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.
Molecular Psychiatry
September 1, 2023
Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff et al.
48 citations
Repeated low doses of psilocybin, similar to human microdosing, were tested in rats. The regimen was well tolerated, causing no signs of anhedonia, anxiety, or altered movement, and did not downregulate or desensitize 5-HT2A receptors. The treatment increased resilience to injection stress, reduced self-grooming (a proxy for compulsive actions), and raised 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
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.
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 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.
January 5, 2023
Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff et al.
5 citations
preprint
Repeated low doses of psilocybin, a serotonergic psychedelic drug, were given to rats in a regimen that mimics human microdosing. The rats tolerated the doses well, showing no signs of anhedonia, anxiety, or altered movement. The treatment did not downregulate or desensitize the 5-HT2A receptor. It did impart resilience against stress from repeated injections and reduced self-grooming frequency, a proxy for compulsive actions. Additionally, it increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
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.
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.
Neuropharmacology
July 15, 2018
Maria Amat-Foraster, Anders A. Jensen, Niels Plath et al.
Sub-anesthetic doses of ketamine (1, 2, and 5 mg/kg intravenously) decreased the firing rate of neurons in the reticular thalamic nucleus, mediodorsal and centromedial thalamic nuclei, and layer VI of the medial prefrontal cortex in anesthetized male Wistar rats. Ketamine also reduced low-frequency oscillations across these areas while increasing gamma oscillations in the medial prefrontal cortex and mediodorsal/centromedial thalamic nuclei. Lower doses (0.25 and 0.5 mg/kg) had no effect. Unlike phencyclidine, ketamine's inhibition of reticular thalamic nucleus neurons did not disinhibit excitatory neurons in other areas, likely due to concurrent NMDA receptor blockade there. The early transient inhibition may relate to psychotomimetic effects, while prolonged gamma increases may underlie antidepressant action.
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.