The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents
Núria Nadal‐gratacós, Pol Puigseslloses, Laura Hernández‐guzmán, Nicola Weiss, Eline Pottie, Clara Riera-Colomer, Virginie Lardeux, Nathalie Thiriet, Fuhua Wang, Liselott Källsten, Irene Pérez-esteban, Gabriel Ketsela, Joel Margall, Xavier Berzosa, David Pubill, Marta Rodríguez‐arias, Miren Ettcheto, Ján Kehr, Christophe P Stove, Marcello Solinas, Harald H. Sitte, Elena Escubedo, Raúl López‐arnau
Molecular Psychiatry November 14, 2025 DOI: 10.1038/s41380-025-03341-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice and rats |
| Interventions | 25C-NBF 25B-NBF 25I-NBF |
| Keywords | Phenethylamine Antidepressant Dopamine Reboxetine Monoamine neurotransmitter Conditioned place preference Anhedonia Nucleus accumbens Drugs of abuse Pharmacology Hallucinogen Mechanism of action |
| Key points | 25C-NBF shows rapid antidepressant-like effects in a chronic corticosterone model of anhedonia without abuse potential or sensorimotor gating deficits. |
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.