Psilocybin and other psychedelic compounds are being studied for therapeutic use, but little is known about norbaeocystin, a pathway intermediate, due to difficulties obtaining it. Researchers developed a new E. coli platform to produce gram-scale amounts of norbaeocystin, finding that even minor genetic changes required reoptimization of production. In vivo tests on Long-Evans rats showed a dose response to psilocybin, but norbaeocystin did not elicit any pharmacological response, suggesting it and its metabolites may not strongly bind to the serotonin 2A receptor. This work enables future studies of norbaeocystin in animal models and supports the safety of using cell broth as a drug delivery vehicle.
Tryptamine psychedelics produce their effects mainly by activating serotonin 2A receptors, but many also affect other targets. 4-MeO-MiPT, a compound that both activates 5-HT2A receptors and blocks the serotonin transporter (SERT), produces blunted psychedelic effects in humans. In mice, 4-MeO-MiPT and its analogs with stronger SERT blockade showed fewer head twitch responses (a proxy for psychedelic-like effects) than their 4-hydroxy counterparts. Pretreating mice with the SERT inhibitor fluoxetine reduced head twitch responses from 4-hydroxy compounds to levels seen with the 4-methoxy analogs. The findings suggest that dual 5-HT2A/SERT ligands may have therapeutic potential with reduced acute psychedelic effects.