The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents
Year: 2025
Type: article
Abstract: Psychedelics have garnered significant interest for their therapeutic potential in mental health conditions such as depression, anxiety, and post-traumatic stress disorder. While research has primarily focused on well-studied psychedelics, phenethylamine derivatives have also gathered interest for their potential therapeutic applications. Thus, this study aims to investigate the pharmacological profile, safety and therapeutic potential of novel N-(2-fluorobenzyl) phenethylamine analogs (NBFs) of the 2C-X series—25C-NBF, 25B-NBF, and 25I-NBF. NBFs displayed high affinity and selectivity for the 5-HT2A receptor and demonstrated bias factors (defined in our study as the preference for Gq over β-arrestin pathways at 5-HT2A receptor) similar to that of 5-HT. Acute administration induced moderate head-twitch responses without affecting locomotion or pre-pulse inhibition. Our studies revealed no rewarding effects in mice nor reinforcing effects or changes in accumbal dopamine levels in rats after NBFs administration. Further characterization of 25C-NBF revealed psychoplastogenic effects (dendritogenesis, spinogenesis and increased Bdnf mRNA levels) both in vitro and in vivo. In addition, 25C-NBF reduced despair-like behavior in response to acute stress and exerted rapid antidepressant effects in a model of anhedonia-like behavior induced by chronic corticosterone administration. Taken together, these findings suggest that 25C-NBF, and further analogs, may hold potential as novel antidepressants with a rapid onset of action and a favorable safety profile in terms of no abuse potential or sensorimotor gating deficits.
Source: Molecular Psychiatry
Authors: Núria Nadal-Gratacós, Pol Puigseslloses, Laura Guzmán, Nicola Weiss, Eline Pottie, Clara Riera-Colomer, Virginie Lardeux, Nathalie Thiriet, Fu-Hua Wang, Liselott Källsten, Irene Pérez-Esteban, Gabriel Ketsela, Joel Margall, Xavier Berzosa, David Pubill, Marta Rodríguez-Arias, Miren Ettcheto, Jan Kehr, Christophe Stove, Marcello Solinas, Harald H. Sitte, Elena Escubedo, Raul López-Arnau
Institutions: Universitat de Barcelona, Institut Químic de Sarrià, Universitat Ramon Llull, Biomedical Research Networking Center on Neurodegenerative Diseases, Ghent University, Inserm, Université de Poitiers, Laboratoire de Neurosciences Expérimentales et Cliniques, Universitat de València, Institut de Biomedicina de la Universitat de Barcelona, Institut de Recerca Biomèdica Catalunya Sud, Hospital Universitari Sant Joan de Reus, Al-Ahliyya Amman University, Medical University of Vienna
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: European Commission, Institut National de la Santé et de la Recherche Médicale, Austrian Science Fund, Generalitat de Catalunya, Universiteit Gent, Universitat de Barcelona, Université de Poitiers, Plan Nacional sobre Drogas, Agència de Gestió d'Ajuts Universitaris i de Recerca, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1175115578, G1888088267, G1953887145, G2064873908, Engineering Diffusion Barriers in the Plasma Membrane, G2262748287, G24120701, G2601397997, G288263039, G2903790508, G294895050, G3005324705, G300979063, G3461529875, G3480869486, G3681454997, G3830080739, G4042783231, G410571670, G4238322289, G425668148, G4463252966, G451917667, G498075875, G5080475149, G5195188938, G523076202, G5243814431, G5539308778, G5852091828, G5967599077, G6033112984, G6200523523, G7084143925, G7606645051, G787121397, G8217939449, Transporter-mediated efflux as therapeutic strategy
OpenAlex ID: W4416221484