The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents
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-HT<sub>2A</sub> receptor and demonstrated bias factors (defined in our study as the preference for G<sub>q</sub> over β-arrestin pathways at 5-HT<sub>2A</sub> 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.
Authors
- Elena Escubedo (ORCID: https://orcid.org/0000-0002-5078-366X)
- Gabriel Ketsela (ORCID: https://orcid.org/0000-0003-2480-5906)
- Nicola Weiss (ORCID: https://orcid.org/0000-0002-5487-6505)
- Xavier Berzosa (ORCID: https://orcid.org/0000-0001-5391-5974)
- Nathalie Thiriet (ORCID: https://orcid.org/0000-0002-0076-4946)
- Raúl López‐Arnau (ORCID: https://orcid.org/0000-0001-8904-7398)
- Pol Puigseslloses (ORCID: https://orcid.org/0000-0003-2542-972X)
- Núria Nadal‐Gratacós (ORCID: https://orcid.org/0000-0002-9791-249X)
- David Pubill (ORCID: https://orcid.org/0000-0002-6627-4501)
- Eline Pottie (ORCID: https://orcid.org/0000-0002-9077-4055)
- Laura Hernández‐Guzmán (ORCID: https://orcid.org/0000-0003-3996-9540)
- Marcello Solinas (ORCID: https://orcid.org/0000-0002-0664-5964)
- Miren Ettcheto (ORCID: https://orcid.org/0000-0002-4301-7297)
- Virginie Lardeux
- Marta Rodrı́guez-Arias (ORCID: https://orcid.org/0000-0002-1121-8879)
- Harald H. Sitte (ORCID: https://orcid.org/0000-0002-1339-7444)
- Ján Kehr (ORCID: https://orcid.org/0000-0002-2410-124X)
- Christophe Pol Stove (ORCID: https://orcid.org/0000-0001-7126-348X)
- Clara Riera-Colomer
- Fuhua Wang (ORCID: https://orcid.org/0000-0002-4986-864X)
- Liselott Källsten
- Joel Margall
- Irene Pérez-Esteban
Institutions
- Al-Ahliyya Amman University (JO)
- Statistics Sweden (SE)
- Inserm (FR)
- Universitat de València (ES)
- Ghent University (BE)
- Université de Poitiers (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Institut Botànic de Barcelona (ES)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Institute for Research in Biomedicine (ES)
- Hospital Universitari Sant Joan de Reus (ES)
- CIBBIM-Nanomedicine (ES)
- Universitat Ramon Llull (ES)
- Universitat de Barcelona (ES)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1038/s41380-025-03341-1
- Primary Topic
- Psychedelics and Drug Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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