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.
Journal of Cerebral Blood Flow & Metabolism
April 30, 2014
Anders Ettrup, Sofi Da Cunha‐bang, Brenda Mcmahon et al.
106 citations
A new radioactive tracer, [11C]Cimbi-36, was tested in 29 healthy volunteers for brain imaging using PET scans. This tracer binds to serotonin 2A receptors, which are involved in mood and perception, and is an agonist, meaning it activates the receptor rather than blocking it. High uptake in the brain matched known locations of these receptors. A two-tissue compartment model using arterial blood samples gave the most accurate measurements. In five subjects given a blocker drug (ketanserin), tracer binding decreased in cortical areas but not in the cerebellum, confirming the tracer's specificity and that the cerebellum can serve as a reference region. This is the first agonist PET radioligand to successfully image these receptors in humans.
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.
Behavioural Brain Research
December 28, 2020
Anna U. Odland, Jesper L. Kristensen, Jesper T. Andreasen
60 citations
Psychedelic drugs that activate the 5-HT2A receptor show promise for treating psychiatric disorders like obsessive-compulsive disorder. In a mouse model of compulsive-like behavior (the marble burying test), the 5-HT2A receptor antagonist M100907 blocked the effect of the psychedelic DOI, and the 5-HT2C receptor antagonist SB242084 blocked the effect of citalopram, but neither antagonist blocked the effect of psilocybin. This confirms 5-HT2A receptor activation as a mechanism for reducing compulsive-like digging and suggests that 5-HT2A and 5-HT2C receptors can work in parallel. The results with psilocybin indicate that a mechanism independent of 5-HT2 receptors also contributes to its effect on repetitive digging.
Chemical Research in Toxicology
December 16, 2015
Sebastian Leth-Petersen, Charlotte Gabel‐Jensen, Nic Gillings et al.
43 citations
The metabolism of the potent psychedelic compound 25B-NBOMe, an illicit drug linked to several fatalities, was studied in pigs and humans. The primary metabolic pathway is 5'-demethylation, followed by conjugation to glucuronic acid. These findings were confirmed by carbon-11 labeling of 25B-NBOMe in three different positions and in vivo evaluation in both species.
Journal of Medicinal Chemistry
September 22, 2022
Christian B M Poulie, Eline Pottie, Icaro A Simon et al.
32 citations
The serotonin 2A receptor (5-HT2AR) is responsible for the psychedelic effects of certain drugs, which show promise for treating neuropsychiatric conditions. This work examined how a series of compounds, including 25CN-NBOH, signal through two pathways: Gαq and β-arrestin. Disrupting the interaction with a specific amino acid, Ser1593×36, reduced both pathways' potency and efficacy, with Gαq signaling more strongly affected. This led to the creation of the first effective β-arrestin-biased 5-HT2AR agonists (4a-b and 6e-f), which prefer the β-arrestin pathway over Gαq relative to LSD.
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.
Pharmacological Reviews
October 1, 2022
Anna U. Odland, Jesper L. Kristensen, Jesper T. Andreasen
23 citations
Psychedelic-assisted psychotherapy shows promise for treating mental health disorders, and research on 5-HT2AR agonist psychedelics has grown rapidly. In humans, these compounds alter consciousness and affect emotional, social, and self-referential information processing. The translational value of animal behavior studies is debated. In rodents, acute psychedelic treatment produces head twitches, disrupts sensorimotor gating, stimulates motor activity, inhibits exploration, and shows anxiolytic-like effects while inhibiting repetitive behavior. Effects on depression-like behaviors, cognitive function, and social interaction are discrepant. Lasting effects are sensitive to experimental protocols. Improving animal studies by assessing lasting effects, publishing negative findings, and relating behaviors to neuroplastic changes will enhance translational value.
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.
Journal of Natural Products
August 27, 2021
Camilla B Chan, Christian B M Poulie, Simon S Wismann et al.
13 citations
The term 'false peyote' is commonly applied to Lophophora diffusa, but several other unrelated cacti also share this name due to their resemblance to true peyote (Lophophora williamsii) or similar habitats. Over 40 alkaloids have been isolated from the Lophophora genus, yet only mescaline's pharmacological effects are well-studied. The major alkaloid in L. diffusa is pellotine, a tetrahydroisoquinoline briefly marketed as a sleeping aid in the early 1900s based on reports of its hypnotic properties. Pharmacological experiments on these alkaloids occurred around 1900, with chemical synthesis achieved decades later and biosynthetic pathways reported in the late 1960s. This review outlines the relationship of false peyotes to L. williamsii regarding alkaloid content, synthesis, and pharmacology.
Neuropsychopharmacology
November 12, 2025
Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton et al.
7 citations
A single dose of psilocybin or the selective 5-HT2A receptor agonist 25CN-NBOH reduces immobility in the forced swim test in rats for at least three months, with no decrease in effect size over that period. Both drugs produced similar behavioral effects, indicating that 5-HT2A receptor activation alone is sufficient for long-lasting changes. In the medial prefrontal cortex, layer 5 excitatory pyramidal neurons showed altered resting membrane potential, firing rates, and synaptic excitation months after treatment. However, no changes were found in synaptic density, spine classification, or expression of presynaptic and postsynaptic markers. The results suggest that enduring functional plasticity, rather than structural plasticity, underlies the long-term behavioral effects of psychedelics.
Journal of Medicinal Chemistry
April 22, 2024
Karla Frydenvang, Emil Märcher-Rørsted, Anders A. Jensen et al.
7 citations
Classical psychedelics like psilocybin, LSD, and DMT show promise for treating depression, anxiety, and substance abuse, but their long-term therapeutic effects remain unclear. A new class of compounds, 2,5-dimethoxyphenylpiperidines, has been discovered as selective serotonin 2A receptor (5-HT2AR) agonists. Structure-activity studies identified LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with favorable drug-like properties, offering a potential tool to investigate the receptor's role in persistent therapeutic effects.
Synapse (New York, N.Y.)
March 1, 2025
Yang Wang, Jesper L. Kristensen, Kristi A. Kohlmeier
5 citations
The synthetic psychedelic 25CN-NBOH, which binds strongly to serotonin type 2A receptors, has a dual effect on neurons in the mouse medial prefrontal cortex. Acute application of a high concentration (10 µM) increased the frequency of spontaneous excitatory postsynaptic currents, an effect dependent on serotonin 2A receptor activation and not seen with chronic exposure or a lower concentration (200 nM). However, both concentrations suppressed the firing rate of pyramidal neurons after acute and one-hour exposure. This suppression was independent of serotonin 2A receptors but mediated by M-current channels, as blocking M-currents reversed it. The compound thus enhances excitatory transmission while reducing overall excitability, revealing complex cellular actions that may underlie its therapeutic effects.
ACS Pharmacology & Translational Science
May 29, 2025
Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted et al.
3 citations
A new compound, LPH-5, acts as a potent partial agonist at the 5-HT2A receptor with high selectivity over related 5-HT2B and 5-HT2C receptors. In rats, LPH-5 induced head-twitch responses and produced both acute and persistent antidepressant-like effects. These findings suggest that selective activation of the 5-HT2A receptor alone can produce antidepressant effects, indicating that this receptor is a key component in the therapeutic action of classical psychedelics like psilocybin and LSD.
Translational Psychiatry
January 31, 2026
Jesper L. Kristensen
Psilocybin is a prodrug that is rapidly converted in the body to psilocin, the active compound responsible for its subjective and therapeutic effects. The authors of the reviewed manuscript used computational network pharmacology and molecular docking to investigate how psilocybin might prevent suicide, but they incorrectly treated psilocybin as the active agent. In humans, psilocybin's effects correlate with psilocin plasma concentration and serotonin 2A receptor occupancy, and cryo-EM structures of psilocin bound to that receptor are available. Therefore, discussing psilocybin's binding to proteins is nonsensical for understanding its therapeutic actions in humans.
bioRxiv Preprint Server
April 19, 2024
Anders A. Jensen, Cláudia R. Cecchi, Meghan Hibicke et al.
preprint
A new compound called LPH-5 selectively activates the 5-HT2A receptor, unlike classical psychedelics which also affect related receptors. In rats, LPH-5 produced head-twitch responses (a behavioral marker of 5-HT2A activation) at doses of 0.5-1.0 mg/kg and showed antidepressant-like effects in three different rat models: Flinders Sensitive Line rats, adrenocorticotropic hormone-treated Sprague Dawley rats, and a Wistar Kyoto rat model designed to capture long-term antidepressant effects. The findings suggest that selective 5-HT2A receptor activation is sufficient for antidepressant potential, and that LPH-5 or similar selective compounds could represent a new generation of antidepressant drugs derived from psychedelics.
ACS Chemical Neuroscience
November 16, 2016
Sebastian Leth-Petersen, Ida N Petersen, Anders A. Jensen et al.
The toxic hallucinogen 25B-NBOMe is rapidly broken down by human liver enzymes and has low oral bioavailability. New chemical variants were synthesized by modifying the part of the molecule where metabolism normally occurs. While some analogues resisted breakdown longer and still strongly activated 5-HT2 receptors, all had an intrinsic clearance above 1.3 L/kg/h, indicating they would still be extensively metabolized on first pass through the liver.