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.
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.
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.