The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents
This study investigated 25C-NBF, a psychedelic phenethylamine engineered to act as a highly selective 5-HT2A receptor agonist, and examined whether it could produce rapid antidepressant-like and psychoplastogenic effects in rodents while minimising broader receptor interactions.
The study found that the selective psychedelic compound 25C-NBF:
activated 5-HT2A receptors,
promoted neural plasticity,
and produced rapid antidepressant-like effects in male rodents.
This may be evidence that highly selective 5-HT2A receptor activation may be sufficient to induce psychoplastogenic and antidepressant-related effects, strengthening the mechanistic link between psychedelics, neuroplasticity, and mood improvement.
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.”
Nadal-Gratacós, N., Puigseslloses, P., Guzmán, L. et al. The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents. Mol Psychiatry 31, 1909–1922 (2026). Read Paper
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