Molecular Psychiatry
March 14, 2024
Pol Puigseslloses, Gabriel Ketsela, Nicola Weiss et al.
23 citations
All tested 5-MeO-tryptamines selectively bind to 5-HT1A receptors over 5-HT2A receptors, with computational docking predicting better interaction in the 5-HT1A binding pocket. These compounds also interact with the serotonin transporter (SERT), where molecular size of the amino group influences affinity. 5-MeO-pyr-T acts as the most potent partial 5-HT releaser. All tryptamines elicit the head twitch response in mice, indicating potential hallucinogenic effects primarily mediated by 5-HT2A receptors, but 5-HT1A activation attenuates this response. Tryptamines producing stronger hypothermic responses via 5-HT1A tend to show lower hallucinogenic effects, highlighting opposing roles of the two receptors. Some compounds with low hallucinogenic effects remain potent 5-HT2A agonists, offering insight into non-hallucinogenic therapeutic ligands.
Molecular Psychiatry
October 21, 2025
Pol Puigseslloses, Núria Nadal‐gratacós, Berta Fumàs et al.
1 citation
A novel class of halogenated DMT derivatives—5-F-DMT, 5-Cl-DMT, and 5-Br-DMT—was characterized for pharmacological activity and therapeutic potential. Halogen substitution at the 5-position modulates receptor affinity across serotonin receptors and the serotonin transporter. 5-Br-DMT activated the 5-HT2A receptor but did not induce the head twitch response in mice, suggesting non-hallucinogenic activity. It upregulated immediate early genes linked to neuroplasticity in the mouse prefrontal cortex and hippocampus and promoted dendritic growth in cortical neurons. A single 10 mg/kg dose of 5-Br-DMT in a mouse model of stress-induced depression significantly reduced depressive-like behavior, indicating rapid antidepressant effects. The findings highlight 5-Br-DMT as a non-hallucinogenic psychoplastogen with antidepressant properties.
Molecular Psychiatry
November 14, 2025
Núria Nadal‐gratacós, Pol Puigseslloses, Laura Hernández‐guzmán et al.
Three novel phenethylamine derivatives—25C-NBF, 25B-NBF, and 25I-NBF—show high affinity and selectivity for the 5-HT2A receptor, with signaling bias toward Gq over β-arrestin pathways similar to serotonin. In mice, they cause moderate head-twitch responses without affecting movement or sensorimotor gating. No rewarding or reinforcing effects were observed, and accumbal dopamine levels in rats remained unchanged. 25C-NBF promotes dendritogenesis, spinogenesis, and increased Bdnf mRNA in vitro and in vivo, reduces despair-like behavior after acute stress, and produces rapid antidepressant effects in a chronic corticosterone model of anhedonia. These findings suggest 25C-NBF may offer a fast-acting antidepressant with no abuse potential or sensorimotor deficits.