lindsay P. Cameron, Charlie J. Benson, Lee E. Dunlap et al.
168 citations
Depression and anxiety impose large economic costs, and many patients do not respond to traditional antidepressants. A single dose of DMT, the main psychoactive compound in ayahuasca, initially increased anxiety-like behaviors in adult male rats but later reduced anxiety by speeding the extinction of conditioned fear memories. DMT also decreased immobility in the forced swim test, a standard measure of antidepressant-like effect. These results indicate that DMT produces both antidepressant and anxiety-reducing behavioral effects in rodents, supporting further research into ayahuasca and similar psychedelics as potential treatments for depression and PTSD.
ACS Chemical Neuroscience
March 4, 2019
Lindsay P. Cameron, Charlie J. Benson, Brian C. Defelice et al.
163 citations
Repeated low doses of DMT, a psychedelic compound, produced antidepressant-like effects and improved fear extinction learning in male rats, without affecting working memory or social interaction. The rats also gained significant body weight during the study. The findings suggest that microdosing psychedelics may help alleviate symptoms of mood and anxiety disorders, but potential risks require further study.
ACS Chemical Neuroscience
September 24, 2012
James B. Hanks, Javier González‐maeso
152 citations
The serotonin 5-HT(2A) receptor is the primary target of psychedelic drugs like LSD, mescaline, and psilocybin. These substances produce profound changes in cognition, emotion, and sensory processing that seem uniquely human, raising questions about the validity of animal models. However, recent research indicates that behavioral abnormalities induced by psychedelics in rodents can predict effects in humans. This review examines the behavioral effects of psychedelic drugs in rodent models, evaluates the translational potential of these findings, and identifies areas needing further research to clarify the molecular mechanisms and neural circuits underlying their neuropsychological effects.
ACS Chemical Neuroscience
June 29, 2018
Haden A. Geiger, Madeline G. Wurst, R. Nathan Daniels
139 citations
Psilocybin, the psychoactive compound in magic mushrooms, was first synthesized by Albert Hofmann in the late 1950s and marketed as Indocybin for clinical research. After a rise in popularity and classification as a Schedule I drug in 1970, research declined. Recent preliminary studies suggest psilocybin may help treat obsessive compulsive disorder, alcohol and tobacco addiction, major depressive disorder, and depression in terminally ill cancer patients. This review covers the compound's synthesis, metabolism, pharmacology, adverse effects, and its historical and current importance to neuroscience.
ACS Chemical Neuroscience
January 11, 2023
Ling-Xiao Shao, Pasha A. Davoudian, Alex C. Kwan
131 citations
Psilocybin and ketamine both acutely increase expression of the immediate early gene c-Fos in numerous brain regions of male and female mice, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Some regions showed drug-preferential differences: dorsal raphe and insular cortex for psilocybin, and the CA1 subfield of hippocampus for ketamine. Endogenous levels of the glutamate receptor genes Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both compounds. The findings suggest glutamatergic receptors as a convergent target for the therapeutic effects of psilocybin and ketamine.
ACS Chemical Neuroscience
July 23, 2018
Lindsay P. Cameron, David E. Olson
114 citations
DMT is the foundational molecule for all indole-containing serotonergic psychedelics, with its structure embedded in LSD and psilocybin. Unlike those, DMT is produced by many plants and animals, is a key component of ayahuasca, and is one of the few psychedelics made naturally in mammals, though its biological role remains unknown. This review covers DMT's synthesis, pharmacology, metabolism, adverse effects, and potential medical uses, and discusses its history and importance in psychedelic science.
ACS Chemical Neuroscience
July 12, 2018
Lee E. Dunlap, Anne M. Andrews, David E. Olson
105 citations
MDMA, known as ecstasy, is a small molecule that shapes youth culture similarly to LSD in the 1960s. Structurally related to amphetamine and mescaline, it produces unique subjective effects distinct from psychostimulants or hallucinogens and reliably induces prosocial states. This review covers MDMA's synthesis, pharmacology, metabolism, adverse effects, and potential medical uses. The authors argue MDMA may be the most important compound for the future of psychedelic science, capable of either advancing new research or triggering a second Dark Age for the field.
ACS Chemical Neuroscience
February 20, 2018
David E. Nichols
87 citations
Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 μg) oral doses. Following its accidental discovery in 1943, Sandoz Laboratories supplied it as an experimental drug for psychotherapy and psychiatric insight. The discovery of serotonin in the mammalian brain in 1953 and its structural resemblance to LSD sparked research into serotonin's role in mental disorders. LSD proved physiologically safe and nonaddictive with a low incidence of adverse events in controlled experiments.
ACS Chemical Neuroscience
May 30, 2018
Bruce K. Cassels, Patricio Sáez-briones
84 citations
Mescaline, a cactus alkaloid, has been used for over 6000 years, primarily in peyote (Lophophora williamsii) and wachuma cacti. Spanish colonizers banned these plants, but use persisted and spread. By the late 1800s, mescaline was isolated and shown to cause psychedelic effects; its structure was synthesized in 1929. Its effects mainly involve 5-HT2A serotonin receptor agonism, though it also binds to 5-HT1A and α2A receptors. Most mescaline is excreted unchanged in urine, and its metabolites do not contribute to psychedelic effects. Low potency led to less recreational use compared to more potent analogues. Renewed therapeutic interest may clarify differences among classic hallucinogens.
ACS Chemical Neuroscience
December 15, 2022
Michael J. Cunningham, Hailey A. Bock, Inis C. Serrano et al.
65 citations
Ariadne, a non-hallucinogenic analog of the hallucinogen DOM, demonstrates significant therapeutic potential in treating various conditions. In clinical trials, Ariadne led to rapid remission of psychotic symptoms in schizophrenia and improved cognition in elderly patients. It acts as a 5-HT<sub>2A</sub> receptor agonist with modest selectivity for 5-HT<sub>1</sub>, exhibiting lower signaling potency than DOM. Notably, in a Parkinson’s disease model, Ariadne alleviated severe motor deficits comparable to l-DOPA, positioning it as a promising candidate for future psychiatric and neurological therapies.
ACS Chemical Neuroscience
October 28, 2019
Christian B. M. Poulie, Anders A. Jensen, Adam L. Halberstadt et al.
63 citations
N-Benzylphenethylamines (NBOMes) are synthetic psychedelics derived from phenethylamines like 2C-X compounds, which originate from the natural alkaloid mescaline. Like other classical psychedelics, they primarily activate serotonin 2A (5-HT2A) receptors. Since their emergence as New Psychoactive Substances in 2010, recreational use has caused acute toxicity and lethal outcomes, leading to their classification as Schedule I substances in 2013. Beyond recreational use, NBOMes have become valuable biochemical tools, such as [11C]Cimbi-36 for PET imaging of 5-HT2A and 5-HT2C receptors, and 25CN-NBOH, a highly selective 5-HT2A receptor agonist. This Review covers their history, chemistry, structure-activity relationships, ADME properties, and safety profiles.
ACS Chemical Neuroscience
September 14, 2018
Michael Wasko, Paula A. Witt‐enderby, Christopher K. Surratt
63 citations
Ibogaine, the main psychoactive alkaloid in the West African iboga plant, has a long history of ceremonial use and was once sold as an antidepressant in France before being withdrawn due to adverse effects. In the 1960s, U.S. heroin addicts reported that ibogaine cured their opiate addictions, and animal studies showed it reduces self-administration of opiates, cocaine, amphetamines, and nicotine. Ibogaine has moderate-to-weak affinity for many receptor and transporter proteins, and recent evidence suggests its actions at nicotinic acetylcholine receptor subtypes may explain its antiopiate effects. However, at micromolar levels ibogaine is neurotoxic and cardiotoxic, linked to several deaths.
ACS Chemical Neuroscience
January 6, 2022
D. Kelley, Katy Venable, Aspasia Destouni et al.
41 citations
Comparing gene expression in the prefrontal cortex of a rat stress model and the dorsolateral prefrontal cortex of humans with PTSD reveals 20 overlapping differentially expressed genes, 85% of which change in the same direction. The psychedelic compound N,N-dimethyltryptamine (DMT), alone or combined with the monoamine oxidase inhibitor harmaline (pharmahuasca), reduces reactive oxygen species production in the prefrontal cortex and hippocampus and normalizes expression of genes involved in oxidative stress, inflammation, growth factor signaling, neurotransmission, and neuroplasticity. Harmaline alone has mixed effects on reactive oxygen species.
ACS Chemical Neuroscience
August 1, 2024
Samuel C Woodburn, Caleb M Levitt, Allison M Koester et al.
28 citations
Psilocybin robustly enhances fear extinction in male and female mice when given acutely before testing, across all doses tested. It also produces long-term improvements in extinction retention and reduces fear renewal in a novel context, though these effects depend on dose. Females may respond to a narrower dose range than males. Administration before fear learning or immediately after extinction does not alter behavior, showing that concurrent extinction experience is necessary. Blocking the 5-HT2A receptor eliminates psilocybin's effects on extinction, retention, and renewal, while blocking the 5-HT1A receptor only attenuates the effect on fear renewal. These findings highlight dose, context, and serotonin receptors as key factors in psilocybin's facilitation of fear extinction.
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
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
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
October 6, 2020
Genís Oña, 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.