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 Peer reviewed DOI: 10.1038/s41380-025-03341-1 via OpenAlex
Summary
The novel phenethylamine analog 25C-NBF shows promise as a rapid-acting antidepressant, reducing despair-like behavior and exhibiting psychoplastogenic effects. Unlike other substances, 25C-NBF did not produce rewarding effects or changes in dopamine levels in animal models. The compound demonstrated a favorable safety profile with no abuse potential. These findings suggest that 25C-NBF could be a viable candidate for treating depression and related conditions.
Study at a glance
| Population | mice and rats used for pharmacological testing |
|---|---|
| Key finding | 25C-NBF exhibited rapid antidepressant effects and a favorable safety profile without abuse potential. |
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.