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
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
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
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 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
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
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
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
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
September 25, 2018
Andrey D. Volgin, Oleg A. Yakovlev, Konstantin A. Demin et al.
38 citations
Deliriant hallucinogens, such as atropine and scopolamine, are a distinct class of drugs that induce hyperactivity and dream-like hallucinations by blocking muscarinic acetylcholine receptors. Despite their long history of use and being well-studied in cholinergic physiology, they are the least-studied class of hallucinogens regarding their behavioral and neurological effects. This review comprehensively evaluates the preclinical effects of these drugs in various animal models, detailing their mechanisms of action and potential interactions with other signaling pathways. It parallels experimental and clinical findings to outline future directions for translational research, emphasizing the need for novel approaches and new model organisms to investigate their central nervous system effects.
ACS Chemical Neuroscience
March 9, 2021
Grant C. Glatfelter, Donna Walther, Michael Evans‐brown et al.
29 citations
Eutylone, a new synthetic cathinone appearing in recreational drug markets, acts as a hybrid monoamine transporter compound. In rat brain tissue, eutylone inhibited dopamine and norepinephrine uptake (most potently at dopamine transporters, IC50 = 120 nM) and showed weak partial serotonin-releasing activity. It stimulated locomotion in mice (ED50 = 2 mg/kg), indicating psychostimulant effects similar to pentylone, suggesting abuse liability and risk of adverse effects in humans.
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
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
April 23, 2020
Hideaki Yano, Pramisha Adhikari, Sett Naing et al.
26 citations
Synthetic cannabinoids (SCs) like AM2201 and JWH-018, but not the phytocannabinoid Δ9-tetrahydrocannabinol, act as positive allosteric modulators (PAMs) at the 5-HT1A receptor, a noncannabinoid site. In vitro, AM2201 potentiated 5-HT1A agonist-activated G protein-coupled inwardly rectifying potassium channel currents in neurons. In mice lacking cannabinoid receptor 1, AM2201 also potentiated the hypothermic response to 5-HT1A receptor stimulation. These findings suggest that PAM activity at 5-HT1A receptors may be a novel noncannabinoid mechanism contributing to the adverse effects of certain synthetic cannabinoids.
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.